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disciplines Take the lead in ensuring that projects are run to relevant quality standards and meet appropriate safety standards… Responsibilities This position is within a team of Project and Programme Managers in the Medical Technology Division at Cambridge… enquiries - Manage the Quality team to provide qualityassurance planning and processes within the Project team. Lead the Project Quality… capable Product AssuranceManager to work with the Quality Technical Future Systems Manager to provide Product Assurance (QA) across… ISO9001 and TS16949 maintain, manage, implement and coordinate key quality systems / processes / Quality Management Systems Salary… apply please contact Jayne Baxter at Euro Projects Recruitment Ltd Visit the Euro Projects Recruitment website to search our latest… centre with an understanding of qualityassurance. Reporting to the Quality and Development Manager you will be in contact with operations… position for A QualityAssurance Officer has become available with one of my clients based in Sale. A Quality background is not… Dixons Carphone – Acton, Northern Ireland change within iD. Reporting to the Project Office function, the QualityAssuranceManager will take ownership of the end to end… The QualityAssuranceManager is responsible for all business analysis, test, business process, go to market assurance activities… to the project team and sponsor Assess projectquality and risk Proactively investigate and resolve issues Manage the study… operational excellence and may mentor more junior ProjectManagers, Associate ProjectManagers within the team. The position may also entail… to the project team and sponsor Assess projectquality and risk Proactively investigate and resolve issues Manage the study… of the ProjectManager in Medical Imaging is to provide tactical management, administration, and leadership to project teams in… Influence design quality by applying pro-active design assurance activities Management of all project non-conformances to… The opportunity: Graduate ProjectAssurance Engineer Job Description To provide Assurance support throughout all phases… Develop a qualityassurance and regulatory compliance strategy for the DCRI. Independently plan and manages all audit related… within QualityAssurance executing audits Outstanding communication skills (verbal and written) Ability to manage multiple… Eden Brown Ltd – Gloucester, England permanent ProjectManager. As the projectmanager you would be reporting into the West Midlands office and the first project would… within the project requirements and timescales. Ensure that projects are staffed adequately and led and managed effectively… Key Skills: QualityManager / Fixed Term Contract / 12 Months / QualityAssurance / ISO 13485 / Quality / QA / Internal Auditing… Job Title: QualityManager (12 Month Fixed Term Contract) Position Summary: The position of QualityManager – Maternity… representatives on all projectqualityassurance matters Represent quality management during attendance at project meetings Development… systems, procedures and forms. Manage, prepare and achieve acceptance of all projectquality documentation to meet client requirements… perform audits. Manage cross-functional audit team, and train auditors. Develop and/or managequalityassurance programs related… Promotional Labeling. Represent the QualityAssurance department at meetings and on project teams. Performs other duties as required… maximum efficiency, opportunity for collaboration and qualityassurance. The right person for this job will be someone who… looking for someone who will have a firm grasp on all required project deliverables, allocating work load in conjunction with department… ENGIE are recruiting for a Customer Service QualityAssurance Analyst to be based in Newcastle. This is a permanent full time… Shared Service Centre, reporting to the Customer Service QualityManager. The post holder will assist with the co-ordination… with evidence of successful project management desirable. As Senior QualityAssuranceManager, youll drive the long term… Qualified Person or Trainee QP to join their Quality team as a Senior QualityAssuranceManager. Youll be working on life saving oncology… ProjectManager - Crawley Overview We are currently looking for a ProjectManager requiring a good understanding of project… Lead (facilitate), guide, manage and motivate the Project Team / Program through the project engineering process Ensure… itself on quality and the customer process will be improved with the implementation of the QualityAssuranceManager. Suitable… Do you have experience within a Site Management or QualityAssurance role with a Residential Detail? Do you have a keen… the group including Business Change Managers, Leadership teams; SME's including Assurance, Finance, HR and Technology. What… ProjectManager Andover This role will offer you exposure to a variety of exciting strategic change initiatives across the… SME's to manage and track any MDM and data quality issues, oversee the generation of data quality rules and data quality reporting… You will manage a team of data quality analysts and work with business colleagues to embed the data quality framework and… Quality Assurance Officer Search Consultancy Manchester, England Quality Assurance Manager Dixons Carphone Acton, Northern Ireland Senior Quality Assurance Auditor Vivid Resourcing United Kingdom Project Manager Eden Brown Ltd Gloucester, England MDM & Data Quality Manager RSA Horsham, England Cambridge Consultants, MBDA, Alliance Consulting, ENTECH, Euro Projects Recruitment, Search Consultancy, Dixons Carphone, PAREXEL, Box UK, ERT

2017/10/20 18:50:02

https://www.glassdoor.com/Job/uk-quality-assurance-project-manager-jobs-SRCH_IL.0,2_IN2_KO3,36_IP2.htm

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LIVESTRONG at the YMCA is a FREE twelve-week, small group program designed for adult cancer survivors. Our goal is to help participants build muscle mass and muscle strength, increase flexibility and endurance and improve functional ability. Additional goals include reducing the severity of therapy side effects, preventing unwanted weight changes and improving energy levels and self-esteem. A final goal of the program is to assist participants in developing their own physical fitness program so they can continue to practice a healthy lifestyle, not only as part of their recovery, but as a way of life. In addition to the physical benefits, the program provides participants a supportive environment and a feeling of community with their fellow survivors, Y staff and members. Y cancer exercise trainers work with each participant to fit the program to their individual needs. Trainers are trained in the elements of cancer, post rehab exercise and supportive cancer care. Classes will be offered weekdays with daytime and evening classes. The LIVESTRONG at the YMCA program includes: • Two 75 minute classes per week • Full access to the Y seven days a week CRITERIA FOR PARTICIPATION • Available for individuals currently undergoing cancer treatment or have completed their treatment. • Strong personal desire and commitment to attend classes • Obtain a signed medical clearance form • Participate in an interview with our Intake Specialist, complete a confidential health assessment and program registration forms. PROGRAM LAUNCH DATES March 7-May 27, 2022 Daytime: Tuesday and Thursday 10:45 AM – 12:00 PM Evening: Monday and Wednesday 5:45 PM – 7:00 PM To learn more about LIVESTRONG at the YMCA, contact Colleen Villano, Director of Healthy Living at cvillano@cccymca.org or 203 481 9622 x3217.

2021-12-09T03:37:11Z

https://cccymca.org/blog/2021/10/29/livestrong-at-the-ymca/

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Something went wrong while trying to load the full version of this site. Try hard-refreshing this page to fix the error. Course conditions: Has Augusta National ruined us? pike51 Beautiful, lush, green... perfectly manicured, smooth greens. These are the things we've come to expect when we go out to play golf. Last Friday, we held a charity outing at a local course that isn't exactly in perfect condition. It's a great layout and challenging. But the course isn't overrun with money so they aren't able to eliminate every weed or brown spot. Thing is, we still played golf and had fun. I know that I've thought poorly of some courses because of their condition. I've heard others who refer to courses as "goat tracks". Is it the lush green we see on TV that has us spoiled? The US Open at Pinehurst showed something different. The course was brown, hard, and fast. It looked more like a British Open. British Open... where the game was invented. And then I remember the commentators talking about how course maintenance changed immediately after The Masters was broadcast in color. What is your take on course conditions? Are you a bright green fan boy or will you play anywhere? What is and what isn't acceptable as far as course conditions go? What is the break point of not playing a certain course for you? PIGDivot It's all relative. The greens are where I have a higher standard, because greens that are patchy and/or don't roll true don't give you a true measure of your game. Also, if you are hitting the ball in the fairway every time, but it's a hardpan weed fest in the fairway, that will affect how well you possibly can hit your approach shot. Comparison for you. The weekend course I play at has fast greens, but I'm finding myself missing two footers all over the place. The ball isn't rolling true, even though the greens look decent. Whereas, in my Tuesday evening group the only thing preventing my ball from going in the hole is me leaving putts 6 inches short every darn time; but the ball was center of the cup when it stopped. So you tell me - is it my game that sucks, or are the course conditions affecting my abilities? One other example for you. I went out to the local county 9 hole muni not to long ago and shot my best round ever, with an even par 72. But frankly, if the greens there rolled truer I probably would have been under par, as I missed a few putts here and there that might have gone in had the greens rolled true. I don't expect Augusta National anywhere I play, but it's frustrating when you are striking the ball great, and getting greens in regulation, but walking off with par (or even bogey) every time because you can't make a putt due to course conditions. One final consideration. I have never played consistently on it, but poa annua greens on the west coast definitely create a different level of greens and putting then on bent grass or bermuda greens. We witnessed the Billy Horschel show at "Carnival Bay" last June because his putts were wobbling all over the place. How sad is it that the US Open champion wasn't determined by the level of skill of the golfer, per se, but merely by the guy who happened to luck his way into a few putts going in that might not have for another guy hitting the same shots. Sure, there is a ton of luck involved in golf, but we shouldn't be satisfied with that as the norm when we can (for little money honestly) make the conditions decent enough to eliminate a lot of the "luck" on greens. Release Only in this country do we expect the "picture perfect" condition on a gold course. Some of the Scotland's golf course do not have mowing machine for the fairway, only the local flock of sheep do the trimming. No one rack the bunkers since the bunkers are the nature by product of burrowing animals ( and the location move from season to season ). In Japan, they only green color will be the "greens" they let the grass go dormant , natural color is yellowish and brown. Plus, on top of the expectation level. I'd say if the golfer did not pay the comparable green fees for "exceptional conditioned golf course " like the members of the Augusta ( they pay way more than just the member dues ) and do not have the skill like a professional golfer.....then expect less. Unless they are in a movie production, or in their dream. I dreamt of playing perfect golf courses now and then. azgreg I'm not to picky on fairway condition. All I ask for is decent greens and tee boxes that are level and vaguely point down the fairway with grass on them. Release azgreg You will not like many of the top rated golf courses with tee boxes not completely leveled. : >) Ringoblack I think we are a little spoiled when it comes to course conditions. I recognize, however, that there are and should be different levels of quality depending on the price of playing. I am more likely to tolerate poor fairway conditions than I am greens and tee boxes, which imho should be much better than the fairway. But, again, the cost of playing affects my expectations dramatically. Release Ringoblack Condition of the greens, most definitely because that's a major part of the scoring. I'm not so particular of the conditions of the teeing ground. After all, I do tee up the golf ball and the uneven ground makes it interesting. azgreg Release You will not like many of the top rated golf courses with tee boxes not completely leveled. : >) I get that. let me rephrase. I don't care for tee boxes that are overly crowned like standing on a basketball like some of them on our local munis. Darrell_KC Understanding that golf is a true "rub of the green" sport, I will play on pretty much anything. That being said, last year we went to a course that was always a cheapie but still long course, and it was clear the place is nearly dead. The greens were 50% dead, and by dead i mean sand. Not sanded like we are fixing it. Sand as in like a bunker. You could hit a perfect shot 5 feet right of the hole and have a bunker in your way. Thats completely unreasonable, and the last time i will ever play there. I will play greens that are being repaired, and sanded or arrerated, but that was terrible Ive played muni courses that were little more than grass cut in different lengths and played professionally manicured courses. Other than sheer beauty, i may play a bit better on the professionally manicured courses for the simple fact that the grass isnt hardpan or the ball has a somewhat normal lie. Its not going to be enough for it to make a huge difference for me either way. PIGDivot Let me post an addendum to my earlier reply. I played the local 9-hole muni after work today, which is $10 to walk all the holes you want, and I kid you not that the greens were the best I've ever seen them there. Not as fast as better courses, but honestly, who cares. It was a heck of a lot of fun putting on them too. It was hard to get myself to hit the ball hard enough on slower greens, but the darn thing rolled as true as can be. It was also fun hitting chip shots around the green, because you could throw one right up to the hole and it would just stop within a couple of feet. Good times! I guess my point being that if a $10 county owned muni can have such fabulous greens, then any course should be able to do it. Umfaan I expect my greens to be bikini waxed! Sneakylong Luckily my course has reclaimed water, so watering isn't as much of an issue. However, with joint issues I like hitting off real grass in the fairways. The last few years my course has not over-seeded in the winter (Florida). They actually paint / dye the fairways green so the snowbirds who pay top dollar think they're playing off of live grass fairways and not painted dormant grass. If they played there more often they'd realize the divots never fill in with growing grass. DC300 If I'm spending $60 and up for a round, I expect pretty good conditions, but I'm pretty familiar with the $10 muni and accept that it won't be perfect. You get what you pay for. BigDaddy13440 DC300 I know that what we up here in NY refer to as "$60 and up" courses, that a LOT of the guys here are paying upwards of $125-150 to play. Casolwood in Canastota is a perfect example, we both know it well. I've played similar courses while traveling, and for the $28 with cart that we are paying, those other courses are $60-75. Where I live, I've been told that there are more golf courses in a 30 mile by 60 mile "oval" than there are anywhere else in the United States. We've been pretty damn spoiled with green fees that are more than reasonable. DC300 BigDaddy13440 I know that what we up here in NY refer to as "$60 and up" courses, that a LOT of the guys here are paying upwards of $125-150 to play. Casolwood in Canastota is a perfect example, we both know it well. I've played similar courses while traveling, and for the $28 with cart that we are paying, those other courses are $60-75. Where I live, I've been told that there are more golf courses in a 30 mile by 60 mile "oval" than there are anywhere else in the United States. We've been pretty damn spoiled with green fees that are more than reasonable. That's very true, I have so many good courses I can at for less than $30 for 18, it's crazy. I look at spending $60 or more as a premium to play and honestly only do it once or twice a year. Usually I'll hit those courses on a golf now special for $35-45 so I don't have to fork over the cash, but get the experience. Spoiled. Going to see Peter up in Ontario, it's nothing to see $100 a round, I would play a whole lot less there. I guess I don't have the passion I used to, it seems like it's too much for the reward. A couple of rounds a year there is fine, but I'd be in for $5k in green fees to play what I'd like to and that's just not happening. Release Yeah, Around here, even the Muni courses are $40 - $50 per green fee, walking during the weekends. Average public daily fee golf courses are into the $80-$300 per round now. Price to pay for the progress and thank for those invented the luxury tax added on to the golf fee, and Friday as a weekend rate. Unfortunately the average pay did not keep up with this and certainly not those retirees with fixed income. PA-PLAYA Having worked in the industry for several years and getting to know some of the club superintendents in the area, I've learned to be a little more understanding of certain conditions. Water restrictions, budgeting issues that prevent the ability to chemically treat certain weeds from overtaking the grass, or maybe budgeting issues that prevent a superintendent from having enough greens staff on hand to stay on top of everything. Then you have harsh winters that bring certain diseases like snow mold, or, harsh summers with drought conditions and water restrictions that prevent the superintendent from actually growing grass in the fairways or teeing areas. Some things are preventable, some things aren't. Sometimes it's impossible to determine the how's and why's, sometimes it's not. And some things, no matter the extenuating circumstances, are just downright unacceptable. But I will say this - of the dozen or so supers that I know - they all take pride in their work. If it's a public facility, they're fighting for every last penny of additional maintenance budget money they can get. And not just for new blades on the mowers, or bunker rakes, or new flags to replace the old faded and tattered ones. We're talking everything involved with maintaining grass, manicuring grass, growing grass, maintaining the very soil underneath the grass itself to keep the needed nutrients for healthy grass to grow. All of those guys I'm talking about - they went to school for this stuff... they graduated top-rated turf programs in the state. They know what they're doing. And they network together, as a group, to help each other out. Because let me tell you - when you have pythium blight going on at one facility - that means every course in the entire region is subject to the same fungus conditions. Or poannua infestations... especially since the seeds can be tracked in from different courses via the golfer's shoes. Although they all are fighting for the same needed dollars, as competitors in business, and maybe one course would stand to benefit from another course undergoing some serious challenges as far as conditions, influencing customers to play where conditions are nicer - these supers respect each other greatly and understand how difficult their jobs can be even in the best growing seasons. They don't want to see one of their fellow supers under unneeded stress, or even worse - losing a job because of something that maybe they had little control over. By and large - the average greens superintendent is held hostage by two things: Mother Nature, and budget. And they're all generally fighting the same battles, season to season. What I tend to become impatient with, more than any greenskeeper I've ever come across quite frankly, is fellow golfers just ignoring their part of the obligation. Cigarette butts in the bunkers. Sunflower seeds on the greens. Unraked bunkers, unrepaired divots, ball marks on the greens that literally kills the grass if not repaired properly. Then you have the idiots who don't deserve to be out on a golf course, taking the carts where they're not supposed to, especially if the conditions are mushy and wet. Or taking gouges out of the tee box after a bad tee shot, or taking a divot out of a green after a missed 2-footer. Those are cardinal sins that frankly I cannot and will not tolerate from a playing partner. I'm a member of a private club, a nice private club. I pay the extra money for nicer conditions and the avoidance of a 5-hour round on the weekends. But I see the same stuff happening at my club. The guy who bitches about his ball landing in the center of a divot quite often doesn't replace the ones that came from his club. The same with ball marks on the greens. The same with footprints in the bunker. I picked up no fewer than 5 cigarette butts today that were either in the fringe of a green or in a bunker. I'd like to assume that they were from guests who played in front of us, but even then - members should hold them to a slightly higher standard compared to wherever else they ordinarily play. As golfers - we ourselves can do an enormous amount of good by just being good golfers. Being ready to play when it's our turn, and taking care of the course we're playing on. That is certainly not asking too much from anyone, regardless of whether it's at Pine Valley or the local muni.

2021-11-27T10:51:14Z

https://golfbuzz.com/d/307-course-conditions-has-augusta-national-ruined-us

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Kathy Sullivan: Hearings reveal true costs of Northern Pass | New Hampshire Kathy Sullivan: Hearings reveal true costs of Northern Pass The SEC reviews and approves the development of New Hampshire energy facilities. In order to proceed with its plan to cut a 192-mile long swath of transmission towers through New Hampshire, Northern Pass needs permission from the SEC. As part of that process, the SEC is taking testimony from representatives of Eversource. The hearings are revealing issues with the project, including impacts on traffic and local businesses, as well as safety concerns. While Eversource likes to tout the temporary construction jobs that will be required for the project, existing business owners are facing significant adverse impacts. Alex Ray, owner of The Common Man restaurants, has warned that the impact of construction traffic and road closures will be devastating. One study estimates that the town of Plymouth alone could lose 50 existing jobs. That is a big loss in a town with a population estimated at 6,902. An Eversource vice president responded by saying business owners could "file claims" for reimbursement. That does not ensure a full or even partial recovery of economic loss. Moreover, it does not help the people who work at, but do not own, businesses. What are they supposed to do? Eversource suggested that perhaps it could do night work in Plymouth. "Perhaps" is not good enough. Eversource knows that if the project goes forward, it will disrupt traffic in downtown Plymouth. It already should have developed a plan to present to the town and business owners to review. Then there was the testimony of Lynn Farrington, a traffic engineer for the project. She admitted that she did not analyze the possible adverse impact of construction traffic on businesses along the proposed route. It is during construction that there will be the biggest impact of workers, equipment, and road closings on traffic. Yet Farrington stated that no traffic management plan has been written, although they will "discuss" how to minimize the impacts. It is amazing that the people wanting to build a project affecting so much of the state are providing less information on traffic impacts than a local planning board would require for a proposed Dunkin' Donuts. Did I mention that Eversource also disclosed that some road sections would be closed for three to five weeks during construction? Questions also came up at the hearings about the safety record of PAR Electrical Contractors, Inc., the general contractor for the project, which is responsible for the overall management and the construction of all overhead lines, as well as the substations and transition stations. PAR, based in Houston, Texas, has been cited for eight workplace health and safety violations since 2011. It is a subsidiary of Quanta Services of Houston, which has been fined more than $1,100,000 for health, safety, and wage and hour violations since 2010. In addition to those violations, this past March 23, the State of Alaska announced 11 citations and a total of $700,000 in possible fines against two other Quanta subsidiaries, Quanta Power Generation and Price Gregory International. These penalties are in connection with what officials said could have become a catastrophic failure at an Anchorage facility. According to news accounts, state officials said that the penalties were "considered 'willful citations' because the contractors showed 'indifference' toward workplace safety." Ouch. The hearings will continue. So far, they have not gone well for Eversource. The failure of this out-of-state utility behemoth to contact local New Hampshire businesses that will bear the brunt of construction and traffic impacts seems arrogant, as if such concerns are irrelevant. Meanwhile, a competing proposal from National Grid would use existing towers for 108 of its 110 miles. There would be limited widening of existing rights of way. Based on those two facts alone, that project would be much less disruptive to New Hampshire, its people and its businesses. While more information is needed, right now the National Grid plan, which also includes millions of dollars in fuel assistance annually to low income families, makes Northern Pass look like an even worse deal for New Hampshire.

2018/09/26 05:05:32

http://www.unionleader.com/Kathy-Sullivan-Hearings-reveal-true-costs-of-Northern-Pass-05102017

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How to Get 5x, 10x, or even 20x More Value From Your Cybersecurity Post-Assessment Report - Abangane Digital Solutions Skip to content No results 5 Proven Tools For A Web App Vulnerability Assessment About Us Appointment Articles Blog Call Appointment Cart Certificate in Cyber Security Checkout Contact Us Cybersecurity Sophos Disclaimer Download E-Book Downloads home-final IT Governance & Management Landing Page Network Installations News Office365 Opt-in Privacy Policy Quote Request Quote Request Request a Quote Services Eset Antivirus Managed Services Proofpoint Vulnerability Assessment Services-old T Thank you for signing up Thank you form Training Slide Anything Popup Preview Home Services Training News Blog About Us Contacts Us Search Search Menu How to Get 5x, 10x, or even 20x More Value From Your Cybersecurity Post-Assessment Report Michael Mapuranga December 9, 2021 Cybesecurity So, you’ve completed a vulnerability assessment and a penetration test to ensure that your web and network security is up to par. All you have to do now is wait for the report. What you get instead is a hundred-page essay chock-full of technical jargon and figures from which you can barely extract any useful information. You and your IT department are at a loss as to how to address the issues raised in the report, wasting valuable time that could be spent on more revenue-generating activities. Here’s how to get 5–20x more value out of your cybersecurity post-assessment report, according to our guide. 1. The Executive Summary will set the tone from the start Return the executive summary if it’s difficult to understand. This is not up for discussion. For your executives, a third-party security team should be able to summarize what they did, how long it took, provide an overview of the findings and their thoughts on the test. The executive summary must be communicated in such a way that you understand the severity of the situation and decide on who is adequately prepared to oversee the remediation. The executive summary should not be filled with technical jargon that makes it difficult for you to comprehend and take action. To supplement what you would have read in the executive summary, always inquire, “How did we perform for an organization of our size?”; “How were we able to come to a passing/failing report?” You’re paying for more than just someone to run a Nessus scan or Network Detective Collector on your network; you’re also paying for their analysis. Request it. 2. How to make sense of colour-coded risk ratings When you hire a third-party cyber assessment company, they usually set their own priorities and it may or may not correspond to your company’s scale. A visual representation of colour-coded risks are reported For example, information leakage of a customer’s credit card details in a bank is often rated much higher in comparison with other types of businesses. So you ask, What do the risk ratings mean? If a high-risk vulnerability is reported how quickly should we resolve that issue? Which vulnerabilities are putting our most critical assets at risk? When you’ve made sense of the risk ratings, a well-scoped assessment report should be distributed to various departments within your organization. Ensure that you delegate authority to the appropriate departments. Don’t drop a large report on everyone and expect people to understand how it applies to them, especially when it comes to technical findings. Otherwise, you’ll be burdening people with unnecessary work. 3. You’ll be given suggestions, but you should dig deeper Third-party assessors will provide recommendations on how to go about resolving problems, but focus more on the findings. Rather than requesting that your IT staff or cybersecurity experts fix, say, cross-site scripting issues identified in the report, work on how to manage cross-site scripting. For example, define cross-site scripting so that you and your IT department can understand how it works in your language. Return to the other instances identified in the report and see if you can find any similarities that are related to cross-site scripting. There could be a specific way you’re doing output that’s causing vulnerabilities in your network or web application. You could, for example, use response.write code in your app that is chain-connecting vulnerabilities to cause cross-site scripting. Try to identify if vulnerabilities can be chained together So you ask, where do we really have cross-site scripting, and why do we have it? Is it something that violates our coding guidelines? You’ll begin to notice larger design flaws in your applications and network development, testing, and design processes. It’s like sweeping dust under a carpet if you only fix the vulnerabilities identified in the report and don’t understand anything else (like the analysis). What happens the following year when another assessment is conducted and the same vulnerabilities are discovered? Don’t make your security efforts frugal by trying to plug little holes in your ship while being unaware of other holes because you didn’t bother to look. You must shift your focus and begin looking at vulnerabilities at a higher level, as well as addressing them. 4. Managing Upwards Following the initial assessment and testing, you should consider re-testing, which can be more valuable than the initial assessment because it allows you to see how successful you were in making your applications more robust and secure. If your IT department can complete remediations quickly enough after the re-test, they can adjust the report along the way to reflect, for example, that three high-risk findings were discovered and resolved within a week. Because the remediation was part of the final report, time is saved by not having to explain how exploitable a vulnerability is to upper management. Work is easier to manage when you can respond to it right away. Furthermore, your IT department will have a recorded step-by-step guide of how to recreate an exploit, which they can now use to recreate a penetration test to ensure vulnerabilities have been fixed. Key Takeaway Get a report that outlines what you and your IT team should focus on and how to resolve the issue. You should be aware of how your company could be exploited as well as the timeframe in which you must resolve zero-day vulnerabilities

2022-12-03T09:05:09Z

https://www.abangane.co.zw/how-to-get-5x-10x-or-even-20x-more-value-from-your-cybersecurity-post-assessment-report/

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Sleazy album of never-before-seen evidence photos shows loved-up Ghislaine Maxwell giving Epstein foot rubs on Lolita Express jet, sunbathing on yachts and blowing millions of bucks across Europe Cancun vacationers flee beach as five-man armed gang dressed as SOLDIERS pull up on three jet skis and open fire in vicious cartel battle over tourist drug trade Have they all been listening to Prince Harry?! More than FOUR MILLION Americans quit their jobs in October as the Great Resignation continues Three doses of Pfizer jab are required to provide full protection against Omicron variant, pharma giant admits after study said two doses of vaccine provide 41 times less virus fighting antibodies Number of US states with a confirmed Omicron Covid case reaches 20 while nearly 120,000 Americans test positive for the virus every day - the most since the summer Delta surge Amazon 'plans to regroup today' and deal with huge backlog as Xmas orders come under threat after AWS outage wreaked havoc on deliveries Capitol riot committee is 'moving forward' with contempt charges for Mark Meadows after he fails to show for deposition: Ex-White House Chief-of-Staff previously turned over 38-page PowerPoint called 'Options for Jan 6' Bank of America is accused of 'laundering millions and millions' for disgraced South Carolina lawyer Alex Murdaugh who stole insurance payout from sons of housekeeper, 57, who tripped and died at his home Theranos 'fraudster' Elizabeth Holmes buckles under cross-examination as she admits misleading journalist and claims she forgot about emailing investors with news of huge successes for doomed blood-testing startup Still not over it? Hillary Clinton SOBS as she reads her 2016 victory speech that never was 'Imagine if Mexico and Canada were satellites of China': Tucker stands up for Putin over Russian president's fears about Ukraine joining NATO - and says Biden risks dragging US into 'stupid' war Shocked father posts the 'cruel' list of 'rules to live by' his teenage daughter received from her boss on her first day of work (but some claim it's 'sensible' advice!) Is nothing sacred? NYC homeless man is arrested for torching News Corp's giant 50ft Xmas tree outside its Manhattan HQ Biden commission fails to give him go-ahead to pack Supreme Court: Report offers no opinion on adding additional justices to the current nine Best-ever evidence of a crucifixion is found in the UK: Roman slave who lived up to 1,900 years ago is found buried with a 2 inch nail driven through his heel America's Got Talent contestant Skilyr Hicks is found dead at the age of 23 following battles with depression and substance abuse - after appearing on NBC show in 2013 Jeff Zucker tells CNN staff Chris Cuomo will NOT be paid severance and that he wishes he'd taken action to fire $6m-a-year star sooner CNN silence over Jussie and Don: Anderson Cooper and Don Lemon shows both ignore Empire actor's claim that Lemon texted him during 'fake race attack' scandal Jussie Smollett, 39, arrives with his mom and sister for closing arguments in his 'hoax' race attack trial after getting prosecutor to APOLOGIZE for saying N-word when reading out HIS texts in court Opening statements set to begin TODAY in Kim Potter's manslaughter trial where jurors will be presented starkly different views of the veteran white cop who claims she 'accidentally' shot Daunte Wright during botched traffic stop Biden slams media for 'personal attacks' on Soviet-born pick for bank regulator Saule Omarova who dropped out after she 'lost support of moderate Dems', was forced to deny being communist AND it emerged she was arrested for stealing from T.J. Maxx Stop being mean to me: White House holds secret meetings with news organizations to demand better publicity for Biden - as Washington Post columnist claims president is being treated WORSE than Trump Biden goes to Mass in Washington D.C. to mark the Feast of Immaculate Conception before heading to Kansas City to promote his $1 trillion infrastructure bill Biden will tout Kansas City's FREE bus service as he flies to Missouri to promote new $1.2 trillion infrastructure law Previous Next How virtual reality porn will change YOUR sex life! From ultra-realistic romps with adult stars to sex toys synced to the on-screen action, Tracey Cox says 3D porn is booming (and your partner is probably already watching) Virtual reality adult content market expected to be worth $19bn by 2026 Tracey Cox says that while it seems futuristic, it will quickly become the norm Viewer feels like they're there, in the room, participating in the 'experience' Warns it can be hard for real sex to compete and strays into cheating territory By Tracey Cox for MailOnline Published: 02:55 EST, 13 October 2021 | Updated: 04:16 EST, 13 October 2021 e-mail 75 shares 160 View comments I can usually predict the next sex trend by the emails and messages I get - and right now my inboxes are screaming 'virtual reality porn'! 'I've just discovered my partner with a VR headset on, touching himself,' one woman writes, 'Now I know why he's not interested in sex with me anymore.' The VR porn industry - computer generated simulation of three-dimensional sexual interactions - is big business. The global value of the VR adult content market is expected to rise from more than $700US this year to $19bn by 2026. Pornhub averages half a million views per day of the 3,000 free VR videos it offers. On Christmas Day that can shoot up to 900,000. (Turkey and party hats are clearly either exceedingly boring…or arousing.) Like most new things with technology, VR seems sci-fi right now, but it will quickly become the norm for many people. Currently, VR porn is aimed mostly at straight men – which is probably why I'm getting lots of messages from concerned straight women. Having just been to an art exhibition (the Van Gogh Immersive experience) which included watching a VR video of the painter's experience of Provence, I can see why. It was one of the most extraordinarily sensory experiences of my life – and that was without an orgasm thrown in. So just how threatened should we be by VR porn? Is it as popular as it's made out to be – and what if you find out YOUR partner is watching it? Should you feel threatened if you partner is into VR porn, and does it count as cheating? (stock image) How easy is it to access? For years, VR porn was expensive, scarce and a bit hit and miss. Then the porn industry pumped a lot of time and money into making it more reliable and accessible. It still requires effort and investment in terms of both money and time, though. You can access it on your smart phone but it's not easy (most providers aren't porn friendly) and not very good. RELATED ARTICLES Previous 1 Next What group sex is REALLY like: C4 show speaks to real people... How to stop jealousy ruining YOUR relationship: Expert... Share this article Share Anyone who's serious about VR, invests in a wireless, standalone device - the most popular sells for around £300. (Remember, porn isn't the only thing you can use it for: gamers love it, and you can have 'front row experiences' with friends.) Most are simple plug in and play devices: turn it on, head to a porn site and start watching. Pornhub has thousands of free VR clips to explore. Or, for top notch video quality and longer videos, you can subscribe to a VR specialty studio for anything from $10 to $50 a month. What's so good about it? Normal porn provides arousing images for us to watch. VR is an experience: the viewer feels like they're there, in the room, participating in what's going on. Virtual reality uses many camera lenses to record the same scene from hundreds of angles. When they're put together, you get a 180 or 240 degree view of what's been filmed. Tracey Cox says that VR porn is going to grow in popularity because it provides the realistic 'experience' that the online variety can't match up to In 'normal' porn, bodies aren't life size - VR bodies are. The size and proximal distance is big part of what's so exciting to viewers. 'I've worshipped a certain porn star for years,' one man confessed to me. 'This was like getting to meet – and interact sexually with her – in real life. I couldn't believe how realistic it was. It's provided the best orgasms of my life.' There's also added 'extras' VR porn isn't all pre-recorded: you can watch live cam shows and interact with the girls. DreamCam is one company which broadcasts videos of adult stars who talk and interact with the audience. Clients can also tip and influence what they do. 'It's like you're actually having sex with other people but without the fear of getting caught or being seen at a lap dancing club - which my wife forbids', one man told me. Another company has created a small canister that attaches to VR headsets and releases a sweet, musty scent during the action. There are also sex toys for men that can be synced to the video, allowing them to physically feel what they're watching the person on screen do. I am pro porn if it's ethical and used in moderation and in the right way. But VR takes it to an entirely different level, raising all sorts of new issues and dilemmas. For starters… Is it cheating if your partner is having sex with a virtual person? I don't consider passively watching 2D porn cheating: watching a video of people doing sexy things doesn't equate to being unfaithful in real life. But the minute there's interaction, it changes things. Paying a cam girl to do things specifically for you – without your partner's permission – definitely tips it into dangerous territory for most people. VR porn takes things to an even more threatening level. 'The experience is so realistic, it feels like I'm actually having a relationship with her in real life,' one regular VR user told me. 'I'm single at the moment so it's fine. But I wouldn't do it if I was involved with someone. It's totally different than just watching a video.' Cheating isn't the only issue if your partner is a VR fan If it's that good, how does real life sex compare? Does VR porn stop people enjoying real life sex? The answer to that question is that it can lead to discontentment. Porn already makes it hard for real life sex to compete: there's so much variety, catering for every whim, 'twice a week and only in the missionary position' style sex feels even blander than it already is. VR porn delivers all this and more in a multi-sensory format that's fantastically immersive. CONCERNED ABOUT YOUR PARTNER’S PORN HABITS? Here’s some tips for people worried their partner might be developing a dysfunctional porn habit. Are you over-reacting? Studies show 95 per cent of men watch porn. If you’ve noticed the odd search of porn when you (accidentally, of course) click on the history button, don’t give it another thought. Are you still having sex? Porn sex is lazy sex. Most men have a few favourite sites and a particular type of porn they know will push all the right buttons. If you’re still having enjoyable, regular sex, his solo sessions with porn are nothing to worry about. It’s when he’d rather watch porn and masturbate than have real life sex with you when alarms should ring. So why would he opt for porn over sex with me? It’s quick, it’s easy and it’s ready when he is. Zero effort required. Porn isn’t affected by periods, fat days, moods or arguments. It’s predictable – people aren’t. If he has any erection issues and is embarrassed about them, he might opt for porn rather than have what he sees as an excruciating conversation. Ditto if he premature ejaculates. How much time is he spending watching it? Most studies indicate that men watch around 70 minutes of per week with each session lasting about five to fifteen minutes. If your partner’s clocking up way more than that, you might well have a problem. A good sex therapist or therapist who specialises in addiction can help solve the problem and there are many dedicated porn addiction clinics world-wide as well. <!- - ad: https://mads.dailymail.co.uk/v7/us/femail/none/article/other/mpu_factbox.html?id=mpu_factbox_1 - -> Advertisement The user isn't just an observer, they're a participant. The scenes can be so lifelike, you get lost in them and mistake them for reality. This type of activity produces a pleasure-inducing dopamine release that makes users keep coming back for more. In short: it threatens to be far more addictive than 'normal' porn. VR porn is both effortless and highly satisfying. Faced with the choice of solving a sex problem with a real life partner – something that requires effort, motivation and good communication - or putting on a headset to get your kicks, there are no prizes for guessing what many men will opt for. It's new, exciting and can make real life connections feel second rate. 'To be honest, I struggle to get an erection with my partner if I've been watching it too much,' another man told me. 'Sex feels dull and colourless.' What about the ethical issues? Clients with cash can customise avatars to look exactly how they desire. That might be an avatar that looks like an ex they never quite got over. Or someone they can't have but fantasise about. Someone who is sexually off limits: a boss, your best friend's partner. Some men ask for avatars of their girlfriend or wife because they can then make them do something they won't do in real life. If that's all sounding decidedly creepy and distasteful, that's because it is! Revenge porn could be even more devastating for its victims. It's not all bad news though. VR porn could have lots of pluses Lots of couples already enjoy watching VR porn together for an enhanced erotic experience. It's also a great way to explore a new kink before trying it for real (or to satisfy one that your partner doesn't enjoy, without going outside the relationship). Always wanted to go to a sex party or experience a threesome? Here's your chance to give it a whirl, without the emotional risk to your relationship. I struggled to find women who use VR porn on a regular basic but the few I did speak to, did it with a partner and loved the experience. Some sex therapists and educators are hoping the new technology will help people solve common sex problems. 'How-to' videos could demonstrate sexual techniques; there could be 'classes' teaching women how to masturbate. Preliminary research found VR porn results in much greater arousal compared to the traditional 2D view, so it could be useful for people with low libidos. In the future we will be able to have VR sex with our partners. This will give a much-needed sexual boost to lovers in long distance relationships and make lockdowns and quarantines a whole lot more bearable. Even if you are together physically, it means you can still have sex even if one person doesn't feel well or simply doesn't feel like it. In moderation and especially for people who find it difficult to have sex in real life or can't find someone to have sex with, VR porn is a great way for them to experiment and feel less alone. Some experts believe it makes sex so satisfying, men who find it hard to connect with women in real life, might give up completely and happily settle for VR porn as a substitute for real life experiences. Whichever way you look at it, VR porn – like all porn – is here to stay. It's up to us, as individuals, to navigate our way through the ups and downs and learn to live with it. Visit traceycox.com for Tracey's two products ranges, her podcast, sex advice and her books. Advertisement Share or comment on this article: Tracey Cox says virtual reality porn will be the norm by 2026 e-mail 75 shares Comments 160 Share what you think Newest Oldest Best rated Worst rated View all The comments below have been moderated in advance. View all The views expressed in the contents above are those of our users and do not necessarily reflect the views of MailOnline. We are no longer accepting comments on this article. Bing Site Web Enter search term: Search Advertisement Follow DailyMail Subscribe Daily Mail Follow @dailymail Follow DailyMail Follow MailOnline Follow Daily Mail Femail Today Take that, Tristan! 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Magazine cover Sex Lives Of College Girls is renewed for a second season after a very successful debut... as creator Mindy Kaling says 'yesssss!' Chloe Grace Moretz bundles up in Louis Vuitton coat in NYC... and talks wearing 21lb prosthetic belly for Mother/Android Feeling good as hell! Lizzo makes a splash as she jumps into the ocean during grand finale performance at Miami's Art Basel Selena Gomez grins alongside co-stars Martin Short and Steve Martin as the trio take on a new investigation while filming season two of Only Murders in the Building Karl Lagerfeld's first estate auction fetches $13.5 MILLION - including $1.33m for three cars, $22k for a sculpture of his CAT, and $54k for five pairs of fingerless gloves Advertisement She's no diva! Nicole Kidman touches up her own makeup before sauntering down the red carpet at Being The Ricardos premiere in a stunning Armani Privé gown Being The Ricardos earns modestly positive reviews... as critics spar over Nicole Kidman's transformation into I Love Lucy star Lucille Ball The joys of motherhood! Tennis star Serena Williams, 40, gets glam while her mini-me daughter Olympia, four, pulls on her earring Monica Bellucci, 57, opens up about her desire to 'get old in a peaceful way' - saying she isn't 'obsessed' with maintaining her figure as 'there is nothing we can do' about aging 'Our dating pool really is a puddle!' Paulina Porizkova, 56, enjoys a dinner date with friends who were ALL brought together by a man they met on Raya - and he was there too Joe Rogan slams CNN as 'f****** propagandists' as Chris Cuomo and Don Lemon 'texted Jussie Smollet to tell him cops didn't believe he was victim of a homophobic attack' Tamara Francesconi shows off her sizzling physique in orange and green swirl patterned bikini as she poses up a storm in Mauritius Cagney & Lacey star Sharon Gless questioned her sexuality after kissing and hitting on Rosie O'Donnell Chrissy Teigen sparkles in black glittering dress and tells Ellen DeGeneres that husband John Legend BAILED on getting his and hers tattoos drawn by daughter Luna John Goodman, 69, continues to show off dramatic 200lbs weight loss at The Freak Brothers Experience in LA after hiring personal trainer Advertisement 'I'm not up on things': Meryl Streep, 72, reveals she had no clue what her Don't Look Up co-star Jonah Hill, 37, meant when he called her a GOAT 'We would never disrespect Samantha': Sex And The City's Kristin Davis discusses how Kim Cattrall's absence will be addressed on new show And Just Like That Revealed: What Carrie Bradshaw's swanky NYC apartment in Sex and the City would REALLY be worth today Haley Bennett effortlessly turns heads in cage crinoline dress as she and co-star Peter Dinklage lead the stars attending the UK premiere of Cyrano Derek Hough and girlfriend Hayley Erbert spend the night out at producer Jennifer Klein's holiday party... where they hang out with the Ted Lasso cast Brooke Shields SLAMS 1981 Barbara Walters interview after being grilled over her measurements, being sexualized and THAT Calvin Klein campaign at just 15 Defense computer expert says Josh Duggar's internet connection at car dealership was so vulnerable hackers could have logged on and watched child porn Halle Berry and boyfriend Van Hunt look loved up as they hold hands at the annual Celebration of Black Cinema & Television in LA Father of Rust armorer Hannah Reed claims gun was SABOTAGED by crew member who wanted to 'cause an safety incident' but didn't mean for Halyna Hutchins to die Supermodel Elle Macpherson, 57, strips off into a tiny bikini and relaxes by the pool in footage captured by her fashion photographer ex-husband Gilles Bensimon Dorinda Medley's dating a new man and jokes she wants to see 'medical records' and will 'only leave her house' for nice restaurants Kyle Richards signs on to return as Lindsey Wallace in Halloween Ends: 'So excited and grateful!' Selena Gomez says she 'cried like a baby' when she was nominated for her FIRST Grammy award for Revelacion: 'It was a lovely surprise' Jennifer Garner sports chic pinstripe slacks with a sweater while running errands in Brentwood Home Alone alum Devin Ratray reveals the cast is 'planning a reunion' 31 years after original film (but Macaulay Culkin will skip it) 'Fun and friendly' Kendall Jenner 'makes drinks behind the bar and takes shots with pals' at party in Miami for her tequila brand 818 Tara Reid rocks red dress and blazer for dinner at Craig's in West Hollywood... where she bumps into Sara Foster and Jennifer Meyer Roselyn Sanchez is 'so happy and grateful' to co-host Dick Clark's New Year's Rockin' Eve With Ryan Seacrest in her native Puerto Rico Amber Le Bon exudes elegance in sheer black dress as she poses with Lady Sabrina Percy at jewelry event Rihanna promises new music is coming 'soon, soon, soon'... five YEARS after the release of her last album Anti F1 champ Lewis Hamilton sells NYC penthouse for $49.5m despite never living in property - which boasts FIVE bedrooms, plunge pool and wraparound terrace Max Verstappen's secret weapon! Driver, 24, has one over on rival Lewis Hamilton thanks to his supportive model girlfriend Kelly, 33, who's the daughter of Nelson Piquet I woke up like this! Top cosmetic tattoo artist reveals everything you need to know about permanent makeup - including a surprising NIPPLE trend Now the woke brigade are coming for your Christmas films! Twitter critics say Love Actually 'rewards toxic men' and 'archaic' Bridget Jones champions sexual harassment Lauryn Hill breaks down mid-set at Chicago memorial service to Off-White fashion designer Virgil Abloh: Kanye, Rihanna, Kim Kardashian, and Drake pay their respects Alec Baldwin and wife Hilaria ring in holiday season with passionate kiss as couple retreat to the Hamptons after actor denied pulling trigger on gun that killed cinematographer Jussie Smollett reveals Don Lemon warned him that cops didn't believe account of being beaten up: CNN host ignores revelation on his show Nick Cannon sends the internet into a frenzy over his apparent 'bulge' while hosting his new talk show Ellie Goulding enjoys family outing with husband Caspar Jopling and their son Arthur, 7 months, as they go for stroll in Miami Beach Catherine Zeta-Jones, 52, shows off her toned abs and age-defying looks in skin-tight black activewear as she dances up a storm during photoshoot Vanderpump Rules star Raquel Leviss packs her bags and moves out of the apartment she shared with ex James Kennedy after announcing split Josh Hartnett reveals the one role he regrets turning down that would have set him up for Hollywood superstardom Advertisement DON'T MISS 'I had a ton of sex!' Pregnant Jennifer Lawrence jokes about how she spent acting hiatus... before saying time off was filled with 'cooking and cleaning' Rita Ora puts in a colorful display as she shows off her rainbow manicure after arriving in Australia A birthday princess! Future Dutch queen Amalia is regal in red in official portraits taken at The Hague's Huis ten Bosch Palace to mark her 18th Prince Harry and Charles 'have barely spoken in MONTHS': Relations hit 'an all-time low' after Megxit, accusations of royal racism and billionaire donor scandal Prince Harry's 'concerns' about Saudi billionaire 'did NOT reach Charles': 'Clarence House staff don't remember discussions about tycoon' 'Daddy's little helper': David Beckham and daughter Harper, 10, put on an adorable display as they plant a tree for The Queen's Platinum Jubilee Shanina Shaik dazzles in black sequinned gown with dramatic train detail at Cyrano premiere in Saudi Arabia Amy Adams, 47, swaps red carpet glamour for a very casual ensemble as she goes Christmas shopping in Beverly Hills RHOBH star PK Kemsley was arrested on suspicion of DUI in California a month after his wife Dorit was robbed at gunpoint Vanessa Paradis, 48, cuts a stylish figure in a tasseled black crop top and cape as she joins a chic Lucy Boynton, 27, at Chanel fashion show in Paris 'I got a lot of pushback from my own team': Rebel Wilson admits her management were opposed to her losing weight after 'earning millions as the funny fat girl' Nicole Kidman is the epitome of glamour in strapless Armani Privé gown as she is joined by on-screen husband Javier Bardem at Being The Ricardos premiere Vanessa Bryant lawsuit reveals she's seen photo of Kobe's body taken by cops after deadly helicopter crash that also killed her daughter and idea of images 'torments' her Khloe Kardashian shows off sympathy flowers from Scott Disick after her serial cheater baby daddy Tristan Thompson fathered a child with personal trainer Jane Seymour reunites with Dr. Quinn, Medicine Woman cast 23 years after the show went off the air to celebrate co-star Joe Lando's birthday Pete Davidson and Machine Gun Kelly drive fans wild as they strip down to Calvin Klein underwear on Instagram takeover: 'Hope everyone's horny at home!' Calvin Klein, 79, steps out with long-term boyfriend Kevin Baker, 33, in rare outing as they don matching casual outfits for a low-key lunch date Too Hot To Handle's Nicole O'Brien looks stunning in a busty denim jumpsuit as she steps out for dinner Ashley Graham showcases her burgeoning baby bump ahead of giving birth to twins and reveals: 'My boys are 6lbs EACH!' Tammy Hembrow shares previously unseen video of the moment she told fiancé Matt Poole she was pregnant - and says their baby is 'so loved' Halle Berry, Jennifer Hudson and Taraji P. Henson turn heads in fashion-forward dresses at the annual Celebration of Black Cinema & Television Claudia Schiffer, 51, flaunts her phenomenal frame in a clinging white mini as she struts out of The King's Man premiere after-party in London Saweetie turns up the heat in a bejewelled bodice while Lil Nas X displays his ripped abs in a crop top and kilt as they lead glamour on-stage at iHeartRadio's Jingle Ball Ryan Reynolds cuts a stylish figure as he steps out in a suede green jacket and dark shades for a winter walk Rose McGowan's federal lawsuit against Harvey Weinstein is DISMISSED after she failed to file correct paperwork by deadline: Star claims film mogul sexually assaulted her Wife of fired Chris Cuomo escapes NYC and is seen picking up takeout in Sag Harbor with her beleaguered hubby nowhere in sight Gold FIRST LOOK: Zac Efron plays a drifter who stumbles across a gold nugget in the Australian outback in a trailer Britney Spears enjoys a smoke before taking a jacuzzi dip in a tiny red bikini... as she continues her 40th birthday celebrations with fiancé Sam Asghari in Cabo San Lucas Pete Davidson smokes a joint on red carpet of The Freak Brothers in LA... while love-interest Kim Kardashian attends memorial service with Kanye West Adele fans placed on waiting list for her Las Vegas residency due to 'high demand' as they're informed tickets may NOT be sold if 'demand exceeds supply' Pregnant Jennifer Lawrence flaunts her growing baby bump in a skin-tight polka dot dress with retro Hollywood curls as she blazes the Don't Look Up promo trail Jonah Hill displays his unique fashion sense in a bold floral shirt and purple beanie hat as he joins Leonardo Di Caprio at the Q&A for their film Don't Look Up Leonardo DiCaprio is dapper as he is joined by Jonah Hill and his girlfriend Sarah Brady at Q&A event for Don't Look Up in NYC The Bachelorette: Tayshia Adams tells co-host Kaitlyn Bristowe she's 'heartbroken' over tough split with Zac Clark and emotionally walks off Paul Hollywood, 55, signs autographs while girlfriend Melissa Spalding, 37, looks on as they attend The King's Man premiere afterparty following their red carpet debut 'I feel like a pig s**t in my head': Richard E. Grant is at his wits' end in $300-per-night UK hotel quarantine - after complaining about the 'grim food' Maggie Gyllenhaal wows as she debuts new sleek locks in a clinging silk gown at SFFILM Awards Night 'I was so sad he couldn't see it that I dedicated the film to him': Steven Spielberg reveals the impact West Side Story remake had on his late father Arnold FKA twigs pairs her bold red carpet ensemble with a billowing patterned coat as she departs The King's Man premiere after-party in London Ashley Roberts cuts a chic figure in a lilac shirt and purple flared trousers as she makes a stylish exit from Heart FM Nicole Kidman swaps her gown for an LBD as co-star Javier Bardem storms the stage to play drums at Being The Ricardos premiere after-party Carefree Mark Zuckerberg takes his foil board for a spin in Hawaii as incoming storm seers thousands prepare to evacuate Tom Hiddleston wears a DRESS and wig for fun guest turn in The Play What I Wrote ... joining a slew of mega-stars including Ralph Fiennes, Daniel Radcliffe, and Sting Jennifer Aniston leads casts of upcoming Live In Front Of A Studio Audience on Jimmy Kimmel Live as Kevin Hart jokes about walking because it's gonna be a 's***show' 'It wasn't ugly just that their schedules weren't aligning': Eiza Gonzalez and Paul Rabil SPLIT 'a few weeks ago' after work 'put strain' on their seven-month romance Bindi Irwin shares adorable footage of eight-month-old daughter Grace Warrior meeting a giant tortoise at Australia Zoo The Voice: Ariana Grande gets in on the act as Jim and Sasha Allen perform live during semifinals Jimmy Fallon teams up with with Ariana Grande and Megan Thee Stallion for a new holiday tune It Was A... (Masked Christmas) Gwen Stefani certainly seems in the holiday spirit as she rocks bold red and black ensemble while out in LA Red Hot Chili Peppers bassist Flea quietly arrives in Sydney before going clothes shopping with wife Melody Ehsani The Melbourne-born rocker, 59, was pictured Saturday Bode Miller and wife Morgan reveal they've welcomed a baby girl in a home birth - three and a half years after tragic drowning death of their daughter Emmy Sylvester Stallone, 75, to star as mob boss in drama series Kansas City... in what will be his first leading man role for TV West Side Story's Ansel Elgort and Rachel Zegler promote upcoming film at SiriusXM Studios in LA Beats December in D.C.! Ivanka Trump protects herself from the Florida sun in a wetsuit and denim cutoffs while taking children tubing on a speedboat in Miami Olivia Wilde rocks a sweatshirt from her beau Harry Styles's gender-neutral beauty line while out in Los Angeles Christine Quinn is all legs in pink tweed mini dress after Chrishell Stause revealed she threatened her with legal action 'Let's embrace all the faiths and rituals!' Madonna celebrates the final night of Hanukkah by dressing up as an elf and decorating a Christmas tree 'He had her on his lap during bible time and touched her private area.' Duggar family friend describes how 15-year-old Josh Duggar confessed to molesting his sisters RHONJ star Teresa Giudice, 49, poses with the stunning lookalike daughters she shares with ex-husband Joe Giudice: 'All 4 of you make me so proud' Evan Rachel Wood claims Marilyn Manson threatened 'to f**k' her eight-year-old son with Jamie Bell and 'destroy' families of other alleged victims PICTURED: 'Upset' Khloe Kardashian emerges after discovering Tristan Thompson 'got another woman PREGNANT while they were still together Masked-up Chrissy Teigen and John Legend buy out entire row behind them at NYC's vax-only Radio City Music Hall to watch The Rockettes' with their two kids Fury as Prince Harry says quitting work can be good for your mental health and 'many people around the world have been stuck in jobs that didn't bring them joy' Jussie Smollett testifies attack was 'no hoax' as actor reveals doing drugs and masturbating at bathhouse with one of the Nigerian brothers who beat him up Devious Maids actress Edy Ganem says her marriage to Ryan Oehm 'has come to an end' in amicable split Real Housewives of New York's Luann de Lesseps says she'd love to see a lesbian or transgender woman join the RHONY cast next season Tom Holland and Zendaya open up about their relationship: 'Having a shoulder to cry on has been a huge thing for the pair of us' Selling Sunset star Chrishell Stause clarifies that she was not born at a Shell gas station: 'I hate to disappoint people' Behati Prinsloo cuts a cool figure as she enjoys a leisurely cup of coffee before doing a little Christmas shopping in LA's Palisades Village Mandy Moore celebrates her father's last flight as a pilot following a 42-year-long career: 'It's the end of an era for our family' Emily Ratajkowski brings the Christmas cheer in a red swimsuit that makes the most of her toned body... 9 months after welcoming her first child Willem Dafoe teases Green Goblin has 'more tricks up his sleeve' with upgraded, 'more flexible' costume in Spider-Man: No Way Home Arnold Schwarzenegger enjoys a cigar as he drives classic Excalibur vehicle in Los Angeles Charlie Cox confirmed to return as Daredevil in the Marvel Cinematic Universe by Marvel President Kevin Feige... though it's unclear when Dave Bautista will headline M. Night Shyamalan movie Knock At The Cabin: 'Another dream come true' Kerry Washington shares a behind-the-scenes snap from the set of her new directorial effort Reasonable Doubt Chrissy Teigen beams as she flashes her abs in frayed plaid shirt and sports bra... after sparking controversy by buying entire row of seats at vax-only Radio City Music Hall Leonardo DiCaprio just found out his father George has a small cameo in Paul Thomas Anderson's Licorice Pizza Colin Farrell will play The Penguin and his alter ego Oswald Cobblepot in HBO Max spinoff show of The Batman 'I'm very protective of her': Sex And The City's Mr Big star Chris Noth defends Sarah Jessica Parker after being 'targeted' by Kim Cattrall in 'nasty' feud Taylor Swift and two collaborators are removed from Grammy Album Of The Year nominee contention for Olivia Rodrigo's Sour BTS boybanders join Instagram... and V breaks records amassing 15.6M followers in less than 24 hours Sylvester Stallone's iconic movie memorabilia sells big at auction with his original handwritten Rocky script notes fetching a knockout $437,500 Joe Gorga is pulled off the stage by his wife Melissa as he completely bombs stand-up routine after taking combination of Sudafed and alcohol 'Go f*** yourself': Ridley Scott says 'f*** you' to journalist who said The Last Duel is 'more realistic' than his previous films Little People, Big World star Jacob Roloff announces his wife Isabel Roloff has given birth to their first child, a baby boy Rihanna gives a flash of her tummy in crop top while taking off her puffy coat on romantic night out in NYC with boyfriend A$AP Rocky Colin Farrell, 45, shows off his chiseled body as he goes shirtless while modeling some very short shorts during a jog in Beverly Hills Feeling festive! Crown Princess Victoria of Sweden dazzles in a sparkly sequin two-piece during second day of whirlwind visit to Paris 'I'll be paying for it for a long time': Michael Sheen reveals he's turned himself into a 'not-for-profit' actor after putting his mansions up for sale to help the homeless It's magic! HBO unveils 20th anniversary Harry Potter Reunion trailer and original stars Daniel Radcliffe, Emma Watson and Rupert Grint ALL making appearances Cardi B sizzles in racy lace-up jumpsuit for the launch of her new alcohol infused whipped cream line in Miami The Matrix Resurrections' second trailer unveils Jada Pinkett Smith in old age make-up as Niobe Gemma Arterton wows in a shimmering orange gown at star-studded The King's Man world premiere in London FKA twigs wows in dramatic orange hooded gown as she attends glittering The King's Man premiere in London Aaron Carter 'is back on' with on/off fiancée Melanie Martin as he 'gushes' about her and their newborn son on his now-deleted Instagram... just days after their messy split 'He plays it like Hamlet not comedy': Succession's Jeremy Strong reveals he doesn't see his Kendall character OR the show as funny - leaving his co-stars baffled! Smiling Jill Duggar takes her sons for puppy 'therapy' amid her brother Josh's child porn trial - as she may be called to testify about childhood abuse this week HGTV star Steve Ford ties the knot with Andrea Cargill in outdoor wedding at Pennsylvania resort The Witcher's Henry Cavill reveals his pet dog Kal has saved him 'emotionally and psychologically plenty of times' West Side Story's Rachel Zegler recalls the late Stephen Sondheim telling her she sang 'like a nightingale' in stunning new shoot for ELLE Magazine Scarlett Johansson scintillates in low-cut sequined gown as she wraps her arm around husband Colin Jost at 44th annual Kennedy Center Honors Chris Noth had no idea his And Just Like That co-star Willie Garson had cancer: 'Most of us didn't know' Chris Pine keeps it casual in a denim jacket over a gray shirt and matching jeans as he goes on a solo coffee run near his home in Los Feliz Ron Perlman, 71, hits the red carpet with fiancée Allison Dunbar, 49, at the premiere for Netflix's Don't Look Up John Legend signs up for Las Vegas residency inside Planet Hollywood: 'The setlist will be a cool, career retrospective' Charlotte McKinney is every inch the beach bombshell in zebra string bikini while vacationing with boyfriend Nathan Kostechko in Miami Ioan Gruffudd's new girlfriend Bianca Wallace returns to Instagram after making first appearance with star... as his estranged wife Alice Evans brushes off romance Lily-Rose Depp showcases her incredible figure in a tiny bralet before slipping into ab-flashing crop top for sexy Wonderland cover shoot Braless Demi Rose flashes her VERY ample assets in a skimpy white corset as she seductively reclines on a sunbed during California getaway Empire actor Jussie Smollett could take star turn on the stand today in last-ditch effort to sway jury over his alleged bogus hate-crime claims 'Trying to keep up with David at the gym!' Victoria Beckham shows off her strength in skintight black sportswear during weightlifting session 'C'mon there's no way Joe's still awake right now': SNL star Michael Che roasts Biden at Kennedy Center Honors while David Letterman takes swipe at Trump for never attending Pregnant Jennifer Lawrence makes red carpet debut with baby bump in gold gown alongside Leonardo DiCaprio at Don't Look Up premiere Jonah Hill and girlfriend Sarah Brady twin in matching light blue suits at the Don't Look Up premiere in New York City Gemma Arterton looks chic in a black dress while Ralph Fiennes downs pints at pop-up pub ahead of The King's Man film premiere Florence Pugh says she FAINTED when she got her new septum piercing as she shows off the bling at the NYC Don't Look Up premiere 'I'm so pleased you like my music, Princess Charlotte!' Shakira tweets for Prince William's daughter after he revealed she 'goes crazy' dancing to World Cup song Waka Waka Earl Spencer's daughters Amelia and Eliza, 29, say they 'grew up surrounded by poverty' in Cape Town - despite living with their mother Victoria in a wealthy suburb Sarah Ferguson says she is 'the most persecuted woman' in royal history and 'still loves and stands by' Prince Andrew as Ghislaine Maxwell's trial continues Charles and Harry's relationship 'at rock bottom': Royal experts say father and son now 'appear very distant' after Duke 'expressed concerns' over Saudi billionaire Listen to Prince William choke back tears as he recalls how seeing a boy close to George's age 'on death's door' after a car crash he attended as an air ambulance pilot Lil Wayne is investigated by cops after 'pulling an assault rifle on one of his own bodyguards during an argument at his Hidden Hills home' Mike Tyson proudly poses up a storm with daughter Milan, 13, at his charity fundraiser in California 'I am playing Fred Astaire, yeah!' Tom Holland CONFIRMS he is set to play Hollywood's dancing and singing legend in upcoming biopic Mary J. Blige, 50, slips into tiny Dior bikini for day at the beach in Miami after announcing new album Good Morning Gorgeous Ben Affleck looks VERY fired up during intense conversation with The Tender Bar co-star Lily Rabe at movie theatre in LA 'Sail away, to the cold expanse of space': Grimes releases bitter break-up track 'Player of Games' about Elon Musk and sings 'he'll always love the game, more than he loves me' Alec Baldwin DELETES Twitter account in wake of tearful ABC interview about accidental killing of cinematographer Halyna Hutchins on set of western movie Rust Chris Pratt and his wife Katherine Schwarzenegger take their baby girl Lyla, one, to lunch with her mom Maria Shriver and sister Christina in LA Hollywood film producer Martha De Laurentiis dies of cancer at age 67 of cancer Her first credit was on the 1984 Stephen King adaptation Firestarter Tom Brady and Gisele Bundchen celebrate daughter Vivian's ninth birthday: 'I'm looking forward to many more days of throwing the football together' Rebel Wilson is unrecognizable as the slimmed-down star is greeted by her sister Annachi at Sydney Airport while swamped by an oversized tracksuit Having a Bond girl moment! Rebel Wilson shows off her incredible 70lb weight loss in a plunging orange swimsuit in sultry photo shoot for Fiji Australia Pete Davidson looks handsome in a black tuxedo as he attends The Kennedy Honors without rumored love interest Kim Kardashian Scarlett Johansson glitters in low-cut gold gown as she, Ellie Goulding, and Amy Poehler lead stars on red carpet ahead of the 44th Kennedy Center Honors in D.C. Hilaria Baldwin escapes NYC to the Hamptons one day after husband Alec's TV interview in which he denied pulling trigger on gun that killed Halyna Hutchins Tommy Fury's grudge match against Jake Paul set to be CALLED OFF two weeks before fight, amid claims half-brother of world heavyweight champ has been 'forced to pull out' due to COLD Meryl Streep has a mod moment in a sheer disc dress as she delights at the Don't Look Up world premiere in New York City A royally fun day out! Zara and Mike Tindall wrap up warm as they join Peter Phillips at Legoland's Christmas winter wonderland Prince Andrew goes for a drive then a horseride after news emerged of his FOUR flights on Jeffrey Epstein's Lolita Express private jet Prince William reveals future of royalty: As Duke wins praise for discussing mental health on podcast, Princess Diana's aide PATRICK JEPHSON hails PR coup New agony for the Queen as one of her closest courtiers dies: Duchess of Grafton, the Monarch's loyal Mistress of the Robes, passes away aged 101 Madonna poses in a Keith Haring robe as she pays tribute to friend and late artist in edgy shoot: 'Give me your f***ing money AKA pay taxes' Star Trek actress Nichelle Nichols, 88, lights up Comic Con LA with beaming smile during tribute celebrating her retirement Giggling Kate Beckinsale stuns in a white gown with sleek cape and metallic sleeves as she presents gong at the British Independent Film Awards Doctor Who fans left shocked after Jodie Whittaker's Time Lord makes PAUL HOLLYWOOD GBBO handshake reference in Flux finale Eiza Gonzalez dons Tom Ford ensemble to reunite with Ambulance co-stars Jake Gyllenhaal and Yahya Abdul-Mateen II Genesis and frontman Phil Collins bring the classic hits and more as The Last Domino? reunion tour rolls into NYC's Madison Square Garden Real Housewives Of Salt Lake City: Mary Cosby denies that her church parishioners worship her as God Jessica Alba is every bit the doting mom as she carries son Hayes, three, as she and husband Cash Warren shop for Christmas trees in West Hollywood How to dress like a grown up with Shane Watson: Luxe up your look in head-to-toe winter white UK-based style expert takes inspiration from Rita Ora and Victoria Beckham Ioan Gruffudd makes his FIRST public appearance with new girlfriend Bianca Wallace as couple emerge in LA Fear The Walking Dead: Alicia Clark cuts off her own arm after being bitten by zombie The Walking Dead: World Beyond: Jennifer 'Huck' Mallick dies after stabbing during series finale BTS is set to take an 'extended period of rest' to get 're-inspired and recharge with creative energy' after banner year Encanto is tops again by keeping hold of No. 1 spot at the domestic box office ahead of Ghostbusters: Afterlife MOBO Awards 2021: Leigh-Anne Pinnock showcases her incredible post-baby body in cut-out mini dress before going lingerie-free in VERY risqué leather number MOBO Awards 2021: Skepta takes home Best Grime Act while Dave receives Album Of The Year award as they lead this year's winners MOBO Awards 2021: Leigh-Anne Pinnock stuns in a slashed leather dress as she presents the returning show... three months after giving birth to twins Proud mum Perrie Edwards shares sweet festive clip of baby son Axel taking his first steps after announcing Little Mix split Begbie is BACK! Robert Carlyle shares details of his Trainspotting spin-off series based on sequel novel which sees character return from California to avenge murdered son Scandal actor Joshua Malina says 'cancel culture' doesn't exist with Mel Gibson's return to Lethal Weapon franchise ... citing past allegations of anti-Semitism Chrissy Teigen dons black leather jacket over sports bra and clinging leggings while out with John Legend and their brood in New York Kylie Jenner and Travis Scott are '100% together' romantically despite claims they haven't been a couple in 'two years' per W Magazine's leaked issue Lil Nas X bares six-pack abs in a metallic pink crop top and skirt with cowboy hat at Audacy Beach Festival in Florida Kourtney Kardashian shares adorable photos of son Reign and nephew Saint hamming it up in matching sweats and nameplate necklaces Bono masks up while stepping out for a Sunday afternoon lunch at Gjelina restaurant in Venice Inside the Irwins' Tasmanian getaway: Bindi dotes on daughter Grace, eight months, as she joins her husband Chandler Powell on a bushwalking trip Former Bachelor contestant Sydney Lotuaco gets ENGAGED to beau Nick Wehby: 'He was very much worth the wait!' Vanessa Hudgens dons black fringed jacket as she hangs out on the sideline before singing national anthem at Raiders game in Las Vegas Bachelorette alum Katie Thurston holds hands with new beau John Hersey... just over a month after ending engagement Blake Moynes Paul Walker's brother Cody reunites with Vin Diesel at annual FuelFest festival... just days after marking eight years since Fast & Furious star's tragic death Khloe Kardashian says that Kylie Jenner and Travis Scott 'are very much a couple' following report in W Magazine's leaked issue they haven't been together in 'two years' Vanderpump Rules stars James Kennedy and Raquel Leviss call off engagement after five years together: 'We aren't in love anymore' Scott Disick steps out with a mystery woman in Miami for Art Basel event... months after split with Lisa Rinna's daughter Amelia Hamlin Megan Fox puts on a leggy display in a blazer while beau Machine Gun Kelly rocks a shiny jacket and an odd fang-shaped lip cuff at his nail polish launch Kate Beckinsale wows in structured white gown as she joins glamorous stars Ruth Wilson, Emma Corrin and Lily James at the glittering 24th British Independent Film Awards Justin Bieber performs in Saudi Arabia despite calls for him to cancel the show over the kingdom's human rights record Kim Kardashian celebrates her son Saint's sixth birthday with sweet tribute: 'Thank you for being my bestie' 'Don't touch people': Farrah Abraham confirms conflict gets physical in Teen Mom: Family Reunion Iman Shumpert dons dark brown one-piece while posing with baby daughter Rue Rose in latest SKIMS campaign Halsey shows off her eclectic Christmas tree decorations including ornaments featuring Britney Spears and Harry Styles Travis Barker picks out the perfect Christmas tree with his kids while fiancee Kourtney Kardashian nails a classic cat-eye selfie back at home Today's headlines Most Read Led Zeppelin's hellraising tour manager Richard Cole who 'escorted girls to hotel rooms' and 'kept the band nourished with drugs' dies of cancer aged 75: Jimmy Page pays tribute to 'a brother and friend to the end' Ad Feature Tis the season! 5 expert tips for hosting the ultimate festive drinks party this year Ad Feature Make Christmas magical AND delicious for all! M&S have the perfect online gifts for all this season - and they're guaranteed to have your mouth watering! Ad Feature From a calming routine to the right mattress: Make some new year 'restolutions' with our top 10 tips for getting a great night's sleep (with astronaut-approved science!) Woman back at work after 8 weeks off with mental health issues complains colleagues who picked up the slack and were denied holiday are being 'incredibly hostile' - but is told SHE is in the wrong for not thanking them Do YOU clean your cooker hood? Blogger reveals the top three places you've forgotten to clean including the washing machine filter - and shows how grimy then can REALLY get From high school wedding singer to Hollywood's hot new star: Construction worker's daughter Rachel Zegler, 20, landed her first film role as Maria in West Side Story after spotting casting call on Twitter MORE HEADLINES 'I’ve had to grow really thick skin': Liberal Karlie Kloss, 29, moans about Jared Kushner and Ivanka Trump being her in-laws Shocked father posts the 'cruel' list of 'rules to live by' his teenage daughter received from her boss on her first day of work (but some claim it's 'sensible' advice!) How world's 'most identical twins' are trying to get pregnant at the same time with their shared fiancé by scheduling ovulation and eating the EXACT same diet Monica Bellucci, 57, opens up about her desire to 'get old in a peaceful way' - saying she isn't 'obsessed' with trying to maintain her figure because 'there is nothing we can do' about aging US mother who 'forgave' husband after their twin babies died when he mistakenly left them in a hot car admits that when he was first released from jail on suicide watch she 'didn't care' what happened to him Enough to drive you to divorce! Wives share photos of their husbands' most frustrating behaviour - from ripping open packaging to toilet roll tubes left in the bathroom Welcome to QuitTok! Gen Z employees lauded by Prince Harry for quitting work due to 'bad management, toxic work culture and long hours' celebrate their resignations on social media - but some admit they 'don't have a plan B' MOST READ IN DETAIL Advertisement SHOP BY CATEGORY These are the best Fashion deals you’ll find online. Save up to 50% on Trending when you shop now. Save up to 50% on Women's Clothing when you shop now. Shop our favorite Women's Shoes finds at great prices. Save up to 50% on Maternity Clothing when you shop now. Save up to 50% on Swimwear when you shop now. Find the best deals on Women's Jewelry from your favorite brands. Shop the best selection of deals on Beauty now. Shop our favorite Makeup finds at great prices. Save up to 50% on Skin Care when you shop now. Save up to 50% on Hair when you shop now. Find the best deals on Fragrance from your favorite brands. Shop our favorite Bath & Body finds at great prices. Deals and discounts in Nails you don’t want to miss. 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NEW ARTICLESHomeTop Share Back to top Home U.K. News Sports U.S. Showbiz Australia Femail Health Science Money Video Travel Shop DailyMailTV Sitemap Archive Video Archive Topics Index Mobile Apps Screensaver RSS Text-based site Reader Prints Our Papers Top of page Daily Mail Mail on Sunday This is Money Metro Jobsite Mail Travel Zoopla.co.uk Prime Location Published by Associated Newspapers Ltd Part of the Daily Mail, The Mail on Sunday & Metro Media Group dmg media Contact us How to complain Leadership Team Advertise with us Contributors Work with Us Terms Do not sell my info CA Privacy Notice Privacy policy & cookies

2021-12-08T16:53:21Z

https://www.dailymail.co.uk/femail/article-10084523/Tracey-Cox-says-virtual-reality-porn-norm-2026.html?ns_mchannel=rss&ns_campaign=1490&ito=1490

OSCAR-2201

en

A couple of hundred yards of this sort of manhauling, and your sled will never be the same again. Passes like this are why I prefer my much cheaper but slightly heavier fiberglass sled to Ogita's $5,000 carbon Acapulka model. So much less painful to ruin and replace. On the west end, near Flagler Fiord, Sverdrup Pass raises a second obstacle: steep ramps of bare ice where a summer river has frozen. They're fairly easy to negotiate if you've thought to bring crampons and a long rope to haul the sled up after you, but these two items are not common on manhauling expeditions -- you don't need them on sea ice. Eventually, however, Ogita managed. When I joined an Inuit sovereignty patrol through Sverdrup Pass once, we were even able to horse the snowmobiles up, though it took hours and involved ropes, several men and and a couple of hours of chiseling the ramp with an ice tool to a slightly gentler grade. The trick of traveling in very cold weather (I'm talking -40 or -50, not -20) is perpetual motion. You stay warm thanks to exercise metabolism. No bulky clothes, or even specialty items, required. Just the usual layers: polypro, fleece, shell. At those temperatures, there is no such thing as a lunch stop. No matter how cold it is, of course, you have to pause intermittently, to eat, drink and pee. While manhauling, I do this every hour and a half or two hours. The key is speed: You have to finish these chores and get going again before the exercise heat shuts down and your body cools. It's not necessary to put on a heavy parka if you're fast enough. I've found that seven minutes is the longest break you can take before you pay a price. Longer than that, and you may have to add a layer, then remove it 15 minutes later: very inefficient. Your fingers also go numb, and hurt like hell when feeling returns. Ice climbers call this the screaming barfies; a doctor I traveled with called it reactive hyperemia and suggested that lactic acid builds up during the numb phase. The pain is the lactic acid being reabsorbed. You don't have to have this experience too many times to want to avoid it. After a too-long break, it takes 20 minutes to feel okay again. It's possible to do everything in a few minutes, though you may still be chewing your snack, or holding a half-eaten sandwich in your hand and grabbing a bite in mid-stride for the next few minutes. Towards the end of the day, I sometimes sit down on the sled or kneel down in the snow briefly just to stretch the lower back. But always, I have the seven-minute rule in my head and keep all stops within that time limit. In slightly milder temperatures, such discipline is not necessary but it's a habit now, and on day ski tours here in the Rockies, partners tease me about my restlessness at break time. ExplorersWeb reports that Yasu Ogita of Japan plans to manhaul from Grise Fiord on Ellesmere Island to Siorapaluk, the northernmost village in Greenland. The article states that the route is 1000km. I've done the entire way except the crossing to Greenland, so I can say it's closer to 800km. Still, a good length. I checked the current state of the sea ice in that area using NASA's Worldview satellite imagery, above. The 50km gap between Canada and Greenland is typically the northern terminus of the North Water polynya. Historically, it almost always freezes over, often around the Bache Peninsula, as it has this year. When Frederick Cook and his two Inuit companions walked back to Greenland after their winter on Devon Island in 1909, he claims to have crossed around Bache. Other explorers had it easier: In 1914, Donald MacMillan dogsledded across from Pim Island in just a few hours. And in the early 1970s, some crazy Minnesota snowmobilers went to Greenland from Cape Dunsterville, a section that is so unstable even in good years, it makes my skin crawl to think of the risks they took.

2021-03-03T09:40:41Z

https://www.co.washington.pa.us/106/Larry-Maggi

OSCAR-2109

en

Multiscale dynamics of tight junction remodeling | Journal of Cell Science Multiscale dynamics of tight junction remodeling Saranyaraajan Varadarajan, Rachel E. Stephenson, Ann L. Miller Journal of Cell Science 2019 132: jcs229286 doi: 10.1242/jcs.229286 Published 21 November 2019 Saranyaraajan Varadarajan Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109, United States ORCID record for Ann L. Miller For correspondence: annlm@umich.edu Epithelial cells form tissues that generate biological barriers in the body. Tight junctions (TJs) are responsible for maintaining a selectively permeable seal between epithelial cells, but little is known about how TJs dynamically remodel in response to physiological forces that challenge epithelial barrier function, such as cell shape changes (e.g. during cell division) or tissue stretching (e.g. during developmental morphogenesis). In this Review, we first introduce a framework to think about TJ remodeling across multiple scales: from molecular dynamics, to strand dynamics, to cell- and tissue-scale dynamics. We then relate knowledge gained from global perturbations of TJs to emerging information about local TJ remodeling events, where transient localized Rho activation and actomyosin-mediated contraction promote TJ remodeling to repair local leaks in barrier function. We conclude by identifying emerging areas in the field and propose ideas for future studies that address unanswered questions about the mechanisms that drive TJ remodeling. Epithelia aid in organizing the body by creating tissue barriers – sheets of connected cells with the ability to regulate the quantity and type of materials that cross the tissue. In addition to acting as barriers, epithelial tissues are involved in specialized functions, such as absorption, secretion, transportation and signaling. Almost every organ in our body is covered with or lined by an epithelial tissue that is specifically suited for the task of the organ. Molecules can cross tissues by going either through cells (transcellular transport) or between cells (paracellular transport), and different tissues have different requirements for the strength and selectivity of these barriers. Tight junctions (TJs) are responsible for sealing the paracellular space and discriminating among small solutes, such as ions, water and small uncharged molecules, while generally restricting the passage of larger molecules and microorganisms (Marchiando et al., 2010). These barriers are crucial for establishing concentration gradients across tissues, thereby creating specialized environments (e.g. a low pH in the stomach), and preventing infection. TJs regulate the flux of molecules through the paracellular spaces with a family of transmembrane proteins called claudins, which are capable of forming size- and charge-selective pores, as well as restricting flux. Vertebrate genomes encode a large number of claudins (more than 20 in humans) with diverse pore- and barrier-forming properties (Günzel and Yu, 2013 ; see also Box 1). TJs are connected to the actomyosin cytoskeleton through scaffolding proteins, including ZO family proteins (Box 1), and these cytoskeletal connections are crucial for the structure and function of TJs. The organization and tension of perijunctional actomyosin is regulated by the small GTPase RhoA; thus, RhoA activity must be tightly regulated in space and time for correct TJ formation, maintenance and remodeling (Arnold et al., 2017). Box 1. Molecular organization of TJs The claudin family of transmembrane proteins (yellow and orange), comprising >20 members, oligomerize into strands and interlock with their counterparts on neighboring cells to selectively regulate passage through the paracellular space. Whereas 'barrier-forming' claudins primarily restrict ion flux (i.e. claudins 1, 3, 5, 6, 9, 14 and 19), 'pore-forming' claudins facilitate it by forming size- and charge-specific pores (i.e. claudins 2, 10a, 10b, 15, 17 and 21) (Gunzel and Yu, 2013). Together with claudin strands, junctional adhesion molecules (JAMs, dark blue) also help limit macromolecule flux (Otani et al., 2019). TJ-associated MARVEL proteins (TAMPs, green), such as occludin, tricellulin and MarvelD3, play a variety of roles in signaling, barrier development and TJ strand morphology (Raleigh et al., 2010; Cording et al., 2013; Krug et al., 2009). ZO proteins (light blue) facilitate the formation of a dense plaque of proteins associated with TJs (Beutel et al., 2019; Otani et al., 2019). A ZO protein can multimerize with itself and other ZO proteins (e.g. ZO-1 can bind ZO-2 and ZO-3 in addition to itself), and can bind claudins, JAMs, TAMPs, F-actin (red), scaffolding proteins (e.g. cingulin, pink) and signaling molecules (not illustrated), including GEFs (e.g. Tuba) and transcription factors (e.g. ZONAB) (Shen et al., 2011). For a detailed summary of protein-protein interactions within the TJ, see Shen et al. (2011). Pore and leak pathways for paracellular permeability TJ selectivity is regulated through claudin pores – channels formed by the extracellular domains of claudins – that conduct ions and small molecules on the basis of size and charge. Paracellular permeability through claudin pores is commonly referred to as the 'pore pathway'. Selectivity is based on the composition of pore-forming claudins (both cation and anion pores) and barrier-forming claudins, which restrict the flux of small solutes (Günzel, 2017). Barrier properties of TJs can change in response to various stimuli by 'claudin switching', e.g. by replacing a pore-forming claudin with a barrier-forming claudin (Günzel, 2017). Owing to the large number of highly selective pores, the pore pathway is characterized by its high capacity and high selectivity (Anderson and Van Itallie, 2009; Shen et al., 2011). Transepithelial electrical resistance (TER) measures the magnitude of ion flux across epithelia (increased TER indicates decreased ion permeability), whereas more-refined techniques can measure size and charge selectivity of junctions (Box 2; see also Shen et al., 2011). Box 2. Pore and leak pathways of paracellular permeability Depending on their permeability characteristics, TJ barriers can broadly be divided into two categories: (i) the 'pore pathway', with permeability for ions and small solutes with a radius of ≤4Å (Van Itallie et al., 2008) and, (ii) the 'leak pathway', with permeability for larger (≥4Å) solutes and macromolecules. The barrier to ions is often measured using transepithelial electrical resistance (TER), where electrical current is generated across a monolayer, the voltage is measured and the resistance calculated (Srinivasan et al., 2015). Because cell membranes are good resistors, the electrical current will be carried by ion flux through the paracellular route (Srinivasan et al., 2015). In intact TJs, ion flux will occur through claudin pores. Thus, tissues with a high proportion of barrier-forming claudins, such as bladder and stomach, have higher electrical resistance (see Figure, top left and bottom left), whereas tissues with a high proportion of pore-forming claudins, such as kidney proximal tubule and small intestine, exhibit low electrical resistance (see Figure top right and bottom right). In some situations, tissues can exhibit high macromolecular flux, yet, also high electrical resistance (see Figure, bottom left) (Balda et al., 1996). This paradoxical finding helped researchers to recognize that there must be a second pathway of paracellular permeability: the leak pathway. Notably, high ion flux can also occur at sites where the strand network is disrupted (see Figure, bottom right). Thus, it is important to note that a drop in TER can indicate either an increase in ion flux owing to TJ disruption or an increase in the incorporation and/or opening of pore-forming claudins. To aid in the interpretation of a drop in TER, changes in TJ size and charge selectivity could be measured with methods such as bi-ionic substitution or dilution potential (e.g. Raleigh et al., 2011). Macromolecular flux is typically measured after the addition of traceable macromolecules, such as fluorescent dextrans or PEG oligomers, to one side of the epithelium and following their passage to the other side. PEG oligomers are available in sizes small enough to allow measurement of the upper radius of molecules that travel through the pore pathway, as well as those that use the leak pathway (Van Itallie et al., 2008; Watson et al., 2001). Fluorescent dextrans at different sizes can also be used to measure the size selectivity of the leak pathway (e.g. Otani et al., 2019). However, there are limitations with these techniques, which include averaging of the barrier properties across the entire tissue, preventing one to understand how leaks are affected by changes in cell morphology or cell position in the epithelium. Whereas fluorescent dextrans can be visualized in vivo (e.g. Higashi et al., 2016), the sensitivity of this method might not be sufficient to detect small volumes of molecules breaching the epithelium. More-sensitive assays, such as the highly sensitive Zinc-based ultrasensitive microscopic barrier assay (ZnUMBA) and avidin–biotin sandwich assays (Stephenson et al., 2019; Richter et al., 2016), allow for finer spatial and temporal resolution of flux through the leak pathway. A second pathway, known as the 'leak pathway', allows larger molecules to cross TJs, albeit with less selectivity and a much lower capacity than the pore pathway (Shen et al., 2011). The predominate hypothesis is that leak pathway flux occurs due to the breaking and annealing of claudin strands, which may be influenced by intermolecular associations between claudins, occludin, ZO-1 and the actin cytoskeleton (Fanning et al., 2012; Turner et al., 2014; Van Itallie et al., 2015). Another leak pathway regulator, JAM-A, is sufficient to limit the flux of macromolecules in the absence of claudin strands, suggesting that JAMs serve as a stop-gap measure to protect barrier integrity when claudin strands are disrupted or newly forming (Otani et al., 2019). The presence of redundant mechanisms to regulate the leak pathway underlines the importance of restricting flux of macromolecules via the leak pathway. Cell shape changes challenge epithelial barrier function To effectively limit flux, it is necessary for TJs to be continuous around the perimeter of epithelial cells. However, multiple physiological processes in epithelial tissues involve cell-shape changes that require cell–cell boundaries to expand and contract, thus posing challenges to the continuity of TJs. For example, actomyosin-driven changes of cell shape and cell rearrangements induce the stretching, bending and folding of tissues during developmental morphogenesis (Harris and Tepass, 2010). Other mechanical challenges arise from organ-specific function, including bladder expansion and gut peristalsis. However, it is poorly understood how such dynamic tissues can also act as stable barriers. Because the correct regulation of barrier function is essential for optimal organ function (Marchiando et al., 2010), epithelial cells must possess robust mechanisms for maintaining barrier function while remaining plastic enough to adapt to a changing environment. This Review focuses on how TJ remodeling on several scales contributes to sustained barrier function in the face of cell and tissue dynamics. TJ remodeling across scales TJ dynamics encompass multiple scales – from the molecular composition and dynamics of individual proteins and protein complexes to tissue-scale events, such as mechanical stress – which affect TJ remodeling (Fig. 1). Molecular- and tissue-scale dynamics of TJs have been studied in some detail, although our knowledge of these processes is still incomplete. An even greater gap in knowledge lies in the intermediate scales – at the strand network and cellular scales (Fig. 1). In this section, we will discuss TJ dynamics across scales, the technical limitations that prevent us from fully understanding these remarkable structures, and the interplay between these levels of TJ organization and remodeling. TJs are dynamic at the molecular, strand, cellular and tissue scale. Molecular dynamics include the trafficking of proteins to the TJ, the formation of protein complexes and incorporation of claudins into strands. Strand dynamics include the assembly of strands into networks, dynamic reorganization of these networks at baseline and in response to stimuli, change in network geometry, and the incorporation and removal of claudins from strands. At the cellular scale, TJs undergo local alterations as cell–cell boundaries elongate, shrink or otherwise experience a change in shape, such as during cell division, extrusion or axis elongation. At the tissue scale, TJs change in response to tissue-scale forces (e.g. mechanical forces associated with development or organ function), biochemical signals (e.g. immune response), and differentiation. In turn, the state of the tissue influences the expression and trafficking of different TJ components, ultimately altering the molecular, strand and cellular dynamics of TJs. Strand dynamics The basic unit of the TJ is the claudin-based strand (Fig. 1, strands). Multiple claudin-based strands join together to form elaborate strand networks that vary considerably in complexity and organization from tissue to tissue (Claude and Goodenough, 1973). Because claudins possess diverse pore-forming and barrier-forming properties (Günzel and Yu, 2013; see also Box 1), the composition of claudins within the strand network has a profound effect on ion flux across the tissue (Fig. 1, molecules and strands; Box 2). Less well-understood is how the morphology of the strand network itself impacts barrier function. Owing to the tight packing of TJ strands and the relatively poor z-resolution of light microscopy, the morphology of the TJ strand network has traditionally been viewed by freeze fracture electron microscopy (FFEM). One FFEM study comparing the epithelial strand networks that exhibit different barrier properties found that an increased strand number is generally associated with decreased ion flux (Claude and Goodenough, 1973). However, there are also examples where TJ permeability is independent of strand number (Colegio et al., 2003), suggesting the claudin composition – not just the number of strands – determines permeability. Some treatments that affect barrier properties correspond to rapid changes in strand network configuration. For example, exposure of Necturus (salamander) gallbladder to plant cytokinins causes a rapid but reversible increase in TER (Bentzel et al., 1976; see also Box 2). This treatment also results in the reorganization of TJ strand networks from being mostly parallel relative to the apical membrane to more-disorganized, vertically oriented networks with a higher number of free strand ends (Bentzel et al., 1980). Removal of cytokinins corresponds to a drop in TER and a reorientation of strands to a parallel orientation with very few vertical crosslinks (Bentzel et al., 1980). Similarly, treatment with the actin-depolymerizing drug cytochalasin D, which decreases TER in guinea pig ileum, results in the transformation of the strand network from a regularly crosslinked meshwork to one that is sparse and disorganized (Madara et al., 1986). Thus, in addition to claudin composition, strand density, orientation and crosslinking may impact barrier function (Fig. 1). Mechanical changes in junctional or tissue tension can also alter the strand network morphology by reorienting the strand network or inducing strand breaks (Fig. 2; see also Hull and Staehelin, 1976; Pitelka and Taggart, 1983). Interestingly, radial tension generated by contraction of the apical actomyosin array resulted in networks with more vertically oriented strands, whereas tension generated by tissue stretch generated more parallel TJ strands (Pitelka and Taggart, 1983). This indicates that tissue mechanics may influence strand network morphology, in turn impacting barrier function. Potential mechanisms to elongate the strand network. These include strand straightening and reduction of interstrand crosslinks through strand breakage, reorientation and joining. In addition, network elongation may involve new strand synthesis by incorporation of claudins at free strand ends or de novo strand assembly. Although FFEM is considered the 'gold standard' tool for visualizing TJ strands because it provides high-resolution information about the morphology of the strand network, this technique presents limitations, including limited molecular specificity and dependence on tissue fixation, meaning that strand dynamics cannot be observed over time (Bartle et al., 2018). Improvements to super-resolution imaging techniques might make high-resolution live imaging of the dynamics of epithelial cell TJ strands and proteins that associate with them possible in the future. In the meantime, expression of claudins in fibroblasts, which do not normally make TJs, has been an effective approach to reconstitute dynamic strand networks similar to those seen by FFEM in epithelial cells (Furuse et al., 1998). Because the plane of cell–cell contact in fibroblasts is parallel to the imaging plane and the strands are less densely packed than in native TJs, it is possible to resolve individual strands by using light microscopy or super-resolution microscopy (Sasaki et al., 2003; Kaufmann et al., 2012; Van Itallie et al., 2017). However, it should be noted that reconstituted claudin strands lack the full complement of TJ proteins, meaning that strand dynamics in native TJs could vary substantially. These reconstitution experiments revealed that claudin strands can be remarkably dynamic within the membrane, capable of breaking and annealing, as well as forming transient end-to-side and side-to-side interactions (Sasaki et al., 2003; Van Itallie et al., 2017). These observations led to the hypothesis that the breaking and annealing of TJ strands is the mechanistic basis that underlies the leak pathway (Sasaki et al., 2003; Van Itallie et al., 2017; Zihni et al., 2016), the non-selective flux of macromolecules across tissues (Box 2). To better understand how interactions between claudins and other TJ proteins influence strand dynamics, the TJ proteins ZO-1 and occludin were also introduced into fibroblasts expressing claudin-2. The reconstituted strands that were linked to actin through ZO-1 aligned with actin filaments (Van Itallie et al., 2017). Although the overall size of strand patches was stabilized when they were linked to actin through ZO-1, the dynamic breaking and joining of strands was not changed, indicating that this interaction alone is not sufficient to stabilize strand breaks (Van Itallie et al., 2017). Interestingly, occludin tends to localize to free strand ends and branch points, which are more susceptible to breaking and appear to be sites of claudin incorporation (Van Itallie et al., 2017; see also Fig. 2). Because reconstituted strands are likely to behave differently than native strands, future studies that can observe TJ strands and single-molecule dynamics in vivo would be a major leap forward in our understanding of how proteins, such as ZO-1 and occludin, modify TJ dynamics, as well as how strand dynamics contribute to barrier function. In summary, claudin-based strands form the selectively permeable seal that generates the barrier function of the TJ. Strand organization and function is regulated by multiple factors including mechanical forces that change tissue tension, connection of the transmembrane TJ proteins to the actin cytoskeleton and molecular composition of the TJ. We next discuss the dynamics of TJ proteins at the molecular scale. Fluorescence recovery after photobleaching (FRAP) is a powerful tool for understanding TJ remodeling at the molecular level. FRAP of claudins in individual reconstituted strands in fibroblasts revealed that, once incorporated into strands, claudins are locked in place – there is no fluorescence recovery (Sasaki et al., 2003; Van Itallie et al., 2017). Rather, newly synthesized claudin molecules are likely to be added at strand ends (Van Itallie et al., 2017). In epithelial TJs, FRAP of claudins reveals that they, too, are remarkably stable, with typical mobile fractions between 20 and 35% (Shen et al., 2008; Yu et al., 2010; Raleigh et al., 2011; Capaldo et al., 2014; Higashi et al., 2016). Several studies suggest that claudin stability is associated with claudin function and incorporation into claudin strands. For example, claudin-2 is a pore-forming claudin that is permeable to cations. When occludin serine residue 408 is not phosphorylated, it forms a complex with ZO-1 and claudin-2, and claudin-2 mobility increases. Under these circumstances, TER increases (i.e. ion permeability decreases), indicating loss of claudin-2 pore functionality (Raleigh et al., 2011). A similar pattern is observed when Caco-2 cells are treated with the pro-inflammatory cytokines interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) (Capaldo et al., 2014). Cytokine treatment decreases TER, which is associated with increased mobility of claudin-4, a barrier-forming claudin and decreased mobility of claudin-2 (Capaldo et al., 2014). Additionally, claudins that are capable of forming reconstituted strands in the epithelial-like cell line SF7 have lower mobile fractions than other claudins that are unable to do so (Yamazaki et al., 2011). The simplest interpretation of these results is that incorporation of claudins into strands reduces their diffusion and allows them to act as either pores or diffusion barriers, according to the type of claudin. FRAP and complementary techniques, such as fluorescence loss in photobleaching (FLIP) and photoactivation, have also provided information about the molecular dynamics of TJ proteins over short periods of time (seconds to minutes), demonstrating that FRAP recovery of occludin and claudins occurs through lateral diffusion within the membrane; although diffusion of claudins is more spatially restricted than that of occludin, and the mobile fraction of occludin is higher, between 50 and 80% (Shen et al., 2008; Yu et al., 2010; Raleigh et al., 2011; Van Itallie et al., 2015; Ronaghan et al., 2016; Janosevic et al., 2016). Over longer periods of time (hours), claudins and occludin also behave differently. A recent study using pulse labeling of SNAP- and CLIP-tagged TJ proteins has shown that occludin and claudins move within the TJ in unique ways (Van Itallie et al., 2019). Newly synthesized claudins are trafficked to the basolateral membrane and are incorporated into free strand ends on the basal side of the TJ. As strands mature, claudins move apically and old claudins are removed by endocytosis. By contrast, occludin trafficking is not polarized, and occludin can exchange between TJ and basolateral pools. This further implies that claudins are 'locked in' to strands, whereas occludin is more transiently associated with strands or other TJ structures (Van Itallie et al., 2019). ZO-1 exchange occurs not through diffusion along the membrane but through exchange with a cytoplasmic pool (Shen et al., 2008; Yu et al., 2010). According to FRAP studies, ∼10–50% of ZO-1 is immobile (Shen et al., 2008; Yu et al., 2010; Raleigh et al., 2011; Van Itallie et al., 2015; Higashi et al., 2016). Stabilization at the junction requires the actin-binding region of ZO-1 and might also reflect stable association with structures, such as claudin strands. Recent evidence suggests that ZO family proteins form phase-separated compartments (Beutel et al., 2019, Schwayer et al., 2019), and many TJ proteins, including scaffolding proteins, signaling proteins and the cytoplasmic tails of TJ membrane proteins, are concentrated within these compartments – in some cases as much as 40-fold higher than the cytoplasmic concentration (Beutel et al., 2019). The dense concentration of TJ proteins within these phase-separated compartments is likely to allow for emergent TJ properties, such as the polymerization of claudins into strands, which requires ZO-1 or ZO-2 and their ability to multimerize, as well as the ability of ZO-1 to bind actin (Beutel et al., 2019; Otani et al., 2019; Schwayer et al., 2019; Umeda et al., 2006). Understanding the molecular dynamics and organization of TJ proteins will give us a stronger foundation to explain how TJ strands and molecules respond to cell- and tissue-scale dynamics. Cell-scale dynamics Adherens junctions (AJs) are typically viewed as the main load-bearing actin-associated cell–cell junctions, and their role in force sensing during cell shape change and development has been extensively studied (Charras and Yap, 2018). However, it is less clear how TJs respond to cell shape changes, particularly when existing cell–cell interfaces are elongated or new cell–cell interfaces are established, such as during cell division and cell extrusion (Fig. 1, cells). During cell division, a relatively small portion of the cell–cell junction experiences direct pulling forces from the contractile ring. In Xenopus laevis embryos, FRAP of AJ proteins showed that they are stabilized at the cleavage furrow; however, FRAP does not detectably change for TJ proteins, indicating that AJs are coupled to the forces that are generated by the actomyosin contractile ring (Higashi et al., 2016). Interestingly, ZO-1 intensity at the furrow does increase relative to that at the poles, indicating that some TJ remodeling occurs during cytokinesis (Higashi et al., 2016). Indeed, FFEM showed that TJs in mitotic cells are more disorganized, comprising a higher number of free strand ends than non-mitotic cells (Tice et al., 1979). Cell extrusion presents another potential challenge to epithelial barrier integrity. During extrusion, which occurs due to cell death or overcrowding of healthy cells in the epithelial monolayer, cells are squeezed out of epithelial tissues by their neighbors (Gudipaty and Rosenblatt, 2017). During this process, TJs extend basally to maintain contact between neighboring cells and the extruded cell (Madara, 1990; Guan et al., 2011; Marchiando et al., 2011). Following cell extrusion, new cell–cell interfaces must be formed. During events involving cell-scale dynamics, such as cell division and cell extrusion, major shape changes occur not only in cell interfaces that are directly involved in the process but also in neighboring cells. These cells must then change their shape to accommodate the movements of the dividing or extruding cells. During both cytokinesis and extrusion, the epithelial barrier is largely maintained (Higashi et al., 2016; Rosenblatt et al., 2001; Madara, 1990; Guan et al., 2011; Marchiando et al., 2011). Therefore, gaining a better understanding of the mechanisms that allow TJs to expand and contract, while simultaneously restricting ion and macromolecule flux, is an important goal for this field of research. Tissue-scale dynamics Tissue-scale dynamics include TJ remodeling over extended periods of time and greater distances during development, morphogenesis and in diseased states. For example, maturation of TJs as tissues differentiate during development involves the expression of different sets of tissue-specific TJ proteins and signaling proteins (Günzel and Yu, 2013). Furthermore, tissue-scale mechanical stretching during developmental morphogenesis or organ-specific functions (e.g. bladder filling and voiding) requires significant TJ remodeling. Additionally, disease states, such as pathological inflammation, can influence the morphology, protein composition and barrier function of TJs at the tissue scale by modulating TJ protein expression and trafficking, as well as actomyosin structure (please see the excellent reviews by Luissint et al., 2016; Garcia-Hernandez et al., 2017; Marchiando et al., 2010). During developmental morphogenesis, dynamic remodeling of TJs is not only required to maintain barrier function as epithelial cells undergo shape changes and rearrangements, but TJs also actively help to drive development. Several studies have shown that TJ proteins are crucial for apical-basal polarity, blastocyst and lumen formation, and convergent extension (Moriwaki et al., 2007; Navis and Bagnat, 2015; Baumholtz et al., 2017; Otani et al., 2019). For example, loss of ZO-1 or occludin results in multi-lumen formation in 3D epithelial culture (Odenwald et al., 2018; Otani et al., 2019). Additionally, disruption of claudins impairs expansion of the blastocoel, a fluid-filled lumen, due to a leaky barrier and loss of hydrostatic pressure (Moriwaki et al., 2007). Furthermore, TJ-dependent fluid accumulation generates the hydrostatic pressure essential for lumen formation and expansion during organogenesis, as clearly demonstrated in the zebrafish gut (Navis and Bagnat, 2015). Together, these studies suggest that TJs play a crucial role during development that extends beyond their role in regulating paracellular permeability. Having defined a multiscale framework within which we can consider TJ remodeling, we next highlight a recent study from our lab that unifies TJ and barrier dynamics across scales. Rho flares regulate barrier function on the subcellular scale We recently demonstrated that, when cell–cell junctions elongate in the Xenopus laevis embryonic epithelium, local discontinuities in ZO-1 and occludin, but not claudin-6, often occur along the expanding junction (Stephenson et al., 2019). By using a highly sensitive barrier assay, the zinc-based ultrasensitive microscopic barrier assay (ZnUMBA), we identified that the local breaks correspond to sites of leak pathway flux (Stephenson et al., 2019). Importantly, these leaks were quickly repaired by Rho flares, local activations of RhoA that promote local actin accumulation and myosin II-mediated contraction, which concentrates TJ proteins to reinforce the barrier at sites of local leaks (Fig. 3). TJs are remodeled in response to local changes in tension. Elongation of a junction near a dividing cell (boxed area, magnification shown below) causes local loss of ZO-1 and a breach in barrier function (not shown). Activation of RhoA (green dome) at the site of ZO-1 loss promotes actomyosin-mediated contraction of junctions (blue arrows), which concentrates TJ proteins to repair the barrier leak. Modified with permission from Stephenson et al., 2019. Breaking and annealing of TJ strands is thought to be the means that allows macromolecules to cross the TJ (Zihni et al., 2016). Owing to its indiscriminate nature and increased prevalence in diseased tissues, leak pathway flux could be assumed to be an 'accidental' feature of TJs rather than a purposeful one. We propose that the ability of TJ strands to easily break gives cells the flexibility to change their shape without being constrained by a rigid paracellular barrier. Actomyosin contraction then drives reinforcement of the TJ barrier by locally increasing protein concentration. Because reconstituted strand ends readily re-anneal with one another (Van Itallie et al., 2017), locally increasing protein concentration may facilitate this process (Fig. 1, strands and cells). Additionally, there might be yet-unknown functions of transient increases in permeability; perhaps increased flux contributes to junction remodeling or these strand breaks are necessary for transepithelial migration. Not every instance of junction elongation causes a leak or is followed by contraction. Therefore, Rho flares might be an emergency repair mechanism that kicks in when a TJ is more severely damaged. However, this raises the question: what is the routine maintenance mechanism that allows TJs to elongate gradually while maintaining the barrier? In tissues that have been experimentally stretched, TJ strands align with the axis of tension; they appear highly taut and are reduced in number (Pitelka and Taggart, 1983; Hull and Staehelin, 1976). These features indicate that a reorientation of the strand network in response to stretch could help to cover an expanding area without de novo synthesis of TJ strands (Fig. 2). Breaks in strand networks and free strand ends are also a common feature of remodeling TJ networks (Van Itallie et al., 2019). In reconstituted TJ strands, free ends can rapidly reanneal to existing strands and are also the sites of new claudin incorporation (Van Itallie et al., 2017). Thus, strand reannealing and claudin addition may help TJ strands to cover more linear distance, ensuring that a stretched cell maintains barrier function. In the following section, we speculate on how our knowledge about global perturbations of TJ proteins can be applied to understand TJ remodeling on local, short-term scales. Global perturbation of TJ proteins The function and remodeling of TJs have been studied by using genetic manipulations of specific TJ proteins, as well as by modulating cytoskeletal tension using small-molecule inhibitors or mechanical stretch. In this section, we focus on experiments that test the functions of ZO proteins, occludin and cytoskeletal tension in TJ establishment and barrier function. Double knockout of ZO-1 and ZO-2 in MDCK II cells results in failure to form TJ strands and, thereby, increased flux of ions through the pore pathway and of macromolecules through the leak pathway (Otani et al., 2019). Previous knockdown studies that investigated partial loss of ZO-1 or ZO-2, or of both ZO proteins resulted in a number of less-severe phenotypes, also pointing to the importance of ZO proteins in the regulation of TJ structure and epithelial barrier function (Van Itallie et al., 2009; Fanning et al., 2012; Rodgers et al., 2013; Odenwald et al., 2018; Umeda et al., 2006). Possible reasons for variability among these studies include redundancy between ZO-1 and ZO-2, the use of different epithelial cell lines comprising different baseline levels of TJ proteins, and variations regarding the level of ZO protein knockdown. Nevertheless, common themes that emerged from these studies include that complete or partial loss of ZO proteins correlates with the robust accumulation of F-actin and myosin II, as well as an increased flux of macromolecules through the leak pathway (Van Itallie et al., 2009; Fanning et al., 2012; Rodgers et al., 2013; Odenwald et al., 2018; Umeda et al., 2006; see also Fig. 4A). Notably, this aligns with our finding that the transient TJ breaks prior to Rho flares are, indeed, associated with local reduction of ZO-1, as well as with increased flux via the leak pathway, which is soon followed by local F-actin accumulation (Stephenson et al., 2019; see also Fig. 3). TJs are remodeled in response to tissue-scale changes in tension over longer and shorter periods of time. (A) Sustained global remodeling of TJs through genetic manipulation – specifically ZO-1 and ZO-2 double knockdown. In epithelial cells, double knockdown of ZO-1 and ZO-2 increases the accumulation of perijunctional actomyosin, and cells exhibit increased paracellular flux of large solutes (not illustrated). A magnification of the boxed area is shown below, showing this region before (top) and after (bottom) double knockdown of ZO-1 and ZO-2. (B) Acute global remodeling of TJs through mechanical stimuli. Mechanical stretching of epithelial tissue (indicated by black arrows) also increases accumulation of perijunctional actomyosin, and cells exhibit barrier leaks (not shown). A magnification of the boxed area is shown below, showing this region before (top) and after (bottom) stretch. See text for additional details. Like ZO-1 depletion, genetic perturbation of occludin is also associated with increased flux via the leak pathway (Turner et al., 2014; Buschmann et al., 2013). Interestingly, global knockdown or knockout of occludin has no observable effect on strand network morphology when using FFEM (Yu et al., 2005); thus, how exactly occludin perturbation increases flux via the leak pathway is unknown. However, the local loss of ZO-1 and occludin we observed prior to Rho flares (Stephenson et al., 2019) suggests that Rho flares have a direct role in regulating the barrier to macromolecules. For instance, it is possible that ZO-1 and occludin change the dynamics of TJ strands, thereby, modulating barrier function. However, such a change in TJ strand dynamics would not be visible by FFEM. The function and remodeling of TJs can be altered over shorter periods of time by modulating actomyosin cytoskeletal tension. Acute treatments that inhibit actin polymerization lead to increased paracellular permeability due to mislocalization of TJ proteins, including ZO-1 and occludin (Van Itallie et al., 2009, 2015; Fanning et al., 2012; Shen and Turner, 2005). Further, inhibition of myosin II activity mediated by Rho kinase (ROCK) or myosin light chain kinase (MLCK) alters the contractility of the apical actomyosin bundle, thus, affecting the permeability of TJs (Nusrat et al., 1995; Clayburgh et al., 2004; Walsh et al., 2001). For example, inhibition of ROCK results in increased flux of macromolecules and ions (Walsh et al., 2001). By contrast, inhibition of MLCK stabilizes ZO-1 at TJs by coupling it to the apical actomyosin array, thereby, restricting the flux of ions (Yu et al., 2010). Taken together, these results suggest that, although ROCK and MLCK both regulate myosin II activity through phosphorylation of myosin II regulatory light chain, these kinases have different effects on TJ barrier function. Interestingly, the local reductions in ZO-1 and occludin we detected prior to Rho flares are followed by accumulation of F-actin and myosin II (Fig. 3), and ROCK-mediated myosin II activity is required for efficient reinstatement of ZO-1 at the sites of barrier leaks (Stephenson et al., 2019). Mechanical forces change tissue tension and promote associated changes in the actin cytoskeleton and TJ remodeling at a global scale. For instance, when alveolar epithelial cells are stretched biaxially in a cyclic manner, they exhibit an increase in paracellular permeability and in perijunctional actin levels (Cavanaugh et al., 2001; DiPaolo and Margulies, 2012). Additionally, upon biaxial stretch, the overall levels of ZO-1 and occludin at TJs are reduced, and regions of alternating high and low TJ protein intensities are visible along the junction (Cavanaugh et al., 2001). A similar phenotype, i.e. loss of ZO-1 and occludin at TJs, was observed in biaxially stretched Caco-2 cells (Samak et al., 2014; see also Fig. 4B). These studies suggest that stretch-induced cytoskeletal rearrangements perturb the uniform, continuous localization of TJ proteins along cell–cell junctions, thus disrupting barrier function. However, it remains unclear whether (i) the observed discontinuities in ZO-1 and occludin, indeed, correspond to local barrier breaches and (ii) the discontinuities in ZO-1 and occludin are cause or consequence of stretch-induced cytoskeletal rearrangement. To this end, Samak et al. have shown that inhibition of MLCK prior to experimental tissue stretch attenuated the loss of ZO-1 and occludin, suggesting that MLCK-mediated cytoskeletal rearrangement promotes discontinuities of TJs (Samak et al., 2014). Together, these results highlight the importance of feedback regulation between the actomyosin cytoskeleton and TJ proteins, as TJ proteins respond to actomyosin-mediated mechanical forces, and partial or complete loss of ZO proteins leads to robust accumulation of F-actin and myosin II. However, further studies are required to determine the mechanistic nature of this feedback. Emerging areas in TJ remodeling research So far, we have discussed multiple temporal and spatial scales at which TJs are dynamic, and our current understanding of some of the mechanisms that drive TJ remodeling at global and local scales. We conclude by highlighting two emerging areas in TJ research, mechanotransduction and super-resolution imaging, and outline how future work may enhance our understanding of mechanisms that drive TJ remodeling. Mechanotransduction at the tight junction Mechanotransduction is a process by which cells sense mechanical force and respond by transmitting biochemical signals through cellular signaling pathways. Mechanotransduction at AJs is evident in response to both tissue-scale and locally applied forces (Charras and Yap, 2018; Pinheiro and Bellaïche, 2018). Tensile forces, for example, can change the conformation of mechanosensitive AJ proteins, resulting in the recruitment of additional proteins to reinforce and stabilize junctions (Yonemura et al., 2010; Le Duc et al., 2010; Liu et al., 2010). However, much less is known about mechanotransduction at TJs (Sluysmans et al., 2017). A recent study identified a mechanosensitive pathway that maintains epithelial integrity and barrier function through activation of Rho (Acharya et al., 2018). In that study, the mechanical stretching of cultured epithelial cells activates Rho through the recruitment of a specific Rho guanine nucleotide exchange factor (RhoGEF), p114 RhoGEF. Active Rho then activates the formin mDia1 (also known as Diaph1) to promote actin assembly, which, in turn, strengthens the junctions (Fig. 4B; see also Acharya et al., 2018). Of note, p114 RhoGEF also promotes Rho activation during TJ assembly (Terry et al., 2011; Xu et al., 2013), suggesting that this mechanosensitive pathway may also be at play at TJs. Seminal EM studies carried out in epithelial chick hair cells identified two distinct, yet interconnected, actin populations at junctions: (i) bundles of actin filaments that run parallel to the membrane at the AJ and, (ii) a meshwork of filaments that lies just beneath the TJ (Hirokawa, 1982; Hirokawa et al., 1983). Indeed, these EM data underlie most of the currently held hypotheses about connections of actin to TJs and AJs, leading us to assume that transmission of tension primarily takes place at the AJ. However, more evidence is needed to determine whether AJs are, indeed, the primary load-bearing actin-associated cell–cell junction or whether TJs can also be load-bearing structures. Several pieces of data suggest that reassessment of our current understanding of actin connections to the TJ and AJ is warranted. First, we recently quantified the apico-basal localization of actin with respect to the TJ and AJ in the Xenopus embryonic epithelium, and found that TJ-associated F-actin is more abundant than AJ-associated F-actin in these cells (Higashi et al., 2019). Second, tricellular junctions, the points where three cells come together, may utilize specialized actin connections (see the recent review by Higashi and Miller, 2017). Recent studies have suggested that F-actin makes end-on (versus side-on) connections at tricellular junctions (Yonemura, 2011; Choi et al., 2016). We propose that these end-on actin connections are important for tension transmission and barrier function at tricellular junctions, and recruit different protein partners than side-on actin connections to offset the increased force applied on tricellular junctions (Higashi and Miller, 2017). Third, by using platinum replica EM, a recent examination of connections between actin and junctions in vascular endothelial cells revealed that AJs in these cells connect to Arp2/3-containing branched actin networks but to not bundled actomyosin (Efimova and Svitkina, 2018), raising the question of whether connections to branched actin networks are also important in polarized epithelial cells. Fourth, together, these studies suggest that actin connections to apical cell–cell junctions can differ from the commonly held model of a perijunctional actomyosin ring that runs parallel to the AJ. Future studies should directly investigate whether TJs are load-bearing structures. To this end, the use of tension biosensors – similar to those developed to measure mechanical stresses at focal adhesions and AJs at the molecular level (Grashoff et al., 2010; Hoffman and Yap, 2015) – but, instead, designed to measure tensile force applied on specific TJ proteins, would be immensely useful. By applying our knowledge of mechanotransduction at AJs to that of TJs, it seems possible that TJ proteins also undergo tension-dependent conformational changes analogous to the conformational changes exhibited by AJ proteins, such as α-catenin (Yonemura et al., 2010), and/or that specific proteins are recruited to the TJ under increased tension. Indeed, ZO-1 has recently been shown to undergo a tension-dependent conformational change, opening to a stretched conformation in response to actomyosin-generated force (Spadaro et al., 2017). Here, unfolding of ZO-1 occurs at a level of force similar to that needed to unfold α-catenin in AJs (>5 pN for ZO-1 compared with 5–15 pN for α-catenin) (Spadaro et al., 2017; Yao et al., 2014). This conformational change allows ZO-1 to recruit occludin and a transcription factor to TJs (Spadaro et al., 2017). Supporting the conclusion that ZO-1 is a mechanosensitive protein, FRAP experiments have shown that ZO-1 is stabilized in Xenopus embryos under increased tension (Higashi et al., 2016), suggesting that TJs can, indeed, sense increased tension and respond by stabilizing ZO-1. What are the potential functional effects of mechanotransduction at TJs? Several pieces of evidence suggest that mechanosensitive pathways are important for maintenance of barrier function under tensile stress. Proteins that are known to be recruited to cell–cell junctions in response to tension, such as afadin and vinculin, are necessary to maintain tissue integrity and barrier function under high tension (Choi et al., 2016; Le Duc et al., 2010). Furthermore, a recently identified mechanosensitive pathway helps to maintain epithelial integrity and barrier function by activating Rho at junctions (Acharya et al., 2018). In the future, it will be interesting to further explore mechanotransduction pathways in epithelial tissues that exhibit cyclic stretch and release, such as filling and emptying of the bladder or the lung (Carattino et al., 2013), or gut peristalsis (Trepat et al., 2007), as in these tissues, the ability to sense and respond to force is likely to be essential for barrier maintenance. Additionally, mechanotransduction at TJs was recently shown to play a role in epithelial tissue spreading during zebrafish gastrulation (Schwayer et al., 2019). In that study, accumulation of TJ components, not AJ components, scaled with the tension of the adjacent actomyosin network, indicating that that these TJs are mechanosensitive. Transportation of phase-separated non-junctional ZO-1 clusters towards the TJ by actomyosin-driven flow was required for the mechanosensitivity of these TJs. This study opens the door for future studies of functional roles for TJs in mediating mechanotransduction during developmental or homeostatic processes. Finally, because mechanosensitive junction proteins can also be activated to undergo conformational changes and recruit other proteins in response to locally applied forces, such as the cytokinetic contractile ring (Higashi et al., 2016), it will be interesting to explore whether local TJ remodeling events involve mechanotransduction and whether they are important for barrier function. Super-resolution microscopy of TJ organization and dynamics Traditionally, EM techniques, including transmission electron microscopy (TEM) and FFEM, have been used to obtain an ultrastructural view of TJs. Indeed, these approaches have defined our understanding of the structural organization of TJs (e.g. Farquhar and Palade, 1963; Chalcroft and Bullivant, 1970). However, EM cannot capture dynamic changes in TJ strands or the associated cytoskeleton, which underlie the dynamic regulation of barrier function. Light-microscopy techniques, by contrast, are able to reveal the dynamic nature of TJs but, due to the limit the diffraction of light imposes on spatial resolution, these approaches are limited to a resolution of ∼250 nm (under optimal conditions) (Bartle et al., 2018; Schermelleh et al., 2019). Because the size of TJs and other epithelial cell–cell junctions are near this resolution limit (Bartle et al., 2018), the information one can obtain about TJ composition, structure and dynamics is restricted when using light microscopy. Super-resolution microscopy can bridge the gap between light microscopy and EM. By using different strategies to measure just a subset of fluorophores in the sample, super-resolution microscopy techniques – including stimulated emission depletion (STED) and structural illumination microscopy (SIM), as well as single-molecule localization microscopy techniques, such as fluorescence photoactivated localization microscopy (F-PALM) or stochastic optical reconstruction microscopy (STORM) – overcome the resolution limit of light microscopy, leading to an improved resolution in the range of 20–100 nm (Bartle et al., 2018; Schermelleh et al., 2019; Lambert and Waters, 2017). These techniques combine molecular specificity (i.e. labeling proteins of interest) with high-resolution spatial information. Additionally, they provide an advantage over EM for imaging the actin cytoskeleton associated with TJs, because cells do not have to be treated with harsh fixatives, which often disrupt the cytoskeleton. Recently, several studies have applied super-resolution microscopy techniques to study TJ proteins, and some of these studies reveal novel information about TJ remodeling (Table S1). The emergence of more widely accessible super-resolution microscopy techniques opens new avenues in TJ research and is expected to reveal new insights into the structure and dynamic remodeling of TJs. There are several aspects of barrier biology, in particular, that could benefit from super-resolution imaging: (i) determining the nanoscale organization of claudins and occludin in strand networks in reconstituted systems, epithelial cells, organoids, and/or developing model organisms; (ii) investigating the mechanisms of delivery and incorporation of TJ proteins into sealing strands, as well as TJ protein turnover; (iii) investigating remodeling of TJs during cytokinesis to understand how barrier function is maintained during cell division and; (iv) determining how the actin cytoskeleton is connected to TJs and tricellular junctions, and how these connections are remodeled under different tension conditions. In this Review, we have highlighted the dynamic remodeling of TJs to maintain an effective barrier in response to cell- and tissue-scale forces. We argue that, in order to understand TJ remodeling, we must investigate TJ remodeling at multiple scales. Although the functional roles of many TJ proteins in maintaining an intact barrier have been characterized on an individual basis, it is largely unknown how TJ strands and strand networks are dynamically remodeled in response to physiological or pathological stimuli. To address these questions, we suggest several areas of interest for further investigation. First, understanding the kinetics of claudin strand assembly, will help to answer the question of whether claudins self-assemble or whether other proteins facilitate strand formation. Second, additional structural information about claudins and occludin, including their binding interfaces, will shed light on how strands branch, break and anneal, and might help reveal the exact function of occludin. Finally, observing the dynamics of TJ strand remodeling in epithelial cells will determine how strand networks are dynamically remodeled in vivo. 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M., Schneeberger, E. E., Shen, L. et al. (2011). Occludin S408 phosphorylation regulates tight junction protein interactions and barrier function. J. Cell Biol. 193, 565-582. doi:10.1083/jcb.201010065 Schmauder, R., Gebert, A. and (2016). A novel method for imaging sites of paracellular passage of macromolecules in epithelial sheets. J. Control. Release 229, 70-79. doi:10.1016/j.jconrel.2016.03.018 Rodgers, L. S., Beam, M. T., Fanning, A. S. (2013). Epithelial barrier assembly requires coordinated activity of multiple domains of the tight junction protein ZO-1. J. Cell Sci. 126, 1565-1575. doi:10.1242/jcs.113399 Ronaghan, N. J., Iablokov, V., Zaheer, R., Colarusso, P., Dion, S., Désilets, A., Leduc, R., (2016). The serine protease-mediated increase in intestinal epithelial barrier function is dependent on occludin and requires an intact tight junction. Am. J. Physiol. Gastrointest. Liver Physiol. 311, G466-G479. doi:10.1152/ajpgi.00441.2015 Gangwar, R., Crosby, L. M., Desai, L. P., Waters, C. M. and (2014). Cyclic stretch disrupts apical junctional complexes in Caco-2 cell monolayers by a JNK-2-, c-Src-, and MLCK-dependent mechanism. Am. J. Physiol. Gastrointest. Liver Physiol. 306, G947-G958. doi:10.1152/ajpgi.00396.2013 (2003). Dynamic behavior of paired claudin strands within apposing plasma membranes. Proc. Natl. Acad. Sci. USA 100, 3971-3976. doi:10.1073/pnas.0630649100 Huser, T., Biehlmaier, O. and (2019). Super-resolution microscopy demystified. Nat. Cell Biol. 21, 72-84. doi:10.1038/s41556-018-0251-8 Schwayer, C., Shamipour, S., Pranjic-Ferscha, K., Balda, M., (2019). Mechanosensation of Tight Junctions Depends on ZO-1 Phase Separation and Flow. Cell 179, 937-952. e18. doi:10.1016/j.cell.2019.10.006 (2005). Actin depolymerization disrupts tight junctions via caveolae-mediated endocytosis. Mol. Biol. Cell 16, 3919-3936. doi:10.1091/mbc.e04-12-1089 (2008). The tight junction protein complex undergoes rapid and continuous molecular remodeling at steady state. J. Cell Biol. 181, 683-695. doi:10.1083/jcb.200711165 Vasileva, E., Rouaud, F. and (2017). The role of apical cell-cell junctions and associated cytoskeleton in mechanotransduction. Biol. Cell 109, 139-161. doi:10.1111/boc.201600075 Mean, I., (2017). Tension-dependent stretching activates ZO-1 to control the junctional localization of its interactors. Curr. Biol. 27, 3783-3795.e8. doi:10.1016/j.cub.2017.11.014 Kolli, A. R., Esch, M. B., Shuler, M. L. and (2015). TEER measurement techniques for in vitro barrier model systems. J. Lab. Autom. 20, 107-126. doi:10.1177/2211068214561025 Erofeev, I. S., (2019). Rho flares repair local tight junction leaks. Dev. Cell 48, 445-459.e5. doi:10.1016/j.devcel.2019.01.016 Matter, K . (2011). Spatially restricted activation of RhoA signalling at epithelial junctions by p114RhoGEF drives junction formation and morphogenesis. Nat. Cell Biol. 13, 159-166. doi:10.1038/ncb2156 Tice, L. W., Carter, R. L. and Cahill, M. B. (1979). Changes in tight junctions of rat intestinal crypt cells associated with changes in their mitotic activity. Tissue Cell 11, 293-316. doi:10.1016/0040-8166(79)90043-0 An, S. S., (2007). Universal physical responses to stretch in the living cell. Nature 447, 592-595. doi:10.1038/nature05824 Romero-Calvo, I., Sailer, A. and (2014). The role of molecular remodeling in differential regulation of tight junction permeability. Semin. Cell Dev. Biol. 36, 204-212. doi:10.1016/j.semcdb.2014.09.022 (2006). ZO-1 and ZO-2 independently determine where claudins are polymerized in tight-junction strand formation. Cell 126, 741-754. doi:10.1016/j.cell.2006.06.043 Holmes, J., Gookin, J. L., Coccaro, M. R., Proctor, W., Colegio, O. R. and (2008). The density of small tight junction pores varies among cell types and is increased by expression of claudin-2. J. Cell Sci. 121, 298-305. doi:10.1242/jcs.021485 (2009). ZO-1 stabilizes the tight junction solute barrier through coupling to the perijunctional cytoskeleton. Mol. Biol. Cell 20, 3930-3940. doi:10.1091/mbc.e09-04-0320 Krystofiak, E., (2015). A complex of ZO-1 and the BAR-domain protein TOCA-1 regulates actin assembly at the tight junction. Mol. Biol. Cell 26, 2769-2787. doi:10.1091/mbc.E15-04-0232 Tietgens, A. J. and (2017). Visualizing the dynamic coupling of claudin strands to the actin cytoskeleton through ZO-1. Mol. Biol. Cell 28, 524-534. doi:10.1091/mbc.e16-10-0698 Lidman, K. F., (2019). Newly synthesized claudins but not occludin are added to the basal side of the tight junction. Mol. Biol. Cell 30, 1406-1424. doi:10.1091/mbc.E19-01-0008 (2001). Functional modeling of tight junctions in intestinal cell monolayers using polyethylene glycol oligomers. Am. J. Physiol. Cell Physiol. 281, C388-C397. doi:10.1152/ajpcell.2001.281.2.C388 Tokumasu, R., (2011). Role of claudin species-specific dynamics in reconstitution and remodeling of the zonula occludens. Mol. Biol. Cell 22, 1495-1504. doi:10.1091/mbc.e10-12-1003 Mege, R. M. et al. (2014). Force-dependent conformational switch of alpha-catenin controls vinculin binding. Nat. Commun. 5, 4525. doi:10.1038/ncomms5525 (2011). Cadherin-actin interactions at adherens junctions. Curr. Opin. Cell Biol. 23, 515-522. doi:10.1016/j.ceb.2011.07.001 McCarthy, K. M., McCormack, J. M., Rogers, R. A., Lynch, R. D. and (2005). Knockdown of occludin expression leads to diverse phenotypic alterations in epithelial cells. Am. J. Physiol. Cell Physiol. 288, C1231-C1241. doi:10.1152/ajpcell.00581.2004 (2010). MLCK-dependent exchange and actin binding region-dependent anchoring of ZO-1 regulate tight junction barrier function. Proc. Natl. Acad. Sci. USA 107, 8237-8241. doi:10.1073/pnas.0908869107 (2016). Tight junctions: from simple barriers to multifunctional molecular gates. Nat. Rev. Mol. Cell Biol. 17, 564-580. doi:10.1038/nrm.2016.80

2020/10/31 01:35:39

https://jcs.biologists.org/content/132/22/jcs229286

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Online Sport Games Can Be Quite Enriching For The Sport Enthusiast – runfunstarz On the off chance that you are a lover on record, PC and web based games and you need to make something commendable about this premium, you can really bring in cash playing computer games. Perhaps the most ideal ways is to turn into a game analyzer. To be sure, video and internet game designers and organizations consistently ensure that the games they discharge are of best quality and liberated from glitches as these can regularly disillusion their objective market and adjusting mistakes later can be expensive too. To ensure this, these organizations frequently employ analyzers to play, check and re-check the games and make it report glitches and mistakes. With this chance that video or web based game แทงบอลออนไลน์ darlings and aficionados can bring in cash playing computer games. On the off chance that you are especially intrigued to become one game analyzer, here are a couple of tips to help you land on that extraordinary chance to bring in cash playing computer games. – Participate in competitions. This is probably the best chance where you can met game engineers and organizations who are exploring for conceivable game analyzers. Obviously, it can likewise extend your circles who have a similar interest and energy as you are and you can likewise get clues and experiences on where to track down these brilliant chances. – Do your examination on the web. There are additionally a decent number of sites online that can help you find real employing on game analyzers. You may discover selective locales that can give you a decent rundown of organizations, engineers and people who are searching for game analyzers and organizations who utilize gamers and lovers also. – Get in contact with gaming organizations. In reality, on the off chance that you need to turn into a game analyzer and make money from being one, then, at that point you need to reach out to those organizations recruiting for these positions. Write to game engineers and to video or PC game organizations and state your viewpoint to find a new line of work as a game analyzer. – Get tips from the individuals who have been in the situation previously. Remember that turning into an analyzer isn't just about playing the game yet it can likewise be tied in with playing the game over and over to discover glitches and mistakes. You may not additionally be hoping to play your #1 games as an analyzer yet you may likewise be trying new ones that you may have never experienced. Obviously, you additionally need to consider things like this. – Write about your number one games on the web. This is likewise one approach to stand out enough to be noticed of engineers and organizations. In the event that you can make your investigation and distinguish glitches of your #1 game, you can likewise get freedoms to get paid to discover glitches in new ones too. This is particularly powerful in the event that you love composing and in the event that you have enthusiasm in gaming. You can even set up a site about gaming guides, evening out guides specifically games and acquire a decent standing in the business. This will without a doubt allow you great opportunities to get seen by organizations and those searching for analyzers and appreciate an extraordinary occupation where you bring in cash playing computer games.

2021/09/27 21:55:58

http://www.runfunstarz.co.uk/online-sport-games-can-be-quite-enriching-for-the-sport-enthusiast/

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“Yes absolutely thrilled with the website and service. Thanks also for the addition of the mailing list link. Looks really good. I hope you are pleased as I am with the site. Thanks again for a fabulous site.” “I have also been testing SEO. I am on page 1 on google for bespoke furniture cornwall, bespoke kitchen cornwall and bespoke shelving cornwall. Page 2 for garden furniture cornwall. Good work!” Due to unresolved differences between TRAC and Twyning Parish Council, the TRAC committee have voted unanimously in favour of disbanding TRAC as a charity. We will be in contact with the few paid up members in the next few days to finalise the formalities of this process. In the meantime, at close of play today, the TRAC site will be closed until further notice. Tennis club members with bookings will still be able to use Tennis Club facilities. This will also mean that the competitions planned for this coming Bank Holiday are also now cancelled. Xi Jinping’s Belt and Road Initiative — launched in 2013 with the prosaic ambition of funding infrastructure projects within and outside of China — has attracted two main critiques. Some saw it as an attempt to build neocolonial influence across emerging markets as US power waned. Others saw the failure of specific projects as further evidence of economic over-reach, already widely associated with Chinese ghost towns and bridges to nowhere. To Thomas Orlik, chief economist at Bloomberg Economics, these responses amount to an acute case of what he calls “sinophrenia” — a condition of modern commentary that combines the belief that China will imminently collapse with the belief that it is taking over the world. It may be the sign of a first-rate intelligence to hold two contradictory ideas in your mind at the same time. But Orlik argues that both views focus so intently on their own version of the future that they miss what exactly is happening in the present. As a result, a lightly professorial “yes and no” tone pervades this wide-ranging and nuanced survey of China’s recent economic history which gently challenges the prevailing orthodoxy. The book divides the country’s reform-driven history after the 1976 death of Mao Zedong into distinct cycles: the opening of the economy under Deng Xiaoping; the period from the crackdown after the 1989 Tiananmen demonstrations to the 1997 Asian financial crisis; and the changes associated with China’s 2001 entry into the World Trade Organization.

2021-03-09T00:20:58Z

http://blessedbooks.com/man-times-are-getting-stranger-or-whats-left-of-our-future/

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We’re great believers in the one-stop shopping experience. This naturally makes multi label boutiques our go-to respite for a spot of fuss-free retail therapy. Boasting expertly-curated wares sourced from all over the world, these multi label menswear boutiques in Singapore take away a great deal of the stress that some men associate with shopping, making way for an enjoyable browse and an even likelier result…armloads of new wardrobe candy fit for all you discerning dandies. Actually Independent street wear labels #03-18, Orchard Gateway, 277 Orchard Road, Singapore 238858 | Also available online. One of the ringleaders of the independent street wear retail scene, Actually fills its racks with quirky and personality-fueled premium street labels such as Freitag, HUF, Underground, Vagabond, SSUR and Lazy Oaf, along with an ever-changing mix of tasteful merchandise to keep you interested. Now housed in a single venue at Orchard Gateway, Actually offers a quick escape from the doldrums of mass retail with its curated lineup of local labels such as Coupe Cousu, Yumumu and Ownmuse, alongside lifestyle and concept labels like Spitfire Design and Delfonics. Ambush Sought after cult labels #03-14, The Mandarin Gallery, 333A Orchard Road, Singapore 238967 Ambush is one of the first menswear-dedicated multi-label stores in Singapore, focusing on high end and cutting-edge street wear and sought-after collections from cult labels such as Hood by Air, 10 Deep and Been Trill. More than a decade old, the store is a gathering ground for the most progressive international labels, serving up loudmouthed logo tees, snapbacks and snazzy kicks that turn up the dial on your street cred. Beluga Variety of wardrobe essentials #02-05, The Cathay, 2 Handy Road, Singapore 229233 Don’t let its minimal interior fool you, Beluga has quite a few goodies up its sleeve. Sleek and casual threads from Sweden’s Nikolaj d’etoiles take up room next to printed tees from Italian label Maesna and French label Sixpack. A treat for tropical weather tantrums, Beluga’s in-house label – Grandiosity, produces a fine and affordable range of casual shirts and basic shorts you’ll want to own in every colour. Front Row Fashion hotspot with a loyal following #02-09, Raffles Hotel Arcade, 328 North Bridge Road, Singapore 188719 A tour de force in the heady world of underground fashion, Front Row has built a loyal following on its eclectic and exclusive brand-mix. Since 2005, Front Row has been etching a path for itself in the discovery of up-and-coming local and regional designer labels such as Banwagon, Carrie K. and In Good Company. The fashion destination is also a hotspot for progressive cult labels like Christophe Lemaire from France and FLYNOW from Bangkok. There’s also everyday wear from Japanese label Biro for the more casual and collected folk. Kapok Well curated selection of brands #01-05, National Design Centre, 111 Middle Road, Singapore 188969 | Also available online. Cult multi label boutique Kapok needs no introduction, but here’s one all the same. Largely recognised as the incubator of cool in Hong Kong where it originated, the lifestyle-focused curator brings together a well-edited selection of international and local brands. Taking pride in the value of creativity and craftsmanship, the store carries an extensive range of products that the team foresees to be ‘future classics’, whose wear will extend beyond the season. The coveted list of brands under its roof is constantly expanding but names such as Our Legacy, Common Projects, Commune de Paris, Mismo, Wm. J. Mills & Co and Maison Kitsune should keep the guys very happy. SECTS SHOP Unique multi-label concept store #01-14, Orchard Gateway, 277 Orchard Road, Singapore 238858 | Also available online. The brainchild of the guys behind feted Singaporean label – Depression, the cheekily named Sects Shop is a multi-label concept store like no other. Taking on a pugilistic theme, the menswear-focused store curates brands to form a ring of ‘masters’ that best represent the 5 style categories of casual, preppy, street, edgy and unisex. Surely such pomp and ceremony calls for an impressive lineup? Cult brands such as Korea’s Human Potential, Hong Kong’s Inch Child, Adlib and 11 After 11, and UK’s Killstar form part of the exclusive club. Swagger Intimate lifestyle boutique New store location coming in June 2015. One step through Swagger’s doors and you’ll feel convinced you’ve entered straight into the gentlemen’s era. The intimate lifestyle retail boutique carries a carefully selected range of apparel, leather goods, bags, accessories and grooming products to get you looking your sartorial best. Swagger’s uncompromising standards for heritage and handicraft ensure that only the most distinctive wares from brands such as Wood & Faulk, Lotuff Leather and Bonastre make the cut. The Assembly Store Astounding range of accessories #01-22/23, The Cathay, 2 Handy Road, Singapore 229233. | Also available online. Looking to spiff up your wardrobe? The Assembly Store is the latest multi-label menswear shop to hit town. The store stocks an astounding range of accessories including bags from QWSTION, RAWROW, BrownBreath, Fabrix, Gnome and Bow, and Herschel Supply Co., Bellroy wallets, AARK Collective watches, Pointer shoes and Palladium boots. Head to the adjoining café – The Assembly Ground, for a cuppa and hearty brunch when you’ve had your fill of shopping. The Society of Black Sheep For the quirky individual 220 River Valley Road, Singapore 238278 The Society of Black Sheep stands out for its unlikely take on fashion. Unafraid to trifle with the boundaries of fashion, the store is an ode to the quirky individual who dares to be different. The independent multi-label boutique has several choice options for men including highly conceptual fashion by British brand, Injury, along with the more accessible range of preppy and casual wear by British label Carhartt. SHARE TWEET PIN PRINT DISCOVER THE WORLD'S BEST SHOPS Travelshopa takes you on shopping trips in far off destinations directly from your inbox. Unforgettable shopping experiences start with our monthly destination edition full of wanderlust-inducing shopping inspiration. START SHOPPING You have successfully subscribed. Thank you! ABOUT TRAVELSHOPA Travelshopa is the curated guide to the best local shopping around the world. We are a global network of style conscious shoppers, emerging designers and independent retailers as well as industry professionals across Asia, the Americas and Australia. FOLLOW US EXPLORE MORE LOCAL SHOPPING TIPS Dress for the tropics, for men Dapper Dressing for Men Menswear Designers in Singapore Menswear: Top 5 Online Gift Ideas for Dad Follow Us About Media Sign Up Register Your Brand © 2017 Travelshopa Pte Ltd | All Rights Reserved | Terms & Privacy DISCOVER THE WORLD'S BEST SHOPS Travelshopa takes you on shopping trips in far off destinations directly from your inbox. Unforgettable shopping experiences start with our monthly destination edition full of wanderlust-inducing shopping inspiration.

2021-11-30T22:06:17Z

http://blog.travelshopa.com/2014/11/05/multi-label-boutiques-men/

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Full-time jobs in Python Software Engineer in England - NewsNow Classifieds Full-time jobs in Python Software Engineer in England People Source Consulting are working with one of the most exciting companies within sustainability currently and have successfully placed several Engineers and Managers within the business, and they... Lead Python Software Engineer A lead Python software engineer is needed to join a top tier sports trading firm that specialise in the complex modelling of sporting events. Their aim is to predict... Posted 1 day ago backend software engineer / pytho Posted 1 day ago backend software engineer / python developer *remote / wfh*. Do you have expertise with python and a data centric mindset? You could be progressing your career in a senior role at a... Python developer / backend software engineer *Remo Python developer / backend software engineer *remote / wfh*. Do you have expertise with python and a data centric mindset? 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2021/09/28 13:31:28

https://www.newsnow.co.uk/classifieds/jobs/england--full-time--python-software-engineer

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