Chiral Polymerization in Open Systems From Chiral-Selective Reaction Rates

We investigate the possibility that prebiotic homochirality can be achieved exclusively through chiral-selective reaction rate parameters without any other explicit mechanism for chiral bias. Specifically, we examine an open network of polymerization reactions, where the reaction rates can have chiral-selective values. The reactions are neither autocatalytic nor do they contain explicit enantiomeric cross-inhibition terms. We are thus investigating how rare a set of chiral-selective reaction rates needs to be in order to generate a reasonable amount of chiral bias. We quantify our results adopting a statistical approach: varying both the mean value and the rms dispersion of the relevant reaction rates, we show that moderate to high levels of chiral excess can be achieved with fairly small chiral bias, below 10%. Considering the various unknowns related to prebiotic chemical networks in early Earth and the dependence of reaction rates to environmental properties such as temperature and pressure variations, we argue that homochirality could have been achieved from moderate amounts of chiral selectivity in the reaction rates.Comment: 15 pages, 6 figures, accepted for publication in Origins of Life and Evolution of Biosphere

Admission to acute care hospitals for adolescent substance abuse: a national descriptive analysis

BACKGROUND: Use of alcohol and illicit drugs by adolescents remains a problem in the U.S. Case identification and early treatment can occur within a broad variety of healthcare and non-healthcare settings, including acute care hospitals. The objective of this study is to describe the extent and nature of adolescent admissions to the acute inpatient setting for substance abuse (SA). We use the Agency for Healthcare Research and Quality (AHRQ) 2000 Healthcare Cost and Utilization Project Kids Inpatient Database (HCUP-KID) which includes over 2.5 million admissions for youth age 20 and under to 2,784 hospitals in 27 states in the year 2000. Specifically, this analysis estimates national number of admissions, mean total charges, and mean lengths of stay for adolescents between the ages of 12 and 17 admitted to an acute care hospital for the following diagnostic categories from the AHRQ's Clinical Classifications Software categories: "alcohol-related mental disorders" and "substance-related mental disorders". Frequency and percentage of total admissions were calculated for demographic variables of age, gender and income and for hospital characteristic variables of urban/rural designation and children's hospital designation. RESULTS: SA admissions represented 1.25 percent of adolescent admissions to acute care hospitals. Nearly 90 percent of the admission occurred in non-Children's hospitals. Most were for drug dependence (38%) or non-dependent use of alcohol or drugs (35%). Costs were highest for drug dependence admissions. Nearly half of admissions had comorbid mental health diagnoses. Higher rates of admission were seen in boys, in older adolescents, and in "self-pay" patients. Alcohol and drug rehabilitation/detoxification, alone or in combination with psychological and psychiatric evaluation and therapy, was documented for 38 percent of admissions. Over 50 percent of cases had no documentation of treatment specific to substance use behavior. CONCLUSION: General acute care hospitals have a significant and important opportunity to recognize, treat, and refer adolescents with substance abuse problems. These results suggest that inpatient facilities should develop and implement policies and processes to ensure that adolescent substance abusers admitted to their institutions receive appropriate care during the admission and appropriate referral to community care resources

Heterogeneous nuclear ribonucleoprotein K is over expressed, aberrantly localised and is associated with poor prognosis in colorectal cancer

Heterogeneous ribonucleoprotein K (hnRNP K) is a member of the hnRNP family which has several different cellular roles including transcription, mRNA shuttling, RNA editing and translation. Several reports implicate hnRNP K having a role in tumorigenesis, for instance hnRNP K increases transcription of the oncogene c-myc and hnRNP K expression is regulated by the p53/MDM 2 pathway. In this study comparing normal colon to colorectal cancer by proteomics, hnRNP K was identified as being overexpressed in this type of cancer. Immunohistochemistry with a monoclonal antibody to hnRNP K (which we developed) on colorectal cancer tissue microarray, confirmed that hnRNP K was overexpressed in colorectal cancer (P<0.001) and also showed that hnRNP K had an aberrant subcellular localisation in cancer cells. In normal colon hnRNP K was exclusively nuclear whereas in colorectal cancer the protein localised both in the cytoplasm and the nucleus. There were significant increases in both nuclear (P=0.007) and cytoplasmic (P=0.001) expression of hnRNP K in Dukes C tumours compared with early stage tumours. In Dukes C patient's good survival was associated with increased hnRNP K nuclear expression (P=0.0093). To elaborate on the recent observation that hnRNP K is regulated by p53, the expression profiles of these two proteins were also analysed. There was no correlation between hnRNP K and p53 expression, however, patients who presented tumours that were positive for hnRNP K and p53 had a poorer survival outcome (P=0.045)

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer

We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 x 10(-8)), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 x 10(-9)). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 x 10(-6)) than in HPV-negative (OR = 0.75, P = 0.16) cancers

Gain, Loss and Divergence in Primate Zinc-Finger Genes: A Rich Resource for Evolution of Gene Regulatory Differences between Species

The molecular changes underlying major phenotypic differences between humans and other primates are not well understood, but alterations in gene regulation are likely to play a major role. Here we performed a thorough evolutionary analysis of the largest family of primate transcription factors, the Krüppel-type zinc finger (KZNF) gene family. We identified and curated gene and pseudogene models for KZNFs in three primate species, chimpanzee, orangutan and rhesus macaque, to allow for a comparison with the curated set of human KZNFs. We show that the recent evolutionary history of primate KZNFs has been complex, including many lineage-specific duplications and deletions. We found 213 species-specific KZNFs, among them 7 human-specific and 23 chimpanzee-specific genes. Two human-specific genes were validated experimentally. Ten genes have been lost in humans and 13 in chimpanzees, either through deletion or pseudogenization. We also identified 30 KZNF orthologs with human-specific and 42 with chimpanzee-specific sequence changes that are predicted to affect DNA binding properties of the proteins. Eleven of these genes show signatures of accelerated evolution, suggesting positive selection between humans and chimpanzees. During primate evolution the most extensive re-shaping of the KZNF repertoire, including most gene additions, pseudogenizations, and structural changes occurred within the subfamily homininae. Using zinc finger (ZNF) binding predictions, we suggest potential impact these changes have had on human gene regulatory networks. The large species differences in this family of TFs stands in stark contrast to the overall high conservation of primate genomes and potentially represents a potent driver of primate evolution

The Cumulative Effects of Polymorphisms in the DNA Mismatch Repair Genes and Tobacco Smoking in Oesophageal Cancer Risk

The DNA mismatch repair (MMR) enzymes repair errors in DNA that occur during normal DNA metabolism or are induced by certain cancer-contributing exposures. We assessed the association between 10 single-nucleotide polymorphisms (SNPs) in 5 MMR genes and oesophageal cancer risk in South Africans. Prior to genotyping, SNPs were selected from the HapMap database, based on their significantly different genotypic distributions between European ancestry populations and four HapMap populations of African origin. In the Mixed Ancestry group, the MSH3 rs26279 G/G versus A/A or A/G genotype was positively associated with cancer (OR = 2.71; 95% CI: 1.34–5.50). Similar associations were observed for PMS1 rs5742938 (GG versus AA or AG: OR = 1.73; 95% CI: 1.07–2.79) and MLH3 rs28756991 (AA or GA versus GG: OR = 2.07; 95% IC: 1.04–4.12). In Black individuals, however, no association between MMR polymorhisms and cancer risk was observed in individual SNP analysis. The interactions between MMR genes were evaluated using the model-based multifactor-dimensionality reduction approach, which showed a significant genetic interaction between SNPs in MSH2, MSH3 and PMS1 genes in Black and Mixed Ancestry subjects, respectively. The data also implies that pathogenesis of common polymorphisms in MMR genes is influenced by exposure to tobacco smoke. In conclusion, our findings suggest that common polymorphisms in MMR genes and/or their combined effects might be involved in the aetiology of oesophageal cancer

Coordinate Regulation of Lipid Metabolism by Novel Nuclear Receptor Partnerships

Mammalian nuclear receptors broadly influence metabolic fitness and serve as popular targets for developing drugs to treat cardiovascular disease, obesity, and diabetes. However, the molecular mechanisms and regulatory pathways that govern lipid metabolism remain poorly understood. We previously found that the Caenorhabditis elegans nuclear hormone receptor NHR-49 regulates multiple genes in the fatty acid beta-oxidation and desaturation pathways. Here, we identify additional NHR-49 targets that include sphingolipid processing and lipid remodeling genes. We show that NHR-49 regulates distinct subsets of its target genes by partnering with at least two other distinct nuclear receptors. Gene expression profiles suggest that NHR-49 partners with NHR-66 to regulate sphingolipid and lipid remodeling genes and with NHR-80 to regulate genes involved in fatty acid desaturation. In addition, although we did not detect a direct physical interaction between NHR-49 and NHR-13, we demonstrate that NHR-13 also regulates genes involved in the desaturase pathway. Consistent with this, gene knockouts of these receptors display a host of phenotypes that reflect their gene expression profile. Our data suggest that NHR-80 and NHR-13's modulation of NHR-49 regulated fatty acid desaturase genes contribute to the shortened lifespan phenotype of nhr-49 deletion mutant animals. In addition, we observed that nhr-49 animals had significantly altered mitochondrial morphology and function, and that distinct aspects of this phenotype can be ascribed to defects in NHR-66– and NHR-80–mediated activities. Identification of NHR-49's binding partners facilitates a fine-scale dissection of its myriad regulatory roles in C. elegans. Our findings also provide further insights into the functions of the mammalian lipid-sensing nuclear receptors HNF4α and PPARα

Suicidality among adolescents engaging in nonsuicidal self-injury (NSSI) and firesetting: The role of psychosocial characteristics and reasons for living

Background: Co-occurrence of problem behaviors, particularly across internalizing and externalizing spectra, increases the risk of suicidality (i.e., suicidal ideation and attempt) among youth. Methods: We examined differences in psychosocial risk factors across levels of suicidality in a sample of 77 school-based adolescents engaging in both nonsuicidal self-injury (NSSI) and repeated firesetting. Participants completed questionnaires assessing engagement in problem behaviors, mental health difficulties, negative life events, poor coping, impulsivity, and suicidality. Results: Adolescents endorsing suicidal ideation reported greater psychological distress, physical and sexual abuse, and less problem solving/goal pursuit than those with no history of suicidality; adolescents who had attempted suicide reported more severe NSSI, higher rates of victimization and exposure to suicide, relative to those with suicidal ideation but no history of attempt. Additional analyses suggested the importance of coping beliefs in protecting against suicidality. Conclusions: Clinical implications and suggestions for future research relating to suicide prevention are discussed

Pleiotropy of genetic variants on obesity and smoking phenotypes: Results from the Oncoarray Project of The International Lung Cancer Consortium

Obesity and cigarette smoking are correlated through complex relationships. Common genetic causes may contribute to these correlations. In this study, we selected 241 loci potentially associated with body mass index (BMI) based on the Genetic Investigation of ANthropometric Traits (GIANT) consortium data and calculated a BMI genetic risk score (BMI-GRS) for 17,037 individuals of European descent from the Oncoarray Project of the International Lung Cancer Consortium (ILCCO). Smokers had a significantly higher BMI-GRS than never-smokers (p = 0.016 and 0.010 before and after adjustment for BMI, respectively). The BMI-GRS was also positively correlated with pack-years of smoking (p<0.001) in smokers. Based on causal network inference analyses, seven and five of 241 SNPs were classified to pleiotropic models for BMI/smoking status and BMI/pack-years, respectively. Among them, three and four SNPs associated with smoking status and pack-years (p<0.05), respectively, were followed up in the ever-smoking data of the Tobacco, Alcohol and Genetics (TAG) consortium. Among these seven candidate SNPs, one SNP (rs11030104, BDNF) achieved statistical significance after Bonferroni correction for multiple testing, and three suggestive SNPs (rs13021737, TMEM18; rs11583200, ELAVL4; and rs6990042, SGCZ) achieved a nominal statistical significance. Our results suggest that there is a common genetic component between BMI and smoking, and pleiotropy analysis can be useful to identify novel genetic loci of complex phenotypes