Application of Rat In Situ Single-pass Intestinal Perfusion in the Evaluation of Presystemic Extraction of Indinavir Under Different Perfusion Rates

Background/PurposeFirst-pass effect has been an important concern for oral pharmaceuticals. An in vivo system was developed for measuring different concentrations of pharmaceuticals in the portal vein and hepatic vein (via the inferior vena cava) for delineating presystemic metabolism under different perfusion rates by using indinavir as an exemplary agent.MethodsAn in situ single-pass intestinal perfusion technique was modified from previous studies to concomitantly obtain portal and hepatic venous bloods. Portal and hepatic venous samples were simultaneously taken from rats at appropriate time points using the perfusion model of 1 mg/mL indinavir at flow rates of 0.05, 0.1, 0.5 and 1.0 mL/min. The indinavir concentrations were assayed by binary-gradient high-pressure liquid chromatography with UV detection.ResultsThe mean indinavir concentrations in portal vein concentration−time profiles at different perfusion times under various flow rates were all higher than those obtained for hepatic veins. At flow rates of 0.5 and 1.0 mL/min, in particular, the area under the curve (AUC) and maximal concentration (C max) of indinavir absorption were significantly different between portal veins and hepatic veins (p < 0.05), indicating considerable hepatic involvement in the presystemic extraction of indinavir. The system also has potential for use when estimating the hepatic extraction ratio (E H) and hepatic clearance (Cl H).ConclusionThis in vivo approach could provide another useful tool for improving our basic understanding of the absorption kinetics and hepatic metabolism of pharmaceuticals under development and facilitating the clinical application of such

KOBAS 2.0: a web server for annotation and identification of enriched pathways and diseases

High-throughput experimental technologies often identify dozens to hundreds of genes related to, or changed in, a biological or pathological process. From these genes one wants to identify biological pathways that may be involved and diseases that may be implicated. Here, we report a web server, KOBAS 2.0, which annotates an input set of genes with putative pathways and disease relationships based on mapping to genes with known annotations. It allows for both ID mapping and cross-species sequence similarity mapping. It then performs statistical tests to identify statistically significantly enriched pathways and diseases. KOBAS 2.0 incorporates knowledge across 1327 species from 5 pathway databases (KEGG PATHWAY, PID, BioCyc, Reactome and Panther) and 5 human disease databases (OMIM, KEGG DISEASE, FunDO, GAD and NHGRI GWAS Catalog). KOBAS 2.0 can be accessed at http://kobas.cbi.pku.edu.cn

FLCRM: Functional linear cox regression model

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142963/1/biom12748.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142963/2/biom12748_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142963/3/biom12748-sup-0001-SuppInfo-S1.pd

Interaction between genetic predisposition, smoking, and dementia risk: a population-based cohort study

This is the final version. Available on open access from Nature Research via the DOI in this recordData availability: The data that support the findings of this study are available from the corresponding author on reasonable request.We evaluated whether the association between cigarette smoking and dementia risk is modified by genetic predisposition including apolipoprotein E (APOE) genotype and polygenic risk (excluding the APOE region). We included 193,198 UK Biobank participants aged 60-73 years without dementia at baseline. Of non-APOE-ε4 carriers, 0.89% (95% CI 0.73-1.08%) current smokers developed dementia compared with 0.49% (95% CI 0.44-0.55%) of never smokers (adjusted HR 1.78; 95% CI 1.39-2.29). In contrast, of one APOE-ε4 allele carriers, 1.69% (95% CI 1.31-2.12%) current smokers developed dementia compared with 1.40% (95% CI 1.25-1.55%) of never smokers (adjusted HR 1.06; 95% CI 0.77-1.45); of two APOE-ε4 alleles carriers, 4.90% (95% CI 2.92-7.61%) current smokers developed dementia compared with 3.87% (95% CI 3.11-4.74%) of never smokers (adjusted HR 0.94; 95% CI 0.49-1.79). Of participants with high polygenic risk, 1.77% (95% CI 1.35-2.27%) current smokers developed dementia compared with 1.05% (95% CI 0.91-1.21%) of never smokers (adjusted HR 1.63; 95% CI 1.16-2.28). A significant interaction was found between APOE genotype and smoking status (P = 0.002) while no significant interaction was identified between polygenic risk and smoking status (P = 0.25). APOE genotype but not polygenic risk modified the effect of smoking on dementia risk.National Key Research and Development Program of ChinaAlzheimer’s Research UKNational Institute for Health Research (NIHR)JP Moulton FoundationNational Institute on Aging / National Institutes of HealthAlan Turing Institute / Engineering and Physical Sciences Research Counci

Constraining Bosonic Supersymmetry from Higgs results and 8 TeV ATLAS multi-jets plus missing energy data

The collider phenomenology of models with Universal Extra Dimensions (UED) is surprisingly similar to that of supersymmetric (SUSY) scenarios. For each level-1 bosonic (fermionic) Kaluza-Klein (KK) state, there is a fermionic (bosonic) analog in SUSY and thus UED scenarios are often known as bosonic supersymmetry. The minimal version of UED (mUED) gives rise to a quasi-degenerate particle spectrum at each KK-level and thus, can not explain the enhanced Higgs to diphoton decay rate hinted by the ATLAS collaboration of the Large Hadron Collider (LHC) experiment. However, in the non-minimal version of the UED (nmUED) model, the enhanced Higgs to diphoton decay rate can be easily explained via the suitable choice of boundary localized kinetic (BLK) terms for higher dimensional fermions and gauge bosons. BLK terms remove the degeneracy in the KK mass spectrum and thus, pair production of level-1 quarks and gluons at the LHC gives rise to hard jets, leptons and large missing energy in the final state. These final states are studied in details by the ATLAS and CMS collaborations in the context of SUSY scenarios. We find that the absence of any significant deviation of the data from the Standard Model (SM) prediction puts a lower bound of about 2.1 TeV on equal mass excited quarks and gluons.Comment: 19 page

Effective Field Theory of Nuclear Forces

The application of the effective field theory (EFT) method to nuclear systems is reviewed. The roles of degrees of freedom, QCD symmetries, power counting, renormalization, and potentials are discussed. EFTs are constructed for various energy regimes of relevance in nuclear physics, and are used in systematic expansions to derive nuclear forces in terms of a number of parameters that embody information about QCD dynamics. Two-, three-, and many-nucleon systems, including external probes, are considered.Comment: 83 pages, 20 figures, commissioned for Prog. Part. Nucl. Phy

Myo-inositol supported heterometallic Dy24M2 (M = Ni, Mn) cages

973 project from the Ministry of Science and Technology of China [2012CB821704]; National Natural Science Foundation of China [21371144, 21390390, 90922031]; Foundation for the Author of National Excellent Doctoral Dissertation of PR China [201219]Two heterometallic cage-like Dy24M2 (M = Ni, Mn) cluster compounds have been synthesized through self-assembly of the metal ions and myo-inositol ligand templated by three ClO4- anions

X-ray Polarimetry of the accreting pulsar 1A~0535+262 in the supercritical state with PolarLight

The X-ray pulsar 1A 0535+262 exhibited a giant outburst in 2020, offering us a unique opportunity for X-ray polarimetry of an accreting pulsar in the supercritical state. Measurement with PolarLight yielded a non-detection in 3-8 keV; the 99% upper limit of the polarization fraction (PF) is found to be 0.34 averaged over spin phases, or 0.51 based on the rotating vector model. No useful constraint can be placed with phase resolved polarimetry. These upper limits are lower than a previous theoretical prediction of 0.6-0.8, but consistent with those found in other accreting pulsars, like Her X-1, Cen X-3, 4U 1626-67, and GRO J1008-57, which were in the subcritical state, or at least not confidently in the supercritical state, during the polarization measurements. Our results suggest that the relatively low PF seen in accreting pulsars cannot be attributed to the source not being in the supercritical state, but could be a general feature.Comment: accepted for publication in Ap