bluuebunny/crossref_metadata_2025 huggingface dataset:
Examining and classifying reasons for missing viral loads among adults living with HIV: An extended outcome investigation and ascertainment approach in Western Kenya
Authors: Adhiambo Harriet Fridah , Lewis-Kulzer Jayne , Nyagesoa Edwin , Gimbel Sarah , Akama Eliud , Mangale Dorothy , Montonya Lina , Eshun-Wilson Ingrid , Iguna Sarah , Nyandieka Everlyne , Bukusi Elizabeth , Abuogi Lisa , Odeny Thomas , Petersen Maya L. , Geng Elvin H.
Published: November 2024

Introduction

Gaps in HIV RNA monitoring persist globally impeding the ability to determine clinical progress and outcomes. This study systematically evaluated provider (e.g., guideline non- adherence), system (e.g., laboratory error) and patient-based (e.g., refusal) drivers of missed viral load (VL) monitoring measurements among adults living with HIV in Kenya.

Methods

Adults aged 18-65 years were followed across five health facilities in Kenya as part of a clinical trial (NCT#02338739) where HIV RNA monitoring was done routinely. Instances of missed VL despite being indicated per Kenyan guidelines were identified. An algorithm for assessing root causes of missing HIV RNA was developed and generalized linear models estimated the risk ratios (RR) for patient-level characteristics associated with missed viral load.

Results

Among 1,754 patients (66% female), the prevalence of missed viral load in year one and two was 24.4% and 29.4%, respectively. Drivers for missed viral load measurements included loss to follow up (51.5% in year one and 57.8% in year two), clinician non-adherence with guidelines (36.7% in year one and 32.2% in year two), unknown (10.3% in year one and 8.6% in year two), and requested but not collected (1.5% in year one and 1.3% in year two). Patients aged < 24 years (RR 2.27, 95% CI: 1.66-3.12), those with higher socioeconomic status (RR 1.47, 95% CI: 1.03- 1.91), receiving HIV treatment at a rural clinic (RR 1.22, 95% CI: 1.02-1.46) and with advanced HIV disease (RR 2.39, 95% CI: 1.52-3.73) were more likely to miss VL monitoring.

Conclusions

Missed routine viral load monitoring remains high, primarily due to loss to follow- up, and may substantially alter suppression estimates. Sustainable approaches to keep people living with HIV engaged in care, alongside strengthening providers’ clinical practices and alignment with national guidelines, are necessary for optimizing viral monitoring and accurately assessing viral suppression within public health systems.
Integration of single cell omics with biobank data discoverstranseffects ofSREBF1abdominal obesity risk variants on adipocyte expression of more than 100 genes
Authors: Sukhatme Mihir G. , Kar Asha , Arasu Uma Thanigai , Lee Seung Hyuk T. , Alvarez Marcus , Garske Kristina M. , Gelev Kyla Z. , Rajkumar Sandhya , Das Sankha Subhra , Kaminska Dorota , Männistö Ville , Peltoniemi Hilkka , Heinonen Sini , Säiläkivi Ulla , Saarinen Tuure , Juuti Anne , Pietiläinen Kirsi H. , Pihlajamäki Jussi , Kaikkonen Minna U. , Pajukanta Päivi
Published: November 2024

Given the fast-increasing prevalence of obesity and its comorbidities, it would be critical to improve our understanding of the cell-type level differences between the two key human adipose tissue depots, subcutaneous (SAT) and visceral adipose tissue (VAT), in their depot-specific contributions to cardiometabolic health. We integrated cell-type level RNA- and ATAC-seq data from human SAT and VAT biopsies and cell-lines to comprehensively elucidate transcriptomic, epigenetic, and genetic differences between the two fat depots. We identify cell-type marker genes for tissue specificity and functional enrichment, and show through genome-wide association study (GWAS) and partitioned polygenic risk score (PRS) enrichment analyses that the marker genes upregulated in SAT adipocytes have more prominent roles in abdominal obesity than those of VAT. We also identifySREBF1, a master transcription factor (TF) of fatty acid synthesis and adipogenesis, as specifically upregulated in SAT adipocytes and present in numerous SAT functional pathways. By integrating multi-omics data from an independent human cohort, we further show that the risk allele carrier status of seven abdominal obesity GWAS variants in thecisregion ofSREBF1affects the adipocyte expression of 146 SAT adipocyte marker genes intrans. We replicate this finding independently in the UK Biobank by showing that the partitioned abdominal obesity PRSs of thetransgene sets differ by the regionalSREBF1risk allele carrier status. In summary, we discover the master TF,SREBF1, driving the SAT adipocyte expression profiles of more than a hundred of adipocyte marker genes intrans, a finding that indicates that humantransgenes can be identified by integrating single cell omics with biobank data.
Reduced Vestibular Function is Associated with Cortical Surface Shape Changes in the Frontal Cortex
Authors: Padova Dominic , Ratnanather J. Tilak , Faria Andreia V. , Agrawal Yuri
Published: November 2024

Aging-associated decline in peripheral vestibular function is linked to deficits in executive ability, self-motion perception, and motor planning and execution. While these behaviors are known to rely on the sensorimotor and frontal cortices, the precise pathways involving the frontal and sensorimotor cortices in these vestibular-associated behaviors are unknown. To fill this knowledge gap, this cross-sectional study investigates the relationship between age-related variation in vestibular function and surface shape alterations of the frontal and sensorimotor cortices, considering age, intracranial volume, and sex. Data from 117 participants aged 60+ from the Baltimore Longitudinal Study of Aging, who underwent endorgan-specific vestibular tests (cVEMP for the saccule, oVEMP for the utricle, and vHIT for the horizontal canal) and T1-weighted MRI scans on the same visit, were analyzed. We examined ten brain structures in the putative “vestibular cortex”: the middle-superior part of the prefrontal cortex (SFG_PFC), frontal pole (SFG_pole), and posterior pars of the superior frontal gyrus (SFG), the dorsal prefrontal cortex and posterior pars of middle frontal gyrus (MFG_DPFC, MFG), the pars opercularis, pars triangularis, and pars orbitalis of the inferior frontal gyrus, as well as the precentral gyrus and postcentral gyrus (PoCG) of the sensorimotor cortex. For each region of interest (ROI), shape descriptors were estimated as local compressions and expansions of the population average ROI surface using surface LDDMM. Shape descriptors were linearly regressed onto standardized vestibular variables, age, intracranial volume, and sex. Lower utricular function was linked with surface compression in the left MFG and expansion in the bilateral SFG_pole and left SFG. Reduced canal function was associated with surface compression in the right SFG_PFC and SFG_pole and left SFG. Both reduced saccular and utricular function correlated with surface compression in the posterior medial part of the left MFG. Our findings illuminate the complexity of the relationship between vestibular function and the morphology of the frontal and sensorimotor cortices in aging. Improved understanding of these relationships could help in developing interventions to enhance quality of life in aging and populations with cognitive impairment.
Predicting Treatment-seeking Status for Alcohol Use Disorder Using Polygenic Scores and Machine Learning in a Deeply-Phenotyped Sample
Authors: Jinwala Zeal , Green ReJoyce , Khan Yousef , Gelernter Joel , Kember Rachel L. , Hartwell Emily E.
Published: November 2024

Background

Few individuals with alcohol use disorder (AUD) receive treatment. Previous studies have shown drinking behavior, psychological problems, and substance dependence to predict treatment seeking. However, to date, no studies have incorporated polygenic scores (PGS), a measure of genetic risk for AUD.

Methods

Using the Yale-Penn sample, we identified 9,103 individuals diagnosed with DSM-IV AUD and indicated treatment-seeking status. We implemented a random forest (RF) model to predict treatment-seeking based on 91 clinically relevant phenotypes. We calculated AUD PGS for those with genetic data (African ancestry [AFR] n=3,192, European ancestry [EUR] n=3,553) and generated RF models for each ancestry group, first without and then with PGS. Lastly, we developed models stratified by age (< and ≥40 years old).

Results

66.6% reported treatment seeking (Mage=40.0, 62.4% male). Across models, top predictors included years of alcohol use and related psychological problems, psychiatric diagnoses, and heart disease. In the models without PGS, we found 79.8% accuracy and 0.85 AUC for EUR and 75% and 0.78 for AFR; the addition of PGS did not substantially change these metrics. PGS was the 10thmost important predictor for EUR and 23rdfor AFR. In the age-stratified analysis, PGS ranked 8thfor <40 and 48thfor ≥40 in EUR ancestry, and it ranked 14thfor <40 and 24thfor ≥40 in the AFR sample.

Conclusion

Alcohol use, psychiatric issues, and comorbid medical disorders were predictors of treatment seeking. Incorporating PGS did not substantially alter performance, but was a more important predictor in younger individuals with AUD.

Highlights

While alcohol use problems are common, few individuals seek treatment

We used machine learning in a deeply-phenotyped sample to predict treatment-seeking

We, for the first time, incorporated polygenic risk for alcohol use as a predictor

Alcohol use variables, psychiatric issues, and medical problems were key predictors
A common haplotype in the EXO5 gene can impact its protein structure and dynamics and modulate genome stability and cancer progression
Authors: Mazza Fabio , Dalfovo Davide , Bartocci Alessio , Lattanzi Gianluca , Romanel Alessandro
Published: November 2024

Understanding the impact of common germline variants on protein structure, function, and disease progression is crucial in cancer research. This study presents a comprehensive analysis of the EXO5 gene, which encodes a DNA exonuclease involved in DNA repair previously associated with cancer susceptibility. We employed an integrated approach combining genomic and clinical data analysis, deep learning variant effect prediction, and molecular dynamics simulations to investigate the effects of common EXO5 haplotypes on protein structure, dynamics, and cancer outcomes. We characterized the haplotype structure of EXO5 across diverse human populations, identifying five common haplotypes, and studied their impact on EXO5 protein. Our analyses revealed significant structural and dynamic differences among the EXO5 haplotypes, particularly in their catalytic region. The L151P EXO5 protein variant exhibited the most substantial conformational changes, potentially disruptive for EXO5’s function and nuclear localization. Analysis of TCGA data showed that patients carrying L151P EXO5 had significantly shorter progression-free survival in prostate and pancreatic cancers, and exhibited increased genomic instability. This study highlights the strength of our methodology in uncovering the effects of common genetic variants on protein function and their implications for disease outcomes.
Targeted CRISPR Screens Reveal Genes Essential forCryptosporidiumSurvival in the Host Intestine
Authors: Watson Lucy C , Sala Katarzyna A , Bernitz Netanya , Baumgärtel Lotta , Pallett Mitchell A , Marzook N Bishara , Straker Lorian Cobra , Peng Duo , Collinson Lucy , Sateriale Adam
Published: November 2024

TheCryptosporidiumparasite is one of the leading causes of diarrheal morbidity and mortality in children, and adolescent infections are associated with chronic malnutrition. There are no vaccines available for protection and only one drug approved for treatment that has limited eKicacy. A major barrier to developing new therapeutics is a lack of foundational knowledge ofCryptosporidiumbiology, including which parasite genes are essential for survival and virulence. Here, we iteratively improve the tools for genetically manipulatingCryptosporidiumand develop a targeted CRISPR-based screening method to rapidly assess how the loss of individual parasite genes influence survivalin vivo. Using this method we examine the parasite’s pyrimidine salvage pathway and a set of leadingCryptosporidiumvaccine candidates. From this latter group we determined the parasite gene known as Cp23 to be essential for survival, which was confirmed through inducible knockoutin vitroandin vivo. Parasites deficient in Cp23 were able to replicate within and emerge from infected epithelial cells, yet unable to initiate gliding motility which is essential for the reinfection of neighbouring cells. The targeted screening method presented here is highly versatile and will enable researchers to more rapidly expand the knowledge base forCryptosporidiuminfection biology, paving the way for new therapeutics.
Electrical synapse molecular diversity revealed by proximity-based proteomic discovery
Authors: Michel Jennifer Carlisle , Martin E. Anne , Crow William E. , Kissinger Jane S. , Lukowicz-Bedford Rachel M. , Horrocks Max , Branon Tess C. , Ting Alice Y. , Miller Adam C.
Published: November 2024

Neuronal circuits are composed of synapses that are either chemical, where signals are transmitted via neurotransmitter release and reception, or electrical, where signals pass directly through interneuronal gap junction channels. While the molecular complexity that controls chemical synapse structure and function is well appreciated, the proteins of electrical synapses beyond the gap-junction-forming Connexins are not well defined. Yet, electrical synapses are expected to be molecularly complex beyond the gap junctions. Connexins are integral membrane proteins requiring vesicular transport and membrane insertion/retrieval to achieve function, homeostasis, and plasticity. Additionally, electron microscopy of neuronal gap junctions reveals neighboring electron dense regions termed the electrical synapse density (ESD). To reveal the molecular complexity of the electrical synapse proteome, we used proximity-dependent biotinylation (TurboID) linked to neural Connexins in zebrafish. Proteomic analysis of developing and mature nervous systems identifies hundreds of Connexin-associated proteins, with overlapping and distinct representation during development and adulthood. The identified protein classes span cell adhesion molecules, cytoplasmic scaffolds, vesicular trafficking, and proteins usually associated with the post synaptic density (PSD) of chemical synapses. Using circuits with stereotyped electrical and chemical synapses, we define molecular sub-synaptic compartments of ESD localizing proteins, we find molecular heterogeneity amongst electrical synapse populations, and we examine the synaptic intermingling of electrical and chemical synapse proteins. Taken together, these results reveal a new complexity of electrical synapse molecular diversity and highlight a novel overlap between chemical and electrical synapse proteomes. Moreover, human homologs of the electrical synapse proteins are associated with autism, epilepsy, and other neurological disorders, providing a novel framework towards understanding neuro-atypical states.
BioLLM: A Standardized Framework for Integrating and Benchmarking Single-Cell Foundation Models
Authors: Qiu Ping , Chen Qianqian , Qin Hua , Fang Shuangsang , Zhang Yanlin , Xia Tianyi , Cao Lei , Zhang Yong , Fang Xiaodong , Li Yuxiang , Hu Luni
Published: November 2024

The application and evaluation of single cell foundational models (scFMs) present significant challenges stemming from the heterogeneity of architectural frameworks and coding standards. To address these issues, we introduce BioLLM, a framework facilitating the integration and application of scFMs in single-cell RNA sequencing data analysis. BioLLM provides a universal interface, bridging diverse scFMs into a seamless ecosystem. By mitigating architectural disparities and coding conventions, it empowers researchers with streamlined access to scFMs. With standardized APIs and comprehensive documentation, BioLLM streamlines model switching and comparative analyses, while incorporating best practices for consistent model evaluation. Our comprehensive evaluation of scFMs revealed distinct strengths and limitations, highlighting scGPT’s robust performance across all tasks, both in zero-shot and fine-tuning scenarios. Geneformer and scFoundation also demonstrated strong capabilities in gene-level tasks, benefiting from effective pretraining strategies. In contrast, scBERT underperformed relative to other models, likely attributable to its considerably smaller parameter count and the limited size of the training dataset. Ultimately, BioLLM aims to empower the scientific community to leverage the full potential of foundational models, advancing our understanding of complex biological systems through enhanced single-cell analysis.
Light-Dependent Ethanol Assimilation By Model Red MicroagaGaldieria sulphuraria
Authors: Stadnichuk Igor , Bolychevtseva Yulia
Published: November 2024

The effect of ethanol on the red thermoacidophilic microalgaGaldieria sulphuraria, capable of hemo- and photoheterotrophic growth, was studied. It was found thatG. sulphurariafailed to grow and assimilate ethanol when kept in the dark, in contrast to a wide range of organic compounds known to this alga. Light conditions, on the other hand, activated ethanol uptake from the growth medium and intensify microalgal growth. The known stress effect of ethyl alcohol can be seen in the short-term increase in cellular respiration in the dark and its sustained increase throughout the growth period ofG. sulphurariain the light. Ethanol-induced increase in cellular respiration precedes light activation of photosynthesis. The growth enhancement of ethanol-supplemented culture ofG. sulphurariacompared to photoautotrophic culture is most likely due to the complete oxidation of ethanol during respiration to carbon dioxide and its use by chloroplasts as an additional intracellular substrate for photosynthesis. The absence of ethanol consumption in the dark and its metabolic uptake in the light indicate photoactivation of alcohol dehydrogenase and acetaldehyde dehydrogenase, two key sequential enzymes in the ethanol oxidation pathway.
UniversalEPI: a generalized attention-based deep ensemble model to accurately predict enhancer-promoter interactions across diverse cell types and conditions
Authors: Grover Aayush , Zhang Lin , Muser Till , Häfliger Simeon , Wang Minjia , Yates Josephine , Van Allen Eliezer M. , Theis Fabian J. , Ibarra Ignacio L. , Krymova Ekaterina , Boeva Valentina
Published: November 2024

Interactions between enhancers and gene promoters provide insights into gene regulation. Experimental techniques, including Hi-C, that map these enhancer-promoter interactions (EPIs), have high costs and labor requirements, which limits their use. Therefore, in silico methods have been developed to predict EPIs computationally, but there are challenges with the generalizability and accuracy of existing methods. Here, we introduce UniversalEPI, an attention-based deep ensemble model designed to provide uncertainty-aware predictions of EPIs up to 2 Mb apart, which can generalize across unseen cell types using only DNA sequence and chromatin accessibility (ATAC-seq) data. Benchmarking shows that UniversalEPI significantly outperforms existing approaches in accuracy and efficiency, even though it is a lightweight model that only assesses interactions between accessible chromatin regions. UniversalEPI enables statistical comparison of predicted interactions across conditions, which we demonstrated by tracking the dynamics of EPIs during human macrophage activation. We also used UniversalEPI to assess chromatin dynamics between different cancer cell states in human esophageal adenocarcinoma. Thus, UniversalEPI advances the accuracy and applicability of in silico 3D chromatin modeling to investigate chromatin dynamics in development and disease.
Characterising alphacoronavirus phenotypic traits through diversity-driven selection of spike
Authors: Gallo Giulia , Di Nardo Antonello , Dewantari Aghnia K. , Graham Stephen C. , Bailey Dalan
Published: November 2024

The capacity for viruses to spillover from one host to another is dependent on their ability to bind to and enter cells from a new host. Using a computational approach that maximises phylogenetic diversity, we selected an optimal subset of 40 alphacoronavirus spike proteins, including the two human viruses NL63 and 229E, and characterised their host-range using broad mammalian APN and ACE2 receptor libraries. Based on this data, we were able to determine molecular genotypes that contribute to receptor tropism and identify alphacoronaviruses with broad (generalist) or restricted (specialist) receptor usage. Strikingly, we observed that generalism and specialism can vary significantly between closely related viruses. Using structural information, we identified key residues that determine the bat tropism of 229E-like viruses, as well as residues in the ACE2 receptor that likely restrict NL63 infection of certain mammals. Furthermore, we observed that the host range of certain bat alphacoronaviruses is expanded by TMPRSS2 priming of spike. All APN- and ACE2-using alphaCoVs in our study interacted with the receptor of at least one animal species within ecological proximity to humans, suggesting new routes for spillover. However, most bat alphacoronaviruses did not use any of receptors in our screen, refining our understanding of coronavirus entry. We propose a new approach to investigating receptor usage for viral orders/families/genera, which is not constrained by focused analysis of a limited number of sequences from human-tropic viruses. Understanding phenotypic traits, such as entry, at this genus-wide level can revolutionise our ability to predict zoonotic potential.
Redox-Activated Proton Transfer through a Redundant Network in the QoSite of Cytochromebc1
Authors: Arantes Guilherme M.
Published: November 2024

Proton translocation catalyzed by cytochromebc1(respiratory complex III) during coenzyme-Q redox cycling is a critical bioenergetic process, yet its detailed molecular mechanism remains in-completely understood. Even the specific groups mediating proton transfer following coenzyme-Q oxidation have not been established. In this study, the energetics of proton transfer through multiple proton-conducting wires recently identified in the Qosite was investigated across various reactant redox states using hybrid QM/MM simulations and a specialized reaction coordinate. Key reactive groups and proton transfer mechanisms were characterized, confirming the propionate-A group of hemebLas a plausible proton acceptor. Upon quinol oxidation, a Grotthuss hopping mechanism is activated, facilitating proton transfer along three distinct pathways with comparable energetics. These pathways function redundantly, forming a robust proton-conducting network. A highly conserved tyrosine residue (Y147 inR. sphaeroidesnumbering) was found to be essential for complete proton transfer, whereas participation of H276 and D278 does not appear energetically feasible. Bioenergetic analyses exclude charged closed-shell species as likely intermediates and propose a reaction sequence for quinol oxidation proceeding as QH2→ QH•→ Q0, either via coupled proton-electron transfers or stepwise mechanisms involving open-shell intermediates. These findings elucidate mechanistic details of the Q-cycle and improve our understanding of the catalytic reactions supporting coenzyme-Q redox cycling in respiratory complexes.
GraFusionNet: Integrating Node, Edge, and Semantic Features for Enhanced Graph Representations
Authors: Tahmid Md Toki , Zaman Tanjeem Azwad , Rahman Mohammad Saifur
Published: November 2024

Understanding complex graph-structured data is a cornerstone of modern research in fields like cheminformatics and bioinformatics, where molecules and biological systems are naturally represented as graphs. However, traditional graph neural networks (GNNs) often fall short by focusing mainly on node features while overlooking the rich information encoded in edges. To bridge this gap, we presentGraFusionNet, a framework designed to integrate node, edge, and molecular-level semantic features for enhanced graph classification. By employing a dual-graph autoencoder, GraFusionNet transforms edges into nodes via a line graph conversion, enabling it to capture intricate relationships within the graph structure.

Additionally, the incorporation of Chem-BERT embeddings introduces semantic molecular insights, creating a comprehensive feature representation that combines structural and contextual information. Our experiments on benchmark datasets, such as Tox21 and HIV, highlight GraFusionNet’s superior performance in tasks like toxicity prediction, significantly surpassing traditional models. By providing a holistic approach to graph data analysis, GraFusion-Net sets a new standard in leveraging multi-dimensional features for complex predictive tasks.

CCS CONCEPTS

Computing methodologies → Neural networks.

ACM Reference Format

Md Toki Tahmid, Tanjeem Azwad Zaman, and Mohammad Saifur Rahman. 2018. GraFusionNet: Integrating Node, Edge, and Semantic Features for Enhanced Graph Representations. InProceedings of Make sure to enter the correct conference title from your rights confirmation email (Conference acronym ‘XX). ACM, New York, NY, USA, 9 pages.https://doi.org/XXXXXXX.XXXXXXX
Concomitant suppression of COX-1 and COX-2 is insufficient to induce enteropathy associated with chronic NSAID use
Authors: Barekat Kayla , Ricciotti Emanuela , Ghosh Soumita , Herrmann Christin , Keat Karl , Assenmacher Charles-Antoine , Tanes Ceylan , Wilson Naomi , Sengupta Arjun , Das Ujjalkumar Subhash , Joshi Robin , Ritchie Marylyn D. , Bittinger Kyle , Weljie Aalim , Cadwell Ken , Bushman Frederic D. , Wu Gary D. , FitzGerald Garret A.
Published: November 2024

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used medications for the management of chronic pain; however, they are associated with numerous gastrointestinal (GI) adverse events. Although many mechanisms have been suggested, NSAID-induced enteropathy has been thought to be primarily due to inhibition of both cyclooxygenases (COX) -1 and -2, which results in suppression of prostaglandin synthesis. Yet surprisingly, we found that concomitant postnatal deletion ofCox-1and-2over 10 months failed to cause intestinal injury in mice unless they were treated with naproxen or its structural analog, phenylpropionic acid, which is not a COX inhibitor.Coxdouble knockout mice exhibit a distinct gut microbiome composition and cohousing them with controls rescues their dysbiosis and delays the onset of NSAID-induced GI bleeding. In both the UK Biobank and All of Us human cohorts, coadministration of antibiotics with NSAIDs is associated with an increased frequency of GI bleeding. These results show that prostaglandin suppression plays a trivial role in NSAID-induced enteropathy. However,Coxdeletion causes dysbiosis of the gut microbiome that amplifies the enteropathic response to NSAIDs.
Cryo-EM Structure of AAA + ATPase Thorase Reveals Novel Helical Filament Formation
Authors: Dar Mohamad Aasif , Louder Robert , Cortes Marisol , Chen Rong , Ma Qianqian , Chakrabarti Mayukh , Umanah George K.E. , Dawson Ted M. , Dawson Valina L.
Published: November 2024

The AAA+ (ATPasesassociated with a variety of cellularactivities) ATPase, Thorase, also known as ATAD1, plays multiple roles in synaptic plasticity, mitochondrial quality control and mTOR signaling through disassembling protein complexes like AMPAR and mTORC1 in an ATP-dependent manner. The Oligomerization of Thorase is crucial for its disassembly and remodeling functions. We show that wild-type Thorase forms long helical filamentsin vitro, dependent on ATP binding but not hydrolysis. We report the Cryogenic Electron Microscopy (cryo-EM) structure of the Thorase filament at a resolution of 4 Å, revealing the dimeric arrangement of the basic repeating unit that is formed through a distinct interface compared to the hexameric MSP1/ATAD1E193Q assembly. Structure-guided mutagenesis confirms the role of critical amino acid residues required for filament formation, oligomerization and disassembly of mTORC1 protein complex. Together, our data reveals a novel filament structure of Thorase and provides critical information that elucidates the mechanism underlying Thorase filament formation and Thorase-mediated disassembly of the mTORC1 complex.
Ion channel function of polycystin-2/polycystin-1 heteromer revealed by structure-guided mutagenesis
Authors: Staudner Tobias , Khamseekaew Juthamas , Madej M. Gregor , Geiges Linda , Azemi Bardha , Ziegler Christine , Korbmacher Christoph , Ilyaskin Alexandr V.
Published: November 2024

Autosomal-dominant polycystic kidney disease (ADPKD) is caused by mutations affecting polycystin-1 (PC1) or polycystin-2 (PC2). Recent structural data suggest that PC1 and PC2 can form heterotetrameric ion channels with a 3:1 stoichiometry, with the channel in a closed state. In this hetero-oligomeric formation three PC1 residues (R4100, R4107, and H4111) would work together with two PC2 residues (L677, N681) to block the ion permeation pathway. Here, we provide functional evidence supporting this model. When the pore-blocking residues are replaced by alanines, there is a significant gain-of-function (GOF) effect on PC2/PC1 currents. These PC2/PC1 GOF channels show different selectivity for monovalent cations and reduced Ca2+permeability compared to PC2 homomers. By varying the expression ratio of PC1 and PC2, we found that PC2 preferentially forms heteromeric complexes with PC1 over homomers. Additionally, a re-interpretation of published PC2/PC1 cryo-electron microscopy data, combined with cysteine modification experiments, suggests that the pore-forming domain of PC1 adopts a canonical TRP-like conformation. The novel PC2/PC1 GOF construct offers a promising approach to investigate the functional impact of mutations linked to ADPKD.
Telomere interactions and structural variants in ALT cells revealed with TelSPRITE
Authors: Wilson David G. , Clatterbuck Soper Sarah F. , Pineda Marbin A. , Walker Robert L. , Meltzer Paul S.
Published: November 2024

Acquisition of a telomere maintenance mechanism is essential for cancer cells. In a minority of tumors, telomeres are lengthened via Alternative Maintenance of Telomeres (ALT), a telomerase-independent pathway based on homologous recombination. ALT tumors have heavily rearranged genomes with many structural variants containing telomere repeats. To better understand the genetic evolution of these tumors, we seek to determine if certain genomic loci tend to spatially associate with telomeres in ALT and are especially liable to experience telomere recombination events as a result. Assays that reveal close spatial associations between genomic loci, such as SPRITE and Hi-C, have enabled extensive exploration of genomic spatial organization. However, as analysis pipelines for these next-generation sequencing-based assays typically discard reads aligning to repetitive elements, little is known about the spatial arrangement of telomeres and other repetitive loci in the nucleus. Here, we present TelSPRITE, a novel approach to extracting telomere contact frequencies from SPRITE data. We identify reads containing telomere repeats and sort them into a single bin, quantifying spatial contacts between the telomere bin and the rest of the genome. Our analysis reveals a strong dependency of telomere contact frequency on chromosomal distance from the telomere, consistent with the known effect of linear distance on 3-dimensional spatial contacts. Telomere contacts are also strongly enriched near centromeres, a phenomenon that may be reflective of spatial clustering of heterochromatic regions. ALT cell lines are globally enriched for telomere content and display distinctive intrachromosomal spikes in telomere contact frequency. Our customized analysis of long read sequencing data suggests that loci with high telomere contact frequencies represent structural variants containing telomere repeats in ALT cells. Collectively, our results demonstrate general principles of telomeric spatial organization while also profiling the spectrum of genomic rearrangements in ALT cells.
Comprehensive Proteomic, Ultrastructural and Functional Analysis of Cryopreservation Effects on Marine Mussel Oocytes
Authors: Blanco Sofía , Campos Sara , Reboreda Patricia , Paredes Estefanía , Diz Angel P.
Published: November 2024

Cryopreservation is a valuable tool for preserving marine genetic diversity and supporting selective breeding in aquaculture. The blue mussel (Mytilus galloprovincialis) is an important species for the aquaculture industry and a useful model for studying cryopreservation in marine invertebrates. Declining mussel seed availability over the past decade, combined with the growing demand for year-round hatchery production, has increased interest in developing effective cryopreservation methods for gametes and embryos. However, cryopreservation remains challenging, particularly for marine invertebrate oocytes, as it requires balancing cryoprotectant cytotoxicity with sufficient cell protection during freezing and thawing. Moreover, the molecular, structural, and functional changes associated with oocyte cryopreservation in invertebrates are still poorly understood. This study examines the effects of two commonly used cryoprotectants, dimethyl sulfoxide (DMSO) and ethylene glycol (EG), onM. galloprovincialisoocytes under a monitored slow freezing (MSF) protocol. Using an integrative analytical approach combining proteomics, functional assessments, and ultrastructural analyses, we provide a comprehensive understanding of cryoprotectant-induced changes. Our findings reveal that cryoprotectants cause significant proteomic alterations, with DMSO having more pronounced effects. These alterations are associated with increased oxidative stress, an insufficient antioxidant response, and disruptions in meiosis restart mechanisms, ultimately delaying larval development. Cryoprotectant-induced oxidative stress may also weaken the oocyte membrane, leading to rupture during the MSF protocol and subsequent fertilisation failure post-thawing. These results provide evidence that EG is less cytotoxic than DMSO and suggest that supplementing cryoprotectants with antioxidants and membrane stabilizers could enhance success rates in the cryopreservation of oocytes from mussels and other marine invertebrate species.
Solid-electrolyte-inspired totally asymmetric simple exclusion process with parallel channels and random defects
Authors: Kihara Kai , Nishinari Katsuhiro , Ando Yasunobu , Ezaki Takahiro
Published: November 2024

We propose a simplified probabilistic model to investigate the fundamental physics of particle transport in parallel channels having bypasses and defects, mimicking the distinctive pathways found in a class of solid-electrolyte materials. Our results reveal that increases in the bypass interval and the number of defects induce significant macroscopic density fluctuations, substantially reducing overall flow rates. Notably, we find that the particle flow rate decreases exponentially with the product of bypass interval and defect probability. The decay exponent was dependent on the particle density, which reflects the nonlinear effects of particle congestion. Our findings may suggest that the presence of more bypass sites and fewer defects in the pathways has a significant impact on the performance of electrolyte materials.

Published by the American Physical Society
2024
PyFaults: a Python tool for stacking fault screening
Authors: Combs Sinclair R. , Maughan Annalise E.
Published: November 2024

PyFaults is an open-source Python library designed to model stacking fault disorder in crystalline materials and qualitatively assess the characteristic selective broadening effects in powder X-ray diffraction (PXRD). Here, the main capabilities of PyFaults are presented, including unit cell and supercell model construction, PXRD pattern calculation, assessment against experimental PXRD, and methods for rapid screening of candidate models within a set of possible stacking vectors and fault occurrence probabilities. This program aims to serve as a computationally inexpensive tool for identifying and screening potential stacking fault models in materials with planar disorder. Three diverse case studies, involving GaN, Li2MnO3 and Li3YCl6, are presented to illustrate the program functionality across a range of structure types and stacking fault modalities.
Flight test evaluation of trim tab stabilisation system on a PZL-130 orlik aircraft
Authors: Zajdel Albert , Szczepański Cezary , Filipowicz Maciej , Krawczyk Mariusz , Welcer Michal
Published: November 2024

Purpose

The paper presents the results of the final phase of the project, namely flight tests, aimed at developing a stabilisation system utilizing trim tabs for the PZL-130 Orlik turboprop military trainer aircraft.

Design/methodology/approach

The proposed flight stabilisation system was developed using modern techniques of model-based design, automatic code generation and software and hardware-in-the-loop testing. The project progressed to the flight testing stage, enabling the assessment of the control system’s quality and its final calibration.

Findings

Analysis of the results obtained during flight tests confirmed the high quality of the stabilisation system. Specifically, the anticipated accuracy of both longitudinal and lateral channel stabilisation was achieved.

Originality/value

The proposed flight stabilisation system, utilizing trim tabs, offers several advantages over classic automatic flight systems in terms of weight, energy consumption, structural simplicity and obviates the need for primary control modifications on the aircraft. It was developed using modern techniques of model-based design, automatic code generation and hardware-in-the-loop simulations.
Investigating the confidence business leaders have in business rescue
Authors: Rosslyn-Smith Wesley John
Published: November 2024

Purpose

The study measures business leaders’ perceptions of the likelihood of recovery, the competency of business rescue practitioners and the level of support they are expected to provide to businesses in rescue. By examining these three facets of confidence, using expectancy theory, the study seeks to reveal the perceptions of directors as decision-makers in commencing proceedings by inferring their level of confidence in the business rescue process to the likelihood of directors initiating business rescue proceedings timeously.

Design/methodology/approach

An online survey targeted South African business leaders, especially directors, was developed to recognise the confidence in the business rescue process. The study combined quantitative (Likert scale) and qualitative (open-ended questions) methods. Data were analysed using the expectancy theory, linking behaviour to anticipated outcomes, to derive confidence in the rescue process. Limitations such as the sensitive nature of insolvency and its inherence negative inclinations should be noted.

Findings

The study revealed some complex sentiments surrounding the business rescue proceedings. The responses are indicative of both confidence in and scepticism of the process, offering a nuanced look at South Africa’s insolvency proceedings from outside the confines of the industry itself.

Research limitations/implications

The limitations of the study are notably reflected in its reliance on qualitative insights, which may inherently skew towards negative perceptions due to the nature of the subject – business rescue proceedings. Moreover, despite the anonymity of the survey, there remains a possibility that respondents, who are directors with fiduciary duties, may not have been completely forthcoming. This reticence could stem from an unconscious bias to present themselves and the decisions they make in a more favourable light, thus potentially downplaying or overlooking their own hesitations or misgivings about the business rescue process. This may lead to an underrepresentation of both the depth of scepticism and the complexity of the challenges faced in initiating business rescue proceedings.

Originality/value

The originality of this paper lies in investigating the confidence business leaders have in the business rescue process in the context of South Africa derived from a survey instrument.
Technological distinct capabilities and innovative work behavior of Omani technopreneurs: influences of strategic flexibility and self-efficacy
Authors: Ba Awain Ali Mohsin Salim , Jaboob Ali Said , Ferasso Marcos , Alsheyadi Anwar , Acevedo-Duque Ángel
Published: November 2024

Purpose

This study aims to investigate the relationship between technology-distinct capabilities (TDC) and innovative work behavior (IWB) through the mediating effect of strategic flexibility (SF), to examine the behavior toward technopreneurship (BTT) among Omani small and medium-sized enterprises (SMEs). Furthermore, technopreneur self-efficacy (TSE) is investigated as a moderating variable between TDC and SF.

Design/methodology/approach

Based on the quantitative research design, the survey questionnaire instrument was used to collect data from SMEs’ owners and managers. Using purposive sampling, the study comprised 285 responses from Muscat, Sohar and Al-Buraimi regions. Responses were analyzed through SPSS 25 and Smart PLS 4 using structural equation modeling (SEM).

Findings

The main findings revealed a positive and significant influence of TDC and IWB on SF. In addition, SF mediates the relationship between TDC, IWB and TBB. Results showed no effect of TSE on TDC and SF. The study outlines significant theoretical and practical implications. Dynamic capability (DC) theory provided a framework for understanding the highly competitive Omani business climate. The diffusion of innovation (DOI) provides the way forward to SMEs that how they embrace and induce novel concepts, including SF.

Originality/value

The findings of the study can be used by academics and policymakers to develop policies that support SMEs’ technological innovation and adaptability. In the Omani context, policymakers and public managers can utilize this research to evaluate the different technopreneurship support programs and encourage SMEs to adopt digital technology to capitalize on the nation’s entrepreneurial dynamic.
Career choices: exploring military migrants’ justifications for their enlistment in the British Armed Forces
Authors: Adeoti Adejumoke , Mordi Chima , Adisa Toyin Ajibade
Published: November 2024

Purpose

Using “on justification” theory, this article explores the rationality and justification of the West-African military migrants for joining the British Armed Forces.

Design/methodology/approach

We utilise an interpretive qualitative research methodology in this study. We undertook semi-structured interviews with 42 military migrants who joined the British Armed Forces between 1998 and 2013.

Findings

We identify various factors that influenced the participants’ decision to join the British Armed Forces, such as individual aspirations, the need to find a “path” at a crossroad in life (e.g. a career dilemma or the loss of a parent), economic opportunities and institutional incentives. Military migrants’ career motivations are shaped by their deep affection for the Crown and their desire to give back to the country with which they share a colonial history.

Practical implications

The UK’s Ministry of Defence, government and policymakers could gain valuable insights from this study. The findings could significantly shape their recruitment and retention policies, thereby enhancing the attractiveness of the military profession. This could be a crucial step in addressing the recruitment challenges and personnel deficit currently faced by the British Armed Forces.

Originality/value

This study provides a fresh perspective on the dynamics of the military service of foreign-born veterans. The article focuses on an underrepresented group (West-African military migrants) to enhance our understanding of their career motivations in the British Armed Forces. We identify and categorise the motivations and justifications for military migrants’ enlistment in the British Armed Forces according to seven justifications, each depicting a career pattern informing the participants’ motivations and justifications for their enlistment.
Moving diversity, equity and inclusion research forward with(in) international business: addressing blind spots through critical and reflexive management scholarship
Authors: Rašković Matevž Matt , Hurd Fiona , Onaji-Benson Theresa
Published: November 2024

Purpose

The purpose of this paper is to provide a scene-setting viewpoint that critically examines various diversity, equity and inclusion (DEI) blind spots within the field of international business (IB). These include issues such as social justice, intersectionality, de-colonization, the co-creation of inclusive research practices in indigenous spaces, social dialogue and the gap between DEI rhetoric and reality. An additional aim of the viewpoint is also to contextualise the discussion of DEI blind spots in terms of the six papers which make up the first part of a two-part special issue on DEI in IB".

Design/methodology/approach

The authors build on existing DEI overview works and comment on specific DEI blind spots. The authors also discuss the role of positionality as critical reflexive scholarship practice, which they see as an essential step in problematizing structural inequalities. The authors then discuss six specific areas where DEI blindspots persist within the IB literature and link their discussion to the six papers included in the first part of their DEI special issue.

Findings

Addressing the contradictions between the business and social justice cases for DEI requires addressing the ontological contradictions between the two perspectives through problematizing structural inequalities. A key contribution of the paper is also the discussion around positionality in DEI research and the relevance of positionality statements as part of critical reflexive scholarship in support of a socially just DEI research agenda.

Originality/value

The authors discuss the role DEI research plays and can play within the evolution of the IB discipline. The authors apply a critical management studies perspective to pervasive DEI issues, as well as engage with the topics in the special issue through a unique critical reflexive epistemology which includes their own positionality statements as guest editors and researchers. Their critical discussion and recommendations for future research serve as a kind of whetstone to sharpen IB’s DEI research tools and in turn for IB to help sharpen DEI research’s tools, supporting it to become more socially just.