Epilepsy genetics: a practical guide for adult neurologists

An understanding of epilepsy genetics is important for adult neurologists, as making a genetic diagnosis gives clinical benefit. In this review, we describe the key features of different groups of genetic epilepsies. We describe the common available genetic tests for epilepsy, and how to interpret them

Further evidence supporting a role for gs signal transduction in severe malaria pathogenesis.

With the functional demonstration of a role in erythrocyte invasion by Plasmodium falciparum parasites, implications in the aetiology of common conditions that prevail in individuals of African origin, and a wealth of pharmacological knowledge, the stimulatory G protein (Gs) signal transduction pathway presents an exciting target for anti-malarial drug intervention. Having previously demonstrated a role for the G-alpha-s gene, GNAS, in severe malaria disease, we sought to identify other important components of the Gs pathway. Using meta-analysis across case-control and family trio (affected child and parental controls) studies of severe malaria from The Gambia and Malawi, we sought evidence of association in six Gs pathway candidate genes: adenosine receptor 2A (ADORA2A) and 2B (ADORA2B), beta-adrenergic receptor kinase 1 (ADRBK1), adenylyl cyclase 9 (ADCY9), G protein beta subunit 3 (GNB3), and regulator of G protein signalling 2 (RGS2). Our study amassed a total of 2278 cases and 2364 controls. Allele-based models of association were investigated in all genes, and genotype and haplotype-based models were investigated where significant allelic associations were identified. Although no significant associations were observed in the other genes, several were identified in ADORA2A. The most significant association was observed at the rs9624472 locus, where the G allele (approximately 20% frequency) appeared to confer enhanced risk to severe malaria [OR = 1.22 (1.09-1.37); P = 0.001]. Further investigation of the ADORA2A gene region is required to validate the associations identified here, and to identify and functionally characterize the responsible causal variant(s). Our results provide further evidence supporting a role of the Gs signal transduction pathway in the regulation of severe malaria, and request further exploration of this pathway in future studies

Endocrine responses to overreaching before and after 1 year of weightlifting

This is the publisher's version, also found at http://ehis.ebscohost.com/ehost/external?sid=c58e4c93-cdad-411e-8971-ff871436da4b%40sessionmgr14&vid=3&hid=1

Plasticity of fimbrial genotype and serotype within populations of <em>Bordetella pertussis</em>:analysis by paired flow cytometry and genome sequencing

The fimbriae of Bordetella pertussis are required for colonization of the human respiratory tract. Two serologically distinct fimbrial subunits, Fim2 and Fim3, considered important vaccine components for many years, are included in the Sanofi Pasteur 5-component acellular pertussis vaccine, and the World Health Organization recommends the inclusion of strains expressing both fimbrial serotypes in whole-cell pertussis vaccines. Each of the fimbrial major subunit genes, fim2, fim3, and fimX, has a promoter poly(C) tract upstream of its −10 box. Such monotonic DNA elements are susceptible to changes in length via slipped-strand mispairing in vitro and in vivo, which potentially causes on/off switching of genes at every cell division. Here, we have described intra-culture variability in poly(C) tract lengths and the resulting fimbrial phenotypes in 22 recent UK B. pertussis isolates. Owing to the highly plastic nature of fimbrial promoters, we used the same cultures for both genome sequencing and flow cytometry. Individual cultures of B. pertussis contained multiple fimbrial serotypes and multiple different fimbrial promoter poly(C) tract lengths, which supports earlier serological evidence that B. pertussis expresses both serotypes during infection.</jats:p

Strongly aligned gas-phase molecules at Free-Electron Lasers

We demonstrate a novel experimental implementation to strongly align molecules at full repetition rates of free-electron lasers. We utilized the available in-house laser system at the coherent x-ray imaging beamline at the Linac Coherent Light Source. Chirped laser pulses, i. e., the direct output from the regenerative amplifier of the Ti:Sa chirped pulse amplification laser system, were used to strongly align 2,5-diiodothiophene molecules in a molecular beam. The alignment laser pulses had pulse energies of a few mJ and a pulse duration of 94 ps. A degree of alignment of \left = 0.85 was measured, limited by the intrinsic temperature of the molecular beam rather than by the available laser system. With the general availability of synchronized chirped-pulse-amplified near-infrared laser systems at short-wavelength laser facilities, our approach allows for the universal preparation of molecules tightly fixed in space for experiments with x-ray pulses.Comment: 10 pages, 5 figure

Hsp72 is targeted to the mitotic spindle by Nek6 to promote K-fiber assembly and mitotic progression

Hsp70 proteins represent a family of chaperones that regulate cellular homeostasis and are required for cancer cell survival. However, their function and regulation in mitosis remain unknown. In this paper, we show that the major inducible cytoplasmic Hsp70 isoform, Hsp72, is required for assembly of a robust bipolar spindle capable of efficient chromosome congression. Mechanistically, Hsp72 associates with the K-fiber-stabilizing proteins, ch-TOG and TACC3, and promotes their interaction with each other and recruitment to spindle microtubules (MTs). Targeting of Hsp72 to the mitotic spindle is dependent on phosphorylation at Thr-66 within its nucleotide-binding domain by the Nek6 kinase. Phosphorylated Hsp72 concentrates on spindle poles and sites of MT-kinetochore attachment. A phosphomimetic Hsp72 mutant rescued defects in K-fiber assembly, ch-TOG/TACC3 recruitment and mitotic progression that also resulted from Nek6 depletion. We therefore propose that Nek6 facilitates association of Hsp72 with the mitotic spindle, where it promotes stable K-fiber assembly through recruitment of the ch-TOG-TACC3 complex

Neonatal Metabolomic Profiles Related to Prenatal Arsenic Exposure

Prenatal inorganic arsenic (iAs) exposure is associated with health effects evident at birth and later in life. An understanding of the relationship between prenatal iAs exposure and alterations in the neonatal metabolome could reveal critical molecular modifications, potentially underpinning disease etiologies. In this study, nuclear magnetic resonance (NMR) spectroscopy-based metabolomic analysis was used to identify metabolites in neonate cord serum associated with prenatal iAs exposure in participants from the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort, in GoÌmez Palacio, Mexico. Through multivariable linear regression, ten cord serum metabolites were identified as significantly associated with total urinary iAs and/or iAs metabolites, measured as %iAs, %monomethylated arsenicals (MMAs), and %dimethylated arsenicals (DMAs). A total of 17 metabolites were identified as significantly associated with total iAs and/or iAs metabolites in cord serum. These metabolites are indicative of changes in important biochemical pathways such as vitamin metabolism, the citric acid (TCA) cycle, and amino acid metabolism. These data highlight that maternal biotransformation of iAs and neonatal levels of iAs and its metabolites are associated with differences in neonate cord metabolomic profiles. The results demonstrate the potential utility of metabolites as biomarkers/indicators of in utero environmental exposure

Fully automated closed-loop glucose control compared with standard insulin therapy in adults with type 2 diabetes requiring dialysis: an open-label, randomized crossover trial

Funder: CB was supported by a grant from The Novo Nordisk UK Research FoundationFunder: LB was supported by a grant of the Swiss Society for Endocrinology and a grant of the Diabetes and Swiss Kidney Foundation.Funder: Supported by National Institute for Health Research Cambridge Biomedical Research Centre.Abstract: We evaluated the safety and efficacy of fully closed-loop insulin therapy compared with standard insulin therapy in adults with type 2 diabetes requiring dialysis. In an open-label, multinational, two-center, randomized crossover trial, 26 adults with type 2 diabetes requiring dialysis (17 men, 9 women, average age 68 ± 11 years (mean ± s.d.), diabetes duration of 20 ± 10 years) underwent two 20-day periods of unrestricted living, comparing the Cambridge fully closed-loop system using faster insulin aspart (‘closed-loop’) with standard insulin therapy and a masked continuous glucose monitor (‘control’) in random order. The primary endpoint was time in target glucose range (5.6–10.0 mmol l−1). Thirteen participants received closed-loop first and thirteen received control therapy first. The proportion of time in target glucose range (5.6–10.0 mmol l−1; primary endpoint) was 52.8 ± 12.5% with closed-loop versus 37.7 ± 20.5% with control; mean difference, 15.1 percentage points (95% CI 8.0–22.2; P < 0.001). Mean glucose was lower with closed-loop than control (10.1 ± 1.3 versus 11.6 ± 2.8 mmol l−1; P = 0.003). Time in hypoglycemia (<3.9 mmol l−1) was reduced with closed-loop versus control (median (IQR) 0.1 (0.0–0.4%) versus 0.2 (0.0–0.9%); P = 0.040). No severe hypoglycemia events occurred during the control period, whereas one severe hypoglycemic event occurred during the closed-loop period, but not during closed-loop operation. Fully closed-loop improved glucose control and reduced hypoglycemia compared with standard insulin therapy in adult outpatients with type 2 diabetes requiring dialysis. The trial registration number is NCT04025775