Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation.

The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation

Integrating livelihoods and conservation in protected areas: Understanding the role and stakeholder views on prospects for non-timber forest products, a Bangladesh case study

Protected areas (PAs) represent a key global strategy in biodiversity conservation. In tropical developing countries, the management of PAs is a great challenge as many contain resources on which local communities rely. Collection and trading of non-timber forest products (NTFPs) is a well-established forest-based livelihood strategy, which has been promoted as a potential means for enhanced conservation and improved rural livelihoods in recent years, even though the sustainability or ecological implications have rarely been tested. We conducted an exploratory survey to understand the role and stakeholder views on conservation prospects and perceived ecological feasibility of NTFPs and harvesting schemes in a northeastern PA of Bangladesh, namely the Satchari National Park. Households (n = 101) were interviewed from three different forest dependency categories, adopting a stratified random sampling approach and using a semi-structured questionnaire. The study identified 13 locally important NTFPs, with five being critically important to supporting local livelihoods. Our study suggests that collection, processing and trading in NTFPs constitutes the primary occupation for about 18% of local inhabitants and account for an estimated 19% of their cash annual income. The household consensus on issues relating to NTFPs and their prospective role in conservation was surprisingly high, with 48% of respondents believing that promotion of NTFPs in the PA could have positive conservation value. The majority (71%) of households also had some understanding of the ecological implications of NTFP harvesting, sustainability (53%) and possible management and monitoring regimes (100%). With little known about their real application in the field, our study suggests further investigations are required to understand the ecological compatibility of traditional NTFP harvesting patterns and management. © 2010 Taylor & Francis

Systematic evaluation of immune regulation and modulation

Cancer immunotherapies are showing promising clinical results in a variety of malignancies. Monitoring the immune as well as the tumor response following these therapies has led to significant advancements in the field. Moreover, the identification and assessment of both predictive and prognostic biomarkers has become a key component to advancing these therapies. Thus, it is critical to develop systematic approaches to monitor the immune response and to interpret the data obtained from these assays. In order to address these issues and make recommendations to the field, the Society for Immunotherapy of Cancer reconvened the Immune Biomarkers Task Force. As a part of this Task Force, Working Group 3 (WG3) consisting of multidisciplinary experts from industry, academia, and government focused on the systematic assessment of immune regulation and modulation. In this review, the tumor microenvironment, microbiome, bone marrow, and adoptively transferred T cells will be used as examples to discuss the type and timing of sample collection. In addition, potential types of measurements, assays, and analyses will be discussed for each sample. Specifically, these recommendations will focus on the unique collection and assay requirements for the analysis of various samples as well as the high-throughput assays to evaluate potential biomarkers

A population-specific reference panel empowers genetic studies of Anabaptist populations

Genotype imputation is a powerful strategy for achieving the large sample sizes required for identification of variants underlying complex phenotypes, but imputation of rare variants remains problematic. Genetically isolated populations offer one solution, however population-specific reference panels are needed to assure optimal imputation accuracy and allele frequency estimation. Here we report the Anabaptist Genome Reference Panel (AGRP), the first whole-genome catalogue of variants and phased haplotypes in people of Amish and Mennonite ancestry. Based on high-depth whole-genome sequence (WGS) from 265 individuals, the AGRP contains >12 M high-confidence single nucleotide variants and short indels, of which ~12.5% are novel. These Anabaptist-specific variants were more deleterious than variants with comparable frequencies observed in the 1000 Genomes panel. About 43,000 variants showed enriched allele frequencies in AGRP, consistent with drift. When combined with the 1000 Genomes Project reference panel, the AGRP substantially improved imputation, especially for rarer variants. The AGRP is freely available to researchers through an imputation server

Spatiotemporal Correlations between Blood-Brain Barrier Permeability and Apparent Diffusion Coefficient in a Rat Model of Ischemic Stroke

Variations in apparent diffusion coefficient of water (ADC) and blood-brain barrier (BBB) permeability after ischemia have been suggested, though the correlation between ADC alterations and BBB opening remains to be studied. We hypothesized that there are correlations between the alteration of ADC and BBB permeability. Rats were subjected to 2 h of transient middle cerebral artery occlusion and studied at 3 and 48 h of reperfusion, which are crucial times of BBB opening. BBB permeability and ADC values were measured by dynamic contrast-enhanced MRI and diffusion-weighted imaging, respectively. Temporal and spatial analyses of the evolution of BBB permeability and ADC alteration in cortical and subcortical regions were conducted along with the correlation between ADC and BBB permeability data. We found significant increases in BBB leakage and reduction in ADC values between 3 and 48 h of reperfusion. We identified three MR tissue signature models: high Ki and low ADC, high Ki and normal ADC, and normal Ki and low ADC. Over time, areas with normal Ki and low ADC transformed into areas with high Ki. We observed a pattern of lesion evolution where the extent of initial ischemic injury reflected by ADC abnormalities determines vascular integrity. Our results suggest that regions with vasogenic edema alone are not likely to develop low ADC by 48 h and may undergo recovery

Long-term vitamin E supplementation fails to reduce lipid peroxidation in people at cardiovascular risk: analysis of underlying factors

BACKGROUND: Antioxidant supplementation with vitamin E had no effect in the prevention of cardiovascular diseases (CVD) in three recent large, randomized clinical trials. In order to reassess critically the role of vitamin E in CVD prevention, it is important to establish whether these results are related to a lack of antioxidant action. METHODS: We examined the in vivo antioxidant effect of vitamin E (300 mg/day for about three years) in 144 participants in the Primary Prevention Project (females and males, aged ≥ 50 y, with at least one major CV risk factor, but no history of CVD). Urinary 8-epi-PGF(2α) (isoprostane F(2α)-III or 15-F(2t)-isoP), a validated biomarker of lipid peroxidation, was measured by mass spectrometry. RESULTS: Urinary excretion of 8-epi-PGF(2α) [pg/mg creatinine, median (range)] was 141 (67–498) in treated and 148 (76–561) in untreated subjects (p = 0.10). Taking into account possible confounding variables, multiple regression analysis confirmed that vitamin E had no significant effect on this biomarker. Levels of 8-epi-PGF(2α) were in the normal range for most subjects, except smokers and those with uncontrolled blood pressure or hyperglycemia. CONCLUSIONS: Prolonged vitamin E supplementation did not reduce lipid peroxidation in subjects with major cardiovascular risk factors. The observation that the rate of lipid peroxidation was near normal in a large proportion of subjects may help explain why vitamin E was not effective as an antioxidant in the PPP study and was ineffective for CVD prevention in large scale trials

Factors associated with lack of postnatal care among Palestinian women: A cross-sectional study of three clinics in the West Bank

Dhaher E, Mikolajczyk RT, Maxwell AE, Krämer A. Factors associated with lack of postnatal care among Palestinian women: a cross-sectional study of three clinics in the West Bank. BMC Pregnancy and Childbirth. 2008;8(1): 26.Background: Only about one-third of women in Palestine (West Bank and Gaza) obtain postpartum care. Therefore, the goal of this study was to assess factors associated with lack of postnatal care, women's reasons for not obtaining postnatal care, and their attitudes towards its importance. Methods: In early 2006, a cross-sectional survey was conducted at three clinics run by the Ministry of Health providing Mother and Child Health Care in West Bank, Palestine. A total of 264 postpartum women attending the clinics were interviewed face-to-face, using a structured questionnaire. Results: Although the majority of women considered postnatal care necessary (66.1%), only 36.6% of women obtained postnatal care. The most frequent reason for not obtaining postnatal care was that women did not feel sick and therefore did not need postnatal care (85%), followed by not having been told by their doctor to come back for postnatal care (15.5%). Based on a multivariable analysis, use of postnatal care was higher among women who had experienced problems during their delivery, had a cesarean section, or had an instrumental vaginal delivery than among women who had a spontaneous vaginal delivery. Use of postnatal care was also higher among women who delivered in a private hospital as compared to those who delivered in a public hospital. In addition, we found regional differences. Conclusion: The higher use of postnatal care among high-risk women is appropriate, but some clinically dangerous conditions can also occur in low-risk women. Future efforts should therefore focus on providing postnatal care to a larger number of low-risk women