It is well known that depression is associated with asthma symptoms. We assessed the combined effects of genetic factors and depression on asthma symptom severity using Bayesian network (BN) ...analysis. The common 100 top-ranked single-nucleotide polymorphisms (SNPs) were obtained from two genome-wide association studies of symptom severity in two childhood asthmatics trials (CAMP (Childhood Asthma Management Program) and CARE (Childhood Asthma Research and Education)). Using SNPs plus five discretized variables (depression, anxiety, age, sex, and race), we performed BN analysis in 529 CAMP subjects. We identified two nodes (depression and rs4672619 mapping to
ERBB4
(Erb-B2 receptor tyrosine kinase 4)) that were within the Markov neighborhood of the symptom node in the network and then evaluated the interactive effects of depressive status and rs4672619 genotypes on asthma symptom severity. In childhood asthmatics with homozygous reference alleles, severe depression was related to less severe symptoms. However, in childhood asthmatics with heterozygous alleles and homozygous variant alleles, depression and symptom severity showed a positive correlation (interaction permutation
P
value = 0.019). We then tried to evaluate whether the interactive effects that we found were sustained in another independent cohort of elderly asthmatics. Contrary to the findings from childhood asthmatics, elderly asthmatics with homozygous reference alleles showed a positive correlation between depression and symptom severity, and elderly asthmatics with heterozygous alleles and homozygous variant alleles showed a negative correlation (interaction permutation
P
value = 0.003). In conclusion, we have identified a novel SNP, rs4672619, that shows interactive effects with depression on asthma symptom severity in childhood and elderly asthmatics in opposite directions.
A novel mutation affects how depression influences the severity of asthma symptoms, with opposite effects in children and the elderly. Depression is known to affect the severity of symptoms experienced by patients with chronic disorders, such as asthma. Heung-Woo Park at Seoul National University College of Medicine in South Korea and coworkers investigated how genetic factors might influence the interaction between depression and asthma. Using previously collected genetic data, the researchers identified a mutation linked with both asthma and depression. In children with the mutation, depression was linked to severe asthma symptoms; children with depression but without the mutation experienced milder symptoms. The researchers observed the opposite relationship in a group of elderly patients with asthma. They conclude that further study of this mutation could illuminate ways to improve asthma management strategies.
To identify metabolomic biomarkers predictive of Intensive Care Unit (ICU) mortality in adults.
Comprehensive metabolomic profiling of plasma at ICU admission to identify biomarkers associated with ...mortality has recently become feasible.
We performed metabolomic profiling of plasma from 90 ICU subjects enrolled in the BWH Registry of Critical Illness (RoCI). We tested individual metabolites and a Bayesian Network of metabolites for association with 28-day mortality, using logistic regression in R, and the CGBayesNets Package in MATLAB. Both individual metabolites and the network were tested for replication in an independent cohort of 149 adults enrolled in the Community Acquired Pneumonia and Sepsis Outcome Diagnostics (CAPSOD) study.
We tested variable metabolites for association with 28-day mortality. In RoCI, nearly one third of metabolites differed among ICU survivors versus those who died by day 28 (N = 57 metabolites, p<.05). Associations with 28-day mortality replicated for 31 of these metabolites (with p<.05) in the CAPSOD population. Replicating metabolites included lipids (N = 14), amino acids or amino acid breakdown products (N = 12), carbohydrates (N = 1), nucleotides (N = 3), and 1 peptide. Among 31 replicated metabolites, 25 were higher in subjects who progressed to die; all 6 metabolites that are lower in those who die are lipids. We used Bayesian modeling to form a metabolomic network of 7 metabolites associated with death (gamma-glutamylphenylalanine, gamma-glutamyltyrosine, 1-arachidonoylGPC(20:4), taurochenodeoxycholate, 3-(4-hydroxyphenyl) lactate, sucrose, kynurenine). This network achieved a 91% AUC predicting 28-day mortality in RoCI, and 74% of the AUC in CAPSOD (p<.001 in both populations).
Both individual metabolites and a metabolomic network were associated with 28-day mortality in two independent cohorts. Metabolomic profiling represents a valuable new approach for identifying novel biomarkers in critically ill patients.
Thionylimido Complexes McGeachie, Liam J. R.; Carpenter‐Warren, Cameron L.; Cordes, David B. ...
Zeitschrift für anorganische und allgemeine Chemie (1950),
November 30, 2020, Letnik:
646, Številka:
22
Journal Article
Recenzirano
Odprti dostop
An improved route to d‐block and main group NSO complexes is presented including the synthesis of the first antimony(V) complexes, (Ar3Sb(NSO)2), and copper examples CuBipy(PPh3)NSO. The structures ...of eight complexes are reported. The observed variation in M–N–S bond angles is due to the combination of orbital overlap (ligand‐to‐metal bonding) and the degree of ionicity of the bonding.
To determine whether the presence of posterior ponticles markedly increases by 30% or more, the incidence of major rotational stenosis of vertebral arteries.
Doppler ultrasound studies were performed ...in 3 private chiropractic clinics and in the radiology department of a public hospital, and magnetic resonance angiography (MRA) studies were made in the latter location. Thirty-two chiropractic patients had Doppler velocimetery, and 16 of these patients had MRA scanning. The outcome measures included changes in Doppler velocimetry signals and MRA images indicative of marked rotational stenosis of vertebral arteries.
All vertebral arteries from the 32 patients displayed no signs indicative of marked rotational stenosis.
The findings of this study show that the incidence of major rotational stenosis of vertebral arteries is not markedly increased by the presence of posterior ponticles.
Dynamin is a GTPase enzyme involved in membrane constriction and fission during endocytosis. Phospholipid binding via its pleckstrin homology domain maximally stimulates dynamin activity. We ...developed a series of surface-active small-molecule inhibitors, such as myristyl trimethyl ammonium bromide (MiTMAB) and octadecyltrimethyl ammonium bromide (OcTMAB), and we now show MiTMAB targets the dynamin-phospholipid interaction. MiTMAB inhibited dynamin GTPase activity, with a Ki of 940 +/- 25 nM. It potently inhibited receptor-mediated endocytosis (RME) of transferrin or epidermal growth factor (EGF) in a range of cells without blocking EGF binding, receptor number, or autophosphorylation. RME inhibition was rapidly reversed after washout. The rank order of potency for a variety of MiTMAB analogs on RME matched the rank order for dynamin inhibition, suggesting dynamin recruitment to the membrane is a primary cellular target. MiTMAB also inhibited synaptic vesicle endocytosis in rat brain nerve terminals (synaptosomes) without inducing depolarization or morphological defects. Therefore, the drug rapidly and reversibly blocks multiple forms of endocytosis with no acute cellular damage. The unique mechanism of action of MiTMAB provides an important tool to better understand dynamin-mediated membrane trafficking events in a variety of cells.
Objective: To determine whether lumen narrowing in vertebral arteries during atlanto-axial rotation is due to stretch or localized compression. Design and Setting: Experiments with models were made ...in a private chiropractic clinic, whereas studies of cadaveric specimens were performed in an anatomy laboratory. Doppler ultrasound and magnetic resonance angiography (MRA) studies were carried out in the radiology department of a public hospital. Patients: Eight patients had their vertebral arteries examined by use of a Doppler velocimeter and MRA. Main Outcome Measure: Stenosis of the vertebral arteries caused by stretch, localized compression, or kinking. Results: All 16 vertebral arteries from the 8 patients displayed no changes in their lumen dimensions with full cervical rotation, although curves in each of the arteries did change. The model and cadaveric vertebral arteries demonstrated localized compression or kinking of the vessel wall with atlanto-axial rotation contralaterally but revealed no evidence of major contribution of stretching to stenosis. Conclusion: The lumen of vertebral arteries is usually unaffected by atlanto-axial rotation. In cases where there is stenosis, this is mainly due to localized compression or kinking. These findings are relevant to premanipulative screening of vertebral arteries with Doppler ultrasound scanning. (J Manipulative Physiol Ther 2002;25:370-83)
It is not controversial that study design considerations and challenges must be addressed when investigating the linkage between single omic measurements and human phenotypes. It follows that such ...considerations are just as critical, if not more so, in the context of multi-omic studies. In this review, we discuss (1) epidemiologic principles of study design, including selection of biospecimen source(s) and the implications of the timing of sample collection, in the context of a multi-omic investigation, and (2) the strengths and limitations of various techniques of data integration across multi-omic data types that may arise in population-based studies utilizing metabolomic data.
Genetic risk loci have been identified for a wide range of diseases through genome-wide association studies (GWAS), but the relevant functional mechanisms have been identified for only a small ...proportion of these GWAS-identified loci. By integrating results from the largest current GWAS of chronic obstructive disease (COPD) with expression quantitative trait locus (eQTL) analysis in whole blood and sputum from 121 subjects with COPD from the ECLIPSE Study, this analysis identifies loci that are simultaneously associated with COPD and the expression of nearby genes (COPD eQTLs). After integrative analysis, 19 COPD eQTLs were identified, including all four previously identified genome-wide significant loci near HHIP, FAM13A, and the 15q25 and 19q13 loci. For each COPD eQTL, fine mapping and colocalization analysis to identify causal shared eQTL and GWAS variants identified a subset of sites with moderate-to-strong evidence of harboring at least one shared variant responsible for both the eQTL and GWAS signals. Transcription factor binding site (TFBS) analysis confirms that multiple COPD eQTL lead SNPs disrupt TFBS, and enhancer enrichment analysis for loci with the strongest colocalization signals showed enrichment for blood-related cell types (CD3 and CD4+ T cells, lymphoblastoid cell lines). In summary, integrative eQTL and GWAS analysis confirms that genetic control of gene expression plays a key role in the genetic architecture of COPD and identifies specific blood-related cell types as likely participants in the functional pathway from GWAS-associated variant to disease phenotype.
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