High energy exchange: proteins that make or break phosphoramidate bonds

AbstractSeveral proteins that catalyze phosphoryl transfer reactions involving phosphohistidine residues have recently been structurally characterized. The architecture of two histidine kinases defines a new protein kinase fold. The diverse folds of several phosphotransfer proteins appear to be designed to foster protein–protein interactions between transfer partners

Establishment and operation of a Good Manufacturing Practice-compliant allogeneic Epstein-Barr virus (EBV)-specific cytotoxic cell bank for the treatment of EBV-associated lymphoproliferative disease

Funded by Wellcome Trust Translational Award SNBTSPeer reviewedPublisher PD

Data on optimisation of a multiplex HRM-qPCR assay for native and invasive crayfish as well as the crayfish plague in four river catchments

The data presented here corresponds to the research paper “Simultaneous detection of invasive signal crayfish, endangered white-clawed crayfish and the crayfish plague using environmental DNA”. A crayfish-specific assay was designed and optimised using three real-time PCR supermixes (SYBR™ Green, SsoFast™ EvaGreen® and HOT FIREPol® EvaGreen®). Diagnostic high resolution melt (HRM) data from direct application of assay on both ex-situ eDNA water samples and field samples from four catchments (two in Wales, two in England) is presented in this article, displaying positive HRM profiles for invasive signal crayfish (Pacifastacus leniusculus), native white-clawed crayfish (Austropotamobius pallipes) and crayfish plague causal agent (Aphanomyces astaci). Keywords: Pacifastacus leniusculus, Austropotamobius pallipes, Crayfish plague, HRM-qPCR, eDN

Linear and Non-linear associations between vitamin D and grip strength: a Mendelian Randomisation study in UK Biobank

BACKGROUND: Low vitamin D status is a widespread phenomenon. Similarly, muscle weakness, often indicated by low grip strength, is another public health concern; however, the vitamin D-grip strength relationship is equivocal. It is important to understand whether variation in vitamin D status causally influences muscle strength to elucidate whether supplementation may help prevent/treat muscle weakness. METHODS: UK Biobank participants, aged 37-73 years, with valid data on Vitamin D status (circulating 25-hydroxyvitamin D (25(OH)D) concentration) and maximum grip strength were included (N=368,890). We examined sex-specific cross-sectional associations between 25(OH)D and grip strength. Using Mendelian randomisation (MR), we estimated the strength of the 25(OH)D-grip strength associations using genetic instruments for 25(OH)D as our exposure. Crucially, because potential effects of vitamin D supplementation on strength could vary by underlying 25(OH)D status, we allowed for non-linear relationships between 25(OH)D and strength in all analyses. RESULTS: Mean(SD) of 25(OH)D was 50(21)nmol/L in males and females. In cross-sectional analyses there was evidence of non-linear associations between 25(OH)D and strength: e.g., compared to males with 50nmol/L circulating 25(OH)D, males with 75nmol/L had 0.36kg (0.31,0.40) stronger grip; males with 25nmol/L had 1.01kg (95% CI: 0.93,1.08) weaker grip. In MR analyses, linear and non-linear models fitted the data similarly well: e.g., 25nmol/L higher circulating 25(OH)D in males was associated with 0.25kg (-0.05,0.55) greater grip (regardless of initial 25(OH)D status). Results were similar, albeit weaker, for females. CONCLUSIONS: Using two different methods to triangulate evidence, our findings suggest moderate to small causal links between circulating 25(OH)D and grip strength

Hydro-PE: gridded datasets of historical and future Penman-Monteith potential evaporation for the United Kingdom

We present two new potential evaporation datasets for the United Kingdom: a historical dataset, Hydro-PE HadUKGrid, which is derived from the HadUK-Grid gridded observed meteorology (1969&ndash;2021); and a future dataset, Hydro-PE UKCP18 RCM, which is derived from UKCP18 regional climate projections (1980&ndash;2080). Both datasets are suitable for hydrological modelling, and provide Penman-Monteith potential evapotranspiration parameterised for short grass, with and without a correction for interception on days with rainfall. The potential evapotranspiration calculations have been formulated to closely follow the methodology of the existing Meteorological Office Rainfall and Evaporation Calculation System (MORECS) potential evapotranspiration, which has historically been widely used by hydrological modellers in the United Kingdom. The two datasets have been created using the same methodology, to allow seamless modelling from past to future. Hydro-PE HadUK-Grid shows good agreement with MORECS in much of the United Kingdom, although Hydro-PE HadUK Grid is higher in the mountainous regions of Scotland and Wales. This is due to differences in the underlying meteorology, in particular the wind speed, which are themselves due to the different spatial scales of the data. Hydro-PE HadUK-Grid can be downloaded from https://doi.org/10.5285/9275ab7e-6e93-42bc-8e72-59c98d409deb (Brown et al., 2022) and Hydro-PE UKCP18 RCM can be downloaded from https://doi.org/10.5285/eb5d9dc4-13bb-44c7-9bf8-c5980fcf52a4 (Robinson et al., 2021).</p

Sub-concussive Hit Characteristics Predict Deviant Brain Metabolism in Football Athletes

Magnetic resonance spectroscopy and helmet telemetry were used to monitor the neural metabolic response to repetitive head collisions in 25 high school American football athletes. Specific hit characteristics were determined highly predictive of metabolic alterations, suggesting that sub-concussive blows can produce biochemical changes and potentially lead to neurological problems

A mutation in the serine protease TMPRSS4 in a novel pediatric neurodegenerative disorder

Background: To elucidate the genetic basis of a novel neurodegenerative disorder in an Old Order Amish pedigree by combining homozygosity mapping with exome sequencing. Methods and results. We identified four individuals with an autosomal recessive condition affecting the central nervous system (CNS). Neuroimaging studies identified progressive global CNS tissue loss presenting early in life, associated with microcephaly, seizures, and psychomotor retardation; based on this, we named the condition Autosomal Recessive Cerebral Atrophy (ARCA). Using two unbiased genetic approaches, homozygosity mapping and exome sequencing, we narrowed the candidate region to chromosome 11q and identified the c.995C \u3e T (p.Thr332Met) mutation in the TMPRSS4 gene. Sanger sequencing of additional relatives confirmed that the c.995C \u3e T genotype segregates with the ARCA phenotype. Residue Thr332 is conserved across species and among various ethnic groups. The mutation is predicted to be deleterious, most likely due to a protein structure alteration as demonstrated with protein modelling. Conclusions: This novel disease is the first to demonstrate a neurological role for a transmembrane serine proteases family member. This study demonstrates a proof-of-concept whereby combining exome sequencing with homozygosity mapping can find the genetic cause of a rare disease and acquire better understanding of a poorly described protein in human development. © 2013 Lahiry et al.; licensee BioMed Central Ltd

A mutation in the serine protease TMPRSS4 in a novel pediatric neurodegenerative disorder

Background: To elucidate the genetic basis of a novel neurodegenerative disorder in an Old Order Amish pedigree by combining homozygosity mapping with exome sequencing. Methods and results. We identified four individuals with an autosomal recessive condition affecting the central nervous system (CNS). Neuroimaging studies identified progressive global CNS tissue loss presenting early in life, associated with microcephaly, seizures, and psychomotor retardation; based on this, we named the condition Autosomal Recessive Cerebral Atrophy (ARCA). Using two unbiased genetic approaches, homozygosity mapping and exome sequencing, we narrowed the candidate region to chromosome 11q and identified the c.995C \u3e T (p.Thr332Met) mutation in the TMPRSS4 gene. Sanger sequencing of additional relatives confirmed that the c.995C \u3e T genotype segregates with the ARCA phenotype. Residue Thr332 is conserved across species and among various ethnic groups. The mutation is predicted to be deleterious, most likely due to a protein structure alteration as demonstrated with protein modelling. Conclusions: This novel disease is the first to demonstrate a neurological role for a transmembrane serine proteases family member. This study demonstrates a proof-of-concept whereby combining exome sequencing with homozygosity mapping can find the genetic cause of a rare disease and acquire better understanding of a poorly described protein in human development. © 2013 Lahiry et al.; licensee BioMed Central Ltd

FYN is overexpressed in human prostate cancer

To test the hypothesis that FYN , a member of the SRC family of kinases (SFKs), is up-regulated in prostate cancer, as FYN is functionally distinct from other SFKs, and interacts with FAK and paxillin (PXN), regulators of cell morphology and motility. MATERIALS AND METHODS Through data-mining in Oncomine ( http://www.oncomine.org ), cell-line profiling with immunoblotting, quantitative reverse transcription and polymerase chain reaction (RT-PCR) and immunohistochemical analysis, we described FYN expression in prostate cancer. The analysis included 32 cases of prostate cancer, nine of prostatic intraepithelial neoplasia (PIN) and 19 normal prostates. Samples were scored for the percentage of stained glands and intensity of staining (from 0 to 3). Each sample was assigned a composite score generated by multiplying percentage and intensity. RESULTS Data-mining showed an eight times greater FYN expression in prostate cancer than in normal tissue; this was specific to FYN and not present for other SFKs. Expression of FYN in prostate cancer cell lines (LNCaP, 22Rv1, PC3, DuPro) was detected using quantitative RT-PCR and immunoblotting. Expression of FYN and its signalling partners FAK and PXN was detected in human tissue. Comparing normal with cancer samples, there was a 2.1-fold increase in median composite score for FYN ( P  < 0.001) 1.7-fold increase in FAK ( P  < 0.001), and a doubling in PXN ( P  < 0.05). There was a 1.7-fold increase in FYN ( P  < 0.05) and a 1.6-fold increase in FAK ( P  < 0.01) in cancer compared with PIN. CONCLUSIONS These studies support the hypothesis that FYN and its related signalling partners are up-regulated in prostate cancer, and support further investigation into the role of the FYN as a therapeutic target.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71987/1/j.1464-410X.2008.08009.x.pd