bluuebunny/crossref_metadata_2025 huggingface dataset:
Model of multiple synfire chains explains cortical spatio-temporal spike patterns
Authors: Kleinjohann Alexander , Berling David , Stella Alessandra , Tetzlaff Tom , Grün Sonja
Published: August 2022

It has been postulated that information processing in the brain is based on precise temporal correlation of neural activity across populations of neurons. In a recent study we found spatio-temporal spike patterns in experimental recordings from monkey motor cortex, and here we study if those could be explained by a synfire chain (SFC) like model. The model is composed of groups of neurons connected in feed-forward manner from one group to the next with high convergence and divergence. When activated, e.g., by a current pulse to the first group, spiking activity in the SFC is synchronous within neurons of the same group and propagates from group to group. When a few neurons from different groups are recorded from such an SFC, and the SFC is repeatedly activated, we would find a spatio-temporal spike pattern repeating across trials. Here, we take the statistics of the STPs found in the experimental data from 20 sessions as a reference to compare to a simulated network. Distributions of the data we take into account include 1) the pattern sizes, i.e. the number of neurons involved in the patterns, 2) the number of patterns a single neuron is involved in, 3) the durations of the patterns, and 4) the spatial distances of the patterns across the electrode array used to record the data. For the simulations, we embed SFC(s) in an anatomical model of the respective layer of the motor cortex, defined by its height and the density of the neurons. Model parameters are the length of the SFC, the number of neurons per group, the spatial extent of each neuronal group, and the distance between subsequent groups. Given the size and reach of the Utah array electrodes, we derive the probability of recording neurons from the SFC network. An SFC is considered detected if at least two neurons from two different groups are recorded. We find that depending on the model parameters, an embedded SFC can be detected with high probability, despite the massive subsampling of the cortex by the Utah array. Furthermore, to achieve multiple membership of a neuron in different patterns, we embed multiple SFCs that overlap. The fitting of the model to the pattern data constrains the spatial SFC parameters: the chains have to be broadly distributed in space and contain many neurons per group to match the experimental results.
Genetic basis ofArabidopsis thalianaresponses to infection by naïve and adapted isolates of turnip mosaic virus
Authors: Butković Anamarija , Ellis Thomas James , González Rubén , Jaegle Benjamin , Nordborg Magnus , Elena Santiago F.
Published: August 2022

Plant viruses account for enormous agricultural losses worldwide, and the most effective way to combat them is to identify genetic material conferring plant resistance to these pathogens. Aiming to identify genetic associations with responses to infection, we screened a large panel ofArabidopsis thaliananatural inbred lines for four disease-related traits caused by infection byA. thaliana-naïve and -adapted isolates of the natural pathogen turnip mosaic virus (TuMV). We detected a strong, replicable association in a 1.5 Mb region on chromosome 2 with a 10-fold increase in relative risk of systemic necrosis. The region contains several plausible causal genes as well as abundant structural variation, including an insertion of aCopiatransposon into a Toll/interleukin receptor (TIR-NBS-LRR) coding for a gene involved in defense, that could be either a driver or a consequence of the disease-resistance locus. When inoculated with TuMV, loss-of-function mutant plants of this gene exhibited different symptoms than wild-type plants. The direction and severity of symptom differences depended on the adaptation history of the virus. This increase in symptoms severity was specific for infections with the adapted isolate. Necrosis-associated alleles are found worldwide, and their distribution is consistent with a trade-off between resistance during viral outbreaks and a cost of resistance otherwise, leading to negative frequency-dependent selection.
Human ATG3 contains a non-canonical LIR motif crucial for its enzymatic activity in autophagy
Authors: Farnung Jakob , Muhar Matthias , Liang Jin Rui , Tolmachova Kateryna A. , Benoit Roger M. , Corn Jacob E. , Bode Jeffrey W.
Published: August 2022

Macroautophagy is one of two major degradation systems in eukaryotic cells. Regulation and control of autophagy is often achieved through the presence of short peptide sequences called LC3 interacting regions (LIR) in autophagy-involved proteins. Using a combination of new protein-derived activity-based probes, protein modelling and X-ray crystallography, we identified a non-canonical LIR motif in the human E2 enzyme responsible for LC3 lipidation, ATG3. The LIR motif is present in the flexible region of ATG3 and adopts an uncommon β-sheet structure binding to the backside of LC3. We show that the β-sheet conformation is crucial for its interaction with LC3. In cellulo studies provide evidence that LIRATG3 is required for LC3 lipidation and ATG3∼LC3 thioester formation. Removal of LIRATG3 negatively impacts the rate of thioester transfer from ATG7 to ATG3.

Abstract Figure
Can pseudotopological models for SMC-driven DNA loop extrusion explain the traversal of physical roadblocks bigger than the SMC ring size?
Authors: Pradhan Biswajit , Barth Roman , Kim Eugene , Davidson Iain F. , van der Torre Jaco , Peters Jan-Michael , Dekker Cees
Published: August 2022

DNA loop extrusion by structural-maintenance-of-chromosome (SMC) complexes has emerged as a primary organizing principle for chromosomes. The mechanism by which SMC motor proteins extrude DNA loops is still unresolved and much debated. The ring-like structure of SMC complexes prompted multiple models where the extruded DNA is topologically or pseudotopologically entrapped within the ring during loop extrusion. However, recent experiments showed the passage of roadblocks much bigger than the SMC ring size, suggesting a nontopological mechanism. Recently, attempts were made to reconcile the observed passage of large roadblocks with a pseudotopological mechanism. Here we examine the predictions of these pseudotopological models, and find that they are not consistent with some experimental data on SMC roadblock encounters. Particularly, these models predict the formation of two loops and that roadblocks will reside near the stem of the loop upon encounter – both in contrast to experimental observations. Overall, the experimental data reinforce the notion of a nontopological mechanism for extrusion of DNA.
Monkeypox Knowledge Graph: A comprehensive representation embedding chemical entities and associated biology of Monkeypox
Authors: Karki Reagon , Zaliani Andrea , Gadiya Yojana , Gribbon Philip
Published: August 2022

The outbreak of Monkeypox virus (MPXV) infection in May 2022 is declared a global health emergency by WHO. As of 28th July, 21067 cases have been confirmed and the numbers are on the rise. Unfortunately, MPXV pathophysiology and its underlying mechanisms are not yet understood. Likewise, the knowledge of biochemicals and drugs used against MPXV and their downstream effects is sparse. In this work, using Knowledge Graph (KG) representations we have depicted chemical and biological aspects of MPXV. To achieve this, we have collected and rationally assembled several biological study results, assays, drug candidates, and preclinical evidence to form a dynamic and comprehensive network. The KG is compliant with FAIR annotations allowing seamless transformation and integration to/with other formats and infrastructures.

Availability and implementation

The Monkeypox knowledge graph is publicly available at https://github.com/Fraunhofer-ITMP/mpox-kg

Supplementary information

Supplementary data are available at Bioinformatics online.

Contact

Reagon.Karki@itmp.fraunhofer.de
Monkeypox DNA correlates with virus infectivity in clinical samples
Authors: Paran Nir , Yahalom-Ronen Yfat , Shifman Ohad , Lazar Shirley , Ben-Ami Ronen , Yakubovsky Michal , Levy Itzchak , Feinsod Anat Wieder , Amit Sharon , Katzir Michal , Oren Noga Carmi , Levcovich Ariela , Hershman-Sarafov Mirit , Paz Alona , Thomas Rebecca , Tamir Hadas , Cherry-Mimran Lilach , Erez Noam , Melamed Sharon , Barlev-Gross Moria , Karmi Shay , Politi Boaz , Achdout Hagit , Weiss Shay , Levy Haim , Schuster Ofir , Beth-Din Adi , Israely Tomer
Published: August 2022

In light of the alarming global spread of Monkeypox and the lack of data regarding virus infectivity in clinical specimens, we examined virus infectivity and its correlation with PCR results, the currently available diagnostic tool. Due to the high risk of Monkeypox virus infection, only a limited number of approved BSL-3 laboratories employed with vaccinated staff, including ourselves, are capable of determining Monkeypox virus infectivity. We show strong correlation between viral DNA content and virus infectivity in clinical specimens. Moreover, we define a PCR threshold value which correspond to non-infectious virus, and suggest that our data can be translated into informed decision-making regarding risk assessment, protective measures and guidelines for Monkeypox patients.
Cerebral blood volume sensitive layer-fMRI in the human auditory cortex at 7 Tesla: Challenges and capabilities
Authors: Faes Lonike K. , De Martino Federico , Huber Laurentius (Renzo)
Published: August 2022

The development of ultra high field (UHF) fMRI signal readout strategies and contrasts has led to the possibility of imaging the human brain in vivo and non-invasively at increasingly higher spatial resolutions of cortical layers and columns. One emergent layer-fMRI acquisition method with increasing popularity is the cerebral blood volume (CBV) sensitive sequence named vascular space occupancy (VASO). This approach has been shown to be mostly sensitive to locally-specific changes of laminar microvasculature, without unwanted biases of trans-laminar draining veins. Until now, however, VASO has not been applied in the technically challenging cortical area of the primary auditory cortex. Here, we developed a VASO imaging protocol for auditory neuroscientific applications. We describe the main challenges we encountered and the solutions we have adopted to mitigate them. With our optimized protocol, we investigate laminar responses to sounds. Finally, as proof of concept for future investigations, we map the topographic representation of frequency preference (tonotopy) in the auditory cortex.

Highlights

Layer fMRI VASO in the auditory cortex is challenging due to its physiology

After protocol optimization we show the applicability of VASO to the auditory cortex

Topographic maps obtained with VASO respect the large-scale tonotopic organization that has previously been shown with BOLD fMRI data.
Glabridin induces paraptosis-like cell death via ER stress in breast cancer cells
Authors: Cui Xiang , Cui Min
Published: August 2022

Glabridin, a polyphenolic flavonoid isolated from the root of the glycyrrhiza glabra, has been demonstrated to have anti-tumor properties in human malignancies. This study found that glabridin decreased the viability of human breast cancer MDA-MB-231 and MCF7 cells in a dose-dependent manner that was not involved in the caspase-3 cascade. Glabridin promoted the formation of extensive cytoplasmic vacuolation by increasing the expression of endoplasmic reticulum (ER) stress markers BiP, XBP1s, and CHOP. The transmission electron microscopy and fluorescence with the ER chaperon KDEL suggested that the vacuoles were derived from ER. Glabridin-induced vacuolation was blocked when protein synthesis was inhibited by cycloheximide, demonstrating that protein synthesis is crucial for this process. Furthermore, we determined that glabridin causes loss of mitochondrial membrane potential as well as the production of reactive oxygen species, both of which lead to mitochondrial dysfunction. These features are consistent with a kind of programmed cell death described as paraptosis. This work reports for the first time that glabridin could induce paraptosis-like cell death, which may give new therapeutic approaches for apoptosis-resistant breast cancers.
An Algorithm for Sequence Location Approximation using Nuclear Families (ASLAN) Validates Regions of the Telomere-to-Telomere Assembly and Identifies New Hotspots for Genetic Diversity
Authors: Chrisman Brianna , He Chloe , Jung Jae-Yoon , Stockham Nate , Paskov Kelley , Washington Peter , Wall Dennis P.
Published: August 2022

1

Although it is heavily relied on to study genetic contributors to health and disease, the current human reference genome (GRCh38) is incomplete in two major ways: firstly, it is missing large sections of heterochromatic sequence, and secondly, as a singular, linear reference genome it does not represent the full spectrum of genetic diversity that exists in the human species. In order to better understand and characterize gaps in GRCh38 and genetic diversity, we developed a method - ASLAN, an Algorithm for Sequence Location Approximation using Nuclear families - that identifies the region of origin of short reads that do not align to the GRCh38. Using unmapped reads and variant calls from whole genome sequencing (WGS) data from nuclear families, ASLAN relies on a maximum likelihood model to identify the most likely region of the genome that a subsequence belongs to, given the phasing information of family and the distribution of the subsequence in the unmapped reads. Validating ASLAN on a synthetically generated dataset, and on true reads originating from the alternative haplotypes in the decoy genome, we show that ASLAN can localize more than 90% of 100-basepair sequences with above 92% accuracy and around 1 megabase of resolution. We then run ASLAN on 100-mers from unmapped reads from WGS from over 700 families, and compare ASLAN localizations to alignment of the 100-mers to the T2T-CHM13 assembly, recently released by the Telomere-to-telomere (T2T) consortia. We find that many unmapped reads in GRCh38 originate from telomeres and centromeres that are gaps in the GRCh38 reference. We also confirm that ASLAN localizations are in high concordance with T2T-CHM13 alignments, except in the centromeres of the acrocentric chromosomes. Comparing ASLAN localizations and T2T-CHM13 alignments, we identify sequences missing from T2T-CHM13 or sequences with high divergence from their aligned region in T2T-CHM13, thus highlighting new hotspots for genetic diversity.
Pattern formation and bistability in a synthetic intercellular genetic toggle
Authors: de Freitas Magalhães Bárbara , Fan Gaoyang , Sontag Eduardo , Josić Krešimir , Bennett Matthew R.
Published: August 2022

Differentiation within multicellular organisms is a complex process that helps to establish spatial patterning and tissue formation within the body. Often, the differentiation of cells is governed by morphogens and intercellular signaling molecules that guide the fate of each cell, frequently using toggle-like regulatory components. Synthetic biologists have long sought to recapitulate patterned differentiation with engineered cellular communities and various methods for differentiating bacteria have been invented. Here, we couple a synthetic co-repressive toggle switch with intercellular signaling pathways to create a “quorum-sensing toggle.” We show that this circuit not only exhibits population-wide bistability in a well-mixed liquid environment, but also generates patterns of differentiation in colonies grown on agar containing an externally supplied morphogen. If coupled to other metabolic processes, circuits such as the one described here would allow for the engineering of spatially patterned, differentiated bacteria for use in biomaterials and bioelectronics.
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

Introduction

Fibrosis 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.

Methods

We 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.

Results

HSB-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.

Conclusions

Histological 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

Inhibitory 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

Recent 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.

Three-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

The 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

Triglyceride-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

The “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.

IMPORTANCE

The 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

Background

Weight 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.

Methods

Data 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.

Results

The 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).

Discussion

Weight 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

One 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

Immunosuppressed 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

Cognitive 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.
Transforming product development and production to be lean for improving business performance
Authors: Bubber Deepak , Jain Rakesh Kumar , Babber Gulshan , Shashi
Published: August 2022

Purpose

In this study, the authors assess the current state of lean product development and the lean production shop floor, along with the impact of the former on process quality and the latter on product quality and customer complaint reduction. The interplay between process and product quality and customer complaint reduction is assessed, along with their impacts on business performance.

Design/methodology/approach

Data were collected from 377 managers working at auto-component manufacturing firms in India. Confirmatory factor analysis was used for scale validation, and structural equation modelling was employed to test the research hypotheses.

Findings

The results of the statistical analyses reveal the positive influence of a lean production shop floor on process quality and lean product development on product quality and customer complaint reduction, and thereby on business performance.

Practical implications

The findings of this research provide insights into the interplay between lean and quality factors and their influence on customer complaint reduction and business performance. Practitioners can use the proposed model to strategically design unique products and improve the efficiency and effectiveness of the production shop floor, which can help enhance the product and process quality. This can reduce customer dissatisfaction and improve the business performance.

Originality/value

Few studies have simultaneously investigated the influence of lean product development and lean production shop floors in the Indian manufacturing context. To the best of our knowledge, this study is one of the first attempts to include customer complaint reduction as a construct in a lean model. It helps identify and prioritise the enablers of business performance and provides valuable insights for practitioners to strengthen lean implementation to attain a competitive edge.
Disagreement in economic forecasts and equity returns: risk or mispricing?
Authors: Bali Turan G. , Brown Stephen J. , Tang Yi
Published: August 2022

Purpose

This paper investigates the role of economic disagreement in the cross-sectional pricing of individual stocks. Economic disagreement is quantified with ex ante measures of cross-sectional dispersion in economic forecasts from the Survey of Professional Forecasters (SPF), determining the degree of disagreement among professional forecasters over changes in economic fundamentals.

Design/methodology/approach

The authors introduce a broad index of economic disagreement based on the innovations in the cross-sectional dispersion of economic forecasts for output, inflation and unemployment so that the index is a shock measure that captures different aspects of disagreement over economic fundamentals and also reflects unexpected news or surprise about the state of the aggregate economy. After building the broad index of economic disagreement, the authors test out-of-sample performance of the index in predicting the cross-sectional variation in future stock returns.

Findings

Univariate portfolio analyses indicate that decile portfolios that are long in stocks with the lowest disagreement beta and short in stocks with the highest disagreement beta yield a risk-adjusted annual return of 7.2%. The results remain robust after controlling for well-known pricing effects. The results are consistent with a preference-based explanation that ambiguity-averse investors demand extra compensation to hold stocks with high disagreement risk and the investors are willing to pay high prices for stocks with large hedging benefits. The results also support the mispricing hypothesis that the high disagreement beta provides an indirect way to measure dispersed opinion and overpricing.

Originality/value

Most literature measures disagreement about individual stocks with the standard deviation of earnings forecasts made by financial analysts and examines the cross-sectional relation between this measure and individual stock returns. Unlike prior studies, the authors focus on disagreement about the economy instead of disagreement about earnings growth. The authors' argument is that disagreement about the economy is a major factor that would explain disagreement about stock fundamentals. The authors find that disagreement in economic forecasts does indeed have a significant impact on the cross-sectional pricing of individual stocks.
A novel ROA optimized Bi-LSTM based MPPT controller for grid connected hybrid solar-wind system
Authors: T. Dharma Raj , C. Kumar , G. Subramaniam , T. Dhanesh Raj , J. Jasper
Published: August 2022

Purpose

Renewable energy sources such as solar photovoltaic (PV) and wind are ubiquitous because of their lower environmental impact. Output from solar PV and wind turbines is unstable; hence, this article aims to propose an effective controller to extract maximum available power.

Design/methodology/approach

By focusing on the varying nature of solar irradiance and wind speed, the paper presents the maximum power point tracking (MPPT) technique for renewable energy sources, and power regulation is made by the novel inverter design. Moreover, a DC–DC boost converter is adopted with solar PV, and a doubly fed induction generator is connected with the wind turbine. The proposed MPPT technique is used with the help of a rain optimization algorithm (ROA) based on bi-directional long short-term memory (Bi-LSTM) (ROA_Bi-LSTM). In addition, the sinusoidal pulse width modulation inverter is used for DC–AC power conversion.

Findings

The proposed MPPT technique has jointly tracked the maximum power from solar PV and wind under varying climatic conditions. The power flow to the transmission line is stabilized to protect the load devices from unregulated frequency and voltage deviations. The power to the smart grid is regulated by three-level sinusoidal pulse width modulation inverter.

Originality/value

The methodology and concept of the paper are taken by the author on their own. They have not taken a duplicate copy of any other research article.
Ranked generic criteria for EPC contractor selection
Authors: Dissanayake Nayana , Xia Bo , Skitmore Martin , Trigunarsyah Bambang , Menadue Vanessa
Published: August 2022

Purpose

The purpose of this study was to prioritize the appropriate generic contractor selection criteria for Engineering–Procurement–Construction (EPC) projects in the construction industry.

Design/methodology/approach

Proceeding from a review of previous studies and validation by a small group of experts, a preliminary set of 16 criteria was first identified. This was followed by three rounds of Delphi surveys: firstly, with 64 experienced participants confirming the relevance of the 16 criteria; secondly, with a reduced subgroup of 47 more experienced participants scoring the importance of each; and finally, providing the opportunity for these 47 to revise their scores in the light of knowing the aggregated results of the previous round.

Findings

The results show the consensus view, of which the most important criteria are ranked as past performance, project understanding, technical attributes, key personnel, health and safety, past experience, time, management, financial, contractual and legal, quality, cost, relationships, environmental and sustainability, organizational and industrial relations, and geographic location.

Originality/value

The findings are useful for both practitioners and academics in making a significant contribution to the body of knowledge of the EPC process. This will assist in providing a better understanding of criteria importance and pave the way to developing an EPC contractor selection model involving the criteria most needed to objectively identify potential contractors and evaluate tenders.