snu-aidas/HVMap-dataset huggingface dataset:
Multiple-dose activated charcoal in acute self-poisoning: a randomised controlled trial

BACKGROUND The case-fatality for intentional self-poisoning in the rural developing world is 10-50-fold higher than that in industrialised countries, mostly because of the use of highly toxic pesticides and plants. We therefore aimed to assess whether routine treatment with multiple-dose activated charcoal, to interrupt enterovascular or enterohepatic circulations, offers benefit compared with no charcoal in such an environment. METHODS We did an open-label, parallel group, randomised, controlled trial of six 50 g doses of activated charcoal at 4-h intervals versus no charcoal versus one 50 g dose of activated charcoal in three Sri Lankan hospitals. 4632 patients were randomised to receive no charcoal (n=1554), one dose of charcoal (n=1545), or six doses of charcoal (n=1533); outcomes were available for 4629 patients. 2338 (51%) individuals had ingested pesticides, whereas 1647 (36%) had ingested yellow oleander (Thevetia peruviana) seeds. Mortality was the primary outcome measure. Analysis was by intention to treat. The trial is registered with controlled-trials.com as ISRCTN02920054. FINDINGS Mortality did not differ between the groups. 97 (6.3%) of 1531 participants in the multiple-dose group died, compared with 105 (6.8%) of 1554 in the no charcoal group (adjusted odds ratio 0.96, 95% CI 0.70-1.33). No differences were noted for patients who took particular poisons, were severely ill on admission, or who presented early. INTERPRETATION We cannot recommend the routine use of multiple-dose activated charcoal in rural Asia Pacific; although further studies of early charcoal administration might be useful, effective affordable treatments are urgently needed.
Post-prenylation-processing enzymes as new targets in oncogenesis

RAS and many other oncogenic proteins undergo a complex series of post-translational modifications that are initiated by the addition of an isoprenoid lipid through a process known as prenylation. Following prenylation, these proteins usually undergo endoproteolytic processing by the RCE1 protease and then carboxyl methylation by a unique methyltransferase known as isoprenylcysteine carboxyl methyltransferase (ICMT). Although inhibitors that have been designed to target the prenylation step are now in advanced-stage clinical trials, their utility and efficacy seem to be limited. Recent findings, however, indicate that the inhibition of these post-prenylation-processing steps — particularly that of ICMT-catalysed methylation — might provide a better approach to the control of cancer-cell proliferation.
Trends in sugar-sweetened beverage consumption among youth and adults in the United States: 1999-2010.

BACKGROUND Reducing sugar-sweetened beverage (SSB) consumption is a recommended strategy to promote optimal health. OBJECTIVE The objective was to describe trends in SSB consumption among youth and adults in the United States. DESIGN We analyzed energy intake from SSBs among 22,367 youth aged 2-19 y and 29,133 adults aged ≥20 y who participated in a 24-h dietary recall as part of NHANES, a nationally representative sample of the US population with a cross-sectional design, between 1999 and 2010. SSBs included soda, fruit drinks, sports and energy drinks, sweetened coffee and tea, and other sweetened beverages. Patterns of SSB consumption, including location of consumption and meal occasion associated with consumption, were also examined. RESULTS In 2009-2010, youth consumed a mean (±SE) of 155 ± 7 kcal/d from SSBs, and adults consumed an age-adjusted mean (±SE) of 151 ± 5 kcal/d from SSBs--a decrease from 1999 to 2000 of 68 kcal/d and 45 kcal/d, respectively (P-trend < 0.001 for each). In 2009-2010, SSBs contributed 8.0% ± 0.4% and 6.9% ± 0.2% of daily energy intake among youth and adults, respectively, which reflected a decrease compared with 1999-2000 (P-trend < 0.001 for both). Decreases in SSB consumption, both in the home and away from home and also with both meals and snacks, occurred over the 12-y study duration (P-trend < 0.01 for each). CONCLUSION A decrease in SSB consumption among youth and adults in the United States was observed between 1999 and 2010.
All dosage compensation is local: Gene-by-gene regulation of sex-biased expression on the chicken Z chromosome

Recent reports have suggested that birds lack a mechanism of wholesale dosage compensation for the Z sex chromosome. This discovery was rather unexpected, as all other animals investigated with chromosomal mechanisms of sex determination have some method to counteract the effects of gene dosage of the dominant sex chromosome in males and females. Despite the lack of a global mechanism of avian dosage compensation, the pattern of gene expression difference between males and females varies a great deal for individual Z-linked genes. This suggests that some genes may be individually dosage compensated, and that some less-than-global pattern of dosage compensation, such as local or temporal, exists on the avian Z chromosome. We used global gene expression profiling in males and females for both somatic and gonadal tissue at several time points in the life cycle of the chicken to assess the pattern of sex-biased gene expression on the Z chromosome. Average fold-change between males and females varied somewhat among tissue time-point combinations, with embryonic brain samples having the smallest gene dosage effects, and adult gonadal tissue having the largest degree of male bias. Overall, there were no neighborhoods of overall dosage compensation along the Z. Taken together, this suggests that dosage compensation is regulated on the Z chromosome entirely on a gene-by-gene level, and can vary during the life cycle and by tissue type. This regulation may be an indication of how critical a given gene's functionality is, as the expression level for essential genes will be tightly regulated in order to avoid perturbing important pathways and networks with differential expression levels in males and females.
Disruption of the 5S RNP–Mdm2 interaction significantly improves the erythroid defect in a mouse model for Diamond-Blackfan anemia

Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by haploinsufficiency of genes encoding ribosomal proteins (RPs). Perturbed ribosome biogenesis in DBA has been shown to induce a p53-mediated ribosomal stress response. However, the mechanisms of p53 activation and its relevance for the erythroid defect remain elusive. Previous studies have indicated that activation of p53 is caused by the inhibition of mouse double minute 2 (Mdm2), the main negative regulator of p53, by the 5S ribonucleoprotein particle (RNP). Meanwhile, it is not clear whether this mechanism solely mediates the p53-dependent component found in DBA. To approach this question, we crossed our mouse model for RPS19-deficient DBA with Mdm2C305F knock-in mice that have a disrupted 5S RNP–Mdm2 interaction. Upon induction of the Rps19 deficiency, Mdm2C305F reversed the p53 response and improved expansion of hematopoietic progenitors in vitro, and ameliorated the anemia in vivo. Unexpectedly, disruption of the 5S RNP–Mdm2 interaction also led to selective defect in erythropoiesis. Our findings highlight the sensitivity of erythroid progenitor cells to aberrations in p53 homeostasis mediated by the 5S RNP–Mdm2 interaction. Finally, we provide evidence indicating that physiological activation of the 5S RNP-Mdm2-p53 pathway may contribute to functional decline of the hematopoietic system in a cell-autonomous manner over time.
MotifMap: integrative genome-wide maps of regulatory motif sites for model species

BACKGROUND A central challenge of biology is to map and understand gene regulation on a genome-wide scale. For any given genome, only a small fraction of the regulatory elements embedded in the DNA sequence have been characterized, and there is great interest in developing computational methods to systematically map all these elements and understand their relationships. Such computational efforts, however, are significantly hindered by the overwhelming size of non-coding regions and the statistical variability and complex spatial organizations of regulatory elements and interactions. Genome-wide catalogs of regulatory elements for all model species simply do not yet exist. RESULTS The MotifMap system uses databases of transcription factor binding motifs, refined genome alignments, and a comparative genomic statistical approach to provide comprehensive maps of candidate regulatory elements encoded in the genomes of model species. The system is used to derive new genome-wide maps for yeast, fly, worm, mouse, and human. The human map contains 519,108 sites for 570 matrices with a False Discovery Rate of 0.1 or less. The new maps are assessed in several ways, for instance using high-throughput experimental ChIP-seq data and AUC statistics, providing strong evidence for their accuracy and coverage. The maps can be usefully integrated with many other kinds of omic data and are available at http://motifmap.igb.uci.edu/.   CONCLUSIONS MotifMap and its integration with other data provide a foundation for analyzing gene regulation on a genome-wide scale, and for automatically generating regulatory pathways and hypotheses. The power of this approach is demonstrated and discussed using the P53 apoptotic pathway and the Gli hedgehog pathways as examples.
Whole-genome fingerprint of the DNA methylome during human B cell differentiation

We analyzed the DNA methylome of ten subpopulations spanning the entire B cell differentiation program by whole-genome bisulfite sequencing and high-density microarrays. We observed that non-CpG methylation disappeared upon B cell commitment, whereas CpG methylation changed extensively during B cell maturation, showing an accumulative pattern and affecting around 30% of all measured CpG sites. Early differentiation stages mainly displayed enhancer demethylation, which was associated with upregulation of key B cell transcription factors and affected multiple genes involved in B cell biology. Late differentiation stages, in contrast, showed extensive demethylation of heterochromatin and methylation gain at Polycomb-repressed areas, and genes with apparent functional impact in B cells were not affected. This signature, which has previously been linked to aging and cancer, was particularly widespread in mature cells with an extended lifespan. Comparing B cell neoplasms with their normal counterparts, we determined that they frequently acquire methylation changes in regions already undergoing dynamic methylation during normal B cell differentiation.
LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression

LIN28B regulates developmental processes by modulating microRNAs (miRNAs) of the let-7 family. A role for LIN28B in cancer has been proposed but has not been established in vivo. Here, we report that LIN28B showed genomic aberrations and extensive overexpression in high-risk neuroblastoma compared to several other tumor entities and normal tissues. High LIN28B expression was an independent risk factor for adverse outcome in neuroblastoma. LIN28B signaled through repression of the let-7 miRNAs and consequently resulted in elevated MYCN protein expression in neuroblastoma cells. LIN28B–let-7–MYCN signaling blocked differentiation of normal neuroblasts and neuroblastoma cells. These findings were fully recapitulated in a mouse model in which LIN28B expression in the sympathetic adrenergic lineage induced development of neuroblastomas marked by low let-7 miRNA levels and high MYCN protein expression. Interference with this pathway might offer therapeutic perspectives.
Inflammatory monocyte/macrophage modulation by liposome-entrapped spironolactone ameliorates acute lung injury in mice.

AIM To examine the therapeutic/preventive potential of liposome-encapsulated spironolactone (SP; Lipo-SP) for acute lung injury (ALI) and fibrosis. MATERIALS & METHODS Lipo-SP was prepared by the film-ultrasonic method, and physicochemical and pharmacokinetic characterized for oral administration (10 and 20 mg/kg for SP-loaded liposome; 20 mg/kg for free SP) in a mouse model bleomycin-induced ALI. RESULTS Lipo-SP enhanced bioavailability of SP with significant amelioration in lung pathology. Mechanistically, SP-mediated mineralocorticoid receptor antagonism contributes to inflammatory monocyte/macrophage modulation via an inhibitory effect on Ly6C(hi) monocytosis-directed M2 polarization of alveolar macrophages. Moreover, Lipo-SP at lower dose (10 mg/kg) exhibited more improvement in body weight gain. CONCLUSION Our data highlight Lipo-SP as a promising approach with therapeutic/preventive potential for ALI and fibrosis.
Reduction of transmission from malaria patients by artemisinin combination therapies: a pooled analysis of six randomized trials

BACKGROUND Artemisinin combination therapies (ACT), which are increasingly being introduced for treatment of Plasmodium falciparum malaria, are more effective against sexual stage parasites (gametocytes) than previous first-line antimalarials and therefore have the potential to reduce parasite transmission. The size of this effect is estimated in symptomatic P. falciparum infections. METHODS Data on 3,174 patients were pooled from six antimalarial trials conducted in The Gambia and Kenya. Multivariable regression was used to investigate the role of ACT versus non-artemisinin antimalarial treatment, treatment failure, presence of pre-treatment gametocytes and submicroscopic gametocytaemia on transmission to mosquitoes and the area under the curve (AUC) of gametocyte density during the 28 days of follow up. RESULTS ACT treatment was associated with a significant reduction in the probability of being gametocytaemic on the day of transmission experiments (OR 0.20 95% CI 0.16-0.26), transmission to mosquitoes by slide-positive gametocyte carriers (OR mosquito infection 0.49 95% CI 0.33-0.73) and AUC of gametocyte density (ratio of means 0.35 95% CI 0.31-0.41). Parasitological treatment failure did not account for the difference between ACT and non-artemisinin impact. The presence of slide-positive gametocytaemia prior to treatment significantly reduced ACT impact on gametocytaemia (p < 0.001). Taking account of submicroscopic gametocytaemia reduced estimates of ACT impact in a high transmission setting in Kenya, but not in a lower transmission setting in the Gambia. CONCLUSION Treatment with ACT significantly reduces infectiousness of individual patients with uncomplicated falciparum malaria compared to previous first line treatments. Rapid treatment of cases before gametocytaemia is well developed may enhance the impact of ACT on transmission.
Skeletal Myogenic Progenitors Originating from Embryonic Dorsal Aorta Coexpress Endothelial and Myogenic Markers and Contribute to Postnatal Muscle Growth and Regeneration

Skeletal muscle in vertebrates is derived from somites, epithelial structures of the paraxial mesoderm, yet many unrelated reports describe the occasional appearance of myogenic cells from tissues of nonsomite origin, suggesting either transdifferentiation or the persistence of a multipotent progenitor. Here, we show that clonable skeletal myogenic cells are present in the embryonic dorsal aorta of mouse embryos. This finding is based on a detailed clonal analysis of different tissue anlagen at various developmental stages. In vitro, these myogenic cells show the same morphology as satellite cells derived from adult skeletal muscle, and express a number of myogenic and endothelial markers. Surprisingly, the latter are also expressed by adult satellite cells. Furthermore, it is possible to clone myogenic cells from limbs of mutant c-Met-/- embryos, which lack appendicular muscles, but have a normal vascular system. Upon transplantation, aorta-derived myogenic cells participate in postnatal muscle growth and regeneration, and fuse with resident satellite cells. The potential of the vascular system to generate skeletal muscle cells may explain observations of nonsomite skeletal myogenesis and raises the possibility that a subset of satellite cells may derive from the vascular system.
Accelerating Policy Decisions to Adopt Haemophilus influenzae Type b Vaccine: A Global, Multivariable Analysis

BACKGROUND Adoption of new and underutilized vaccines by national immunization programs is an essential step towards reducing child mortality. Policy decisions to adopt new vaccines in high mortality countries often lag behind decisions in high-income countries. Using the case of Haemophilus influenzae type b (Hib) vaccine, this paper endeavors to explain these delays through the analysis of country-level economic, epidemiological, programmatic and policy-related factors, as well as the role of the Global Alliance for Vaccines and Immunisation (GAVI Alliance). METHODS AND FINDINGS Data for 147 countries from 1990 to 2007 were analyzed in accelerated failure time models to identify factors that are associated with the time to decision to adopt Hib vaccine. In multivariable models that control for Gross National Income, region, and burden of Hib disease, the receipt of GAVI support speeded the time to decision by a factor of 0.37 (95% CI 0.18-0.76), or 63%. The presence of two or more neighboring country adopters accelerated decisions to adopt by a factor of 0.50 (95% CI 0.33-0.75). For each 1% increase in vaccine price, decisions to adopt are delayed by a factor of 1.02 (95% CI 1.00-1.04). Global recommendations and local studies were not associated with time to decision. CONCLUSIONS This study substantiates previous findings related to vaccine price and presents new evidence to suggest that GAVI eligibility is associated with accelerated decisions to adopt Hib vaccine. The influence of neighboring country decisions was also highly significant, suggesting that approaches to support the adoption of new vaccines should consider supply- and demand-side factors.
Six-Year Follow-Up of Impact of Co-proxamol Withdrawal in England and Wales on Prescribing and Deaths: Time-Series Study

BACKGROUND The analgesic co-proxamol (paracetamol/dextropropoxyphene combination) has been widely involved in fatal poisoning. Concerns about its safety/effectiveness profile and widespread use for suicidal poisoning prompted its withdrawal in the UK in 2005, with partial withdrawal between 2005 and 2007, and full withdrawal in 2008. Our objective in this study was to assess the association between co-proxamol withdrawal and prescribing and deaths in England and Wales in 2005-2010 compared with 1998-2004, including estimation of possible substitution effects by other analgesics. METHODS AND FINDINGS We obtained prescribing data from the NHS Health and Social Care Information Centre (England) and Prescribing Services Partneriaeth Cydwasanaethau GIG Cymru (Wales), and mortality data from the Office for National Statistics. We carried out an interrupted time-series analysis of prescribing and deaths (suicide, open verdicts, accidental poisonings) involving single analgesics. The reduction in prescribing of co-proxamol following its withdrawal in 2005 was accompanied by increases in prescribing of several other analgesics (co-codamol, paracetamol, codeine, co-dydramol, tramadol, oxycodone, and morphine) during 2005-2010 compared with 1998-2004. These changes were associated with major reductions in deaths due to poisoning with co-proxamol receiving verdicts of suicide and undetermined cause of -21 deaths (95% CI -34 to -8) per quarter, equating to approximately 500 fewer suicide deaths (-61%) over the 6 years 2005-2010, and -25 deaths (95% CI -38 to -12) per quarter, equating to 600 fewer deaths (-62%) when accidental poisoning deaths were included. There was little observed change in deaths involving other analgesics, apart from an increase in oxycodone poisonings, but numbers were small. Limitations were that the study was based on deaths involving single drugs alone and changes in deaths involving prescribed morphine could not be assessed. CONCLUSIONS During the 6 years following the withdrawal of co-proxamol in the UK, there was a major reduction in poisoning deaths involving this drug, without apparent significant increase in deaths involving other analgesics.
Apolipoprotein E genotype and concussion in college athletes.

OBJECTIVE To evaluate the association between apolipoprotein E (APOE) polymorphisms (E2, C/T Arg158Cys; E4, T/C Cys112Arg; and promoter, g-219t) and the history of concussion in college athletes. We hypothesized that carrying 1 or more APOE rare (or minor) allele assessed in this study would be associated with having a history of 1 or more concussions. DESIGN Multicenter cross-sectional study. SETTING University athletic facilities. PARTICIPANTS One hundred ninety-six male football (n = 163) and female soccer (n = 33) college athletes volunteered. INTERVENTIONS Written concussion history questionnaire and saliva samples for genotyping. MAIN OUTCOME MEASURES Self-reported history of a documented concussion and rare APOE genotype (E2, E4, promoter). RESULTS There was a significant association (Wald χ² = 3.82; P = 0.05; odds ratio = 9.8) between carrying all APOE rare alleles and the history of a previous concussion. There was also a significant association (Wald χ² = 3.96, P = 0.04, odds ratio = 8.4) between carrying the APOE promoter minor allele and experiencing 2 or more concussions. CONCLUSIONS Carriers of all 3 APOE rare (or minor) alleles assessed in this study were nearly 10 times more likely to report a previous concussion and may be at a greater risk of concussion versus noncarriers. Promoter minor allele carriers were 8.4 times more likely to report multiple concussions and may be at a greater risk of multiple concussions versus noncarriers. Research involving larger samples of individuals with multiple concussions and carriers of multiple APOE rare alleles is warranted.
Plasma soluble corin and N-terminal pro-atrial natriuretic peptide levels in pregnancy induced hypertension.

OBJECTIVE One of the theories involved in the pathogenesis of pregnancy induced hypertension involves salt and water retention. We aimed to measure the proenzyme convertase corin, responsible for pro-atrial natriuretic peptide (ANP) cleavage to active ANP, in plasma of hypertensive pregnant females. STUDY DESIGN Sixty pregnant females suffering from pregnancy induced hypertension in second and third trimesters of pregnancy were compared to twenty eight healthy pregnant females of the same gestational period. Concomitant urine and plasma samples were collected for the determination of some biochemical parameters. Plasma soluble corin and N-terminal (NT) pro-ANP (1-98) values were determined in both groups using enzyme immunoassays. RESULTS Plasma soluble corin mean value was significantly higher in the patient group compared to the control group. Upon dividing the patient group according to blood pressure, plasma NT pro-ANP showed significantly higher mean value in the group with blood pressure⩾140/90mmHg compared to the group with blood pressure<140/90mmHg and control group. CONCLUSIONS High plasma soluble corin and NT pro-ANP values in hypertensive pregnant females particularly those with blood pressure⩾140/90mmHg speculates an ANP receptor/ post receptor signaling defect, which would aggravate the pregnancy induced hypertensive state.