snu-aidas/HVMap-dataset huggingface dataset:
The Incidence and Repetition of Hospital-Treated Deliberate Self Harm: Findings from the World's First National Registry

BACKGROUND Suicide is a significant public health issue with almost one million people dying by suicide each year worldwide. Deliberate self harm (DSH) is the single most important risk factor for suicide yet few countries have reliable data on DSH. We developed a national DSH registry in the Republic of Ireland to establish the incidence of hospital-treated DSH at national level and the spectrum and pattern of presentations with DSH and repetition. METHODS AND FINDINGS Between 2003 and 2009, the Irish National Registry of Deliberate Self Harm collected data on DSH presentations to all 40 hospital emergency departments in the country. Data were collected by trained data registration officers using standard methods of case ascertainment and definition. The Registry recorded 75,119 DSH presentations involving 48,206 individuals. The total incidence rate fell from 209 (95% CI: 205-213) per 100,000 in 2003 to 184 (95% CI: 180-189) per 100,000 in 2006 and increased again to 209 (95% CI: 204-213) per 100,000 in 2009. The most notable annual changes were successive 10% increases in the male rate in 2008 and 2009. There was significant variation by age with peak rates in women in the 15-19 year age group (620 (95% CI: 605-636) per 100,000), and in men in the 20-24 age group (427 (95% CI: 416-439) per 100,000). Repetition rates varied significantly by age, method of self harm and number of previous episodes. CONCLUSIONS Population-based data on hospital-treated DSH represent an important index of the burden of mental illness and suicide risk in the community. The increased DSH rate in Irish men in 2008 and 2009 coincided with the advent of the economic recession in Ireland. The findings underline the need for developing effective interventions to reduce DSH repetition rates as a key priority for health systems.
A Common Mechanism of Cellular Death Induced by Bactericidal Antibiotics

Antibiotic mode-of-action classification is based upon drug-target interaction and whether the resultant inhibition of cellular function is lethal to bacteria. Here we show that the three major classes of bactericidal antibiotics, regardless of drug-target interaction, stimulate the production of highly deleterious hydroxyl radicals in Gram-negative and Gram-positive bacteria, which ultimately contribute to cell death. We also show, in contrast, that bacteriostatic drugs do not produce hydroxyl radicals. We demonstrate that the mechanism of hydroxyl radical formation induced by bactericidal antibiotics is the end product of an oxidative damage cellular death pathway involving the tricarboxylic acid cycle, a transient depletion of NADH, destabilization of iron-sulfur clusters, and stimulation of the Fenton reaction. Our results suggest that all three major classes of bactericidal drugs can be potentiated by targeting bacterial systems that remediate hydroxyl radical damage, including proteins involved in triggering the DNA damage response, e.g., RecA.
Endothelium-mediated relaxation of porcine collateral-dependent arterioles is improved by exercise training.

BACKGROUND Endothelium-dependent modulation of coronary tone is impaired in the collateral-dependent coronary microcirculation. We used a porcine model of chronic coronary occlusion and collateral development to evaluate the hypothesis that exercise training enhances endothelium-mediated relaxation and increases endothelial nitric oxide synthase (ecNOS) mRNA levels of collateral-dependent microvasculature. METHODS AND RESULTS Adult female miniature swine were subjected to chronic, progressive ameroid occlusion of the proximal left circumflex coronary artery (LCx); after 2 months, animals were randomly exposed to 16-week exercise-training (EX group; treadmill running) or sedentary (SED group; cage confinement) protocols. After completion of EX or SED programs, coronary arterioles ( approximately 100 microm in diameter) were isolated from collateral-dependent LCx (distal to occlusion) and nonoccluded left anterior descending coronary artery (LAD) regions of each heart. Arterioles were studied by in vitro videomicroscopy or frozen for ecNOS mRNA analysis (RT-PCR techniques). Relaxation to the endothelium-dependent vasodilator bradykinin was decreased (P<0.05) in arterioles isolated from collateral-dependent LCx versus nonoccluded LAD regions of SED animals. Bradykinin-mediated relaxation, however, was not different in LCx versus LAD arterioles isolated from EX animals. Nitroprusside-induced relaxation was unaffected by either chronic occlusion or exercise. Importantly, ecNOS mRNA expression was significantly decreased in arterioles isolated from LCx versus LAD regions of SED animals. After training, ecNOS mRNA expression was not different between LAD and LCx arterioles. CONCLUSIONS These data indicate that exercise training enhances bradykinin-mediated relaxation of collateral-dependent LCx arterioles isolated after chronic coronary occlusion, most likely because of effects on ecNOS mRNA expression and increased production of NO.
Loss of the RhoGAP SRGP-1 promotes the clearance of dead and injured cells in Caenorhabditis elegans

Multicellular animals rapidly clear dying cells from their bodies. Many of the pathways that mediate this cell removal are conserved through evolution. Here, we identify srgp-1 as a negative regulator of cell clearance in both Caenorhabditis elegans and mammalian cells. Loss of srgp-1 function results in improved engulfment of apoptotic cells, whereas srgp-1 overexpression inhibits apoptotic cell corpse removal. We show that SRGP-1 functions in engulfing cells and functions as a GTPase activating protein (GAP) for CED-10 (Rac1). Interestingly, loss of srgp-1 function promotes not only the clearance of already dead cells, but also the removal of cells that have been brought to the verge of death through sublethal apoptotic, necrotic or cytotoxic insults. In contrast, impaired engulfment allows damaged cells to escape clearance, which results in increased long-term survival. We propose that C. elegans uses the engulfment machinery as part of a primitive, but evolutionarily conserved, survey mechanism that identifies and removes unfit cells within a tissue.
Collagen/Polypropylene composite mesh biocompatibility in abdominal wall reconstruction.

BACKGROUND Intraperitoneal placement of polypropylene mesh leads to extensive visceral adhesions and is contraindicated. Different coatings are used to improve polypropylene mesh properties. Collagen is a protein with unique biocompatibility and cell ingrowth enhancement potential. A novel acetic acid extracted collagen coating was developed to allow placement of polypropylene mesh in direct contact with viscera. The authors' aim was to evaluate the long-term influence of acetic acid extracted collagen coating on surgical aspects and biomechanical properties of polypropylene mesh implanted in direct contact with viscera, including complications, adhesions with viscera, strength of incorporation, and microscopic inflammatory reaction. METHODS Forty adult Wistar rats were divided into two groups: experimental (polypropylene mesh/acetic acid extracted collagen coating) and control (polypropylene mesh only). Astandardized procedure of mesh implantation was performed. Animals were killed 3 months after surgery and analyzed for complications, mesh area covered by adhesions, type of adhesions, strength of incorporation, and intensity of inflammatory response. RESULTS The mean adhesion area was lower for polypropylene mesh/acetic acid extracted collagen coating (14.5 percent versus 69.9 percent, p < 0.001). Adhesion severity was decreased in the experimental group: grades 0 and 1 were more frequent (p < 0.04 and p < 0.002, respectively) and grade 3 was less frequent (p < 0.0001). An association between adhesion area and severity was found (p < 0.0001). Complications, strength of incorporation, and intensity of inflammatory response to the mesh were similar. CONCLUSIONS Visceral adhesions to polypropylene mesh are significantly reduced because of acetic acid extracted collagen coating. The collagen coating does not increase complications or induce alterations of polypropylene mesh incorporation.
Microvessel Density and Status of p53 Protein as Potential Prognostic Factors for Adjuvant Anthracycline Chemotherapy in Retrospective Analysis of Early Breast Cancer Patients Group

A considerable subgroup of patients with early breast cancer does not address benefits of anthracycline based chemotherapy. The aim of this retrospective study was to investigate the effect of microvessel density (MVD) and status of p53 protein on 5-year disease free survival (DFS) in the group of breast cancer patients treated with anthracyclines in adjuvant setting. Correlations between MVD, p53 status and other clinicopathological parameters were also assessed. MVD and p53 status were analyzed immunohistochemically in the group of 172 women with breast cancer in clinical stage T1-2, N1-N2, M0. There were 123 tumors (71.5 %) with lower MVD (≤ 214.8 microvesells/mm(2)) and 49 (28.5 %) with higher MVD (>214.8 microvesells/mm(2)). The proportion of higher MVD tumors significantly increased in N2 (P = 0.000) and in estrogen (P = 0.046) or progesterone receptors (P = 0.029) negative tumors. p53 positivity was indicated in 50 cancers (29.1 %) and was significantly associated with higher grade (P = 0.000), steroid receptors negativity (P = 0.000), cytokeratin5/6 positivity (P = 0.026), topoisomerase IIα overexpression (P = 0.005) and higher proliferation rate (P = 0.001). In univariate analysis, higher MVD (P = 0.016) and p53 negativity (P = 0.023) were significantly related with longer DFS (median follow-up 36 months). In multivariate Cox regression analysis MVD was independently associated with DFS. These data suggest that higher MVD is favourable prognostic factors for early advanced breast cancer patients after adjuvant anthracycline based chemotherapy.
Ranking of elimination feasibility between malaria-endemic countries

Experience gained from the Global Malaria Eradication Program (1955-72) identified a set of shared technical and operational factors that enabled some countries to successfully eliminate malaria. Spatial data for these factors were assembled for all malaria-endemic countries and combined to provide an objective, relative ranking of countries by technical, operational, and combined elimination feasibility. The analysis was done separately for Plasmodium falciparum and Plasmodium vivax, and the limitations of the approach were discussed. The relative rankings suggested that malaria elimination would be most feasible in countries in the Americas and Asia, and least feasible in countries in central and west Africa. The results differed when feasibility was measured by technical or operational factors, highlighting the different types of challenge faced by each country. The results are not intended to be prescriptive, predictive, or to provide absolute assessments of feasibility, but they do show that spatial information is available to facilitate evidence-based assessments of the relative feasibility of malaria elimination by country that can be rapidly updated.
2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.

OBJECTIVE The 1987 American College of Rheumatology (ACR; formerly the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticised for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. METHODS A joint working group from the ACR and the European League Against Rheumatism developed, in three phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease--this being the appropriate current paradigm underlying the disease construct 'RA'. RESULTS In the new criteria set, classification as 'definite RA' is based on the confirmed presence of synovitis in at least one joint, absence of an alternative diagnosis better explaining the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in four domains: number and site of involved joints (range 0-5), serological abnormality (range 0-3), elevated acute-phase response (range 0-1) and symptom duration (two levels; range 0-1). CONCLUSION This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimise the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct 'RA'.
ImmTAC-redirected tumour cell killing induces and potentiates antigen cross-presentation by dendritic cells

Antigen cross-presentation by dendritic cells (DCs) is thought to play a critical role in driving a polyclonal and durable T cell response against cancer. It follows, therefore, that the capacity of emerging immunotherapeutic agents to orchestrate tumour eradication may depend on their ability to induce antigen cross-presentation. ImmTACs [immune-mobilising monoclonal TCRs (T cell receptors) against cancer] are a new class of soluble bi-specific anti-cancer agents that combine pico-molar affinity TCR-based antigen recognition with T cell activation via a CD3-specific antibody fragment. ImmTACs specifically recognise human leucocyte antigen (HLA)-restricted tumour-associated antigens, presented by cancer cells, leading to T cell redirection and a potent anti-tumour response. Using an ImmTAC specific for a HLA-A*02-restricted peptide derived from the melanoma antigen gp100 (termed IMCgp100), we here observe that ImmTAC-driven melanoma-cell death leads to cross-presentation of melanoma antigens by DCs. These, in turn, can activate both melanoma-specific T cells and polyclonal T cells redirected by IMCgp100. Moreover, activation of melanoma-specific T cells by cross-presenting DCs is enhanced in the presence of IMCgp100; a feature that serves to increase the prospect of breaking tolerance in the tumour microenvironment. The mechanism of DC cross-presentation occurs via ‘cross-dressing’ which involves the rapid and direct capture by DCs of membrane fragments from dying tumour cells. DC cross-presentation of gp100-peptide-HLA complexes was visualised and quantified using a fluorescently labelled soluble TCR. These data demonstrate how ImmTACs engage with the innate and adaptive components of the immune system enhancing the prospect of mediating an effective and durable anti-tumour response in patients.
“Rapid-Impact Interventions”: How a Policy of Integrated Control for Africa's Neglected Tropical Diseases Could Benefit the Poor

Over the past two decades there have been significant achievements in the control of a handful of important human tropical infections [1]. These achievements include the substantive reductions in the prevalence and incidence of the so-called neglected diseases such as lymphatic filariasis, onchocerciasis, guinea worm, leprosy, and trachoma (Box 1) [2]. Each of these neglected diseases is a poverty-promoting and often stigmatizing condition occurring primarily in rural areas of low-income countries (Box 2) [3]. They are ancient afflictions, described in the Bible and other ancient texts, which have burdened humanity for millennia [3]. But now, as a result of aggressive regional vertical interventions, there is a possibility that some neglected tropical infections could be eventually controlled to the point of elimination in some areas of endemicity [2–8]. In the case of guinea worm infection, disease eradication might also soon be possible [9]. Box 2. Common Features of the Neglected Tropical Diseases          Ancient afflictions that have burdened humanity for centuries      Poverty-promoting conditions      Associated with stigma      Rural areas of low-income countries and fragile states      No commercial markets for products that target these diseases      Interventions, when applied, have a history of success
Specificity Residues Determine Binding Affinity for Two-Component Signal Transduction Systems

UNLABELLED Two-component systems (TCS) comprise histidine kinases and their cognate response regulators and allow bacteria to sense and respond to a wide variety of signals. Histidine kinases (HKs) phosphorylate and dephosphorylate their cognate response regulators (RRs) in response to stimuli. In general, these reactions appear to be highly specific and require an appropriate association between the HK and RR proteins. The Myxococcus xanthus genome encodes one of the largest repertoires of signaling proteins in bacteria (685 open reading frames [ORFs]), including at least 127 HKs and at least 143 RRs. Of these, 27 are bona fide NtrC-family response regulators, 21 of which are encoded adjacent to their predicted cognate kinases. Using system-wide profiling methods, we determined that the HK-NtrC RR pairs display a kinetic preference during both phosphotransfer and phosphatase functions, thereby defining cognate signaling systems in M. xanthus. Isothermal titration calorimetry measurements indicated that cognate HK-RR pairs interact with dissociation constants (Kd) of approximately 1 µM, while noncognate pairs had no measurable binding. Lastly, a chimera generated between the histidine kinase, CrdS, and HK1190 revealed that residues conferring phosphotransfer and phosphatase specificity dictate binding affinity, thereby establishing discrete protein-protein interactions which prevent cross talk. The data indicate that binding affinity is a critical parameter governing system-wide signaling fidelity for bacterial signal transduction proteins. IMPORTANCE Using in vitro phosphotransfer and phosphatase profiling assays and isothermal titration calorimetry, we have taken a system-wide approach to demonstrate specificity for a family of two-component signaling proteins in Myxococcus xanthus. Our results demonstrate that previously identified specificity residues dictate binding affinity and that phosphatase specificity follows phosphotransfer specificity for cognate HK-RR pairs. The data indicate that preferential binding affinity is the basis for signaling fidelity in bacterial two-component systems.
Rapamycin passes the torch: a new generation of mTOR inhibitors

Mammalian target of rapamycin (mTOR) is an atypical protein kinase that controls growth and metabolism in response to nutrients, growth factors and cellular energy levels, and it is frequently dysregulated in cancer and metabolic disorders. Rapamycin is an allosteric inhibitor of mTOR, and was approved as an immuno-suppressant in 1999. In recent years, interest has focused on its potential as an anticancer drug. However, the performance of rapamycin and its analogues (rapalogues) has been undistinguished despite isolated successes in subsets of cancer, suggesting that the full therapeutic potential of targeting mTOR has yet to be exploited. A new generation of ATP-competitive inhibitors that directly target the mTOR catalytic site display potent and comprehensive mTOR inhibition and are in early clinical trials.
Dynamic capsule restructuring by the main pneumococcal autolysin LytA in response to the epithelium

Bacterial pathogens produce complex carbohydrate capsules to protect against bactericidal immune molecules. Paradoxically, the pneumococcal capsule sensitizes the bacterium to antimicrobial peptides found on epithelial surfaces. Here we show that upon interaction with antimicrobial peptides, encapsulated pneumococci survive by removing capsule from the cell surface within minutes in a process dependent on the suicidal amidase autolysin LytA. In contrast to classical bacterial autolysis, during capsule shedding, LytA promotes bacterial survival and is dispersed circumferentially around the cell. However, both autolysis and capsule shedding depend on the cell wall hydrolytic activity of LytA. Capsule shedding drastically increases invasion of epithelial cells and is the main pathway by which pneumococci reduce surface bound capsule during early acute lung infection of mice. The previously unrecognized role of LytA in removing capsule to combat antimicrobial peptides may explain why nearly all clinical isolates of pneumococci conserve this enzyme despite the lethal selective pressure of antibiotics.
YEASTRACT: providing a programmatic access to curated transcriptional regulatory associations in Saccharomyces cerevisiae through a web services interface

The YEAst Search for Transcriptional Regulators And Consensus Tracking (YEASTRACT) information system (http://www.yeastract.com) was developed to support the analysis of transcription regulatory associations in Saccharomyces cerevisiae. Last updated in June 2010, this database contains over 48,200 regulatory associations between transcription factors (TFs) and target genes, including 298 specific DNA-binding sites for 110 characterized TFs. All regulatory associations stored in the database were revisited and detailed information on the experimental evidences that sustain those associations was added and classified as direct or indirect evidences. The inclusion of this new data, gathered in response to the requests of YEASTRACT users, allows the user to restrict its queries to subsets of the data based on the existence or not of experimental evidences for the direct action of the TFs in the promoter region of their target genes. Another new feature of this release is the availability of all data through a machine readable web-service interface. Users are no longer restricted to the set of available queries made available through the existing web interface, and can use the web service interface to query, retrieve and exploit the YEASTRACT data using their own implementation of additional functionalities. The YEASTRACT information system is further complemented with several computational tools that facilitate the use of the curated data when answering a number of important biological questions. Since its first release in 2006, YEASTRACT has been extensively used by hundreds of researchers from all over the world. We expect that by making the new data and services available, the system will continue to be instrumental for yeast biologists and systems biology researchers.
Mechanisms that Specify Promoter Nucleosome Location and Identity

The chromatin architecture of eukaryotic gene promoters is generally characterized by a nucleosome-free region (NFR) flanked by at least one H2A.Z variant nucleosome. Computational predictions of nucleosome positions based on thermodynamic properties of DNA-histone interactions have met with limited success. Here we show that the action of the essential RSC remodeling complex in S. cerevisiae helps explain the discrepancy between theory and experiment. In RSC-depleted cells, NFRs shrink such that the average positions of flanking nucleosomes move toward predicted sites. Nucleosome positioning at distinct subsets of promoters additionally requires the essential Myb family proteins Abf1 and Reb1, whose binding sites are enriched in NFRs. In contrast, H2A.Z deposition is dispensable for nucleosome positioning. By regulating H2A.Z deposition using a steroid-inducible protein splicing strategy, we show that NFR establishment is necessary for H2A.Z deposition. These studies suggest an ordered pathway for the assembly of promoter chromatin architecture.