bluuebunny/crossref_metadata_2025 huggingface dataset:
Sildenafil’s Effectiveness in the Primary Coronary Slow Flow Phenomenon: A Randomized Controlled Clinical Trial
Authors: Andishmand Abbas , Seyedhossaini Seyedmostafa , Namayandeh Seyedeh Mahdieh , Mirjalili Seyed Reza , Adelzadeh Elnaz , Entezari Amin
Published: January 2024

Background

On the one hand, the coronary slow flow phenomenon (CSFP) may cause recurrence of chest pain, prompting medical examinations and further healthcare expenses, and on the other side, it can result in myocardial infarction, ventricular arrhythmia, and sudden cardiac death.

Objectives

Due to the lack of agreement on the optimal treatment for CSFP, we decided to examine the effectiveness of sildenafil in this context.

Methods

We assessed the eligibility of 196 CSFP patients to participate in a 12-week, triple-blind, randomized, placebo-controlled study for receiving either 50 mg daily oral sildenafil or placebo. We evaluated the efficacy of sildenafil based on exercise tolerance test parameters, severity of angina, adverse effects, and major adverse cardiovascular events.

Results

Twenty eligible patients were randomly allocated in a 1:1 ratio to two groups. Sildenafil demonstrated significant efficacy in improving angina severity, with all recipients achieving a Class I angina severity, contrasting with a 40% attainment in the placebo group (P=0.011). Notably, Sildenafil induced statistically significant reductions in systolic and diastolic blood pressure, unlike the placebo group. Although a reduction in the QT interval favored Sildenafil (−21 millisecond vs +3 milliseconds), statistical significance was not reached (P=0.09 vs. P=0.67). Moreover, Sildenafil markedly improved Duke Treadmill Score (DTS) (P=0.005), while the placebo group showed non-significant improvement. Concurrently, the Sildenafil group exhibited significant enhancements in functional capacity (METs) and maximum heart rate during exercise testing compared to the placebo group.

Conclusions

We suggest that a daily low dose of sildenafil could be a valuable therapeutic option for CSFP.

Graphical abstract
The Paradigm Shift: Reclassification of SARS-CoV-2 and Longitudinal Immune Responses in Japanese Healthcare Workers
Authors: Chano Tokuhiro , Kita Hiroko , Yamashita Tomoko , Fujimura Hirokazu , Ikemoto Toshiyuki
Published: January 2024

Under the aegis of the National Infectious Diseases Act, the virus transitioned from a Category 2 menace to Category 5, analogous to seasonal influenza. The current study has investigated the protracted immune responses of healthcare workers (HCWs) towards SARS-CoV-2 in Japan. One year subsequent to the systematically implemented SARS-CoV-2 vaccination campaign among HCWs, humoral and cellular immune responses were sustained at levels as high as or higher than those immediately following the 3rd booster vaccination. Persisting immunity has highlighted the resilience and lasting memory exhibited in HCW defense against the virus.
Discordant effects ofex-vivoJAK inhibition on inflammatory responses in colonic compared to ileal mucosa
Authors: Kaboub Kawsar , Abu-Taha Hanan , Arrouasse Jessica , Shaham-Barda Efrat , Wasserberg Nir , Hayman-Manzur Lucille , Friedenberg Adi , Levy-Barda Adva , Goren Idan , Yanai Henit , Levi Zohar , Banai-Eran Hagar , Avni-Biron Irit , Ollech Jacob E , Cohen-Kedar Sarit , Dotan Iris , Rabinowitz Keren M
Published: January 2024

Background & aims

Janus kinase (JAK) inhibitors modulating JAK-STAT (signal transducers and activators of transcription) signaling pathway, are used for the treatment of patients with inflammatory bowel diseases (IBD). We aimed to identify the molecular effects of JAK inhibition in the human intestinal mucosa, considering the IBD location and phenotype.

Methods

Colonic and ileal explants from patients with ulcerative colitis (UC), Crohn’s disease (CD), or non-IBD controls (NC) were treatedex-vivowith the JAK inhibitor, tofacitinib. Phosphorylated STAT (p-STAT) levels were assessed by Western blot and Immunofluorescence. Inflammatory genes expression was assessed with Nanostring nCounter system. Human intestinal organoids were used to assess JAK inhibitors’ effects on p-STATs and iNOS expression.

Results

Explants were collected from 68 patients (NC=28; UC=20; CD=20). JAK inhibition reduced p-STAT1/3/5 expression in all explants. While p-STAT inhibition rates varied among patients (10%-88%), higher inhibition rates were observed in colonic compared to ileal explants. Significant alterations in 120 of 255 inflammatory genes were observed in colonic explants, while only 30 were observed in ileal NC explants. In colonic explants from UC, significant alterations were observed in 5 genes, includingSTAT1andNOS2. Various JAK inhibitors reduced IFN-γ-induced increase in p-STAT1 and iNOS expression in organoids.

Conclusions

A site-specific anti-inflammatory effect of JAK inhibition by tofacitinib was noticed, whereby the colon was more robustly affected than the ileum.Ex-vivoresponse to tofacitinib is individual. JAK inhibition may attenuate inflammation by decreasing iNOS expression.Ex-vivomucosal platforms may be a valuable resource for studying drug impact and evaluating personalized treatment effects.
Heat Shock Proteins Function as Signaling Molecules to Mediate Neuron-Glia Communication During Aging
Authors: Wu Jieyu , Yang Olivia Jiaming , Soderblom Erik J. , Yan Dong
Published: January 2024

The nervous system is primarily composed of neurons and glia, and the communication between them plays profound roles in regulating the development and function of the brain. Neuron-glia signal transduction is known to be mediated by secreted or juxtacrine signals through ligand-receptor interactions on the cell membrane. Here, we report a novel mechanism for neuron-glia signal transduction, wherein neurons transmit proteins to glia through extracellular vesicles, activating glial signaling pathways. We find that in the amphid sensory organ ofCaenorhabditis elegans, different sensory neurons exhibit varying aging rates. This discrepancy in aging is governed by the crosstalk between neurons and glia. We demonstrate that early-aged neurons can transmit heat shock proteins (HSP) to glia via extracellular vesicles. These neuronal HSPs activate the IRE1-XBP1 pathway, further increasing their expression in glia, forming a positive feedback loop. Ultimately, the activation of the IRE1-XBP-1 pathway leads to the transcriptional regulation of chondroitin synthases to protect glia-embedded neurons from aging-associated functional decline. Therefore, our studies unveil a novel mechanism for neuron-glia communication in the nervous system and provide new insights into our understanding of brain aging.
DAMM for the detection and tracking of multiple animals within complex social and environmental settings
Authors: Kaul Gaurav , McDevitt Jonathan , Johnson Justin , Eban-Rothschild Ada
Published: January 2024

Accurate detection and tracking of animals across diverse environments are crucial for behavioral studies in various disciplines, including neuroscience. Recently, machine learning and computer vision techniques have become integral to the neuroscientist’s toolkit, enabling high-throughput behavioral studies. Despite advancements in localizing individual animals in simple environments, the task remains challenging in complex conditions due to intra-class visual variability and environmental diversity. These limitations hinder studies in ethologically- relevant conditions, such as when animals are concealed within nests or in obscured environments. Moreover, current tools are laborious and time-consuming to employ, requiring extensive, setup-specific annotation and model training/validation procedures. To address these challenges, we introduce the ’Detect Any Mouse Model’ (DAMM), a pretrained object detector for localizing mice in complex environments, capable of robust performance with zero to minimal additional training on new experimental setups. Our approach involves collecting and annotating a diverse dataset that encompasses single and multi-housed mice in various lighting conditions, experimental setups, and occlusion levels. We utilize the Mask R-CNN architecture for instance segmentation and validate DAMM’s performance with no additional training data (zero-shot inference) and with few examples for fine-tuning (few-shot inference). DAMM excels in zero- shot inference, detecting mice, and even rats, in entirely unseen scenarios and further improves with minimal additional training. By integrating DAMM with the SORT algorithm, we demonstrate robust tracking, competitively performing with keypoint-estimation-based methods. Finally, to advance and simplify behavioral studies, we made DAMM accessible to the scientific community with a user-friendly Python API, shared model weights, and a Google Colab implementation.

Significance

Present deep learning tools for animal localization require extensive laborious annotation and time-consuming training for the creation of setup-specific models, slowing scientific progress. Additionally, the effectiveness of these tools in naturalistic settings is impeded by visual variability of objects and environmental diversity, hindering animal detection in complex environments. Our study presents the ’Detect Any Mouse Model’ (DAMM), a robustly validated object detector designed for localizing mice in complex environments. DAMM excels in generalization, robustly performing with zero to minimal additional training on previously unseen setups and multi-animal scenarios. Its integration with the SORT algorithm permits robust tracking, competitively performing with keypoint-estimation-based tools. These developments, along with our dissemination of DAMM, mark a significant step forward in streamlining ethologically-relevant animal behavioral studies.
Thermodynamic analog of integrate-and-fire neuronal networks by maximum entropy modelling
Authors: Simões T. S. A. N. , Filho C. I. N. Sampaio , Herrmann H. J. , Andrade J. S. , de Arcangelis L.
Published: January 2024

Relying on maximum entropy arguments, certain aspects of time-averaged experimental neuronal data have been recently described using Ising-like models, allowing the study of neuronal networks under an analogous thermodynamical framework. Here, we apply for the first time the Maximum Entropy method to an Integrate-and-fire (IF) model that can be tuned at criticality, offering a controlled setting for a systematic study of criticality and finite-size effects in spontaneous neuronal activity, as opposed to experiments. We show that generalized Ising models that accurately predict the average local activities and correlation functions between neurons of the IF model networks in the critical state exhibit a spin glass phase for low temperatures, having mostly negative intrinsic fields and a bimodal distribution of interaction constants that tends to become unimodal for larger networks. Results appear to be affected by sample-to-sample connectivity variations and subsampling. Furthermore, we also found that networks with higher percentage of inhibitory neurons lead to Ising-like systems with reduced thermal fluctuations. Finally, considering only neuronal pairs associated with the largest correlation functions allows the study of larger system sizes.

Author summary

Brain activity, either stimulated or spontaneous,in vivoorin vitro, exhibits complex spatiotemporal behavior. Trying to make sense of it, several research groups have analyzed time-averaged experimental neuronal data using maximum entropy arguments, mapping the neuronal dynamics into a generalized Ising-like model and allowing to study neuronal data using tools typical of critical phenomena. However, the intricacy of real biological networks in experimental settings pose challenges in the precision and reliability of the neuronal measurements. Here, we apply for the first time the Maximum Entropy Method to an Integrate-and-fire model with synaptic plasticity, providing a foundation for a more systematic and comprehensive study of spontaneous brain activity. We show that generalized Ising models are able to reproduce the numerical time-averaged data of local activities and correlation functions of integrate-and-fire neurons and predict qualitatively higher-order quantities such as the three-point correlation functions across triplets of neurons. We show that subsampling affects the efficiency of the mapping and that the analogous thermodynamics functions of the Ising-like models depend on sample-to-sample network variations and on the presence of inhibition in the neural network.
CellDemux:coherent genetic demultiplexing in single-cell and single-nuclei experiments
Authors: Zoodsma Martijn , Zhan Qiuyao , Kumar Saumya , Botey-Bataller Javier , Li Wenchao , Zhou Liang , Alaswad Ahmed , Liu Zhaoli , Zhang Zhenhua , Zhang Bowen , Xu Cheng-Jian , Li Yang
Published: January 2024

Multiplexed single-cell experiment designs are superior in terms of reduced batch effects, increased cost-effectiveness, throughput and statistical power. However, current computational strategies using genetics to demultiplex single-cell (sc) libraries are limited when applied to single-nuclei (sn) sequencing data (e.g., snATAC-seq and snMultiome). Here, we presentCellDemux: a computational framework for genetic demultiplexing within and across data modalities, including single-cell, single-nuclei and paired snMultiome measurements.CellDemuxuses a consensus approach, leveraging modality-specific tools to robustly identify non-empty oil droplets and singlets, which are subsequently demultiplexed to donors. Notable,CellDemuxdemonstrates good performance in demultiplexing snMultiome data and is generalizable to single modalities, i.e. snATAC-seq and sc/snRNA-seq libraries. We benchmarkCellDemuxon 187 genetically multiplexed libraries from 800 samples (scRNA-seq, snATAC-seq, CITE-seq and snMultiome), confidently identifying and assigning cells to 88% of donors. In paired snMultiome libraries,CellDemuxachieves consistent demultiplexing across data modalities. Moreover, analysis of 38 snATAC libraries from 149 samples shows thatCellDemuxretains more genetically demultiplexed nuclei for downstream analyses compared to existing methods. In summary,CellDemuxis a modular and robust framework that deconvolves donors from genetically multiplexed single-cell and single-nuclei RNA/ATAC/Multiome libraries.
PYK2 in the dorsal striatum of Huntington’s disease R6/2 mouse model
Authors: Al-Massadi Omar , Pins Benoit de , Longueville Sophie , Giralt Albert , Irinopoulou Theano , Savariradjane Mythili , Subashi Enejda , Ginés Silvia , Caboche Jocelyne , Betuing Sandrine , Girault Jean-Antoine
Published: January 2024

Huntington’s disease (HD) is a devastating disease due to autosomal dominant mutation in theHTTgene. Its pathophysiology involves multiple molecular alterations including transcriptional defects. We previously showed that in HD patients and mouse model, the protein levels of the non-receptor tyrosine kinase PYK2 were decreased in the hippocampus and that viral expression of PYK2 improved the hippocampal phenotype. Here, we investigated the possible contribution of PYK2 in the striatum, a major brain region altered in HD. PYK2 mRNA levels were decreased in the striatum and hippocampus of R6/2 mice, a severe HD model. PYK2 protein levels were also decreased in the dorsal striatum of R6/2 mice and in the putamen of human patients. PYK2 knockout by itself did not result in motor symptoms observed in HD mouse models. Yet, we examined whether PYK2 deficiency participated in the R6/2 mice phenotype by expressing PYK2 in the dorsal striatum using AAV vectors. With an AAV1/Camk2apromoter, we did not observe significant improvement of body weight, clasping, motor activity and coordination (rotarod) alterations observed in R6/2 mice. With an AAV9/SYN1promoter we found an improvement of body weight loss and a tendency to better rotarod performance. DARPP-32 immunofluorescence was increased following AAV9/SYN1-PYK2 injection compared to AAV9/SYN1-GFP, suggesting a possible partial beneficial effect on striatal projection neurons. We conclude that PYK2 mRNA and protein levels are decreased in the striatum as in hippocampus of HD patients and mouse models. However, in contrast to hippocampus, striatal viral expression of PYK2 has only a slight effect on the R6/2 model striatal motor phenotype.

Highlights

Huntington’s disease is a lethal genetic disease altering striatum, cortex, and hippocampus

Restoring PYK2 levels in hippocampus improved hippocampal phenotype of a Huntington mouse model

We show that PYK2 levels are decreased in the striatum of R6/2 mice and human patients

Viral expression of PYK2 in the striatum has only a small effect on R6/2 mouse model motor phenotype but improves weight loss
A novel glutathione peroxidase-based biosensor disentangles differential subcellular accumulation of H2O2 and lipid hydroperoxides
Authors: Exposito-Rodriguez Marino , Reeder Brandon , Brooke Greg N. , Hough Michael A. , Laissue Philippe P. , Mullineaux Philip M.
Published: January 2024

Hydrogen peroxide (H2O2) and lipid hydroperoxides (LOOH) are initiators and transducers of inter- and intra-cellular signaling in response to diverse environmental, pathological and developmental cues. The accumulation of both H2O2and LOOH is often temporally and spatially coincident in tissues, but it is unknown if this coincidence extends to subcellular compartments. If distinct accumulation of different peroxides occurs at this smaller spatial scale, then it would be an important factor in signaling specificity. Fusion of the redox-sensitive (ro)GFP2 to theSaccharomyces cerevisiae(yeast) OXIDANT RECEPTOR PEROXIDASE1 (ORP1), also known as GLUTATHIONE PEROXIDASE3 (GPX3), created a now widely used biosensor that is assumed to detect H2O2in vivo.This is despite monomeric GPX enzymes, such as ORP1/GPX3, possessing wide peroxide substrate specificities. Consequently, we confirmedin vitrothat roGFP2-ORP1 is not only oxidized by H2O2, but also by phospholipid fatty acid peroxides generated in lecithin-derived liposomes by lipoxygenase-catalyzed peroxidation. This led us to doubt that roGFP2-ORP1in vivois specific for H2O2. To address this issue of peroxide specificity, we constructed a modified biosensor called roGFP2-synORP1. This version has greatly diminished reactivity towards phospholipid fatty acid peroxides but retains high sensitivity for H2O2. These two roGFP2-based biosensors, targeted to chloroplasts, cytosol and the nucleus, were quantitatively imaged in parallel inNicotiana benthamianaabaxial epidermal cells experiencing high light- and herbicide-induced photo-oxidative stress. From differential patterns of oxidation of these probes, we inferred that the chloroplasts accumulated both peroxide types. In contrast, LOOH and H2O2accumulated exclusively in the cytosol and nucleus respectively. Therefore, this suggests that the signalling networks initiated by different peroxides will have a distinct spatial component.
Fructose vs. Glucose: Modulating Stem Cell Growth and Function Through Sugar Supplementation
Authors: Elsaid Salaheldeen , Wu Xiangdong , Tee Sui Seng
Published: January 2024

In multicellular organisms, stem cells are impacted by microenvironmental resources such as nutrient availability and oxygen tension for their survival, growth, and differentiation1,2. However, the acessibility of these resources in the pericellular environment greatly varies from organ to organ3–5. This divergence in resource availability leads to variations in the potency and differentiation potential of stem cells4,6. Moreover, hexose and oxygen levels modulate cytokine production which is crucial for cell-cell communication7,8as well as growth, and differentiation of stem cell9,10.

Hence, this study aims to explore the distinct effects of glucose and fructose, as well as different oxygen tensions, on the growth dynamics, cytokine production, and differentiation of stem cells.
Strategy for unlimited cycles of scarless oligonucleotide directed gene editing inChlamydomonas reinhardtii
Authors: Ross Ian L. , Budiman Sabar , Le Hong Phuong , Xiong Dake , Hemker Fritz , Millen Elizabeth A. , Oey Melanie , Hankamer Ben
Published: January 2024

CRISPR/Cas9 gene editing in the model green algaChlamydomonas reinhardtiirelies on the use of selective marker genes to enrich for non-selectable target mutations. This becomes challenging when many sequential modifications are required in a single cell line, as useful markers are limited. Here we demonstrate a cyclical selection process which only requires a single marker gene to identify an almost infinite sequential series of CRISPR-based target gene modifications. TheNIA1(Nit1, NR; nitrate reductase) gene was this selectable marker. In the forward stage of the cycle, a stop codon was engineered into theNIA1gene at the CRISPR target location. Cells retaining the wild typeNIA1gene were killed by chlorate, whileNIA1knockout mutants survived. In the reverse phase of the cycle, the stop codon engineered into theNIA1gene during the forward phase was edited back to the wild type sequence. Using nitrate as the sole nitrogen source, here only the reverted wild type cells survived. By using CRISPR to specifically deactivate and reactivate theNIA1gene, a marker system was established that flipped back and forth between chlorate- and auxotrophic (nitrate) based selection. This provided a scarless cyclical marker system that enabled an indefinite series of CRISPR edits in other, non-selectable genes. Here, we demonstrate that this ‘Sequential CRISPR via Recycling Endogenous Auxotrophic Markers(SCREAM)’ technology enables an essentially limitless series of genetic modifications to be introduced to a single cell lineage ofC. reinhardtiiin a fast and efficient manner to complete complex genetic engineering.
Claudin-4 modulates autophagy via SLC1A5/LAT1 as a tolerance mechanism for genomic instability in ovarian cancer
Authors: Villagomez Fabian R. , Lang Julie , Webb Patricia , Neville Margaret , Woodruff Elizabeth R. , Bitler Benjamin G.
Published: January 2024

Genome instability is key for tumor heterogeneity and derives from defects in cell division and DNA damage repair. Tumors show tolerance for this characteristic, but its accumulation is regulated somehow to avoid catastrophic chromosomal alterations and cell death. Claudin-4 is upregulated and closely associated with genome instability and worse patient outcome in ovarian cancer. This protein is commonly described as a junctional protein participating in processes such as cell proliferation and DNA repair. However, its biological association with genomic instability is still poorly-understood. Here, we used CRISPRi and a claudin mimic peptide (CMP) to modulate the cladudin-4 expression and its function, respectively inin-vitro(high-grade serous carcinoma cells) andin-vivo(patient-derived xenograft in a humanized-mice model) systems. We found that claudin-4 promotes a protective cellular-mechanism that links cell-cell junctions to genome integrity. Disruption of this axis leads to irregular cellular connections and cell cycle that results in chromosomal alterations, a phenomenon associated with a novel functional link between claudin-4 and SLC1A5/LAT1 in regulating autophagy. Consequently, claudin-4’s disruption increased autophagy and associated with engulfment of cytoplasm-localized DNA. Furthermore, the claudin-4/SLC1A5/LAT1 biological axis correlates with decrease ovarian cancer patient survival and targeting claudin-4in-vivowith CMP resulted in increased niraparib (PARPi) efficacy, correlating with increased tumoral infiltration of T CD8+ lymphocytes. Our results show that the upregulation of claudin-4 enables a mechanism that promotes tolerance to genomic instability and immune evasion in ovarian cancer; thus, suggesting the potential of claudin-4 as a translational target for enhancing ovarian cancer treatment.
Spaceflight alters host-gut microbiota interactions
Authors: Gonzalez E. , Lee M.D. , Tierney B.T. , Lipieta N. , Flores P. , Mishra M. , Beckett N. , Karouia F. , Barker R. , Jansen R.J. , Green S.J. , Weging S. , Broddrick J. , Kelliher J. , Singh N.K. , Bezdan D. , Galazska J. , Brereton N.J.B
Published: January 2024

The rodent habitat on the International Space Station has provided crucial insights into the impact of spaceflight on mammals, including observation of symptoms characteristic of liver disease, insulin resistance, osteopenia and myopathy. Although these physiological responses can involve the microbiome when observed on Earth, changes in host-microbiota interactions during spaceflight are still being elucidated. Here, NASA GeneLab multiomic data from the Rodent Research 6 mission are used to determine changes to gut microbiota and murine host colon and liver gene expression after 29 and 56-days of spaceflight. Using hybrid amplicon and whole metagenome sequencing analysis, significant spaceflight-associated alterations to 42 microbiome species were identified. These included relative reductions of bacteria associated with bile acid and butyrate metabolism, such asExtibacter murisandDysosmobacter welbionis.Functional prediction suggested over-representation of fatty acid and bile acid metabolism, extracellular matrix interactions, and antibiotic resistance genes within the gut microbiome, while host intestinal and hepatic gene expression described corresponding changes to host bile acid and energy metabolism, and immune suppression from spaceflight. Taken together, these changes imply that interactions at the host-gut microbiome interface contribute to spaceflight pathology and highlight how these interactions might critically influence human health and the feasibility of long-duration spaceflight.
Accurate inference of population history in the presence of background selection
Authors: Cousins Trevor , Tabin Daniel , Patterson Nick , Reich David , Durvasula Arun
Published: January 2024

1

All published methods for learning about demographic history make the simplifying assumption that the genome evolves neutrally, and do not seek to account for the effects of natural selection on patterns of variation. This is a major concern, as ample work has demonstrated the pervasive effects of natural selection and in particular background selection (BGS) on patterns of genetic variation in diverse species. Simulations and theoretical work have shown that methods to infer changes in effective population size over time (Ne(t)) become increasingly inaccurate as the strength of linked selection increases. Here, we introduce an extension to the Pairwise Sequentially Markovian Coalescent (PSMC) algorithm, PSMC+, which explicitly co-models demographic history and natural selection. We benchmark our method using forward-in-time simulations with BGS and find that our approach improves the accuracy of effective population size inference. Leveraging a high resolution map of BGS in humans, we infer considerable changes in the magnitude of inferred effective population size relative to previous reports. Finally, we separately inferNe(t) on the X chromosome and on the autosomes in diverse great apes without making a correction for selection, and find that the inferred ratio fluctuates substantially through time in a way that differs across species, showing that uncorrected selection may be an important driver of signals of genetic difference on the X chromosome and autosomes.
Diencephalic and Neuropeptidergic Dysfunction in Zebrafish with Autism Risk Mutations
Authors: Capps Mary E.S. , Moyer Anna J. , Conklin Claire L. , Martina Verdion , Torija-Olson Emma G. , Klein Morgan C. , Gannaway William C. , Calhoun Caleb C.S. , Vivian Michael D. , Thyme Summer B.
Published: January 2024

Hundreds of human mutations are linked to autism and related disorders, yet the functions of many of these mutated genes during vertebrate neurodevelopment are unclear. We generated 27 zebrafish mutants with presumptive protein-truncating mutations or specific missense variants corresponding to autism-risk alleles in 17 human genes. We observed baseline and stimulus-driven behavioral changes at larval stages, as well as social behavior differences in lines tested as juveniles. Imaging whole-brain activity revealed a near identical activity map for mutations in the unrelated geneskmt5bandhdlbpa, defined by increased activity mainly in the diencephalon. Mutating 7 of the 17 risk genes resulted in substantial brain size differences. Using RNA sequencing, we further defined molecular drivers of the observed phenotypes, identifying targetable disruptions in neuropeptide signaling, neuronal maturation, and cell proliferation. This multi-modal screen nominated brain regions, cell types, and molecular pathways that may contribute to autism susceptibility.

Teaser

Zebrafish screen uncovers diencephalon, social interaction, and neuropeptidergic signaling phenotypes in ASD risk mutants.
Strategic vaccine stockpiles for regional epidemics of emerging viruses: a geospatial modeling framework
Authors: Carlson Colin J. , Garnier Romain , Tiu Andrew , Luby Stephen , Bansal Shweta
Published: January 2024

Multinational epidemics of emerging infectious diseases are increasingly common, due to anthropogenic pressure on ecosystems and the growing connectivity of human populations. Early and efficient vaccination can contain outbreaks and prevent mass mortality, but optimal vaccine stockpiling strategies are dependent on pathogen characteristics, reservoir ecology, and epidemic dynamics. Here, we model major regional outbreaks of Nipah virus and Middle East respiratory syndrome, and use these to develop a generalized framework for estimating vaccine stockpile needs based on spillover geography, spatially-heterogeneous healthcare capacity and spatially-distributed human mobility networks. Because outbreak sizes were highly skewed, we found that most outbreaks were readily contained (median stockpile estimate for MERS-CoV: 2,089 doses; Nipah: 1,882 doses), but the maximum estimated stockpile need in a highly unlikely large outbreak scenario was 2-3 orders of magnitude higher (MERS-CoV: ∼87,000 doses; Nipah ∼1.1 million doses). Sensitivity analysis revealed that stockpile needs were more dependent on basic epidemiological parameters (i.e., death and recovery rate) and healthcare availability than any uncertainty related to vaccine efficacy or deployment strategy. Our results highlight the value of descriptive epidemiology for real-world modeling applications, and suggest that stockpile allocation should consider ecological, epidemiological, and social dimensions of risk.
An Oxford Nanopore Technology-Based Hepatitis B Virus Sequencing Protocol Suitable For Genomic Surveillance Within Clinical Diagnostic Settings
Authors: Tshiabuila Derek , Choga Wonderful , James San E. , Maponga Tongai , Preiser Wolfgang , van Zyl Gert , Moir Monika , van Wyk Stephanie , Giandhari Jennifer , Pillay Sureshnee , Anyaneji Ugochukwu J. , Lessells Richard J. , Naidoo Yeshnee , Sanko Tomasz Janusz , Wilkinson Eduan , Tegally Houriiyah , Baxter Cheryl , Martin Darren P. , de Oliveira Tulio
Published: January 2024

Chronic hepatitis B virus (HBV) infection remains a significant public health concern, particularly in Africa, where there is a substantial burden. HBV is an enveloped virus, with isolates being classified into ten phylogenetically distinct genotypes (A – J) determined based on full-genome sequence data or reverse hybridization-based diagnostic tests. In practice, limitations are noted in that diagnostic sequencing, generally using Sanger sequencing, tends to focus only on the S-gene, yielding little or no information on intra-patient HBV genetic diversity with very low-frequency variants and reverse hybridization detects only known genotype-specific mutations. To resolve these limitations, we developed an Oxford Nanopore Technology (ONT)-based HBV genotyping protocol suitable for clinical virology, yielding complete HBV genome sequences and extensive data on intra-patient HBV diversity. Specifically, the protocol involves tiling-based PCR amplification of HBV sequences, library preparation using the ONT Rapid Barcoding Kit, ONT GridION sequencing, genotyping using Genome Detective software, recombination analysis using jpHMM and RDP5 software, and drug resistance profiling using Geno2pheno software. We prove the utility of our protocol by efficiently generating and characterizing high-quality near full-length HBV genomes from 148 left-over diagnostic Hepatitis B patient samples obtained in the Western Cape province of South Africa, providing valuable insights into the genetic diversity and epidemiology of HBV in this region of the world.
Differential gene expression analysis of spatial transcriptomic experiments using spatial mixed models
Authors: Ospina Oscar E. , Soupir Alex C. , Manjarres-Betancur Roberto , Gonzalez-Calderon Guillermo , Yu Xiaoqing , Fridley Brooke L.
Published: January 2024

Spatial transcriptomics (ST) assays represent a revolution in the way the architecture of tissues is studied, by allowing for the exploration of cells in their spatial context. A common element in the analysis is the delineation of tissue domains or “niches” followed by the detection of differentially expressed genes to infer the biological identity of the tissue domains or cell types. However, many studies approach differential expression analysis by using statistical approaches often applied in the analysis of non-spatial scRNA data (e.g., two-sample t-tests, Wilcoxon rank sum test), hence neglecting the spatial dependency observed in ST data. In this study, we show that applying linear mixed models with spatial correlation structures using spatial random effects effectively accounts for the spatial autocorrelation and reduces inflation of type-I error rate that is observed in non-spatial based differential expression testing. We also show that spatial linear models with an exponential correlation structure provide a better fit to the ST data as compared to non-spatial models, particularly for spatially resolved technologies that quantify expression at finer scales (i.e., single-cell resolution).
An unconventional regulatory circuitry involving Aurora B controls anaphase onset and error-free chromosome segregation in trypanosomes
Authors: Ballmer Daniel , Lou Hua Jane , Ishii Midori , Turk Benjamin E. , Akiyoshi Bungo
Published: January 2024

Accurate chromosome segregation during mitosis requires that all chromosomes establish stable bi-oriented attachments with the spindle apparatus. Kinetochores form the interface between chromosomes and spindle microtubules and as such are under tight control by complex regulatory circuitry. As part of the chromosomal passenger complex (CPC), the Aurora B kinase plays a central role within this circuitry by destabilizing improper kinetochore-microtubule attachments and relaying the attachment status to the spindle assembly checkpoint, a feedback control system that delays the onset of anaphase by inhibiting the anaphase-promoting complex/cyclosome. Intriguingly, Aurora B is conserved even in kinetoplastids, an evolutionarily divergent group of eukaryotes, whose kinetochores are composed of a unique set of structural and regulatory proteins. Kinetoplastids do not have a canonical spindle checkpoint and it remains unclear how their kinetochores are regulated to ensure the fidelity and timing of chromosome segregation. Here, we show inTrypanosoma brucei, the kinetoplastid parasite that causes African sleeping sickness, that inhibition of Aurora B using an analogue-sensitive approach arrests cells in metaphase, with a reduction in properly bi-oriented kinetochores. Aurora B phosphorylates several kinetochore proteinsin vitro, including the N-terminal region of the divergent Bub1-like protein KKT14. Depletion of KKT14 partially overrides the cell cycle arrest caused by Aurora B inhibition, while overexpression of a non-phosphorylatable KKT14 protein results in a prominent delay in the metaphase-to-anaphase transition. Finally, we demonstrate using a nanobody-based system that re-targeting the catalytic module of the CPC to the outer kinetochore is sufficient to promote mitotic exit but causes massive chromosome mis-segregation in anaphase. Our results indicate that the CPC and KKT14 are involved in an unconventional pathway controlling mitotic exit and error-free chromosome segregation in trypanosomes.
Boosting entrepreneurial competences beyond business and management–related disciplines. The case of engineering programs
Authors: Berbegal-Mirabent Jasmina , Gil-Doménech Dolors , Manresa Alba
Published: January 2024

Purpose

This study addresses the challenge of integrating entrepreneurial competences development into the traditionally structured engineering curriculum, recognizing its potential contribution to job creation. Specifically, this study proposes a course design that intersects project management and entrepreneurial disciplines, adopting a challenge-based learning approach.

Design/methodology/approach

Considering a list of common features that entrepreneurs and engineers—in the role of project managers—should excel at, and building upon the principles of experiential learning, this study proposes and describes a course design that is expected to help engineering students develop entrepreneurial competences. Through a series of assessment instruments and descriptive statistics, the study evaluates its implementation in a pilot test applied in a Project Management course at a Spanish university.

Findings

The results demonstrate a significant improvement in students' entrepreneurial competences after completing the course. Noteworthy variations in receptiveness to skill development among different personality profiles are observed. Gender differences are minimal, with the exception of women exhibiting heightened self-perception in the autonomy dimension.

Originality/value

This study explores the common features shared by two often-disconnected disciplines, namely engineering and entrepreneurship. It suggests that integrating both perspectives through a challenge-based course design can enhance entrepreneurial competences among engineering students without compromising the specific knowledge gained from engineering programs. Engaging students in such pedagogical experiences not only fosters entrepreneurial competences but also contributes to their professional and personal growth.
Configuring mobile app update strategy for growth: An empirical analysis of a landscape search model
Authors: Wang Fei , Nan Ning , Zhao Jing
Published: January 2024

Purpose

This study attempts to discover effective strategies for mobile commerce applications (apps) to grow their consumer base by releasing app strategic updates. Drawing on the landscape search model from strategy research, this study conceptualizes mobile app update strategy as three interdependent decisions, i.e. what business elements are changed in an app strategic update, how substantial the changes are and when strategic updates are released relative to the competitive environment.

Design/methodology/approach

Using a field data set of 1,500 strategic updates of seven rival apps in the mobile travel market, this study integrated fuzzy set qualitative comparative analysis (fsQCA) with econometric analysis to analyze how app strategic update decisions interdependently influence app performance.

Findings

This study identified three effective and one ineffective mobile app update strategies from the mixed-method analysis, which verified the complex interdependency of app strategic update decisions. A general takeaway from these strategies is that a complex strategy problem on the mobile platform must be solved with respect to the constraints and capabilities of mobile technology.

Originality/value

This study moves beyond a linear view of the relationship between app update frequency and app performance and provides a holistic view of how and why app strategic update decisions mutually influence one another in their impact on app performance. This work makes contributions by identifying interdependency as a conceptual bridge between strategy and mobile app literature and developing an empirically testable version of the landscape search model.
How can I serve you better? Unlocking the digital D2C barriers for regional food products
Authors: Joshi Shivam , Sengar Anita , Nautiyal Atri
Published: January 2024

Purpose

The digital direct-to-consumer (D2C) approach has seen widespread adoption across many industries, but its application to regional food products has been slower. This study aims to identify and rank the most significant challenges to the widespread use of digital D2C for regional food products.

Design/methodology/approach

A multi-criteria decision-making method called a fuzzy analytic hierarchy process (FAHP) was used to determine the order in which these obstacles were evaluated. Thirty-five barriers were identified and categorized into six categories named technological, operational, sociocultural, financial, market and institutional and regulatory barriers.

Findings

Market barriers ranked as the top barrier, and the technological barrier ranked the least significant amongst the main barrier categories for the adoption of digital D2C model for the regional food products. Lack of consumer awareness ranked number one globally, and lack of government subsidies ranked the least amongst the thirty-five identified barriers. Operational barriers came out to be second most significant barrier followed by institutional and regulatory barrier, sociocultural barrier, financial barrier and technological barrier.

Research limitations/implications

The findings of this research were derived through a numerical examination of data gathered from the Indian setting. It follows that the technological, sociocultural, financial, market, operational and institutional constraints, among others, outlined here are all unique to India. Because of the unique nature of the Indian setting, the results of this study can only be used there and not elsewhere. It is possible that future research will broaden the aims of this one and refine its methodology. Digital D2C adoption for regional food products may be prioritized and ranked using quantitative and qualitative data sources like ANP and TOPSIS. It is possible that similar studies may be conducted in nations which have a different set of operational, technological, sociocultural market and financial and regulatory barriers. Conceptual framework can be formed by integrating TAM and TPB to understand the buying behavior of regional food products via digital D2C.

Originality/value

This research is the first to identify challenges to the widespread use of the digital D2C model for regional food products. Policymakers and other interested parties can use this information to better understand the difficulties of expanding the distribution of regional food products beyond their immediate regions.
Unlocking the relationships between developmental human resource practices, psychological collectivism and knowledge hiding: the moderating role of affective organizational commitment
Authors: Yang Chengchuan , Tang Chunyong , Xu Nan , Lai Yanzhao
Published: January 2024

Purpose

This study aims to draw on social exchange theory and reciprocity norm to examine the direct effects and mechanisms through which developmental human resources (HR) practices influence employee knowledge hiding behaviors. Additionally, the authors investigate the mediating role of psychological collectivism and the moderating role of affective organizational commitment.

Design/methodology/approach

To test the research model, the authors employed a three-stage time-lagged study design and surveyed a sample of 302 employees in China. The authors utilized confirmatory factor analysis, hierarchical regression analysis and the bootstrapping method using statistical product and service solutions (SPSS) and analysis of moment structures (AMOS) to test the hypotheses.

Findings

The findings indicate the following: (1) Developmental HR practices are negatively associated with playing dumb and evasive hiding, but positively linked with rationalized hiding; (2) Psychological collectivism serves as a mediating factor in the relationship between developmental HR practices and knowledge hiding; (3) Affective organizational commitment not only moderates the relationship between developmental HR practices and psychological collectivism, but also reinforces the indirect impact of developmental HR practices on knowledge hiding.

Originality/value

This study offers a fresh perspective on previous research regarding the impact of developmental HR practices on employee behavior. Furthermore, it provides practical recommendations for organizations to enhance knowledge management by fostering stronger emotional connections between employees and the organization.
Cultural change in servitization – a conceptual review and framework
Authors: Biesinger Benjamin , Hadwich Karsten , Bruhn Manfred
Published: January 2024

Purpose

(Digital) servitization, referring to service-driven strategies and their increasing implementation in manufacturing, is one of the most rapidly growing areas in industrial service research. However, the cultural change involved in successful servitization is a phenomenon that is widely observed but poorly understood. This research aims to clarify the processes of social construction as manufacturers change their organizational culture to transform into industrial service providers.

Design/methodology/approach

This research takes a systematic approach to integrate disparate literature on servitization into a cohesive framework for cultural change, which is purposefully augmented by rationale culled from organizational learning and sensemaking literature.

Findings

The organizational learning framework for cultural change in servitization introduces a dynamic perspective on servitizing organizations by explaining social processes between organizational and member-level cultural properties. It identifies three major cultural orientations toward service, digital and learning that govern successful servitization.

Originality/value

This research contributes to the servitization literature by presenting a new approach to reframe and explore cultural change processes across multiple levels, thus providing a concrete starting point for further research in this area.
Creating Colonial Christian Cultures in Canterbury: St. Augustine's Missionary College*
Authors: Manktelow Emily J.
Published: January 2024

Throughout the nineteenth century, religion and Empire became increasingly fused in the Victorian imagination through a lens of providentialism that saw Empire as an instrument for worldwide Christianisation. This article uses the case of St. Augustine's Missionary College to explore the creation of a distinctly colonial Christian culture in Canterbury. This culture was both created and curated through networks and connections made between Canterbury and colonial dioceses, the imagined world of letters fostered by the College, and the presence in Canterbury of “foreign students” whose apparently exemplary lives brought the Empire home to the “garden of England.” Reinforcing the important point that Britain was part of a mutually‐constituted Empire, this article demonstrates how colonial cultures in Britain could be sustained through various means–cultural, social, and here institutional. It moreover uses the case of St. Augustine's to showcase the increasingly self‐conscious links between religion and Empire within Established Anglicanism as colonisation forged the city of Canterbury into the head of a colonial and global Anglican Communion.