Multidimensional Assessment of Asthma Identifies Clinically Relevant Phenotype Overlap: A Cross-Sectional Study.

BACKGROUND:Asthma is a heterogeneous disease with multiple phenotypes; however, the relevance of phenotype overlap remains largely unexplored. OBJECTIVE:To examine the relationship between phenotype overlap and clinical and inflammatory profiles of asthma. METHODS:In this cross-sectional study, adult participants with stable asthma (n = 522) underwent multidimensional assessments. The 10 most common phenotypes of asthma were defined and then classified into those commonly associated with Type (T) 2 or non-T2 inflammation. Furthermore, phenotype overlap scores (POS), representing the cumulative concomitant phenotypes, were used to analyze its association with clinical and inflammatory asthmatic profiles. RESULTS:Among the 522 participants, 73.4% (n = 383) had phenotype overlap, and mixed T2 and non-T2 inflammation coexisted in 47.5% (n = 248). T2 POS was positively associated with eosinophils, IgE, and fractional exhaled nitric oxide (FeNO), and negatively with Asthma Quality of Life Questionnaire (AQLQ), sputum neutrophils, IL-17A, IL-8, and TNF-α. Non-T2 POS was positively associated with Asthma Control Questionnaire, neutrophils and sputum IL-8, and negatively with AQLQ, forced expiratory volume in 1 s, blood eosinophils, IgE, and FeNO (all P < .05). Patients with phenotypes that are associated with mixed T2 and non-T2 inflammation had elevated T2 inflammation biomarkers but worse asthma control. Both T2 (adjusted β = -0.191, P = .035) and non-T2 (adjusted β = 0.310, P < .001) POS were significantly associated with severe exacerbations. CONCLUSIONS:Phenotype overlap is extremely common in asthmatic patients and significantly associated with clinical and inflammatory profiles. Patients with phenotypes associated with mixed T2 and non-T2 inflammation might be unresponsive to medications owing to increased non-T2 inflammation. Multidimensional asthma assessment identifies clinically relevant phenotype overlap

Activating signal cointegrator 2 required for liver lipid metabolism mediated by liver X receptors in mice

Activating signal cointegrator 2 (ASC-2), a cancer-amplified transcriptional coactivator of nuclear receptors and many other transcription factors, contains two LXXLL-type nuclear receptor interaction domains. Interestingly, the second LXXLL motif is highly specific to the liver X receptors (LXRs). In cotransfection, DN2, an ASC-2 fragment encompassing this motif, exerts a potent dominant-negative effect on transactivation by LXRs, which is rescued by ectopic coexpression of the full-length ASC-2 but not by other LXXLL-type coactivators, such as SRC-1 and TRAP220. In contrast, DN2/m, in which the LXXLL motif is mutated to LXXAA to abolish the interactions with LXRs, is without any effect. Accordingly, expression of DN2, but not DN2/m, in transgenic mice results in phenotypes that are highly homologous to those previously observed with LXRalpha(-/-) mice, including a rapid accumulation of large amounts of cholesterol and down-regulation of the known lipid-metabolizing target genes of LXRalpha in the liver upon being fed a high-cholesterol diet. These results identify ASC-2 as a physiologically important transcriptional coactivator of LXRs and demonstrate its pivotal role in the liver lipid metabolism.open1136sciescopu

Quantifying Inactive Lithium in Lithium Metal Batteries

Inactive lithium (Li) formation is the immediate cause of capacity loss and catastrophic failure of Li metal batteries. However, the chemical component and the atomic level structure of inactive Li have rarely been studied due to the lack of effective diagnosis tools to accurately differentiate and quantify Li+ in solid electrolyte interphase (SEI) components and the electrically isolated unreacted metallic Li0, which together comprise the inactive Li. Here, by introducing a new analytical method, Titration Gas Chromatography (TGC), we can accurately quantify the contribution from metallic Li0 to the total amount of inactive Li. We uncover that the Li0, rather than the electrochemically formed SEI, dominates the inactive Li and capacity loss. Using cryogenic electron microscopies to further study the microstructure and nanostructure of inactive Li, we find that the Li0 is surrounded by insulating SEI, losing the electronic conductive pathway to the bulk electrode. Coupling the measurements of the Li0 global content to observations of its local atomic structure, we reveal the formation mechanism of inactive Li in different types of electrolytes, and identify the true underlying cause of low Coulombic efficiency in Li metal deposition and stripping. We ultimately propose strategies to enable the highly efficient Li deposition and stripping to enable Li metal anode for next generation high energy batteries

Genetic approaches to understanding the causes of stuttering

Stuttering is a common but poorly understood speech disorder. Evidence accumulated over the past several decades has indicated that genetic factors are involved, and genetic linkage studies have begun to identify specific chromosomal loci at which causative genes are likely to reside. A detailed investigation of one such region on chromosome 12 has identified mutations in the GNPTAB gene that are associated with stuttering in large families and in the general population. Subsequent studies identified mutations in the functionally related GNPTG and NAGPA genes. Mutations in these genes disrupt the lysosomal targeting pathway that generates the Mannose 6-phosphate signal, which directs a diverse group of enzymes to their target location in the lysosome of the cell. While mutations in these three genes can be identified in less than 10% of cases of familial stuttering, this knowledge allows a variety of new studies that can help identify the neuropathology that underlies this disorder

Remote Manipulation of Droplets on a Flexible Magnetically Responsive Film

The manipulation of droplets is used in a wide range of applications, from lab-on-a-chip devices to bioinspired functional surfaces. Although a variety of droplet manipulation techniques have been proposed, active, fast and reversible manipulation of pure discrete droplets remains elusive due to the technical limitations of previous techniques. Here, we describe a novel technique that enables active, fast, precise and reversible control over the position and motion of a pure discrete droplet with only a permanent magnet by utilizing a magnetically responsive flexible film possessing actuating hierarchical pillars on the surface. This magnetically responsive surface shows reliable actuating capabilities with immediate field responses and maximum tilting angles of ???90??. Furthermore, the magnetic responsive film exhibits superhydrophobicity regardless of tilting angles of the actuating pillars. Using this magnetically responsive film, we demonstrate active and reversible manipulation of droplets with a remote magnetic force.open0

Protein profiling in hepatocellular carcinoma by label-free quantitative proteomics in two west african populations.

Background Hepatocellular Carcinoma is the third most common cause of cancer related death worldwide, often diagnosed by measuring serum AFP; a poor performance stand-alone biomarker. With the aim of improving on this, our study focuses on plasma proteins identified by Mass Spectrometry in order to investigate and validate differences seen in the respective proteomes of controls and subjects with LC and HCC. Methods Mass Spectrometry analysis using liquid chromatography electro spray ionization quadrupole time-of-flight was conducted on 339 subjects using a pooled expression profiling approach. ELISA assays were performed on four significantly differentially expressed proteins to validate their expression profiles in subjects from the Gambia and a pilot group from Nigeria. Results from this were collated for statistical multiplexing using logistic regression analysis. Results Twenty-six proteins were identified as differentially expressed between the three subject groups. Direct measurements of four; hemopexin, alpha-1-antitrypsin, apolipoprotein A1 and complement component 3 confirmed their change in abundance in LC and HCC versus control patients. These trends were independently replicated in the pilot validation subjects from Nigeria. The statistical multiplexing of these proteins demonstrated performance comparable to or greater than ALT in identifying liver cirrhosis or carcinogenesis. This exercise also proposed preliminary cut offs with achievable sensitivity, specificity and AUC statistics greater than reported AFP averages. Conclusions The validated changes of expression in these proteins have the potential for development into high-performance tests usable in the diagnosis and or monitoring of HCC and LC patients. The identification of sustained expression trends strengthens the suggestion of these four proteins as worthy candidates for further investigation in the context of liver disease. The statistical combinations also provide a novel inroad of analyses able to propose definitive cut-offs and combinations for evaluation of performance

Allopurinol Reduces the Lethality Associated with Acute Renal Failure Induced by Crotalus durissus terrificus Snake Venom: Comparison with Probenecid

In Brazil, among registered snake bites, those by the genus Crotalus originate the highest mortality rate. The rattlesnake Crotalus durissus terrificus is the most frequently implicated in these accidents. The kidney is a particularly vulnerable organ to the venom of this rattlesnake. In fact, the most serious complication of Crotalus snake bite is the renal dysfunction, and among the fatal cases of Crotalus bites in Brazil 5% are patients treated with antivenom. The hyperuricemia has been observed in human accidents with snake venoms, but this parameter has not received any special attention as a relevant factor in the etiology of renal dysfunction caused by these venoms. This study examined the effects of treatments with low-cost and low-risk uricostatic (allopurinol) and uricosuric (probenecid) drugs on the envenomation by C. d. terrificus, showing that allopurinol and probenecid mitigated certain nephrotoxic effects, as well as the survival of envenomed mice was improved through the effects of allopurinol on reduction of oxidative stress and intracellular formation of uric acid. This new knowledge provides consistent evidences linking uric acid with the renal dysfunction induced by rattlesnake bites and that the allopurinol deserves to be clinically evaluated as an approach complementary to anti-snake venom serotherapy

CNx-modified Fe3O4 as Pt nanoparticle support for the oxygen reduction reaction

A novel electrocatalyst support material, nitrogendoped carbon (CNx)-modified Fe3O4 (Fe3O4-CNx), was synthesized through carbonizing a polypyrrole-Fe3O4 hybridized precursor. Subsequently, Fe3O4-CNx-supported Pt (Pt/Fe3O4-CNx) nanocomposites were prepared by reducing Pt precursor in ethylene glycol solution and evaluated for the oxygen reduction reaction (ORR). The Pt/Fe3O4-CNx catalysts were characterized by X-ray diffraction, Raman spectra, X-ray photoelectron spectroscopy, scanning electron microscopy, and transmission electron microscopy. The electrocatalytic activity and stability of the as-prepared electrocatalysts toward ORR were studied by cyclic voltammetry and steady-state polarization measurements. The results showed that Pt/ Fe3O4-CNx catalysts exhibited superior catalytic performance for ORR to the conventional Pt/C and Pt/C-CNx catalysts.Web of Scienc