H-1, N-15 and C-13 assignment of the amyloidogenic protein medin using fast-pulsing NMR techniques

Thirty-one proteins are known to form extracellular fibrillar amyloid in humans. Molecular information about many of these proteins in their monomeric, intermediate or fibrillar form and how they aggregate and interact to form the insoluble fibrils is sparse. This is because amyloid proteins are notoriously difficult to study in their soluble forms, due to their inherent propensity to aggregate. Using recent developments in fast NMR techniques, band-selective excitation short transient and band-selective optimized flip-angle short-transient heteronuclear multiple quantum coherence we have been able to assign a 5 kDa full-length amyloidogenic protein called medin. Medin is the key protein component of the most common form of localised amyloid with a proposed role in aortic aneurysm and dissection. This assignment will now enable the study of the early interactions that could influence initiation and progression of medin aggregation. The chemical shifts have been deposited in the BioMagRes-Bank accession Nos. 25399 and 26576

Gestational weight gain and group prenatal care: A systematic review and meta-analysis

Abstract Background Group visits for chronic medical conditions in non-pregnant populations have demonstrated successful outcomes including greater weight loss compared to individual visits for weight management. It is plausible that group prenatal care can similarly assist women in meeting gestational weight gain goals. The purpose of this study was to evaluate the effect of group vs. traditional prenatal care on gestational weight gain. Methods A keyword search of Medline, Embase, Scopus, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, clinicaltrials.gov, and Google Scholar was performed up to April 2017. Studies were included if they compared gestational weight gain in a group prenatal care setting to traditional prenatal care in either randomized controlled trials, cohort, or case-control studies. The primary and secondary outcomes were excessive and adequate gestational weight gain according to the Institute of Medicine guidelines. Heterogeneity was assessed with the Q test and I2 statistic. Pooled relative risks (RRs) and confidence intervals (CI) were reported with random-effects models from the randomized controlled trials (RCT) and cohort studies. Results One RCT, one secondary analysis of an RCT, one study with “random assignment”, and twelve cohort studies met the inclusion criteria for a total of 13,779 subjects. Thirteen studies used the CenteringPregnancy model, defined by 10 sessions that emphasize goal setting and self-monitoring. Studies targeted specific populations such as adolescents, African-Americans, Hispanics, active-duty military or their spouses, and women with obesity or gestational diabetes. There were no significant differences in excessive [7 studies: pooled rates 47% (1806/3582) vs. 43% (3839/8521), RR 1.09, 95% CI 0.97–1.23] or adequate gestational weight gain [6 studies: pooled rates 31% (798/2875) vs. 30% (1410/5187), RR 0.92, 95% CI 0.79–1.08] in group and traditional prenatal care among the nine studies that reported categorical gestational weight gain outcomes in the meta-analysis. Conclusions Group prenatal care was not associated with excessive or adequate gestational weight gain in the meta-analysis. Since outcomes were overall inconsistent, we propose that prenatal care models (e.g., group vs. traditional) should be evaluated in a more rigorous fashion with respect to gestational weight gain

Movement as Translation: Dancers in Dialogue

This chapter explores the creative process of translating a series of images into a live artwork, performed by two professional dancers. The process is documented in an introduction written by the artist and a transcribed conversation between the visual artist and dancers. These provide an insight into intersemiotic translation from the perspective of the makers and performers. Including first hand experiences of those translating and performing the material, the descriptions probe the process of translation that incorporates collaboration, embodiment and improvisation

An integrated whole genome analysis of Mycobacterium tuberculosis reveals insights into relationship between its genome, transcriptome and methylome.

Human tuberculosis disease (TB), caused by Mycobacterium tuberculosis (Mtb), is a complex disease, with a spectrum of outcomes. Genomic, transcriptomic and methylation studies have revealed differences between Mtb lineages, likely to impact on transmission, virulence and drug resistance. However, so far no studies have integrated sequence-based genomic, transcriptomic and methylation characterisation across a common set of samples, which is critical to understand how DNA sequence and methylation affect RNA expression and, ultimately, Mtb pathogenesis. Here we perform such an integrated analysis across 22 M. tuberculosis clinical isolates, representing ancient (lineage 1) and modern (lineages 2 and 4) strains. The results confirm the presence of lineage-specific differential gene expression, linked to specific SNP-based expression quantitative trait loci: with 10 eQTLs involving SNPs in promoter regions or transcriptional start sites; and 12 involving potential functional impairment of transcriptional regulators. Methylation status was also found to have a role in transcription, with evidence of differential expression in 50 genes across lineage 4 samples. Lack of methylation was associated with three novel variants in mamA, likely to cause loss of function of this enzyme. Overall, our work shows the relationship of DNA sequence and methylation to RNA expression, and differences between ancient and modern lineages. Further studies are needed to verify the functional consequences of the identified mechanisms of gene expression regulation

Evaluating the use of rodents as in vitro, in vivo and ex vivo experimental models for the assessment of tyrosine kinase inhibitor-induced cardiotoxicity: a systematic review

\ua9 The Author(s) 2025. Tyrosine kinase inhibitors (TKIs) are widely used in cancer therapy yet are strongly associated with acute and chronic cardiotoxicity in patients. There is a critical need to advance our understanding of the pathophysiology that underlies TKI-mediated cardiotoxicity, and central to this is the use of reproducible and relevant preclinical models, which are employed in the evaluation of TKIs across the drug discovery pipeline. We have conducted a systematic review of the literature to determine how rodent models are used in the measurement of TKI-induced cardiotoxicity, focusing on animal reports, physiological cardiac outputs, histopathology, and biomarkers. A PRISMA-compliant systematic review was conducted using PubMed, Scopus, and Web of Science to identify studies reporting on TKI-induced cardiotoxicity in rodents. Only controlled in vivo, primary in vitro, and ex vivo studies using rats, mice, hamsters or guinea pigs were included. Data were extracted on species, strain, sex, age, experimental design, and cardiac outcomes with risk of bias analyses performed using the SYRCLE and SciRAP tools. Among 92 studies, sunitinib, imatinib, and sorafenib were the most frequently examined TKIs, with cardiotoxicity exhibited as altered cardiac functional parameters, fibrotic changes, arrhythmias, and elevated cardiac biomarkers. Rats (51 studies) and mice (46 studies) were predominantly used to study the effects of TKIs, whilst guinea pigs were underrepresented, limiting insights into electrophysiological changes that are associated with cardiotoxicity. Most studies used male rodents, and only two studies assessed age-related effects. Comparison between species strains was rarely conducted, despite evidence of this being a contributing factor to pre-disposition to cardiotoxicity. Rodent models were shown to replicate TKI-induced cardiotoxic effects observed in humans, but risk of bias analyses revealed limited evidence for study randomisation, inconsistent blinding, lack of sex-balanced studies, and poor strain diversity. Poor methodological quality and reporting across studies compromised reproducibility and interpretation of clinical relevance. Our study highlights the need for implementation of standardised protocols, strain, sex and age-stratified analyses to better support preclinical-to-clinical translation, as well as improve the safety of TKIs for patients and ensure more ethical use of animals in research

"Fuel for the Damage Induced": Untargeted Metabolomics in Elite Rugby Union Match Play.

The metabolic perturbations caused by competitive rugby are not well characterized. Our aim is to utilize untargeted metabolomics to develop appropriate interventions, based on the metabolic fluctuations that occur in response to this collision-based team sport. Seven members of an English Premiership rugby squad consented to provide blood, urine, and saliva samples daily, over a competitive week including gameday (GD), with physical demands and dietary intake also recorded. Sample collection, processing and statistical analysis were performed in accordance with best practice set out by the metabolomics standards initiative employing 700 MHz NMR spectroscopy. Univariate and multivariate statistical analysis were employed to reveal the acute energy needs of this high intensity sport are met via glycolysis, the TCA cycle and gluconeogenesis. The recovery period after cessation of match play and prior to training recommencing sees a re-entry to gluconeogenesis, coupled with markers of oxidative stress, structural protein degradation, and reduced fatty acid metabolism. This novel insight leads us to propose that effective recovery from muscle damaging collisions is dependent upon the availability of glucose. An adjustment in the periodisation of carbohydrate to increase GD+1 provision may prevent the oxidation of amino acids which may also be crucial to allay markers of structural tissue degradation. Should we expand the 'Fuel for the work required' paradigm in collision-based team sports to include 'Fuel for the damage induced'

NMR structure of Hsp12, a protein induced by and required for dietary restriction-induced lifespan extension in yeast.

Dietary restriction (DR) extends lifespan in yeast, worms, flies and mammals, suggesting that it may act via conserved processes. However, the downstream mechanisms by which DR increases lifespan remain unclear. We used a gel based proteomic strategy to identify proteins whose expression was induced by DR in yeast and thus may correlate with longevity. One protein up-regulated by DR was Hsp12, a small heat shock protein induced by various manipulations known to retard ageing. Lifespan extension by growth on 0.5% glucose (DR) was abolished in an hsp12Δ strain, indicating that Hsp12 is essential for the longevity effect of DR. In contrast, deletion of HSP12 had no effect on growth under DR conditions or a variety of environmental stresses, indicating that the effect of Hsp12 on lifespan is not due to increased general stress resistance. Unlike other small heat shock proteins, recombinant Hsp12 displayed negligible in vitro molecular chaperone activity, suggesting that its cellular function does not involve preventing protein aggregation. NMR analysis indicated that Hsp12 is monomeric and intrinsically unfolded in solution, but switches to a 4-helical conformation upon binding to membrane-mimetic SDS micelles. The structure of micelle-bound Hsp12 reported here is consistent with its recently proposed function as a membrane-stabilising 'lipid chaperone'. Taken together, our data suggest that DR-induced Hsp12 expression contributes to lifespan extension, possibly via membrane alterations

Acute heat stress amplifies exercise‐induced metabolomic perturbations and reveals variation in circulating amino acids in endurance‐trained males

Using untargeted metabolomics, we aimed to characterise the systemic impact of environmental heat stress during exercise. Twenty-three trained male triathletes (◂◽.▸ = 64.8 ± 9.2 ml kg min−1) completed a 30-min exercise test in hot (35°C) and temperate (21°C) conditions. Venous blood samples were collected immediately pre- and post-exercise, and the serum fraction was assessed via untargeted 1H-NMR metabolomics. Data were analysed via uni- and multivariate analyses to identify differences between conditions. Mean power output was higher in temperate (231 ± 36 W) versus hot (223 ± 31 W) conditions (P 0.05). Environmental heat stress increased glycolytic metabolite abundance and led to distinct alterations in the circulating amino acid availability, including increased alanine, glutamine, leucine and isoleucine. The data highlight the need for additional exercise nutrition and metabolism research, specifically focusing on protein requirements for exercise under heat stress

Diagnostic and cost utility of whole exome sequencing in peripheral neuropathy.

OBJECTIVE: To explore the diagnostic utility and cost effectiveness of whole exome sequencing (WES) in a cohort of individuals with peripheral neuropathy. METHODS: Singleton WES was performed in individuals recruited though one pediatric and one adult tertiary center between February 2014 and December 2015. Initial analysis was restricted to a virtual panel of 55 genes associated with peripheral neuropathies. Patients with uninformative results underwent expanded analysis of the WES data. Data on the cost of prior investigations and assessments performed for diagnostic purposes in each patient was collected. RESULTS: Fifty patients with a peripheral neuropathy were recruited (median age 18 years; range 2-68 years). The median time from initial presentation to study enrollment was 6 years 9 months (range 2 months-62 years), and the average cost of prior investigations and assessments for diagnostic purposes AU$4013 per patient. Eleven individuals received a diagnosis from the virtual panel. Eight individuals received a diagnosis following expanded analysis of the WES data, increasing the overall diagnostic yield to 38%. Two additional individuals were diagnosed with pathogenic copy number variants through SNP microarray. CONCLUSIONS: This study provides evidence that WES has a high diagnostic utility and is cost effective in patients with a peripheral neuropathy. Expanded analysis of WES data significantly improves the diagnostic yield in patients in whom a diagnosis is not found on the initial targeted analysis. This is primarily due to diagnosis of conditions caused by newly discovered genes and the resolution of complex and atypical phenotypes