snu-aidas/HVMap-dataset huggingface dataset:
Immune Activation with HIV Vaccines

The development of a safe and effective HIV vaccine is perhaps the most important and challenging goal remaining in HIV-AIDS research. Recent progress using a poxvirus vector prime and envelope protein boost strategy demonstrated a modest but statistically significant level of efficacy and established the concept that a vaccine could prevent HIV infection (1), and approaches to boost durability and efficacy are currently in the planning stages (2). But the results of two vaccine concepts based on recombinant adenovirus serotype-5 (rAd5) (3–5) pointed to a potential major problem—that such vaccines might increase susceptibility to HIV infection. This also raised the question of whether the problem extends to some or all of the other recombinant adenovirus vectors currently in development or to other vector-based vaccines.
Distribution of dystrophin- and utrophin-associated protein complexes during activation of human neutrophils.

OBJECTIVE Dystrophins, utrophins, and their associated proteins are involved in structural and signaling roles in nonmuscle tissues; however, description of these proteins in neutrophils remained unexplored. Therefore we characterize the pattern expression, and the cellular distribution of dystrophin and utrophin gene products and dystrophin-associated proteins (i.e., beta-dystroglycan, alpha-syntrophin, and alpha-dystrobrevins) in relation to actin filaments in resting and activated with formyl-methionyl-leucyl-phenylalanine human neutrophils. MATERIALS AND METHODS Resting and fMLP-activated human neutrophils were analyzed by immunoblot and by confocal microscopy analysis. Immunoprecipitation assays were performed to corroborate the presence of protein complexes. RESULTS Immunoprecipitation assays and confocal analysis demonstrated the presence of two dystrophin-associated protein complexes in resting and activated neutrophils: the former formed by Dp71d/Dp71Delta(110)(m) and dystrophin-associated proteins (beta-dystroglycan, alpha-syntrophin, alpha-dystrobrevin-1, and -2), while the latter contains Up400, instead of Dp71d/Dp71Delta(110)(m), as a central component of the dystrophin-associated protein complexes (DAPC). Confocal analysis also showed the subcellular redistribution of Dp71d/Dp71Delta(110)(m) approximately DAPC and Up400 approximately DAPC in F-actin-based structures displayed during activation process with fMLP. CONCLUSIONS Our study showed the existence of two protein complexes formed by Dp71d/Dp71Delta(110)(m) or Up400 associated with DAPs in resting and fMLP-treated human polymorphonuclears. The interaction of these complexes with the actin cytoskeleton is indicative of their dynamic participation in the chemotaxis process.
Global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: a systematic analysis

BACKGROUND The annual number of hospital admissions and in-hospital deaths due to severe acute lower respiratory infections (ALRI) in young children worldwide is unknown. We aimed to estimate the incidence of admissions and deaths for such infections in children younger than 5 years in 2010. METHODS We estimated the incidence of admissions for severe and very severe ALRI in children younger than 5 years, stratified by age and region, with data from a systematic review of studies published between Jan 1, 1990, and March 31, 2012, and from 28 unpublished population-based studies. We applied these incidence estimates to population estimates for 2010, to calculate the global and regional burden in children admitted with severe ALRI in that year. We estimated in-hospital mortality due to severe and very severe ALRI by combining incidence estimates with case fatality ratios from hospital-based studies. FINDINGS We identified 89 eligible studies and estimated that in 2010, 11·9 million (95% CI 10·3-13·9 million) episodes of severe and 3·0 million (2·1-4·2 million) episodes of very severe ALRI resulted in hospital admissions in young children worldwide. Incidence was higher in boys than in girls, the sex disparity being greatest in South Asian studies. On the basis of data from 37 hospital studies reporting case fatality ratios for severe ALRI, we estimated that roughly 265,000 (95% CI 160,000-450,000) in-hospital deaths took place in young children, with 99% of these deaths in developing countries. Therefore, the data suggest that although 62% of children with severe ALRI are treated in hospitals, 81% of deaths happen outside hospitals. INTERPRETATION Severe ALRI is a substantial burden on health services worldwide and a major cause of hospital referral and admission in young children. Improved hospital access and reduced inequities, such as those related to sex and rural status, could substantially decrease mortality related to such infection. Community-based management of severe disease could be an important complementary strategy to reduce pneumonia mortality and health inequities. FUNDING WHO.
Risk of breast cancer in relation to blood lipids: a prospective study of 31,209 Norwegian women

In this prospective study, the relationship between blood lipids and breast cancer risk was examined. Between 1977 and 1983, 31,209 Norwegian women, 20 to 54 years of age, attended a health screening carried out by the Norwegian National Health Screening Services. The screening consisted of a questionnaire, anthropometric measurements, and nonfasting blood drawn for analysis of total serum cholesterol (TC), triglyceride (TG), and high density lipoprotein (HDL) cholesterol. Low density lipoprotein (LDL) cholesterol was calculated by the Friedewald's formula. During the seven to 13 years of follow-up, 302 breast cancer cases were identified by linkage to the Norwegian Cancer Registry. After adjustment for some of the known risk factors of breast cancer, the relative risk of women in the highest quartile of TC compared with women in the lowest quartile was 0.87 (95 percent confidence interval [CI]=0.61–1.23). The corresponding relative risks and CIs were 0.82 (CI=0.58–1.16) for TG, 1.02 (CI=0.73–1.42) for HDL, and 0.93 (CI=0.67–1.29) for LDL. No association between breast cancer risk and blood lipids was found in the total population, nor when the data were divided into those diagnosed before or after the age of 50 as a dividing line between pre- and postmenopausal diagnosis.
Involvement of lysosomal dysfunction in autophagosome accumulation and early pathologies in adipose tissue of obese mice

Whether obesity accelerates or suppresses autophagy in adipose tissue is still debatable. To clarify dysregulation of autophagy and its role in pathologies of obese adipose tissue, we focused on lysosomal function, protease maturation and activity, both in vivo and in vitro. First, we showed that autophagosome formation was accelerated, but autophagic clearance was impaired in obese adipose tissue. We also found protein and activity levels of CTSL (cathepsin L) were suppressed in obese adipose tissue, while the activity of CTSB (cathepsin B) was significantly enhanced. Moreover, cellular senescence and inflammasomes were activated in obese adipose tissue. In 3T3L1 adipocytes, downregulation of CTSL deteriorated autophagic clearance, upregulated expression of CTSB, promoted cellular senescence and activated inflammasomes. Upregulation of CTSB promoted additional activation of inflammasomes. Therefore, we suggest lysosomal dysfunction observed in obese adipose tissue leads to lower autophagic clearance, resulting in autophagosome accumulation. Simultaneously, lysosomal abnormalities, including deteriorated CTSL function and compensatory activation of CTSB, caused cellular senescence and inflammasome activation. Our findings strongly suggest lysosomal dysfunction is involved in early pathologies of obese adipose tissue.
Effects of Hypoxia and Oxidative Stress on Expression of Neprilysin in Human Neuroblastoma Cells and Rat Cortical Neurones and Astrocytes

Pathogenesis of Alzheimer’s disease (AD), which is characterised by accumulation of extracellular deposits of β-amyloid peptide (Aβ) in the brain, has recently been linked to vascular disorders such as ischemia and stroke. Aβ is constantly produced in the brain from amyloid precursor protein (APP) through its cleavage by β- and γ-secretases and certain Aβ species are toxic for neurones. The brain has an endogenous mechanism of Aβ removal via proteolytic degradation and the zinc metalloproteinase neprilysin (NEP) is a critical regulator of Aβ concentration. Down-regulation of NEP could predispose to AD. By comparing the effects of hypoxia and oxidative stress on expression and activity of the Aβ-degrading enzyme NEP in human neuroblastoma NB7 cells and rat primary cortical neurones we have demonstrated that hypoxia reduced NEP expression at the protein and mRNA levels as well as its activity. On contrary in astrocytes hypoxia increased NEP mRNA expression.
Genetics and Beyond – The Transcriptome of Human Monocytes and Disease Susceptibility

BACKGROUND Variability of gene expression in human may link gene sequence variability and phenotypes; however, non-genetic variations, alone or in combination with genetics, may also influence expression traits and have a critical role in physiological and disease processes. METHODOLOGY/PRINCIPAL FINDINGS To get better insight into the overall variability of gene expression, we assessed the transcriptome of circulating monocytes, a key cell involved in immunity-related diseases and atherosclerosis, in 1,490 unrelated individuals and investigated its association with >675,000 SNPs and 10 common cardiovascular risk factors. Out of 12,808 expressed genes, 2,745 expression quantitative trait loci were detected (P<5.78x10(-12)), most of them (90%) being cis-modulated. Extensive analyses showed that associations identified by genome-wide association studies of lipids, body mass index or blood pressure were rarely compatible with a mediation by monocyte expression level at the locus. At a study-wide level (P<3.9x10(-7)), 1,662 expression traits (13.0%) were significantly associated with at least one risk factor. Genome-wide interaction analyses suggested that genetic variability and risk factors mostly acted additively on gene expression. Because of the structure of correlation among expression traits, the variability of risk factors could be characterized by a limited set of independent gene expressions which may have biological and clinical relevance. For example expression traits associated with cigarette smoking were more strongly associated with carotid atherosclerosis than smoking itself. CONCLUSIONS/SIGNIFICANCE This study demonstrates that the monocyte transcriptome is a potent integrator of genetic and non-genetic influences of relevance for disease pathophysiology and risk assessment.
ARID1A mutations in endometriosis-associated ovarian carcinomas.

BACKGROUND Ovarian clear-cell and endometrioid carcinomas may arise from endometriosis, but the molecular events involved in this transformation have not been described. METHODS We sequenced the whole transcriptomes of 18 ovarian clear-cell carcinomas and 1 ovarian clear-cell carcinoma cell line and found somatic mutations in ARID1A (the AT-rich interactive domain 1A [SWI-like] gene) in 6 of the samples. ARID1A encodes BAF250a, a key component of the SWI–SNF chromatin remodeling complex. We sequenced ARID1A in an additional 210 ovarian carcinomas and a second ovarian clear-cell carcinoma cell line and measured BAF250a expression by means of immunohistochemical analysis in an additional 455 ovarian carcinomas. RESULTS ARID1A mutations were seen in 55 of 119 ovarian clear-cell carcinomas (46%), 10 of 33 endometrioid carcinomas (30%), and none of the 76 high-grade serous ovarian carcinomas. Seventeen carcinomas had two somatic mutations each. Loss of the BAF250a protein correlated strongly with the ovarian clear-cell carcinoma and endometrioid carcinoma subtypes and the presence of ARID1A mutations. In two patients, ARID1A mutations and loss of BAF250a expression were evident in the tumor and contiguous atypical endometriosis but not in distant endometriotic lesions. CONCLUSIONS These data implicate ARID1A as a tumor-suppressor gene frequently disrupted in ovarian clear-cell and endometrioid carcinomas. Since ARID1A mutation and loss of BAF250a can be seen in the preneoplastic lesions, we speculate that this is an early event in the transformation of endometriosis into cancer. (Funded by the British Columbia Cancer Foundation and the Vancouver General Hospital–University of British Columbia Hospital Foundation.).
Non-canonical PI3K-Cdc42-Pak-Mek-Erk Signaling Promotes Immune-Complex-Induced Apoptosis in Human Neutrophils

Neutrophils are peripheral blood leukocytes that represent the first line of immune cell defense against bacterial and fungal infections but are also crucial players in the generation of the inflammatory response. Many neutrophil cell surface receptors regulate important cellular processes via activation of agonist-activated PI3Ks. We show here that activation of human neutrophils with insoluble immune complexes drives a previously uncharacterized, PI3K-dependent, non-canonical, pro-apoptotic signaling pathway, FcγR-PI3Kβ/δ-Cdc42-Pak-Mek-Erk. This is a rare demonstration of Ras/Raf-independent activation of Erk and of PI3K-mediated activation of Cdc42. In addition, comparative analysis of immune-complex- and fMLF-induced signaling uncovers key differences in pathways used by human and murine neutrophils. The non-canonical pathway we identify in this study may be important for the resolution of inflammation in chronic inflammatory diseases that rely on immune-complex-driven neutrophil activation.
Age as a risk factor for thrombocytopenia and anaemia in children treated for acute uncomplicated falciparum malaria.

BACKGROUND & OBJECTIVES Anaemia is commonly observed in children with malaria, but reports on leucocyte and platelet count abnormalities associated with malaria are inconsistent. This study examined the effect of age, gender, parasite density and temperature on haematological parameters in children with acute uncomplicated malaria. METHODS Haematological parameters were determined in children with acute uncomplicated malaria, and these were correlated with age, sex, temperature and parasite density. Statistical analysis was done using SAS 9.1. RESULTS Six hundred and ninety five children with acute uncomplicated malaria participated in the study. The mean age was 51.7 months +/- 33.8. At presentation, anaemia occurred in 43.8% of the patients and children <5 yr had a significantly lower haematocrit (28.4% +/- 4.8) than that of older children (32.8% +/- 4.8) (p <0.001), but the haematocrit was not significantly different by days 14 and 28. There was no difference between both sexes. Leucocytosis was more frequently seen than leucopenia (9.5% vs 3%). Thrombocytopenia was found in 59.3% of enrolled patients. More than half of the patients with thrombocytopenia had recovered by Day 28. Baseline platelet count was related to Day 14 (r = 0.6, p < 0.0001) and Day 28 (r = 0.2, p = 0.0015) and the haematocrit on Day 28 (r = 0.12, p = 0.00197). Platelet count showed no correlation with temperature, parasite density and leucocyte count. Haematocrit correlated with age (r = 0.4, p < 0.0001); but not with parasite density or temperature. Leucocyte count showed no correlation with age or parasite density. CONCLUSION While thrombocytopenia was the most common haematological finding and may be of diagnostic importance, anaemia and leucocytosis were more common in the under fives.
Structure-based drug design identifies polythiophenes as antiprion compounds

Prions cause transmissible spongiform encephalopathies for which no treatment exists. Prions consist of PrPSc, a misfolded and aggregated form of the cellular prion protein (PrPC). We explore the antiprion properties of luminescent conjugated polythiophenes (LCPs) that bind and stabilize ordered protein aggregates. By administering a library of structurally diverse LCPs to the brains of prion-infected mice via osmotic minipumps, we found that antiprion activity required a minimum of five thiophene rings bearing regularly spaced carboxyl side groups. Solid-state nuclear magnetic resonance analyses and molecular dynamics simulations revealed that anionic side chains interacted with complementary, regularly spaced cationic amyloid residues of model prions. These findings allowed us to extract structural rules governing the interaction between LCPs and protein aggregates, which we then used to design a new set of LCPs with optimized binding. The new set of LCPs showed robust prophylactic and therapeutic potency in prion-infected mice, with the lead compound extending survival by >80% and showing activity against both mouse and hamster prions as well as efficacy upon intraperitoneal administration into mice. These results demonstrate the feasibility of targeted chemical design of compounds that may be useful for treating diseases of aberrant protein aggregation such as prion disease.
MHC class I antigen presentation: learning from viral evasion strategies

The cell surface display of peptides by MHC class I molecules to lymphocytes provides the host with an important surveillance mechanism to protect against invading pathogens. However, in turn, viruses have evolved elegant strategies to inhibit various stages of the MHC class I antigen presentation pathway and prevent the display of viral peptides. This Review highlights how the elucidation of mechanisms of viral immune evasion is important for advancing our understanding of virus–host interactions and can further our knowledge of the MHC class I presentation pathway as well as other cellular pathways.
Vascular responsiveness in isolated perfused kidneys of diabetic hypertensive rats.

OBJECTIVE The aim of this study was to investigate whether diabetes and hypertension cause additive effects in the responses to various vasoconstrictor and vasodilator agents, in isolated perfused kidneys obtained from streptozotocin (STZ)-diabetic Wistar-Kyoto (WKY) rats and from diabetic spontaneously hypertensive rats (SHR). METHODS SHR and WKY rats were administered STZ 55 mg/kg by intravenous injection into a lateral tail vein at age 12 weeks. Eight weeks later the kidneys were isolated and perfused via the left renal artery with a physiological salt solution. Renal perfusion pressure was measured continuously. Concentration response curves were plotted for various vasoconstrictor and vasodilator agents. RESULTS Both the diabetic and the hypertensive state were associated with an increased wet kidney weight. The contractile responses of the renal arterial system to phenylephrine (PhE), serotonin (5-HT) and angiotensin II (Ang II) in terms both of the maximal rise in perfusion pressure (mmHg) and of the sensitivity (log EC50) were the same in preparations from diabetic WKY rats and in those from normoglycaemic WKY rats. The maximal contractile responses both to PhE and to Ang II were enhanced in kidneys from SHR compared with those in kidneys from their normotensive controls, whereas simultaneously occurring diabetes impaired this sensitization. After precontraction with 3 x 10(-6) mol/l PhE both endothelium-dependent (methacholine) and endothelium-independent (sodium nitroprusside) vasodilator drugs caused the same vasodilator response in the preparations taken from the four groups of animals. CONCLUSION In isolated perfused kidneys obtained from STZ-diabetic WKY rats and SHR, the isolated diabetic state did not influence the vasoconstriction caused by various agonists. However, the enhanced vascular reactivity in the hypertensive state was blunted by simultaneously occurring diabetes mellitus. Endothelium-dependent and -independent vasorelaxation in this model was not affected neither by the hypertensive nor by the diabetic state.
DNA methylation and healthy human aging

The process of aging results in a host of changes at the cellular and molecular levels, which include senescence, telomere shortening, and changes in gene expression. Epigenetic patterns also change over the lifespan, suggesting that epigenetic changes may constitute an important component of the aging process. The epigenetic mark that has been most highly studied is DNA methylation, the presence of methyl groups at CpG dinucleotides. These dinucleotides are often located near gene promoters and associate with gene expression levels. Early studies indicated that global levels of DNA methylation increase over the first few years of life and then decrease beginning in late adulthood. Recently, with the advent of microarray and next-generation sequencing technologies, increases in variability of DNA methylation with age have been observed, and a number of site-specific patterns have been identified. It has also been shown that certain CpG sites are highly associated with age, to the extent that prediction models using a small number of these sites can accurately predict the chronological age of the donor. Together, these observations point to the existence of two phenomena that both contribute to age-related DNA methylation changes: epigenetic drift and the epigenetic clock. In this review, we focus on healthy human aging throughout the lifetime and discuss the dynamics of DNA methylation as well as how interactions between the genome, environment, and the epigenome influence aging rates. We also discuss the impact of determining 'epigenetic age' for human health and outline some important caveats to existing and future studies.
Molecular basis of synaptic vesicle cargo recognition by the endocytic sorting adaptor stonin 2

Synaptic transmission depends on clathrin-mediated recycling of synaptic vesicles (SVs). How select SV proteins are targeted for internalization has remained elusive. Stonins are evolutionarily conserved adaptors dedicated to endocytic sorting of the SV protein synaptotagmin. Our data identify the molecular determinants for recognition of synaptotagmin by stonin 2 or its Caenorhabditis elegans orthologue UNC-41B. The interaction involves the direct association of clusters of basic residues on the surface of the cytoplasmic domain of synaptotagmin 1 and a beta strand within the mu-homology domain of stonin 2. Mutation of K783, Y784, and E785 to alanine within this stonin 2 beta strand results in failure of the mutant stonin protein to associate with synaptotagmin, to accumulate at synapses, and to facilitate synaptotagmin internalization. Synaptotagmin-binding-defective UNC-41B is unable to rescue paralysis in C. elegans stonin mutant animals, suggesting that the mechanism of stonin-mediated SV cargo recognition is conserved from worms to mammals.