bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Metformin Treatment on the Circulating Proteome
Authors: Connolly Ben , McCreight Laura , Slieker Roderick C , Bedair Khaled F , Donnelly Louise , de Klerk Juliette A , Beulens JWJ , Elders PM ,   IMI-DIRECT,   IMI-RHAPSODY, Bergström Göran , Hong Mun-Guan , Koivula Robert W. , Franks Paul W. , ‘t Hart Leen , Schwenk Jochen M , Gummesson Anders , Pearson Ewan R
Published: June 2024

Objective

Metformin is one of the most used drugs worldwide. However, its mechanism of action remains uncertain. Given the potential to reveal novel insights into the pleiotropic effects of metformin treatment, we aimed to undertake a comprehensive analysis of circulating proteins.

Research Design and Methods

We analysed 1195 proteins using the SomaLogic platform in 1175 participants, using cross- sectional data from the GoDARTS and DCS cohorts; 450 proteins using the Olink platform in 784 participants, using cross-sectional data from IMI-DIRECT; and combined longitudinal data from the IMPOCT, RAMP and S3WP-T2D cohorts with 372 proteins in 98 participants using the Olink platform. Finally, we performed systems level analysis on the longitudinal OLINK data to identify any possible relationships for the proteins changing concentration following metformin exposure.

Results

Overall, 97 proteins were associated with metformin exposure in at least one of the studies (Padj<0.05), and 10 proteins (EpCAM, SPINK1, t-PA, Gal-4, TFF3, TF, FAM3C, COL1A1, SELL, CD93) were associated in two independent studies. Four proteins, REG4, GDF15, REG1A, and OMD were consistently associated across all studies and platforms. Gene-set enrichment analysis revealed that the effect of metformin exposure was on intestinal tissues. In the longitudinal analysis 18% of proteins were significantly altered by metformin.

Conclusions

These data provide further insight into the mechanism of action of metformin, potentially identifying novel targets for diabetes treatment, and highlight the need to account for metformin exposure in proteomic studies and where protein biomarkers are used for clinical care where metformin treatment will generate false positive results.

Highlights

In the most comprehensive proteomic analysis of metformin exposure to date, we showed 97 proteins to be associated with metformin exposure in at least one study.

14 proteins were consistently associated with metformin exposure in 2 or more platforms or studies.

Gene enrichment analysis shows that the strongest protein set is of intestinal origin.

These data provide further insight into the mechanism of action of metformin, potentially identify novel targets for diabetes treatment and highlight the need to account for metformin exposure in proteomic studies and where protein biomarkers are used for clinical care.
Piloting a minimum data set for older people living in care homes in England: a developmental study
Authors: Gordon Adam L , Rand Stacey , Crellin Elizabeth , Allan Stephen , Tracey Freya , De Corte Kaat , Lloyd Therese , Brine Richard , Carroll Rachael E , Towers Ann-Marie , Burton Jennifer Kirsty , Akdur Gizdem , Hanratty Barbara , Webster Lucy , Palmer Sinead , Jones Liz , Meyer Julienne , Spilsbury Karen , Killett Anne , Wolters Arne T , Peryer Guy , Goodman Claire
Published: June 2024

Background

We developed a prototype minimum data set (MDS) for English care homes, assessing feasibility of extracting data directly from digital care records (DCRs) with linkage to health and social care data.

Methods

Through stakeholder development workshops, literature reviews, surveys and public consultation we developed an aspirational MDS. We identified ways to extract this from existing sources including DCRs and routine health and social care datasets. To address gaps we added validated measures of delirium, cognitive impairment, functional independence and Quality of Life to DCR software. Following routine health and social care data linkage to DCRs, we compared variables recorded across multiple data sources, using a hierarchical approach to reduce missingness where appropriate. We reported proportions of missingness, mean and standard deviation (SD) or frequencies (%) for all variables.

Results

We recruited 996 residents from 45 care homes in three English Integrated Care Systems. 727 residents had data included in the MDS. Additional data were well completed (<35% missingness at wave 1). Competition for staff time, staff attrition, and software-related implementation issues contributed to missing DCR data. Following data linkage and combining variables where appropriate, missingness was reduced (<=4% where applicable).

Discussion

Integration of health and social care is predicated on access to data and interoperability. Despite governance challenges we safely linked care home DCRs to statutory health and social care datasets to create a viable prototype MDS for English care homes. We identified issues around data quality, governance, data plurality and data completion essential to MDS implementation going forward.

Key points

There is a range of resident information across DCRs, health and social care datasets, which can be combined to provide a more complete picture of residents.

We developed and implemented a Minimum Dataset linking care home digital care records to statutory health and social care records.

Information governance for linking data across multiple data owners and data processors is complex and time consuming.

Standardisation across Digital Care Records Systems would enable data to be used more effectively across the care home sector.

Establishing shared priorities across key stakeholders interested in care home data is essential for effective MDS implementation.
Association of Post-Acute Sequelae of COVID-19 with respiratory system diagnoses: a population-based case-control study of Region Stockholm
Authors: Lindberg Pia , Ljunggren Gunnar , Lee Seika , Kolosenko Iryna , Runold Michael , Piontkovskaya Kristina , Wachtler Caroline , Fedorowski Artur , Carlsson Axel C. , Wheelock Åsa M.
Published: June 2024

Objectives

Post Acute Sequelae of COVID-19 (PASC) is an important health concern after the COVID-19 pandemic. We aimed to investigate the prevalence of respiratory system disorders before and after the pandemic onset in individuals with and without PASC.

Methods

We designed a case-control study was designed to investigate the prevalence of respiratory system-related diagnoses in adult, non-hospitalized PASC patients (cases) in 2019, 12 months before and 6 months after the PASC diagnosis compared to matched controls without PASC. Data was extracted from the Stockholm Region’s database warehouse (VAL).

Results

Higher diagnostic rates for common respiratory illnesses were observed among PASC patients in 2019 and 12 months before PASC diagnosis, which then slightly decreased 6 months after PASC diagnosis. PASC patients showed more pre-pandemic respiratory diagnoses compared to controls: in 2019 they had higher incidence of acute upper respiratory tract infection (OR 2.47 for males, 2.22 for females), asthma (OR 1.76 (males), 1.95 (females)), and bronchitis (OR 2.15 (males), 2.71 (females)) compared to controls.

Conclusions

This study highlights that individuals with PASC have a higher prevalence of respiratory disorders both before and after their COVID-19 diagnosis. Notably, asthma and other respiratory conditions were more common in PASC patients compared to matched controls. Our study demonstrates that individuals with asthma are more likely to develop PASC, even if asthma does not increase the severity of acute COVID-19. These findings underscore the need for further investigation into the underlying mechanisms connecting respiratory illnesses and PASC. Understanding the long-term consequences of COVID-19 in individuals with pre-existing conditions will be crucial for refining clinical management strategies and improving patients outcomes.
Student learning performance and satisfaction with a flipped classroom in undergraduate dental pharmacology education
Authors: Galvin Shelia , Lucitt Margaret
Published: June 2024

Introduction

The flipped classroom (FC) model of blended learning has become more feasible with the advancement of digital technology platforms. Monitoring a FC approach in curriculum delivery provides an opportunity to evaluate its impact on student exam outcomes and satisfaction. Presented here is examination performances and learning experiences in undergraduate dental students taking pharmacological course material using a FC approach compared to that of a traditional classroom (TC) model.

Method

Ninety- seven students experiencing a FC delivery is compared to 129 students taking a TC approach over 2 academic years. Course lecture topics, scheduling and assessment are consistent across both modes of delivery. At the end of each academic year an anonymous student survey with a closed end question was conducted to gain student feedback regarding course satisfaction.

Results

The FC positively improved student examination performances compared to the TC approach with a seven percent increase in the percentage mean exam grade and a 15% increase in the number of students obtaining exam grades greater than 50%. An increase in the proportion of students achieving higher grades overall is seen in the FC versus the TC approach from the frequency distribution of exam results. The students also rated the FC more positively in the feedback satisfaction compared to the TC student cohort.

Conclusion

In summary the student exam grades and feedback here indicate the FC having a positive impact on student outcomes and experience compared to the TC approach. These findings provide evidence to dental pharmacological educators that a FC curriculum delivery can lead to an improvement in student performances in this subject area.
Tumor Spectrum and Temporal Cancer Trends in adult carriers of Li-Fraumeni syndrome: Implications for Personalized Screening Strategies inTP53R337H carriers
Authors: Galante Pedro A. F. , Guardia Gabriela D. A. , Pisani Janina , Sandoval Renata L. , Barros-Filho Mateus C. , Gifoni Ana Carolina Leite Vieira Costa , Patrão Diogo F. C. , Ashton-Prolla Patricia , de Vasconcellos Vitor Fiorin , Freycon Claire , Levine Arnold , Hainaut Pierre , Achatz Maria Isabel
Published: June 2024

Background

Li-Fraumeni Syndrome (LFS) is a predisposition associated with early onset malignant tumors caused by germline pathogenic variants in the TP53 gene. Although rare worldwide, LFS is prevalent in Southern Brazil due to a founder pathogenic variant, c.1010G>A, p.Arg337His (R337H), discovered through its association with risk of childhood adrenal cortical carcinoma.

Methods

Here, we have analyzed tumor patterns, cancer risk, sex differences and temporal tumor trends in a cohort of 303 adult R337H carriers and we have compared them with those of 405 adult carriers of otherTP53variants typical of LFS.

Findings

Compared to the latter, R337H carriers had a lower cumulative risk of developing cancer (54% for R337H vs 78% for otherTP53variants at age 50 years). Female R337H carriers were at a higher risk than males (65% vs 30% at age 50 years) and had a higher risk of developing a second primary cancer, underscoring a strong sex bias not observed in carriers of other variants. The most common cancers were breast (75%), soft tissue sarcoma (9%) and lung cancer (8%) in females, and soft tissue sarcoma (30%), prostate (13%) and lung cancer (12%) in males. Common second malignancies were breast cancer in females and lung cancer in males.

Interpretations

Overall, this study confirms that R337H is associated with a lifetime risk of multiple cancers of the LFS spectrum but with incomplete penetrance, particularly in males. Our findings suggest that R337H carriers would benefit from adapted lifetime and surveillance strategies for risk reduction.

Funding

São Paulo Research Foundation and Hospital Sírio-Libanês.
Absence of Evidence is Not Evidence of Absence:The many flaws in the case against transgenerational epigenetic inheritance of pathogen avoidance inC. elegans
Authors: Kaletsky Rachel , Moore Rebecca , Sengupta Titas , Seto Renee , Ceballos-Llera Borja , Murphy Coleen T.
Published: June 2024

After examining the data and methods presented in Gainey, et al.,bioRxiv, 20241we conclude that the authors did not use an experimental paradigm that would have allowed them to replicate our results on transgenerational epigenetic inheritance (TEI) of learned avoidance that we regularly observe2–5. That is, we agree with the authors that their experiments show no evidence of TEI. However, there are substantial differences in their execution of every step of the work that also make it impossible for the authors to claim that they are replicating our experiments or protocols. Based on these differences, we do not believe there is an issue of “robustness” and “reliability” in our TEI findings, but rather that Hunter and colleagues have in fact not tested thecentralcondition of TEI - that is, small RNA production by bacteria and subsequent uptake byC. elegans- nor have they carried out proper behavioral and imaging assays to assess this behavior. Our subsequent work shows that indeed this example of transgenerational epigenetic inheritance is not just observed in laboratory settings with PA14, but is also induced by wild strains ofPseudomonas, exhibiting its robustness. Just as we offered advice and training to Hunter and colleagues, we are happy to advise anyone who wishes to learn this assay.

We have now performed the experiments in the absence of azide, a deviation from our protocol that Hunter and colleagues deliberately made, and found that this omission may account for most if not all of the differences from our results. It is disingenuous for the authors to have presented their work as if they have used our protocol, given the fact that they chose to not use the same conditions for the most basic assay used in the work, the chemotaxis assay, which would have been necessary to replicate in order to reproduce our work. Therefore, Gainey et al.’s claims that our protocol or results are “irreproducible” are not supported by their evidence.
Peptidomimetic inhibitors targeting TrkB/PSD-95 signaling improves cognition and seizure outcomes in an Angelman Syndrome mouse model
Authors: Huie Emily Z. , Yang Xin , Rioult-Pedotti Mengia S. , Naik Mandar , Huang Yu-Wen Alvin , Silverman Jill L , Marshall John
Published: June 2024

Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder with profoundly debilitating symptoms with no FDA-approved cure or therapeutic. Brain-derived neurotrophic factor (BDNF), and its receptor TrkB, have a well-established role as regulators of synaptic plasticity, dendritic outgrowth, dendritic spine formation and maintenance. Previously, we reported that the association of PSD-95 with TrkB is critical for intact BDNF signaling in the AS mouse model, as illustrated by attenuated PLCγ and PI3K signaling and intact MAPK pathway signaling. These data suggest that drugs tailored to enhance the TrkB-PSD-95 interaction may provide a novel approach for the treatment of AS and a variety of NDDs. To evaluate this critical interaction, we synthesized a class of high-affinity PSD-95 ligands that bind specifically to the PDZ3 domain of PSD-95, denoted as Syn3 peptidomimetic ligands. We evaluated Syn3 and its analog D-Syn3 (engineered using dextrorotary (D)-amino acids)in vivousing theUbe3aexon 2 deletion mouse model of AS. Following systemic administration of Syn3 and D-Syn3, we demonstrated improvement in the seizure domain of AS. Learning and memory using the novel object recognition assay also illustrated improved cognition following Syn3 and D-Syn3, along with restored long-term potentiation. Finally, D-Syn3 treated mice showed a partial rescue in motor learning. Neither Syn3 nor D-Syn3 improved gross exploratory locomotion deficits, nor gait impairments that have been well documented in the AS rodent models. These findings highlight the need for further investigation of this compound class as a potential therapeutic for AS and other genetic NDDs.
CLCC1 promotes hepatic neutral lipid flux and nuclear pore complex assembly
Authors: Mathiowetz Alyssa J. , Meymand Emily S. , Deol Kirandeep K. , Parlakgül Güneş , Lange Mike , Pang Stephany P. , Roberts Melissa A. , Torres Emily F. , Jorgens Danielle M. , Zalpuri Reena , Kang Misun , Boone Casadora , Zhang Yaohuan , Morgens David W. , Tso Emily , Zhou Yingjiang , Talukdar Saswata , Levine Tim P. , Ku Gregory , Arruda Ana Paula , Olzmann James A.
Published: June 2024

Imbalances in lipid storage and secretion lead to the accumulation of hepatocyte lipid droplets (LDs) (i.e., hepatic steatosis). Our understanding of the mechanisms that govern the channeling of hepatocyte neutral lipids towards cytosolic LDs or secreted lipoproteins remains incomplete. Here, we performed a series of CRISPR-Cas9 screens under different metabolic states to uncover mechanisms of hepatic neutral lipid flux. Clustering of chemical-genetic interactions identified CLIC-like chloride channel 1 (CLCC1) as a critical regulator of neutral lipid storage and secretion. Loss of CLCC1 resulted in the buildup of large LDs in hepatoma cells and knockout in mice caused liver steatosis. Remarkably, the LDs are in the lumen of the ER and exhibit properties of lipoproteins, indicating a profound shift in neutral lipid flux. Finally, remote homology searches identified a domain in CLCC1 that is homologous to yeast Brl1p and Brr6p, factors that promote the fusion of the inner and outer nuclear envelopes during nuclear pore complex assembly. Loss of CLCC1 lead to extensive nuclear membrane herniations, consistent with impaired nuclear pore complex assembly. Thus, we identify CLCC1 as the human Brl1p/Brr6p homolog and propose that CLCC1-mediated membrane remodeling promotes hepatic neutral lipid flux and nuclear pore complex assembly.
The Leader of the Capsid protein fromFeline calicivirusmust be palmitoylated and form oligomers through disulfide bonds for efficient viral replication
Authors: Peñaflor-Téllez Yoatzin , Gómez de la Madrid Jaury , Monge-Celestino Erick Ignacio , Pérez-Ibáñez Carolina , Miguel-Rodríguez Carlos Emilio , Gutiérrez-Escolano Ana Lorena
Published: June 2024

Feline calicivirus(FCV), a member of theVesivirusgenus and a model for studying of the members of theCaliciviridae, has been used to understand the biology and viral replication of etiological agents of medical and veterinary importance. The leader of the capsid (LC) protein is exclusive to theVesivirusgenus members whose importance for a successful viral replication has been demonstrated; however, its cell localization, post-translational modifications, and specific functions throughout the viral replication cycle are poorly understood. We have determined that the expression of the LC protein from FCV in a virus-free system is located at the mitochondria and induces apoptosis; furthermore, thein vitrocharacterization of a purified LC protein showed that it has viroporin characteristics. Here, using an LC-reactive serum, the LC protein expression kinetics, cellular localization, post-translational modifications, and association with cellular PDI proteins in FCV infected cells was determined. We found that the LC protein is present on the membrane of infected cells and in the supernatants, independently of cell lysis, which suggests that it is actively secreted. Moreover, we found that LC protein is palmitoylated during infection and that palmitoylation inhibition alters its levels and subcellular localization. Finally, we determined that the LC protein forms oligomers dependent on disulfide bonds mediated by PDI activity. In addition, it interacts with PDIA3, a disulfide isomerase known as an important factor in the replication of several viruses. The results indicate that the LC protein from FCV might have multiple roles during FCV replication.

IMPORTANCE

Feline calicivirus (FCV) is a highly transmissible virus that represents a significant cause of upper respiratory infection in domestic and wild cats worldwide. FCV also serves as one of the most valuable models for studying calicivirus biology, as unlike most members of the family, known to cause diseases in animals and humans, it can be easily grown in cell culture. Since there are no efficacious vaccines or antivirals against most caliciviruses, studying their molecular biology and the relationship between viral and cellular components is essential for developing strategies for their prevention and control.
Sleep, NMDA Receptor Subunits, and the Compensatory Pathway: Understanding Contextual Fear Conditioning in the Absence of the Dorsal Hippocampus
Authors: Kant Deepika , Jha Sushil K.
Published: June 2024

The loss of the dorsal hippocampus (DH) results in profound deficits in contextual fear-conditioned (CxFC) memory. Nonetheless, CxFC memories can still form without the DH, specifically with multiple trials at three-day intervals. The infralimbic cortex (IL) is pivotal in initiating this compensatory process post-DH loss, but the precise factors remain elusive. Our study aims to delineate key factors of compensatory CxFC in DH absence by investigating the effects of sleep deprivation (SD) and NMDA receptor subunits NR2A and NR2B. Using a DH-lesioned rat model, we conducted two conditioning trials separated by three days and assessed fear response during the subsequent test. We observed that DH-lesioned animals exhibited to SD (DHL-SD) did not elicit a compensatory CxFC response, displaying significantly impaired freezing during the second test. Conversely, DH-lesioned non-sleep-deprived animals (DHL-NSD) compensated for DH loss and exhibited robust CxFC responses during the second test. Moreover, inhibiting NR2B subunits in the IL during initial CxFC training disrupted the formation of compensatory fear memory in DH-lesioned animals, while NR2A subunit blockade showed no significant effect. These emphasize the adverse impact of SD on compensatory memory and the critical role of NR2B subunits in facilitating compensatory CxFC memory formation following DH loss.
The impact of parvalbumin interneurons on visual discrimination depends on strength and timing of activation and task difficulty
Authors: Kukovska Lilia , Poort Jasper
Published: June 2024

Parvalbumin-expressing (PV) cells are the most common class of inhibitory interneurons in the visual cortex. They are densely connected to excitatory cells and play important roles in balancing cortical circuit activity and learning. PV cell activation is a tool to inactivate cortical regions to establish their role in visual processing. However, it is not established how moderate activation affects behaviour and how effects depend on activation strength, timing and task difficulty. We therefore investigated how these three major factors affect performance of mice in a go/no-go orientation discrimination task. We tested discrimination performance with different strength and timing of PV cell activation in V1 and with different task difficulty levels. We found that PV cell activation improved performance in easy discriminations when stimulating with moderate laser powers only during the initial 120 ms from stimulus onset, corresponding to the initial feedforward processing sweep across the cortical hierarchy. In the same animals, PV cell activation did not aid performance in difficult discriminations. However, in both easy and difficult discriminations, optimal behavioural performance required undisturbed late phase activity beyond 120 ms, highlighting the importance of sustained activity in V1. Combining the optogenetic activation of PV cells with two-photon imaging showed that behavioural changes were associated with changes in stimulus response selectivity in V1. Thus, our results demonstrate that early and sustained activity in V1 is crucial for perceptual discrimination and delineate specific conditions when PV cell activation shapes neuronal selectivity to improve behaviour.

Effects of moderate optogenetic PV cell activation on behaviour are time window specific

Benefits of increased PV cell-mediated inhibition depend on task difficulty

Optimal behavioural performance requires sustained V1 activity in both easy and difficult discriminations

Behavioural changes with PV cell activation are reflected by changes in the selectivity of V1 neurons
pQEB1: a hospital outbreak plasmid lineage carryingblaKPC-2
Authors: Moran Robert A. , Behruznia Mahboobeh , Holden Elisabeth , Garvey Mark I. , McNally Alan
Published: June 2024

While conducting genomic surveillance of carbapenemase-producing Enterobacteriaceae (CPEs) from patient colonisation and clinical infections at Birmingham’s Queen Elizabeth Hospital (QE), we identified an N-type plasmid lineage, pQEB1, carrying several antibiotic resistance genes including the carbapenemase geneblaKPC-2. The pQEB1 lineage is concerning due to its conferral of multi-drug resistance, its host range and apparent transmissibility, and its potential for acquiring further resistance genes. Representatives of pQEB1 were found in three sequence types (STs) ofCitrobacter freundii, two STs ofEnterobacter cloacae, and three species ofKlebsiella. Hosts of pQEB1 were isolated from 11 different patients who stayed in various wards throughout the hospital complex over a 13-month period from January 2023 to February 2024. At present, the only representatives of the pQEB1 lineage in GenBank were carried by anEnterobacter hormaecheiisolated from a blood sample at the QE in 2016 and aKlebsiella pneumoniaeisolated from a urine sample at University Hospitals Coventry and Warwickshire (UHCW) in May 2023. The UHCW patient had been treated at the QE.

Long-read whole-genome sequencing was performed on Oxford Nanopore R10.4.1 flow cells, facilitating comparison of complete plasmid sequences. We identified structural variants of pQEB1 and defined the molecular events responsible for them. These have included IS26-mediated inversions and acquisitions of multiple insertion sequences and transposons, including carriers of mercury or arsenic resistance genes. We found that a particular inversion variant of pQEB1 was strongly associated with the QE Liver speciality after appearing in November 2023, but was found in different specialities and wards in January/February 2024. That variant has so far been seen in five different bacterial hosts from six patients, consistent with recent and ongoing inter-host and inter-patient transmission of pQEB1 in this hospital setting.
Investigating Statistical Power of Differential Abundance Studies
Authors: Agronah Michael , Bolker Benjamin M.
Published: June 2024

Identifying microbial taxa that differ in abundance between groups (control/treatment, healthy/diseased, etc.) is important for both basic and applied science. As in all scientific research, microbiome studies must have good statistical power to detect taxa with substantially different abundance between treatments; low power leads to poor precision and biased estimates via the “winner’s curse”. Several studies have raised concerns about low power in microbiome studies. In this study, we investigate statistical power in differential abundance analysis. In particular, we present a novel approach for estimating the statistical power to detect effects at the level of individual taxa as a function of effect size (fold change) and mean abundance. We analysed seven real case-control microbiome datasets and developed a novel method for simulating microbiome data. We illustrate how power varies with effect size and mean abundance; our results suggest that typical differential abundance studies are underpowered for detecting changes in individual taxon.
Exposure of negative-sense viral RNA in the cytoplasm initiates innate immunity to West Nile virus
Authors: Genoyer Emmanuelle , Wilson Jonathan , Ames Joshua M. , Stokes Caleb , Moreno Dante , Etzyon Noa , Oberst Andrew , Gale Michael
Published: June 2024

For many RNA viruses, immunity is triggered when RIG-I-like receptors (RLRs) detect viral RNA. However, only a minority of infected cells undergo innate immune activation. By examining these “first responder” cells during West Nile virus infection, we found that specific accumulation of anti- genomic negative-sense viral RNA (-vRNA) underlies innate immune activation and that RIG-I preferentially interacts with -vRNA. However, flaviviruses sequester -vRNA into membrane-bound replication compartments away from cytosolic sensors. We found that single-stranded -vRNA accumulates outside of replication compartments in “first responder” cells, rendering it accessible to RLRs. Exposure of this -vRNA occurs at late timepoints of infection, is linked to viral assembly, and depends on the expression of viral structural proteins. These findings reveal that while most infected cells replicate high levels of vRNA, release of -vRNA from replication compartments during assembly occurs at low frequency and is critical for initiation of innate immunity during flavivirus infection.
Spiking networks that efficiently process dynamic sensory features explain receptor information mixing in somatosensory cortex
Authors: Koren Veronika , Emanuel Alan J. , Panzeri Stefano
Published: June 2024

How do biological neural systems efficiently encode, transform and propagate information between the sensory periphery and the sensory cortex about sensory features evolving at different time scales? Are these computations efficient in normative information processing terms? While previous work has suggested that biologically plausible models of of such neural information processing may be implemented efficiently within a single processing layer, how such computations extend across several processing layers is less clear. Here, we model propagation of multiple time-varying sensory features across a sensory pathway, by extending the theory of efficient coding with spikes to efficient encoding, transformation and transmission of sensory signals. These computations are optimally realized by a multilayer spiking network with feedforward networks of spiking neurons (receptor layer) and recurrent excitatory-inhibitory networks of generalized leaky integrate-and-fire neurons (recurrent layers). Our model efficiently realizes a broad class of feature transformations, including positive and negative interaction across features, through specific and biologically plausible structures of feedforward connectivity. We find that mixing of sensory features in the activity of single neurons is beneficial because it lowers the metabolic cost at the network level. We apply the model to the somatosensory pathway by constraining it with parameters measured empirically and include in its last node, analogous to the primary somatosensory cortex (S1), two types of inhibitory neurons: parvalbumin-positive neurons realizing lateral inhibition, and somatostatin-positive neurons realizing winner-take-all inhibition. By implementing a negative interaction across stimulus features, this model captures several intriguing empirical observations from the somatosensory system of the mouse, including a decrease of sustained responses from subcortical networks to S1, a non-linear effect of the knock-out of receptor neuron types on the activity in S1, and amplification of weak signals from sensory neurons across the pathway.
Arid1bhaploinsufficiency in cortical inhibitory interneurons causes cell-type-dependent changes in cellular and synaptic development
Authors: Marshall Alec H. , Boyle Danielle J. , Hanson Meretta A. , Nagarajan Devipriyanka , Bibi Noor , Safa Alireza , Johantges Aidan C. , Wester Jason C.
Published: June 2024

Autism spectrum disorder (ASD) presents with diverse cognitive and behavioral abnormalities beginning during early development. Although the neural circuit mechanisms remain unclear, recent work suggests pathology in cortical inhibitory interneurons (INs) plays a crucial role. However, we lack fundamental information regarding changes in the physiology of synapses to and from INs in ASD. Here, we used transgenic mice to conditionally knockout one copy of the high confidence ASD risk geneArid1bfrom the progenitors of parvalbumin-expressing fast-spiking (PV-FS) INs and somatostatin-expressing non-fast-spiking (SST-NFS) INs. In brain slices, we performed paired whole-cell recordings between INs and excitatory projection neurons (PNs) to investigate changes in synaptic physiology. In neonates, we found reduced synaptic input to INs but not PNs, with a concomitant reduction in the frequency of spontaneous network events, which are driven by INs in immature circuits. In mature mice, we found a reduction in the number of PV-FS INs in cortical layers 2/3 and 5. However, changes in PV-FS IN synaptic physiology were cortical layer and PN cell-type dependent. In layer 5, synapses from PV-FS INs to subcortical-projecting PNs were weakened. In contrast, in layer 2/3, synapses to and from PV-FS INs and corticocortical-projecting PNs were strengthened, leading to enhanced feedforward inhibition of input from layer 4. Finally, we found a novel synaptic deficit among SST-NFS INs, in which excitatory synapses from layer 2/3 PNs failed to facilitate. Our data highlight that changes in unitary synaptic dynamics among INs in ASD depend on neuronal cell-type.
Integrated multi-platform approaches to gain insights into ecosystem’s fundamental ecology and habitat specific alterations
Authors: Nagar Shekhar , Talwar Chandni , Negi Ram Krishan
Published: June 2024

The increasing availability of metagenome-assembled genomes and environmental metagenomes provides unprecedented access to the metabolic potential and functional differences within the habitats. The hot spring microbiome with its diverse habitats and relatively well-characterized microbial inhabitants offers an opportunity to investigate core and habitat specific community structures at an ecosystem scale. Here, we employed tailored genome-resolved metagenomics and a novel approach that offers metagenomic overlaps to investigate the core and habitat-specific microbial diversity and multifunctionality of microbial residents of three habitats: microbial mat, sediment and water. We recovered 6% of the Ecosystem core community (ECC) in the habitats suggesting the widespread acquisition of Proteobacteria involving in the diverging trajectories of the hot spring and 72% of the Habitat specific community (HSC) in microbial mat, sediment and water habitats offers insights into specific adaptations due to extreme conditions. Strain-level resolution of metagenome-assembled genomes defined the habitat specific genotypes (HSGs) and comparative metagenomic analysis exposed ecosystem-core genotypes (ECGs). Further, the functional attributes of ECGs revealed a complete metabolic potential of nitrate reduction, ammonia assimilation and sulfate reduction. The highest cycling entropy scores (H’) of N cycle suggested the enrichment of nitrogen fixing microbes commonly present in all three habitats. While specifically HSGs possessed the amino acid transport and metabolism functions in microbial mat (9.5%) and water (13%) and 19% of translation, ribosomal structure and biogenesis in sediment. Our findings provide insights into population structure and multifunctionality in the different habitats of hot spring and form specific hypotheses about habitat adaptation. The results illustrated the supremacy of using genome-resolved metagenomics and ecosystem core metagenomics postulating the differential ecological functions rather than that of explaining the presence of functions within ecosystem.
Protein absorption in the zebrafish gut is regulated by interactions between lysosome rich enterocytes and the microbiome
Authors: Childers Laura , Park Jieun , Wang Siyao , Liu Richard , Barry Robert , Watts Stephen A. , Rawls John F. , Bagnat Michel
Published: June 2024

Dietary protein absorption in neonatal mammals and fishes relies on the function of a specialized and conserved population of highly absorptive lysosome rich enterocytes (LREs). The gut microbiome has been shown to enhance absorption of nutrients, such as lipids, by intestinal epithelial cells. However, whether protein absorption is also affected by the gut microbiome is poorly understood. Here, we investigate connections between protein absorption and microbes in the zebrafish gut. Using live microscopy-based quantitative assays, we find that microbes slow the pace of protein uptake and degradation in LREs. While microbes do not affect the number of absorbing LRE cells, microbes lower the expression of endocytic and protein digestion machinery in LREs. Using transgene assisted cell isolation and single cell RNA-sequencing, we characterize all intestinal cells that take up dietary protein. We find that microbes affect expression of bacteria-sensing and metabolic pathways in LREs, and that some secretory cell types also take up protein and share components of protein uptake and digestion machinery with LREs. Using custom-formulated diets, we investigated the influence of diet and LRE activity on the gut microbiome. Impaired protein uptake activity in LREs, along with a protein-deficient diet, alters the microbial community and leads to increased abundance of bacterial genera that have the capacity to reduce protein uptake in LREs. Together, these results reveal that diet-dependent reciprocal interactions between LREs and the gut microbiome regulate protein absorption.
Acetaminophen Overdose Reveals Protease-Activated Receptor 4 as a Low-Expressing but Potent Receptor on the Hepatic Endothelium
Authors: Rajala Rahul , Cleuren Audrey C.A. , Griffin Courtney T.
Published: June 2024

Background & Aims

Hepatic endothelial cell (EC) dysfunction and centrilobular hepatocyte necrosis occur with acetaminophen (APAP) overdose. The protease thrombin, which is acutely generated during APAP overdose, can signal through protease-activated receptors 1 and 4 (PAR1/PAR4). PAR1 is a high-affinity thrombin receptor that is known to signal on ECs, whereas PAR4 is a low-affinity thrombin receptor, and evidence for its expression and function on ECs is mixed. This study aims to exploit the high levels of thrombin generated during APAP overdose to determine (1) if hepatic endothelial PAR4 is a functional receptor, and (2) endothelial-specific functions for PAR1 and PAR4 in a high thrombin setting.

Methods

We generated mice with conditional deletion(s) ofPar1/Par4in ECs and overdosed them with APAP. Hepatic vascular permeability, erythrocyte congestion/bleeding, and liver function were assessed following overdose. Additionally, we investigated the expression levels of endothelial PARs and how they influence transcription in APAP-overdosed liver ECs using endothelial Translating Ribosome Affinity Purification followed by next-generation sequencing (TRAPseq).

Results

We found that mice deficient in high-expressing endothelialPar1or low-expressingPar4had equivalent reductions in APAP-induced hepatic vascular instability but no effect on hepatocyte necrosis. Additionally, mice with loss of endothelialPar1andPar4had reduced permeability at an earlier time point after APAP overdose when compared to mice singly deficient in either receptor in ECs. We also found that endothelial PAR1—but not PAR4—can regulate transcription in hepatic ECs.

Conclusions

Low-expressing PAR4 can react similarly to high-expressing PAR1 in APAP-overdosed hepatic ECs, demonstrating that PAR4 is a potent thrombin receptor. Additionally, these receptors are functionally redundant but act divergently in their expression and ability to influence transcription in hepatic ECs.

NOMENCLATURE

F2randF2rl3are the gene names for PAR1 and PAR4, respectively. For simplicity, we hereafter refer to these genes asPar1andPar4.
Lysosome damage triggers acute formation of ER to lysosomes membrane tethers mediated by the bridge-like lipid transport protein VPS13C
Authors: Wang Xinbo , Xu Peng , Bentley-DeSousa Amanda , Hancock-Cerutti William , Cai Shujun , Johnson Benjamin T , Tonelli Francesca , Shao Lin , Talaia Gabriel , Alessi Dario R. , Ferguson Shawn M. , De Camilli Pietro
Published: June 2024

Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson’s disease (PD). Here we show that VPS13C, a bridge-like lipid transport protein and a PD gene, is a sensor of lysosome stress/damage. Upon lysosome membrane perturbation, VPS13C rapidly relocates from the cytosol to the surface of lysosomes where it tethers their membranes to the ER. This recruitment depends on Rab7 and requires a signal at the damaged lysosome surface that releases an inhibited state of VPS13C which hinders access of its VAB domain to lysosome-bound Rab7. While another PD protein, LRRK2, is also recruited to stressed/damaged lysosomes, its recruitment occurs at much later stages and by different mechanisms. Given the role of VPS13 proteins in bulk lipid transport, these findings suggest that lipid delivery to lysosomes by VPS13C is part of an early protective response to lysosome damage.
Reconnecting sustainability reporting with earnings management: empirical evidence from Kuwait
Authors: Masmoudi Sana , Ben Salem Mamoun
Published: June 2024

Purpose

This study aims to examine the impact of environmental, social and governance (ESG) reporting on accruals-based earnings management (AEM) activities in Kuwait.

Design/methodology/approach

Based on a random-effects regression analysis, this study examines the relationship between sustainability reporting (SR), as determined by the intensity degree method and EM, as measured by AEM, using panel data from 37 listed Kuwaiti companies on the Kuwait Stock Exchange between 2017 and 2021.

Findings

Empirical results reveal that SR affects EM in Kuwait. It appears that socially responsible Kuwaiti firms concentrate their efforts on fostering transparency and integrity in their interactions with stakeholders rather than engaging in misleading practices.

Practical implications

This study suggests a range of practical implications in Kuwait and similar economies. The findings highlight that SR can be advantageous for individuals, policymakers and corporations by promoting positive impact, addressing sustainability targets, building stakeholder confidence, reducing the risk of exposure to environmental, social and ethical liabilities and enhancing public well-being.

Originality/value

This study creates a unique ESG data set for Kuwait, unavailable in academic research. Building upon previous study that focused only on the environmental aspect (Gerged et al., 2020), this research, however, adopts a broader approach by investigating the overall impact of ESG reporting on EM in Kuwait, making it the first study to explore this relationship in this country.
Economic policy uncertainty and environmental, social and governance (ESG) disclosure: the moderating effects of board network centrality and political connections
Authors: Harjoto Maretno Agus , Wang Yan
Published: June 2024

Purpose

This study aims to examine the relationship between economic policy uncertainty (EPU) and environmental, social and governance (ESG) disclosure and the moderating role of board network centrality and political connections on the nexus between EPU and ESG.

Design/methodology/approach

Using a sample of the UK Financial Times Stock Exchange (FTSE) 350 firms during 2007 to 2018, this study examines the relationship between EPU and the ESG disclosure and the moderating effects of board centrality and board political connections using multivariate regression analysis.

Findings

The results show that firms tend to increase their ESG disclosure when EPU rises. The results also reveal that EPU is negatively associated with firms’ financial performance and ESG performance is less evident for firms with higher ESG disclosure scores and is observed only when board centrality is relatively low and the political connections are absent. The study finds further evidence to support the hypotheses during periods of heightened conflicts (i.e. global financial crisis and the Brexit referendum).

Practical implications

This study offers practical insights for corporate managers who attempt to preserve and enhance their firms’ competitive advantages via maintaining its stakeholders support through greater ESG disclosure during heightened EPU periods.

Originality/value

By integrating the resource-based view (RBV) and the signaling theory, this study extends the signaling theory and RBV by examining the relationship between EPU and ESG disclosure as a signal to its stakeholders and information advantages that board centrality and political connections bring to the company to reduce information asymmetry between the firms and its stakeholders during EPU.
Magnetostatic analysis by BEM for multiply connected problem
Authors: Ishibashi Kazuhisa , Andjelic Zoran , Lage Christian , Di Barba Paolo
Published: June 2024

Purpose

The purpose of this study is to demonstrate the novel approach in treating multiply connected problems in magnetostatic.

Design/methodology/approach

The new double layer approach (DLA) to be proposed is based on the use of the exciting double layer on the cut-surface. Applying Ampere’s circuital law to the circuital path along a toroidal core of M–C model, this paper derives unified exciting potential (UEP) from the common exciting potential. The UEP is applicable to the simply or M–C analysis. To check the effectiveness of the UEP, this paper analyze typical M–C problems and compares the results with those of other benchmark problems and also those obtained by surface charge method (SCM). Because the SCM encounters a cancellation error, this paper overcomes this problem by using the concept of direct boundary element method (BEM).

Findings

Using the improved DLA, this paper analyzed a typical multiply connected model and compared the results with those of the SCM, which has been improved to overcome cancellation errors. This paper has confirmed that the results obtained by the improved DLA are the same as those obtained by the improved SCM and Steklov–Poincaré operator formulation, tested at the well-known benchmark problems given in Andjelic et al. (2010). From these results, this paper concluded that the Improved DLA works well and that the improved SCM becomes available for analyzing both the simply and multiply connected problems.

Originality/value

Expanding a concept of the exciting double layer on the cut-surface, this paper improve the DLA to analyze the M–C problems. Applying Ampere’s circuital law to the full circuital path along the toroidal core of M–C problem, this paper derive UEP from the original exciting potential to get the governing BIE. The BIE is applicable to either simply or multiply connected analysis.