Trajectory-Based Time-Resolved Mechanism for Benzene Reductive Elimination from Cyclopentadienyl Mo/W Phenyl Hydride Complexes.

Calculated potential energy structures and landscapes are very often used to define the sequence of reaction steps in an organometallic reaction mechanism and interpret kinetic isotope effect (KIE) measurements. Underlying most of this structure-to-mechanism translation is the use of statistical rate theories without consideration of atomic/molecular motion. Here we report direct dynamics simulations for an organometallic benzene reductive elimination reaction, where nonstatistical intermediates and dynamic-controlled pathways were identified.

BAY-9835: Discovery of the First Orally Bioavailable ADAMTS7 Inhibitor.

The matrix metalloprotease ADAMTS7 has been identified by multiple genome-wide association studies as being involved in the development of coronary artery disease. Subsequent research revealed the proteolytic function of the enzyme to be relevant for atherogenesis and restenosis after vessel injury. Based on a publicly known dual ADAMTS4/ADAMTS5 inhibitor, we have in silico designed an ADAMTS7 inhibitor of the catalytic domain, which served as a starting point for an optimization campaign.

Cross-Trait Mendelian Randomization Study to Investigate Whether Migraine Is a Risk Factor for Multiple Sclerosis.

Background And Objectives: Migraine is common among people with multiple sclerosis (MS), but the reasons for this are unknown. We tested 3 hypothesized mechanisms for this observed comorbidity, including migraine is a risk factor of MS, genetic variants are shared between the conditions, and migraine is because of MS.

Methods: Data were from 2 sources: publicly available summary statistics from genome-wide association studies of MS (N = 115,748) and migraine (N = 375,752 and N = 361,141) and a case-control study of MS recruited from the Kaiser Permanente Northern California Health Plan (N = 1,991).

Multiple Micronutrients, Lutein, and Docosahexaenoic Acid Supplementation during Lactation: A Randomized Controlled Trial.

Breastfed infants require an adequate supply of critical nutrients for growth, tissue functions, and health. Recommended intakes for several nutrients are considerably higher in lactating than non-lactating women but are not always met with habitual diets. We report a randomized, double-blind clinical trial in 70 healthy lactating women in Germany evaluating the effects of supplementation with multiple micronutrients, lutein, and docosahexaenoic acid (DHA) compared to placebo on maternal nutrient status and milk composition.

Pregnancy does not modify the risk of MS in genetically susceptible women.

Objective: To use the case-only gene-environment (G [Formula: see text] E) interaction study design to estimate interaction between pregnancy before onset of MS symptoms and established genetic risk factors for MS among White adult females.

Methods: We studied 2,497 female MS cases from 4 cohorts in the United States, Sweden, and Norway with clinical, reproductive, and genetic data. Pregnancy exposure was defined in 2 ways: (1) [Formula: see text] live birth pregnancy before onset of MS symptoms and (2) parity before onset of MS symptoms.

Heme-Fe Superoxide, Peroxide and Hydroperoxide Thermodynamic Relationships: Fe-O Complex H-Atom Abstraction Reactivity.

Establishing redox and thermodynamic relationships between metal-ion-bound O and its reduced (and protonated) derivatives is critically important for a full understanding of (bio)chemical processes involving dioxygen processing. Here, a ferric heme peroxide complex, [(F)Fe-(O)] () (F = tetrakis(2,6-difluorophenyl)porphyrinate), and a superoxide complex, [(F)Fe-(O)] (), are shown to be redox interconvertible. Using Cr(η-CH), an equilibrium state where and are present is established in tetrahydrofuran (THF) at -80 °C, allowing determination of the reduction potential of as -1.

Diagnostic Performance of a 10-Minute Gadolinium-Enhanced Brain MRI Protocol Compared with the Standard Clinical Protocol for Detection of Intracranial Enhancing Lesions.

Background And Purpose: The development of new MR imaging scanners with stronger gradients and improvement in coil technology, allied with emerging fast imaging techniques, has allowed a substantial reduction in MR imaging scan times. Our goal was to develop a 10-minute gadolinium-enhanced brain MR imaging protocol with accelerated sequences and to evaluate its diagnostic performance compared with the standard clinical protocol.

Materials And Methods: Fifty-three patients referred for brain MR imaging with contrast were scanned with a 3T scanner.

Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk.

Objective: We sought to estimate the causal effect of low serum 25(OH)D on multiple sclerosis (MS) susceptibility that is not confounded by environmental or lifestyle factors or subject to reverse causality.

Methods: We conducted mendelian randomization (MR) analyses using an instrumental variable (IV) comprising 3 single nucleotide polymorphisms found to be associated with serum 25(OH)D levels at genome-wide significance. We analyzed the effect of the IV on MS risk and both age at onset and disease severity in 2 separate populations using logistic regression models that controlled for sex, year of birth, smoking, education, genetic ancestry, body mass index at age 18-20 years or in 20s, a weighted genetic risk score for 110 known MS-associated variants, and the presence of one or more HLA-DRB1*15:01 alleles.

Decrease of VEGF-A in myeloid cells attenuates glioma progression and prolongs survival in an experimental glioma model.

Background: Glioblastomas are highly vascularized tumors with a prominent infiltration of macrophages/microglia whose role in promoting glioma growth, invasion, and angiogenesis has not been fully elucidated.

Methods: The contribution of myeloid-derived vascular endothelial growth factor (VEGF) to glioma growth was analyzed in vivo in a syngeneic intracranial GL261 glioma model using a Cre/loxP system to knock out the expression of VEGF-A in CD11b + myeloid cells. Changes in angiogenesis-related gene expression profile were analyzed in mutant bone marrow-derived (BMD) macrophages in vitro.

Novel zinc-binding site in the E2 domain regulates amyloid precursor-like protein 1 (APLP1) oligomerization.

The amyloid precursor protein (APP) and the APP-like proteins 1 and 2 (APLP1 and APLP2) are a family of multidomain transmembrane proteins possessing homo- and heterotypic contact sites in their ectodomains. We previously reported that divalent metal ions dictate the conformation of the extracellular APP E2 domain (Dahms, S. O.

Interaction between adolescent obesity and HLA risk genes in the etiology of multiple sclerosis.

Objective: We investigated potential interactions between human leukocyte antigen (HLA) genotype and body mass index (BMI) status in relation to the risk of developing multiple sclerosis (MS).

Methods: We used 2 case-control studies, one with incident cases (1,510 cases, 2,017 controls) and one with prevalent cases (937 cases, 609 controls). Subjects with different genotypes and BMI were compared with regard to incidence of MS by calculating odds ratios (ORs) with 95% confidence intervals (CIs) employing logistic regression.

In-silico model of skin penetration based on experimentally determined input parameters. Part II: mathematical modelling of in-vitro diffusion experiments. Identification of critical input parameters.

This work describes a framework for in-silico modelling of in-vitro diffusion experiments illustrated in an accompanying paper [S. Hansen, A. Henning, A.

Acidification reduces mitochondrial calcium uptake in rat cardiac mitochondria.

Cardiac ischemia-reperfusion (I/R) injury is accompanied by intracellular acidification that can lead to cytosolic and mitochondrial calcium overload. However, the effect of cytosolic acidification on mitochondrial pH (pHm) and mitochondrial Ca2+ (Cam2+) handling is not well understood. In the present study, we tested the hypothesis that changes in pHm during cytosolic acidification can modulate Cam2+ handling in cardiac mitochondria.