The neglected hepatitis C virus genotypes 4, 5 and 6: an international consensus report

Hepatitis C virus (HCV) genotypes 4, 5 and 6 represent >20% of all HCV cases worldwide. HCV-4 is mainly seen in Egypt, where it represents 90% of all HCV cases. Antischistosomal therapy was the main cause of contamination there, followed by procedures performed by informal providers and traditional healers such as dental care, wound treatment, circumcision, deliveries, excision and scarification. It is also highly prevalent in sub-Saharan Africa and in the Middle East. In Europe, its prevalence has recently increased particularly among intravenous drug users and in immigrants. HCV-5 is mainly found in South Africa, where it represents 40% of all HCV genotypes, but four pockets of HCV-5 were found in France, Spain, Syria and Belgium and sporadic cases were found elsewhere. The mode of transmission is mainly iatrogenic and transfusion. HCV-6 is found in Hong Kong, Vietnam, Thailand and Myanmar and also in American and Australian from Asian origin. The response to treatment in HCV-4 is intermediate between HCV-1 and HCV-2 and HCV-3. A sustained viral response is achieved in 43-70% with pegylated interferon and ribavirin. It is higher in Egyptians than Europeans and Africans and is negatively related to insulin resistance and to the severity of fibrosis. It increases to >80% with 24 weeks of therapy only if a rapid virological response is achieved. In HCV-5, a sustained virological response is achieved in >60% with 48 weeks of therapy. HCV-6 is also considered an easy-to-treat genotype, leading to a response in 60-85% of cases. © 2009 John Wiley & Sons A/S.link_to_subscribed_fulltex

Initiation of T cell signaling by CD45 segregation at 'close contacts'.

It has been proposed that the local segregation of kinases and the tyrosine phosphatase CD45 underpins T cell antigen receptor (TCR) triggering, but how such segregation occurs and whether it can initiate signaling is unclear. Using structural and biophysical analysis, we show that the extracellular region of CD45 is rigid and extends beyond the distance spanned by TCR-ligand complexes, implying that sites of TCR-ligand engagement would sterically exclude CD45. We also show that the formation of 'close contacts', new structures characterized by spontaneous CD45 and kinase segregation at the submicron-scale, initiates signaling even when TCR ligands are absent. Our work reveals the structural basis for, and the potent signaling effects of, local CD45 and kinase segregation. TCR ligands have the potential to heighten signaling simply by holding receptors in close contacts.The authors thank R.A. Cornall, M.L. Dustin and P.A. van der Merwe for comments on the manuscript and S. Ikemizu for useful discussions about the structure. We also thank W. Lu and T. Walter for technical support with protein expression and crystallization, the staff at Diamond Light Source beamlines I02, I03 and I04-1 (proposal mx10627) and European Synchrotron Radiation Facility beamlines ID23EH1 and ID23EH2 for assistance at the synchrotrons, G. Sutton for assistance with MALS experiments, and M. Fritzsche for advice on the calcium analysis. This work was funded by the Wellcome Trust (098274/Z/12/Z to S.J.D.; 090532/Z/09/Z to R.J.C.G.; 090708/Z/09/Z to D.K.), the UK Medical Research Council (G0700232 to A.R.A.), the Royal Society (UF120277 to S.F.L.) and Cancer Research UK (C20724/A14414 to C.S.; C375/A10976 to E.Y.J.). The Oxford Division of Structural Biology is part of the Wellcome Trust Centre for Human Genetics, Wellcome Trust Core Award Grant Number 090532/Z/09/Z. We acknowledge financial support from Instruct, an ESFRI Landmark Project. The OPIC electron microscopy facility was funded by a Wellcome Trust JIF award (060208/Z/00/Z).This is the author accepted manuscript. The final version is available from Nature Publishing Group via https://doi.org/10.1038/ni.339

Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin

Immune responses to autoantigens are in part controlled by deletion of autoreactive cells through genetically regulated selection mechanisms. We have directly analyzed peripheral CD4+ proinsulin (PI) 76–90 (SLQPLALEGSLQKRG)-specific T cells using soluble fluorescent major histocompatibility complex class II tetramers. Subjects with type I diabetes and healthy controls with high levels of peripheral proinsulin-specific T cells were characterized by the presence of a disease-susceptible polymorphism in the insulin variable number of tandem repeats (INS-VNTR) gene. Conversely, subjects with a ‘protective' polymorphism in the INS-VNTR gene had nearly undetectable levels of proinsulin tetramer-positive T cells. These results strongly imply a direct relationship between genetic control of autoantigen expression and peripheral autoreactivity, in which proinsulin genotype restricts the quantity and quality of the potential T-cell response. Using a modified tetramer to isolate low-avidity proinsulin-specific T cells from subjects with the susceptible genotype, transcript arrays identified several induced pro-apoptotic genes in the control, but not diabetic subjects, likely representing a second peripheral mechanism for maintenance of tolerance to self antigens

Anthropic resource exploitation and use of the territory at the onset of social complexity in the Neolithic-Chalcolithic Western Pyrenees: a multi-isotope approach

Carbon (δ13C) and nitrogen (δ15N) stable isotope analyses from bone collagen provide information about the dietary protein input, while strontium isotopes (87Sr/86Sr) from tooth enamel give us data about provenance and potential territorial mobility of past populations. To date, isotopic results on the prehistory of the Western Pyrenees are scarce. In this article, we report human and faunal values of the mentioned isotopes from the Early-Middle Neolithic site of Fuente Hoz (Anuntzeta) and the Late Neolithic/Early Chalcolithic site of Kurtzebide (Letona, Zigoitia). The main objectives of this work are to analyze the dietary and territorial mobility patterns of these populations. Furthermore, as an additional aim, we will try to discuss social ranking based on the isotope data and existing literature on this topic in the region of study. Our results show that, based on the bioavailable Sr values, both purported local and non-local humans were buried together at the sites. Additionally, they suggest similar resource consumption based on C3 terrestrial resources (i.e. ovicaprids, bovids, and suids) as the main part of the protein input. Overall, this study sheds light on how individuals from different backgrounds were still buried together and shared the same dietary lifestyle at a time in the Prehistory of Iberia when social complexities started to appear

TRY plant trait database - enhanced coverage and open access

Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Synergistic Reversal of Intrahepatic HCV-Specific CD8 T Cell Exhaustion by Combined PD-1/CTLA-4 Blockade

Viral persistence is associated with hierarchical antiviral CD8 T cell exhaustion with increased programmed death-1 (PD-1) expression. In HCV persistence, HCV-specific CD8 T cells from the liver (the site of viral replication) display increased PD-1 expression and a profound functional impairment that is not reversed by PD-1 blockade alone. Here, we report that the inhibitory receptor cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is preferentially upregulated in PD-1+ T cells from the liver but not blood of chronically HCV-infected patients. PD-1/CTLA-4 co-expression in intrahepatic T cells was associated with a profound HCV-specific effector dysfunction that was synergistically reversed by combined PD-1/CTLA-4 blockade in vitro, but not by blocking PD-1 or CTLA-4 alone. A similar effect was observed in circulating HCV-specific CD8 T cells with increased PD-1/CTLA-4 co-expression during acute hepatitis C. The functional response to combined blockade was directly associated with CTLA-4 expression, lost with CD28-depletion and CD4-independent (including CD4+FoxP3+ Tregs). We conclude that PD-1 and CTLA-4 pathways both contribute to virus-specific T cell exhaustion at the site of viral replication by a redundant mechanism that requires combined PD-1/CTLA-4 blockade to reverse. These findings provide new insights into the mechanisms of virus-specific T cell dysfunction, and suggest that the synergistic effect by combined inhibitory receptor blockade might have a therapeutic application against chronic viral infection in vivo, provided that it does not induce autoimmunity

Earliest evidence for the ivory trade in southern Africa : isotopic and ZooMS analysis of seventh-tenth century AD ivory from KwaZulu-Natal

KwaGandaganda, Ndondondwane and Wosi were major Early Farming Community settlements in what is today the KwaZulu-Natal province of South Africa. These sites have yielded, among other remains, abundant evidence of ivory and ivory working dating to the seventh–tenth centuries ad, pre-dating by approximately 200 years the better-known ivory artefacts from sites in the Limpopo River Valley and surrounding regions. We report the results of carbon, nitrogen and strontium isotope analysis to explore the origins and procurement of this ivory, in combination with Zooarchaeology by Mass Spectrometry (ZooMS) to identify the species of animals from which it was derived. All of the ivory studied using ZooMS was elephant, despite the presence of hippopotamus remains on all three sites. Some ivory was probably obtained from elephant herds that lived close to the sites, in the densely wooded river valleys favoured by both elephants and early farmers. Other material came from savannah environments further afield. Ivory found at these three sites was drawn from different catchments, implying a degree of landscape/resource partitioning even at this early stage. These communities clearly invested substantial effort in obtaining ivory from across the region, which speaks to the importance of this commodity in the economy of the time. We suggest that some ivory items were for local use, but that some may have been intended for more distant markets via Indian Ocean trade

High Affinity Antigen Recognition of the Dual Specific Variants of Herceptin Is Entropy-Driven in Spite of Structural Plasticity

The antigen-binding site of Herceptin, an anti-human Epidermal Growth Factor Receptor 2 (HER2) antibody, was engineered to add a second specificity toward Vascular Endothelial Growth Factor (VEGF) to create a high affinity two-in-one antibody bH1. Crystal structures of bH1 in complex with either antigen showed that, in comparison to Herceptin, this antibody exhibited greater conformational variability, also called “structural plasticity”. Here, we analyzed the biophysical and thermodynamic properties of the dual specific variants of Herceptin to understand how a single antibody binds two unrelated protein antigens. We showed that while bH1 and the affinity-improved bH1-44, in particular, maintained many properties of Herceptin including binding affinity, kinetics and the use of residues for antigen recognition, they differed in the binding thermodynamics. The interactions of bH1 and its variants with both antigens were characterized by large favorable entropy changes whereas the Herceptin/HER2 interaction involved a large favorable enthalpy change. By dissecting the total entropy change and the energy barrier for dual interaction, we determined that the significant structural plasticity of the bH1 antibodies demanded by the dual specificity did not translate into the expected increase of entropic penalty relative to Herceptin. Clearly, dual antigen recognition of the Herceptin variants involves divergent antibody conformations of nearly equivalent energetic states. Hence, increasing the structural plasticity of an antigen-binding site without increasing the entropic cost may play a role for antibodies to evolve multi-specificity. Our report represents the first comprehensive biophysical analysis of a high affinity dual specific antibody binding two unrelated protein antigens, furthering our understanding of the thermodynamics that drive the vast antigen recognition capacity of the antibody repertoire

Abrasive, Silica Phytoliths and the Evolution of Thick Molar Enamel in Primates, with Implications for the Diet of Paranthropus boisei

Background: Primates—including fossil species of apes and hominins—show variation in their degree of molar enamel thickness, a trait long thought to reflect a diet of hard or tough foods. The early hominins demonstrated molar enamel thickness of moderate to extreme degrees, which suggested to most researchers that they ate hard foods obtained on or near the ground, such as nuts, seeds, tubers, and roots. We propose an alternative hypothesis—that the amount of phytoliths in foods correlates with the evolution of thick molar enamel in primates, although this effect is constrained by a species ’ degree of folivory. Methodology/Principal Findings: From a combination of dietary data and evidence for the levels of phytoliths in plant families in the literature, we calculated the percentage of plant foods rich in phytoliths in the diets of twelve extant primates with wide variation in their molar enamel thickness. Additional dietary data from the literature provided the percentage of each primate’s diet made up of plants and of leaves. A statistical analysis of these variables showed that the amount of abrasive silica phytoliths in the diets of our sample primates correlated positively with the thickness of their molar enamel, constrained by the amount of leaves in their diet (R 2 = 0.875; p,.0006). Conclusions/Significance: The need to resist abrasion from phytoliths appears to be a key selective force behind the evolution of thick molar enamel in primates. The extreme molar enamel thickness of the teeth of the East African homini

Horizontal versus familial transmission of Helicobacter pylori.

Transmission of Helicobacter pylori is thought to occur mainly during childhood, and predominantly within families. However, due to the difficulty of obtaining H. pylori isolates from large population samples and to the extensive genetic diversity between isolates, the transmission and spread of H. pylori remain poorly understood. We studied the genetic relationships of H. pylori isolated from 52 individuals of two large families living in a rural community in South Africa and from 43 individuals of 11 families living in urban settings in the United Kingdom, the United States, Korea, and Colombia. A 3,406 bp multilocus sequence haplotype was determined for a total of 142 H. pylori isolates. Isolates were assigned to biogeographic populations, and recent transmission was measured as the occurrence of non-unique isolates, i.e., isolates whose sequences were identical to those of other isolates. Members of urban families were almost always infected with isolates from the biogeographic population that is common in their location. Non-unique isolates were frequent in urban families, consistent with familial transmission between parents and children or between siblings. In contrast, the diversity of H. pylori in the South African families was much more extensive, and four distinct biogeographic populations circulated in this area. Non-unique isolates were less frequent in South African families, and there was no significant correlation between kinship and similarity of H. pylori sequences. However, individuals who lived in the same household did have an increased probability of carrying the same non-unique isolates of H. pylori, independent of kinship. We conclude that patterns of spread of H. pylori under conditions of high prevalence, such as the rural South African families, differ from those in developed countries. Horizontal transmission occurs frequently between persons who do not belong to a core family, blurring the pattern of familial transmission that is typical of developed countries. Predominantly familial transmission in urban societies is likely a result of modern living conditions with good sanitation and where physical contact between persons outside the core family is limited and regulated by societal rules. The patterns observed in rural South African families may be representative of large parts of the developing world