α-Lactosylceramide Protects Against iNKT-Mediated Murine Airway Hyperreactivity and Liver Injury Through Competitive Inhibition of Cd1d Binding.

Invariant natural killer T (iNKT) cells, which are activated by T cell receptor (TCR)-dependent recognition of lipid-based antigens presented by the CD1d molecule, have been shown to participate in the pathogenesis of many diseases, including asthma and liver injury. Previous studies have shown the inhibition of iNKT cell activation using lipid antagonists can attenuate iNKT cell-induced disease pathogenesis. Hence, the development of iNKT cell-targeted glycolipids can facilitate the discovery of new therapeutics. In this study, we synthesized and evaluated α-lactosylceramide (α-LacCer), an α-galactosylceramide (α-GalCer) analog with lactose substitution for the galactose head and a shortened acyl chain in the ceramide tail, toward iNKT cell activation. We demonstrated that α-LacCer was a weak inducer for both mouse and human iNKT cell activation and cytokine production, and the iNKT induction by α-LacCer was CD1d-dependent. However, when co-administered with α-GalCer, α-LacCer inhibited α-GalCer-induced IL-4 and IFN-γ production from iNKT cells. Consequently, α-LacCer also ameliorated both α-GalCer and GSL-1-induced airway hyperreactivity and α-GalCer-induced neutrophilia when co-administered in vivo. Furthermore, we were able to inhibit the increases of ConA-induced AST, ALT and IFN-γ serum levels through α-LacCer pre-treatment, suggesting α-LacCer could protect against ConA-induced liver injury. Mechanistically, we discerned that α-LacCer suppressed α-GalCer-stimulated cytokine production through competing for CD1d binding. Since iNKT cells play a critical role in the development of AHR and liver injury, the inhibition of iNKT cell activation by α-LacCer present a possible new approach in treating iNKT cell-mediated diseases

SARS-CoV-2 Transmission in Alberta, British Columbia, and Ontario, Canada, December 25, 2019, to December 1, 2020

Objective: This study aimed to investigate coronavirus disease (COVID-19) epidemiology in Alberta, British Columbia, and Ontario, Canada. Methods: Using data through December 1, 2020, we estimated time-varying reproduction number, R t , using EpiEstim package in R, and calculated incidence rate ratios (IRR) across the 3 provinces. Results: In Ontario, 76% (92 745/121 745) of cases were in Toronto, Peel, York, Ottawa, and Durham; in Alberta, 82% (49 878/61 169) in Calgary and Edmonton; in British Columbia, 90% (31 142/34 699) in Fraser and Vancouver Coastal. Across 3 provinces, R t dropped to ≤ 1 after April. In Ontario, R t would remain \u3c 1 in April if congregate-setting-associated cases were excluded. Over summer, R t maintained \u3c 1 in Ontario, ~1 in British Columbia, and ~1 in Alberta, except early July when R t was \u3e 1. In all 3 provinces, R t was \u3e 1, reflecting surges in case count from September through November. Compared with British Columbia (684.2 cases per 100 000), Alberta (IRR = 2.0; 1399.3 cases per 100 000) and Ontario (IRR = 1.2; 835.8 cases per 100 000) had a higher cumulative case count per 100 000 population. Conclusions: Alberta and Ontario had a higher incidence rate than British Columbia, but R t trajectories were similar across all 3 provinces

Pulmonary IL- 33 orchestrates innate immune cells to mediate respiratory syncytial virus- evoked airway hyperreactivity and eosinophilia

BackgroundRespiratory syncytial virus (RSV) infection is epidemiologically linked to asthma. During RSV infection, IL- 33 is elevated and promotes immune cell activation, leading to the development of asthma. However, which immune cells are responsible for triggering airway hyperreactivity (AHR), inflammation and eosinophilia remained to be clarified. We aimed to elucidate the individual roles of IL- 33- activated innate immune cells, including ILC2s and ST2+ myeloid cells, in RSV infection- triggered pathophysiology.MethodsThe role of IL- 33/ILC2 axis in RSV- induced AHR inflammation and eosinophilia were evaluated in the IL- 33- deficient and YetCre- 13 Rosa- DTA mice. Myeloid- specific, IL- 33- deficient or ST2- deficient mice were employed to examine the role of IL- 33 and ST2 signaling in myeloid cells.ResultsWe found that IL- 33- activated ILC2s were crucial for the development of AHR and airway inflammation, during RSV infection. ILC2- derived IL- 13 was sufficient for RSV- driven AHR, since reconstitution of wild- type ILC2 rescued RSV- driven AHR in IL- 13- deficient mice. Meanwhile, myeloid cell- derived IL- 33 was required for airway inflammation, ST2+ myeloid cells contributed to exacerbation of airway inflammation, suggesting the importance of IL- 33 signaling in these cells. Local and peripheral eosinophilia is linked to both ILC2 and myeloid IL- 33 signaling.ConclusionsThis study highlights the importance of IL- 33- activated ILC2s in mediating RSV- triggered AHR and eosinophilia. In addition, IL- 33 signaling in myeloid cells is crucial for airway inflammation.Respiratory syncytial virus induces ILC2 to produce IL- 5 and IL- 13 through IL- 33, which is crucial for the development of airway hyperreactivity and airway inflammation. Myeloid cell- derived IL- 33 and suppression of tumorigenicity 2- positive myeloid cells contribute to cytokine production and cellular inflammation in airway. Both ILC2 and myeloid cell IL- 33 signaling contribute to local and peripheral eosinophilia.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154896/1/all14091.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154896/2/all14091-sup-0001-Supinfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154896/3/all14091_am.pd

Biochemical and Structural Insights into the Mechanisms of SARS Coronavirus RNA Ribose 2′-O-Methylation by nsp16/nsp10 Protein Complex

The 5′-cap structure is a distinct feature of eukaryotic mRNAs, and eukaryotic viruses generally modify the 5′-end of viral RNAs to mimic cellular mRNA structure, which is important for RNA stability, protein translation and viral immune escape. SARS coronavirus (SARS-CoV) encodes two S-adenosyl-L-methionine (SAM)-dependent methyltransferases (MTase) which sequentially methylate the RNA cap at guanosine-N7 and ribose 2′-O positions, catalyzed by nsp14 N7-MTase and nsp16 2′-O-MTase, respectively. A unique feature for SARS-CoV is that nsp16 requires non-structural protein nsp10 as a stimulatory factor to execute its MTase activity. Here we report the biochemical characterization of SARS-CoV 2′-O-MTase and the crystal structure of nsp16/nsp10 complex bound with methyl donor SAM. We found that SARS-CoV nsp16 MTase methylated m7GpppA-RNA but not m7GpppG-RNA, which is in contrast with nsp14 MTase that functions in a sequence-independent manner. We demonstrated that nsp10 is required for nsp16 to bind both m7GpppA-RNA substrate and SAM cofactor. Structural analysis revealed that nsp16 possesses the canonical scaffold of MTase and associates with nsp10 at 1∶1 ratio. The structure of the nsp16/nsp10 interaction interface shows that nsp10 may stabilize the SAM-binding pocket and extend the substrate RNA-binding groove of nsp16, consistent with the findings in biochemical assays. These results suggest that nsp16/nsp10 interface may represent a better drug target than the viral MTase active site for developing highly specific anti-coronavirus drugs

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis