Threats of Longline Fishing to Global Albatross Diversity.
Albatrosses are among the most threatened seabird species. Often entangled in gillnets or hooked while longline fishing gear is being set, albatrosses are affected by fishing. This is assumed to be especially true in cases where illegal longline fishing vessels are involved, as they are less likely to implement the bycatch mitigation measures implemented to reduce the risk of albatrosses being caught on their hooks. This is the assumption that was tested in the current study, which uses environmental criminology as its guiding theoretical framework. Using the spatial units of one-half-degree by one-half-degree longitude/latitude cells, this research examined the patterns of concentration of potentially illegal longlining efforts and their relationships to commercially sought-out and illegally caught (i.e., CRAAVED-concealable, removable, abundant, accessible, valuable, enjoyable, disposable) fish species concentrations, as well as their effects on the average risk of albatrosses. The results indicated that (a) potentially illegal longlining activity is spatially concentrated; (b) this concentration is exhibited in areas with the highest concentrations of the presence of CRAAVED fish; and (c) the average risk score of albatrosses, as measured by their International Union for Conservation of Nature (IUCN) Red List status, is significantly higher in the areas where illegal longlining vessels are found controlling for the activities of legal longlining vessels. These findings provide strong grounding that illegal longline fishing poses a particularly serious threat to the survival of albatrosses. These activities, however, are not randomly spread across the vast oceans, but rather are highly spatially concentrated. Therefore, the bird conservation lobby should work closely with regional fisheries management organizations to devise and implement targeted interventions aimed at reducing potential illegal longline fishing, which, in turn, will likely have positive effects on albatrosses.


Large-scale synthesis of uniform lanthanide-doped NaREF4 upconversion/downshifting nanoprobes for bioapplications.
Lanthanide (Ln3+)-doped NaREF4 (RE = rare earth) nanocrystals (NCs) are one of the most widely studied upconversion and downshifting luminescent nanoprobes. However, the size and optical performance of the Ln3+-doped NaREF4 NCs produced by the available lab-scale synthesis may vary from batch to batch, which inevitably limits their practical bioapplications. Herein, we report the synthesis of uniform Ln3+-doped NaREF4 NCs via a facile solid-liquid-thermal-decomposition (SLTD) method by directly employing NaHF2 powder as a fluoride and sodium precursor. The proposed SLTD strategy is easy to perform, time-saving and cost-effective, making it ideal for scale-up syntheses. Particularly, over 63 g of β-NaGdF4:Yb,Er@NaYF4 core/shell NCs with narrow size variation (<7%) were synthesized via a one-pot reaction. By virtue of their superior upconversion and downshifting luminescence, we employed the synthesized core/shell nanoprobes for the in vitro detection of prostate-specific antigen with a limit of detection down to 1.8 ng mL-1, and for in vivo near-infrared imaging with a high signal-to-noise ratio of 12. These findings may pave the way for the commercialization of Ln3+-doped nanoprobes in bioassay kits for versatile clinical applications.


Risk factors for extended duration of acute diarrhea in young children.
We sought to identify predictors of extended duration of diarrhea in young children, which contributes substantially to the nearly 1 1/2 million annual diarrheal deaths globally. We followed 6-35 month old Nepalese children enrolled in the placebo-arm of a randomized controlled trial with 391 episodes of acute diarrhea from the day they were diagnosed until cessation of the episode. Using multiple logistic regression analysis, we identified independent risk factors for having diarrhea for more than 7 days after diagnosis. Infants had a 17 (95% CI 3.5, 83)-fold and toddlers (12 to 23 month olds) a 9.9 (95% CI 2.1, 47)-fold higher odds of having such illness duration compared to the older children. Not being breastfed was associated with a 9.3 (95% CI 2.4, 35.7)-fold increase in the odds for this outcome. The odds also increased with increasing stool frequency. Furthermore, having diarrhea in the monsoon season also increased the risk of prolonged illness. We found that high stool frequency, not being breastfed, young age and acquiring diarrhea in the rainy season were risk factors for prolonged diarrhea. In populations such as ours, breastfeeding may be the most important modifiable risk factor for extended duration of diarrhea.


Expression of Human Cytokine Genes Associated with Chronic Hepatitis B Disease Progression.
Hepatitis viruses are non-cytopathic viruses that lead to the infection and pathogenesis of liver diseases as a result of immunologically mediated events. To investigate the expression of human inflammatory cytokines in chronic hepatitis B patients according to the severity of the infection. We recruited a total of 120 patients, 40 of whom from cirrhotic, 40 non-cirrhotic, and 40 acute flare chronic hepatitis B and 40 healthy controls. For all groups total cellular RNA was extracted from whole blood samples, genomic DNA was eliminated, and cDNA was synthesized using the RT2 first strand kit, as instructed by the manufacturer. The real-time profiler PCR array was performed on a master cycler ep realplex and the data were analyzed using an online data analysis software. Non-cirrhotic chronic hepatitis B patients were found to significantly upregulate interleukin 10 receptors that regulate the balance between T helpers 1 and 2. On the other hand, patients with cirrhosis were found to have significant upregulated interleukin 3 gene expression. Our finding suggests that upregulation of anti-inflammatory and downregulation of pro-inflammatory cytokines may play a role in the progression of non-cirrhotic chronic hepatitis B patients to cirrhotic and acute flare. However, a multi-center study with a larger sample size is needed to confirm our findings.


Aqueous extracts of some medicinal plants are as toxic as Imidacloprid to the sweet potato whitefly, Bemisia tabaci.
Aqueous extracts of nine plants, known to have medicinal activity, were tested for their toxicity against the sweet potato whitefly, Bemisia tabaci Genn. (Homoptera: Aleurodidae) compared to the toxicity of the insecticide, Imidacloprid. Extracts of Lepidiuim sativum L. (Brassicales: Brassicaceae) killed 71 % of early stage nymphs, which was not significantly different from mortality caused by Imidacloprid. Treatment of pupae with three plant extracts, L. sativum, Achillea biebersteinii L. (Asterales: Asteraceae), or Retama raetam (Forssk.) Webb and Berthel (Fabales: Fabaceae) prevented adult development, and treatment with R. raetam extract killed adults, at levels that were not significantly different from Imidacloprid. None of the other plants showed significant toxicity. However extracts of four plants, Pimpinella anisum L. (Apiales: Apiaceae), Galium longifolium (Sibth. and SM.) (Gentianales: Rubiaceae), R. raetam and Ballota undulata Bentham (Lamiales: Lamiaceae) had a repellent effect.


High-Fat Diet Causes Mitochondrial Dysfunction as a Result of Impaired ADP Sensitivity.
Although molecular approaches altering mitochondrial content have implied a direct relationship between mitochondrial bioenergetics and insulin sensitivity, paradoxically, consumption of a high-fat (HF) diet increases mitochondrial content while inducing insulin resistance. We hypothesized that despite the induction of mitochondrial biogenesis, consumption of an HF diet would impair mitochondrial ADP sensitivity in skeletal muscle of mice and therefore manifest in mitochondrial dysfunction in the presence of ADP concentrations indicative of skeletal muscle biology. We found that HF consumption increased mitochondrial protein expression; however, absolute mitochondrial respiration and ADP sensitivity were impaired across a range of biologically relevant ADP concentrations. In addition, HF consumption attenuated the ability of ADP to suppress mitochondrial H2O2 emission, further suggesting impairments in ADP sensitivity. The abundance of ADP transport proteins were not altered, but the sensitivity to carboxyatractyloside-mediated inhibition was attenuated after HF consumption, implicating alterations in adenine nucleotide translocase (ANT) ADP sensitivity in these observations. Moreover, palmitoyl-CoA is known to inhibit ANT, and modeling intramuscular palmitoyl-CoA concentrations that occur after HF consumption exacerbated the deficiency in ADP sensitivity. Altogether, these data suggest that an HF diet induces mitochondrial dysfunction secondary to an intrinsic impairment in mitochondrial ADP sensitivity that is magnified by palmitoyl-CoA.


Vanadium stimulates the (Na+,K+) pump in friend erythroleukemia cells and blocks erythropoiesis.
Friend murine erythroleukemia cells underwent apparently normal erythropoiesis when treated with dimethyl sulfoxide. One of the earliest events associated with this induction was a decrease in ouabain sensitive 86Rb+ uptake, an assay of the plasma membrane Na,K(ATPase). Ammonium vanadate (10 microM) blocked differentiation of these cells without affecting cell viability. Vanadium was taken up by Friend cells and prevented the dimethyl sulfoxide-induced decrease in ouabain sensitive 86Rb+ uptake. Vanadate reactivated 86Rb+ transport previously inhibited by dimethyl sulfoxide treatment but had no affect on 86Rb+ transport in untreated cells. These results suggest an essential role for the (Na,K)ATPase in cell differentiation.


ProteomeTools: Systematic Characterization of 21 Post-translational Protein Modifications by Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) Using Synthetic Peptides.
The analysis of the post-translational modification (PTM) state of proteins using mass spectrometry-based bottom-up proteomic workflows has evolved into a powerful tool for the study of cellular regulatory events that are not directly encoded at the genome level. Besides frequently detected modifications such as phosphorylation, acetylation and ubiquitination, many low abundant or less frequently detected PTMs are known or postulated to serve important regulatory functions. To more broadly understand the LC-MS/MS characteristics of PTMs, we synthesized and analyzed ∼5,000 peptides representing 21 different naturally occurring modifications of lysine, arginine, proline and tyrosine side chains and their unmodified counterparts. The analysis identified changes in retention times, shifts of precursor charge states and differences in search engine scores between modifications. PTM-dependent changes in the fragmentation behavior were evaluated using eleven different fragmentation modes or collision energies. We also systematically investigated the formation of diagnostic ions or neutral losses for all PTMs, confirming 10 known and identifying 5 novel diagnostic ions for lysine modifications. To demonstrate the value of including diagnostic ions in database searching, we reprocessed a public data set of lysine crotonylation and showed that considering the diagnostic ions increases confidence in the identification of the modified peptides. To our knowledge, this constitutes the first broad and systematic analysis of the LC-MS/MS properties of common and rare PTMs using synthetic peptides, leading to direct applicable utility for bottom-up proteomic experiments.


Antigens and antibodies cross-reactive to the murine mammary tumor virus in human breast cyst fluids.
Human breast cyst fluids were shown to contain low concentrations of IgA (15-78 micrograms/ml) and IgG (33-145 micrograms/ml). The IgA:IgG ratios in individual breast cyst fluids ranged from 1:0.6 to 1:4. These levels are considerably higher than their ratio in serum (1:7). IgA from 33% of the 40 fluids examined, and IgG from 10% of the fluids, reacted with the murine mammary tumor virus (MuMTV). The reactivity was detected by an enzyme-linked immunosorbent assay that measures antibody binding to both the envelope glycoprotein and core protein of the virus. In a second series of experiments. IgA from 28% of 40 breast cyst fluids reacted only with MuMTV while IgA from 30% of the fluids was reactive with both MuMTV and the Rauscher murine leukemia virus. Antigen reactive with antiserum to the 28,000-dalton MuMTV core protein (p28), was also identified in a 165,000-g pellet fraction from breast cyst fluids. In individual fluids, the extent of IgA binding to MuMTV was positively correlated (P less than or equal to 0.01) with the binding of anti-p28 antibody to the pellet of the breast cyst fluid. Fractions with the buoyant density of retroviruses (1.16-1.18 g/ml) or their cores (1.21-1.25 g/ml) were isolated from breast cyst fluids. These fractions contained a DNA polymerase capable of utilizing the reverse transcriptase-specific template, dG12-18 x poly rCm. In addition, they reacted with antiserum to MuMTV p 28 but not with antiserum to the 30,000-dalton Rauscher murine leukemia virus core protein.


Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association.
The American Heart Association, in conjunction with the National Institutes of Health, annually reports on the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2020 Statistical Update is the product of a full year's worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year's edition includes data on the monitoring and benefits of cardiovascular health in the population, metrics to assess and monitor healthy diets, an enhanced focus on social determinants of health, a focus on the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors, implementation strategies, and implications of the American Heart Association's 2020 Impact Goals. Each of the 26 chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, healthcare administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.


Recent advances in understanding HIV evolution.
The human immunodeficiency virus (HIV) evolves rapidly owing to the combined activity of error-prone reverse transcriptase, recombination, and short generation times, leading to extensive viral diversity both within and between hosts. This diversity is a major contributing factor in the failure of the immune system to eradicate the virus and has important implications for the development of suitable drugs and vaccines to combat infection. This review will discuss the recent technological advances that have shed light on HIV evolution and will summarise emerging concepts in this field.


A cost effective model for appropriate administration of red cell units and salvaging un-transfused red cell units by using temperature sensitive indicators for blood component transportation in a hospital setting.
A rule called "30-min rule" defines that red cell unit cannot be used if it has been out of blood bank refrigerator for over 30 min. This rule is useful to guide initiation of transfusion, but is inadequate for deciding whether to reuse or discard units received-back at blood transfusion services (BTS). A simple cost-effective temperature-sensitive indicator was evaluated to decide upon reuse (cold chain was uninterrupted) or discard (where cold chain was interrupted) in a simulation exercise. Temperature-sensitive indicators TH-F™ that irreversibly changed color from white to red demonstrated that heat excursion has occurred and the cumulative temperature has exceeded 10°C for over 30 min, were used in outdated red cells for simulating units, which are not used and received-back. These units were also tagged with a standard temperature monitoring device, which was a re-usable credit card sized device, which would log the actual time and temperature. In few units percent hemolysis was also calculated. Statistically insignificant elevation in average temperature was noted in 102 simulated units at the time of return to BTS (Δ 0.04°C), despite the fact that these units were in the transport box for over 4 h. The average supernatant hemoglobin in these units was 0.24%, much below the prescribed threshold. Transportation of blood in controlled conditions with temperature-sensitive indicator is a cost-effective model to save blood, a precious human resource.


HIV-1 and the Mycobacterium tuberculosis granuloma: A systematic review and meta-analysis.
Infection with HIV-1 greatly increases the risk of active tuberculosis (TB). Although hypotheses suggest HIV-1 disrupts Mycobacterium tuberculosis (Mtb) granuloma function, few studies have examined this directly. The objective of this study was to determine what evidence exists about the effect HIV-1 co-infection has upon Mtb granulomas. A systematic search of PubMed, Web of Science, and Medline up to 20 March 2015 was conducted, to identify studies comparing Mtb-infected tissue from HIV-1 infected and uninfected persons, or HIV-1 infected persons with stratified peripheral CD4 T cell (pCD4) counts. We summarized findings that focused on how HIV-1 changes granuloma formation, bacterial presence, cellular composition, and cytokine production. Nineteen studies with a combined sample size of 899 persons were included. Although studies frequently were limited by variable or inadequately described definitions of outcomes and analytical methods, HIV-1 was found to be associated with increased bacillary load within Mtb-infected tissue. Reductions in pCD4 counts within co-infected persons associated with both poorer granuloma formation and higher bacterial load. The high degree of heterogeneity among studies combined with experimental limitations made it difficult to conclusively support previously published and prevalent hypotheses about HIV-1/Mtb co-infection granulomas. To elucidate the validity of these hypotheses we have described areas that can be improved in future studies in order to clarify the influence HIV-1 co-infection has upon the Mtb granuloma.


Representativeness, legitimacy and power in public involvement in health-service management.
Public participation in health-service management is an increasingly prominent policy internationally. Frequently, though, academic studies have found it marginalized by health professionals who, keen to retain control over decision-making, undermine the legitimacy of involved members of the public, in particular by questioning their representativeness. This paper examines this negotiation of representative legitimacy between staff and involved users by drawing on a qualitative study of service-user involvement in pilot cancer-genetics services recently introduced in England, using interviews, participant observation and documentary analysis. In contrast to the findings of much of the literature, health professionals identified some degree of representative legitimacy in the contributions made by users. However, the ways in which staff and users constructed representativeness diverged significantly. Where staff valued the identities of users as biomedical and lay subjects, users themselves described the legitimacy of their contribution in more expansive terms of knowledge and citizenship. My analysis seeks to show how disputes over representativeness relate not just to a struggle for power according to contrasting group interests, but also to a substantive divergence in understanding of the nature of representativeness in the context of state-orchestrated efforts to increase public participation. This divergence might suggest problems with the enactment of such aspirations in practice; alternatively, however, contestation of representative legitimacy might be understood as reflecting ambiguities in policy-level objectives for participation, which secure implementation by accommodating the divergent constructions of those charged with putting initiatives into practice.


Epidemiological comparison of injuries in school and senior club rugby.
To determine the frequency, nature, circumstances, and outcome of schoolboy rugby injuries and to compare these injuries with those occurring in senior rugby clubs. The study was a prospective cohort study, conducted on 1705 (98%) of 1736 eligible players from nine Edinburgh schools and 1169 (96%) of 1216 eligible players from all 26 senior Scottish Rugby Union clubs (South District) who provided personal details before the 1993-1994 rugby season. Adult linkpersons were appointed to notify the circumstances of all injury episodes occurring in matches or in rugby related training. 154 school players (9%) experienced 210 separate injuries in 186 injury episodes, 80% of which arose in matches. The prevalence rate of schoolboy match injuries was 86.8 (95% confidence interval 73.4 to 100.2) per 1000 player-seasons. Senior club match injury prevalence was much higher at 367.0 (339.4 to 394.6) per 1000 player-seasons. Club players had a higher rate of match injury than school-boys for all injury types. One third of schoolboy match injury episodes occurred in September and the majority of match injury episodes were associated with tackling (40%) or with being tackled (24%). Nine per cent of schoolboy match injury episodes were classified as severe, compared to 13% for clubs. Sixteen per cent (n = 23) of all schoolboy match injury episodes resulted in missed school attendance compared with 27% (n = 117) of all senior club match injury episodes which involved loss of employment or education. Schoolboy rugby is much safer than senior club rugby and the outcome of injuries that do occur is less disruptive. The relatively high rate of match injury in September migh be reduced by a more intensive period of preseason training.


Non-malarial febrile illness: a systematic review of published aetiological studies and case reports from Africa, 1980-2015.
The availability of reliable point-of-care tests for malaria has heralded a paradigm shift in the management of febrile illnesses away from presumptive antimalarial therapy. In the absence of a definitive diagnosis, health care providers are more likely to prescribe empirical antimicrobials to those who test negative for malaria. To improve management and guide further test development, better understanding is needed of the true causative agents and their geographic variability. A systematic review of published literature was undertaken to characterise the spectrum of pathogens causing non-malaria febrile illness in Africa (1980-2015). Literature searches were conducted in English and French languages in six databases: MEDLINE, EMBASE, Global Health (CABI), WHO Global Health Library, PASCAL, and Bulletin de la Société Française de Parasitologie (BDSP). Selection criteria included reporting on an infection or infections with a confirmed diagnosis, defined as pathogens detected in or cultured from samples from normally sterile sites, or serological evidence of current or past infection. A number of published articles (rather than incidence or prevalence) reporting a given pathogen were presented. A total of 16,523 records from 48 African countries were screened, of which 1065 (6.4%) met selection criteria. Bacterial infections were reported in 564 (53.0%) records, viral infections in 374 (35.1%), parasitic infections in 47 (4.4%), fungal infections in nine (0.8%), and 71 (6.7%) publications reported more than one pathogen group. Age range of the study population was not specified in 233 (21.9%) publications. Staphylococcus aureus (18.2%), non-typhoidal Salmonella (17.3%), and Escherichia coli (15.4%) were the commonly reported bacterial infections whereas Rift Valley fever virus (7.4%), yellow fever virus (7.0%), and Ebola virus (6.7%) were the most commonly reported viral infections. Dengue virus infection, previously not thought to be widespread in Africa, was reported in 54 (5.1%) of articles. This review summarises the published reports of non-malaria pathogens that may cause febrile illness in Africa. As the threat of antimicrobial resistance looms, knowledge of the distribution of infectious agents causing fever should facilitate priority setting in the development of new diagnostic tools and improved antimicrobial stewardship. PROSPERO, CRD42016049281.


Cross-phase modulation in optical fibers.
When pulse pairs copropagate in a fiber, each pulse chirps the other through cross-phase modulation (XPM). In particular, XPM causes spectral broadening of signal pulses during Raman or parametric optical pulse amplification. We have studied XPM experimentally in the fiber Raman amplification soliton laser. We show that experimentally observed spectra can be explained by a simple model that concentrates on the phase change as a function of pulse walk-off.


Changes in Neural Activity Underlying Working Memory after Computerized Cognitive Training in Older Adults.
Computerized cognitive training (CCT) may counter the impact of aging on cognition, but both the efficacy and neurocognitive mechanisms underlying CCT remain controversial. In this study, 35 older individuals were randomly assigned to Cogmed adaptive working memory (WM) CCT or an active control CCT, featuring five weeks of five ∼40 min sessions per week. Before and after the 5-week intervention, event-related potentials were measured while subjects completed a visual n-back task with three levels of demand (0-back, 1-back, 2-back). The anterior P3a served as an index of directing attention and the posterior P3b as an index of categorization/WM updating. We hypothesized that adaptive CCT would be associated with decreased P3 amplitude at low WM demand and increased P3 amplitude at high WM demand. The adaptive CCT group exhibited a training-related increase in the amplitude of the anterior P3a and posterior P3b in response to target stimuli across n-back tasks, while subjects in the active control CCT group demonstrated a post-training decrease in the anterior P3a. Performance did not differ between groups or sessions. Larger overall P3 amplitudes were strongly associated with better task performance. Increased post-CCT P3 amplitude correlated with improved task performance; this relationship was especially robust at high task load. Our findings suggest that adaptive WM training was associated with increased orienting of attention, as indexed by the P3a, and the enhancement of categorization/WM updating processes, as indexed by the P3b. Increased P3 amplitude was linked to improved performance; however. there was no direct association between adaptive training and improved performance.


The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(-/-) mice and results in a mouse with spinal muscular atrophy.
Proximal spinal muscular atrophy (SMA) is a common motor neuron disease in humans and in its most severe form causes death by the age of 2 years. It is caused by defects in the telomeric survival motor neuron gene ( SMN1 ), but patients retain at least one copy of a highly homologous gene, centromeric SMN ( SMN2 ). Mice possess only one survival motor neuron gene ( Smn ) whose loss is embryonic lethal. Therefore, to obtain a mouse model of SMA we created transgenic mice that express human SMN2 and mated these onto the null Smn (-/-)background. We show that Smn (-/-); SMN2 mice carrying one or two copies of the transgene have normal numbers of motor neurons at birth, but vastly reduced numbers by postnatal day 5, and subsequently die. This closely resembles a severe type I SMA phenotype in humans and is the first report of an animal model of the disease. Eight copies of the transgene rescues this phenotype in the mice indicating that phenotypic severity can be modulated by SMN2 copy number. These results show that SMA is caused by insufficient SMN production by the SMN2 gene and that increased expression of the SMN2 gene may provide a strategy for treating SMA patients.


Aged Muscle Demonstrates Fiber-Type Adaptations in Response to Mechanical Overload, in the Absence of Myofiber Hypertrophy, Independent of Satellite Cell Abundance.
Although sarcopenia, age-associated loss of muscle mass and strength, is neither accelerated nor exacerbated by depletion of muscle stem cells, satellite cells, we hypothesized that adaptation in sarcopenic muscle would be compromised. To test this hypothesis, we depleted satellite cells with tamoxifen treatment of Pax7(CreER)-DTA mice at 4 months of age, and 20 months later subjected the plantaris muscle to 2 weeks of mechanical overload. We found myofiber hypertrophy was impaired in aged mice regardless of satellite cell content. Even in the absence of growth, vehicle-treated mice mounted a regenerative response, not apparent in tamoxifen-treated mice. Further, myonuclear accretion occurred in the absence of growth, which was prevented by satellite cell depletion, demonstrating that myonuclear addition is insufficient to drive myofiber hypertrophy. Satellite cell depletion increased extracellular matrix content of aged muscle that was exacerbated by overload, potentially limiting myofiber growth. These results support the idea that satellite cells regulate the muscle environment, and that their loss during aging may contribute to fibrosis, particularly during periods of remodeling. Overload induced a fiber-type composition improvement, independent of satellite cells, suggesting that aged muscle is very responsive to exercise-induced enhancement in oxidative capacity, even with an impaired hypertrophic response.


The Effect of Randomly Providing Nutri-Score Information on Actual Purchases in Colombia.
Recently, front-of-package (FOP) food labeling systems have captured the attention of researchers and policy makers. Several Latin American governments are currently considering employing different FOP labeling systems. However, there is much need for more research-based evidence in these countries. In this paper, we study whether food-purchasing decisions and the nutritional qualities of those purchases are influenced by randomly informing some customers and not others about an FOP label known as Nutri-Score. We also separate the information effect from the effect of being aware of the system. We combined a randomized field intervention in a university cafeteria in Bogotá, Colombia with data from an after-purchase survey and receipts. We found that randomly providing information on Nutri-Score increased total expenditure by $0.18. Additional spending on healthier items was 21% or $0.26 higher, with no change for less healthy items. Expenditure estimates were higher among customers who were aware of the system's existence. Customers in the study were also 10% more likely to buy a healthier item than control customers were, and the concentration of protein in their purchases was greater. Information on the Nutri-Score system increased the store's sales. This potential financial incentive may facilitate the implementation of Nutri-Score.


Triphenylamine groups improve blocking behavior of phenoxazine dyes in cobalt-electrolyte-based dye-sensitized solar cells.
Novel phenoxazine dyes are successfully introduced as sensitizers into dye-sensitized solar cells (DSCs) with cobalt-based electrolyte. In sensitizers with triphenylamine (TPA) groups recombination from electrons in the TiO2 conduction band to the cobalt(III) species is suppressed. The effect of the steric properties of the phenoxazine sensitizers on the overall device performance and on recombination and regeneration processes is compared. Optimized DSCs sensitized with IB2 having two TPA groups in combination with tris(2,2'-bipyridyl) cobalt(II/III) yield efficiencies of 6.3%, similar to that of IB3, which is equipped with mutiple alkoxy groups. TH310 with only one TPA group gives lower efficiency and open circuit voltage, while IB1 without TPA groups performs even worse. These results demonstrate that both TPA groups on the IB2 are needed for an efficient blocking effect. These results reveal a possible new role for TPA units in DSC sensitizer design.


Course of depression symptoms between 3 and 8 months after delivery using two screening tools (EPDS and HSCL-10) on a sample of Sudanese women in Khartoum state.
Effects of depression on parenting and on cognitive development of newborns are augmented when symptoms continue throughout the first postnatal year. Current classification systems recognize maternal depression as postnatal if symptoms commence within four to six weeks. Traditional cultural rituals in Sudan offer new mothers adequate family support in the first 6-8 weeks postpartum. The course of postnatal depression symptoms beyond that period is not explored in such settings. We therefore aim to investigate the change in screening status and in severity of depression and distress symptoms between three and eight months postpartum among a sample of Sudanese women using the Edinburgh Postnatal Depression Scale (EPDS) and a locally used tool: the 10-items Hopkins Symptoms Checklist (HSCL-10). Three hundred pregnant women in their 2nd or 3rd trimester were recruited from two clinics in Khartoum state. They were followed up and screened for depression symptoms eight months after delivery by EPDS at ≥12, and by HSCL-10 at ≥1.85. The same sample was previously screened for depression at three months after birth. Prevalence of postnatal depression symptoms by EPDS was lower at eight months compared to three months after birth (3.6% at eight months (8/223) compared to 9.2% at three months (22/238), p < 0.001). Eight Mothers exhibited depression symptoms eight months after birth. Depressed mothers at three months had a 56% reduction in EPDS mean scores by eight months and 96.4% of participants either remained in the same EPDS category, or improved eight months after birth. Four participants with major depression symptoms at eight months were also depressed three months after birth and four participants had new onset depression symptoms. The HSCL-10 measured higher distress than EPDS across the two screening points (19.3% at three months, 9.1% at eight months postpartum, p < 0.001). Nonetheless, the two tests correlated positively at both points. Repeated screenings by EPDS (depression surveillance) is recommended during the first postnatal year because a subset of mothers can have symptoms beyond the early postnatal period. Existing depression screening instruments can be assessed for their validity to detect PND.


Folate intake and the risk of neural tube defects: an estimation of dose-response.
Studies have shown that folic acid supplementation in early pregnancy markedly reduces the risk of neural tube defects (NTDs). Investigation of the relation between relative dose of supplemental folic acid or total folate intake and NTD risk is limited. We used data from 23,228 women, predominantly from the northeastern United States, enrolled between October 1984 and June 1987 in a prospective study of early prenatal exposures and pregnancy outcomes. Diet and vitamin intake data were gathered in the early second trimester. NTDs were ascertained through prenatal testing and by report of the delivering physician. Data analyses included multiple logistic regression and restricted spline regression modeling. For each additional 500 dietary folate equivalents consumed per day, the prevalence of NTDs decreased by 0.78 cases (95% confidence interval [CI] = 0.47-1.09) per 1,000 pregnancies. Compared with women having the lowest total folate intakes (0-149 folate equivalents per day), the prevalence of NTDs declined by 34%, 30%, 56% and 77% among the offspring of those women consuming 150-399, 400-799, 800-1199 and > or = 1200 folate equivalents per day, respectively (P-value for linear trend = 0.016). Our results suggest that NTD risk declines markedly with modest increases of total folate in early pregnancy. Total folate dose, rather than supplemental folate alone, should be considered in formulating public health guidelines for NTD prevention.


Exercise increases mitochondrial PGC-1alpha content and promotes nuclear-mitochondrial cross-talk to coordinate mitochondrial biogenesis.
Endurance exercise is known to induce metabolic adaptations in skeletal muscle via activation of the transcriptional co-activator peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α). PGC-1α regulates mitochondrial biogenesis via regulating transcription of nuclear-encoded mitochondrial genes. Recently, PGC-1α has been shown to reside in mitochondria; however, the physiological consequences of mitochondrial PGC-1α remain unknown. We sought to delineate if an acute bout of endurance exercise can mediate an increase in mitochondrial PGC-1α content where it may co-activate mitochondrial transcription factor A to promote mtDNA transcription. C57Bl/6J mice (n = 12/group; ♀ = ♂) were randomly assigned to sedentary (SED), forced-endurance (END) exercise (15 m/min for 90 min), or forced endurance +3 h of recovery (END+3h) group. The END group was sacrificed immediately after exercise, whereas the SED and END+3h groups were euthanized 3 h after acute exercise. Acute exercise coordinately increased the mRNA expression of nuclear and mitochondrial DNA-encoded mitochondrial transcripts. Nuclear and mitochondrial abundance of PGC-1α in END and END+3h groups was significantly higher versus SED mice. In mitochondria, PGC-1α is in a complex with mitochondrial transcription factor A at mtDNA D-loop, and this interaction was positively modulated by exercise, similar to the increased binding of PGC-1α at the NRF-1 promoter. We conclude that in response to acute altered energy demands, PGC-1α re-localizes into nuclear and mitochondrial compartments where it functions as a transcriptional co-activator for both nuclear and mitochondrial DNA transcription factors. These results suggest that PGC-1α may dynamically facilitate nuclear-mitochondrial DNA cross-talk to promote net mitochondrial biogenesis.


[CACH/VWM syndrome and leucodystrophies related to EIF2B mutations].
A new leukoencephalopathy, the CACH syndrome (Childhood Ataxia with Central nervous system Hypomyelination) or VWM (Vanishing White Matter) was identified on clinical and MRI criteria. Classically, this disease is characterized by (1) an onset between 2 and 5 years of age, with a cerebello-spastic syndrome exacerbated by episodes of fever or head trauma leading to death after 5 to 10 years of disease evolution, (2) a diffuse involvement of the white matter on cerebral MRI with a CSF-like signal intensity (cavitation), (3) a recessive autosomal mode of inheritance, (4) neuropathologic findings consistent with a cavitating orthochromatic leukodystrophy with increased number of oligodendrocytes with sometimes "foamy" aspect. A total of 148 cases have been reported so far. This disease is linked to mutations in the five EIF2B genes encoding the five subunits of the eukaryotic initiation factor 2B (eIF2B), involved in the protein synthesis and its regulation under cellular stresses. Clinical symptoms are variable, from fatale infantile forms (Cree leukoencephalopathy) and congenital forms associated with extra-neurological affections, to juvenile and adult forms (ovarioleukodystrophy) characterized by cognitive and behaviour dysfunctions and by a slow progression of the disease, leading to the term of eIF2B-related leukoencephalopathies. Prevalence of these remains unknown. Diagnosis lays on the detection of EIF2B mutations, affecting predominantly the EIF2B5 gene. A decrease in the intrinsic activity of the eIF2B factor (the guanine exchange activity, GEF) in lymphoblasts from patients seems to have a diagnostic value. The patho-physiology of the disease would involve a deficiency in astrocytes maturation leading to an increased susceptibility of the white matter to cellular stress. No specific treatment exists except the "prevention" of cellular stress. Corticosteroids sometimes proved to be useful in acute phases. Prognosis seems to correlate with the age of onset, the earliest forms being more severe.


Adaptive affinity propagation with spectral angle mapper for semi-supervised hyperspectral band selection.
Band selection is a commonly used approach for dimensionality reduction in hyperspectral imagery. Affinity propagation (AP), a new clustering algorithm, is addressed in many fields, and it can be used for hyperspectral band selection. However, this algorithm cannot get a fixed number of exemplars during the message-passing procedure, which limits its uses to a great extent. This paper proposes an adaptive AP (AAP) algorithm for semi-supervised hyperspectral band selection and investigates the effectiveness of distance metrics for improving band selection. Specifically, the exemplar number determination algorithm and bisection method are addressed to improve AP procedure, and the relations between selected exemplar numbers and preferences are established. Experiments are conducted to evaluate the proposed AAP-based band selection algorithm, and the results demonstrate that the proposed method outperforms other popular methods, with lower computational cost and robust results.


Aphidicolin-resistant and -sensitive base excision repair in wild-type and DNA polymerase beta-defective mouse cells.
Several DNA polymerases (Pols) can add complementary bases at the gap created during the base excision repair (BER). To characterize the BER resynthesis step, the repair of a single abasic site by wild-type and Pol beta-defective mouse cell extracts was analysed in the presence of aphidicolin, a specific inhibitor of replicative Pols. We show that there is a competition between distributive and processive Pols for the nucleotide addition at the primer terminus. In wild-type cell extracts, the initial nucleotide insertion involves mainly Pol beta but the elongation step is carried out by a replicative Pol. Conversely, in Pol beta-null cell extracts the synthesis step is carried out by a replicative Pol without any switching to an auxiliary polymerase. We present evidence that short-patch repair synthesis occurs even in the absence of both Pol beta and replicative Pols. Exogeneously added purified human Pol lambda was unable to stimulate this back-up synthesis.


Automated quantitative gait analysis in animal models of movement disorders.
Accurate and reproducible behavioral tests in animal models are of major importance in the development and evaluation of new therapies for central nervous system disease. In this study we investigated for the first time gait parameters of rat models for Parkinson's disease (PD), Huntington's disease (HD) and stroke using the Catwalk method, a novel automated gait analysis test. Static and dynamic gait parameters were measured in all animal models, and these data were compared to readouts of established behavioral tests, such as the cylinder test in the PD and stroke rats and the rotarod tests for the HD group. Hemiparkinsonian rats were generated by unilateral injection of the neurotoxin 6-hydroxydopamine in the striatum or in the medial forebrain bundle. For Huntington's disease, a transgenic rat model expressing a truncated huntingtin fragment with multiple CAG repeats was used. Thirdly, a stroke model was generated by a photothrombotic induced infarct in the right sensorimotor cortex. We found that multiple gait parameters were significantly altered in all three disease models compared to their respective controls. Behavioural deficits could be efficiently measured using the cylinder test in the PD and stroke animals, and in the case of the PD model, the deficits in gait essentially confirmed results obtained by the cylinder test. However, in the HD model and the stroke model the Catwalk analysis proved more sensitive than the rotarod test and also added new and more detailed information on specific gait parameters. The automated quantitative gait analysis test may be a useful tool to study both motor impairment and recovery associated with various neurological motor disorders.


Longitudinal investigation of protozoan parasites in meat lamb farms in southern Western Australia.
In this study, 96 faecal samples were collected from pregnant Merino ewes, at two broad-acre, commercial sheep farms in southern Western Australia, on two separate occasions (16 and 2 weeks prior to lambing). Following lambing, 111 (Farm A) and 124 (Farm B) female crossbred lambs (2-6 weeks old), were individually identified using ear tags (a numbered tag and a radio-frequency tag). A total of 1155 faecal samples were collected only from these individually identified lambs on five separate sampling occasions. All samples were screened using PCR to detect Cryptosporidium (18S rRNA and actin loci) and Giardia duodenalis (glutamate dehydrogenase and triosephosphate isomerise loci). The overall prevalences (lambs positive for a parasite on at least one of the five samplings) at Farm A and B were 81.3% and 71.4%, respectively for Cryptosporidium and similarly 67.3% and 60.5% for Giardia, respectively. Cryptosporidium and Giardia prevalences at individual samplings ranged between 18.5 and 42.6% in lambs and were <10% in the ewes. Cryptosporidium xiaoi was the most prevalent species detected at all five samplings and was also isolated from lamb dam water on Farm B. Cryptosporidium ubiquitum was most commonly detected in younger lambs and Cryptosporidium parvum was detected in lambs at all five samplings, typically in older lambs and as part of a mixed species infection with C. xiaoi. A novel, possibly new genotype (sheep genotype I), was identified in six Cryptosporidium isolates from Farm B. Giardia duodenalis assemblage E was the most common genotype detected at all five samplings, with greater proportions of assemblage A and mixed assemblage A and E infections identified in older lambs. This longitudinal study identified high overall prevalences of Cryptosporidium and Giardia in lambs grazed extensively on pastures, while reinforcing that sampling a random selection of animals from a flock/herd on one occasion (point prevalence), underestimates the overall prevalence of these parasites in the flock/herd across an extended time period. Based on these findings, grazing lambs were identified as a low risk source of zoonotic Cryptosporidium and Giardia species/genotypes, with these protozoa detected at all five samplings in some lambs, indicating that these individuals were either unable to clear the naturally acquired protozoan infections or were repeatedly re-infected from their environment or other flock members.


Changing platforms without stopping the train: experiences of data management and data management systems when adapting platform protocols by adding and closing comparisons.
There is limited research and literature on the data management challenges encountered in multi-arm, multi-stage platform and umbrella protocols. These trial designs allow both (1) seamless addition of new research comparisons and (2) early stopping of accrual to individual comparisons that do not show sufficient activity. FOCUS4 (colorectal cancer) and STAMPEDE (prostate cancer), run from the Medical Research Council Clinical Trials Unit (CTU) at UCL, are two leading UK examples of clinical trials implementing adaptive platform protocol designs. To date, STAMPEDE has added five new research comparisons, closed two research comparisons following pre-planned interim analysis (lack of benefit), adapted the control arm following results from STAMPEDE and other relevant trials, and completed recruitment to six research comparisons. FOCUS4 has closed one research comparison following pre-planned interim analysis (lack of benefit) and added one new research comparison, with a number of further comparisons in the pipeline. We share our experiences from the operational aspects of running these adaptive trials, focusing on data management. We held discussion groups with STAMPEDE and FOCUS4 CTU data management staff to identify data management challenges specific to adaptive platform protocols. We collated data on a number of case report form (CRF) changes, database amendments and database growth since each trial began. We found similar adaptive protocol-specific challenges in both trials. Adding comparisons to and removing them from open trials provides extra layers of complexity to CRF and database development. At the start of an adaptive trial, CRFs and databases must be designed to be flexible and scalable in order to cope with the continuous changes, ensuring future data requirements are considered where possible. When adding or stopping a comparison, the challenge is to incorporate new data requirements while ensuring data collection within ongoing comparisons is unaffected. Some changes may apply to all comparisons; others may be comparison-specific or applicable only to patients recruited during a specific time period. We discuss the advantages and disadvantages of the different approaches to CRF and database design we implemented in these trials, particularly in relation to use and maintenance of generic versus comparison-specific CRFs and databases. The work required to add or remove a comparison, including the development and testing of changes, updating of documentation, and training of sites, must be undertaken alongside data management of ongoing comparisons. Adequate resource is required for these competing data management tasks, especially in trials with long follow-up. A plan is needed for regular and pre-analysis data cleaning for multiple comparisons that could recruit at different rates and periods of time. Data-cleaning activities may need to be split and prioritised, especially if analyses for different comparisons overlap in time. Adaptive trials offer an efficient model to run randomised controlled trials, but setting up and conducting the data management activities in these trials can be operationally challenging. Trialists and funders must plan for scalability in data collection and the resource required to cope with additional competing data management tasks.


Targeting HIV-1 RNase H: N'-(2-Hydroxy-benzylidene)-3,4,5-Trihydroxybenzoylhydrazone as Selective Inhibitor Active against NNRTIs-Resistant Variants.
HIV-1 infection requires life-long treatment and with 2.1 million new infections/year, faces the challenge of an increased rate of transmitted drug-resistant mutations. Therefore, a constant and timely effort is needed to identify new HIV-1 inhibitors active against drug-resistant variants. The ribonuclease H (RNase H) activity of HIV-1 reverse transcriptase (RT) is a very promising target, but to date, still lacks an efficient inhibitor. Here, we characterize the mode of action of N'-(2-hydroxy-benzylidene)-3,4,5-trihydroxybenzoylhydrazone (compound 13), an N-acylhydrazone derivative that inhibited viral replication (EC50 = 10 µM), while retaining full potency against the NNRTI-resistant double mutant K103N-Y181C virus. Time-of-addition and biochemical assays showed that compound 13 targeted the reverse-transcription step in cell-based assays and inhibited the RT-associated RNase H function, being >20-fold less potent against the RT polymerase activity. Docking calculations revealed that compound 13 binds within the RNase H domain in a position different from other selective RNase H inhibitors; site-directed mutagenesis studies revealed interactions with conserved amino acid within the RNase H domain, suggesting that compound 13 can be taken as starting point to generate a new series of more potent RNase H selective inhibitors active against circulating drug-resistant variants.


Strumpell's pure familial spastic paraplegia: case study and review of the literature.
A family with pure Strumpell's familial paraplegia is presented. There were 11 afflicted members involving three generations. The mode of inheritance was dominant, the onset in the first decade, and in this family the disease was mild. Literature data from 104 families with 536 members dating from 1880 are tabulated. This report confirms others regarding mode of inheritance, age of onset, distribution between sexes, and disease manifestations. However, contrary to other reports, we found the dominant and recessive form of pure Strumpell's familial spastic paraplegia to be similar in severity. There are now clinical and pathological data supporting the separation of pure Strumpell's familial spastic paraplegia from the other heredodegenerative diseases of the nervous system.


Antimetastatic effects of PSK (Krestin), a protein-bound polysaccharide obtained from basidiomycetes: an overview.
PSK, a protein-bound polysaccharide obtained from cultured mycelia of Coriolus versicolor in basidiomycetes, is a biological response modifier, diverse operations of which include an antitumor action. We have previously reviewed recent research which had demonstrated that in animals, PSK has a preventive effect on chemical carcinogen-induced, radiation-induced, and spontaneously developed carcinogenesis (Kobayashi et al., Cancer Epidemiol., Biomarkers & Prev., 2: 271-276, 1993). We now focus on the effects of PSK once the progression of carcinogenesis has begun, and review what is now known of the preventive action of PSK on cancer metastasis. Recent research reports that PSK suppresses pulmonary metastasis of methylcholanthrene-induced sarcomas, human prostate cancer DU145M, and lymphatic metastasis of mouse leukemia P388, and that it has prolonged the survival period in spontaneous metastasis models. PSK also suppresses the metastasis of rat hepatoma AH60C, mouse colon cancer colon 26, and mouse leukemia RL male 1 in artificial metastasis models. PSK influences the steps of cancer metastasis in a number of ways: (a) by suppression of intravasation through the inhibition of tumor invasion, adhesion and production of cell matrix-degrading enzymes; (b) by suppression of tumor cell attachment to endothelial cells through the inhibition of tumor cell-induced platelet aggregation; (c) by suppression of tumor cell migration after extravasation through the inhibition of tumor cell motility; and (d) by suppression of tumor growth after extravasation through the inhibition of angiogenesis, the modulation of cytokine production, and the augmentation of effector cell functions. In addition, PSK has suppressed the malignant progression of mouse tumor cells through superoxide trapping.(ABSTRACT TRUNCATED AT 250 WORDS)


Actin foci facilitate activation of the phospholipase C-γ in primary T lymphocytes via the WASP pathway.
Wiscott Aldrich Syndrome protein (WASP) deficiency results in defects in calcium ion signaling, cytoskeletal regulation, gene transcription and overall T cell activation. The activation of WASP constitutes a key pathway for actin filament nucleation. Yet, when WASP function is eliminated there is negligible effect on actin polymerization at the immunological synapse, leading to gaps in our understanding of the events connecting WASP and calcium ion signaling. Here, we identify a fraction of total synaptic F-actin selectively generated by WASP in the form of distinct F-actin 'foci'. These foci are polymerized de novo as a result of the T cell receptor (TCR) proximal tyrosine kinase cascade, and facilitate distal signaling events including PLCγ1 activation and subsequent cytoplasmic calcium ion elevation. We conclude that WASP generates a dynamic F-actin architecture in the context of the immunological synapse, which then amplifies the downstream signals required for an optimal immune response.


Right Hemispheric Contributions to Fine Auditory Temporal Discriminations: High-Density Electrical Mapping of the Duration Mismatch Negativity (MMN).
That language processing is primarily a function of the left hemisphere has led to the supposition that auditory temporal discrimination is particularly well-tuned in the left hemisphere, since speech discrimination is thought to rely heavily on the registration of temporal transitions. However, physiological data have not consistently supported this view. Rather, functional imaging studies often show equally strong, if not stronger, contributions from the right hemisphere during temporal processing tasks, suggesting a more complex underlying neural substrate. The mismatch negativity (MMN) component of the human auditory evoked-potential provides a sensitive metric of duration processing in human auditory cortex and lateralization of MMN can be readily assayed when sufficiently dense electrode arrays are employed. Here, the sensitivity of the left and right auditory cortex for temporal processing was measured by recording the MMN to small duration deviants presented to either the left or right ear. We found that duration deviants differing by just 15% (i.e. rare 115 ms tones presented in a stream of 100 ms tones) elicited a significant MMN for tones presented to the left ear (biasing the right hemisphere). However, deviants presented to the right ear elicited no detectable MMN for this separation. Further, participants detected significantly more duration deviants and committed fewer false alarms for tones presented to the left ear during a subsequent psychophysical testing session. In contrast to the prevalent model, these results point to equivalent if not greater right hemisphere contributions to temporal processing of small duration changes.


Genes related to apoptosis predict necrosis of the liver as a phenotype observed in rats exposed to a compendium of hepatotoxicants.
Some of the biochemical events that lead to necrosis of the liver are well-known. However, the pathogenesis of necrosis of the liver from exposure to hepatotoxicants is a complex biological response to the injury. We hypothesize that gene expression profiles can serve as a signature to predict the level of necrosis elicited by acute exposure of rats to a variety of hepatotoxicants and postulate that the expression profiles of the predictor genes in the signature can provide insight to some of the biological processes and molecular pathways that may be involved in the manifestation of necrosis of the rat liver. Rats were treated individually with one of seven known hepatotoxicants and were analyzed for gene expression by microarray. Liver samples were grouped by the level of necrosis exhibited in the tissue. Analysis of significantly differentially expressed genes between adjacent necrosis levels revealed that inflammation follows programmed cell death in response to the agents. Using a Random Forest classifier with feature selection, 21 informative genes were identified which achieved 90%, 80% and 60% prediction accuracies of necrosis against independent test data derived from the livers of rats exposed to acetaminophen, carbon tetrachloride, and allyl alcohol, respectively. Pathway and gene network analyses of the genes in the signature revealed several gene interactions suggestive of apoptosis as a process possibly involved in the manifestation of necrosis of the liver from exposure to the hepatotoxicants. Cytotoxic effects of TNF-alpha, as well as transcriptional regulation by JUN and TP53, and apoptosis-related genes possibly lead to necrosis. The data analysis, gene selection and prediction approaches permitted grouping of the classes of rat liver samples exhibiting necrosis to improve the accuracy of predicting the level of necrosis as a phenotypic end-point observed from the exposure. The strategy, along with pathway analysis and gene network reconstruction, led to the identification of 1) expression profiles of genes as a signature of necrosis and 2) perturbed regulatory processes that exhibited biological relevance to the manifestation of necrosis from exposure of rat livers to the compendium of hepatotoxicants.


Cancer-Associated Venous Thromboembolic Disease, Version 1.2015.
The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease outline strategies for treatment and prevention of venous thromboembolism (VTE) in adult patients with a diagnosis of cancer or for whom cancer is clinically suspected. VTE is a common complication in patients with cancer, which places them at greater risk for morbidity and mortality. Therefore, risk-appropriate prophylaxis is an essential component for the optimal care of inpatients and outpatients with cancer. Critical to meeting this goal is ensuring that patients get the most effective medication in the correct dose. Body weight has a significant impact on blood volume and drug clearance. Because obesity is a common health problem in industrialized societies, cancer care providers are increasingly likely to treat obese patients in their practice. Obesity is a risk factor common to VTE and many cancers, and may also impact the anticoagulant dose needed for safe and effective prophylaxis. These NCCN Guidelines Insights summarize the data supporting new dosing recommendations for VTE prophylaxis in obese patients with cancer.


A better sequence-read simulator program for metagenomics.
There are many programs available for generating simulated whole-genome shotgun sequence reads. The data generated by many of these programs follow predefined models, which limits their use to the authors' original intentions. For example, many models assume that read lengths follow a uniform or normal distribution. Other programs generate models from actual sequencing data, but are limited to reads from single-genome studies. To our knowledge, there are no programs that allow a user to generate simulated data following non-parametric read-length distributions and quality profiles based on empirically-derived information from metagenomics sequencing data. We present BEAR (Better Emulation for Artificial Reads), a program that uses a machine-learning approach to generate reads with lengths and quality values that closely match empirically-derived distributions. BEAR can emulate reads from various sequencing platforms, including Illumina, 454, and Ion Torrent. BEAR requires minimal user input, as it automatically determines appropriate parameter settings from user-supplied data. BEAR also uses a unique method for deriving run-specific error rates, and extracts useful statistics from the metagenomic data itself, such as quality-error models. Many existing simulators are specific to a particular sequencing technology; however, BEAR is not restricted in this way. Because of its flexibility, BEAR is particularly useful for emulating the behaviour of technologies like Ion Torrent, for which no dedicated sequencing simulators are currently available. BEAR is also the first metagenomic sequencing simulator program that automates the process of generating abundances, which can be an arduous task. BEAR is useful for evaluating data processing tools in genomics. It has many advantages over existing comparable software, such as generating more realistic reads and being independent of sequencing technology, and has features particularly useful for metagenomics work.


Properties of rat liver microsomal stearoyl-coenzyme A desaturase.
1. Rat liver microsomal stearoyl-CoA desaturase activity was shown to be stimulated by both bovine serum albumin and a basic cytoplasmic protein from rat liver. 2. Partially purified desaturase is unaffected by either of these two proteins. 3. Bovine serum albumin appears to exert its effect on the crude system by protecting the desaturase substrate, stearoly-CoA, from the action of endogenous thiolesterases. 4. By using partially purified enzyme preparations, it was possible to establish the substate specificity of the delta9-fatty acyl-CoA desaturase with the C14, C15, C16, C17, C18 and C19 fatty acyl-CoA substrates. Maximum enzyme activity was shown with stearoyl-CoA decreasing with both palmitoyl-CoA and nonadecanoyl-CoA, as reported previously for free fatty acids. 5. Both cytochrome b5 and NADH-cytochrome b5 reductase (EC 18.104.22.168) are required for these studies and a method is described for the purification of homogeneous preparations of detergent-isolated cytochrome b5 from rat liver. 6. From amino acid analyses, a comparison was made of the hydrophobicity of the membrane portion of cytochrome b5 with the hydrophobicity reported for stearoyl-CoA desaturase. The close resemblance of the two values suggested that unlike cytochrome b5 and its reductase, the stearoyl-CoA desaturase may be largely buried in the endoplasmic reticulum.


Intensive iron-chelation therapy with desferrioxamine in iron-loading anaemias.
1. Urinary iron excretion after desferrioxamine has been examined in nine patinets with different iron-loading anaemias. Particular attention has been paid to individual variation in response and the kinetics of iron removal in order to determine the most efficient and convenient method of administration. 2. Twelve-hour subcutaneous infusions of desferrioxamine were comparable with intravenous infusions and gave a mean value of 62% more iron excretion than similar intramuscular bolus doses (range 20--125%). 3. Increasing doses as 12 h subcutaneous infusions produced a linear increase in iron excretion, which was followed by a tendency to reach a plateau. Iron excretion varied greatly between patients, was not related solely to age or estimated iron load, and in most cases was increased by ascorbic acid saturation. 4. Maximum iron-excretion rates were achieved after 3--6 and then maintained throughout an infusion. With bolus injections excretion rates declined rapidly after the first 6 h, during which approximately 60% of the total iron excretion occurred. 5. The dose and method of administration should be 'tailor-made' for each patient. Overnight 12 h subcutaneous infusions can be both as effective as similar doses given over 24 h and a practical way of achieving substantial negative iron balance. 6. Since children receiving regular blood transfusions for congenital anaemias such as thalassaemia usually die at the end of the second decade, this approach to iron chelation offers the possibility of alleviating what have hitherto been fatal-iron loading states.


Prevention of cardioembolic stroke in patients with atrial fibrillation.
Atrial fibrillation (AF) is the most common cardiac arrhythmia and an important independent stroke risk factor, especially in the elderly. This article provides the reader with an overview as well as an update on primary and secondary stroke prevention strategies in patients with AF. Vitamin K antagonists remain the cornerstone therapy in AF patients at high risk of stroke. Both aspirin monotherapy and the combination of aspirin and clopidogrel are inferior to vitamin K antagonists in patients with AF. The new direct thrombin inhibitor dabigatran is at least as effective as warfarin and leads to a significant and clinically relevant decrease in hemorrhagic stroke and intracranial bleeds. Interventional therapies such as percutaneous closure of the left atrial appendage or radiofrequency catheter ablation have not yet been proven to decrease the stroke risk in patients with AF.


Role of a multidisciplinary team (MDT) in the diagnosis, treatment, and outcomes of inflammatory bowel disease: a single Chinese center's experience.
The incidence of inflammatory bowel disease (IBD) with a poor prognosis is increasing, and a single field is not capable of fully diagnosing and comprehensively treating IBD. The purpose of the current study was to explore the role of a multidisciplinary team (MDT) in the diagnosis and treatment of IBD. Subjects were 55 patients with IBD who underwent surgery at this hospital before the establishment of a MDT (before June 2016) and 276 patients who were discussed by a MDT; 72 of the latter patients underwent surgery. The preoperative rate of diagnosis, preoperative basic nutritional status, frequency of emergency surgery, and surgical complications in the two groups were compared to determine whether the MDT significantly affected the diagnosis and treatment of IBD and to explore trends in the types of patients with IBD and treatment decision-making since the establishment of MDT. Results revealed that the MDT significantly improved preoperative diagnostic accuracy for patients with IBD who underwent surgery (p < 0.005), and the frequency of elective surgery decreased significantly (p < 0.005). There were significant differences in the rate of clinical recurrence (p < 0.005) and the rate of additional surgery (p < 0.01) between the two groups, with higher rates in the control group. In terms of preoperative nutritional status, the proportion of decreased serum albumin and hemoglobin in the experimental group was significantly lower than that in the control group (p < 0.05). MDT plays a positive role in accurate preoperative diagnosis, improvement of preoperative preparations, and a reduction in postoperative adverse events for patients with IBD undergoing surgery.


Chiari network: a protective filter against pulmonary embolism in a case of polycythaemia.
The Chiari network, a net-like structure within the right atrium, has been described as an embryonic remnant of no clinical significance. Its role in facilitating paradoxical arterial embolic events and as a potential site for thrombus formation however, has been reported in the literature. This case illustrates the protective filter-effect of the Chiari network in a 79-year-old Caucasian man with an unknown diagnosis of polycythaemia rubra vera who presented with clinical signs and symptoms of deep vein thrombosis. Transoesophageal echocardiogram confirmed entrapment of a thrombus within the Chiari network, which was not visualised following treatment on repeat scanning 1 month later. Here the authors describe how the Chiari network may have prevented the occurrence of a fatal massive pulmonary embolism in a patient with a high pro-thrombotic tendency, and review the current literature regarding the action of this anatomic variant as risk factor or protector.


Synthesis and characterization of an O(6)-2'-deoxyguanosine-alkyl-O(6)-2'-deoxyguanosine interstrand cross-link in a 5'-GNC motif and repair by human O(6)-alkylguanine-DNA alkyltransferase.
O(6)-2'-Deoxyguanosine-alkyl-O(6)-2'-deoxyguanosine interstrand DNA cross-links (ICLs) with a four and seven methylene linkage in a 5'-GNC- motif have been synthesized and their repair by human O6-alkylguanine-DNA alkyltransferase (hAGT) investigated. Duplexes containing 11 base-pairs with the ICLs in the center were assembled by automated DNA solid-phase synthesis using a cross-linked 2'-deoxyguanosine dimer phosphoramidite, prepared via a seven step synthesis which employed the Mitsunobu reaction to introduce the alkyl lesion at the O(6) atom of guanine. Introduction of the four and seven carbon ICLs resulted in no change in duplex stability based on UV thermal denaturation experiments compared to a non-cross-linked control. Circular dichroism spectra of these ICL duplexes exhibited features of a B-form duplex, similar to the control, suggesting that these lesions induce little overall change in structure. The efficiency of repair by hAGT was examined and it was shown that hAGT repairs both ICL containing duplexes, with the heptyl ICL repaired more efficiently relative to the butyl cross-link. These results were reproducible with various hAGT mutants including one that contains a novel V148L mutation. The ICL duplexes displayed similar binding affinities to a C145S hAGT mutant compared to the unmodified duplex with the seven carbon containing ICLs displaying slightly higher binding. Experiments with CHO cells to investigate the sensitivity of these cells to busulfan and hepsulfam demonstrate that hAGT reduces the cytotoxicity of hepsulfam suggesting that the O(6)-2'-deoxyguanosine-alkyl-O(6)-2'-deoxyguanosine interstrand DNA cross-link may account for at least part of the cytotoxicity of this agent.


Effects of photobiomodualtion therapy on breast cancer-related lymphoedema: A systematic review and meta-analysis of randomised controlled trials.
Lymphoedema characterised by the persistent accumulation of the interstitial fluid in peripheral tissues post breast cancer treatments. Photobiomodualtion therapy (PBMT) is widely used as supportive care in patients with breast cancer or breast cancer-related lymphoedema (BCRL). This systematic review and meta-analysis analysed the effectiveness and safety of PBMT for the treatment of BCRL. PubMed, EMBASE, PEDro, SCOPUS, CINAHL, and Cochrane Central Register of Controlled Trials were searched for RCTs on PBMT published before July 2019. Randomised controlled trials (RCTs) that evaluated the efficacy of PBMT on BCRL were included. The primary outcome was the arm circumference or volume, and secondary outcomes were grip strength and pain scores. This study is registered with PROSPERO (number CRD 42018102107). We reviewed nine RCTs that included 316 patients and six studies for mata-analysis. We found no significant difference in the reduction of the arm circumference or arm volume after treatment, one month, and three month follow-up between the PBMT and control groups. Studies revealed no significant differences in the reduction in grip strength and pain scores at 0, 1, 2, and 3 month between the PBMT and control groups. Although PBMT demonstrated a slight improvement in reducing arm circumference and arm volume, the results of our meta-analysis did not show significant benefits in relieving of lymphoedema. Further trials are needed to recruit more participants, and to evaluate the long-term efficacy and safety of PBMT in management of breast cancer-related lymphoedema.


Self-sampling for analysis of respiratory viruses in a large-scale epidemiological study in Sweden.
Viral diagnosis of respiratory tract infections has so far required sampling by health professionals,hampering large-scale epidemiological studies of virus-specific disease outcomes. As part of a population-based, prospective study of work-related risk factors for transmission of viral infections (SWEDE-I), we developed a scheme for self-sampling with nasal swabs. Random selection from the gainfully employed population of a medium-sized town in central Sweden resulted in a study cohort of 2,237 men and women aged 25 to 63 years. From September 2011 through May 2012, the cohort reported all instances of respiratory tract infection or gastroenteritis and participants concomitantly sent self-sampled nasal swabs for analysis using regular mail. Diagnosis of 14 viruses was performed. A total of 1,843 samples were received. The week-wise average delay between disease on set and arrival of the specimens at the laboratory varied between four and six days, and the corresponding median delay was between 3.5 and six days. In line with previous community-based studies, picorna- and coronaviruses dominated in specimens obtained from the self-sampling scheme. The results of self-sampling were contrasted to those from contemporaneous routine clinical sampling, on the same age group, in the adjacent Stockholm county. Although higher proportions of positive samples for respiratory syncytial virus and influenza were observed in the clinical sampling scheme, estimations of seasonality for influenza A and picornaviruses derived from both schemes were similar. Our findings show that nasal self-sampling is feasible in large-scale surveillance of respiratory infections and opens new prospects for population based,virologically verified research on virus spread,burden of disease, and effects of environmental factors or interventions.


Correspondence: Laparoscopic repair of abdominal wall hernia--"How I do it"--synopsis of a seemingly straightforward technique.
Abdominal wall hernia repairs are commonly performed worldwide in general surgery. There is still no agreed consensus on the optimal surgical approach. Since the turn of the twenty-first century, minimally invasive techniques have gained in popularity as they combine the advantages of limited abdominal wall dissection, reduced post-operative pain and risk of complications, and shorter hospital stay. Although the added cost incurred by using sophisticated laparoscopic instruments may be quite substantial, it is precisely counterbalanced by an improved morbidity rate, faster discharge home and time to return to work. Laparoscopic abdominal wall hernia repair is often challenging, as it requires good anatomical knowledge, eye-hand coordination and diversified laparoscopic skills. The objective of this article is not to present another set of personal data and to compare it with already published results on this matter, but simply to offer comprehensive guidelines on the practical aspects of this relatively new technique. Some of these steps have already been discussed but most of the time in a scattered way in the surgical literature, while others are the fruit of a personal expertise grasped over the years.


"Hotspots" in trauma memories in the treatment of post-traumatic stress disorder: a replication.
"Hotspots" refer to memories of detailed moments of peak emotional distress during a traumatic event. This study investigates hotspot frequency, and the emotions and cognitions contained in hotspots of memory for trauma, to replicate a previous study in this area (Holmes, Grey, & Young, 2005). Participants were patients receiving treatment for post-traumatic stress disorder (PTSD) at a specialist outpatient clinic after experiencing a range of traumatic events. The main finding was that, after fear, the most common emotions reported were anger and sadness. Cognitions related to psychological threat to the self were more common than those related to physical threat.


Chlamydia pneumoniae is genetically diverse in animals and appears to have crossed the host barrier to humans on (at least) two occasions.
Chlamydia pneumoniae is a common human and animal pathogen associated with a wide range of diseases. Since the first isolation of C. pneumoniae TWAR in 1965, all human isolates have been essentially clonal, providing little evolutionary insight. To address this gap, we investigated the genetic diversity of 30 isolates from diverse geographical locations, from both human and animal origin (amphibian, reptilian, equine and marsupial). Based on the level of variation that we observed at 23 discreet gene loci, it was clearly evident that the animal isolates were more diverse than the isolates of human origin. Furthermore, we show that C. pneumoniae isolates could be grouped into five major genotypes, A-E, with A, B, D and E genotypes linked by geographical location, whereas genotype C was found across multiple continents. Our evidence strongly supports two separate animal-to-human cross species transfer events in the evolutionary history of this pathogen. The C. pneumoniae human genotype identified in the USA, Canada, Taiwan, Iran, Japan, Korea and Australia (non-Indigenous) most likely originated from a single amphibian or reptilian lineage, which appears to have been previously geographically widespread. We identified a separate human lineage present in two Australian Indigenous isolates (independent geographical locations). This lineage is distinct and is present in Australian amphibians as well as a range of Australian marsupials.


Ethnic differences in potentially preventable hospitalizations among Asian Americans, Native Hawaiians, and other Pacific Islanders: implications for reducing health care disparities.
A serious challenge to eliminating US health disparities stems from the inability to reliably measure outcomes, particularly for numerically small populations. Our study aimed to produce reliable estimates of health care quality among Native Hawaiian (NH), Other Pacific Islander (PI), and Asian American (AA) subgroups. Prevention Quality Indicators (PQIs) from the Agency for Healthcare Research and Quality were used to calculate 3 PQI composites and 8 individual chronic condition indicators. Data sources were the Healthcare Cost and Utilization Project State Inpatient Databases and the Hawaii Health Survey. Risk-adjusted PQI rates for adults were computed for 2005 through 2007. Relative rates for 2007 were calculated for each racial/ethnic group and compared to Whites. Statistical significance was based on P < .05 from a two-sided t test. The combined AANHPI group had higher overall and chronic PQI composite rates than Whites in 2007. When disaggregated into discrete racial/ethnic subgroups, Chinese and Japanese had lower rates than Whites for all 3 composites, whereas NH and Other PI subgroups typically had the worst health outcomes. Trends in PQI rates from 2005 through 2007 showed persistent gaps between groups, especially across chronic PQIs. Despite recent efforts to reduce racial/ethnic health care disparities, significant gaps remain in potentially preventable hospitalization rates. Practical tools that measure inequities across diverse, numerically small populations may suggest ways to optimally funnel limited resources toward improving racial/ethnic differences in health outcomes.


Changing fruit and vegetable consumption among children: the 5-a-Day Power Plus program in St. Paul, Minnesota.
A randomized school based trial sought to increase fruit and vegetable consumption among children using a multicomponent approach. The intervention, conducted in 20 elementary schools in St. Paul, targeted a multiethnic group of children who were in the fourth grade in spring 1995 and the fifth grade in fall 1995. The intervention consisted of behavioral curricula in classrooms, parental involvement, school food service changes, and industry support and involvement. Lunchroom observations and 24-hour food recalls measured food consumption. Parent telephone surveys and a health behavior questionnaire measured psychosocial factors. The intervention increased lunchtime fruit consumption and combined fruit and vegetable consumption, lunchtime vegetable consumption among girls, and daily fruit consumption as well as the proportion of total daily calories attributable to fruits and vegetables. Multicomponent school-based programs can increase fruit and vegetable consumption among children. Greater involvement of parents and more attention to increasing vegetable consumption, especially among boys, remain challenges in future intervention research.


Laboratory investigations in the diagnosis of septicaemia and malaria.
During a three month prospective study, 229 in-patients with fever, admitted to St. Mary's Hospital, Mumias, were examined for bacterial and malarial causes of fever. Blood cultures taken from patients appeared to contain true pathogens in 51 (22%) cases. Nine different bacterial species were identified from positive blood cultures of which four predominated: Salmonella typhi (46%), Streptococcus pneumoniae (19%), Salmonella enteritidis (12%), Salmonella typhimurium (8%). S. enteritidis and S. typhimurium isolates were mostly multi-antibiotic resistant, compared to S. typhi isolates which were relatively susceptible to the antibiotics used in the hospital. Only 70% of the S. pneumoniae isolates were susceptible to penicillin. Among 227 patients in whom a thick blood-film for malaria parasites and HIV serology were performed, only 25 (11%) revealed malaria parasites. HIV-1 antibodies were detected in 51 (22%) patients. Without appropriate laboratory examinations, the majority of the diagnoses would have been missed and no optimal treatment would have been administered. This may increase resistance to antimalarials and antibiotics.


Area-Level Variation and Human Papillomavirus Vaccination among Adolescents and Young Adults in the United States: A Systematic Review.
Understanding how human papillomavirus (HPV) vaccination coverage varies by geography can help to identify areas of need for prevention and control efforts. A systematic review of the literature was conducted using a combination of keywords (HPV vaccination, geography, neighborhoods, and sociodemographic factors) on Medline and Embase databases. Studies had to provide information on HPV vaccination by area-level variables, be conducted in the United States, and be published in English (analyzing data from January 2006 to February 2020). Conference abstracts and opinion pieces were excluded. Of 733 records identified, 25 were included for systematic review. Across studies, the average initiation rate was 40.5% (range, 6.3%-78.0%). The average rate of completion was 23.4% (range, 1.7%-55.2%). Geographic regions and area-level factors were associated with HPV vaccination, including zip code tabulation area-level poverty, urbanicity/rurality, racial/ethnic composition, and health service region characteristics. Only three studies utilized geospatial approaches. None accounted for geospatial-temporal associations. Individual-level and area-level factors and their interactions are important for characterizing HPV vaccination. Results demonstrate the need to move beyond existing multilevel methods and toward the adoption of geospatial approaches that allow for the mapping and detection of geographic areas with low HPV vaccination coverage.


[What factors are important for the successful implementation of guidelines?].
The influence of a guideline on clinical practice depends on the extent to which the recommendations in the guideline are acted upon (degree of adherence). To assess the degree of adherence to recommendations in evidence-based guidelines and to discuss factors that influence adherence. Review of the literature. results In several studies the average degree of adherence to recommendations in guidelines was no higher than 60 to 70%, but the percentage differed markedly, depending on the particular guidelines and the individual professionals involved. The degree of adherence was influenced by a large number of factors; these were connected with the guideline itself, the efforts made by the professional organisations, the organisation of care and institutional management, the individual professional, and the patient. The implementation of a guideline actually begins before and during the formulation of the guideline. Mistakes made in the preparatory phase can have a negative effect on adherence and often it may no longer be possible to correct these mistakes at a later stage. If the implementation is to be successful, numerous strategies have to be adopted along the way; for instance, the target-group has to be made aware of the guideline and be encouraged to accept it. Guideline development is not an aim in itself, but should be seen as part of a quality circle in which implementation and evaluation also play an important role.


Functional analysis of HOXD9 in human gliomas and glioma cancer stem cells.
HOX genes encode a family of homeodomain-containing transcription factors involved in the determination of cell fate and identity during embryonic development. They also behave as oncogenes in some malignancies. In this study, we found high expression of the HOXD9 gene transcript in glioma cell lines and human glioma tissues by quantitative real-time PCR. Using immunohistochemistry, we observed HOXD9 protein expression in human brain tumor tissues, including astrocytomas and glioblastomas. To investigate the role of HOXD9 in gliomas, we silenced its expression in the glioma cell line U87 using HOXD9-specific siRNA, and observed decreased cell proliferation, cell cycle arrest, and induction of apoptosis. It was suggested that HOXD9 contributes to both cell proliferation and/or cell survival. The HOXD9 gene was highly expressed in a side population (SP) of SK-MG-1 cells that was previously identified as an enriched-cell fraction of glioma cancer stem-like cells. HOXD9 siRNA treatment of SK-MG-1 SP cells resulted in reduced cell proliferation. Finally, we cultured human glioma cancer stem cells (GCSCs) from patient specimens found with high expression of HOXD9 in GCSCs compared with normal astrocyte cells and neural stem/progenitor cells (NSPCs). Our results suggest that HOXD9 may be a novel marker of GCSCs and cell proliferation and/or survival factor in gliomas and glioma cancer stem-like cells, and a potential therapeutic target.


Polygyny and HIV in Malawi.
We review the relationship between polygyny and HIV and identify a positive individual-level correlation, and a negative ecological correlation. We subsequently examine two mechanisms that contribute to the individual-level correlation. First, we find that men in polygynous marriages have more extramarital sex than men in monogamous unions (both in terms of self reports and in terms of spousal reports of the suspicion of adultery). Second, we find evidence of adverse selection of HIV positive women into polygynous unions via an investigation of the relationship between marriage order and polygyny status. We conclude with reflections about possible explanations for the distinct individual and ecological correlations.


Regulatory T cells in transplantation.
Our ability to harness tolerance mechanisms will have a major impact in organ transplantation. It should enable drug minimization, and eventually, the elimination of all immunosuppressive drugs. An improved understanding of the biology of regulatory T cells will make it possible to replace current induction regimens with those favouring the selective vaccination of T cells that prevent graft rejection. Once regulation is established, the continued supply of graft antigens should empower T cell regulation to become the dominant natural mechanism to prevent graft rejection.


Structure of the c(10) ring of the yeast mitochondrial ATP synthase in the open conformation.
The proton pore of the F(1)F(o) ATP synthase consists of a ring of c subunits, which rotates, driven by downhill proton diffusion across the membrane. An essential carboxylate side chain in each subunit provides a proton-binding site. In all the structures of c-rings reported to date, these sites are in a closed, ion-locked state. Structures are here presented of the c(10) ring from Saccharomyces cerevisiae determined at pH 8.3, 6.1 and 5.5, at resolutions of 2.0 Å, 2.5 Å and 2.0 Å, respectively. The overall structure of this mitochondrial c-ring is similar to known homologs, except that the essential carboxylate, Glu59, adopts an open extended conformation. Molecular dynamics simulations reveal that opening of the essential carboxylate is a consequence of the amphiphilic nature of the crystallization buffer. We propose that this new structure represents the functionally open form of the c subunit, which facilitates proton loading and release.


Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia.
Eltrombopag is an oral thrombopoietin-receptor agonist. This study evaluated the efficacy of eltrombopag for increasing platelet counts and reducing the need for platelet transfusions in patients with thrombocytopenia and chronic liver disease who are undergoing an elective invasive procedure. We randomly assigned 292 patients with chronic liver disease of diverse causes and platelet counts of less than 50,000 per cubic millimeter to receive eltrombopag, at a dose of 75 mg daily, or placebo for 14 days before a planned elective invasive procedure that was performed within 5 days after the last dose. The primary end point was the avoidance of a platelet transfusion before, during, and up to 7 days after the procedure. A key secondary end point was the occurrence of bleeding (World Health Organization [WHO] grade 2 or higher) during this period. A platelet transfusion was avoided in 104 of 145 patients who received eltrombopag (72%) and in 28 of 147 who received placebo (19%) (P<0.001). No significant difference between the eltrombopag and placebo groups was observed in bleeding episodes of WHO grade 2 or higher, which were reported in 17% and 23% of patients, respectively. Thrombotic events of the portal venous system were observed in 6 patients who received eltrombopag, as compared with 1 who received placebo, resulting in the early termination of the study. The incidence and severity of other adverse events were similar in the eltrombopag and placebo groups. Eltrombopag reduced the need for platelet transfusions in patients with chronic liver disease who were undergoing elective invasive procedures, but it was associated with an increased incidence of portal-vein thrombosis, as compared with placebo. (Funded by GlaxoSmithKline; ELEVATE ClinicalTrials.gov number, NCT00678587.).


RIFRAF: a frame-resolving consensus algorithm.
Protein coding genes can be studied using long-read next generation sequencing. However, high rates of indel sequencing errors are problematic, corrupting the reading frame. Even the consensus of multiple independent sequence reads retains indel errors. To solve this problem, we introduce Reference-Informed Frame-Resolving multiple-Alignment Free template inference algorithm (RIFRAF), a sequence consensus algorithm that takes a set of error-prone reads and a reference sequence and infers an accurate in-frame consensus. RIFRAF uses a novel structure, analogous to a two-layer hidden Markov model: the consensus is optimized to maximize alignment scores with both the set of noisy reads and with a reference. The template-to-reads component of the model encodes the preponderance of indels, and is sensitive to the per-base quality scores, giving greater weight to more accurate bases. The reference-to-template component of the model penalizes frame-destroying indels. A local search algorithm proceeds in stages to find the best consensus sequence for both objectives. Using Pacific Biosciences SMRT sequences from an HIV-1 env clone, NL4-3, we compare our approach to other consensus and frame correction methods. RIFRAF consistently finds a consensus sequence that is more accurate and in-frame, especially with small numbers of reads. It was able to perfectly reconstruct over 80% of consensus sequences from as few as three reads, whereas the best alternative required twice as many. RIFRAF is able to achieve these results and keep the consensus in-frame even with a distantly related reference sequence. Moreover, unlike other frame correction methods, RIFRAF can detect and keep true indels while removing erroneous ones. RIFRAF is implemented in Julia, and source code is publicly available at https://github.com/MurrellGroup/Rifraf.jl. Supplementary data are available at Bioinformatics online.


Selection based on the size of the black tie of the great tit may be reversed in urban habitats.
A standard approach to model how selection shapes phenotypic traits is the analysis of capture-recapture data relating trait variation to survival. Divergent selection, however, has never been analyzed by the capture-recapture approach. Most reported examples of differences between urban and nonurban animals reflect behavioral plasticity rather than divergent selection. The aim of this paper was to use a capture-recapture approach to test the hypothesis that divergent selection can also drive local adaptation in urban habitats. We focused on the size of the black breast stripe (i.e., tie width) of the great tit (Parus major), a sexual ornament used in mate choice. Urban great tits display smaller tie sizes than forest birds. Because tie size is mostly genetically determined, it could potentially respond to selection. We analyzed capture/recapture data of male great tits in Barcelona city (N = 171) and in a nearby (7 km) forest (N = 324) from 1992 to 2008 using MARK. When modelling recapture rate, we found it to be strongly influenced by tie width, so that both for urban and forest habitats, birds with smaller ties were more trap-shy and more cautious than their larger tied counterparts. When modelling survival, we found that survival prospects in forest great tits increased the larger their tie width (i.e., directional positive selection), but the reverse was found for urban birds, with individuals displaying smaller ties showing higher survival (i.e., directional negative selection). As melanin-based tie size seems to be related to personality, and both are heritable, results may be explained by cautious personalities being favored in urban environments. More importantly, our results show that divergent selection can be an important mechanism in local adaptation to urban habitats and that capture-recapture is a powerful tool to test it.


Recent Progress in Deciphering the Etiopathogenesis of Primary Membranous Nephropathy.
Primary membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. Discovery of several antibodies has contributed to an increased understanding of MN. Antibodies against the M-type phospholipase A2 receptor (PLA2R) are present in 50-100% with primary MN and are associated with a lower frequency of spontaneous remission. High levels are linked with a higher probability of treatment resistance, higher proteinuria, and impaired renal function, as well as a more rapid decline of kidney function during follow-up. Immunologic remission precedes reduction of proteinuria by months. Pretransplant evaluation of PLA2R antibodies is warranted to predict recurrence of disease following renal transplantation. Several risk alleles related to the PLA2R1 gene and within the HLA loci have been identified, whereas epitope spreading of PLA2R may predict treatment response. More recently, thrombospondin type 1 domain-containing 7A (THSD7A) antibodies have been discovered in primary MN. Several other rare antigens have been described, including antibodies against neutral endopeptidase as a cause of antenatal MN and circulating cationic bovine serum albumin as an antigen with implications in childhood MN. This review focuses on the progress with a special focus on diagnostic accuracy, predictive value, and treatment implications of the established and proposed antigens.