A re-appraisal of the petrogenesis and tectonic setting of the Ordovician Fishguard Volcanic Group, SW Wales

The Fishguard Volcanic Group represents an excellently preserved example of a volcanic sequence linked to the closure of the Iapetus Ocean. This study re-examines the petrogenesis and proposed tectonic setting for the Llanvirn (467–458 Ma) Fishguard Volcanic Group, South Wales, UK. New major and trace element geochemical data and petrographic observations are used to reevaluate the magma chamber processes, mantle melting and source region. The new data reveal that the Fishguard Volcanic Group represents a closely related series of basalts, basaltic andesites, dacites and rhyolites originating from a spinel lherzolite source which had been modified by subduction components. The rocks of the Fishguard Volcanic Group are co-genetic and the felsic members are related to the more primitive basalts mainly by low-pressure fractional crystallization. The geochemistry of the lavas was significantly influenced by subduction processes associated with a coeval arc, while significant amounts of assimilation of continental crust along with fractional crystallization appear to have contributed to the compositions of the most evolved lavas. The Fishguard Volcanic Group was erupted into a back-arc basin where extensive rifting but no true seafloor spreading had occurred

Oceanic mafic magmatism in the Siletz terrane, NW North America: Fragments of an Eocene oceanic plateau?

The Siletz terrane, a predominantly mafic accreted oceanic terrane, is located in the Cascadia Forearc region of Oregon, Washington and Vancouver Island. The terrane represents a late Paleocene – Eocene large igneous province that consists of pillow lavas, massive flows and intrusive sheets. Previously it has been proposed that the Siletz terrane represents either an accreted oceanic plateau, hotspot island chain, backarc basin, island arc, or a sequence of slab window volcanics. A province-wide geochemical reassessment of the terrane, including new high precision Sr-Pb-Nd-Hf isotope, has been used to assess the validity of the proposed tectonomagmatic models for the Siletz terrane. The trace element data show little evidence of crustal contamination, or an arc signature, and the samples have rare earth element (REE) patterns that are flat to light REE enriched. These features are similar to other oceanic plateaus such as the Ontong Java and the Caribbean. Initial isotope ratios range from 206Pb/204 Pb: 18.751 to 19.668, 207Pb/204Pb: 15.507–15.661, 207Pb/204Pb: 38.294–39.2128, 176Hf/177Hf: 0.28300–0.28316 (εHf: 9.0 to 14.5), 143Nd/144Nd: 0.51282–0.51299 (εNd: 5.0 to 8.1) and 87Sr/86Sr: 0.70302–0.70380. These data are consistent with a mantle source of the Siletz terrane that appears to have been heterogeneous and slightly enriched. The enriched signature has characteristics of both EM2 and HIMU components and this, combined with a calculated mantle potential temperature well above ambient mantle, indicates derivation of the Siletz magmatism from a mantle plume, possibly the Yellowstone Hotspot. We therefore conclude that the Siletz terrane represents an accreted oceanic plateau

A statistical and biological response to an informatics appraisal of healthy aging gene signatures

Jacob and Speed did not identify even a single example of a ‘150-gene-set’ that was statistically significant at classifying Alzheimer’s disease (AD) samples, or age in independent studies. We attempt to clarify the various misunderstandings

Glomerular disease and acute kidney injury in Sudan: Demographics, histological diagnosis and outcome

Background. Acute kidney injury (AKI) is a relatively common clinical condition, associated with high rates of mortality. Although there is extensive literature on the nature and consequence of AKI in the developed world, much less is known in the developing world and more specifically in sub-Saharan Africa (SSA).Objectives. To describe the demographics, histological diagnosis and clinical course of patients presenting with AKI to a single centre in Sudan.Methods. Retrospective data were collected on 100 consecutive patients with AKI and an active urinary sediment, who underwent diagnostic native percutaneous renal biopsy.Results. The mean (standard deviation) age of those biopsied was 33.6 (14.1) years of age, with a preponderance (58%) of females. The most common clinical indications for biopsy were AKI associated with haematuria and proteinuria (72%), AKI and proteinuria (22.5%) or AKI and haematuria (5%). The frequencies of the most common primary glomerulonephritides (GN) were focal segmental GN (15%) and mesangiocapillary GN (8%). Lupus nephritis was the most frequent secondary GN associated with AKI (31%) and the most common overall histological diagnosis. Peak creatinine, but not oliguria, at presentation predicted likelihood of remaining dialysis-dependent. Age at presentation but not baseline renal function by estimated glomerular filtration rate (eGFR), was associated with the likelihood of having residual chronic kidney disease following an episode of AKI.Conclusions. The data suggested differences in the pattern of intrinsic renal/glomerular disease leading to AKI to those published and mainly derived from the developed world and patients in SSA

Petrogenesis of Siletzia: the world’s youngest oceanic plateau

Siletzia is an accreted Palaeocene-Eocene Large Igneous Province, preserved in the northwest United States and southern Vancouver Island. Although previous workers have suggested that components of Siletzia were formed in tectonic settings including back arc basins, island arcs and ocean islands, more recent work has presented evidence for parts of Siletzia to have formed in response to partial melting of a mantle plume. In this paper, we integrate geochemical and geochronological data to investigate the petrogenetic evolution of the province. The major element geochemistry of the Siletzia lava flows is used to determine the compositions of the primary magmas of the province, as well as the conditions of mantle melting. These primary magmas are compositionally similar to modern Ocean Island and Mid-Ocean Ridge lavas. Geochemical modelling of these magmas indicates they predominantly evolved through fractional crystallisation of olivine, pyroxenes, plagioclase, spinel and apatite in shallow magma chambers, and experienced limited interaction with crustal components. Further modelling indicates that Siletzia magmatism was derived from anomalously hot mantle, consistent with an origin in a mantle plume. This plume has been suggested to have been the same as that responsible for magmatism within the Yellowstone Plateau. Trace element compositions of the most primitive Siletzia lavas are similar to suites associated with the Yellowstone Mantle Plume, suggesting that the two provinces were derived from compositionally similar sources. Radiogenic isotope systematics for Siletzia consistently overlap with some of the oldest suites of the Yellowstone Magmatic Province. Therefore, we suggest Siletzia and the Yellowstone Mantle Plume are part of the same, evolving mantle plume system. Our new geochronological data show the province was emplaced during the time when Eocene sea surface temperatures were their highest. The size of Siletzia makes the province a potential contributing factor to the biospheric perturbation observed in the early Eocene

A coding and non-coding transcriptomic perspective on the genomics of human metabolic disease

Genome-wide association studies (GWAS), relying on hundreds of thousands of individuals, have revealed > 200 genomic loci linked to metabolic disease (MD). Loss of insulin sensitivity (IS) is a key component of MD and we hypothesized that discovery of a robust IS transcriptome would help reveal the underlying genomic structure of MD. Using 1,012 human skeletal muscle samples, detailed physiology and a tissue-optimized approach for the quantification of coding (> 18,000) and non-coding (> 15,000) RNA (ncRNA), we identified 332 fasting IS-related genes (CORE-IS). Over 200 had a proven role in the biochemistry of insulin and/or metabolism or were located at GWAS MD loci. Over 50% of the CORE-IS genes responded to clinical treatment; 16 quantitatively tracking changes in IS across four independent studies (P = 0.0000053: negatively: AGL, G0S2, KPNA2, PGM2, RND3 and TSPAN9 and positively: ALDH6A1, DHTKD1, ECHDC3, MCCC1, OARD1, PCYT2, PRRX1, SGCG, SLC43A1 and SMIM8). A network of ncRNA positively related to IS and interacted with RNA coding for viral response proteins (P < 1 × 10−48), while reduced amino acid catabolic gene expression occurred without a change in expression of oxidative-phosphorylation genes. We illustrate that combining in-depth physiological phenotyping with robust RNA profiling methods, identifies molecular networks which are highly consistent with the genetics and biochemistry of human metabolic disease

The effects of resistance exercise training on macro- and micro-circulatory responses to feeding and skeletal muscle protein anabolism in older men

The anabolic effects of dietary protein on skeletal muscle depend on adequate skeletal muscle perfusion, which is impaired in older people. This study explores fed state muscle microvascular blood flow, protein metabolism and exercise training status in older men. We measured leg blood flow (LBF), muscle microvascular blood volume (MBV) and muscle protein turnover under post-absorptive and fed state (i.v. Glamin to double amino acids, dextrose to sustain glucose ∼7–7.5 mmol l−1) conditions in two groups: 10 untrained men (72.3 ± 1.4 years; body mass index (BMI) 26.5 ± 1.15 kg m2) and 10 men who had undertaken 20 weeks of fully supervised, whole-body resistance exercise training (RET) (72.8 ± 1.4 years; BMI 26.3 ± 1.2 kg m2). We measured LBF by Doppler ultrasound and muscle MBV by contrast-enhanced ultrasound. Muscle protein synthesis (MPS) was measured using [1, 2-13C2] leucine with breakdown (MPB) and net protein balance (NPB) by ring-[D5] phenylalanine tracers. Plasma insulin was measured via ELISA and indices of anabolic signalling (e.g. Akt/mTORC1) by immunoblotting from muscle biopsies. Whereas older untrained men did not exhibit fed-state increases in LBF or MBV, the RET group exhibited increases in both LBF and MBV. Despite our hypothesis that enhanced fed-state circulatory responses would improve anabolic responses to nutrition, fed-state increases in MPS (∼50–75%; P < 0.001) were identical in both groups. Finally, whereas only the RET group exhibited fed-state suppression of MPB (∼–38%; P < 0.05), positive NPB achieved was similar in both groups. We conclude that RET enhances fed-state LBF and MBV and restores nutrient-dependent attenuation of MPB without robustly enhancing MPS or NPB

Forming a consensus opinion to inform long COVID support mechanisms and interventions: a modified Delphi approach

BackgroundCurrent approaches to support patients living with post-COVID condition, also known as Long COVID, are highly disparate with limited success in managing or resolving a well-documented and long-standing symptom burden. With approximately 2.1 million people living with the condition in the UK alone and millions more worldwide, there is a desperate need to devise support strategies and interventions for patients.MethodsA three-round Delphi consensus methodology was distributed internationally using an online survey and was completed by healthcare professionals (including clinicians, physiotherapists, and general practitioners), people with long COVID, and long COVID academic researchers (round 1 n = 273, round 2 n = 186, round 3 n = 138). Across the three rounds, respondents were located predominantly in the United Kingdom (UK), with 17.3–15.2% (round 1, n = 47; round 2 n = 32, round 2 n = 21) of respondents located elsewhere (United States of America (USA), Austria, Malta, United Arab Emirates (UAE), Finland, Norway, Malta, Netherlands, Iceland,Canada, Tunisie, Brazil, Hungary, Greece, France, Austrailia, South Africa, Serbia, and India). Respondents were given ∼5 weeks to complete the survey following enrolment, with round one taking place from 02/15/2022 to 03/ 28/22, round two; 05/09/2022 to 06/26/2022, and round 3; 07/14/2022 to 08/09/2022. A 5-point Likert scale of agreement was used and the opportunity to include free text responses was provided in the first round.FindingsFifty-five statements reached consensus (defined as >80% agree and strongly agree), across the domains of i) long COVID as a condition, ii) current support and care available for long COVID, iii) clinical assessments for long COVID, and iv) support mechanisms and rehabilitation interventions for long COVID, further sub-categorised by consideration, inclusion, and focus. Consensus reached proposes that long COVID requires specialised, comprehensive support mechanisms and that interventions should form a personalised care plan guided by the needs of the patients. Supportive approaches should focus on individual symptoms, including but not limited tofatigue, cognitive dysfunction, and dyspnoea, utilising pacing, fatigue management, and support returning to daily activities. The mental impact of living with long COVID, tolerance to physical activity, emotional distress and well-being, and research of pre-existing conditions with similar symptoms, such as myalgic encephalomyelitis,should also be considered when supporting people with long COVID.InterpretationWe provide an outline that achieved consensus with stakeholders that could be used to inform the design and implementation of bespoke long COVID support mechanisms

Training-induced improvements in knee extensor force accuracy are associated with reduced vastus lateralis motor unit firing variability

New Findings: What is the central question of this study? Can bilateral knee extensor force accuracy be improved following 4 weeks of unilateral force accuracy training and are there any subsequent alterations to central and/or peripheral motor unit features? What is the main finding and its importance? In the trained limb only, knee extensor force tracking accuracy improved with reduced motor unit firing rate variability in the vastus lateralis, and there was no change to neuromuscular junction transmission instability. Interventional strategies to improve force accuracy may be directed to older/clinical populations where such improvements may aid performance of daily living activities. Abstract: Muscle force output during sustained submaximal isometric contractions fluctuates around an average value and is partly influenced by variation in motor unit (MU) firing rates. MU firing rate (FR) variability seemingly reduces following exercise training interventions; however, much less is known with respect to peripheral MU properties. We therefore investigated whether targeted force accuracy training could lead to improved muscle functional capacity and control, in addition to determining any alterations of individual MU features. Ten healthy participants (seven females, three males, 27±6 years, 170±8cm, 69±16kg) underwent a 4-week supervised, unilateral knee extensor force accuracy training intervention. The coefficient of variation for force (FORCECoV) and sinusoidal wave force tracking accuracy (FORCESinu) were determined at 25% maximal voluntary contraction (MVC) pre- and post-training. Intramuscular electromyography was utilised to record individual MU potentials from the vastus lateralis (VL) muscles at 25% MVC during sustained contractions, pre- and post-training. Knee extensor muscle strength remained unchanged following training, with no improvements in unilateral leg-balance. FORCECoV and FORCESinu significantly improved in only the trained knee extensors by ∼13% (P =0.01) and ∼30% (P <0.0001), respectively. MU FR variability significantly reduced in the trained VL by ∼16% (n =8; P= 0.001), with no further alterations to MU FR or neuromuscular junction transmission instability. Our results suggest muscle force control and tracking accuracy is a trainable characteristic in the knee extensors, which is likely explained by the reduction in MU FR variability which was apparent in the trained limb only

Molecular Transducers of Human Skeletal Muscle Remodeling under Different Loading States

Loading of skeletal muscle changes the tissue phenotype reflecting altered metabolic and functional demands. In humans, heterogeneous adaptation to loading complicates the identification of the underpinning molecular regulators. A within-person differential loading and analysis strategy reduces heterogeneity for changes in muscle mass by ∼40% and uses a genome-wide transcriptome method that models each mRNA from coding exons and 3′ and 5′ untranslated regions (UTRs). Our strategy detects ∼3–4 times more regulated genes than similarly sized studies, including substantial UTR-selective regulation undetected by other methods. We discover a core of 141 genes correlated to muscle growth, which we validate from newly analyzed independent samples (n = 100). Further validating these identified genes via RNAi in primary muscle cells, we demonstrate that members of the core genes were regulators of protein synthesis. Using proteome-constrained networks and pathway analysis reveals notable relationships with the molecular characteristics of human muscle aging and insulin sensitivity, as well as potential drug therapies