bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterizing and Predicting Post-Acute Sequelae of SARS CoV-2 infection (PASC) in a Large Academic Medical Center in the US
Authors: Fritsche Lars G. , Jin Weijia , Admon Andrew J. , Mukherjee Bhramar
Published: October 2022

Objective

A growing number of Coronavirus Disease-2019 (COVID-19) survivors are affected by Post-Acute Sequelae of SARS CoV-2 infection (PACS). Using electronic health records data, we aimed to characterize PASC-associated diagnoses and to develop risk prediction models.

Methods

In our cohort of 63,675 COVID-19 positive patients, 1,724 (2.7 %) had a recorded PASC diagnosis. We used a case control study design and phenome-wide scans to characterize PASC-associated phenotypes of the pre-, acute-, and post-COVID-19 periods. We also integrated PASC-associated phenotypes into Phenotype Risk Scores (PheRSs) and evaluated their predictive performance.

Results

In the post-COVID-19 period, known PASC symptoms (e.g., shortness of breath, malaise/fatigue) and musculoskeletal, infectious, and digestive disorders were enriched among PASC cases. We found seven phenotypes in the pre-COVID-19 period (e.g., irritable bowel syndrome, concussion, nausea/vomiting) and 69 phenotypes in the acute-COVID-19 period (predominantly respiratory, circulatory, neurological) associated with PASC. The derived pre- and acute-COVID-19 PheRSs stratified risk well, e.g., the combined PheRSs identified a quarter of the COVID-19 positive cohort with an at least 2.9-fold increased risk for PASC.

Conclusions

The uncovered PASC-associated diagnoses across categories highlighted a complex arrangement of presenting and likely predisposing features, some with a potential for risk stratification approaches.

Graphical Abstract
Gene-vegetarianism interactions in calcium, testosterone, and eGFR identified in genome-wide analysis across 30 biomarkers
Authors: Francis Michael , Ye Kaixiong
Published: October 2022

Existing vegetarian cohort studies have not considered the effects of genetic differences on health outcomes. First, we reduced inconsistencies among self-identified vegetarians in UK Biobank by utilizing two dietary surveys. Vegetarians were matched 1:4 with nonvegetarians for traditional association analyses, revealing significant effects of vegetarianism in 15/30 biomarkers. Cholesterol measures plus Vitamin D were significantly lower in vegetarians, while triglycerides were higher. A genome-wide association study revealed no genome-wide significant (GWS) associations with vegetarianism status. We performed genome-wide gene-vegetarianism interaction analyses for 30 biomarker traits (N=147,253). We detected a GWS interaction in calcium at rs72952628 (P=4.47×10−8). rs72952628 is inMMAA, a B12metabolism gene; B12has high deficiency potential in vegetarians. Gene-based interaction tests revealed two significant genes,RNF168in testosterone (P=1.45×10−6) andDOCK4in eGFR (P=6.76×10−7), which have previously been associated with testicular and renal traits, respectively. These findings indicate genotype can influence biomarker levels across vegetarians.
The Antidepressant Advisor (ADeSS): A Decision Support System for Antidepressant Treatment for Depression in UK primary care – a feasibility study
Authors: Harrison Phillippa , Carr Ewan , Goldsmith Kimberley , Young Allan H. , Ashworth Mark , Fennema Diede , Duan Suqian , Barrett Barbara , Zahn Roland
Published: October 2022

Objectives

To develop and probe the first computerised decision-support tool to provide antidepressant treatment guidance to GPs in UK primary care.

Design

A parallel group, cluster-randomised controlled feasibility trial, where individual participants were blind to treatment allocation.

Setting

South London NHS GP practices.

Participants

Ten practices and eighteen patients with treatment-resistant current major depressive disorder (MDD).

Interventions

Practices were randomised to two treatment arms: 1) treatment-as-usual, 2) computerised decision support tool.

Results

Ten GP practices participated in the trial, which was within our target range (8-20). However, practice and patient recruitment were slower than anticipated and only 18 of 86 intended patients were recruited. This was due to fewer than expected patients being eligible for the study, as well as disruption resulting from the Covid-19 pandemic. Only one patient was lost to follow-up. There were no serious or medically important adverse events during the trial. GPs in the ‘Decision tool’ arm indicated moderate support for the tool. A minority of patients fully engaged with the mobile app-based tracking of symptoms, medication adherence and side effects.

Conclusions

Overall, the trial is not feasible in the current form and would need to be modified as follows to overcome its limitations: 1) inclusion of patients who have only tried one SSRI, rather than two, to improve recruitment and pragmatic relevance of the study, 2) approaching community pharmacists to implement tool recommendations rather than GPs, 3) further funding to directly interface between the decision support tool and self-reported symptom app, 4) increasing the geographic reach by not requiring detailed diagnostic assessments and replacing this with supported remote self-report.

Ethics and dissemination

The study has received NHS ethical approval from the London - Camberwell St Giles Research Ethics Committee (ref:17/LO/2074).

Trial registration number

ClinicalTrials.govIdentifier:NCT03628027

Strengths and limitations of this study

The Antidepressant Advisor tool was incorporated into an existing GP healthcare record system for ease of use by GPs

We were unable to recruit a sufficient number of participants to estimate effect sizes for future trials

The eligibility criteria for participants to have tried two antidepressants before entering the study limited the number of eligible participants
Stochastic Spatiotemporal Simulation of a General Reaction System
Authors: Loza Andrew J. , Sherman Marc S.
Published: October 2022

Biological systems frequently contain biochemical species present as small numbers of slowly diffusing molecules, leading to fluctuations that invalidate deterministic analyses of system dynamics. The development of mathematical tools that account for the spatial distribution and discrete number of reacting molecules is vital for understanding cellular behavior and engineering biological circuits. Here we present an algorithm for an event-driven stochastic spatiotemporal simulation of a general reaction process that bridges well-mixed and unmixed systems. The algorithm is based on time-varying particle probability density functions whose overlap in time and space is proportional to reactive propensity. We show this to be mathematically equivalent to the Gillespie algorithm in the specific case of fast diffusion. We develop a computational implementation of this algorithm and provide a Fourier transformation-based approach which allows for near constant computational complexity with respect to the number of individual particles of a given species. To test this simulation method, we examine reaction and diffusion limited regimes of a bimolecular association-dissociation reaction. In the reaction limited regime where mixing occurs between individual reactions, equilibrium numbers of components match the expected values from mean field methods. In the diffusion limited regime, however, spatial correlations between newly dissociated species persist, leading to rebinding events and a shift the in the observed molecular counts. In the final part of this work, we examine how changes in enzyme efficiency can emerge from changes in diffusive mobility alone, as may result from protein complex formation.
Impact evaluation of score classes and annotation regions in deep learning-based dairy cow body condition prediction
Authors: Nagy Sára Ágnes , Kilim Oz , Csabai István , Gábor György , Solymosi Norbert
Published: October 2022

Body condition scoring is a simple method to estimate the energy supply of dairy cattle. Our study aimed to investigate the accuracy with which supervised machine learning, a deep convolutional neural network, can be used to retrieve body condition score (BCS) classes estimated by an expert. Using a simple action camera, we recorded images of animals’ rumps in three large-scale farms. The images were annotated with three different-sized boxes by an expert. A Faster-RCNN pre-trained model was trained on 12 and 3 BCS classes. Training in 12 classes, with a 0 error range, the Cohen’s kappa value yielded minimal agreement. Allowing an error range of 0.25, we obtained a minimum or week agreement. With an error range of 0.5, we had strong or almost perfect agreements. The kappa values of the approach trained on 3 classes show that we can classify all animals into BCS categories with at least moderate agreement. Furthermore, CNNs trained in 3 BCS classes show a remarkably higher proportion of strong agreement than those trained in 12 classes. The prediction precision based on training with various annotation regions showed no meaningful differences.
Atypical cortical encoding of speech identifies children with Dyslexia versus Developmental Language Disorder
Authors: Araújo João , Simons Benjamin D , Peter Varghese , Mandke Kanad , Kalashnikova Marina , Macfarlane Annabel , Gabrielczyk Fiona , Wilson Angela , Di Liberto Giovanni M. , Burnham Denis , Goswami Usha
Published: October 2022

Slow cortical oscillations play a crucial role in processing the speech envelope, which is perceived atypically by children with Developmental Language Disorder (DLD) and developmental dyslexia. Here we use electroencephalography (EEG) and natural speech listening paradigms to identify neural processing patterns that characterize dyslexic versus DLD children. Using a story listening paradigm, we show that atypical power dynamics and phase-amplitude coupling between delta and theta oscillations characterize dyslexic and DLD children groups, respectively. We further identify EEG common spatial patterns (CSP) during speech listening across delta, theta and beta oscillations describing dyslexic versus DLD children. A linear classifier using four deltaband CSP variables predicted dyslexia status (0.77 AUC). Crucially, these spatial patterns also identified children with dyslexia in a rhythmic syllable task EEG, suggesting a core developmental deficit in neural processing of speech rhythm. These findings suggest that there are distinct atypical neurocognitive mechanisms underlying dyslexia and DLD.
SiPhyNetwork: An R package for Simulating Phylogenetic Networks
Authors: Justison Joshua A. , Solis-Lemus Claudia , Heath Tracy A.
Published: October 2022

Gene flow is increasingly recognized as an important macroevolutionary process. The many mechanisms that contribute to gene flow (e.g., introgression, hybridization, lateral gene transfer) uniquely affect the diversification of dynamics of species, making it important to be able to account for these idiosyncrasies when constructing phylogenetic models. Existing phylogenetic-network simulators for macroevolution are limited in the ways they model gene flow.

We present SiPhyNetwork, an R package for simulating phylogenetic networks under a birth-death-hybridization process.

Our package unifies the existing birth-death-hybridization models while also extending the toolkit for modeling gene flow. This tool can create patterns of reticulation such as hybridization, lateral gene transfer, and introgression.

Specifically, we model different reticulate events by allowing events to either add, remove, or keep constant the number of lineages. Additionally, we allow reticulation events to be trait-dependent, creating the ability to model the expanse of isolating mechanisms that prevent gene flow. This tool makes it possible for researchers to model many of the complex biological factors associated with gene flow in a phylogenetic context.
How Does White Matter Registration Affect Tractography Alignment?
Authors: Amorosino Gabriele , Olivetti Emanuele , Jovicich Jorge , Avesani Paolo
Published: October 2022

Tractography is a powerful method to represent the structural connectivity of the brain white matter. Nevertheless, the comparison of these data structures between two individuals is still an open challenge because of their complexity, e.g. digital representation of millions of fibers as polylines. The scientific community spent a meaningful effort to develop new methods of white matter registration aiming to take advantage of diffusion MRI models. Despite the effort to improve the registration of the white matter, little is known about the effect of the registration on tractogram alignment. The main issue for an empirical evaluation is the lack of ground truth, e.g. a sample of data where the correct alignment is validated by experts. This work aims to overcome this drawback by proposing an evaluation framework based on the matching of homologous fiber structures, e.g. known neuroanatomical bundles. The contribution is a quantitative comparison of how the most representative methods of white matter registration affect tractogram alignment.
Membrane-active peptides escape drug-resistance in cancer
Authors: Benfield Aurélie H. , Vernen Felicitas , Young Reuben S.E. , Nadal-Bufí Ferran , Hammerlindl Heinz , Craik David J. , Schaider Helmut , Lawrence Nicole , Blanksby Stephen J. , Henriques Sónia Troeira
Published: October 2022

Acquired drug-resistance is a recurring problem in cancer treatment, and this is particularly true for patients with metastatic melanoma that carry a BRAF V600E mutation. In the current study, we explored the use of membrane-active peptides as an alternative therapeutic modality to target drug-resistant melanoma cells. We produced slow-cycling and drug-resistant melanoma cells using dabrafenib, a small molecule drug that targets tumor cells with BRAF V600E mutation, and characterised their lipidome and proteome to investigate the role of membrane lipids in acquired drug-resistance. Despite some changes in the lipid composition, tested anti-melanoma membrane-active cyclic peptides (cTI and cGm) killed melanoma cells that are sensitive, tolerant, or resistant to dabrafenib. Importantly, melanoma cells did not develop resistance to cTI or cGm, nor changed their lipid composition with long-term peptide treatment. Therefore, these peptides are well suited as templates to design therapeutic leads to target drug-resistant metastatic melanoma cells and/or as co-treatment with small molecule drugs.
RecGraph: adding recombinations to sequence-to-graph alignments
Authors: Avila Jorge , Bonizzoni Paola , Ciccolella Simone , Della Vedova Gianluca , Denti Luca , Monti Davide , Pirola Yuri , Porto Francesco
Published: October 2022

The transition towards graph pangenomes is posing several new challenging questions, most notably how to extend the classical notion of read alignment from a sequence-to-sequence to a sequence-to-graph setting. Especially on variation graphs, where paths corresponding to individual genomes are labeled, notions of alignments that are strongly inspired by the classical ones are usually able to capture only variations that can be expressed by mismatches or gaps, such as SNPs or short insertions and deletions.

On the other hand the recent investigation of pangenomes at bacterial scale (Colquhoun et al, 2021) shows that most tools are tailored for human pangenomes and are not suited to bacteria which exhibit, among other characteristics, a larger variability. Such variability leads to the need for incorporating a greater flexibility when computing an alignment.

In this paper, we extend the usual notion of sequence-to-graph alignment by including recombinations among the variations that explicitly represented and evaluated in an alignment. From a computational modeling point of view, a recombination corresponds to identifying a new path of the variation graph which is a mosaic of two different paths, possibly joined by a new arc.

We provide a dynamic programming algorithm for computing an optimal alignment that allows recombinations with an affine penalty. We have implemented our approach with the tool RecGraph and we have analyzed its accuracy over some over some bacterial pangenome graphs.
TLR7/8 stress response drives histiocytosis in SLC29A3 disorders
Authors: Shibata Takuma , Sato Ryota , Taoka Masato , Saitoh Shin-Ichiroh , Komine Mayumi , Yamaguchi Kiyoshi , Goyama Susumu , Motoi Yuji , Kitaura Jiro , Izawa Kumi , Yamauchi Yoshio , Tsukamoto Yumiko , Ichinohe Takeshi , Fujita Etsuko , Hiranuma Ryosuke , Fukui Ryutaro , Furukawa Yoichi , Kitamura Toshio , Takai Toshiyuki , Tojo Arinobu , Ohtsuki Mamitaro , Ohto Umeharu , Shimizu Toshiyuki , Ozawa Manabu , Yoshida Nobuaki , Isobe Toshiaki , Latz Eicke , Mukai Kojiro , Taguchi Tomohiko , Miyake Kensuke
Published: October 2022

SLC29A3, also known as ENT3, is a lysosomal transmembrane protein that transports nucleosides from the lysosomes to the cytoplasm1. Loss-of-function mutations inSLC29A3cause lysosomal nucleoside storage and histiocytosis: phagocyte accumulation in multiple organs2,3. However, little is known about the mechanism through which lysosomal nucleoside storage drives histiocytosis. Herein, histiocytosis inSlc29a3−/−mice was demonstrated to depend on TLR7, which senses a combination of nucleosides and oligoribonucleotides4,5. TLR7 responded to lysosomal nucleoside storage and enhanced proliferation of Ly6ChiCX3CR1lowimmature monocytes and their maturation into Ly6Clowphagocytes inSlc29a3−/−mice. Because accumulated nucleosides primarily originated from cell corpse phagocytosis, TLR7 in immature monocytes recognized nucleoside storage as lysosomal stress and increased phagocyte numbers. This non-inflammatory compensatory response is referred to as the TLR7 stress response where Syk, GSK3β, β-catenin, and mTORC1 serve as downstream signalling molecules. In SLC29A3 disorders, histiocytosis accompanies inflammation6,7. Nucleoside storage failed to induce pro-inflammatory cytokine production inSlc29a3−/−mice, but enhanced ssRNA-dependent pro-inflammatory cytokine production in Ly6Chiclassical monocytes and peripheral macrophages, not proliferating immature monocytes. Patient-derived monocytes harbouring G208RSLC29A3mutation showed higher survival and proliferation in the presence of M-CSF and produced larger amounts of IL-6 upon ssRNA stimulation than did those derived from healthy subjects. A TLR8 antagonist inhibited the survival/proliferation of patient-derived macrophages. These results demonstrated that TLR7/8 responses to lysosomal nucleoside stress drive SLC29A3 disorders.
Within-animal comparison of microdialysis and fiber photometry in amphetamine-exposed mice
Authors: Ejdrup Aske L. , Wellbourne-Wood Joel , Dreyer Jakob K. , Guldhammer Nina , Lycas Matthew D. , Gether Ulrik , Hall Benjamin J. , Sørensen Gunnar
Published: October 2022

A fundamental concept in neuroscience is the transmission of information between neurons via neurotransmitters, -modulators, and – peptides. For the past decades the gold standard for measuring neurochemicals in awake animals has been microdialysis (MD). The emergence of genetically encoded fluorescence-based biosensors, as well as in vivo optical techniques such as fiber photometry (FP), have introduced technologically distinct means of measuring neurotransmission. To directly compare MD and FP, we performed concurrent within-animal recordings of extracellular dopamine (DA) in the dorsal striatum (DS) before and after administration of amphetamine in awake, freely behaving mice expressing the dopamine sensor dLight1.3b. We show that despite temporal differences, MD- and FP-based readouts of DA correlate well within mice. Down-sampling of FP data showed temporal correlation to MD data, with less variance observed using FP. We also present evidence that DA fluctuations periodically reach low levels and naïve animals have rapid, pre-drug DA dynamics measured with FP that correlate to the subsequent pharmacodynamics of amphetamine as measured with MD and FP.
The endogenous modulation of visual plasticity in human adults
Authors: Chen Yiya , Gao Yige , He Zhifen , Sun Zhouyuan , Mao Yu , Hess Robert F. , Zhang Peng , Zhou Jiawei
Published: October 2022

The adult human visual system can exhibit a degree of neuroplastic change under the right conditions which has implications for future treatments to recover vision loss that have occurred in infancy. The exogenous factors that promote neuroplastic change have been the focus of human psychophysical, electrophysiological and neuroimaging research over the last decade. What has not been considered is the importance of endogenous factors. In this study we modulate the neural oscillations that determines the internal neural state to demonstrate that endogenous factors play a critical role in not only baseline contrast sensitivity but also the extent to which the adult visual system can undergo neuroplastic change in binocular balance.
A Model For Hierarchical Memory Storage in Piriform Cortex
Authors: Kumar Achint
Published: October 2022

How the brain stores and retrieves memories is an important unsolved problem in neuroscience. It is commonly believed that memories are represented in the brain by distinct patterns of neural activity. Attractor dynamics has been proposed as one of the theoretical frameworks for learning and memory in neural networks. However, most of the prior theoretical work typically assumes that the neural network consists of fully-connected, binary neurons and that neuronal representations of memories are uncorrelated. In this paper, we propose a model consisting of continuously varying, rate-based, sparse neural network with a local learning rule which stores correlated patterns organized into multiple uncorrelated classes. We perform analytical calculations to compute maximum storage capacity and basin of attraction. It is found that increasing pattern correlation decreases storage capacity, and increasing the memory load decreases basin of attraction. We also study rate-based and spiking based neural network with separate excitatory and inhibitory populations and tight EI balance. Recent experimental work indicates that piriform cortex exhibits attractor dynamics and possibly stores hierarchically correlated patterns. So, we consider this work as a model for olfactory memory storage.
ISG15 is required for the dissemination ofVaccinia virusextracellular virions
Authors: Bécares Martina , Albert Manuel , Tarrega Celine , Coloma Rocío , Falqui Michela , Luhmann Emma K. , Radoshevich Lilliana , Guerra Susana
Published: October 2022

Viruses have developed many different strategies to counteract immune responses, andVaccinia virus(VACV) is one of a kind in this aspect. To ensure an efficient infection, VACV undergoes a complex morphogenetic process resulting in the production of two types of infective virions: intracellular mature virus (MV) and extracellular enveloped virus (EV), whose spread depends on different dissemination mechanisms. MVs disseminate after cell lysis, whereas EVs are released or propelled in actin tails from living cells. Here we show that ISG15 participates in the control of VACV dissemination. Infection ofIsg15-/-mouse embryonic fibroblasts with VACV International Health Department-J (IHD-J) strain resulted in decreased EV production, concomitant with reduced induction of actin tails and the abolition of comet-shaped plaque formation, comparing withIsg15+/+cells. Transmission electron microscopy revealed accumulation of intracellular and a decrease in extracellular virus particles in the absence of Interferon Stimulated Gene 15 (ISG15), consistent with altered virus egress. Immunoblot and quantitative proteomic analysis of sucrose gradient-purified virions from both genotypes reported differences in protein levels and composition of viral proteins present on virions, suggesting an ISG15-mediated control of viral proteome. Last, the generation of a recombinant IHD-J expressing V5-tagged ISG15 (IHD-J-ISG15) allowed us to identify several viral proteins as potential ISG15 targets, highlighting the proteins A34 and A36, essential for EV formation. Altogether, our results indicate that ISG15 is an important host factor in the regulation of VACV dissemination.

Author Summary

Viral infections are a constant battle between the virus and the host. While the host’s only goal is victory, the main purpose of the virus is to spread and conquer new territories at the expense of the host’s resources. Along millions of years of incessant encounters, Poxviruses have developed a unique strategy consisting in the production two specialized “troops”: intracellular mature virions (MVs) and extracellular virions (EVs). MVs mediate transmission between hosts, and EVs ensure advance on the battlefield mediating the long-range dissemination.

The mechanism by which the virus ‘decides’ to shed from the primary site of infection and its significant impact in viral transmission is not yet fully established. Here, we demonstrate that this process is finely regulated by ISG15/ISGylation, an interferon-induced ubiquitin-like protein with broad antiviral activity. Studying the mechanism that viruses use during infection could result in new ways of understanding our perpetual war against disease and how we might win the next great battle.
Evidence for an one-step mechanism of endosymbiont-induced thelytoky in the parasitoid wasp,Muscidifurax uniraptor
Authors: Wang Yidong , Verhulst Eveline C.
Published: October 2022

Wolbachiamanipulates host reproduction in various haplodiploid insect species, in which fertilized eggs normally develop into diploid females while unfertilized eggs develop into haploid males. Females infected with a thelytoky-inducingWolbachiaproduce diploid daughters from unfertilized eggs (thelytoky), but in some infected species diploid males spontaneously occur in low numbers. This suggests that diploidization and feminization are induced separately. In theWolbachia-infected thelytokous parasitoid wasp,Muscidifurax uniraptor, occasional males have been found but with unknown ploidy. Therefore, we studied the mechanism ofWolbachia-induced thelytoky inM. uniraptorin the context of sex determination. We started by feeding different concentrations of tetracycline (antibiotic) toM. uniraptorfemales to gradually reduce theWolbachiatitre. We found that a decreasedWolbachiatitre leads to an increased proportion of haploid male offspring, but we found no diploid males. Next, we studied the effect ofWolbachiainfection on the expression and splicing of the sex determination genestransformer(Mutra) andtransformer-2(Mutra2) in female ovaries and conclude thatWolbachiadoes neither affect the expression nor the splicing ofMutraandMutra2. We then measuredMutraandMutra2expression levels in developing zygotes at different time points and found a two-foldMutraexpression increase inWol+ compared toWol-. Finally, we used the sexually reproducing sister species,Muscidifurax raptorellusand artificially created triploid females to determine whether diploidization is sufficient for feminization. These triploid females, when virgin, produced haploid sons and diploid daughters, showing that inMuscidifuraxfeminization solely depends on ploidy level. This strongly suggests thatWolbachiaonly needs to induce diploidization and that bi-allelicMutraexpression is sufficient for female development.
Membrane curvature-generating proteins crucial for autophagosome formation
Authors: Wang Ning , Shibata Yoko , Paulo Joao A. , Gygi Steven P. , Rapoport Tom A.
Published: October 2022

Autophagy is essential for cellular homeostasis and begins with the formation of a phagophore, a cup-like membrane sheet consisting of two closely apposed lipid bilayers connected by a highly curved rim. How the membrane sheet forms, bends, and eventually generates an autophagosome that enwraps cargo remains enigmatic. Specifically, it is unclear how the high membrane curvature of the phagophore rim, an energetically unfavorable state, is stabilized. Here, we demonstrate that phagophore formation requires the conserved, membrane curvature-generating REEP1 proteins. The REEP1 family proteins (REEP1-4 in vertebrates) differ from the related endoplasmic reticulum-shaping REEPs in abundance and membrane topology. In fission yeast, the single REEP1 ortholog is involved in both bulk and selective autophagy. It is recruited at early stages of phagophore formation and required for their maturation into autophagosomes. The function of REEP1 relies on its ability to generate high membrane curvature and its localization to the phagophore rim. Mammalian REEP1 proteins also associate with phagophores upon induction of autophagy and colocalize with early autophagic markers. We propose that REEP1 proteins stabilize the phagophore’s highly curved rim so that the two membrane sheets are kept in close proximity to form the autophagosome. Defective autophagy may underlie the effect of curvature-compromising mutations in human REEP1 proteins linked to neurological disease.
Representational similarity learning reveals a graded multidimensional semantic space in the human anterior temporal cortex
Authors: Cox Christopher R. , Rogers Timothy T. , Shimotake Akihiro , Kikuchi Takayuki , Kunieda Takeharu , Miyamoto Susumu , Takahashi Ryosuke , Matsumoto Riki , Ikeda Akio , Ralph Matthew A. Lambon
Published: October 2022

Neurocognitive models of semantic memory have proposed that the ventral anterior temporal lobes (vATLs) encode a graded and multidimensional semantic space—yet neuroimaging studies seeking brain regions that encode semantic structure rarely identify these areas. In simulations we show that this discrepancy may arise from a crucial mismatch between theory and analysis approach. Utilizing an analysis recently formulated to investigate graded multidimensional representations,representational similarity learning(RSL), we decoded semantic structure from ECoG data collected from the vATL cortical surface while participants named line drawings of common items. The results reveal a graded, multidimensional semantic space encoded in neural activity across the vATL, which evolves over time and simultaneously expresses both broad and finer-grained semantic structure amongst animate and inanimate concepts. The work resolves the apparent discrepancy within the semantic cognition literature and, more importantly, suggests a new approach to discovering representational structure in neural data more generally.

Conflict of interest

The Department of Epilepsy, Movement Disorders, and Physiology, Kyoto University Graduate School of Medicine conducts Industry-Academia Collaboration Courses, supported by Eisai Co., Ltd, Nihon Kohden Corporation, Otsuka Pharmaceutical Co., and UCB Japan Co., Ltd.
Transcriptomic Profiling of Plasma Extracellular Vesicles Enables Reliable Annotation of the Cancer-specific Transcriptome and Molecular Subtype
Authors: Bahrambeigi Vahid , Lee Jaewon J. , Branchi Vittorio , Rajapakshe Kimal I. , Xu Zhichao , Henry Jason T. , Kun Wang , Stephens Bret M. , Dhebat Sarah , Hurd Mark W. , Sun Ryan , Yang Peng , Ruppin Eytan , Wang Wenyi , Kopetz Scott , Maitra Anirban , Guerrero Paola A.
Published: October 2022

Longitudinal monitoring of patients with advanced cancers is crucial to evaluate both disease burden and treatment response. Current liquid biopsy approaches mostly rely on the detection of DNA-based biomarkers. However, plasma RNA analysis can unleash tremendous opportunities for tumor state interrogation and molecular subtyping. Through the application of deep learning algorithms to the deconvolved transcriptomes of RNA within plasma extracellular vesicles (evRNA), we successfully predict consensus molecular subtypes in metastatic colorectal cancer patients. We further demonstrate the ability to monitor changes in transcriptomic subtype under treatment selection pressure and identify molecular pathways in evRNA associated with recurrence. Our approach also identified expressed gene fusions and neoepitopes from evRNA. These results demonstrate the feasibility of transcriptomic-based liquid biopsy platforms for precision oncology approaches, spanning from the longitudinal monitoring of tumor subtype changes to identification of expressed fusions and neoantigens as cancer-specific therapeutic targets,sansthe need for tissue-based sampling.

Statement of significance

We have developed an approach to interrogate changes in cancer molecular subtypes and differentially expressed genes, through the analysis and deconvolution of RNA sequencing of plasma EVs. Serial analyses of tumor-encoded transcriptomes in liquid biopsies can enable facile cancer detection and monitor for recurrences and therapy-induced tumor evolution.
Effect of age and sex on gene expression-based radiation biodosimetry using mouse peripheral blood
Authors: Broustas Constantinos G. , Shuryak Igor , Duval Axel J. , Amundson Sally A.
Published: October 2022

Blood-based gene expression profiles that can reconstruct radiation exposure are being developed as a practical approach to radiation biodosimetry. However, age and sex could potentially limit the accuracy of the approach. In this study, we determined the impact of age on the peripheral blood cell gene expression profile of female mice exposed to radiation and identified differences and similarities with a previously obtained transcriptomic signature of male mice. Young (2 months) and old (24 months) female mice were irradiated with 4 Gy X-rays, total RNA was isolated from blood 24hr later and subjected to whole genome microarray analysis. Dose reconstruction analyses using a gene signature trained on gene expression data from irradiated young male mice showed accurate reconstruction of 0 or 4 Gy doses with root mean square error of ± 0.75 Gy (R^2 = 0.90) in young female mice. Although dose reconstruction for irradiated old female mice was less accurate than young female mice, the deviation from the actual radiation dose was not statistically significant. Pathway analysis of differentially expressed genes revealed that after irradiation, apoptosis-related functions were overrepresented, whereas functions related to quantities of various immune cell subtypes were underrepresented, among differentially expressed genes from young female mice, but not older animals. Furthermore, young mice significantly upregulated genes involved in phagocytosis, a process that eliminates apoptotic cells and preserves tissue homeostasis. Both functions were also overrepresented in young, but not old, male mice following 4 Gy X-irradiation. Lastly, functions associated with neutrophil activation that is essential for killing invading pathogens and regulating the inflammatory response were predicted to be uniquely enriched in young but not old female mice. This work supports the concept that peripheral blood gene expression profiles can be identified in mice that accurately predict physical radiation dose exposure irrespective of age and sex. However, inclusion of age and sex as biological factors is essential for effectively predicting radiation injury and for developing radiation medical countermeasures.
A subpopulation of peripheral sensory neurons expressing the Mas-related G Protein-Coupled Receptor d (Mrgprd) generates pain hypersensitivity in painful diabetic neuropathy
Authors: George Dale S , Jayaraj Nirupa D , Ren Dongjun , Miller Rachel E. , Malfait Anne-Marie , Miller Richard J , Menichella Daniela M
Published: October 2022

Painful diabetic neuropathy (PDN) is one of the most common and intractable complications of diabetes. PDN is characterized by neuropathic pain accompanied by dorsal root ganglion (DRG) nociceptor hyperexcitability, axonal degeneration, and loss of cutaneous innervation. However, the complete molecular profile underlying the hyper-excitable cellular phenotype of DRG nociceptors in PDN has not been elucidated. This gap in our knowledge is a critical barrier to developing effective, mechanism-based, and disease-modifying therapeutic approaches which are urgently needed to relieve the symptoms of PDN. Using single-cell RNA sequencing we demonstrated an increased expression of the Mas-related G Protein-Coupled Receptor d (Mrgprd) in a subpopulation of DRG neurons in the well-established High-Fat Diet (HFD) mouse model of PDN.In vivocalcium imaging allowed us to demonstrate that activation of Mrgprd receptors expressed by cutaneous afferents produced DRG neuron hyper-excitability and oscillatory calcium waves. Furthermore, Mrgprd-positive cutaneous afferents persist in diabetic mice skin. Importantly, limiting Mrgprd signaling or Mrgprd-positive DRG neuron excitability, reversed mechanical allodynia in the HFD mouse model of PDN. Taken together, our data highlights a key role of Mrgprd-mediated DRG neuron excitability in the generation and maintenance of neuropathic pain in a mouse model of PDN. Hence, we propose Mrgprd as a promising accessible target for developing effective therapeutics currently unavailable for treating neuropathic pain in PDN. Furthermore, understanding which DRG neurons cell type is mediating mechanical allodynia in PDN is of fundamental importance to our basic understanding of somatosensation and may provide an important way forward for identifying cell-type-specific therapeutics to optimize neuropathic pain treatment and nerve regeneration in PDN.
Characterisation of organised smooth endoplasmic reticulum suggests a route towards synthetic compartmentalisation
Authors: Sandor Andras , Samalova Marketa , Brandizzi Federica , Kriechbaumer Verena , Moore Ian , Fricker Mark D , Sweetlove Lee J
Published: October 2022

Engineering of subcellular compartmentalisation is one of synthetic biology’s key challenges. Among different approaches,de novoconstruction of a synthetic compartment is the most coveted but also most difficult option. Restructuring the endoplasmic reticulum (ER), via the introduction of recombinant oligomerising ER-membrane resident proteins, is an alternative starting point for building a new compartment. The presence of such proteins leads to a massive expansion of the ER and the formation of organised smooth endoplasmic reticulum (OSER), a large membranous compartment. However, OSER is poorly characterised and our understanding of its effect on the underlying biology of the plant is limited. Here we characterise a range of OSER compartments and show how the structure of the inducing polyprotein constructs affect the final compartment morphology, with the cytosolic-facing antiparallel oligomerisation domain demonstrated to be an essential component to trigger OSER formation. We show that while OSER retains a connection to the ER, a diffusional barrier exists to both the ER and the cytosol. Using high-resolution quantitative image analysis, we also show that the presence of this large compartment does not disrupt the rest of the ER network. Moreover, transgenicArabidopsisconstitutively expressing the compartment-forming polyproteins grew and developed normally. These properties collectively suggest that OSER could be developed as a plant synthetic biology tool for compartmentalisation, combining the benefits of several existing strategies. Only a single protein construct is necessary to induce its formation, and the compartment retains a delimiting membrane and a diffusional barrier to the rest of the cell.
Disentangling contact and ensemble epistasis in a riboswitch
Authors: Wonderlick Daria R. , Widom Julia R. , Harms Michael J.
Published: October 2022

Mutations introduced into macromolecules often exhibit epistasis, where the effect of one mutation alters the effect of another. Knowledge of the mechanisms that lead to epistasis is important for understanding how macromolecules work and evolve, as well as for effective macromolecular engineering. Here we investigate the interplay between “contact epistasis” (epistasis arising from physical interactions between mutated residues) and “ensemble epistasis” (epistasis that occurs when a mutation redistributes the conformational ensemble of a macromolecule, thus changing the effect of the second mutation). We argue that the two mechanisms can be distinguished in allosteric macromolecules by measuring epistasis at differing allosteric effector concentrations. Contacts give rise to epistasis in the microscopic equilibrium constants describing the conformational ensemble. Ensemble epistasis manifests in thermodynamic observables, such as the energy of ligand binding or enzyme activation, that depend on the concentration of allosteric effector. Using this framework, we experimentally investigated the origins of epistasis in three mutant cycles introduced into the adenine riboswitch aptamer domain. We found evidence for both contact and ensemble epistasis in all cycles. Further, we found that the two mechanisms of epistasis can interact with each other. For example, in one mutant cycle we observe contact epistasis of 6 kcal/mol attenuated by the ensemble to only 1.5 kcal/mol in the final thermodynamic observable. Finally, our work yields simple heuristics for identifying contact and ensemble epistasis using limited experimental measurements.

Statement of significance

Mutations to protein or RNA molecules often have different effects when introduced individually versus together. To understand and engineer biological macromolecules, we must identify the mechanistic origins of this phenomenon. Here, we measured the interplay between direct, physical interactions between mutations (“contact epistasis”) and indirect interactions mediated by conformational ensembles (“ensemble epistasis”). We introduced pairs of mutations into an RNA molecule that transitions between several different conformations. We found epistasis arising from both contacts and the ensemble, and that the two mechanisms could synergize with one another. Our work reveals that one must consider the effects of mutations on multiple conformations to understand epistasis and suggests a few rules-of-thumb for disentangling contact and ensemble epistasis in other macromolecules.
Crystal structure of bis{3-(3-bromo-4-methoxyphenyl)-5-[6-(1H-pyrazol-1-yl)pyridin-2-yl]-1,2,4-triazol-3-ato}iron(II) methanol disolvate
Authors: Znovjyak Kateryna , Fritsky Igor O. , Sliva Tatiana Y. , Amirkhanov Vladimir M. , Malinkin Sergey O. , Shova Sergiu , Seredyuk Maksym
Published: October 2022

The unit cell of the title compound, [FeII(C17H12BrN6O)2]·2MeOH, consists of a charge-neutral complex molecule and two independent molecules of methanol. In the complex molecule, the two tridentate ligand molecules 2-[5-(3-bromo-4-methoxyphenyl)-4H-1,2,4-triazol-3-yl]-6-(1H-pyrazol-1-yl)pyridine coordinate to the FeIIion through the N atoms of the pyrazole, pyridine and triazole groups, forming a pseudo-octahedral coordination sphere around the central ion. In the crystal, neighbouring asymmetric molecules are linked through weak C—H(pz)...π(ph) interactions into chains, which are then linked into layers by weak C–H...N/C interactions. Finally, the layers stack into a three-dimensional network linked by weak interlayer C—H...π interactions between the methoxy groups and the phenyl rings. The intermolecular contacts were quantified using Hirshfeld surface analysis and two-dimensional fingerprint plots, revealing the relative contributions of the contacts to the crystal packing to be H...H 34.2%, H...C/C...H 25.2%, H...Br/Br...H 13.2%, H...N/N...H 12.2% and H...O/O...H 4.0%. The average Fe—N bond distance is 1.949 Å, indicating the low-spin state of the FeIIion. Energy framework analysis at the HF/3–21 G theory level was performed to quantify the interaction energies in the crystal structure.
1-Hydroxy-4-methylpyridinium chloride
Authors: Saini Aarti , Dhanwant Kisturi , Thirumoorthi Ramalingam
Published: October 2022

The title salt, C6H8NO+·Cl−, contains two cations and two anions in the asymmetric unit. The components are linked by O—H...Cl and C—H...Cl hydrogen bonds, leading to tetra- (square-planar) or penta-coordinated (square-pyramidal) chloride ions. The title salt is isostructural with its bromide analogue.
Mobile self-efficacy as predictor of mobile-based personal digital archiving practices: a study of Pakistani undergraduates
Authors: Ali Irfan , Warraich Nosheen Fatima
Published: October 2022

Purpose

The purpose of this study is to investigate the impact of mobile self-efficacy on personal digital archiving (PDA) practices of undergraduate students.

Design/methodology/approach

This study used a quantitative research design for achieving the objectives. The population consisted of undergraduate students from public sector universities (the top five) of Punjab, Pakistan, listed in the Higher Education Commission recognized general universities. The data were analysed by using SmartPLS, mobile self-efficacy was the independent variable that consisted of two constructs (basic mobile phone operations and using the internet and emails). PDA practices was the dependent variable (information backup, clearing and deleting).

Findings

The analysis consisted of two major parts: first the assessment of measurement model and second the structural equation modelling analysis. A significant impact of mobile self-efficacy (basic mobile phone operations, using internet and email) was found on all the sub-constructs (information backup, information clearing and information deleting) of PDA practices. However, using internet and email has no significant impact on the information clearing practices of undergraduate students of Pakistani universities.

Originality/value

This study is a valuable addition to the extant literature because no comprehensive research has been carried out on the impact of mobile self-efficacy and PDA through mobile phones. It also contributes theoretically in the form of the development of a validated instrument on mobile-based PDA. Additionally, it possesses practical value for information literacy instruction programs.
The composition of data economy: a bibliometric approach and TCCM framework of conceptual, intellectual and social structure
Authors: Olaleye Sunday Adewale , Mogaji Emmanuel , Agbo Friday Joseph , Ukpabi Dandison , Gyamerah Adusei Akwasi
Published: October 2022

Purpose

The data economy mainly relies on the surveillance capitalism business model, enabling companies to monetize their data. The surveillance allows for transforming private human experiences into behavioral data that can be harnessed in the marketing sphere. This study aims to focus on investigating the domain of data economy with the methodological lens of quantitative bibliometric analysis of published literature.

Design/methodology/approach

The bibliometric analysis seeks to unravel trends and timelines for the emergence of the data economy, its conceptualization, scientific progression and thematic synergy that could predict the future of the field. A total of 591 data between 2008 and June 2021 were used in the analysis with the Biblioshiny app on the web interfaced and VOSviewer version 1.6.16 to analyze data from Web of Science and Scopus.

Findings

This study combined findable, accessible, interoperable and reusable (FAIR) data and data economy and contributed to the literature on big data, information discovery and delivery by shedding light on the conceptual, intellectual and social structure of data economy and demonstrating data relevance as a key strategic asset for companies and academia now and in the future.

Research limitations/implications

Findings from this study provide a steppingstone for researchers who may engage in further empirical and longitudinal studies by employing, for example, a quantitative and systematic review approach. In addition, future research could expand the scope of this study beyond FAIR data and data economy to examine aspects such as theories and show a plausible explanation of several phenomena in the emerging field.

Practical implications

The researchers can use the results of this study as a steppingstone for further empirical and longitudinal studies.

Originality/value

This study confirmed the relevance of data to society and revealed some gaps to be undertaken for the future.