IL-13-induced airway mucus production is attenuated by MAPK13 inhibition

Increased mucus production is a common cause of morbidity and mortality in inflammatory airway diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the precise molecular mechanisms for pathogenic mucus production are largely undetermined. Accordingly, there are no specific and effective anti-mucus therapeutics. Here, we define a signaling pathway from chloride channel calcium-activated 1 (CLCA1) to MAPK13 that is responsible for IL-13–driven mucus production in human airway epithelial cells. The same pathway was also highly activated in the lungs of humans with excess mucus production due to COPD. We further validated the pathway by using structure-based drug design to develop a series of novel MAPK13 inhibitors with nanomolar potency that effectively reduced mucus production in human airway epithelial cells. These results uncover and validate a new pathway for regulating mucus production as well as a corresponding therapeutic approach to mucus overproduction in inflammatory airway diseases

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Multi-Platform Next-Generation Sequencing of the Domestic Turkey (Meleagris gallopavo): Genome Assembly and Analysis

The combined application of next-generation sequencing platforms has provided an economical approach to unlocking the potential of the turkey genome

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Emergency Department patients with suicide risk: Differences in care by acute alcohol use

OBJECTIVE: To compare Emergency Department (ED) care of suicidal patients with and without documented acute alcohol use. METHODS: Retrospective chart review of randomly sampled patient visits (n=800; January 2014 to December 2015) at an urban ED with universal screening for suicide risk. Eligible visits were by adults (18+ years) who screened positive for suicide risk at the ED visit (i.e., suicidal ideation in past two weeks or suicide attempt in past six months). Analyses compared those with and without documentation of acute alcohol use. RESULTS: Among these patients with suicide risk, 19% had documented acute alcohol use (versus 43% with no use and 38% without documentation); individuals with acute alcohol use were more often male and aged 35-59years. Overall, 62% were evaluated by a mental health professional in the ED. Individuals with acute alcohol use were significantly less likely (vs those without use) to be evaluated by a mental health professional in the ED (odds ratio 0.49, 95%CI 0.28-0.87) after adjustment for age, recent suicide ideation, current suicide plan, self-harm as a chief complaint, contact with family, and ED disposition. CONCLUSIONS: Although alcohol use can increase suicide risk, ED patients with acute use appear to receive less thorough suicide risk assessments

Emergency Department patients with suicide risk: Differences in care by acute alcohol use

OBJECTIVE: To compare Emergency Department (ED) care of suicidal patients with and without documented acute alcohol use. METHODS: Retrospective chart review of randomly sampled patient visits (n=800; January 2014 to December 2015) at an urban ED with universal screening for suicide risk. Eligible visits were by adults (18+ years) who screened positive for suicide risk at the ED visit (i.e., suicidal ideation in past two weeks or suicide attempt in past six months). Analyses compared those with and without documentation of acute alcohol use. RESULTS: Among these patients with suicide risk, 19% had documented acute alcohol use (versus 43% with no use and 38% without documentation); individuals with acute alcohol use were more often male and aged 35-59years. Overall, 62% were evaluated by a mental health professional in the ED. Individuals with acute alcohol use were significantly less likely (vs those without use) to be evaluated by a mental health professional in the ED (odds ratio 0.49, 95%CI 0.28-0.87) after adjustment for age, recent suicide ideation, current suicide plan, self-harm as a chief complaint, contact with family, and ED disposition. CONCLUSIONS: Although alcohol use can increase suicide risk, ED patients with acute use appear to receive less thorough suicide risk assessments

LCF Life of As-Deposited and Annealed NiCr-Y Coatings for Oxidation and Hot Corrosion Protection of Disk Alloys

Increasing temperatures in aero gas turbines is resulting in oxidation and hot corrosion attack of turbine disks. Since disks are sensitive to low cycle fatigue (LCF), any environmental attack, and especially hot corrosion pitting, can seriously degrade the life of the disk. Application of metallic coatings is one means of protecting disk alloys from this environmental attack. However, the presence of a metallic coating can degrade the LCF life of a disk alloy. Therefore, coatings must be designed which are not only resistant to oxidation and corrosion attack, but do not significantly degrade the LCF life of the alloy.Three different NiCr-Y coating compositions (29, 35.5, 44 wt.% Cr, all with 0.1 wt.% Y) were applied at two thicknesses by Plasma Enhanced Magnetron Sputtering (PEMS) to two similar Ni-based disk alloys. One Ni-35.5Cr-0.1Y coating also received a thin ZrO2 overcoat. The coated samples were also given a short thermal anneal in a low PO2 environment to encourage bonding of the coating and substrate as well as initiating formation of a chromia scale. Without further environmental exposure, the LCF life of coated and uncoated samples was evaluated at 760C in air. The LCF lifetime of all coated samples was less than that of uncoated samples. The LCF life scaled with the Cr content and the high-Cr, thin coating showed the highest LCF life. Pre and post-test characterization of the various coatings, including identification of crack initiation sites, will be presented and the effect of the coating on the LCF life discussed

Single Cell High Dimensional Analysis of Human Peripheral Blood Mononuclear Cells Reveals Unique Intermediate Monocyte Subsets Associated with Sex Differences in Coronary Artery Disease

Monocytes are associated with human cardiovascular disease progression. Monocytes are segregated into three major subsets: classical (cMo), intermediate (iMo), and nonclassical (nMo). Recent studies have identified heterogeneity within each of these main monocyte classes, yet the extent to which these subsets contribute to heart disease progression is not known. Peripheral blood mononuclear cells (PBMC) were obtained from 61 human subjects within the Coronary Assessment of Virginia (CAVA) Cohort. Coronary atherosclerosis severity was quantified using the Gensini Score (GS). We employed high-dimensional single-cell transcriptome and protein methods to define how human monocytes differ in subjects with low to severe coronary artery disease. We analyzed 487 immune-related genes and 49 surface proteins at the single-cell level using Antibody-Seq (Ab-Seq). We identified six subsets of myeloid cells (cMo, iMo, nMo, plasmacytoid DC, classical DC, and DC3) at the single-cell level based on surface proteins, and we associated these subsets with coronary artery disease (CAD) incidence based on Gensini score (GS) in each subject. Only frequencies of iMo were associated with high CAD (GS > 32), adj.p = 0.024. Spearman correlation analysis with GS from each subject revealed a positive correlation with iMo frequencies (r = 0.314, p = 0.014) and further showed a robust sex-dependent positive correlation in female subjects (r = 0.663, p = 0.004). cMo frequencies did not correlate with CAD severity. Key gene pathways differed in iMo among low and high CAD subjects and between males and females. Further single-cell analysis of iMo revealed three iMo subsets in human PBMC, distinguished by the expression of HLA-DR, CXCR3, and CD206. We found that the frequency of immunoregulatory iMo_HLA-DR+CXCR3+CD206+ was associated with CAD severity (adj.p = 0.006). The immunoregulatory iMo subset positively correlated with GS in both females (r = 0.660, p = 0.004) and males (r = 0.315, p = 0.037). Cell interaction analyses identified strong interactions of iMo with CD4+ effector/memory T cells and Tregs from the same subjects. This study shows the importance of iMo in CAD progression and suggests that iMo may have important functional roles in modulating CAD risk, particularly among females