Social-ecological influences on interpersonal support in people with physical disability.
People with physical disability report lower amounts of emotional and informational social support compared with other populations but it is unclear how influences at the broader societal level impact support in this population. To address this question, Berkman and Glass's social-ecological model was used to examine the influence of upstream factors on interpersonal support in people with physical disability. It was predicted that these factors would influence support even after controlling for the traditional measures linked to social support. 331 adult participants with physical disability (43% female; mean age = 42.7; 88% White) completed an online cross-sectional survey measuring types and sources of social support, social integration, disability impact in social domains, environmental barriers, and relevant psychosocial variables such as depression. A hierarchical linear regression analysis showed that level of disability, perceived tangible support, social integration, depressive symptoms, environmental barriers, occupational independence, and having family or friends as primary support sources were significantly associated with perceived support at the final step (R(2) = .60, F(22, 255) = 17.68, p < .001). The social-ecological measures, environmental barriers and social integration, had the largest associations with interpersonal support. Results demonstrate the importance of measuring distinct support constructs and how the broader social environment may matter more in interpersonal support perceptions for people with disability than typical measures studied in the literature. Improving environmental factors will help improve social support.


The clinical significance of PYCR1 expression in renal cell carcinoma.
Pyrroline-5-carboxylate reductase 1 (PYCR1) is an enzyme involved in cell metabolism and is upregulated in cancer. However, the correlations of PYCR1 expression with the clinicopathological features and prognosis of renal cell carcinoma (RCC) remain unclear. The purpose of this study was to identify the expression of PYCR1 and its clinical relevance in RCC patients.PYCR1 mRNA expression differences between RCC and the adjacent normal renal tissues were assessed using the Cancer Genome Atlas database (TCGA). Subsequently, the expression of PYCR1 mRNA and protein were evaluated by quantitative real-time polymerase chain reaction, Western blot, and immunochemistry using 30 paired frozen samples of RCC and the adjacent normal renal tissues. The protein expression of PYCR1 was evaluated by immunostaining formalin-fixed, paraffin-embedded sections of RCC samples from 96 patients who underwent radical nephrectomy, and its relationship with clinical features were analyzed. Nonpaired t tests were used to statistically analyze the differences between the 2 groups. Cox univariable and multivariable analyses of overall survival (OS) among RCC patients were performed.The expression of PYCR1 mRNA was significantly upregulated in RCC tissues compared to adjacent normal renal tissues in the TCGA database (P < .01). The area under the receiver operating characteristic curve value was 0.748. The expression of PYCR1 mRNA and protein was significantly upregulated in RCC compared with that in paired normal renal tissues (P < .01). Higher PYCR1 levels were associated with metastasis (P < .01). Kaplan-Meier survival curves indicated that higher PYCR1 expression was correlated with poorer OS. Therefore, PYCR1 may act as a novel prognostic marker and therapeutic target in the diagnosis and treatment of RCC.


Investigating the Role of Interpersonal Sensitivity, Anger, and Perfectionism in Social Anxiety.
The investigation of personality characteristics and emotional experiences of the people suffering from anxiety disorders is one of the most important issues which are considered by researchers and clinicians. Perfectionism, sensitivity to interpersonal rejection, and anger are personality traits related to social anxiety. In social anxiety disorder, it has also been focused on anger as a personality characteristic and as an emotional condition. The main purpose of this work is to investigate the role of these variables in predicting social anxiety among a nonclinical group of Iranian students. In this cross-sectional study, 131 students completed the self-report version of Liebowitz Social Anxiety Scale Self-Report version (LSAS-SR), Frost Multidimensional Perfectionism Scale (FMPS), Interpersonal Sensitivity Measure (IPSM), and State and Trait Anger Expression Inventory. Multiple linear regressions were conducted to examine the concurrent associations between perfectionism, interpersonal sensitivity and quality of emotional experience, and expression of anger with severity of self-report social anxiety. Greater levels of FMPS total were significantly associated with a greater level of LSAS total, fear, and avoidance of social and functional situations (P = 0.022, P = 0.024, and P = 0.006). Moreover, a significant positive correlation between IPSM total (P = 0.015) with fear and also between anger expression index (P = 0.009) with avoidance subscale were found. In accordance to the previous researches, we found that perfectionism, interpersonal sensitivity, anger experience, and anger expression skills are related to social anxiety. How these personality traits are related to fear and avoidance of social situations and their concurrent effects on predicting social anxiety were discussed.


Neural stem cells and cell replacement therapy: making the right cells.
The past few years have seen major advances in the field of NSC (neural stem cell) research with increasing emphasis towards its application in cell-replacement therapy for neurological disorders. However, the clinical application of NSCs will remain largely unfeasible until a comprehensive understanding of the cellular and molecular mechanisms of NSC fate specification is achieved. With this understanding will come an increased possibility to exploit the potential of stem cells in order to manufacture transplantable NSCs able to provide a safe and effective therapy for previously untreatable neurological disorders. Since the pathology of each of these disorders is determined by the loss or damage of a specific neural cell population, it may be necessary to generate a range of NSCs able to replace specific neurons or glia rather than generating a generic NSC population. Currently, a diverse range of strategies is being investigated with this goal in mind. In this review, we focus on the relationship between NSC specification and differentiation and discuss how this information may be used to direct NSCs towards a particular fate.


Ultra-low friction between boundary layers of hyaluronan-phosphatidylcholine complexes.
The boundary layers coating articular cartilage in synovial joints constitute unique biomaterials, providing lubricity at levels unmatched by any human-made materials. The underlying molecular mechanism of this lubricity, essential to joint function, is not well understood. Here we study the interactions between surfaces bearing attached hyaluronan (hyaluronic acid, or HA) to which different phosphatidylcholine (PC) lipids had been added, in the form of small unilamellar vesicles (SUVs or liposomes), using a surface force balance, to shed light on possible cartilage boundary lubrication by such complexes. Surface-attached HA was complexed with different PC lipids (hydrogenated soy PC (HSPC), 1,2-dimyristoyl-sn-glycero-3-PC (DMPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-PC (POPC)), followed by rinsing. Atomic force microscopy (AFM) and cryo-scanning electron microscopy (Cryo-SEM) were used to image the HA-PC surface complexes following addition of the SUVs. HA-HSPC complexes provide very efficient lubrication, with friction coefficients as low as μ∼0.001 at physiological pressures P≈150atm, while HA-DMPC and HA-POPC complexes are efficient only at low P (up to 10-20atm). The friction reduction in all cases is attributed to hydration lubrication by highly-hydrated phosphocholine groups exposed by the PC-HA complexes. The greater robustness at high P of the HSPC (C16(15%),C18(85%)) complexes relative to the DMPC ((C14)2) or POPC (C16, C18:1) complexes is attributed to the stronger van der Waals attraction between the HSPC acyl tails, relative to the shorter or un-saturated tails of the other two lipids. Our results shed light on possible lubrication mechanisms at the articular cartilage surface in joints. Can designed biomaterials emulate the unique lubrication ability of articular cartilage, and thus provide potential alleviation to friction-related joint diseases? This is the motivation behind the present study. The principles of cartilage lubrication have attracted considerable attention for decades, and several models have been proposed to elucidate it, however, the mechanism of this ultralow friction is still not clear. In this paper we explore the recent suggestion that its efficient lubrication arises from boundary layers of hyaluronan-lipid complexes at its surface, in particular exploring a range of different phosphatidylcholines (PCs) mimicking the wide range of PCs in synovial joints. The present study suggests a synergistic lubricating behavior of the different lipids in living joints, and potential treatment directions using such biomaterial complexes for widespread cartilage-friction-related diseases such as osteoarthritis.


Human brain networks: a graph theoretical analysis of cortical connectivity normative database from EEG data in healthy elderly subjects.
Moving from the hypothesis that aging processes modulate brain connectivity networks, 170 healthy elderly volunteers were submitted to EEG recordings in order to define age-related normative limits. Graph theory functions were applied to exact low-resolution electromagnetic tomography on cortical sources in order to evaluate the small-world parameter as a representative model of network architecture. The analyses were carried out in the whole brain-as well as for the left and the right hemispheres separately-and in three specific resting state subnetworks defined as follows: attentional network (AN), frontal network (FN), and default mode network (DMN) in the EEG frequency bands (delta, theta, alpha 1, alpha 2, beta 1, beta 2, gamma). To evaluate the stability of the investigated parameters, a subgroup of 32 subjects underwent three separate EEG recording sessions in identical environmental conditions after a few days interval. Results showed that the whole right/left hemispheric evaluation did not present side differences, but when individual subnetworks were considered, AN and DMN presented in general higher SW in low (delta and/or theta) and high (gamma) frequency bands in the left hemisphere, while for FN, the alpha 1 band was lower in the left with respect to the right hemisphere. It was also evident the test-retest reliability and reproducibility of the present methodology when carried out in clinically stable subjects.Evidences from the present study suggest that graph theory represents a reliable method to address brain connectivity patterns from EEG data and is particularly suitable to study the physiological impact of aging on brain functional connectivity networks.


Role of dietary sulphate in the regulation of methanogenesis in the human large intestine.
Hydrogen produced during colonic fermentation may be excreted, or removed by H2 consuming bacteria such as methanogenic and sulphate reducing bacteria. In vitro, sulphate reducing bacteria compete with methanogenic bacteria for hydrogen when sulphate is present. In this study the hypothesis that sulphate in the diet could alter CH4 production in vivo has been tested. Six methane excreting volunteers were fed a low sulphate diet (1.6 mmol/d) for 34 days with the addition of 15 mmol sodium sulphate from days 11-20. Breath methane was measured and viable counts and metabolic activities of methanogenic bacteria and sulphate reducing bacteria determined in faeces. Whole gut transit time and daily stool weight were also measured. When sulphate was added to the diet, breath methane excretion decreased in three of the subjects while faecal sulphate reduction rates rose from 7.5 (0.5) to 20.3 (4.3) nmol SO4 reduced/h/g faeces. Sulphate reducing bacteria, which were not detected during the control diet, were found and viable counts of methanogenic bacteria fell from 10(7)-10(9)/g faeces to 10(6)/g. Methanogenic counts and breath CH4 recovered after sulphate addition was stopped. No change was found in the other three subjects. Faecal weights and transit times were not different between study periods. It is concluded that methanogenesis is regulated by dietary sulphate if sulphate reducing bacteria are present. Dietary sulphate may allow growth of sulphate reducing bacteria which inhibit the growth of methanogenic bacteria. This may explain the absence of CH4 in the breath of many people in western populations.


Cardiovascular risk-factor reduction in elderly patients with cardiac disease.
As a result of increased numbers of elderly persons in the United States, many of whom have coronary heart disease, the mean age of patients in coronary care programs following a myocardial infarction is now greater than age 65 years. One third of cardiac operations on adults are performed on elderly patients. Despite the fact that in the United States utilization of interventions such as coronary artery bypass grafting and angioplasty is on the rise in elderly patients, there appears to be some reluctance to manage risk factors in this group. The four major modifiable risk factors for the development and progression of coronary artery disease are hypertension, hypercholesterolemia, habitual smoking, and physical infectivity. The effectiveness of risk-factor modification for the secondary prevention of events of cardiac morbidity and mortality has been described for younger persons; however, less is known for elderly persons. The purpose of this review is to focus on these four major risk factors in elderly patients with cardiac disease by describing the effectiveness of modification of these factors, methods for doing so, and considerations for the future of such interventions.


Widely tunable persistent micelle templates via homopolymer swelling.
The combination of precision control with wide tunability remains a challenge for the fabrication of porous nanomaterials suitable for studies of nanostructure-behavior relationships. Polymer micelle templates broadly enable porous materials, however micelle equilibration hampers independent pore and wall size control. Persistent micelle templates (PMT) have emerged as a kinetic controlled platform that uniquely decouples the control of pore and wall dimensions. Here, chain exchange is inhibited to preserve a constant template dimension (pore size) despite the shifting equilibrium while materials are added between micelles. Early PMT demonstrations were synthesis intensive with limited 1-1.3× pore size tuning for a given polymer. Here we demonstrate PMT swelling with homopolymer enables 1-3.2× (13.3-41.9 nm) pore size variation while maintaining a monomodal distribution with up to 250 wt% homopolymer, considerably higher than the ∼90 wt% limit found for equilibrating micelles. These swollen PMTs enabled nanomaterial series with constant pore size and precision varied wall-thickness. Kinetic size control here is unexpected since the homopolymer undergoes dynamic exchange between micelles. The solvent selection influenced the time window before homopolymer phase separation, highlighting the importance of considering homopolymer-solvent interactions. This is the first PMT demonstration with wide variation of both the pore and wall dimensions using a single block polymer. Lastly this approach was extended to a 72 kg mol-1 block polymer to enable a wide 50-290 nm range of tunable macropores. Here the use of just two different block polymers and one homopolymer enabled wide ranging pore sizes spanning from 13.3-290 nm (1-22×).


Variability of the midfacial muscles: analysis of 50 hemifacial cadaver dissections.
The region of the midface represents a challenging area to both reconstructive and aesthetic surgeons. An anatomic study was performed that attempted to identify patterns and variations of the muscular anatomy. The goals of this study were twofold: to identify patterns and variability of the midfacial muscles that might impact on reconstructive efforts and to attempt to correlate this anatomy with features of the overlying soft tissues, specifically the nasolabial crease. Fifty hemifacial cadaver dissections were performed. The information collected was assembled into a large data base, and statistical significance was analyzed using Fisher's exact probability test. Results demonstrated that, although a great degree of variability exists with respect to the midfacial muscles, seven distinct patterns of these muscles did emerge. The most common pattern was the presence of a levator alae nasi, levator labii superioris, and zygomaticus major, which occurred in 44 percent of specimens. Specimens that possessed a risorius, zygomaticus minor, or both, were relatively uncommon. The consistent presence of the levators suggests adding a superior vector to recreate a smile in facial reanimation surgery. Two important anatomic variations were noted. A bifid zygomaticus major was found to be present in 34 percent of individuals. Because the inferior bundle had a dermocutaneous insertion, this anomaly may represent the anatomic correlate of a cheek "dimple." A second anomaly noted was the lateral cheek crease, which appeared to be associated with a cutaneous attachment from the underlying platysma muscle. However, no correlation could be found for facial muscle pattern and the overlying nasolabial crease structure. This lack of correlation may indicate that the facial muscles alone do not dictate the structure of the nasolabial crease and that other dynamic factors are involved in determining this feature of the aging face.


Quantum supremacy using a programmable superconducting processor.
The promise of quantum computers is that certain computational tasks might be executed exponentially faster on a quantum processor than on a classical processor1. A fundamental challenge is to build a high-fidelity processor capable of running quantum algorithms in an exponentially large computational space. Here we report the use of a processor with programmable superconducting qubits2-7 to create quantum states on 53 qubits, corresponding to a computational state-space of dimension 253 (about 1016). Measurements from repeated experiments sample the resulting probability distribution, which we verify using classical simulations. Our Sycamore processor takes about 200 seconds to sample one instance of a quantum circuit a million times-our benchmarks currently indicate that the equivalent task for a state-of-the-art classical supercomputer would take approximately 10,000 years. This dramatic increase in speed compared to all known classical algorithms is an experimental realization of quantum supremacy8-14 for this specific computational task, heralding a much-anticipated computing paradigm.


Health sensitivity: Age differences in the within-person coupling of individuals' physical health and well-being.
Well-being and physical health are central indicators of quality of life in old age. Research from a between-person difference perspective finds that people in better health than their peers also report higher well-being than their peers. However, we know very little about whether changes in one domain are accompanied by changes in the other domain, particularly at the within-person level. In the present study, we introduce the construct of health sensitivity, that is, how susceptible an individuals' well-being is to changes in physical health. In doing so, we used 9-wave longitudinal data covering 17 years from the Health and Retirement Study (N = 21,689; 50-109 year olds; 55% women) and applied multilevel modeling to examine the covariation of central indicators of well-being (depressive affect) and health (functional limitations) simultaneously at both the between-person and within-person level. At the within-person level, we found evidence of health sensitivity-on occasions when a typical person experienced more functional limitations than usual, he or she also reported more depressive affect-and that health sensitivity decreased with age. Survival analysis revealed that health sensitivity was related to mortality hazards, controlling for mean levels of health and well-being. We discuss the theoretical importance of examining within-person associations between health and well-being and consider practical implications. (PsycINFO Database Record


Cannabis for inflammatory bowel disease.
The marijuana plant Cannabis sativa has been used for centuries as a treatment for a variety of ailments. It contains over 60 different cannabinoid compounds. Studies have revealed that the endocannabinoid system is involved in almost all major immune events. Cannabinoids may, therefore, be beneficial in inflammatory disorders. In murine colitis, cannabinoids decrease histologic and microscopic inflammation. In humans, cannabis has been used to treat a plethora of gastrointestinal problems, including anorexia, emesis, abdominal pain, diarrhea, and diabetic gastroparesis. Despite anecdotal reports on medical cannabis in inflammatory bowel disease (IBD), there are few controlled studies. In an observational study in 30 patients with Crohn's disease (CD), we found that medical cannabis was associated with improvement in disease activity and reduction in the use of other medications. In a more recent placebo-controlled study in 21 chronic CD patients, we showed a decrease in the CD activity index >100 in 10 of 11 subjects on cannabis compared to 4 of 10 on placebo. Complete remission was achieved in 5 of 11 subjects in the cannabis group and 1 of 10 in the placebo group. Yet, in an additional study, low-dose cannabidiol did not have an effect on CD activity. In summary, evidence is gathering that manipulating the endocannabinoid system can have beneficial effects in IBD, but further research is required to declare cannabinoids a medicine. We need to establish the specific cannabinoids, as well as appropriate medical conditions, optimal dose, and mode of administration, to maximize the beneficial effects while avoiding any potential harmful effects of cannabinoid use.


Automated lipid identification and quantification by multidimensional mass spectrometry-based shotgun lipidomics.
This article presents the strategies underlying the automated identification and quantification of individual lipid molecular species through array analysis of multidimensional mass spectrometry-based shotgun lipidomics (MDMS-SL) data, which are acquired directly from lipid extracts after direct infusion and intrasource separation. The automated analyses of individual lipid molecular species in the program employ a strategy in which MDMS-SL data from building block analyses using precursor ion scans, neutral loss scans, or both are used to identify individual molecular species, followed by quantitation. Through this strategy, the program screens and identifies species in a high-throughput fashion from a built-in database of over 36,000 potential lipid molecular species constructed employing known building blocks. The program then uses a two-step procedure for quantitation of the identified species possessing a linear dynamic range over 3 orders of magnitude and reverifies the results when necessary through redundant quantification of multidimensional mass spectra. This program is designed to be easily adaptable for other shotgun lipidomics approaches that are currently used for mass spectrometric analysis of lipids. Accordingly, the development of this program should greatly accelerate high-throughput analysis of lipids using MDMS-based shotgun lipidomics.


ABCB1 gene polymorphisms are associated with the severity of major depressive disorder and its response to escitalopram treatment.
ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1) is a drug transporter protein expressed on the epithelial cells of the intestine and the endothelial cells of the blood-brain barrier. Intestinal ABCB1 actively transports drugs from the cell membrane and prevents them from entering the blood stream whereas the blood-brain barrier ABCB1 prevents drugs from entering the central nervous system. In this study, we tested whether genetic polymorphisms within the ABCB1 gene are associated with the severity of depression and the effectiveness of the antidepressant, escitalopram (S-CIT), in treating major depressive disorder (MDD). Twenty single nucleotide polymorphisms in the ABCB1 gene were selected and genotyped in 100 MDD patients who had undergone S-CIT treatment continuously for 8 weeks. The serum concentrations of S-CIT and its metabolites (S-desmethylcitalopram and S-didesmethylcitalopram) were then measured at weeks 2, 4, and 8. The ABCB1 genotypes of rs1922242 (P=0.0028) and rs1202184 (P=0.0021) showed significant association with the severity of depressive symptoms as assessed by the Hamilton Rating Scale for Depression adjusted with Hamilton Rating Scale for Anxiety. The haplotype block, rs1882478-rs2235048-rs2235047-rs1045642-rs6949448 (from intron 27 to intron 26), of ABCB1 was found strongly associated with the remission rate (global P=0.003, d.f.=69) in which haplotype T-T-T-C-C was associated with a slower remission rate on S-CIT treatment (P=0.001). The haplotypes may not be indicators of the severity of depression or anxiety. Our findings suggest that single nucleotide polymorphisms in the ABCB1 gene may be indicators of the severity of depression and of the likely S-CIT treatment remission response in MDD.


Phytochemicals Approach for Developing Cancer Immunotherapeutics.
Phytochemicals or their derived compounds are being increasingly recognized as potentially potent complementary treatments for cancer. Among them, some phytochemicals are being actively evaluated for use as adjuvants in anticancer therapies. For instance, shikonin and hypericin were found to induce immunogenic cell death of specific cancer cells, and this effect was able to further activate the recognition activity of tumor cells by the host immune system. On the other hand, some derivatives of phytochemicals, such as dihydrobenzofuran lignan (Q2-3) have been found to induce the secretion of an endogenous anticancer factor, namely IL-25, from non-malignant cells. These findings suggest that phytochemicals or their derivatives confer a spectrum of different pharmacological activities, which contrasts with the current cytotoxic anticancer drugs commonly used in clinics. In this review, we have collected together pertinent information from recent studies about the biochemical and cellular mechanisms through which specific phytochemicals regulate target immune systems in defined tumor microenvironments. We have further highlighted the potential application of these immunotherapeutic modifiers in cell-based cancer vaccine systems. This knowledge provides useful technological support and know how for future applications of phytochemicals in cancer immunotherapy.


Exertional rhabdomyolysis: attrition through exercise, a case series and review of the literature.
Rhabdomyolysis is a common syndrome that can range from asymptomatic to a severe life-threatening condition. It is the result of acute muscle fiber necrosis leading to cell lysis and subsequent transfer of those byproducts into the circulatory system.1-3 The most significant constituent of these byproducts is myoglobin, which has been known to cause renal failure in 10?50% of patients that develop rhabdomyolysis.4,5 In addition, the electrolytes contained within these cells are leached into the blood stream, which can lead to significant electrolyte abnormalities. The etiology of rhabdomyolysis is broad and includes inherited diseases, drugs, toxins, muscle compression or overexertion, infections, and more. This syndrome may carry a mortality rate ranging from 7?80%.3,6 We describe five patients assigned to various companies within 160th Special Operations Aviation Regiment (Airborne) that developed exertional rhabdomyolysis of the bilateral upper extremities between June 2011 and January 2012. In this case series we will describe the events leading up to the diagnosis, lack of risk factors or family history, diagnostic criteria, treatment, and future concerns related to the condition.


Use of enhanced interleukin-2 formulations for improved immunotherapy against cancer.
The use of interleukin-2 (IL-2) for the stimulation of an effector immune response against metastatic cancer dates back to the early 1980s. Administration of unmodified IL-2, either alone or together with antigen-specific approaches, has resulted in remarkably long-term survival of some patients suffering from metastatic melanoma. However, such treatment is usually hampered by the appearance of toxic adverse effects, which has motivated the engineering of modified IL-2 formulations showing reduced toxicity while being more potent at stimulating anti-tumor effector immune cells. In this review we summarize and discuss the features and biological relevance of several enhanced IL-2 formulations, compare these to IL-15-based therapeutics, and try to foreshadow their potential in immunological research and immunotherapy.


Compartmentalization of GABA synthesis by GAD67 differs between pancreatic beta cells and neurons.
The inhibitory neurotransmitter GABA is synthesized by the enzyme glutamic acid decarboxylase (GAD) in neurons and in pancreatic β-cells in islets of Langerhans where it functions as a paracrine and autocrine signaling molecule regulating the function of islet endocrine cells. The localization of the two non-allelic isoforms GAD65 and GAD67 to vesicular membranes is important for rapid delivery and accumulation of GABA for regulated secretion. While the membrane anchoring and trafficking of GAD65 are mediated by intrinsic hydrophobic modifications, GAD67 remains hydrophilic, and yet is targeted to vesicular membrane pathways and synaptic clusters in neurons by both a GAD65-dependent and a distinct GAD65-independent mechanism. Herein we have investigated the membrane association and targeting of GAD67 and GAD65 in monolayer cultures of primary rat, human, and mouse islets and in insulinoma cells. GAD65 is primarily detected in Golgi membranes and in peripheral vesicles distinct from insulin vesicles in β-cells. In the absence of GAD65, GAD67 is in contrast primarily cytosolic in β-cells; its co-expression with GAD65 is necessary for targeting to Golgi membranes and vesicular compartments. Thus, the GAD65-independent mechanism for targeting of GAD67 to synaptic vesicles in neurons is not functional in islet β-cells. Therefore, only GAD65:GAD65 homodimers and GAD67:GAD65 heterodimers, but not the GAD67:GAD67 homodimer gain access to vesicular compartments in β-cells to facilitate rapid accumulation of newly synthesized GABA for regulated secretion and fine tuning of GABA-signaling in islets of Langerhans.


Insect-inspired estimation of egomotion.
Tangential neurons in the fly brain are sensitive to the typical optic flow patterns generated during egomotion. In this study, we examine whether a simplified linear model based on the organization principles in tangential neurons can be used to estimate egomotion from the optic flow. We present a theory for the construction of an estimator consisting of a linear combination of optic flow vectors that incorporates prior knowledge about the distance distribution of the environment and about the noise and egomotion statistics of the sensor. The estimator is tested on a gantry carrying an omnidirectional vision sensor. The experiments show that the proposed approach leads to accurate and robust estimates of rotation rates, whereas translation estimates are of reasonable quality, albeit less reliable.


Calculation of light delay for coupled microrings by FDTD technique and Padé approximation.
The Padé approximation with Baker's algorithm is compared with the least-squares Prony method and the generalized pencil-of-functions (GPOF) method for calculating mode frequencies and mode Q factors for coupled optical microdisks by FDTD technique. Comparisons of intensity spectra and the corresponding mode frequencies and Q factors show that the Padé approximation can yield more stable results than the Prony and the GPOF methods, especially the intensity spectrum. The results of the Prony method and the GPOF method are greatly influenced by the selected number of resonant modes, which need to be optimized during the data processing, in addition to the length of the time response signal. Furthermore, the Padé approximation is applied to calculate light delay for embedded microring resonators from complex transmission spectra obtained by the Padé approximation from a FDTD output. The Prony and the GPOF methods cannot be applied to calculate the transmission spectra, because the transmission signal obtained by the FDTD simulation cannot be expressed as a sum of damped complex exponentials.


Immunoglobulin secretion and phosphorylation of common proteins are induced by IL-2, IL-4, and IL-6 in the factor responsive human B cell line, SKW6.4.
After the binding of IL-2, IL-4, or IL-6 to their respective receptors on activated human B cells, a multistep cascade of intracellular events is initiated that results in the secretion of Ig. However, it is not known whether these different cytokine receptors use common or divergent signal transduction pathways to stimulate Ig secretion. Therefore, we examined the signaling mechanisms used by a human lymphoblastoid cell line arrested at a late stage of differentiation, SKW6.4, that secretes IgM following stimulation with IL-2, IL-4, or IL-6 alone. Our study demonstrated that IL-2, IL-4, and IL-6-stimulation of IgM secretion by SKW6.4 cells was inhibited by either the serine/threonine kinase inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperizine dihydrochloride (H7) or the tyrosine kinase inhibitor, genistein. To investigate the early phosphorylation events initiated by these cytokines, a membrane-enriched preparation from SKW6.4 cells was isolated in a manner that minimized the disruption of membrane protein complexes and then incubated with IL-2, IL-4, or IL-6 in the presence of [gamma-32P]ATP. IL-2, IL-4, and IL-6 stimulated the rapid serine/threonine phosphorylation of 47-, 49-, and 91-kDa proteins. However, in contrast to the 47- and 49-kDa proteins that remained phosphorylated for up to 30 min poststimulation, the 91-kDa protein was rapidly dephosphorylated within 15 min of stimulation. The observation that serine/threonine phosphorylation of the same proteins was stimulated by IL-2, IL-4, and IL-6 suggested that the cytokines activated either different protein kinases with the same substrate specificity or the same protein kinase. In addition, stimulation of intact SKW6.4 cells with either IL-2, IL-4, or IL-6 induced the phosphorylation of two proteins with molecular masses of 45- to 50-kDa and 85 to 90-kDa. Taken together, our data demonstrate that activation of both a serine/threonine kinase and a tyrosine kinase is involved in the IL-2, IL-4, and IL-6-stimulation of IgM secretion by SKW6.4 cells and activation of the same or a similar serine/threonine protein kinase is an early step in the signal transduction pathway used by these cytokines.


Deconstructing isolation-by-distance: The genomic consequences of limited dispersal.
Geographically limited dispersal can shape genetic population structure and result in a correlation between genetic and geographic distance, commonly called isolation-by-distance. Despite the prevalence of isolation-by-distance in nature, to date few studies have empirically demonstrated the processes that generate this pattern, largely because few populations have direct measures of individual dispersal and pedigree information. Intensive, long-term demographic studies and exhaustive genomic surveys in the Florida Scrub-Jay (Aphelocoma coerulescens) provide an excellent opportunity to investigate the influence of dispersal on genetic structure. Here, we used a panel of genome-wide SNPs and extensive pedigree information to explore the role of limited dispersal in shaping patterns of isolation-by-distance in both sexes, and at an exceedingly fine spatial scale (within ~10 km). Isolation-by-distance patterns were stronger in male-male and male-female comparisons than in female-female comparisons, consistent with observed differences in dispersal propensity between the sexes. Using the pedigree, we demonstrated how various genealogical relationships contribute to fine-scale isolation-by-distance. Simulations using field-observed distributions of male and female natal dispersal distances showed good agreement with the distribution of geographic distances between breeding individuals of different pedigree relationship classes. Furthermore, we built coalescent simulations parameterized by the observed dispersal curve, population density, and immigration rate, and showed how incorporating these extensions to Malécot's theory of isolation-by-distance allows us to accurately reconstruct observed sex-specific isolation-by-distance patterns in autosomal and Z-linked SNPs. Therefore, patterns of fine-scale isolation-by-distance in the Florida Scrub-Jay can be well understood as a result of limited dispersal over contemporary timescales.


Glyburide ameliorates motor coordination and glucose homeostasis in a child with diabetes associated with the KCNJ11/S225T, del226-232 mutation.
Gain-of-function mutations of KCNJ11 can cause permanent neonatal diabetes mellitus, but only rarely after 6 months of age. Specific uncommon mutations KCNJ11give rise to a syndrome defined as developmental delay, epilepsy, and neonatal diabetes (DEND), or - more frequently - to a milder sub-type lacking epilepsy, denoted as intermediate-DEND (iDEND). Our aim was to consider a possible monogenic etiology in a 12-yr-old boy with early onset diabetes and mild neurological features. We studied a subject diagnosed with diabetes at 21 months of age, and negative to type 1 diabetes autoantibodies testing. He had learning difficulties during primary school, and a single episode of seizures at the age of 10 yr. We performed direct DNA sequencing of the KCNJ11 gene with subsequent functional study of mutated channels in COSm6 cells. The patient's clinical response to oral glyburide (Glyb) was assessed. Motor coordination was evaluated before and after 6 and 12 months of Glyb therapy. Sequencing of the KCNJ11 gene detected the novel, spontaneous mutation S225T, combined with deletion of amino acids 226-232. In vitro studies revealed that the mutation results in a K(ATP) channel with reduced sensitivity to the inhibitory action of ATP. Glyb improved diabetes control (hemoglobin A1c on insulin: 52 mmol/mol/6.9%; on Glyb: 36 mmol/mol/5.4%) and also performance on motor coordination tests that were impaired before the switch of therapy. We conclude that KCNJ11/S225T, del226-232 mutation caused a mild iDEND form in our patient. KCNJ11 should be considered as the etiology of diabetes even beyond the neonatal period if present in combination with negative autoantibody testing and even mild neurological symptoms.


Applying the Stages of Change model to Type 2 diabetes care in Trinidad: a randomised trial.
To improve glycaemic control among Type 2 diabetics using patient-physician consultations guided by the Stages of Change (SOC) model. A randomised trial was conducted. After ensuring concealment of allocation, Type 2 diabetics were randomly assigned to receive the intervention or the control. The intervention consisted of identifying each patient's Stage of Change for managing their diabetes by diet, exercise and medications, and applying personalised, stage-specific care during the patient-physician consultations based on the SOC model. Patients in the control group received routine care. The variables of interest were effect on glycaemic control (measured by the difference in HbA1c levels) and patients' readiness to change (measured by identifying patients' SOC for managing their diabetes by diet, exercise and medications). Participants were primarily over age 50, male and Indo-Trinidadian. Most had received only a primary school education and over 65% had a monthly income of $320 USD/month or less. Sixty-one Type 2 diabetics participated in each arm. Three patients were lost to follow-up in the intervention arm. After 48 weeks, there was an overall increase in HbA1c of 0.52% (SE 0.17) and 1.09% (SE 0.18) for both the intervention and control groups respectively. There was a relative reduction in HbA1c of 0.57% (95% CI 0.07, 1.07) with the intervention group compared to the control (p = 0.025). For exercise and diet there was an overall tendency for participants in the intervention arm to move to a more favourable SOC, but little change was noted with regards medication use. The result suggests a tendency to a worsening of glycaemic control in this population despite adopting more favourable SOC for diet and exercise. We hypothesized that harsh social conditions prevailing at the time of the study overrode the clinical intervention.


Intrathecal baclofen and muscimol, but not midazolam, are antinociceptive using the rat-formalin model.
Both gamma-aminobutyric acid (GABA)A and GABAB receptor subtypes have been implicated in spinally mediated antinociception in acute pain models. In the current study, the formalin test was used as a model of protracted nociception to examine the effect of intrathecally (i.t.) administered baclofen (GABAB agonist), muscimol (GABAA agonist) or midazolam (a benzodiazepine) on antinociception. At doses that did not affect motor function, baclofen (0.3 and 1.0 micrograms, i.t.) decreased the flinch response in a dose-dependent manner during Phase 1 and Phase 2. This effect was reversible by the GABAB-specific antagonist, CGP35348 ([P-(3-aminopropyl)-P-diethoxymethyl-phosphinic acid]). Muscimol (0.3 and 1.0 microgram i.t.) evoked a dose-dependent, bicuculline-reversible decrease in flinching during Phase 1 and Phase 2, but midazolam had no effect on either phase. No attenuation of the quiescent period between Phase 1 and Phase 2 was seen upon administration of baclofen, muscimol or midazolam. Additionally, no increase in nocifensive behavior was observed upon administration of either GABAA or GABAB antagonists alone. Therefore, our conclusions are that both GABAA and GABAB agonists are antinociceptive at the spinal cord level and that endogenous spinal GABA levels are insufficient for a GABA potentiator to act alone in an antinociceptive manner.


Transport efficiency and workload distribution in a mathematical model of the thick ascending limb.
The thick ascending limb (TAL) is a major NaCl reabsorbing site in the nephron. Efficient reabsorption along that segment is thought to be a consequence of the establishment of a strong transepithelial potential that drives paracellular Na(+) uptake. We used a multicell mathematical model of the TAL to estimate the efficiency of Na(+) transport along the TAL and to examine factors that determine transport efficiency, given the condition that TAL outflow must be adequately dilute. The TAL model consists of a series of epithelial cell models that represent all major solutes and transport pathways. Model equations describe luminal flows, based on mass conservation and electroneutrality constraints. Empirical descriptions of cell volume regulation (CVR) and pH control were implemented, together with the tubuloglomerular feedback (TGF) system. Transport efficiency was calculated as the ratio of total net Na(+) transport (i.e., paracellular and transcellular transport) to transcellular Na(+) transport. Model predictions suggest that 1) the transepithelial Na(+) concentration gradient is a major determinant of transport efficiency; 2) CVR in individual cells influences the distribution of net Na(+) transport along the TAL; 3) CVR responses in conjunction with TGF maintain luminal Na(+) concentration well above static head levels in the cortical TAL, thereby preventing large decreases in transport efficiency; and 4) under the condition that the distribution of Na(+) transport along the TAL is quasi-uniform, the tubular fluid axial Cl(-) concentration gradient near the macula densa is sufficiently steep to yield a TGF gain consistent with experimental data.


Current practice in handling and reporting needle biopsies: A hospital-based survey.
Core-needle biopsy (CNB) is a minimally invasive screening and diagnostic tool which provides intact tissue fragments for histopathological examination. This study was conducted to review the current practices of handling and reporting CNBs performed for core-needle biopsies from four organ systems which are frequently encountered in our institution. These include breast, prostate, soft tissues, and lymph nodes. This was a retrospective study conducted at a tertiary care hospital. CNB reports of breast, prostate, soft tissue, and lymph nodes were accessed and categorized based on the site of biopsy, number, and average length of the cores. The CNB reports were categorized into diagnostic or nondiagnostic. In case of diagnosis of malignancy, reports were recorded as structured or nonstructured reports. Fisher's exact test and Chi-square tests were applied to check the significance of the results obtained on comparing the number of cores and size of cores with the outcome of report. Out of 16,300 surgical pathology specimens received, 400 were CNBs comprising breast (n = 211), prostate (n = 108), soft tissue (n = 50), and lymph node (n = 31). Majority of the CNBs had 2-5 cores and the size of the core was ≥0.5 cm, which accounted for most of the reports which were diagnostic. There was a lack of clinical and radiological detail in many of the cases. Out of the malignant cases diagnosed, structured reports were given in 30% of breast, 79.3% of prostate, 41.7% soft tissue, and 60% of lymph node needle biopsies. The audit helped to identify areas of improvement in CNB services.


Physician Burnout and the Calling to Care for the Dying: A National Survey.
Physician burnout raises concerns over what sustains physicians' career motivations. We assess whether physicians in end-of-life specialties had higher rates of burnout and/or calling to care for the dying. We also examined whether the patient centeredness of the clinical environment was associated with burnout. In 2010 to 2011, we conducted a national survey of US physicians from multiple specialties. Primary outcomes were a validated single-item measure of burnout or sense of calling to end-of-life care. Primary predictors of burnout (or calling) included clinical specialty, frequency of encounters with dying patients, and patient centeredness of the clinical environments ("My clinical environment prioritizes the need of the patient over maximizing revenue"). Adjusted response rate among eligible respondents was 62% (1156 of 1878). Nearly a quarter of physicians (23%) experienced burnout, and rates were similar across all specialties. Half of the responding physicians (52%) agreed that they felt called to take care of patients who are dying. Burned-out physicians were more likely to report working in profit-centered clinical environments (multivariate odds ratio [OR] of 1.9; confidence interval [CI]: 1.3-2.8) or experiencing emotional exhaustion when caring for the dying (multivariate OR of 2.1; CI: 1.4-3.0). Physicians who identified their work as a calling were more likely to work in end-of-life specialties, to feel emotionally energized when caring for the dying, and to be religious. Physicians from end-of-life specialties not only did not have increased rates of burnout but they were also more likely to report a sense of calling in caring for the dying.


Fatal disseminated Cryptococcus gattii infection in New Mexico.
We report a case of fatal disseminated infection with Cryptococcus gattii in a patient from New Mexico. The patient had no history of recent travel to known C. gattii-endemic areas. Multilocus sequence typing revealed that the isolate belonged to the major molecular type VGIII. Virulence studies in a mouse pulmonary model of infection demonstrated that the strain was less virulent than other C. gattii strains. This represents the first documented case of C. gattii likely acquired in New Mexico.


Robust model-based analysis of single-particle tracking experiments with Spot-On.
Single-particle tracking (SPT) has become an important method to bridge biochemistry and cell biology since it allows direct observation of protein binding and diffusion dynamics in live cells. However, accurately inferring information from SPT studies is challenging due to biases in both data analysis and experimental design. To address analysis bias, we introduce 'Spot-On', an intuitive web-interface. Spot-On implements a kinetic modeling framework that accounts for known biases, including molecules moving out-of-focus, and robustly infers diffusion constants and subpopulations from pooled single-molecule trajectories. To minimize inherent experimental biases, we implement and validate stroboscopic photo-activation SPT (spaSPT), which minimizes motion-blur bias and tracking errors. We validate Spot-On using experimentally realistic simulations and show that Spot-On outperforms other methods. We then apply Spot-On to spaSPT data from live mammalian cells spanning a wide range of nuclear dynamics and demonstrate that Spot-On consistently and robustly infers subpopulation fractions and diffusion constants.


Phylogeography of Burkholderia pseudomallei Isolates, Western Hemisphere.
The bacterium Burkholderia pseudomallei causes melioidosis, which is mainly associated with tropical areas. We analyzed single-nucleotide polymorphisms (SNPs) among genome sequences from isolates of B. pseudomallei that originated in the Western Hemisphere by comparing them with genome sequences of isolates that originated in the Eastern Hemisphere. Analysis indicated that isolates from the Western Hemisphere form a distinct clade, which supports the hypothesis that these isolates were derived from a constricted seeding event from Africa. Subclades have been resolved that are associated with specific regions within the Western Hemisphere and suggest that isolates might be correlated geographically with cases of melioidosis. One isolate associated with a former World War II prisoner of war was believed to represent illness 62 years after exposure in Southeast Asia. However, analysis suggested the isolate originated in Central or South America.


A Review of Current Patient Matching Techniques.
As healthcare organizations strive to improve quality of care and patient safety, it becomes paramount that they identify patients correctly and match records accurately both within and across institutions. Continuous care and population health benefits can be optimized when providers can have a comprehensive view of a patient's health record through seamless health information exchange. Various patient matching techniques have emerged to facilitate accurate patient identification. In this paper, we present a review of existing patient matching techniques, analyzed based on accuracy, cost and execution time.


Combining Phylogenetic and Network Approaches to Identify HIV-1 Transmission Links in San Mateo County, California.
The HIV epidemic in San Mateo County is sustained by multiple overlapping risk groups and is an important hub for HIV transmission in northern California. Limited access to care has led historically to delayed clinical presentation, higher rates of opportunistic infections, and an increased prevalence of antiretroviral drug resistance. The virologic and clinical consequences of treatment within these multiple ethnic and behavioral groups are poorly understood, highlighting the need for efficient surveillance strategies that are able to elucidate transmission networks and drug resistance patterns. We obtained sequence data from a group of 316 HIV-positive individuals in the San Mateo AIDS Program over a 14-year period and integrated epidemiologic, phylogenetic, and network approaches to characterize transmission clusters, risk factors and drug resistance. Drug resistance mutations were identified using the Stanford HIV Drug Resistance Database. A maximum likelihood tree was inferred in RAxML and subjected to clustering analysis in Cluster Picker. Network analysis using pairwise genetic distances was performed in HIV-TRACE. Participants were primarily male (60%), white Hispanics and non-Hispanics (32%) and African American (20.6%). The most frequent behavior risk factor was male-male sex (33.5%), followed by heterosexual (23.4%) and injection drug use (9.5%). Nearly all sequences were subtype B (96%) with subtypes A, C, and CRF01_AE also observed. Sequences from 65% of participants had at least one drug resistance mutation. Clustered transmissions included a higher number of women when compared to non-clustered individuals and were more likely to include heterosexual or people who inject drugs (PWID). Detailed analysis of the largest network (N = 47) suggested that PWID played a central role in overall transmission of HIV-1 as well as bridging men who have sex with men (MSM) transmission with heterosexual/PWID among primarily African American men. Combined phylogenetic and network analysis of HIV sequence data identified several overlapping risk factors in the epidemic, including MSM, heterosexual and PWID transmission with a disproportionate impact on African Americans and a high prevalence of drug resistance.


Data visualization in the neurosciences: overcoming the curse of dimensionality.
In publications, presentations, and popular media, scientific results are predominantly communicated through graphs. But are these figures clear and honest or misleading? We examine current practices in data visualization and discuss improvements, advocating design choices which reveal data rather than hide it.


Genomic variability of within-host hepatitis C variants in acute infection.
Interactions between the host immune system and the viral variants determine persistence of hepatitis C virus (HCV) infection after the acute phase of infection. This study describes the genetic variability of within-host HCV viral variants in acute infection and correlates it with host- and virus-related traits and infection outcome. Next generation sequence data (Illumina, MiSeq platform) of viral genomes from 116 incident acute infections (within 180 days of infection) were analysed to determine all the single nucleotide polymorphism (SNP) frequencies above a threshold of 0.1%. The variability of the SNPs for the full open reading frame of the genome as well as for each protein coding region were compared using mean standardized Shannon entropy (SE) values calculated separately for synonymous and nonsynonymous mutations. The envelope glycoproteins regions (E1 and E2) had the highest SE values (indicating greater variability) followed by the NS5B region. Nonsynonymous mutations rather than synonymous mutations were the main contributors to genomic variability in acute infection. The mean difference of Shannon entropy was also compared between subjects after categorizing the samples according to host and virus-related traits. Host IFNL3 allele CC polymorphism at rs12979860 (vs others) and viral genotype 1a (vs 3a) were associated with higher genomic variability across the viral open reading frame. Time since infection, host gender or continent of origin was not associated with the viral genomic variability. Viral genomic variability did not predict spontaneous clearance.


Multilevel correlates of satisfaction with neighborhood availability of fresh fruits and vegetables.
Little is known about influences on perceptions of neighborhood food environments, despite their relevance for food-shopping behaviors and food choices. This study examined relationships between multilevel factors (neighborhood structure, independently observed neighborhood food environment, and individual socioeconomic position) and satisfaction with neighborhood availability of fruits and vegetables. The multilevel regression analysis drew on data from a community survey of urban adults, in-person audit and mapping of food stores, and the 2000 Census. Satisfaction with neighborhood availability of fruits and vegetables was lower in neighborhoods that were farther from a supermarket and that had proportionately more African-American residents. Neighborhood poverty and independently observed neighborhood fruit and vegetable characteristics (variety, prices, and quality) were not associated with satisfaction. Individual education modified relationships between neighborhood availability of smaller food stores (small grocery stores, convenience stores, and liquor stores) and satisfaction. Individual-level and neighborhood-level factors affect perceptions of neighborhood food environments.


A single subtype of avian pneumovirus circulates among Minnesota turkey flocks.
The recent emergence of avian pneumovirus (APV) infection among US turkey flocks has resulted in a major economic threat to the turkey industry. In order to elucidate the molecular epidemiology of APV, comparative sequence analysis of the fusion (F) protein gene of APV was performed for 3 cell culture-adapted isolates and 10 APV positive clinical samples recovered from US turkey flocks. Relatively modest levels of nucleotide and amino acid sequence divergence were identified, suggesting the prevalence of a single lineage of APV among US turkey flocks. Additionally, numerous polymorphisms were identified that were only represented in the clinical samples but not in the in vitro propagated isolates of APV. Phylogenetic analyses confirm that the subtype of APV circulating in the upper Midwestern United States is evolutionarily related to, but distinct from, European APV subgroups A and B. Overall, the results of the present investigation suggest that there has been only a single recent introduction of APV into US turkey populations in the upper Midwestern United States.


A clinicopathologic study of 81 patients with ependymomas and proposal of diagnostic criteria for anaplastic ependymoma.
Optimal histologic criteria for the classification of and grading of ependymomas, including their anaplastic forms, remain elusive. This is especially true because of the poor correlation of these criteria with clinical outcome. The aim of this study was to identify the histopathologic parameters that could distinguish different prognostic groups of patients with ependymomas. Eighty-one patients with ependymal tumors, including those originally diagnosed ependymomas, anaplastic ependymomas and myxopapillary ependymomas, were enrolled in this study. Thirteen histologic parameters, including hypercellularity, nuclear pleomorphism, mitoses, endothelial proliferation, necrosis, clear cell, thrombi, dystrophic calcification, psammoma bodies, bone, cartilage, Rosenthal fibers and MIB-1 labeling index (LI), were evaluated in each patient and correlated with clinical outcome. We assigned one score for each histopathologic parameter evaluated and used a stepwise selection method with entry model based on the significance of the log-rank statistic to formulate a scoring model. Four parameters were chosen in this process, including mitoses > or = 4/10 hpf (1.7/mm2), hypercellularity, endothelial proliferation and necrosis. The sum of these four parameters (scores) was the histopathologic score of the tumor. The progression-free survival (PFS) and overall survival (OS) of patients with histopathologic scores 0 and 1 were significantly better than those with histopathologic scores 2, 3 and 4 (p < 0.001 and p = 0.005, respectively). Because of the latter finding, we proposed that anaplastic ependymoma could be diagnosed by the presence of any two of the aforementioned four parameters. Multivariate analyses including clinical and histopathologic variables showed that histopathologic score > or = 2 and subtotal resection were the factors related to increased risk of recurrence, while histopathologic score > or = 2 was the only factor related to overall survival. Based on the above findings, we concluded that histopathology is an important prognostic indicator for patients with ependymomas.


Flavones Inhibit LPS-Induced Atrogin-1/MAFbx Expression in Mouse C2C12 Skeletal Myotubes.
Muscle atrophy is a complex process that occurs as a consequence of various stress events. Muscle atrophy-associated genes (atrogenes) such as atrogin-1/MAFbx and MuRF-1 are induced early in the atrophy process, and the increase in their expression precedes the loss of muscle weight. Although antioxidative nutrients suppress atrogene expression in skeletal muscle cells, the inhibitory effects of flavonoids on inflammation-induced atrogin-1/MAFbx expression have not been clarified. Here, we investigated the inhibitory effects of flavonoids on lipopolysaccharide (LPS)-induced atrogin-1/MAFbx expression. We examined whether nine flavonoids belonging to six flavonoid categories inhibited atrogin-1/MAFbx expression in mouse C2C12 myotubes. Two major flavones, apigenin and luteolin, displayed potent inhibitory effects on atrogin-1/MAFbx expression. The pretreatment with apigenin and luteolin significantly prevented the decrease in C2C12 myotube diameter caused by LPS stimulation. Importantly, the pretreatment of LPS-stimulated myoblasts with these flavones significantly inhibited LPS-induced JNK phosphorylation in C2C12 myotubes, resulting in the significant suppression of atrogin-1/MAFbx promoter activity. These results suggest that apigenin and luteolin, prevent LPS-mediated atrogin-1/MAFbx expression through the inhibition of the JNK signaling pathway in C2C12 myotubes. Thus, these flavones, apigenin and luteolin, may be promising agents to prevent LPS-induced muscle atrophy.


Effects of hydrogen peroxide on isolated trachealis muscle of horses.
During acute bouts of recurrent airway obstruction (heaves) in horses, neutrophils that are capable of increased production of reactive oxygen species accumulate in the airways. In the study reported here, the effect of hydrogen peroxide (H2O2; 1 microM to 0.1M), one of these reactive oxygen species products, on the responses of isolated trachealis muscle of horses was determined. Before and after incubation with H2O2, contractile responses to acetylcholine, electrical field stimulation (EFS), 127 mM KCl, and relaxation responses to isoproterenol and activation of the nonadrenergic noncholinergic inhibitory response (iNANC) were evaluated. Beginning at 1 mM, H2O2 contracted trachealis muscle in a concentration-dependent manner. This contraction was unaffected by atropine (1 microM), tetrodotoxin (1 microM), or 1 microM meclofenamate. Contraction of trachealis muscle in response to H2O2 is, therefore, not attributable to release of prostaglandins, acetylcholine, or other neurotransmitters. Above a concentration of 0.1 mM, H2O2 depressed the responses to EFS, acetylcholine, and KCl in a concentration-dependent manner. At 0.1M, H2O2 decreased the maximal responses to EFS, acetylcholine, and KCl by 62.7 +/- 7.2, 60.58 +/- 6.12, and 37.8 +/- 9.54%, respectively. In the presence of meclofenamate (1 microM), partial but significant protection against 1 to 100 mM H2O2 was observed. In tracheal strips contracted with 0.3 microM methacholine, H2O2 had no effect on the isoproterenol concentration-response curve. Up to a concentration of 100 mM, H2O2 had no effect on iNANC response. However, in the presence of 100 mM H2O2, this response was abolished in 2 of 4 horses. We conclude that high concentrations of H2O2 affected the responses of airway smooth muscle by actions on neurotransmission, muscarinic receptors, and downstream from receptors; some of the H2O2 effects were in part mediated by cyclooxygenase products; and H2O2 had no effect on beta-adrenergic- or iNANC-induced relaxation.


Major Threat to Malaria Control Programs by Plasmodium falciparum Lacking Histidine-Rich Protein 2, Eritrea.
False-negative results for Plasmodium falciparum histidine-rich protein (HRP) 2-based rapid diagnostic tests (RDTs) are increasing in Eritrea. We investigated HRP gene 2/3 (pfhrp2/pfhrp3) status in 50 infected patients at 2 hospitals. We showed that 80.8% (21/26) of patients at Ghindae Hospital and 41.7% (10/24) at Massawa Hospital were infected with pfhrp2-negative parasites and 92.3% (24/26) of patients at Ghindae Hospital and 70.8% (17/24) at Massawa Hospital were infected with pfhrp3-negative parasites. Parasite densities between pfhrp2-positive and pfhrp2-negative patients were comparable. All pfhrp2-negative samples had no detectable HRP2/3 antigen and showed negative results for HRP2-based RDTs. pfhrp2-negative parasites were genetically less diverse and formed 2 clusters with no close relationships to parasites from Peru. These parasites probably emerged independently by selection in Eritrea. High prevalence of pfhrp2-negative parasites caused a high rate of false-negative results for RDTs. Determining prevalence of pfhrp2-negative parasites is urgently needed in neighboring countries to assist case management policies.


OpenMS: a flexible open-source software platform for mass spectrometry data analysis.
High-resolution mass spectrometry (MS) has become an important tool in the life sciences, contributing to the diagnosis and understanding of human diseases, elucidating biomolecular structural information and characterizing cellular signaling networks. However, the rapid growth in the volume and complexity of MS data makes transparent, accurate and reproducible analysis difficult. We present OpenMS 2.0 (http://www.openms.de), a robust, open-source, cross-platform software specifically designed for the flexible and reproducible analysis of high-throughput MS data. The extensible OpenMS software implements common mass spectrometric data processing tasks through a well-defined application programming interface in C++ and Python and through standardized open data formats. OpenMS additionally provides a set of 185 tools and ready-made workflows for common mass spectrometric data processing tasks, which enable users to perform complex quantitative mass spectrometric analyses with ease.


Why do festival goers drink? Assessment of drinking motives using the DMQ-R SF in a recreational setting.
The aim of this study is to confirm the four-dimensional structure and other measurement properties of the Drinking Motives Questionnaire Revised Short Form (DMQ-R SF) among young Hungarian adults in a recreational setting. In a 'Health Tent' at Europe's biggest music and cultural festival, 390 attendees (mean age 23.6, SD = 4.4) completed the DMQ-R SF and answered other alcohol-related questions. Data were analysed by confirmatory factor analysis, repeated measures anova and structural equation modelling. The results confirmed the good measurement properties of the DMQ-R SF in terms of factor loadings, model fit and internal consistency. These statistics were similar for men and women. For both genders, social motives were the most frequently indicated motivational dimension, followed by coping, conformity and enhancement. Social motives were consistently related to drinking, and coping to alcohol-related problems. It seems that the DMQ-R SF is a useful instrument for measuring the motivation to engage in drinking in recreational settings, such as parties, clubs and festivals, where hard-to-reach target groups vulnerable to risky drinking behaviour are present, but time for filling out questionnaires is restricted.


Predictive validity of a three-dimensional model of performance anxiety in the context of tae-kwon-do.
We tested the predictive validity of the recently validated three-dimensional model of performance anxiety (Chang, Hardy, & Markland, 2009) with elite tae-kwon-do competitors (N = 99). This conceptual framework emphasized the adaptive potential of anxiety by including a regulatory dimension (reflected by perceived control) along with the intensity-oriented dimensions of cognitive and physiological anxiety. Anxiety was assessed 30 min before a competitive contest using the Three-Factor Anxiety Inventory. Competitors rated their performance on a tae-kwon-do-specific performance scale within 30 min after completion of their contest. Moderated hierarchical regression analyses revealed initial support for the predictive validity of the three-dimensional performance anxiety model. The regulatory dimension of anxiety (perceived control) revealed significant main and interactive effects on performance. This dimension appeared to be adaptive, as performance was better under high than low perceived control, and best vs. worst performance was associated with highest vs. lowest perceived control, respectively. Results are discussed in terms of the importance of the regulatory dimension of anxiety.


Managing borders during public health emergencies of international concern: a proposed typology of cross-border health measures.
The near universal adoption of cross-border health measures during the COVID-19 pandemic worldwide has prompted significant debate about their effectiveness and compliance with international law. The number of measures used, and the range of measures applied, have far exceeded previous public health emergencies of international concern. However, efforts to advance research, policy and practice to support their effective use has been hindered by a lack of clear and consistent definition. Based on a review of existing datasets for cross-border health measures, such as the Oxford Coronavirus Government Response Tracker and World Health Organization Public Health and Social Measures, along with analysis of secondary and grey literature, we propose six categories to define measures more clearly and consistently - policy goal, type of movement (travel and trade), adopted by public or private sector, level of jurisdiction applied, stage of journey, and degree of restrictiveness. These categories are then brought together into a proposed typology that can support research with generalizable findings and comparative analyses across jurisdictions. Addressing the current gaps in evidence about travel measures, including how different jurisdictions apply such measures with varying effects, in turn, enhances the potential for evidence-informed decision-making based on fuller understanding of policy trade-offs and externalities. Finally, through the adoption of standardized terminology and creation of an agreed evidentiary base recognized across jurisdictions, the typology can support efforts to strengthen coordinated global responses to outbreaks and inform future efforts to revise the WHO International Health Regulations (2005). The widespread use of cross-border health measures during the COVID-19 pandemic has prompted significant reflection on available evidence, previous practice and existing legal frameworks. The typology put forth in this paper aims to provide a starting point for strengthening research, policy and practice.


Dietary patterns and heritability of food choice in a UK female twin cohort.
To examine the contribution of genetic factors to food choice, we determined dietary patterns from food frequency questionnaires in 3262 UK female twins aged 18 to 79 years. Five distinct dietary patterns were identified (fruit and vegetable, high alcohol, traditional English, dieting, low meat) that accounted for 22% of the total variance. These patterns are similar to those found in other singleton Western populations, and were related to body mass index, smoking status, physical activity and deprivation scores. Older subjects had higher scores on the fruit and vegetable and traditional English patterns, while lower social deprivation was associated with higher scores for fruit and vegetable, and lower scores for traditional English patterns. All 5 patterns were heritable, with estimates ranging from 41% to 48%. Among individual dietary components, a strongly heritable component was identified for garlic (46%), coffee (41%), fruit and vegetable sources (49%), and red meat (39%). Our results indicate that genetic factors have an important influence in determining food choice and dietary habits in Western populations. The relatively high heritability of specific dietary components implicates taste perception as a possible target for future genetic studies.


Increasing illness among people out of labor market - A Danish register-based study.
In spite of decades of very active labor market policies, 25% of Denmark's population in the working ages are still out-of-work. The aim of this study was to investigate whether that is due to consistent or even increasing prevalence of ill health. For the period of 2002-2011, we investigated if i) the prevalence of four chronic diseases (cardiovascular disease, diabetes, cancer and mental disorders) among those out-of-work had changed, ii) the occurrence of new cases of those diseases were higher among those who were already out-of-work, or iii) if non-health-related benefits were disproportionately given to individuals recently diagnosed with a disease compared to those without disease. The study was register-based and comprised all Danish residents aged 20-60. During the study period, the prevalence of cardiovascular diseases and mental disorders increased among both employed and non-employed people. The increased prevalence for mental disorder was particularly high among people receiving means-tested benefits. Disease incidence was higher among people outside rather than inside the labor market, especially for mental disorders. Employed people with incident diseases had an unsurprisingly increased risk of leaving the labor market. However, a high proportion of people with incident mental disorders received low level means-tested benefits in the three years following this diagnosis, which is concerning. Men treated for mental disorders in 2006 had high excess probability of receiving a cash-benefit, OR = 4.83 (4.53-5.14) for the period 2007-2010. The estimates were similar for women.


Cholesterol does not cause coronary heart disease in contrast to stress.
The belief that coronary atherosclerosis is due to high cholesterol from increased saturated fat intake originated from experiments in herbivorous animals. It was reinforced by reports allegedly demonstrating this sequence of events in various populations but ignoring contradictory data. The idea has been perpetuated by powerful forces using similar tactics to preserve the profit and the reputations of those who promote this doctrine. Opponents find it difficult to publish their scientifically supported opinions. The advent of statins has further fuelled this fallacious lipid hypothesis, despite compelling evidence that their effect is not due to cholesterol lowering and that serious side effects have been suppressed and alleged benefits have been hyped. The adverse effects of the cholesterol campaign on health, quality of life, the economy and medical research are inestimable. It is imperative that public health officials, physicians and patients are apprised of proof that it is misguided, malicious and malignant.


MYO15A (DFNB3) mutations in Turkish hearing loss families and functional modeling of a novel motor domain mutation.
Myosin XVA is an unconventional myosin which has been implicated in autosomal recessive nonsyndromic hearing impairment (ARNSHI) in humans. In Myo15A mouse models, vestibular dysfunction accompanies the autosomal recessive hearing loss. Genomewide homozygosity mapping and subsequent fine mapping in two Turkish families with ARNSHI revealed significant linkage to a critical interval harboring a known deafness gene MYO15A on chromosome 17p13.1-17q11.2. Subsequent sequencing of the MYO15A gene led to the identification of a novel missense mutation, c.5492G-->T (p.Gly1831Val) and a novel splice site mutation, c.8968-1G-->C. These mutations were not detected in additional 64 unrelated ARNSHI index patients and in 230 Turkish control chromosomes. Gly1831 is a conserved residue located in the motor domains of the different classes of myosins of different species. Molecular modeling of the motor head domain of the human myosin XVa protein suggests that the Gly1831Val mutation inhibits the powerstroke by reducing backbone flexibility and weakening the hydrophobic interactions necessary for signal transmission to the converter domain.


Thyroid hormone analog 3,5-diiodothyropropionic acid promotes healthy vasculature in the adult myocardium independent of thyroid effects on cardiac function.
Patients with hypothyroidism are at a higher risk for coronary vascular disease. Patients with diabetes and related vascular complications also have an increased incidence of low thyroid function. While thyroid hormones (THs) may be key regulators of a healthy vasculature, potential undesirable side effects hinder their use in the treatment of vascular disorders. TH analogs such as 3,5-diiodothyropropionic acid (DITPA) may provide a safer treatment option. However, the relative potency of DITPA on vascular growth, cardiac function, and metabolism is poorly understood. We hypothesized that the vascular growth-promoting effects of DITPA can be obtained with a minimum effect on cardiac function. Thyroidectomized Sprague-Dawley rats were given slow-release pellets with either thyroxine (T4, 2.7 or 5.2 mg) or DITPA (80 mg) for 6 wk and were compared with placebo. Heart mass, body mass, body temperature, serum THs, cardiac function (echocardiograms and hemodynamics), and myocardial arteriolar density were determined. Hypothyroidism led to reductions in cardiac function, heart mass, body temperature, and myocardial arterioles. High-dose T4 prevented arteriolar loss and the development of hypothyroidism. Low-dose T4 partially prevented the reduction in cardiac function but had minimal effects on arteriolar loss. In contrast, DITPA treatment prevented myocardial arteriolar loss but not the progression of hypothyroid-induced changes in cardiac function. The results suggested that DITPA can promote a healthy vasculature independently from its thyroid-related metabolic effects. Drugs in this class may provide new therapeutic options for patients with vascular disease.


The cost of nurse-sensitive adverse events.
The aim of this study was to describe the methodology for nursing leaders to determine the cost of adverse events and effective levels of nurse staffing. The growing transparency of quality and cost outcomes motivates healthcare leaders to optimize the effectiveness of nurse staffing. Most hospitals have robust cost accounting systems that provide actual patient-level direct costs. These systems allow an analysis of the cost consumed by patients during a hospital stay. By knowing the cost of complications, leaders have the ability to justify the cost of improved staffing when quality evidence shows that higher nurse staffing improves quality. An analysis was performed on financial and clinical data from hospital databases of 3,200 inpatients. The purpose was to establish a methodology to determine actual cost per case. Three diagnosis-related groups were the focus of the analysis. Five adverse events were analyzed along with the costs. A regression analysis reported that the actual direct cost of an adverse event was dollars 1,029 per case in the congestive heart failure cases and dollars 903 in the surgical cases. There was a significant increase in the cost per case in medical patients with urinary tract infection and pressure ulcers and in surgical patients with urinary tract infection and pneumonia. The odds of pneumonia occurring in surgical patients decreased with additional registered nurse hours per patient day. Hospital cost accounting systems are useful in determining the cost of adverse events and can aid in decision making about nurse staffing. Adverse events add costs to patient care and should be measured at the unit level to adjust staffing to reduce adverse events and avoid costs.


Abdominal aortic aneurysm, Leriche's syndrome, inguinal herniation, and smoking.
We previously found an increase in serum proteolytic activity in smokers with direct inguinal herniation and a similar imbalance in smokers with abdominal aortic aneurysm (AAA), but not in smokers with Leriche's syndrome (LS). If the protease imbalance in the blood of smokers with AAA or herniation is a causal factor, these conditions should be associated. Therefore, we determined whether this is true using patients with LS as control subjects. The frequency of inguinal herniation was significantly higher in the AAA population (N = 341; 25.8%) than in patients with LS (N = 417; 14.6%). In addition, patients with AAA had more severe herniation (direct, bilateral, recurrent, or earlier onset) and had more pronounced leukocytosis (9,000/cu mm v 8,190/cu mm). These data suggest that increased blood proteolytic activity may play a role in the development of both AAA and adult inguinal herniation but not LS. Men who smoke manifest different systemic effects.


Simplified White Blood Cell Differential: An Inexpensive, Smartphone- and Paper-Based Blood Cell Count.
Sorting and measuring blood by cell type is extremely valuable clinically and provides physicians with key information for diagnosing many different disease states including: leukemia, autoimmune disorders, bacterial infections, etc. Despite the value, the present methods are unnecessarily costly and inhibitive particularly in resource poor settings, as they require multiple steps of reagent and/or dye additions and subsequent rinsing followed by manual counting using a hemocytometer, or they require a bulky, expensive equipment such as a flow cytometer. While direct on-paper imaging has been considered challenging, paper substrate offers a strong potential to simplify such reagent/dye addition and rinsing. In this work, three-layer paper-based device is developed to automate such reagent/dye addition and rinsing via capillary action, as well as separating white blood cells (WBCs) from whole blood samples. Direct onpaper imaging is demonstrated using a commercial microscope attachment to a smartphone coupled with a blue LED and 500 nm long pass optical filter. Image analysis is accomplished using an original MATLAB code, to evaluate the total WBC count, as well as differential WBC count, i.e., granulocytes (primarily neutrophils) vs. agranulocytes (primarily lymphocytes). Only a finger-prick of whole blood is required for this assay. The total assay time from finger-prick to data collection is under five minutes. Comparison with a hemocytometry-based manual counting corroborates the accuracy and effectiveness of the proposed method. This approach could be potentially used to help make blood cell counting technologies more readily available, especially in resource poor, point-of-care settings.


Abnormal sperm in mice lacking the Taf7l gene.
TFIID is a general transcription factor required for transcription of most protein-coding genes by RNA polymerase II. TAF7L is an X-linked germ cell-specific paralogue of TAF7, which is a generally expressed component of TFIID. Here, we report the generation of Taf7l mutant mice by homologous recombination in embryonic stem cells by using the Cre-loxP strategy. While spermatogenesis was completed in Taf7l(-/Y) mice, the weight of Taf7l(-/Y) testis decreased and the amount of sperm in the epididymides was sharply reduced. Mutant epididymal sperm exhibited abnormal morphology, including folded tails. Sperm motility was significantly reduced, and Taf7l(-/Y) males were fertile with reduced litter size. Microarray profiling revealed that the abundance of six gene transcripts (including Fscn1) in Taf7l(-/Y) testes decreased more than twofold. In particular, FSCN1 is an F-action-bundling protein and thus may be critical for normal sperm morphology and sperm motility. Although deficiency of Taf7l may be compensated in part by Taf7, Taf7l has apparently evolved new specialized functions in the gene-selective transcription in male germ cell differentiation. Our mouse studies suggest that mutations in the human TAF7L gene might be implicated in X-linked oligozoospermia in men.


Denisovan Ancestry in East Eurasian and Native American Populations.
Although initial studies suggested that Denisovan ancestry was found only in modern human populations from island Southeast Asia and Oceania, more recent studies have suggested that Denisovan ancestry may be more widespread. However, the geographic extent of Denisovan ancestry has not been determined, and moreover the relationship between the Denisovan ancestry in Oceania and that elsewhere has not been studied. Here we analyze genome-wide single nucleotide polymorphism data from 2,493 individuals from 221 worldwide populations, and show that there is a widespread signal of a very low level of Denisovan ancestry across Eastern Eurasian and Native American (EE/NA) populations. We also verify a higher level of Denisovan ancestry in Oceania than that in EE/NA; the Denisovan ancestry in Oceania is correlated with the amount of New Guinea ancestry, but not the amount of Australian ancestry, indicating that recent gene flow from New Guinea likely accounts for signals of Denisovan ancestry across Oceania. However, Denisovan ancestry in EE/NA populations is equally correlated with their New Guinea or their Australian ancestry, suggesting a common source for the Denisovan ancestry in EE/NA and Oceanian populations. Our results suggest that Denisovan ancestry in EE/NA is derived either from common ancestry with, or gene flow from, the common ancestor of New Guineans and Australians, indicating a more complex history involving East Eurasians and Oceanians than previously suspected.


A Systematic Review of Scientific Studies and Case Reports on Music and Obsessive-Compulsive Disorder.
Obsessive-compulsive disorder (OCD) is a severe psychiatric disorder, which can be associated with music-related symptoms. Music may also be used as an adjunct treatment for OCD. Following the PRISMA guidelines, we performed a systematic literature review exploring the relationship between music and OCD by using three online databases: PubMed, the Web of Science, and PsycINFO. The search terms were "obsessive compulsive disorder", "OCD", "music", and "music therapy". A total of 27 articles were utilised (n = 650 patients/study participants) and grouped into three categories. The first category comprised case reports of patients with musical obsessions in patients with OCD. Most patients were treated with selective serotonin reuptake inhibitors (SSRIs) or a combination of an SSRI and another pharmacological or a non-pharmacological treatment, with variable success. Studies on the music perception of people with OCD or obsessive-compulsive personality traits represented the second category. People with OCD or obsessive-compulsive personality traits seem to be more sensitive to tense music and were found to have an increased desire for harmony in music. Three small studies on music therapy in people with OCD constituted the third category. These studies suggest that patients with OCD might benefit from music therapy, which includes listening to music.


Search for triboson [Formula: see text] production in pp collisions at [Formula: see text] [Formula: see text] with the ATLAS detector.
This paper reports a search for triboson [Formula: see text] production in two decay channels ([Formula: see text] and [Formula: see text] with [Formula: see text]) in proton-proton collision data corresponding to an integrated luminosity of 20.3 [Formula: see text] at a centre-of-mass energy of 8 [Formula: see text] with the ATLAS detector at the Large Hadron Collider. Events with exactly three charged leptons, or two leptons with the same electric charge in association with two jets, are selected. The total number of events observed in data is consistent with the Standard Model (SM) predictions. The observed 95% confidence level upper limit on the SM [Formula: see text] production cross section is found to be 730 fb with an expected limit of 560 fb in the absence of SM [Formula: see text] production. Limits are also set on WWWW anomalous quartic gauge couplings.


Uncovering curvilinear relationships between conscientiousness and job performance: how theoretically appropriate measurement makes an empirical difference.
The personality trait of conscientiousness has seen considerable attention from applied psychologists due to its efficacy for predicting job performance across performance dimensions and occupations. However, recent theoretical and empirical developments have questioned the assumption that more conscientiousness always results in better job performance, suggesting a curvilinear link between the 2. Despite these developments, the results of studies directly testing the idea have been mixed. Here, we propose this link has been obscured by another pervasive assumption known as the dominance model of measurement: that higher scores on traditional personality measures always indicate higher levels of conscientiousness. Recent research suggests dominance models show inferior fit to personality test scores as compared to ideal point models that allow for curvilinear relationships between traits and scores. Using data from 2 different samples of job incumbents, we show the rank-order changes that result from using an ideal point model expose a curvilinear link between conscientiousness and job performance 100% of the time, whereas results using dominance models show mixed results, similar to the current state of the literature. Finally, with an independent cross-validation sample, we show that selection based on predicted performance using ideal point scores results in more favorable objective hiring outcomes. Implications for practice and future research are discussed.


HIV acquisition among women from selected areas of the United States: a cohort study.
Women account for 23% of newly diagnosed HIV infections in the United States, but there are few recent, well-characterized cohorts of U.S. women in whom behavior characteristics and HIV acquisition have been well-described. To evaluate HIV incidence and describe behaviors among U.S. women residing in areas of high HIV prevalence. Multisite, longitudinal cohort of women who had HIV rapid testing and audio computer-assisted self-interviews at baseline and every 6 months for up to 12 months. (ClinicalTrials.gov: NCT00995176) 10 urban and periurban communities with high HIV prevalence and poverty rates, located in the northeastern and southeastern United States. Venue-based sampling was used to recruit women aged 18 to 44 years who recently had unprotected sex and had 1 or more additional personal or partner risk factors and no self-reported previous HIV diagnosis. HIV prevalence and incidence, frequency of HIV risk behaviors, and health status perceptions. Among 2099 high-risk women (85.9% black and 11.7% of Hispanic ethnicity), 32 (1.5%) were diagnosed with HIV infection at enrollment. Annual HIV incidence was 0.32% (95% CI, 0.14% to 0.74%). Older age, substance use, and knowing a partner had HIV were associated with HIV prevalence. Ten women died during the study (0.61% per year). Longitudinal assessment of risk behaviors was limited to a maximum of 12 months. There were few incident HIV infections, precluding identification of characteristics predictive of HIV acquisition. This study enrolled a cohort of women with HIV incidence substantially higher than the Centers for Disease Control and Prevention national estimate in the general population of U.S. black women. Concerted efforts to improve preventive health care strategies for HIV and overall health status are needed for similar populations. National Institutes of Health.


Trends in net survival from pancreatic cancer in six European Latin countries: results from the SUDCAN population-based study.
Pancreatic cancer represents a real clinical challenge. The aim of the SUDCAN collaborative study was to compare the net survival from pancreatic cancer between six European Latin countries (Belgium, France, Italy, Portugal, Spain and Switzerland) and provide trends in net survival and dynamics of excess mortality rates up to 5 years after diagnosis. The data were extracted from the EUROCARE-5 database. First, net survival was studied over the period 2000-2004 using the Pohar-Perme estimator. For trend analyses, the study period was specific to each country. Results were reported from 1992 to 2004 in France, Italy, Spain and Switzerland and from 2000 to 2004 in Belgium and Portugal. These analyses were carried out using a flexible excess rate modelling strategy. There were little differences between countries in age-standardized net survivals (2000-2004). The 5-year net survival was poor (range: 6-10%). The changes in net survival from 1992 to 2004 were mostly related to early survival and patients aged 60 years. A slight decrease in the excess mortality rate between 1992 and 2004 was observed, limited to the 18 months after diagnosis. This study confirmed that, despite some improvement, survival from pancreatic cancer is still poor throughout European Latin countries. The major improvements in clinical imaging did not result in improvements in prognosis. Development of truly innovative treatments is highly needed to improve prognosis.


Complete Genome Sequence and Methylome of Salmonella enterica subsp. enterica Cerro, a Frequent Dairy Cow Serovar.
Salmonella enterica subsp. enterica serovar Cerro is an infrequent pathogen of humans and other mammals but is frequently isolated from the hindgut of asymptomatic cattle in the United States. To further understand the genomic determinants of S. Cerro specificity for the bovine hindgut, the genome of isolate CFSAN001588 was fully sequenced and deposited in the GenBank database.


Nuclear physics: quantitative single-cell approaches to nuclear organization and gene expression.
The internal workings of the nucleus remain a mystery. A list of component parts exists, and in many cases their functional roles are known for events such as transcription, RNA processing, or nuclear export. Some of these components exhibit structural features in the nucleus, regions of concentration or bodies that have given rise to the concept of functional compartmentalization--that there are underlying organizational principles to be described. In contrast, a picture is emerging in which transcription appears to drive the assembly of the functional components required for gene expression, drawing from pools of excess factors. Unifying this seemingly dual nature requires a more rigorous approach, one in which components are tracked in time and space and correlated with onset of specific nuclear functions. In this chapter, we anticipate tools that will address these questions and provide the missing kinetics of nuclear function. These tools are based on analyzing the fluctuations inherent in the weak signals of endogenous nuclear processes and determining values for them. In this way, it will be possible eventually to provide a computational model describing the functional relationships of essential components.


Sin mutations of histone H3: influence on nucleosome core structure and function.
Sin mutations in Saccharomyces cerevisiae alleviate transcriptional defects that result from the inactivation of the yeast SWVI/SNF complex. We have investigated the structural and functional consequences for the nucleosome of Sin mutations in histone H3. We directly test the hypothesis that mutations in histone H3 leading to a SWI/SNF-independent (Sin) phenotype in yeast lead to nucleosomal destabilization. In certain instances this is shown to be true; however, nucleosomal destabilization does not always occur. Topoisomerase I-mediated relaxation of minichromosomes assembled with either mutant histone H3 or wild-type H3 together with histones H2A, H2B, and H4 indicates that DNA is constrained into nucleosomal structures containing either mutant or wild-type proteins. However, nucleosomes containing particular mutant H3 molecules (R116-H and T118-I) are more accessible to digestion by micrococcal nuclease and do not constrain DNA in a precise rotational position, as revealed by digestion with DNase I. This result establishes that Sin mutations in histone H3 located close to the dyad axis can destabilize histone-DNA contacts at the periphery of the nucleosome core. Other nucleosomes containing a distinct mutant H3 molecule (E105-K) associated with a Sin phenotype show very little change in nucleosome structure and stability compared to wild-type nucleosomes. Both mutant and wild-type nucleosomes continue to restrict the binding of either TATA-binding protein/transcription factor IIA (TFIIA) or the RNA polymerase III transcription machinery. Thus, different Sin mutations in histone H3 alter the stability of histone-DNA interactions to various extents in the nucleosome while maintaining the fundamental architecture of the nucleosome and contributing to a common Sin phenotype.


Well-dispersed cellulose nanocrystals in hydrophobic polymers by in situ polymerization for synthesizing highly reinforced bio-nanocomposites.
In nanocomposites, dispersing hydrophilic nanomaterials in a hydrophobic matrix using simple and environmentally friendly methods remains challenging. Herein, we report a method based on in situ polymerization to synthesize nanocomposites of well-dispersed cellulose nanocrystals (CNCs) and poly(vinyl acetate) (PVAc). We have also shown that by blending this PVAc/CNC nanocomposite with poly(lactic acid) (PLA), a good dispersion of the CNCs can be reached in PLA. The outstanding dispersion of CNCs in both PVAc and PLA/PVAc matrices was shown by different microscopy techniques and was further supported by the mechanical and rheological properties of the composites. The in situ PVAc/CNC nanocomposites exhibit enhanced mechanical properties compared to the materials produced by mechanical mixing, and a theoretical model based on the interphase effect and dispersion that reflects this behavior was developed. Comparison of the rheological and thermal behaviors of the mixed and in situ PVAc/CNC also confirmed the great improvement in the dispersion of nanocellulose in the latter. Furthermore, a synergistic effect was observed with only 0.1 wt% CNCs when the in situ PVAc/CNC was blended with PLA, as demonstrated by significant increases in elastic modulus, yield strength, elongation to break and glass transition temperature compared to the PLA/PVAc only material.