bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid histological quantification of muscle fibrosis and lysosomal activity using the HSB colour space
Authors: Hildyard John C.W. , Foster Emma M.A. , Wells Dominic J. , Piercy Richard J. 
Published: August 2022

ABSTRACTIntroductionFibrosis is a key feature of many chronic myopathic disorders, such as in the muscle-wasting condition, Duchenne muscular dystrophy. Fibrosis disrupts skeletal muscle architecture, limits muscle function, impairs regeneration and might reduce efficacy of therapeutic interventions: quantifying muscle fibrosis is thus of key value in monitoring disease progression (or response to treatment) in both pre-clinical and clinical settings. Fibrosis can be visualised histologically via staining with picrosirius red, but its quantification can be time consuming and subject to investigator bias: a rapid, reliable and user-friendly means of quantifying muscle fibrosis in histological images is currently lacking.MethodsWe investigated whether the Hue/Saturation/Brightness (HSB) colour-space could be used to quantify connective tissue content in picrosirius red (PSR)-stained muscle sections, using multiple healthy and dystrophic muscles, sampled from two animal models of Duchenne muscular dystrophy (the mdx mouse and the DE50-MD dog), at different ages.ResultsHSB-based analysis allows muscle fibres, connective tissue and slide background to be readily distinguished in PSR images using only a minimal set of parameters, and correctly identifies fibrotic accumulation under conditions where progressive fibrosis is expected. We have developed an imageJ macro that allows semi-automated high-throughput measurement of fibrotic accumulation, and then further extended our method to demonstrate its validity with another histological stain (acid phosphatase) to quantify lysosomal activity.ConclusionsHistological analysis of muscle pathology is challenging and time consuming, especially with large collections of images: our methods permit fibrotic accumulation to be quantified in such collections rapidly and easily in open-source software, with minimal hardware requirements, and the underlying methodology can be readily extended to other colorimetric histopathological stains.
Cell-type specific effects of somatostatin on corticocortical information processing in the anterior cingulate cortex
Authors: Riedemann Therese , Sutor Bernd 
Published: August 2022

SummaryInhibitory modulation of glutamatergic information processing is a prerequisite for proper network function. Among the many groups of interneurons, somatostatin-expressing interneurons (SOM-INs) seem to play an important role in the maintenance of physiological brain activity. We have previously shown that bath application of somatostatin (SOM) causes a reduction in pyramidal cell (PC) excitability. However, the mechanisms of action of the peptide on cortical synaptic circuits are still unclear. To gain further insight into the function of SOM-INs, we analyzed the effect of SOM on synaptic transmission in PCs, in SOM-INs and in layer 1 interneurons (L1-INs) of the anterior cingulate cortex. We found that SOM produced pronounced postsynaptic effects in PCs while having little or no postsynaptic effects on either IN type. Accordingly, it is proposed here, that SOM - by acting differentially on SOM-INs and L1-INs - increases spontaneous GABAergic transmission, while at the same time, decreasing spontaneous glutamatergic transmission. In addition, we show that SOM specifically modulates GABAB receptor (GABABR)-mediated synaptic transmission but has little effect on GABAA receptor-mediated (GABAAR) transmission.
Deep neural network automated segmentation of cellular structures in volume electron microscopy
Authors: Gallusser Benjamin , Maltese Giorgio , Di Caprio Giuseppe , Vadakkan Tegy John , Sanyal Anwesha , Somerville Elliott , Sahasrabudhe Mihir , O’Connor Justin , Weigert Martin , Kirchhausen Tom 
Published: August 2022

SummaryRecent advances in automated segmentation using deep neural network models allow identification of intracellular structures. This study describes a new pipeline to train a convolutional neural network for rapid and efficient detection of structures of wide range in size and complexity.AbstractThree-dimensional electron microscopy is an important imaging modality in contemporary cell biology. Identification of intracellular structures is laborious and time-consuming, however, and impairs effective use of a potentially powerful tool. Resolving this bottleneck is therefore a critical next step in frontier biomedical imaging. We describeAutomatedSegmentation of intracellular substructures inElectronMicroscopy(ASEM), a new pipeline to train a convolutional neural network to detect structures of wide range in size and complexity. We obtain for each structure a dedicated model based on a small number of sparsely annotated ground truth annotations from only one or two cells. To improve model generalization to different imaging conditions, we developed a rapid, computationally effective strategy to refine an already trained model by including a few additional annotations. We show the successful automated identification of mitochondria, Golgi apparatus, endoplasmic reticulum, nuclear pore complexes, caveolae, clathrin coated pits and coated vesicles in cells imaged by focused ion beam scanning electron microscopy with quasi-isotropic resolution. ASEM enabled us to uncover a wide range of membrane-nuclear pore diameters within a single cell and to derive morphological metrics from clathrin coated pits and vesicles at all stages of maturation consistent with the classical constant-growth assembly model.
Ecophysiology and genomics of the brackish water adapted SAR11 subclade IIIa
Authors: Lanclos V. Celeste , Rasmussen Anna N. , Kojima Conner Y. , Cheng Chuankai , Henson Michael W. , Faircloth Brant C. , Francis Christopher A. , Thrash J. Cameron 
Published: August 2022

AbstractThe Order Pelagibacterales (SAR11) is the most abundant group of heterotrophic bacterioplankton in global oceans and comprises multiple subclades with unique spatiotemporal distributions. Subclade IIIa is the primary SAR11 group in brackish waters and shares a common ancestor with the dominant freshwater IIIb (LD12) subclade. Despite its dominance in brackish environments, subclade IIIa lacks systematic genomic or ecological studies. Here, we combine closed genomes from new IIIa isolates, new IIIa MAGS from San Francisco Bay (SFB), and 466 high-quality publicly available SAR11 genomes for the most comprehensive pangenomic study of subclade IIIa to date. Subclade IIIa represents a taxonomic family containing three genera (denoted as subgroups IIIa.1, IIIa.2, and IIIa.3) that had distinct ecological distributions related to salinity. The expansion of taxon selection within subclade IIIa also established previously noted metabolic differentiation in subclade IIIa compared to other SAR11 subclades such as glycine/serine prototrophy, mosaic glyoxylate shunt presence, and polyhydroxyalkanoate synthesis potential. Our analysis further shows metabolic flexibility among subgroups within IIIa. Additionally, we find that subclade IIIa.3 bridges the marine and freshwater clades based on its potential for compatible solute transport, iron utilization, and bicarbonate management potential. Pure culture experimentation validated differential salinity ranges in IIIa.1 and IIIa.3 and provided the first IIIa cell size and volume data. This study is an important step forward for understanding the genomic, ecological, and physiological differentiation of subclade IIIa and the overall evolutionary history of SAR11.
Pla2g12b is Essential for Expansion of Nascent Lipoprotein Particles
Authors: Thierer James H. , Foresti Ombretta , Yadav Pradeep Kumar , Wilson Meredith H. , Moll Tabea , Shen Meng-Chieh , Busch-Nentwich Elisabeth M. , Morash Margaret , Mohlke Karen L. , Rawls John F. , Malhotra Vivek , Hussain M. Mahmood , Farber Steven A. 
Published: August 2022

SUMMARYTriglyceride-rich lipoproteins (TRLs) are micelle-like particles that enable efficient transport of lipids throughout the bloodstream, but also promote atherosclerotic cardiovascular disease. Despite this central relevance to cardiovascular disease, very little is known about how lipids are loaded onto nascent TRLs prior to secretion. Here we show that Pla2g12b, a gene with no previously described function, concentrates components of the TRL biogenesis machinery along the ER membrane to ensure efficient delivery of lipids to nascent TRLs. We find that the lipid-poor TRLs secreted in PLA2G12B-/- mice and zebrafish support surprisingly normal growth and physiology while conferring profound resistance to atherosclerosis, and demonstrate that these same processes are conserved in human cells. Together these findings shed new light on the poorly understood process of TRL expansion, ascribe function to the previously uncharacterized gene Pla2g12b, and reveal a promising new strategy to remodel serum lipoproteins to prevent cardiovascular disease.
Mechanism by which PF-3758309, a Pan Isoform Inhibitor of p21-Activated Kinases, Blocks Reactivation of HIV-1 Latency
Authors: Vargas Benni , Boslett James , Yates Nathan A. , Sluis-Cremer Nicolas 
Published: August 2022

ABSTRACTThe “block and lock” strategy is one approach that might elicit a sterilizing cure for HIV-1 infection. The “block” refers to a compound’s ability to inhibit latent HIV-1 proviral transcription, while the “lock” refers to its capacity to induce permanent proviral silencing. We identified PF-3758309, a pan-isoform inhibitor of p21-activated kinases (PAKs), as a potent inhibitor of HIV-1 latency reversal (Vargas et al., Antimicrob Agents Chemother. 2019;63(2):e01744-18). The goal of this study was to define the mechanism(s) involved. We found that both 24ST1NLESG cells (a cell line model of HIV-1 latency) and purified CD4+ naïve and central memory T cells express high levels of PAK2, and lower levels of PAK1 and PAK4. Knockdown of PAK1 or PAK2, but not PAK4, in 24ST1NLESG cells resulted in a modest, but statistically significant decrease in the magnitude of HIV-1 latency reversal. Overexpression of PAK1 significantly increased the magnitude of latency reversal. A phospho-protein array analysis revealed that PF-3758309 down-regulates the NF-κB signaling pathway, which provides the most likely mechanism by which PF-3758309 inhibits latency reversal. Finally, we used cellular thermal shift assays combined with liquid chromatography and mass spectrometry to ascertain whether PF-3758309 off-target binding contributed to its activity. In 24ST1NLESG cells and in peripheral blood mononuclear cells, PF-3758309 bound to mitogen-activated protein kinase 1 and protein kinase A; however, knockdown of either of these kinases did not impact HIV-1 latency reversal. Collectively, our study suggests that PAK1 and PAK2 play a key role in the maintenance of HIV-1 latency.IMPORTANCEThe persistence of latent, replication-competent HIV-1 proviruses in resting CD4+ T cells, and other cellular reservoirs, represents a major barrier to a cure. The “block and lock” strategy is one approach proposed to elicit a sterilizing cure for HIV-1 infection. In this study, we define the mechanism by which PF-3758309, a pan-isoform p21-activated kinase (PAK) inhibitor, blocks the reversal of HIV-1 latency. Our data show that PAK1 and PAK2 play a role in the maintenance of HIV-1 latency, and further suggest that PAK inhibitors, such as PF-3758309, could form part of “block and lock” therapeutic strategies.
A closer look at weight loss interventions in primary care: A systematic review and meta-analysis
Authors: Perreault Leigh , Kramer E. Seth , Smith Peter C. , Schmidt Darren , Argyropoulos Christos 
Published: August 2022

ABSTRACTBackgroundWeight loss observed in clinical trials has failed to translate into real world clinical settings. The objective of the current review was to quantify patient weight loss using various approaches tested in primary care and to unveil relevant contextual factors that could improve patient weight loss on a long-term basis.MethodsData were compiled from Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Scopus, and Web of Science from inception to October 30, 2022. Only randomized clinical trials conducted in people with overweight or obesity in a primary care setting where the intervention was administered by a primary care provider for at least 6 months were included. All investigators identified studies and independently abstracted data using COVIDENCE systematic review software. Quality assessment and risk of bias of individual studies was assessed in the context of the primary outcome using the template provided by COVIDENCE.ResultsThe seven studies included 2,187 people with obesity who had weight-related comorbidities or risk factors. Substantial heterogeneity in the outcomes was observed, as well as bias toward lack of published studies showing no effect. The random effect model estimated a treatment effect for the aggregate efficacy of primary care interventions −3.54 kg (95% CI: - 5.61 kg to −1.47 kg). Interventions that included a medication component (alone or as part of a multipronged intervention) achieved a greater weight reduction by −2.94 kg (p<0.0001). In all interventions, efficacy declined with time (reduction in weight loss by 0.53 kg per six months, 95%CI: 0.04-1.0 kg, p-value=0.04).DiscussionWeight loss interventions administered by a primary care provider can lead to modest weight loss. Weight loss is approximately doubled if anti-obesity medication is part of the treatment strategy. Nevertheless, weight loss is attenuated over time and underscores the need for long-term treatment.
Electronic health record signatures identify undiagnosed patients with Common Variable Immunodeficiency Disease
Authors: Johnson Ruth , Stephens Alexis V. , Knyazev Sergey , Kohn Lisa A. , Freund Malika K. , Bondhus Leroy , Hill Brian L. , Schwarz Tommer , Zaitlen Noah , Arboleda Valerie A. , Butte Manish J. , Pasaniuc Bogdan 
Published: August 2022

AbstractOne of the most common human inborn errors of immunity (IEI) is Common Variable Immunodeficiency (CVID), a heterogeneous group of disorders characterized by a state of functional and/or quantitative antibody deficiency and impaired B-cell responses. Although over 30 genes have been associated with the CVID phenotype, over half the CVID patients have no identified monogenic variant. There are currently no existing laboratory or genetic tests to definitively diagnose CVID and none are expected to be available in the near future. The extensive heterogeneity of CVID phenotypes causes patients with CVID to face a 5 to 15 years of delay in diagnosis and initiation of treatment, leading to a critical diagnosis odyssey. In this work, we present PheNet, an algorithm that identifies patients with CVID from their electronic health record data (EHR). PheNet computes the likelihood of a patient having CVID by learning phenotypic patterns, EHR-signatures, from a high-quality, clinically curated list of bona fide CVID patients identified from the UCLA Health system (N=197). The prediction model attains superior accuracy versus state-of-the-art methods, where we find that 57% of cases could be detected within the top 10% of individuals ranked by the algorithm compared to 37% identified by previous phenotype risk scores. In a retrospective analysis, we show that 64% of CVID patients at UCLA Health could have been identified by PheNet more than 8 months earlier than they had been clinically diagnosed. We validate our approach using a discovery dataset of ∼880K patients in the UCLA Health system to identify 74 of the top 100 patients ranked by PheNet score (top 0.01% PheNet percentile) as highly probable to have CVID in a clinical blinded chart review by an immune specialist.
COVID-19 convalescent plasma for the treatment of immunocompromised patients: a systematic review
Authors: Senefeld Jonathon W. , Franchini Massimo , Mengoli Carlo , Cruciani Mario , Zani Matteo , Gorman Ellen K. , Focosi Daniele , Casadevall Arturo , Joyner Michael J 
Published: August 2022

AbstractImmunosuppressed patients have increased risk for morbidity and mortality from COVID-19 because they less frequently mount antibody responses to vaccines and often cannot tolerate small-molecule antivirals. The Omicron variant of concern of SARS-CoV-2 has progressively defeated anti-Spike mAbs authorized so far, paving the way to a return to COVID-19 convalescent plasma (CCP) therapy. In this systematic review we performed a metanalysis of 9 controlled studies (totaling 535 treated patients and 1365 controls and including 4 randomized controlled trials), an individual patient data analysis of 125 case reports/series (totaling 265 patients), and a descriptive analysis of 13 uncontrolled large case series without individual patient data available (totaling 358 patients). The metanalysis of controlled studies showed a risk ratio for mortality of 0.65 (risk difference -0.11) in treatment with CCP versus standard of care for immunosuppressed COVID-19 patients. On the basis of this evidence, we encourage initiation of high-titer CCP from vaccinees(‘hybrid plasma’) in immunocompromised patients.
Cognitive subgroups of affective and non-affective psychosis show differences in medication and cortico-subcortical brain networks
Authors: Bracher Katharina M , Wohlschlaeger Afra , Koch Kathrin , Knolle Franziska 
Published: August 2022

AbstractCognitive deficits are prevalent in individuals with psychosis and are associated with neurobiological changes, potentially serving as an endophenotype for psychosis. Using the HCP-Early-Psychosis-dataset (n=226), we aimed to investigate cognitive subtypes (deficit/intermediate/spared) through data-driven clustering in affective (AP) and non-affective psychosis patients (NAP) and controls (HC). We explored differences between three clusters in symptoms, cognition, medication, and grey matter volume. Applying principal component analysis, we selected features for clustering. Features that explained most variance were scores for intelligence, verbal recognition and comprehension, auditory attention, working memory, reasoning and executive functioning. Fuzzy K-Means clustering on those features revealed that the subgroups significantly varied in cognitive impairment, clinical symptoms, and, importantly, also in medication and grey matter volume in fronto-parietal and subcortical networks. The spared cluster (86%HC, 37%AP, 17%NAP) exhibited unimpaired cognition, lowest symptoms/medication, and grey matter comparable to controls. The deficit cluster (4%HC, 10%AP, 47%NAP) had impairments across all domains, highest symptoms scores/medication dosage, and pronounced grey matter alterations. The intermediate deficit cluster (11%HC, 54%AP, 36%NAP) showed fewer deficits than the second cluster, but similar symptoms/medication/grey matter to the spared cluster. Controlling for medication, cognitive scores correlated with grey matter changes and negative symptoms across all patients. Our findings generally emphasize the interplay between cognition, brain structure, symptoms, and medication in AP and NAP, and specifically suggest a possible mediating role of cognition, highlighting the potential of screening cognitive changes to aid tailoring treatments and interventions.
Investigation of the effect of sloping head fault in solid riveting on the strength of the joint
Authors: Soylak Mustafa , Erturun Veysel 
Published: August 2022

Purpose
The purpose of this study is to investigate how the sloping head fault in solid riveting affects the strength of the joint and to develop an efficient system for the solution of the problem.

Design/methodology/approach
For rivet joints, 1.2-mm thick 2024-T3 plates were used. AD 2117 T4 solid rivets with a diameter of 3.2 mm were chosen for the joints. A new riveting mechanism has been created unmatched in the literature for solid rivets. In the riveting process, the bucking bar surface is positioned at a right angle to the riveting process axis. Alternative 5°, 10° and 15° fault angles were obtained. During the riveting process, a total of eight different test samples were produced, four for each of the tension-shear and cross-tension joints, by making 0°, 5°, 10° and 15° angles to the bucking bar. To determine the mechanical properties of the prepared samples, cross-tensile and linear tensile-shear tests were performed on a universal tensile testing machine. Special apparatus has been designed and produced for cross-tensile tests.

Findings
As a result of the tensile-shear tests, the decrease in the joint at 15° was 25% compared to the joint at 0°. There is no systematic change in elongation. As a result of the cross-tensile tests, there was a decrease in the cross-tensile force toward the sample with an error of 15°. Compared to the 0° joint, this decrease was approximately 14.5% in the 10° joint, while the decrease in the 15° faulty joint was 25.8%. It has been understood that riveting with an angle of 0° affects the strength very much.

Originality/value
A new riveting mechanism has been created unmatched in the literature for solid rivets. Experimentally, it has been shown that forged rivets can be made very economically and properly. It has been experimentally proven how much the rivet head shape formed in the wrong forged rivet application changes the result.
Systematic review of systematic reviews on psychological therapies for people who have intellectual disabilities: 1. Quality appraisal
Authors: Clarke Charlotte , Kellett Stephen , Beail Nigel 
Published: August 2022

Purpose
This paper aims to assess the quality of systematic reviews on the effectiveness of psychological therapy for adults with intellectual disabilities (ID) and mental health difficulties.

Design/methodology/approach
Four electronic databases were used: Cochrane, PsycINFO, PubMed and Scopus. Studies were included if they were a systematic review focused primarily on psychological therapy for adults with ID and mental health difficulties. Systematic reviews focused on anger were also considered for inclusion. These reviews were rated for quality on the Amstar-2, a quality rating tool designed to evaluate systematic reviews.

Findings
Twelve relevant systematic reviews were identified, which included seven reviews focused primarily on cognitive behavioural therapy, two on psychodynamic therapy and three on third-wave therapies. The AMSTAR-2 indicated that all 12 reviews were of “critically low” quality. Thus, there are significant problems with the evidence base.

Originality/value
To the best of the authors’ knowledge, this is the first systematic review of systematic reviews of the effectiveness of psychological therapies for people who have ID. It provides an overview of the quality of the evidence base into one place.