Synchronous vs. asynchronous dynamics of diffusion-controlled reactions

An analytical method based on the classical ruin problem is developed to compute the mean reaction time between two walkers undergoing a generalized random walk on a 1d lattice. At each time step, either both walkers diffuse simultaneously with probability $p$ (synchronous event) or one of them diffuses while the other remains immobile with complementary probability (asynchronous event). Reaction takes place through same site occupation or position exchange. We study the influence of the degree of synchronicity $p$ of the walkers and the lattice size $N$ on the global reaction's efficiency. For odd $N$, the purely synchronous case ($p=1$) is always the most effective one, while for even $N$, the encounter time is minimized by a combination of synchronous and asynchronous events. This new parity effect is fully confirmed by Monte Carlo simulations on 1d lattices as well as for 2d and 3d lattices. In contrast, the 1d continuum approximation valid for sufficiently large lattices predicts a monotonic increase of the efficiency as a function of $p$. The relevance of the model for several research areas is briefly discussed.Comment: 21 pages (including 12 figures and 4 tables), uses revtex4.cls, accepted for publication in Physica

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms

Rare and common genetic determinants of metabolic individuality and their effects on human health

Garrod’s concept of ‘chemical individuality’ has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant–metabolite associations (P < 1.25 × 10−11) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant–metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships

First dose behavioral tolerance to phencyclidine on food-rewarded bar pressing behavior in the rat

The behavioral effects of single doses of phencyclidine (PCP) were examined in drug-naive adult male Holtzman rats trained to press a bar on a fixed ratio (4) schedule (FR 4 ), i.e., a reward of sugarsweetened milk was earned on every fourth bar press. Groups of rats (four to eight rats per group) received specific doses of PCP which were held constant for each group throughout the study. Dose-response curves for PCP given in doses of 1.0, 1.8, 2.4, and 3.2 mg/kg IP were first determined and then redetermined at weekly intervals. A drug-free interval of 7–8 days was maintained between injections given weekly over a period of 4 weeks. The final dose of PCP was administered after a 4-week drug-free period. Evidence was obtained for first dose behavioral tolerance as shown by the significantly shortened duration of suppression of bar pressing on subsequent injections. Although subsequent weekly effects of equal doses of PCP showed no significant differences, they all differed significantly from the first injection. The reduced response to PCP was shown to be due to learned behavioral tolerance as demonstrated when PCP (3.2 mg/kg IP) was given to drug-naive animals in their home cages and 1 week later given the second dose in the operant behavioral situation. Under these circumstances, the second dose of PCP showed a similarly protracted depression of FR 4 responding as other animals given the drug for the first time in the operant situation. Subsequent weekly injections in the operant situation produced similar behavioral tolerance.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46412/1/213_2004_Article_BF00426513.pd

To hit or not to hit, that is the question -genome-wide structure-based druggability predictions for <i>pseudomonas aeruginosa </i>proteins

Pseudomonas aeruginosa is a Gram-negative bacterium known to cause opportunistic infections in immune-compromised or immunosuppressed individuals that often prove fatal. New drugs to combat this organism are therefore sought after. To this end, we subjected the gene products of predicted perturbative genes to structure-based druggability predictions using DrugPred. Making this approach suitable for large-scale predictions required the introduction of new methods for calculation of descriptors, development of a workflow to identify suitable pockets in homologous proteins and establishment of criteria to obtain valid druggability predictions based on homologs. We were able to identify 29 perturbative proteins of P. aeruginosa that may contain druggable pockets, including some of them with no or no drug-like inhibitors deposited in ChEMBL. These proteins form promising novel targets for drug discovery against P. aeruginosa

Publisher Correction:Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals (Nature Genetics, (2020), 52, 12, (1314-1332), 10.1038/s41588-020-00713-x)

In the version of this article originally published, the e-mail address of corresponding author Patricia B. Munroe was incorrect. The error has been corrected in the HTML and PDF versions of the article

An evaluation of prescribing practices for community-acquired pneumonia (CAP) in Mongolia

BACKGROUND: Community-acquired pneumonia (CAP) is a significant cause of morbidity and mortality in all age groups worldwide. It may be classified as mild/moderate or severe, the latter usually requiring hospitalisation. Although, there are many studies reported in relation to CAP, there is relatively little known about the treatment of CAP and its antibiotic use in Mongolia. The study aim was to evaluate prescribing practices for the treatment of mild/moderate CAP in Mongolia with respect to national prescribing guidelines. METHODS: Written prescriptions with a written diagnosis of CAP included were collected prospectively and sequentially for ten weeks from a purposefully selected sample of community pharmacies in rural and urban areas of Mongolia. The data collected included the patient's age, gender, medication details, frequency and number of doses prescribed. Evaluation was with respect to the Mongolian Standard Treatment Guidelines (2005, 2008). Statistical differences between groups were tested using the Chi-squared and Fisher's exact tests.RESULTS: Prescriptions were collected from 22 pharmacies and represented the prescribing practices of 118 doctors. The study enrolled 394 (193 adults and 201 children) patients, with a median age for children of 2.0 years (range: 0.03-12) and adults of 33.0 years (range: 13--92).The most commonly prescribed drugs were amino penicillins, vitamins, and mucolytics, with the median number of drugs being three per prescription. Inappropriate drug selection was similar for adults (57.7%) and children (56.6%), and the major reason for an overall frequency of inappropriate prescribing for adults were 89.0% and for children 78.0%. Doctors in urban areas prescribed more inappropriate drugs than those in rural areas for both children and adults, p = .0014. The proportion of prescribed injections was 28.4% for adults and 9.0% for children, and for adults was significantly higher in urban areas. The prescribing standard for non-hospitalized patients in Mongolia states that injections should not be prescribed. CONCLUSIONS: The high level of inappropriate prescribing for mild/moderate CAP highlights the need to develop comprehensive and reliable procedures nationwide to improve prescribing practices in Mongolia

Therapeutic opportunities within the DNA damage response

The DNA damage response (DDR) is essential for maintaining the genomic integrity of the cell, and its disruption is one of the hallmarks of cancer. Classically, defects in the DDR have been exploited therapeutically in the treatment of cancer with radiation therapies or genotoxic chemotherapies. More recently, protein components of the DDR systems have been identified as promising avenues for targeted cancer therapeutics. Here, we present an in-depth analysis of the function, role in cancer and therapeutic potential of 450 expert-curated human DDR genes. We discuss the DDR drugs that have been approved by the US Food and Drug Administration (FDA) or that are under clinical investigation. We examine large-scale genomic and expression data for 15 cancers to identify deregulated components of the DDR, and we apply systematic computational analysis to identify DDR proteins that are amenable to modulation by small molecules, highlighting potential novel therapeutic targets

Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health

Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health