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19023280 | The impact of obesity and arthritis on active life expectancy in older Americans. | This article examines the relationship of obesity and arthritis to length of life and length of disabled life in older American men and women. Secondary data analysis is conducted on three waves of the Asset and Health Dynamics Among the Oldest Old (AHEAD) survey (n = 7,381). Using integrated Markov chains, total, active, and disabled life expectancy in Americans aged > or =70 is estimated, with and without obesity and arthritis. Results indicate that neither obesity nor arthritis is related to the length of life for older men and women, alone or bination. However, both conditions are significantly individually associated with increased length of disabled life in older men (1.4 years attributable to obesity; 1.2 years to arthritis at age 70; P < 0.05) and women (1.7 years attributable to obesity; 2.1 years to arthritis at age 70; P < 0.05). In addition, bination of the two is significantly related to decreased active life, with nearly 50 and 60% of remaining life for 70-year-old men and women lived with disability, respectively (P < 0.05). Coupled with the fact that both obesity and arthritis are growing in prevalence, these findings represent one of the few clearly negative health trends in older adults today. These results should provide incentives for health-care professionals to make concerted efforts to address both conditions in clinical settings. |
19023281 | Waist circumference as a cardiovascular and metabolic risk in Japanese patients with type 2 diabetes. | Excess waist circumference (WC) is a frequently used indicator of abdominal obesity and/or cardiovascular disease (CVD) risk. Nonetheless, search of the literature revealed no prospective studies on the association between WC and CVD events in diabetic patients. In this study, the clinical significance and implications of WC as a cardiovascular and metabolic risk indicator was prospectively investigated in Japanese patients with type 2 diabetes. For this purpose, baseline data on WC, hypertension, and dyslipidemia were collected and subsequent CVD (coronary heart disease and stroke) events during the following 8 years were studied in 1,424 Japanese type 2 diabetic patients, and the cross-sectional/longitudinal associations between WC and CVD risk factors/events were analyzed. Mean WC levels were significantly increased according to the number of coexisting risk factors. However, no significant difference in mean WC between subgroups with and without CVD events was noted, and excess WC alone was not predictive of subsequent CVD events either in male or female subjects even after adjustment for age, smoking, hypertension, and dyslipidemia. In female patients, excess WC (> or =80 cm) was predictive of CVD events only with the coexistence of hypertension. In Japanese diabetic patients, excess WC alone, although a good marker for clustering of CVD risk factors, did not raise the risk of CVD events unless panied by hypertension in female patients. Further investigations are necessary before WC as a risk factor can be utilized in clinical settings for the management of diabetes in this population. |
19023282 | Erythrocyte membrane phosphatidylserine exposure in obesity. | It has been suggested that increased erythrocyte membrane phosphatidylserine (PS) exposure could contribute to hypercoagulability and hemorheological disturbances in obesity. The aim of our study was to evaluate PS exposure in obese patients and in a control group and to correlate this with hemorheological properties, i.e., erythrocyte aggregability (EA) and deformability, and to evaluate the effect of weight loss on these parameters. An anthropometric and analytical evaluation was performed at baseline and after 3 months on a diet (very low-calorie diet for 4 weeks and low-calorie diet for 2 months) on 49 severe or morbid obese patients (37 women, 12 men) and 55 healthy volunteers (39 women, 16 men). PS exposure on erythrocyte membrane was performed by flow cytometry. Erythrocyte aggregation was measured using the Myrenne MA(1) and the Sefam aggregometer. Erythrocyte deformability was determined in a stress diffractometer. Prothrombin fragment F1+2 (F1+2) was determined as a marker of the hypercoagulable state, and plasma malondialdehyde (MDA) as an indicator of oxidative stress. Obese patients had a higher EA index, higher PS exposure on erythrocyte membranes and higher levels of MDA and F1+2. The differences in erythrocyte aggregation and F1+2 between obese patients and the control group were maintained after adjusting for PS exposure. After 3 months of diet, a significant reduction in PS exposure on erythrocyte membrane was observed. Obese patients show increased PS exposure on erythrocyte membrane, with no effect on rheological properties. Increased PS exposure could contribute to hypercoagulability in these patients. Weight loss obtained with diet treatment reduces PS exposure on erythrocyte membrane. |
19023283 | Transcription-coupled DNA repair: two decades of progress and surprises. | Expressed genes are scanned by translocating RNA polymerases, which sensitively detect DNA damage and initiate transcription-coupled repair (TCR), a subpathway of nucleotide excision repair that removes lesions from the template DNA strands of actively transcribed genes. Human hereditary diseases that present a deficiency only in TCR are characterized by sunlight sensitivity without enhanced skin cancer. Although multiple gene products are implicated in TCR, we still lack an understanding of the precise signals that can trigger this pathway. Futile cycles of TCR at naturally occurring non-canonical DNA structures might contribute to genomic instability and genetic disease. |
19023284 | Translational control of localized mRNAs: restricting protein synthesis in space and time. | As highlighted by recent genome-wide analyses in diverse organisms and cell types, subcellular targeting of mRNAs has emerged as a major mechanism for cells to establish functionally partments and structures. For protein synthesis to be spatially restricted, translation of localizing mRNAs is silenced during their transport and is activated when they reach their final destination. Such a precise translation pattern is controlled by repressors, which are specifically recruited to transport ribonucleoprotein particles and block translation at different steps. Functional studies have revealed that the inactivation of these repressors, either by pre-localized proteins or in response to conserved signalling pathways, triggers local protein synthesis. |
19023285 | The regulation of human embryo and stem-cell research in the United Kingdom. | In the United Kingdom, the derivation of human embryonic stem (ES) cells falls under the 1990 Human Fertilisation and Embryology (HFE) Act and subsequent amendments that were adopted in 2001. These laws do not regulate research with ES cells, which follows specific national guidelines. Owing to rapid progress in science and to changes in legal and public opinion, the current British Government proposed further radical amendments in a new HFE Bill. These will have important consequences for research and clinical practice that involve both embryos and stem cells. |
19023305 | Post-NICE 2008: Antibiotic prophylaxis prior to dental procedures for patients with pulmonary arteriovenous malformations (PAVMs) and hereditary haemorrhagic telangiectasia. | Recently published guidance from NICE highlights that antibiotic prophylaxis is no longer required for patients with structural heart disease at risk of infective endocarditis. The American Heart Association has published similarly less interventive guidance. Individuals with pulmonary arteriovenous malformations and hereditary haemorrhagic telangiectasia are at risk of brain abscess from dental bacteraemias. In this article we explore why these patients do not fall into the groups considered by NICE and provide mendations to reduce their risks of dental bacteraemias, including optimising dental hygiene and use of antibiotic prophylaxis prior to dental procedures. |
19023306 | Why we must reduce dental prescription of antibiotics: European Union Antibiotic Awareness Day. | The prescription of antibiotics in dentistry is relatively small but nonetheless significant. With the emergence of bacterial species resistant to antibiotics there is a need to e vigilant about their prescription and with this, an urgent requirement for both professional and public understanding of the appropriate use of this ponent of treatment. |
19023307 | Isolated atrial fibrillation (IAF) after local anaesthesia with epinephrine in an anxious dental patient. | Cardiac arrhythmias are not mon in dental practice, depending on many factors, including patient features, dental treatment and drugs administered. We describe a case of isolated atrial fibrillation (IAF) developed, in a young patient, soon after a supraperiosteal injection. The patient was admitted to hospital and recovered spontaneously. Since stress is a possible cause of IAF, this may has been triggered by endogenous and/or exogenous epinephrine. We highlight the need for careful preoperative evaluation, including anxiety assessment and treatment in all dental patients. |
19023308 | Dental implants and squamous cell carcinoma in the at risk patient--report of three cases. | Osseointegrated dental implants are increasingly used in the rehabilitation of the dental patient. They have a particular role in dental rehabilitation following treatment for oral cancer. Data is presented that suggests that, in the at risk patient, squamous cell carcinoma may develop in association with dental implants. |
19023310 | Angiotensin converting enzyme inhibitors and delayed onset, recurrent angioedema of the head and neck. | Angiotensin converting enzyme (ACE) inhibitors are monly prescribed, effective medication in the treatment of hypertension and heart failure. Several side-effects of dental relevance can occur including angioedema of the lips, mouth and throat. This adverse effect is well reported and can be fatal, but it is not always recognised by clinicians, as the angioedema does not always have a clear relationship with mencement of the medication. The cases of angioedema reported here all presented in a dental setting and highlight both the delayed onset and the chronic recurrent nature of ACE inhibitor induced angioedema. |
19023309 | An unusual case of immediate hypersensitivity reaction associated with an amalgam restoration. | This report describes a case of immediate hypersensitivity reaction associated with the ponent of amalgam restorations. The release of mercury induced an acute reaction which resulted in erythematous lesions, severe burning and itchy sensation and difficulty in breathing. Skin patch test results indicated a very strong positive reaction to mercury. Amalgam restorations were replaced posite filling material. The patient, her family and her dental practitioner were strictly advised to use alternative restorative materials in case of a need for restoration. |
19023317 | Chairside teaching and the perceptions of dental teachers in the UK. | This study outlines how dental tutors at the chairside view their teaching and describes what are considered important current issues, requirements and mendations for good chairside teaching practice. A qualitative analysis was undertaken of stakeholder perceptions of chairside teaching from both a single dental school study and a UK wide evaluation workshop. The evaluation of good chairside teaching showed that training requirements might be quite different for different stakeholders in chairside teaching. Further, this evaluation process may serve as a process model for institutional change for improvements in chairside teaching. This article is the second of a series of three and evaluates chairside teaching on a UK wide scale. The first, investigated the perceptions of stakeholders of chairside teaching at a single dental school. The third provides educational tools to encourage collaboration and sharing good chairside teaching practice. A further panying article reviews some of the educational methodology and innovations in teaching and learning that may be applied to dentistry. |
19023331 | Aggresome-forming TTRAP mediates pro-apoptotic properties of Parkinson's disease-associated DJ-1 missense mutations. | Mutations in PARK7 DJ-1 have been associated with autosomal-recessive early-onset Parkinson's disease (PD). This gene encodes for an atypical peroxiredoxin-like peroxidase that may act as a regulator of transcription and a redox-dependent chaperone. Although large gene deletions have been associated with a loss-of-function phenotype, the pathogenic mechanism of several missense mutations is less clear. By performing a yeast two-hybrid screening from a human fetal brain library, we identified TRAF and TNF receptor-associated protein (TTRAP), an ubiquitin-binding domain-containing protein, as a novel DJ-1 interactor, which was able to bind the PD-associated mutations M26I and L166P more strongly than wild type. TTRAP protected neuroblastoma cells from apoptosis induced by proteasome impairment. In these conditions, endogenous TTRAP relocalized to a detergent-insoluble fraction and formed cytoplasmic aggresome-like structures. Interestingly, both DJ-1 mutants blocked the TTRAP protective activity unmasking a c-jun N-terminal kinase (JNK)- and p38-MAPK (mitogen-activated protein kinase)-mediated apoptosis. These results suggest an active role of DJ-1 missense mutants in the control of cell death and position TTRAP as a new player in the arena of neurodegeneration. |
19023330 | Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response. | Cellular stress responses can be activated following functional defects in organelles such as mitochondria and the endoplasmic reticulum. Mitochondrial dysfunction caused by loss of the serine protease HtrA2 leads to a progressive movement disorder in mice and has been linked to parkinsonian neurodegeneration in humans. Here, we demonstrate that loss of HtrA2 results in transcriptional upregulation of nuclear genes characteristic of the integrated stress response, including the transcription factor CHOP, selectively in the brain. We also show that loss of HtrA2 results in the accumulation of unfolded proteins in the mitochondria, defective mitochondrial respiration and enhanced production of reactive oxygen species that contribute to the induction of CHOP expression and to neuronal cell death. CHOP expression is also significantly increased in Parkinson's disease patients' brain tissue. We therefore propose that this brain-specific transcriptional response to stress may be important in the advance of neurodegenerative diseases. |
19023334 | Antioxidant status in the aqueous humour of patients with glaucoma associated with exfoliation syndrome. | To establish the antioxidant status of the aqueous humour in a associated with exfoliation syndrome (XFG) and pare it to primary open-angle a (POAG) and cataract patients. |
19023333 | The tumor suppressor protein PML controls apoptosis induced by the HIV-1 envelope. | Promyelomonocytic leukemia (PML) is a prominent oncosuppressor whose inactivation is involved in the pathogenesis of hematological and epithelial cancers. Here, we report that PML aggregated in nuclear bodies in syncytia elicited by the envelope plex (Env) of human immunodeficiency virus-1 (HIV-1) in vitro. PML aggregation occurred after the fusion of nuclei (karyogamy) within syncytia but before the apoptotic program was activated. The aggregation of PML was detectable in syncytia present in the brain or lymph nodes from patients with HIV-1 infection, as well as in a fraction of blood leukocytes, correlating with viral status. Using a range of specific inhibitors of PML (the oncogenic PML/RARalpha fusion product or specific small interfering RNAs), we demonstrated that, in Env-elicited syncytia, PML was required for activating phosphorylation of ataxia telangiectasia mutated (ATM), which colocalized with PML in nuclear bodies, in a plex that also involved topoisomerase IIbeta-binding protein 1. PML knockdown thus inhibited the ATM-dependent DNA damage response that culminates in the activation of p53, p53-dependent transcription of pro-apoptotic genes and cell death. Infection of CD4-expressing cells with HIV-1 also induced syncytial apoptosis, which could be suppressed by inhibiting PML. Altogether, these data indicate that PML activation is a critical early event that participates in the apoptotic demise of HIV-1-elicited syncytia. |
19023337 | The plight of the precari. | On the heels of a new law, scientists in Italy are facing precarious times yet again. |
19023332 | The enigma of caspase-2: the laymen's view. | Proteolysis of cellular substrates by caspases (cysteine-dependent aspartate-specific proteases) is one of the hallmarks of apoptotic cell death. Although the activation of apoptotic caspases is considered a 'late-stage' event in apoptosis signaling, past mitment stage, one caspase family member, caspase-2, splits the cell munity into half - those searching for evidence of an apical initiator function of this molecule and those considering it as an amplifier of the apoptotic caspase cascade, at best, if relevant for apoptosis at all. This review screens past and present biochemical as well as genetic evidence for caspase-2 function in cell death signaling and beyond. |
19023349 | [Courses for cancer patients--15 years' experience at The Montebello Centre in Norway]. | The Montebello Centre offers cancer patients and their relatives courses of 5-10 days duration aimed at improving their coping with their disease. |
19023350 | [Hormone treatment of prostate cancer in Norway]. | The aim of our study was to determine the association between hormone treatment of prostate cancer and survival for those affected. |
19023351 | [Allogeneic stem cell transplantation in adults with acute lymphoblastic leukaemia]. | The success rate for chemotherapy of adults with acute lymphoblastic leukaemia in pares favourably with that in international reports, but improvements are still needed. Allogeneic stem cell transplantation is an option for patients up to 60 years and may contribute to improving the e for these patients. |
19023352 | [Mortality surveillance in an intensive care unit]. | Annual reports from Norwegian Intensive Care Units include risk-adjusted mortality data. Annual variation may be difficult to interpret due to random variation and changes in case mix. Several methods have been developed for continuous monitoring of treatment results in clinical practices where it is possible to calculate a risk for a certain e, usually risk of death. We have used the cumulative risk adjusted mortality chart Variable Life Adjusted Display (VLAD) to further illustrate our treatment results. |
19023353 | [Quality of diabetes care in Norwegian general practice]. | The prevalence of diabetes is increasing. Good diabetes care reduces macro and plications. Quality of care was assessed against predefined review criteria based on key mendations in national guidelines |
19023354 | [Menstrual migraine]. | Migraine is twice as prevalent in women than men. Changing levels of estrogen appear to trigger menstrual migraine. This article reviews clinical characteristics, pathophysiology and treatment of menstrual migraine. |
19023355 | [Human anaplasmosis--a hidden disease in Norway?]. | Ticks and tick-borne infections will most probably increase in Norway due to global warming, regrowth of pastures and an increasing number of cervids. A. phagocytophilum is already mon infection among domestic ruminants and cervids in tick (Ixodes ricinus) infested areas in Norway. |
19023372 | [Drug resistance in tuberculosis]. | The emergence of drug-resistant tuberculosis is one of the main challenges in the bat against tuberculosis. The objective of the article is to discuss the main causes for emergence of drug resistance, describe the epidemiology of drug-resistant tuberculosis with focus on the situation in Norway and advise on how this should be managed. |
19023373 | [Drug resistance in HIV infection]. | Access to antiretroviral therapy has turned HIV infection into a chronic viral infection that requires lifelong therapy. Resistance to antiretroviral drugs remains an important limitation to long-term successful treatment. Testing of resistance and close clinical follow-up are important measures for choosing the right treatment |
19023374 | [Viral drug resistance]. | More and more viral infections are treated with antiviral drugs, and resistance against these drugs is steadily increasing. Our aim is to give a general understanding of viral resistance and its clinical significance. |
19023375 | [Resistance in influenza viruses]. | Influenza virus infection can be prevented and treated with antiviral drugs. The usage of such drugs in Norway has been infrequent, however, they are an ponent in our pandemic preparedness planning, as it will probably be difficult to get access to the appropriate vaccine in time before the pandemic reaches the country. The first generation of influenza drugs acquired resistance to a large degree, in contrast to the modern neuraminidase inhibitors that until recently have had minor problems with resistance. |
19023376 | [Drug resistance in the treatment of invasive fungal infections]. | The incidence of invasive fungal infections is increasing in parallel with an increase of patients with immunodeficiencies. Resistance to these drugs is ing a problem in spite of increased and improved treatment options. |
19023377 | Determination of ultraviolet cosine-corrected irradiances and aerosol optical thickness by combined measurements with a Brewer spectrophotometer and a multifilter rotating shadowband radiometer. | Combined measurements of diffuse-to-global radiation ratio and global spectral irradiances in the UV are used to derive cosine-corrected UV irradiances and aerosol optical depth (AOD). The diffuse-to-global radiation ratio is used first in the cosine correction of the global irradiance, then to calculate absolutely calibrated direct irradiances. The Beer-Lambert law is applied to derive the UV AOD using independent measurements of the extraterrestrial solar flux. The AOD can be derived with an uncertainty of about 0.03 at 60 degrees solar zenith angle. The method was applied to measurements obtained with two UV multifilter rotating shadowband radiometers (UV-MFRSRs) and a MK III Brewer spectrophotometer on the Island of Lampedusa in the Central Mediterranean during two periods of 2002 and 2004. The derived AOD at 318 and 332 nm pared with UV AOD measured at 318, 320, and 368 nm with different techniques. The retrieved bining MFRSR and Brewer measurements, is in good agreement with the optical depth derived with the other methods. |
19023378 | Experimental confirmation of potential swept source optical coherence tomography performance limitations. | Optical coherence tomography (OCT) has demonstrated considerable potential for a wide range of medical applications. Initial work was done in the time domain OCT (TD-OCT) approach, but recent interest has been generated with spectral domain OCT (SD-OCT) approaches. While SD-OCT offers higher data acquisition rates and no movable parts, we recently pointed out theoretical inferior aspects to its performance relative to TD-OCT. In this paper we focus on specific limitations of swept source OCT (SS-OCT), as this is the more versatile of the two SD-OCT embodiments. We present experimental evidence of reduced imaging penetration, increased low frequency noise, higher multiple scattering (which can be worsened still via aliasing), increased need to control the distance from the sample, and saturation of central bandwidth frequencies. We conclude that for scenarios where the dynamic range is relatively low (e.g., retina), the distance from the sample is relatively constant, or high acquisition rates are needed, SS-OCT has a role. However, when penetration remains important in the setting of a relatively high dynamic range, acquisition rates above video rate are not needed, or the distance to the tissue is not constant, TD-OCT may be the superior approach. |
19023380 | Absorption and related optical dispersion effects on the spectral response of a surface plasmon resonance sensor. | Surface plasmon resonance (SPR) sensing is an optical technique that allows real time detection of small changes in the physical properties, in particular in the refractive index, of a dielectric medium near a metal film surface. One way to increase the SPR signal shift is then to incorporate a substance possessing a strong dispersive refractive index in the range of the plasmon resonance band. In this paper, we investigate the impact of materials possessing a strong dispersive index integrated to the dielectric medium on the SPR reflectivity profile. We present theoretical results based on chromophore absorption spectra and on their associated refractive index obtained from the Lorentz approach and Kramers-Krönig equations. As predicted by the theory, the experimental results show an enhancement of the SPR response, maximized when the chromophore absorption band coincides with the plasmon resonant wavelength. This shows that chromophores labeling can provide a potential way for SPR response enhancement. |
19023379 | Optimization of design and operating parameters of a space-based optical-electronic system with a distributed aperture. | Using a gradient optimization method with objective functions formulated in terms of a signal-to-noise ratio (SNR) calculated at given values of the prescribed spatial ground resolution, optimization problems of geometrical parameters of a distributed optical system and a charge-coupled device of a space-based optical-electronic system are solved for samples of the optical systems consisting of two and three annular subapertures. The modulation transfer function (MTF) of the distributed aperture is expressed in terms of an average MTF taking residual image alignment (IA) and optical path difference (OPD) errors into account. The results show optimal solutions of the optimization problems depending on diverse variable parameters. The information on the magnitudes of the SNR can be used to determine the number of the subapertures and their sizes, while the information on the SNR decrease depending on the IA and OPD errors can be useful in design of a bination control system to produce the necessary requirements to its accuracy on the basis of the permissible deterioration in the image quality. |
19023381 | Complex refractive index of nonspherical particles in the visible near infrared region: application to Bacillus subtilis spores. | A method is presented for the estimation of optical constants in the ultraviolet-visible-near-infrared (UV-Vis-NIR) region of nonspherical particles in a suspension at concentrations where multiple scattering is significant. The optical constants are obtained by an inversion technique using the adding-doubling method to solve the radiative transfer equation bination with the single scattering theories for modelling scattering by nonspherical particles. Two methods for describing scattering by single scattering are considered: the T-matrix method and the approximate putationally simpler Rayleigh-Gans-Debye (RGD) approximation. The method is then applied to obtain the optical constants of Bacillus subtilis spores in the wavelength region 400-1200 nm. It is found that the optical constants obtained using the RGD approximation matches those obtained using the T-matrix method to within experimental error. |
19023382 | Resolution analysis of a gradient-index rod and a gradient-index lens array. | The physical optics analysis of a gradient-index (GRIN) rod and a GRIN lens array with aberrations is presented. We investigated the optical path length and aberration of a GRIN rod without definition of the stop plane. We also defined an effective aberration transmission function to include aberrations into physical optics analysis. Our theoretical results of impulse responses agree excellently with experiments. For a single GRIN rod, we obtained a theoretical value of 10.3 microm and an experimental value of 10.4 microm for the full width at half-maximum of the intensity point-spread function. For a GRIN array, the theoretical value of 19.2 microm and the experimental measurement of 19.9 microm agree to within 4%. This physical optics methodology with aberrations included can be applied to optical design software. The resolution difference in xerographic process for test material along the "parallel-to-perpendicular" directions is observed. It agrees with the theoretical result for the intensity impulse response of the GRIN array calculated with a second-order correction. |
19023383 | Fiber optic distributed temperature and strain sensing system based on Brillouin light scattering. | We present an original method to improve the spatial resolution of a Brillouin distributed temperature and strain sensing system (DTSS). This method is shown to substantially improve the spatial resolution, while simultaneously strengthening the Brillouin backscattered light, which is based on bination of an internal modulation of the laser source and an external modulator to generate two separate light pulses with different central wavelengths and pulse widths. Moreover, a novel Brillouin signal detection method, which we called isogenous heterodyne detection, is introduced, which is equivalent to a heterodyne detection scheme but is only with Rayleigh and Brillouin backscattered light without the need of an extra reference light. These new technical approaches have been incorporated into a fiber optic DTSS with 13 km single-mode fiber, which clearly successfully demonstrated all the advantages over conventional DTSS approaches in theory and the feasibility in experiment. |
19023384 | Power control and temperature sensing for fiber-powered active sensors. | We report on a feedback optical power control technique applied to fiber powering active sensors. The active sensor consists of one laser: a 1310 nm Fabry-Perot laser or a 1550 nm distributed feedback laser. In order to power up these elements, a remote high-power laser operating at 1480 nm was used. Light conversion to electricity was achieved using indium phosphide photovoltaic cell proper to operate from 1000 to 1600 nm. Results show that the proposed control system provided sensor optical power with variation less than 0.2 dB when the temperature changed from 23 to 100 degrees C or for fiber link attenuation variation from 0 to 10 dB. |
19023385 | Fabrication of extreme-ultraviolet blazed gratings by use of direct argon-oxygen ion-beam etching through a rectangular photoresist mask. | We present a simple method to fabricate blazed gratings used in the extreme-ultraviolet wavelength region. The method uses an argon and oxygen ion beam to etch directly the fused silica substrate through a rectangular profile photoresist grating mask. The blaze angle can be significantly reduced by using oxygen, and the profile evolution under ion-beam bombardment can be simplified when a rectangular mask is used. A simple geometric model is built to analyze the etching process. The etched grating groove profile is approximately triangular with a sharp apex angle provided the aspect ratio of the mask ridge is properly chosen; the blaze angle is directly proportional to the ion-beam grazing incident angle for a fixed oxygen partial pressure. Gratings of a 2400 line/mm groove density and 0.5-3 degrees blaze angles have been fabricated, which confirms the convenience of this method and the effectiveness of the etching model. |
19023386 | Closed-loop phase-shifting homodyne interferometry using heterodyne phase detection. | A phase-shifting homodyne interferometer with feedback control by heterodyne phase detection is developed. The backreflected beam from a reference flat with a small wedge angle and an internal heterodyne detection system are utilized to obtain heterodyne beat signals for the feedback error signal. Using a digital high-speed lock-in amplifier, interference fringe stabilization, and accurate pi/2 phase shifts when micrometer-order vibrations are applied have been successfully demonstrated with a general nonpolarizing homodyne interferometer configuration. |
19023387 | Approach for determining the refractive-index profile of graded-index planar waveguides. | We measured the modal indices of a planar waveguide made from GeSeSb glass sandwiched between SiO(2) and air by using the prism-coupling technique. Based on the measured indices of the TE modes, we determined the position of the turning point corresponding to each mode of the waveguide by using the inverse WKB method. Using the modified fitting criterion introduced previously [Appl. Opt. 33, 3227 (1994)], we accurately determined the spatial profile of the refractive index for such a waveguide. Such a graded-index profile is probably caused positional variation of the GeSeSb guiding layer. |
19023388 | Building blocks for nonpolarizing optical coatings. | The problem of designing nonpolarizing beam splitters with as broad a spectral band as practical has not been clearly understood. The effort of the work reported here has been to glean understanding from the various results of a contest for such designs and further studies of what might be the underlying principles and behaviors that are involved in such designs. A few key layer patterns have been observed, and the importance of symmetry in these patterns has been discovered. Four-layer building blocks have been found that relate to the two quarter-wave optical thickness pairs used as building blocks in normal-incidence designs. |
19023389 | Pressure and velocity dependence of the material removal rate in the fast polishing process. | Based on the direct contact between the wafer and the pad, the pressure and velocity dependence of the material removal rate (MRR) in the fast polishing process (FPP) is investigated. There are three assumptions of the FPP material removal mechanism: the normal distribution of abrasive size, a periodic roughness of the pad surface, and the plastic contact between wafer-abrasive and pad-abrasive interfaces. Based on the particular FPP, a novel movement of the wafer is analyzed and a MRR equation is developed. The experiments with parameters of pressure and velocity are shown to verify the equation. Thus, a better understanding of the fundamental mechanism involved in FPP can be obtained. |
19023390 | Investigation of amplification process on the third Stokes line of H2 under ultraviolet laser irradiation. | An amplification process was investigated in the third stimulated Raman scattering (SRS) line of H2 excited with a 266 nm laser beam generated from the fourth harmonic of a Nd:YAG laser. The unexpected intensity enhancement observed at the third Stokes SRS line around 397.8 nm is attributed to the seeding of the self-generated H-epsilon Balmer line at 397 nm of atomic hydrogen by pumping the H2 molecule with a high-energy laser pulse at 266 nm. It is worth mentioning that in our case the SRS spectrum of H2 showed a quite different intensity pattern from the usual SRS spectra of hydrogen. The pulse energy and pressure dependence of all the SRS lines in general and the third Stokes SRS line in particular were investigated, and in all respects the amplified SRS line at 397.8 nm pletely different characteristics that have not been reported in previous publications. The conversion efficiency (CE) of all the SRS lines in the hydrogen 266 nm SRS spectrum was also estimated, and 36% CE was achieved at the 397.78 nm line. To support our claim for amplification at the third Stokes line by seeding of the H-epsilon Balmer line of atomic hydrogen, parative study was also carried out by pumping hydrogen gas with 355 nm (less energy per photon) and 266 nm laser beams. It is worth noting that amplification of the third Stokes SRS line was observed only with the 266 nm pump laser, where dissociation of H2 and excitation of atomic hydrogen take place, and not with the 355 nm pump laser. |
19023391 | Metal-mesh achromatic half-wave plate for use at submillimeter wavelengths. | A metal-mesh achromatic half-wave plate (HWP) has been designed, manufactured, and tested for potential use in millimeter and submillimeter astronomical instruments. The prototype device presented here is based on a 12-grid Shatrow [IEEE Trans. Antennas Propag. 43, 109 (1995)] recipe to operate over the frequency range of 120-180 GHz. Transmission line modeling and finite-element analysis [Ansoft HFSS website: were used to optimize the design geometrical parameters in terms of the device transmission, reflection, absorption, phase-shift, and cross-polarization as a function of frequency. The resulting prototype device was constructed and characterized using incoherent radiation from a polarizing Fourier transform spectrometer to explore its frequency and polarization behavior. These measurements are shown to be in excellent agreement with the models. Lists of the achieved HWP performance characteristics are reported. |
19023392 | Fluorescence polarization standard for near infrared spectroscopy and microscopy. | We present studies of polarized absorption [linear dichroism (LD)] and fluorescence polarization of the styryl derivative (LDS 798) embedded in oriented poly(vinyl alcohol) (PVA) films. These films were oriented by progressive stretching up to eight folds. Both vertical and ponents of absorptions and fluorescence were measured and dichroic ratios were determined for different film stretching ratios. The dichroic ratio and fluorescence anisotropy values were analyzed as a function of PVA film stretching ratio by fitting according to the previously developed theory. For maximum stretching ratios, exceptionally high anisotropy (approximately 0.8) and polarization (approximately 0.9) values have been measured. The stretched films have high polarization values also for isotropic excitation in a wide spectral range (500-700 nm). Such films can be conveniently used as high polarization standards and we envision they will also have applications in near infrared (NIR) imaging microscopy, where they can be used for correcting an instrumental factor in polarization measurements. |
19023393 | Solar glint from oriented crystals in cirrus clouds. | Solar scattering on oriented cirrus crystals near the specular reflection direction is modeled using a mix bining geometric optics and diffraction effects at three wavelengths in the visible and infrared domains. Different potential sources of phase function broadening around the specular direction, such as multiple scattering, solar disk, or tilt effects, are studied by means of a Monte Carlo method. The radiance detected by an airborne sensor located a few kilometers above the cirrus cloud and pointing in the specular scattering direction is calculated at four solar zenith angles showing a dramatic increase of the signal in relation to the usual assumption of random crystal orientation. |
19023394 | Atmospheric hydroxyl radical (OH) abundances from ground-based ultraviolet solar spectra: an improved retrieval method. | The Fourier Transform Ultraviolet Spectrometer (FTUVS) instrument has recorded a long-term data record of the atmospheric column abundance of the hydroxyl radical (OH) using the technique of high resolution solar absorption spectroscopy. We report new efforts in improving the precision of the OH measurements in order to better model the diurnal, seasonal, and interannual variability of odd hydrogen (HO(x)) chemistry in the stratosphere, which, in turn, will improve our understanding of ozone chemistry and its long-term changes. Until the present, the retrieval method has used a single strong OH absorption line P(1)(1) in the near-ultraviolet at 32,341 cm(-1). We describe a new method that uses an average based on spectral fits to multiple lines weighted by line strength and fitting precision. We have also made a number of improvements in the ability to fit a model to the spectral feature, which substantially reduces the scatter in the measurements of OH abundances. |
19023395 | Omnidirectional narrow bandpass filter based on metal-dielectric thin films. | We show that a metal-dielectric Fabry-Perot (FP) structure can exhibit an omnidirectional transmission for p-polarized light, which means a passband is independent of the incidence angle of light. The omnidirectional passband occurs when the sum of the reflection phase shift at the metal-spacer interface and the propagation shift in the spacer region is almost 2pi for every incidence angle. We numerically and experimentally demonstrate such an omnidirectional narrow bandpass filter in an air/Ag/ZnS/Ag/glass structure. Moreover, we introduce an antireflection coating on both sides of the metal-dielectric FP structure. The transmittance will increase obviously, while the omnidirectional property remains the same. |
19023396 | Influences of misalignment of control mirror of axisymmetric-structural CO2 laser on phase locking. | Based on the principle of phase locking of an bination CO2 laser under the normal state condition, the mechanisms of phase locking are analyzed when the control mirror is misaligned. Then the overlapping rate (OR) of the mode volume is introduced: the main influences on phase locking are the OR, the average life of the light wave, the root mean square phase error, and the mode coupling coefficient; these influences on phase locking are studied. The distribution of the light intensity reflects the effect of phase locking. It is shown that the misaligned angle has little influence on the phase locking if it is within tolerance. |
19023397 | Generation of an optical vortex with a segmented deformable mirror. | We present a method for the creation of optical vortices by using a deformable mirror. Optical vortices of integer and fractional charge were successfully generated at a wavelength of 633 nm and observed in the far field (2000 mm). The obtained intensity patterns proved to be in agreement with the theoretical predictions on integer and fractional charge optical vortices. Interference patterns between the created optical vortex carrying beams and a reference plane wave were also produced to verify and confirm the existence of the phase singularities. |
19023398 | Ray-tracing methodology: application of spatial analytic geometry in the ray-optic model of optical tweezers. | Traditional solid geometry ray-tracing method plex in analyzing the orientation of gradient forces and calculating incident angle of optic rays upon a microsphere. We present a new ray-tracing methodology based on spatial analytic geometry in the ray-optic model. For a single ray upon a microsphere, the directions of transmission and trapping forces are depicted by spatial vectors in a Cartesian coordinate system. At the same time, the polarized direction of a single focused ray can be transformed by a matrix of rotational coordinates. According to the relations of vectors, the trapping forces can be expressed identically. We use this new method to discuss differences of trapping forces in the cases of various states of unpolarized and polarized beams, and also show the reasons for differences in transverse force between measurement and theoretical results. Our simulative results show that this method can be applied identically to calculating both transverse and axial trapping forces, and also for different polarizations of a laser beam. |
19023399 | Experimental study of an ultrasmall pixel, one-dimensional liquid-crystal device. | A one-dimensional, ultrasmall pixel liquid-crystal (LC) device is experimentally demonstrated. The device has a one-dimensional array of ten 1 mm long, interdigitated, reflective gold electrodes on a glass substrate and mon transparent electrode on the opposite substrate. The interdigitated electrodes are 2 microm wide, separated by a 1 microm interelectrode gap. Operating as a dynamic, reflective, 3 microm pitch diffractive grating, the device simulates the performance of a reflective, ultrasmall, 3 microm pixel, spatial light modulator (SLM). It was shown that, for a proper choice of LC cell thickness (less than 2 microm), LC material (Merck's BL006 high-birefringence mixture), and driving conditions, the device can attain relatively high diffraction efficiency, thus demonstrating the practical feasibility of a 3 microm pixel, LC SLM. |
19023400 | Exploring microbial diversity and taxonomy using SSU rRNA hypervariable tag sequencing. | Massively parallel pyrosequencing of hypervariable regions from small subunit ribosomal RNA (SSU rRNA) genes can sample a munity two or three orders of magnitude more deeply per dollar and per hour than capillary sequencing of full-length SSU rRNA. As with full-length rRNA surveys, each sequence read is a tag surrogate for a single microbe. However, rather than assigning taxonomy by creating gene trees de novo that include all experimental sequences and certain reference taxa, pare the hypervariable region tags to an extensive database of rRNA sequences and assign taxonomy based on the best match in a Global Alignment for Sequence Taxonomy (GAST) process. The resulting taxonomic census provides information on position and diversity of the munity. To determine the effectiveness of using only hypervariable region tags for assessing munity membership, pared the taxonomy assigned to the V3 and V6 hypervariable regions with the taxonomy assigned to full-length SSU rRNA sequences isolated from both the human gut and a deep-sea hydrothermal vent. The hypervariable region tags and full-length rRNA sequences provided equivalent taxonomy and measures of relative abundance of munities, even for tags up to 15% divergent from their nearest reference match. The greater sampling depth per dollar afforded by massively parallel pyrosequencing reveals many more members of the "rare biosphere" than does capillary sequencing of the full-length gene. In addition, tag sequencing eliminates cloning bias and the sequences are short enough to pletely sequenced in a single read, maximizing the number of organisms sampled in a run while minimizing chimera formation. This technique allows the cost-effective exploration of changes in munity structure, including the rare biosphere, over space and time and can be applied immediately to initiatives, such as the Human Microbiome Project. |
19023401 | Structural and thermodynamic approach to peptide immunogenicity. | In the conventional paradigm of humoral immunity, B cells recognize their cognate antigen target in its native form. However, it is well known that relatively unstable peptides bearing only partial structural resemblance to the native protein can trigger antibodies recognizing higher-order structures found in the native protein. On the basis of sound thermodynamic principles, this work reveals that stability of immunogenic proteinlike motifs is a critical parameter rationalizing the diverse humoral immune responses induced by different linear peptide epitopes. In this paradigm, peptides with a minimal amount of stability (DeltaG(x)<0 kcal/mol) around a proteinlike motif (x) are capable of inducing antibodies with similar affinity for both peptide and native protein, more weakly stable peptides (DeltaG(x)>0 kcal/mol) trigger antibodies recognizing full protein but not peptide, and unstable peptides (DeltaG(x)>8 kcal/mol) fail to generate antibodies against either peptide or protein. Immunization experiments involving peptides derived from the autoantigen histidyl-tRNA synthetase verify that selected peptides with varying relative stabilities predicted by molecular dynamics simulations induce antibody responses consistent with this theory. Collectively, these studies provide insight pertinent to the structural basis of immunogenicity and, at the same time, validate this form of thermodynamic and molecular modeling as an approach to probe the development/evolution of humoral immune responses. |
19023402 | Hypermutability of damaged single-strand DNA formed at double-strand breaks and uncapped telomeres in yeast Saccharomyces cerevisiae. | The major DNA repair pathways operate on damage in double-strand DNA because they use the intact strand as a template after damage removal. Therefore, lesions in transient single-strand stretches of chromosomal DNA are expected to be especially threatening to genome stability. To test this hypothesis, we designed systems in budding yeast that could generate many kilobases of persistent single-strand DNA next to double-strand breaks or uncapped telomeres. The systems allowed controlled restoration to the double-strand state after applying DNA damage. We found that lesions induced by UV-light and methyl methanesulfonate can be tolerated in long single-strand regions and are hypermutagenic. The hypermutability required PCNA monoubiquitination and was largely attributable to translesion synthesis by the error-prone DNA polymerase zeta. In support of multiple lesions in single-strand DNA being a source of hypermutability, analysis of the UV-induced mutants revealed strong strand-specific bias and unexpectedly high frequency of alleles with widely separated multiple mutations scattered over several kilobases. Hypermutability and multiple mutations associated with lesions in transient stretches of long single-strand DNA may be a source of carcinogenesis and provide selective advantage in adaptive evolution. |
19023403 | The coordination of centromere replication, spindle formation, and kinetochore-microtubule interaction in budding yeast. | The kinetochore is a plex that assembles on centromeric DNA to mediate chromosome-microtubule interaction. Most eukaryotic cells form the spindle and establish kinetochore-microtubule interaction during mitosis, but budding yeast cells finish these processes in S-phase. It has long been noticed that the S-phase spindle in budding yeast is shorter than that in metaphase, but the biological significance of this short S-phase spindle structure remains unclear. We addressed this issue by using ask1-3, a temperature-sensitive kinetochore mutant that exhibits partially elongated spindles at permissive temperature in the presence of hydroxyurea (HU), a DNA synthesis inhibitor. After exposure to and removal of HU, ask1-3 cells show a delayed anaphase entry. This delay depends on the spindle checkpoint, which monitors kinetochore-microtubule interaction defects. Overproduction of microtubule-associated protein Ase1 or Cin8 also induces spindle elongation in HU-arrested cells. The spindle checkpoint-dependent anaphase entry delay is also observed after ASE1 or CIN8 overexpression in HU-arrested cells. Therefore, the shorter spindle in S-phase cells is likely to facilitate proper chromosome-microtubule interaction. |
19023404 | Neutrality and robustness in evo-devo: emergence of lateral inhibition. | Embryonic development is defined by the hierarchical dynamical process that translates genetic information (genotype) into a spatial gene expression pattern (phenotype) providing the positional information for the correct unfolding of the organism. The nature and evolutionary implications of genotype-phenotype mapping still remain key topics in evolutionary developmental biology (evo-devo). We have explored here issues of neutrality, robustness, and diversity in evo-devo by means of a simple model of gene regulatory networks. The small size of the system allowed an exhaustive analysis of the entire fitness landscape and the extent of its neutrality. This analysis shows that evolution leads to a class of robust genetic networks with an expression pattern characteristic of lateral inhibition. This class is a repertoire of distinct implementations of this key developmental process, the diversity of which provides valuable clues about its underlying causal principles. |
19023405 | A motor function for the DEAD-box RNA helicase, Gemin3, in Drosophila. | The survival motor neuron (SMN) protein, the determining factor for spinal muscular atrophy (SMA), plexed with a group of proteins in human cells. Gemin3 is the only RNA helicase in the plex. Here, we report the identification of Drosophila melanogaster Gemin3 and investigate its function in vivo. Like in vertebrates, Gemin3 physically interacts with SMN in Drosophila. Loss of function of gemin3 results in lethality at larval and/or prepupal stages. Before they die, gemin3 mutant larvae exhibit declined mobility and expanded neuromuscular junctions. Expression of a dominant-negative transgene and knockdown of Gemin3 in mesoderm cause lethality. A less severe Gemin3 disruption in developing muscles leads to flightless adults and flight muscle degeneration. Our findings suggest that Drosophila Gemin3 is required for larval development and motor function. |
19023406 | Phylogenetic dependency networks: inferring patterns of CTL escape and codon covariation in HIV-1 Gag. | HIV avoids elimination by cytotoxic T-lymphocytes (CTLs) through the evolution of escape mutations. Although there is mounting evidence that these escape pathways are broadly consistent among individuals with similar human leukocyte antigen (HLA) class I alleles, previous population-based studies have been limited by the inability to simultaneously account for HIV codon covariation, linkage disequilibrium among HLA alleles, and the confounding effects of HIV phylogeny when attempting to identify HLA-associated viral evolution. We have developed a statistical model of evolution, called a phylogenetic dependency network, that accounts for these three sources of confounding and identifies the primary sources of selection pressure acting on each HIV codon. Using synthetic data, we demonstrate the utility of this approach for identifying sites of HLA-mediated selection pressure and codon evolution as well as the deleterious effects of failing to account for all three sources of confounding. We then apply our approach to a large, clinically-derived dataset of Gag p17 and p24 sequences from a multicenter cohort of 1144 HIV-infected individuals from British Columbia, Canada (predominantly HIV-1 clade B) and Durban, South Africa (predominantly HIV-1 clade C). The resulting phylogenetic dependency network is dense, containing 149 associations between HLA alleles and HIV codons and 1386 associations among HIV codons. These associations include plete reconstruction of several recently defined escape pensatory mutation pathways and agree with emerging data on patterns of epitope targeting. The phylogenetic dependency network adds to the growing body of literature suggesting that sites of escape, order of escape, pensatory mutations are largely consistent even across different clades, although we also identify several differences between clades. As recent case studies have demonstrated, understanding both plexity and the consistency of immune escape has important implications for CTL-based vaccine design. Phylogenetic dependency networks represent a major step toward systematically expanding our understanding of CTL escape to diverse populations and whole viral genes. |
19023407 | A role for oxidized DNA precursors in Huntington's disease-like striatal neurodegeneration. | Several human neurodegenerative disorders are characterized by the accumulation of 8-oxo-7,8-dihydroguanine (8-oxodG) in the DNA of affected neurons. This can occur either through direct oxidation of DNA guanine or via incorporation of the oxidized nucleotide during replication. Hydrolases that degrade oxidized purine nucleoside triphosphates normally minimize this incorporation. hMTH1 is the major human hydrolase. It degrades both 8-oxodGTP and 8-oxoGTP to the corresponding monophosphates. To investigate whether the incorporation of oxidized nucleic acid precursors contributes to neurodegeneration, we constructed a transgenic mouse in which the human hMTH1 8-oxodGTPase is expressed. hMTH1 expression protected embryonic fibroblasts and mouse tissues against the effects of oxidants. Wild-type mice exposed to 3-nitropropionic acid develop neuropathological and behavioural symptoms that resemble those of Huntington's disease. hMTH1 transgene expression conferred a dramatic protection against these Huntington's disease-like symptoms, including weight loss, dystonia and gait abnormalities, striatal degeneration, and death. In plementary approach, an in vitro genetic model for Huntington's disease was also used. hMTH1 expression protected progenitor striatal cells containing an expanded CAG repeat of the huntingtin gene from toxicity associated with expression of the mutant huntingtin. The findings implicate oxidized nucleic acid precursors in the neuropathological features of Huntington's disease and identify the utilization of oxidized nucleoside triphosphates by striatal cells as a significant contributor to the pathogenesis of this disorder. |
19023408 | Indistinguishable landscapes of meiotic DNA breaks in rad50+ and rad50S strains of fission yeast revealed by a novel rad50+ recombination intermediate. | The fission yeast Schizosaccharomyces pombe Rec12 protein, the homolog of Spo11 in other organisms, initiates meiotic bination by creating DNA double-strand breaks (DSBs) and ing covalently linked to the DNA ends of the break. This protein-DNA linkage has previously been detected only in mutants such as rad50S in which break repair is impeded and DSBs accumulate. In the budding yeast Saccharomyces cerevisiae, the DSB distribution in a rad50S mutant is markedly different from that in wild-type (RAD50) meiosis, and it was suggested that this might also be true for other organisms. Here, we show that we can detect Rec12-DNA linkages in Sc. pombe rad50(+) cells, which are proficient for DSB repair. In contrast to the results from Sa. cerevisiae, genome-wide microarray analysis of Rec12-DNA reveals indistinguishable meiotic DSB distributions in rad50(+) and rad50S strains of Sc. pombe. These results confirm our earlier findings describing the occurrence of widely spaced DSBs primarily in large intergenic regions of DNA and demonstrate the relevance and usefulness of fission yeast studies employing rad50S. We propose that the differential behavior of rad50S strains reflects a major difference in DSB regulation between the two species--specifically, the requirement for the plex for DSB formation in budding yeast but not in fission yeast. Use of rad50S and related mutations may be a useful method for DSB analysis in other species. |
19023410 | Newly discovered ebola virus associated with hemorrhagic fever outbreak in Uganda. | Over the past 30 years, Zaire and Sudan ebolaviruses have been responsible for large hemorrhagic fever (HF) outbreaks with case fatalities ranging from 53% to 90%, while a third species, Côte d'Ivoire ebolavirus, caused a single non-fatal HF case. In November 2007, HF cases were reported in Bundibugyo District, Western Uganda. Laboratory investigation of the initial 29 suspect-case blood specimens by classic methods (antigen capture, IgM and IgG ELISA) and a recently developed random-primed pyrosequencing approach quickly identified this to be an Ebola HF outbreak associated with a newly discovered ebolavirus species (Bundibugyo ebolavirus) distantly related to the Côte d'Ivoire ebolavirus found in western Africa. Due to the sequence divergence of this new virus relative to all previously recognized ebolaviruses, these findings have important implications for design of future diagnostic assays to monitor Ebola HF disease in humans and animals, and ongoing efforts to develop effective antivirals and vaccines. |
19023409 | Order-based representation in random networks of cortical neurons. | The wide range of time scales involved in neural excitability and synaptic transmission might lead to ongoing change in the temporal structure of responses to recurring stimulus presentations on a trial-to-trial basis. This is probably the most severe biophysical constraint on putative time-based primitives of stimulus representation in neuronal networks. Here we show that in spontaneously developing large-scale random networks of cortical neurons in vitro the order in which neurons are recruited following each stimulus is a naturally emerging representation primitive that is invariant to significant temporal changes in spike times. With a relatively small number of randomly sampled neurons, the information about stimulus position is fully retrievable from the recruitment order. The effective connectivity that makes order-based representation invariant to time warping is characterized by the existence of stations through which activity is required to pass in order to propagate further into the network. This study uncovers a simple invariant in a noisy biological network in vitro; its applicability under in vivo constraints remains to be seen. |
19023411 | Role of amphipathic helix of a herpesviral protein in membrane deformation and T cell receptor downregulation. | Lipid rafts are membrane microdomains that function as platforms for signal transduction and membrane trafficking. Tyrosine kinase interacting protein (Tip) of T lymphotropic Herpesvirus saimiri (HVS) is targeted to lipid rafts in T cells and downregulates TCR and CD4 surface expression. Here, we report that the membrane-proximal amphipathic helix preceding Tip's transmembrane (TM) domain mediates lipid raft localization and membrane deformation. In turn, this motif directs Tip's lysosomal trafficking and selective TCR downregulation. The amphipathic helix binds to the negatively charged lipids and induces liposome tubulation, the TM domain mediates oligomerization, and cooperation of the membrane-proximal helix with the TM domain is sufficient for localization to lipid rafts and partments, especially the mutivesicular bodies. These findings suggest that the membrane-proximal amphipathic helix and TM domain provide HVS Tip with the unique ability to deform the cellular membranes in lipid rafts and to downregulate TCRs potentially through MVB formation. |
19023412 | A genetically hard-wired metabolic transcriptome in Plasmodium falciparum fails to mount protective responses to lethal antifolates. | Genome sequences of Plasmodium falciparum allow for global analysis of drug responses to antimalarial agents. It was of interest to learn how DNA microarrays may be used to study drug action in malaria parasites. In one large, tightly controlled study involving 123 microarray hybridizations between cDNA from isogenic drug-sensitive and drug-resistant parasites, a lethal antifolate (WR99210) failed to over-produce RNA for the genetically proven principal target, dihydrofolate reductase-thymidylate synthase (DHFR-TS). This transcriptional rigidity carried over to metabolically related RNA encoding folate and pyrimidine biosynthesis, as well as to the rest of the parasite genome. No genes were reproducibly up-regulated by more than 2-fold until 24 h after initial drug exposure, even though clonal viability decreased by 50% within 6 h. We predicted and showed that while the parasites do not mount protective transcriptional responses to antifolates in real time, P. falciparum cells transfected with human DHFR gene, and adapted to long-term WR99210 exposure, adjusted the hard-wired transcriptome itself to thrive in the presence of the drug. A system-wide incapacity for changing RNA levels in response to specific metabolic perturbations may contribute to selective vulnerabilities of Plasmodium falciparum to lethal antimetabolites. In addition, such regulation affects how DNA microarrays are used to understand the mode of action of antimetabolites. |
19023413 | Cell cycle- and chaperone-mediated regulation of H3K56ac incorporation in yeast. | Acetylation of histone H3 lysine 56 is a covalent modification best known as a mark of newly replicated chromatin, but it has also been linked to replication-independent histone replacement. Here, we measured H3K56ac levels at single-nucleosome resolution in asynchronously growing yeast cultures, as well as in yeast proceeding synchronously through the cell cycle. We developed a quantitative model of H3K56ac kinetics, which shows that H3K56ac is largely explained by the genomic replication timing and the turnover rate of each nucleosome, suggesting that cell cycle profiles of H3K56ac should reveal most first-time nucleosome incorporation events. However, since the deacetylases Hst3/4 prevent use of H3K56ac as a marker for histone deposition during M phase, we also directly measured M phase histone replacement rates. We report a global decrease in turnover rates during M phase and a further specific decrease in turnover at several early origins of replication, which switch from rapidly replaced in G1 phase to stably bound during M phase. Finally, by measuring H3 replacement in yeast deleted for the H3K56 acetyltransferase Rtt109 and its two co-chaperones Asf1 and Vps75, we find evidence that Rtt109 and Asf1 preferentially enhance histone replacement at rapidly replaced nucleosomes, whereas Vps75 appears to inhibit histone turnover at those loci. These results provide a broad perspective on histone replacement/incorporation throughout the cell cycle and suggest that H3K56 acetylation provides a positive-feedback loop by which replacement of a nucleosome enhances subsequent replacement at the same location. |
19023414 | Gene regulation in primates evolves under tissue-specific selection pressures. | Regulatory changes have long been hypothesized to play an important role in primate evolution. To identify adaptive regulatory changes in humans, we performed a genome-wide survey for genes in which regulation has likely evolved under natural selection. To do so, we used a multi-species microarray to measure gene expression levels in livers, kidneys, and hearts from six humans, chimpanzees, and rhesus macaques. parative gene expression data allowed us to identify a large number of genes, as well as specific pathways, whose inter-species expression profiles are consistent with the action of stabilizing or directional selection on gene regulation. Among the latter set, we found an enrichment of genes involved in metabolic pathways, consistent with the hypothesis that shifts in diet underlie many regulatory adaptations in humans. In addition, we found evidence for tissue-specific selection pressures, as well as lower rates of protein evolution for genes in which regulation evolves under natural selection. These observations are consistent with the notion that adaptive circumscribed changes in gene regulation have fewer deleterious pleiotropic pared with changes at the protein sequence level. |
19023416 | Extracellular DNA chelates cations and induces antibiotic resistance in Pseudomonas aeruginosa biofilms. | Biofilms are surface-adhered munities encased in an extracellular posed of DNA, bacterial polysaccharides and proteins, which are up to 1000-fold more antibiotic resistant than planktonic cultures. To date, extracellular DNA has been shown to function as a structural support to maintain Pseudomonas aeruginosa biofilm architecture. Here we show that DNA is a ponent of P. aeruginosa biofilms. At physiologically relevant concentrations, extracellular DNA has antimicrobial activity, causing cell lysis by chelating cations that stabilize lipopolysaccharide (LPS) and the outer membrane (OM). DNA-mediated killing occurred within minutes, as a result of perturbation of both the outer and inner membrane (IM) and the release of cytoplasmic contents, including genomic DNA. Sub-inhibitory concentrations of DNA created a cation-limited environment that resulted in induction of the PhoPQ- and PmrAB-regulated cationic antimicrobial peptide resistance operon PA3552-PA3559 in P. aeruginosa. Furthermore, DNA-induced expression of this operon resulted in up to 2560-fold increased resistance to cationic antimicrobial peptides and 640-fold increased resistance to aminoglycosides, but had no effect on beta-lactam and fluoroquinolone resistance. Thus, the presence of extracellular DNA in the biofilm matrix contributes to cation gradients, genomic DNA release and inducible antibiotic resistance. DNA-rich environments, including biofilms and other infection sites like the CF lung, are likely the in vivo environments where extracellular pathogens such as P. aeruginosa encounter cation limitation. |
19023415 | Gamma-linolenic and stearidonic acids are required for basal immunity in Caenorhabditis elegans through their effects on p38 MAP kinase activity. | Polyunsaturated fatty acids (PUFAs) form a class of essential micronutrients that play a vital role in development, cardiovascular health, and immunity. The influence of lipids on the immune response is plex and diverse, with multiple studies pointing to the beneficial effects of long-chain fatty acids in immunity. However, the mechanisms through which PUFAs modulate innate immunity and the effects of PUFA deficiencies on innate immune functions remain to be clarified. Using the Caenorhabditis elegans-Pseudomonas aeruginosa host-pathogen system, we present genetic evidence that a Delta6-desaturase FAT-3, through its two 18-carbon products--gamma-linolenic acid (GLA, 18:3n6) and stearidonic acid (SDA, 18:4n3), but not the 20-carbon PUFAs arachidonic acid (AA, 20:4n6) and eicosapentaenoic acid (EPA, 20:5n3)--is required for basal innate immunity in vivo. Deficiencies in GLA and SDA result in increased susceptibility to bacterial infection, which is associated with reduced basal expression of a number of immune-specific genes--including spp-1, lys-7, and lys-2--that encode antimicrobial peptides. GLA and SDA are required to maintain basal activity of the p38 MAP kinase pathway, which plays important roles in protecting metazoan animals from infections and oxidative stress. Transcriptional and functional analyses of fat-3-regulated genes revealed that fat-3 is required in the intestine to regulate the expression of infection- and stress-response genes, and that distinct sets of genes are specifically required for immune function and oxidative stress response. Our study thus uncovers a mechanism by which these 18-carbon PUFAs affect basal innate immune function and, consequently, the ability of an organism to defend itself against bacterial infections. The conservation of p38 MAP kinase signaling in both stress and immune responses further encourages exploring the function of GLA and SDA in humans. |
19023417 | A critical role of a cellular membrane traffic protein in poliovirus RNA replication. | Replication of many RNA viruses is panied by extensive remodeling of intracellular membranes. In poliovirus-infected cells, ER and Golgi stacks disappear, while new clusters of vesicle-like structures form sites for viral RNA synthesis. Virus replication is inhibited by brefeldin A (BFA), implicating ponents(s) of the cellular secretory pathway in virus growth. Formation of characteristic vesicles induced by expression of viral proteins was not inhibited by BFA, but they were functionally deficient. GBF1, a guanine nucleotide exchange factor for the small cellular GTPases, Arf, is responsible for the sensitivity of virus infection to BFA, and is required for virus replication. Knockdown of GBF1 expression inhibited virus replication, which was rescued by catalytically active protein with an intact N-terminal sequence. We identified a mutation in GBF1 that allows growth of poliovirus in the presence of BFA. Interaction between GBF1 and viral protein 3A determined the e of infection in the presence of BFA. |
19023420 | Behavioral sequence analysis reveals a novel role for beta2* nicotinic receptors in exploration. | Nicotinic acetylcholine receptors (nAChRs) are widely expressed throughout the central nervous system and modulate neuronal function in most mammalian brain structures. The contribution of defined nAChR subunits to a specific behavior is thus difficult to assess. Mice deleted for beta2-containing nAChRs (beta2-/-) have been shown to be hyperactive in an open-field paradigm, without determining the origin of this hyperactivity. We here develop a quantitative description of mouse behavior in the open field based upon first order Markov and variable length Markov chain analysis focusing on the time-organized sequence that behaviors posed of. This description reveals that this hyperactivity is the consequence of the absence of specific inactive states or "stops". These stops are associated with a scanning of the environment in wild-type mice (WT), and they affect the way that animals organize their sequence of behaviors pared with stops without scanning. They characterize a specific "decision moment" that is reduced in beta2-/- mutant mice, suggesting an important role of beta2-nAChRs in the strategy used by animals to explore an environment and collect information in order to organize their behavior. This integrated analysis of the displacement of an animal in a simple environment offers new insights, specifically into the contribution of nAChRs to higher brain functions and more generally into the principles that organize sequences of behaviors in animals. |
19023419 | A RAC/CDC-42-independent GIT/PIX/PAK signaling pathway mediates cell migration in C. elegans. | P21 activated kinase (PAK), PAK interacting exchange factor (PIX), and G protein coupled receptor kinase interactor pose a highly conserved signaling module controlling cell migrations, immune system signaling, and the formation of the mammalian nervous system. Traditionally, this signaling module is thought to facilitate the function of RAC and CDC-42 GTPases by allowing for the recruitment of a GTPase effector (PAK), a GTPase activator (PIX), and a scaffolding protein (GIT) as a regulated signaling unit to specific subcellular locations. Instead, we report here that this signaling module functions independently of RAC/CDC-42 GTPases in vivo to control the cell shape and migration of the distal tip cells (DTCs) during morphogenesis of the Caenorhabditis elegans gonad. In addition, this RAC/CDC-42-independent PAK pathway functions in parallel to a classical GTPase/PAK pathway to control the guidance aspect of DTC migration. Among the C. elegans PAKs, only PAK-1 functions in the GIT/PIX/PAK pathway independently of RAC/CDC42 GTPases, while both PAK-1 and MAX-2 are redundantly utilized in the GTPase/PAK pathway. Both RAC/CDC42-dependent and -independent PAK pathways function with the integrin receptors, suggesting that signaling through integrins can control the morphology, movement, and guidance of DTC through discrete pathways. Collectively, our results define a new signaling capacity for the GIT/PIX/PAK module that is likely to be conserved in vertebrates and demonstrate that PAK family members, which are redundantly utilized as GTPase effectors, can act non-redundantly in pathways independent of these GTPases. |
19023418 | the hyphal-associated adhesin and invasin Als3 of Candida albicans mediates iron acquisition from host ferritin. | Iron sequestration by host iron-binding proteins is an important mechanism of resistance to microbial infections. Inside oral epithelial cells, iron is stored within ferritin, and is therefore not usually accessible to pathogenic microbes. We observed that the ferritin concentration within oral epithelial cells was directly related to their susceptibility to damage by the human pathogenic fungus, Candida albicans. Thus, we hypothesized that host ferritin is used as an iron source by this organism. We found that C. albicans was able to grow on agar at physiological pH with ferritin as the sole source of iron, while the baker's yeast Saccharomyces cerevisiae could not. A screen of C. albicans mutants ponents of each of the three known iron acquisition systems revealed that only the reductive pathway is involved in iron utilization from ferritin by this fungus. Additionally, C. albicans hyphae, but not yeast cells, bound ferritin, and this binding was crucial for iron acquisition from ferritin. Transcriptional profiling of wild-type and hyphal-defective C. albicans strains suggested that the C. albicans invasin-like protein Als3 is required for ferritin binding. Hyphae of an Deltaals3 null mutant had a strongly reduced ability to bind ferritin and these mutant cells grew poorly on agar plates with ferritin as the sole source of iron. Heterologous expression of Als3, but not Als1 or Als5, two closely related members of the Als protein family, allowed S. cerevisiae to bind ferritin. Immunocytochemical localization of ferritin in epithelial cells infected with C. albicans showed ferritin surrounding invading hyphae of the wild-type, but not the Deltaals3 mutant strain. This mutant was also unable to damage epithelial cells in vitro. Therefore, C. albicans can exploit iron from ferritin via morphology dependent binding through Als3, suggesting that this single protein has multiple virulence attributes. |
19023421 | The bicarbonate transporter is essential for Bacillus anthracis lethality. | In the pathogenic bacterium Bacillus anthracis, virulence requires induced expression of the anthrax toxin and capsule genes. Elevated CO2/bicarbonate levels, an indicator of the host environment, provide a signal ex vivo to increase expression of virulence factors, but the mechanism underlying induction and its relevance in vivo are unknown. We identified a previously uncharacterized ABC transporter (BAS2714-12) similar to bicarbonate transporters in photosynthetic cyanobacteria, which is essential to the bicarbonate induction of virulence gene expression. Deletion of the genes for the transporter abolished induction of toxin gene expression and strongly decreased the rate of bicarbonate uptake ex vivo, demonstrating that the BAS2714-12 locus encodes a bicarbonate ABC transporter. The bicarbonate transporter deletion strain was avirulent in the A/J mouse model of infection. Carbonic anhydrase inhibitors, which prevent the interconversion of CO2 and bicarbonate, significantly affected toxin expression only in the absence of bicarbonate or the bicarbonate transporter, suggesting that carbonic anhydrase activity is not essential to virulence factor induction and that bicarbonate, and not CO2, is the signal essential for virulence induction. The identification of this novel bicarbonate transporter essential to virulence of B. anthracis may be of relevance to other pathogens, such as Streptococcus pyogenes, Escherichia coli, Borrelia burgdorferi, and Vibrio cholera that regulate virulence factor expression in response to CO2/bicarbonate, and suggests it may be a target for antibacterial intervention. |
19023423 | Convergence among non-sister dendritic branches: an activity-controlled mean to strengthen network connectivity. | The manner by which axons distribute synaptic connections along dendrites remains a fundamental unresolved issue in neuronal development and physiology. We found in vitro and in vivo indications that dendrites determine the density, location and strength of their synaptic inputs by controlling the distance of their branches from those of their neighbors. Such control occurs through collective branch convergence, a behavior promoted by AMPA and NMDA glutamate receptor activity. At hubs of convergence sites, the incidence of axo-dendritic contacts as well as clustering levels, pre- and post-synaptic protein content and secretion capacity of synaptic connections are higher than found elsewhere. This coupling between synaptic distribution and the pattern of dendritic overlapping results in 'Economical Small World Network', a network configuration that enables single axons to innervate multiple and remote dendrites using short wiring lengths. Thus, activity-mediated regulation of the proximity among dendritic branches serves to pattern and strengthen neuronal connectivity. |
19023422 | Interrelationship between dendritic cell trafficking and Francisella tularensis dissemination following airway infection. | Francisella tularensis, the etiological agent of the inhalation tularemia, multiplies in a variety of cultured mammalian cells. Nevertheless, evidence for its in vivo intracellular residence is less conclusive. Dendritic cells (DC) that are adapted for engulfing bacteria and migration towards lymphatic organs could serve as potential targets for bacterial residence and trafficking. Here, we focus on the in vivo interactions of F. tularensis with DC following airway infection of mice. Lethal airway infection of mice with the live vaccine strain (LVS) results in trafficking of a CD11b(high)/CD11c(med)/autofluorescence(low) DC subset from the respiratory tract to the draining mediastinal lymph node (MdLN). Simultaneously, a rapid, massive bacterial colonization of the MdLN occurs, characterized by large bacterial foci formation. Analysis of bacteria in the MdLN revealed a major population of extracellular bacteria, which co-exists with a substantial fraction of intracellular bacteria. The intracellular bacteria are viable and reside in cells sorted for DC marker expression. Moreover, in vivo vital staining experiments indicate that most of these intracellular bacteria ( approximately 75%) reside in cells that have migrated from the airways to the MdLN after infection. The correlation between DC and bacteria accumulation in the MdLN was further demonstrated by manipulating DC migration to the MdLN through two independent pathways. Impairment of DC migration to the MdLN, either by a sphingosine-1-phosphate receptor agonist (FTY720) or by the D prostanoid receptor 1 agonist (BW245C), resulted in reduced bacterial colonization of MdLN. Moreover, BW245C treatment delayed the onset of morbidity and the time to death of the infected mice. Taken together, these results suggest that DC can serve as an inhabitation niche for F. tularensis in the early stages of infection, and that DC trafficking plays a role in pathogen dissemination. This underscores the therapeutic potential of DC migration impairing drugs in tularemia treatment. |
19023424 | Functional characterization of a newly identified group B Streptococcus pullulanase eliciting antibodies able to prevent alpha-glucans degradation. | Streptococcal pullulanases have been recently proposed as ponents of the metabolic machinery involved in bacterial adaptation to host niches. By sequence analysis of the Group B Streptococcus (GBS) genome we found a novel putative surface exposed protein with pullulanase activity. We named such a protein SAP. The sap gene is highly conserved among GBS strains and homologous genes, such as PulA and SpuA, have been described in other pathogenic streptococci. The SAP protein contains two N-terminal carbohydrate-binding motifs, followed by a catalytic domain and a C-terminal LPXTG cell wall-anchoring domain. In vitro analysis revealed that the binant form of SAP is able to degrade alpha-glucan polysaccharides, such as pullulan, glycogen and starch. Moreover, NMR analysis showed that SAP acts as a type I pullulanase. Studies performed on whole bacteria indicated that the presence of alpha-glucan polysaccharides in culture medium up-regulated the expression of SAP on bacterial surface as confirmed by FACS analysis and confocal imaging. Deletion of the sap gene resulted in a reduced capacity of bacteria to grow in medium containing pullulan or glycogen, but not glucose or maltose, confirming the pivotal role of SAP in GBS metabolism of alpha-glucans. As reported for other streptococcal pullulanases, we found specific anti-SAP antibodies in human sera from healthy volunteers. Investigation of the functional role of anti-SAP antibodies revealed that incubation of GBS in the presence of sera from animals immunized with SAP reduced the capacity of the bacterium to degrade pullulan. Of interest, anti-SAP sera, although to a lower extent, also inhibited Group A Streptococcus pullulanase activity. These data open new perspectives on the possibility to use SAP as a potential ponent inducing functional cross-reacting antibodies interfering with streptococcal infections. |
19023427 | Disruption of Nrf2, a key inducer of antioxidant defenses, attenuates ApoE-mediated atherosclerosis in mice. | Oxidative stress and inflammation are two critical factors that drive the formation of plaques in atherosclerosis. Nrf2 is a redox-sensitive transcription factor that upregulates a battery of antioxidative genes and cytoprotective enzymes that constitute the cellular response to oxidative stress. Our previous studies have shown that disruption of Nrf2 in mice (Nrf2(-/-)) causes increased susceptibility to pulmonary emphysema, asthma and sepsis due to increased oxidative stress and inflammation. Here we have tested the hypothesis that disruption of Nrf2 in mice causes increased atherosclerosis. |
19023425 | Viral load, clinical disease severity and cellular immune responses in primary varicella zoster virus infection in Sri Lanka. | In Sri Lanka, varicella zoster virus (VZV) is typically acquired during adulthood with significant associated disease morbidity and mortality. T cells are believed to be important in the control of VZV replication and in the prevention of reactivation. The relationship between viral load, disease severity and cellular immune responses in primary VZV infection has not been well studied. |
19023426 | rBCG induces strong antigen-specific T cell responses in rhesus macaques in a prime-boost setting with an adenovirus 35 tuberculosis vaccine vector. | BCG bined with adenoviral-delivered boosts, represents a reasonable strategy to augment, broaden and prolong immune protection against tuberculosis (TB). We tested BCG (SSI1331) (in 6 animals, delivered intradermally) and a binant (rBCG) AFRO-1 expressing perfringolysin (in 6 animals) followed by two boosts (delivered intramuscullary) with non-replicating adenovirus 35 (rAd35) expressing a fusion posed of Ag85A, Ag85B and TB10.4, for the capacity to induce antigen-specific cellular immune responses in rhesus macaques (Macaca mulatta). Control animals received diluent (3 animals). |
19023442 | Transient responses to rapid changes in mean and variance in spiking models. | The mean input and variance of the total synaptic input to a neuron can vary independently, suggesting two distinct information channels. Here we examine the impact of rapidly varying signals, delivered via these two information conduits, on the temporal dynamics of neuronal firing rate responses. We examine the responses of model neurons to step functions in either the mean or the variance of the input current. Our results show that the temporal dynamics governing response onset depends on the choice of model. Specifically, the existence of a hard threshold introduces an ponent into the response onset of a leaky-integrate-and-fire model that is not present in other models studied here. Other response features, for example a decaying oscillatory approach to a new steady-state firing rate, appear to be more universal among neuronal models. The decay time constant of this approach is a power-law function of noise magnitude over a wide range of input parameters. Understanding how specific model properties underlie these response features is important for understanding how neurons will respond to rapidly varying signals, as the temporal dynamics of the response onset and response decay to new steady-state determine what range of signal frequencies a population of neurons can respond to and faithfully encode. |
19023428 | Coding of visual object features and feature conjunctions in the human brain. | Object recognition is achieved through neural mechanisms reliant on the activity of distributed coordinated neural assemblies. In the initial steps of this process, an object's features are thought to be coded very rapidly in distinct neural assemblies. These features play different functional roles in the recognition process--while colour facilitates recognition, additional contours and edges delay it. Here, we selectively varied the amount and role of object features in an entry-level categorization paradigm and related them to the electrical activity of the human brain. We found that early synchronizations (approx. 100 ms) increased quantitatively when more image features had to be coded, without reflecting their qualitative contribution to the recognition process. Later activity (approx. 200-400 ms) was modulated by the representational role of object features. These findings demonstrate that although early synchronizations may be sufficient for relatively crude discrimination of objects in visual scenes, they cannot support entry-level categorization. This was subserved by later processes of object model selection, which utilized the representational value of object features such as colour or edges to select the appropriate model and achieve identification. |
19023429 | Effectiveness of cellulose sulfate vaginal gel for the prevention of HIV infection: results of a Phase III trial in Nigeria. | This trial evaluated the safety and effectiveness of 6% cellulose sulfate vaginal gel in preventing male-to-female vaginal transmission of HIV, gonorrhea and chlamydial infection. |
19023444 | FRET imaging of hemoglobin concentration in Plasmodium falciparum-infected red cells. | During its intraerythrocytic asexual reproduction cycle Plasmodium falciparum consumes up to 80% of the host cell hemoglobin, in large excess over its metabolic needs. A model of the homeostasis of falciparum-infected red blood cells suggested an explanation based on the need to reduce the colloid-osmotic pressure within the host cell to prevent its premature lysis. Critical for this hypothesis was that the hemoglobin concentration within the host cell be progressively reduced from the trophozoite stage onwards. |
19023443 | "The good into the pot, the bad into the crop!"--a new technology to free stem cells from feeder cells. | A variety of embryonic and adult stem cell lines require an initial co-culturing with feeder cells for non-differentiated growth, self renewal and maintenance of pluripotency. However for many downstream ES cell applications the feeder cells have to be considered contaminations that might interfere not just with the analysis of experimental data but also with clinical application and tissue engineering approaches. Here we introduce a novel technique that allows for the selection of pure feeder-freed stem cells, following stem cell proliferation on feeder cell layers. Complete and reproducible separation of feeder and embryonic stem cells was plished by adaptation of an automated cell selection system that resulted in the aspiration of distinct cell colonies or fraction of colonies according to predefined physical parameters. Analyzing neuronal differentiation we demonstrated feeder-freed stem cells to exhibit differentiation parable to embryonic stem cells differentiated under standard conditions. However, embryoid body growth as well as differentiation of stem cells into cardiomyocytes was significantly enhanced in feeder-freed cells, indicating a feeder cell dependent modulation of lineage differentiation during early embryoid body development. These findings underline the necessity to separate stem and feeder cells before the initiation of in vitro differentiation. plete separation of stem and feeder cells by this new technology results in pure stem cell populations for translational approaches. Furthermore, a more detailed analysis of the effect of feeder cells on stem cell differentiation is now possible, that might facilitate the identification and development of new optimized human or genetically modified feeder cell lines. |
19023446 | Just-in-time information improved decision-making in primary care: a randomized controlled trial. | The "Just-in-time Information" (JIT) librarian consultation service was designed to provide rapid information to answer primary care clinical questions during patient hours. This study evaluated whether information provided by librarians to answer clinical questions positively impacted time, decision-making, cost savings and satisfaction. |
19023445 | A point mutation in translation initiation factor 2B leads to a continuous hyper stress state in oligodendroglial-derived cells. | Mutations in eukaryotic translation initiation factor 2B (eIF2B) cause Childhood Ataxia with CNS Hypomyelination (CACH), also known as Vanishing White Matter disease (VWM). The disease is manifested by loss of brain myelin upon physiological stress. In a previous study, we showed that fibroblasts isolated from CACH/VWM patients are hypersensitive to pharmacologically-induced endoplasmic reticulum (ER) stress. Since brain cells from affected individuals are not available for research, we wished to assess the effect of eIF2B mutation on oligodendroglial-derived cells. |
19023447 | Immunochemical detection of glycated lens crystallins and their circulating autoantibodies in human serum during aging. | The aim of this investigation was to exploit lens-specific glycated crystallins as an immunogen to detect human glycated crystallins and their circulating autoantibodies in human serum during aging in relation to the development of cataract. |
19023448 | Identification of five novel mutations in the long isoform of the USH2A gene in Chinese families with Usher syndrome type II. | Usher syndrome type II (USH2) is the mon form of Usher syndrome, an autosomal recessive disorder characterized by moderate to severe hearing loss, postpuberal onset of retinitis pigmentosa (RP), and normal vestibular function. Mutations in the USH2A gene have been shown to be responsible for most cases of USH2. To further elucidate the role of USH2A in USH2, mutation screening was undertaken in three Chinese families with USH2. |
19023449 | PCNA interacts with Prox1 and represses its transcriptional activity. | Prox1 is a transcription factor which can function either as a transcriptional activator, transcriptional repressor or a transcriptional corepressor. This paper seeks to better understand the role of protein-protein interactions in this multitude of functions. |
19023453 | Boundaries, links and clusters: a new paradigm in spatial analysis? | This paper develops and applies new techniques for the simultaneous detection of boundaries and clusters within a probabilistic framework. The new statistic "little b" (written b(ij)) evaluates boundaries between adjacent areas with different values, as well as links between adjacent areas with similar values. Clusters of high values (hotspots) and low values (coldspots) are then constructed by joining areas abutting locations that are significantly high (e.g., an unusually high disease rate) and that are connected through a "link" such that the values in the adjoining areas are not significantly different. Two techniques are proposed and evaluated for plishing cluster construction: "big B" and the "ladder" approach. pare the statistical power and empirical Type I and Type II error of these approaches to those of wombling and the local Moran test. Significance may be evaluated using distribution theory based on the product of two continuous (e.g., non-discrete) variables. We also provide a "distribution free" algorithm based on resampling of the observed values. The methods are applied to simulated data for which the locations of boundaries and clusters is known, pared and contrasted with clusters found using the local Moran statistic and with polygon Womble boundaries. The little b approach to boundary detection parable to polygon wombling in terms of Type I error, Type II error and empirical statistical power. For cluster detection, both the big B and ladder approaches have lower Type I and Type II error and are more powerful than the local Moran statistic. The new methods are not constrained to find clusters of a pre-specified shape, such as circles, ellipses and donuts, and yield a more accurate description of geographic variation than alternative cluster tests that presuppose a specific cluster shape. We mend these techniques over existing cluster and boundary detection methods that do not provide such prehensive description of spatial pattern. |
19023450 | Different tropism of adenoviruses and adeno-associated viruses to corneal cells: implications for corneal gene therapy. | Diseased corneas are potential targets for viral-based gene therapy to normalize (stimulate or inhibit) the expression of specific proteins. The choice of viral vectors is important to achieve optimal effect. The purpose of this study was pare the tropism to different corneal cells of binant adenovirus (rAV) and binant adeno-associated virus (rAAV) constructs using live rabbit and organ-cultured human corneas. |
19023455 | Accounting for rate instability and spatial patterns in the boundary analysis of cancer mortality maps. | Boundary analysis of cancer maps may highlight areas where causative exposures change through geographic space, the presence of local populations with distinct cancer incidences, or the impact of different cancer control methods. Too often, such analysis ignores the spatial pattern of incidence or mortality rates and overlooks the fact that puted from sparsely populated geographic entities can be very unreliable. This paper proposes a new methodology that accounts for the uncertainty and spatial correlation of rate data in the detection of significant edges between adjacent entities or polygons. Poisson kriging is first used to estimate the risk value and the associated standard error within each polygon, accounting for the population size and the risk puted from raw rates. The boundary statistic is then defined as half the absolute difference between kriged risks. Its reference distribution, under the null hypothesis of no boundary, is derived through the generation of multiple realizations of the spatial distribution of cancer risk values. This paper presents three types of neutral models generated using methods of plexity: mon random shuffle of estimated risk values, a spatial re-ordering of these risks, or p-field simulation that accounts for the population size within each polygon. The approach is illustrated using age-adjusted pancreatic cancer mortality rates for white females in 295 US counties of the Northeast (1970-1994). Simulation studies demonstrate that Poisson kriging yields more accurate estimates of the cancer risk and how its value changes between polygons (i.e. boundary statistic), relatively to the use of raw rates or local empirical Bayes smoother. When used in conjunction with spatial neutral models generated by p-field simulation, the boundary analysis based on Poisson kriging estimates minimizes the proportion of type I errors (i.e. edges wrongly declared significant) while the frequency of these errors is predicted well by the p-value of the statistical test. |
19023451 | Heterozygous expression of myocilin glaucoma mutants increases secretion of the mutant forms and reduces extracellular processed myocilin. | Heterozygous mutations in the myocilin gene (MYOC) cause a by an unknown mechanism. MYOC encodes an extracellular protein of unidentified function that undergoes intracellular endoproteolytic processing in the secretory pathway. It has been described that co-expression of wild-type/mutant myocilin reduces the secretion of the wild-type protein and that single expression of a myocilin mutants reduces its proteolytic processing. However, the effect of wild-type myocilin on mutant myocilin secretion and how mutant myocilin affects the proteolytic processing of wild-type myocilin have not been investigated. We herein analyze these two issues. |
19023454 | Children's Dietary Recalls from Three Validation Studies: Types of Intrusion Vary with Retention Interval. | Using previously collected data of fourth-grade children observed eating school meals and then interviewed, we categorized intrusions (food items reported but not observed eaten) as stretches (on the child's tray) or confabulations (not on the child's tray). We investigated intrusions, confabulations, and stretches, and the role of liking, at different retention intervals (morning interviews about the previous day's intake; evening interviews about that day's intake) and under different reporting-order prompts (forward; reverse). As retention interval between consumption and report increased, the likelihood 1) increased that reported items were intrusions, that reported items were confabulations, and that intrusions were confabulations; and 2) was constant that reported items were stretches. Results concerning reporting-order prompts were inconclusive. Liking ratings were higher for matches (reports of items observed eaten) than stretches, for confabulations than stretches, and for matches than omissions (unreported items observed eaten), but did not vary by retention interval or reporting-order prompts. |
19023456 | TNFalpha-induced activation of NFkappaB protects against UV-induced apoptosis specifically in p53-proficient cells. | The signaling pathways that depend on p53 or NFkappaB transcription factors are ponents of cellular responses to stress. In general, p53 is involved in either activation of cell cycle arrest or induction of apoptosis, while NFkappaB exerts mostly anti-apoptotic functions; both regulatory pathways apparently interfere with each other. Here we aimed to analyze the effects of NFkappaB activation on DNA damage-induced apoptosis, either p53-dependent or p53-independent, in a set of human cell lines. Four cell lines, HCT116 and RKO colon carcinoma, NCI-H1299 lung carcinoma and HL60 myeloblastoma, each of them in two congenic variants either containing or lacking petent p53, were used. Cells were incubated with TNFalpha cytokine to activate NFkappaB and then treated with ultraviolet or ionizing radiation to induce apoptosis, which was assessed by measurement of the sub-G1 cell fraction. We observed that treatment with TNFalpha resulted in a significant reduction in the frequency of apoptotic cells in UV-irradiated p53-proficient lines (with exception of the UV-resistant NCI-H1299 cells). This anti-apoptotic effect was lost when cells were pretreated with parthenolide, an inhibitor of NFkappaB activation. In marked contrast, TNFalpha-pretreatment of p53-deficient lines resulted in an increased frequency of apoptotic cells after UV irradiation (with exception of HL60 cells). Such anti- and pro-apoptotic influence of TNFalpha was less obvious in cells treated with ionizing radiation. The data clearly indicates functional interference of both signaling pathways upon the damage-induced apoptotic response, yet the observed effects are both cell type- and stimulus-specific. |
19023457 | Self-association of Chaetopterus variopedatus sperm histone H1-like. Relevance of arginine content and possible physiological role. | Self-association of histones H1 from calf thymus and from sperm of the marine worm Chaetopterus variopedatus was studied on native and glutaraldehyde cross-linked molecules by PAGE and by salt-induced turbidity measurements. Multiple polymers were generated by native sperm histone H1-like after glutaraldehyde cross-linking while the same treatment on its lysine- or arginine-modified derivatives and on somatic histone H1 failed to induce polymerization. This result suggests the relevance of arginine content in the formation of histone H1-like polymers particularly because Chaetopterus variopedatus and calf thymus histones H1 have similar content of lysine but different K/R ratio (2 and 15, respectively). Salt-induced turbidity experiments confirmed the high tendency of sperm histone H1-like to form oligomers, particularly in the presence of phosphate ions. Native PAGE analysis in the presence of phosphate supported this hypothesis. The reported results suggest that phosphate ions connecting lysine and arginine side chain groups contribute to the interaction of sperm histone H1-like with DNA in chromatin and play a key role in organization and stabilization of the chromatin higher order structures. |
19023462 | Microchip-based cell analysis and clinical diagnosis system. | Cell analysis and clinical diagnosis systems are now ing the largest field of application for microchip-based analytical systems. Technological advantages include: small volume, fast analysis time, highly integrated analytical functions, easy operation and small size. For these purposes, basic methodologies for general micro-integration and basic technologies, including fluidic control and ultrasensitive detection, are required. In this review, we introduce our approach to the general integration of various analytical functions and the application of cell analysis systems with cultured cells in microchannels, as well as practical analytical systems for clinical diagnosis utilizing human serum samples. |