HLA Class I Binding of HBZ Determines Outcome in HTLV-1 Infection

CD8(+) T cells can exert both protective and harmful effects on the virus-infected host. However, there is no systematic method to identify the attributes of a protective CD8(+) T cell response. Here, we combine theory and experiment to identify and quantify the contribution of all HLA class I alleles to host protection against infection with a given pathogen. In 432 HTLV-1-infected individuals we show that individuals with HLA class I alleles that strongly bind the HTLV-1 protein HBZ had a lower proviral load and were more likely to be asymptomatic. We also show that in general, across all HTLV-1 proteins, CD8(+) T cell effectiveness is strongly determined by protein specificity and produce a ranked list of the proteins targeted by the most effective CD8(+) T cell response through to the least effective CD8(+) T cell response. We conclude that CD8(+) T cells play an important role in the control of HTLV-1 and that CD8(+) cells specific to HBZ, not the immunodominant protein Tax, are the most effective. We suggest that HBZ plays a central role in HTLV-1 persistence. This approach is applicable to all pathogens, even where data are sparse, to identify simultaneously the HLA Class I alleles and the epitopes responsible for a protective CD8(+) T cell response

The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia

Cytarabine (ara-C) is the most effective agent for the treatment of acute myeloid leukaemia (AML). Aberrant expression of enzymes involved in the transport/metabolism of ara-C could explain drug resistance. We determined mRNA expression of these factors using quantitative-real-time-PCR in leukemic blasts from children diagnosed with de novo AML. Expression of the inactivating enzyme pyrimidine nucleotidase-I (PN-I) was 1.8-fold lower in FAB-M5 as compared to FAB-M1/2 (P=0.007). In vitro sensitivity to deoxynucleoside analogues was determined using the MTT-assay. Human equilibrative nucleoside transporter-1 (hENT1) mRNA expression and ara-C sensitivity were significantly correlated (rp=−0.46; P=0.001), with three-fold lower hENT1 mRNA levels in resistant patients (P=0.003). hENT1 mRNA expression also seemed to correlate inversely with the LC50 values of cladribine (rp=−0.30; P=0.04), decitabine (rp=−0.29; P=0.04) and gemcitabine (rp=−0.33; P=0.02). Deoxycytidine kinase (dCK) and cytidine deaminase (CDA) mRNA expression seemed to correlate with in vitro sensitivity to gemcitabine (rp=−0.31; P=0.03) and decitabine (rp=0.33; P=0.03), respectively. The dCK/PN-I ratio correlated inversely with LC50 values for gemcitabine (rp=−0.45, P=0.001) and the dCK/CDA ratio seemed to correlate with LC50 values for decitabine (rp=−0.29; 0.04). In conclusion, decreased expression of hENT1, which transports ara-C across the cell membrane, appears to be a major factor in ara-C resistance in childhood AML

Living with diabetes: rationale, study design and baseline characteristics for an Australian prospective cohort study

Background: Diabetes mellitus is a major global public health threat. In Australia, as elsewhere, it is responsible for a sizeable portion of the overall burden of disease, and significant costs. The psychological and social impact of diabetes on individuals with the disease can be severe, and if not adequately addressed, can lead to the worsening of the overall disease picture. The Living With Diabetes Study aims to contribute to a holistic understanding of the psychological and social aspects of diabetes mellitus

From genetics to epigenetics: new perpectives in Tourette Syndrome research

Gilles de la Tourette Syndrome (TS) is a neurodevelopmental disorder marked by the appearance of multiple involuntary motor and vocal tics. TS presents high comorbidity rates with other disorders such as attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). TS is highly heritable and has a complex polygenic background. However, environmental factors also play a role in the manifestation of symptoms. Different epigenetic mechanisms may represent the link between these two causalities. Epigenetic regulation has been shown to have an impact in the development of many neuropsychiatric disorders, however very little is known about its effects on Tourette Syndrome.This review provides a summary of the recent findings in the genetic background of TS, followed by an overview on different epigenetic mechanisms, such as DNA methylation, histone modifications and non-coding RNAs in the regulation of gene expression. Epigenetic studies in other neurological and psychiatric disorders are discussed along with the TS-related epigenetic findings available in the literature to date. Moreover, we are proposing that some general epigenetic mechanisms seen in other neuropsychiatric disorders may also play a role in the pathogenesis of TS

Population dynamic of bony fishes in the southern part of the Caspian Sea

This study was conducted to determine growth parameters, catch and fishing effort trends, stock assessment and Acceptable Biological Catch (ABC) of bony fishes in the Iranian coastal waters of Caspian Sea in the years 2010-2011 and 2011-2012. According to the result, the numbers of beach seines were 131 and 128 and their fishing efforts were observed 50184 and 42255 beach seining during 2010-11 and 2011-12, respectively. The catch per unit of effort CPUE) was calculated 182.9 and 205.6 kg/haul during two sampling periods, respectively. The total catches (including illegal fishing) were also obtained 16601.5 mt and 17034.1 mt during 2010-11 and 2011-12, respectively. The highest proportion of catch was belonged to kutum and golden grey mullet (86% and 88%, respectively) in two fishing seasons aforementioned above. Growth parameters of kutum were estimated as K=0.21/yr, L_∞ = 60.0 cm, t-0 = 0/yr. The Growth parameters were K=0.18/yr, L_∞ = 61.1 cm, t-0 = -0.14/yr for golden gray mullet and were K=0.12/yr, L_∞ = 73.6 cm, t-0 = 0.92/yr for common carp. Based on catch-at-age data, in the years 2010-2011 and 2011-2012, the total biomass, from the biomass-based cohort analysis were estimated 41700mt and 34400 mt for kutum and 14600 mt and 14400 mt for golden grey mullet, respectively. The reference points of F0.1 and F35% were 0.41/yr and 0.34/yr for kutum and 0.36/yr and 0.33/yr for golden grey mullet, respectively. Stock enhancement plays an important role in recovery of kutum stocks in the Iranian coastal waters of Caspian Sea. There is a significantly negative correlation between fingerlings released and condition factor (CF) and recruitment and CF. The different trends for fingerlings, recruitments and CF suggest that CF may be partly density-dependent, declining at high population sizes due to intra-specific competition. Therefore, more research should be conducted to determine the desirable level of artificial propagation. Food consumed by fish species, Rutilus frisii kutum, Rutilus rutilus caspicus, Cyprinus carpio, Liza auratus and Liza saliens were included Foraminifera, Porifera, Annelida, Mollusca, Arthropoda, filamentous algae, fish eggs and detritus.The results showed that Rutilusfrisii kutum generally feed on Balanus and Cerastorderma. The main food item for Cyprinuscarpio, Liza auratus and Liza salienswas detritus. Based on available models, the ABCs were estimated as 6600-7400 mt for kutum and 2200-2800 mt for golden grey mullet (with precautionary approach 6600 mt and 2200 mt for kutum and mullet, respectively) in 2011-12. Two species (kutum and golden grey mullet) are vulnerable to environmental factors, and these factors should be considered in the stock assessment and management of the fish. For two species, the ABC with a lower andmore accurate value based onmore information, should be selectedfor the implementation of a precautionary management approach

Expanding Indications of Liver Transplantation in Spain: Consensus Statement and Recommendations by the Spanish Society of Liver Transplantation

Trasplantament de fetge; Hepatitis C; ConsensTrasplante de hígado; Hepatitis C; ConsensoLiver Transplantation; Hepatitis C; ConsensusBackground. The number of patients awaiting liver transplantation (LT) in Spain has halved from 2015 to 2019 due to the reduction of candidates with hepatitis C and the successful implementation of nonheart beating donation programs across the country. The Spanish Society for Liver Transplantation has committed to take advantage of this situation by developing consensus around potential areas to expand the current indications for LT. The consensus group was composed of 6 coordinators and 23 expert delegates, each one representing an LT institution in Spain. Methods. A modified Delphi approach was used to identify areas to expand indications for LT and to build consensus around paramount aspects, such as inclusion criteria and waitlist prioritization within each area. The scientific evidence and strength of recommendations were assessed by the “Grading of Recommendations Assessment, Development, and Evaluation” system. Results. The consensus process resulted in the identification of 7 potential areas to expand criteria in LT: recipient’s age, hepatocellular carcinoma, alcoholic hepatitis, acute-on-chronic liver failure, hilar and intrahepatic cholangiocarcinoma, and unresectable liver metastases of colorectal cancer. Conclusions. We present the main recommendations issued for each topic, together with their core supporting evidence. These recommendations may allow for expanding criteria for LT homogenously in Spain and may provide a guidance to other countries/institutions facing a similar scenario