bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating understanding, experience and barriers to care for people living with chronic hepatitis B virus infection in Kilifi, Kenya
Authors: Downs Louise O , Odhiambo Juliet , Zaharani Mwanakombo , Chirro Oscar , Safari Benson , Aliyan Nadia , Matthews Philippa C , Kagwanja Nancy 
Published: November 2024

AbstractChronic hepatitis B infection (CHB) is a global health disaster with over 1 million people dying annually from this infection worldwide. A large burden of morbidity and mortality is in the WHO-African Region (WHO-AFRO) however here <5% of people are diagnosed and 0.2% on treatment. Community understanding of HBV is often poor and people living with HBV (PLWHB) can experience stigma and discrimination. However there has been little documentation on the impact of an HBV diagnosis on the lives of PLWHB. We explore the experience of PLWHB in Kilifi, Kenya, including their understanding of the disease, how their diagnosis has changed their lives and what barriers they have experienced when accessing care. We show overall understanding of HBV in this group is good, with most participants knowing transmission routes and available treatment. In the general community however, HBV understanding is poor - there is no local name for the infection other than the symptoms it causes such as swollen tummy and yellow eyes. Many participants felt shocked at their initial diagnosis and had mixed reactions from friends and family. Costs of transport and concerns about lost employment were seen as the biggest barrier to care with many people advocating for decentralised clinics. Stigma was also raised with people feeling isolated, rejected and discriminated against. There was also discomfort around the current integration of HBV and HIV services at KCRH, with concerns over increased stigma, longer waiting times and preferential treatment being given to those living with HIV.Community education, provision of wider testing and advocacy by well-respected community members were mentioned as key methods to reduce HBV transmission. Decentralisation of clinics may improve access to care; however the patient voice must be considered when planning future interventions to ensure these are acceptable and accessible to the community.
The lived experience of social anxiety disorder: A conceptual model based on published literature and social media listening
Authors: Schmidt Ana Lucía , Staunton Hannah , Stein Murray B. , Hayes Anne Marie , Rodriguez-Esteban Raul , Fischer Kathrin , McIver Tammy , Suter Eugénie E. 
Published: November 2024

AbstractSocial anxiety disorder (SAD) affects up to 1 in 8 individuals over their lifetime and is characterized by an intense fear of social situations where there may be exposure to unfamiliar people or possible scrutiny. The analysis of social media data rather than traditional methods (interviews or focus groups) can provide a unique opportunity to understand the lived experience of individuals with SAD, for whom interacting with strangers is challenging. This retrospective observational study reviewed published literature from PubMed and data from Reddit using social media listening (SML). A stepwise analysis in line with US Food and Drug Administration Patient-Focused Drug Development guidelines was performed to develop a conceptual model for SAD. Natural language processing techniques and machine learning approaches were employed to extract symptoms and impacts described by individuals with SAD. Eleven publications from the literature and 535,544 posts from 118,040 Reddit users were included. Clinical and patient experts then refined the conceptual model covering three key symptom domains (physical, negative automatic thoughts, and emotions) and two impact domains (social functioning and occupational/educational functioning). This study provides insights into the lived experience of individuals with SAD and confirms the value of SML when traditional methods are inappropriate.
A Machine Learning Model of Perturb-Seq Data for Use in Space Flight Gene Expression Profile Analysis
Authors: Johnson Liam , Casaletto James , Costes Sylvain , Proctor Caitlin , Sanders Lauren 
Published: November 2024

ABSTRACTThe genetic perturbations caused by spaceflight on biological systems tend to have a system-wide effect which is often difficult to deconvolute into individual signals with specific points of origin. Single cell multi-omic data can provide a profile of the perturbational effects but does not necessarily indicate the initial point of interference within a network. The objective of this project is to take advantage of large scale and genome-wide perturbational or Perturb-Seq datasets by using them to pre-train a generalist machine learning model that is capable of predicting the effects of unseen perturbations in new data. Perturb-Seq datasets are large libraries of single cell RNA sequencing data collected from CRISPR knock out screens in cell culture. The advent of generative machine learning algorithms, particularly transformers, make it an ideal time to re-assess large scale data libraries in order to grasp cell and even organism-wide genomic expression motifs. By tailoring an algorithm to learn the downstream effects of the genetic perturbations, we present a pre-trained generalist model capable of predicting the effects of multiple perturbations in combination, locating points of origin for perturbation in new datasets, predicting the effects of known perturbations in new datasets, and annotation of large-scale network motifs. We demonstrate the utility of this model by identifying key perturbational signatures in RNA sequencing data from spaceflown biological samples from the NASA Open Science Data Repository.
Structural basis for the synergistic assembly of the snRNA export complex
Authors: Dubiez Etienne , Garland William , Brask Maja Finderup , Erba Elisabetta Boeri , Jensen Torben Heick , Kadlec Jan , Cusack Stephen 
Published: November 2024

AbstractThe nuclear cap-binding complex (CBC) and its partner ARS2 play crucial roles in regulating Pol II transcript fate through mutually exclusive interactions with RNA effectors. One such effector, PHAX, mediates the nuclear export of U-rich small nuclear RNAs (snRNAs). Here we present the cryo-EM structure of the snRNA export complex comprising phosphorylated PHAX, CBC, CRM1, Ran-GTP and capped RNA. The central region of PHAX bridges the CBC-bound capped RNA to the CRM1-RanGTP, while also significantly reinforcing cap dinucleotide binding. Additionally, PHAX interacts with a distant region of CRM1 facilitating contacts of an essential phosphorylated region with the prominent basic surface of RanGTP. The importance of these interactions is confirmed byin vitroand in cell mutagenesis experiments. CBC engagement within the snRNA export complex is incompatible with its interactions with other RNA effectors such as ALYREF or NCBP3. Taken together, we demonstrate that snRNA export complex formation requires synergistic binding of all its components, which in turn displaces ARS2 from the CBC, and commits the complex for export.
A genome-scale single cell CRISPRi map oftransgene regulation across human pluripotent stem cell lines
Authors: Feng Claudia , Peets Elin Madli , Zhou Yan , Crepaldi Luca , Usluer Sunay , Dunham Alistair , Braunger Jana M , Su Jing , Strauss Magdalena E , Muraro Daniele , Xian Cheam Kimberly Ai , Bonder Marc Jan , Nogales Edgar Garriga , Cooper Sarah , Bassett Andrew , Leonard Steven , Gu Yong , Fussing Bo , Burke David , Parts Leopold , Stegle Oliver , Velten Britta 
Published: November 2024

AbstractPopulation-scale resources of genetic, molecular, and cellular information form the basis for understanding human genomes, charting the heritable basis of disease, and tracing the effects of mutations. Pooled perturbation assays applied to cellular models, probing the effect of many perturbations coupled with an scRNA-seq readout (Perturb-seq), are especially potent references for interpreting disease-linked mutations or gene expression changes. However, the utility of existing maps has been limited by the comprehensiveness of perturbations possible, and the relevance of their cell line context. Here, we present the first genome-scale CRISPR interference (CRISPRi) perturbation map with single-cell RNA sequencing readout across many human genetic backgrounds in human pluripotent cells. To do so, we establish large-scale CRISPRi screening in human induced pluripotent stem cells from healthy donors, using over 20,000 guide RNAs to target 7,226 genes across 34 cell lines from 26 genetic backgrounds, and gather expression data from nearly 2 million cells. We comprehensively maptransexpression changes induced by the target knockdowns, which complement co-expression patterns in unperturbed cells and facilitate the functional annotation of target genes to biological processes and complexes. Consistency of targeting protein complex members point to protein complexes as a nexus for aggregating transcriptional variation, revealing novel interaction partners. We characterise variation in perturbation effects across donors, with expression quantitative trait loci linked to higher genetic modulation of perturbation effects but overall low replication of trans effects due to knockdown of their corresponding cis regulators. This study pioneers population-scale CRISPR perturbations with single cell readouts that will fuel foundation models for the future of effective modulation of cellular disease phenotypes.
Multi-omics analysis reveals key immunogenic signatures induced by oncolytic Zika virus infection of paediatric brain tumour cells
Authors: Sherwood Matt , Mitsugi Thiago G. , Kaid Carolini , Coke Brandon , Zatz Mayana , Maringer Kevin , Okamoto Oswaldo K. , Ewing Rob M. 
Published: November 2024

AbstractBrain tumours disproportionately affect children and are the largest cause of paediatric cancer-related death. Despite decades of research, paediatric standard-of-care therapy still predominantly relies on surgery, radiotherapy, and systemic use of cytotoxic chemotherapeutic agents, all of which can result in debilitating acute and late effects. Novel therapies that engage the immune system, such as oncolytic viruses (OVs), hold great promise and are desperately needed. Zika virus (ZIKV) infects and destroys aggressive cells from paediatric medulloblastoma, atypical teratoid rhabdoid tumour (ATRT), diffuse midline glioma (DMG), ependymoma and neuroblastoma. Despite this, the molecular mechanisms underpinning this therapeutic response are grossly unknown. By profiling the transcriptome across a time-course, we comprehensively investigated the response of paediatric medulloblastoma and ATRT brain tumour cells to ZIKV infection at the transcriptome level for the first time. We observed conserved TNF signalling pathway and cytokine signalling-related signatures following ZIKV infection. We demonstrated that the canonical TNF-alpha signalling pathway is implicated in oncolysis by reducing the viability of ZIKV-infected brain tumour cells and is a likely contributor to the anti-tumoural immune response through TNF-alpha secretion. Our findings have highlighted TNF-alpha as a potential prognostic marker for oncolytic ZIKV virotherapy. Performing a 49-plex ELISA, we generated the most comprehensive ZIKV-infected cancer cell secretome to date. We demonstrated that ZIKV infection induces a clinically relevant and diverse pro-inflammatory brain tumour cell secretome, thus circumventing the need for transgene modification to boost efficacy. We assessed publicly available scRNA-Seq data to model how the ZIKV-induced secretome may (i) interact with medulloblastoma tumour microenvironment (TME) cells via paracrine signalling and (ii) polarise lymph node immune cells via endocrine signalling. Our modelling has provided significant insight into the cytokine response that orchestrates the diverse anti-tumoural immune response during oncolytic ZIKV infection of brain tumours. Our findings have significantly contributed to understanding the molecular mechanisms governing oncolytic ZIKV infection and will help pave the way towards ZIKV-based virotherapy.
Biomimetic porous silicon for rationally engineered combination therapy to induce immunogenic cell death
Authors: Saarela Silja , Happonen Emilia , Laari Milla-Iida , Mohammed Zakir , Saba Shaghayegh , Liu Ruixian , Klefström Juha , Lehto Vesa-Pekka , Xu Wujun 
Published: November 2024

AbstractCombined chemo-photothermal therapy (CHT-PTT) is a promising treatment for metastatic cancers. It enables the synergistic induction of immunogenic cell death (ICD), while sensitising suppressive tumour microenvironment to immunotherapy. To induce ICD, the rational design of a combined CHT-PTT regimen remains unclear. In the present study, black porous silicon nanoparticles (BPSi NPs) were utilized as both drug carriers and photothermal conversion agents. To enhance their colloidal stability and homotypic targeting, BPSi NP surfaces were modified with polyethylene glycol and further coated with cancer cell membranes (CMs). Six chemotherapeutic drugs with different cell growth inhibition mechanisms were tested against metastatic MDA-MB-231 breast cancer cells to evaluate their ICD induction potentials. Finally, in the combined CHT-PTT, the effect of temperature was evaluated. Based on the analysis of ICD markers, high-mobility group box 1 and calreticulin proteins, we found that bromodomain-containing protein 4 inhibitor, (+)-JQ-1 (JQ1) was the optimal drug, and the mild-hyperthermia temperature of 45 °C was the best temperature setting in the combined CHT-PTT to induce ICD. Thus, our study provides rationally designed CHT-PTT regimen for efficient cancer treatment with high efficacy and low side effects.
Pesticide degradation capacity of a novel strain belonging toSerratia sarumanii(GBS19) with its genomic profile
Authors: Alatassi Gülperi , Baysal Ömür , Silme Ragıp Soner , Örnek Gülçin Pınar , Örnek Hakan , Can Ahmet 
Published: November 2024

ABSTRACTThe use of pesticides in agricultural pest control and the potential for biological degradation of these chemicals are significant factors in environmental conservation. Sustainable pest control strategies should prioritize the preservation of non-target organisms and the maintenance of soil ecosystem dynamics. Initiation from this point, this study aimed to identify microorganisms capable of pesticide biodegradation commonly used in our region’s intensive agricultural fields. The microorganism with the broadest degradation spectrum was identifiedin vitrostudies, and whole-genome sequence analyses indicated that some genomic regions were able to degrade pesticides, which was also confirmed with LC-MS analysis. Detailed genomic analyses linked to allele sequence definitions for ribosomal MLST have classified this strain asSerratia sarumaniiunder theSerratiagenus. Moreover, our findings showed that the introduction of this microorganism can stimulate the degradation of certain pesticides in the environment while, interestingly, simultaneously enhancing the potency of low concentrations of some other pesticides through a synergistic effect. To validate of GBS19 biodegradation capacity, additional studies carried out on 25 pesticide active chemicals using LC-MS chromatographic analysis revealed that theSerratia sarumaniiGBS19 strain is able to biodegrade some active compounds of various pesticides (fludioxonil, fenhexamid, pyrimethanil, and spirodiclofen) by up to 54%, 52%, 46%, and 23%, respectively. These results highlight the degrative properties of our prominent original strain as a gene pool which can be put into practice by transforming into competent strain using recombinant DNA technology.
Structural Basis for Catalysis and Substrate Specificity of a LarA Racemase with a Broad Substrate Spectrum
Authors: Gatreddi Santhosh , Urdiain-Arraiza Julian , Desguin Benoit , Hausinger Robert P. , Hu Jian 
Published: November 2024

AbstractThe LarA family consists of diverse racemases/epimerases that interconvert the diastereomers of a variety of α-hydroxyacids by using a nickel-pincer nucleotide (NPN) cofactor. The hidden redox reaction catalyzed by the NPN cofactor makes LarA enzymes attractive engineering targets for applications. However, how a LarA enzyme binds its natural substrate and recognizes different α-hydroxyacids has not been elucidated. Here, we report three high-resolution structures of the enzyme-substrate complexes of a broad-spectrum LarA enzyme fromIsosphaera pallida(LarAIp). The substrate binding mode reveals an optimal orientation and distance between the hydride donor and acceptor, strongly supporting the proposed proton-coupled hydride transfer mechanism. The experimentally solved structures, together with the structural models of other LarA enzymes, allow us to identify the residues/structural elements critically involved in the interactions with different α-hydroxyacid substrates. Collectively, this work provides a critical structural basis for catalysis and substrate recognition of the diverse enzymes in the LarA family, thus building a foundation for enzyme engineering.
TFEB/HLH-30-mediated expansion of neuronal lysosomal capacity in early adulthood protects dendrite maintenance during aging inCaenorhabditis elegans
Authors: Zhong Ruiling , Richardson Claire E. 
Published: November 2024

AbstractLysosomes are essential for neuronal homeostasis, providing degradation and recycling functions necessary to support neurons’ complex operations and long lifespans. However, the regulation of lysosomal degradative capacity in healthy neurons is poorly understood. Here, we investigate the role of HLH-30, the soleCaenorhabditis eleganshomolog of Transcription Factor EB (TFEB), a master regulator of lysosome biogenesis and autophagy that it is thought to predominantly function in the context of starvation or stress. We demonstrate that HLH-30 is dispensable for neuronal development but acts cell-intrinsically to expand lysosomal degradative capacity during early adulthood. Loss of HLH-30 leads to lysosomal dysfunction and delayed turnover of synaptic vesicle proteins from the synapse. Notably, we show that basal HLH-30 activity is sufficient to expand neuronal lysosomal capacity without nuclear enrichment, in contrast to the nuclear translocation associated with starvation- and stress-induced activation of TFEB and HLH-30. Furthermore, we show that neuronal lysosomal function declines with age in wild-type animals, and this corresponds to a decrease in basal HLH-30-mediated transcription. We further demonstrate that basal HLH-30 activity is crucial for neuron maintenance: lysosomal dysfunction due to inadequate HLH-30 activity leads to dendrite degeneration and aberrant outgrowths. In summary, our study establishes a critical role for HLH-30/TFEB in promoting lysosomal capacity to preserve neuronal homeostasis and structural integrity of mature neuronsin vivo.
Are senior management with academic experience more cautious? Empirical evidence from corporate risk-taking
Authors: He Ping , Zou Ying 
Published: November 2024

Purpose
Based on upper echelons theory, this study aims to explore the impact of senior management’s academic experience on corporate risk-taking and analyze the pathways and potential moderating effects of this relationship.

Design/methodology/approach
This study uses panel data of Chinese A-share listed companies in the Shenzhen Stock Exchange and Shanghai Stock Exchange from 2008 to 2020. An ordinary least squares model is used to test the hypothesis.

Findings
The results indicate that senior management’s academic experience suppresses corporate risk-taking, with investment level and cash reserves being two important channels. The moderation effect test shows that the inhibitory effect becomes more pronounced when senior managers with academic backgrounds occupy chief executive officer or chief financial officer roles. Conversely, when academic executives possess overseas/financial backgrounds or increase their compensation incentives, the strength of this disincentive effect diminishes. Moreover, our extended research finds that this inhibitory effect is more pronounced in state-owned companies and those within a strong Confucian cultural environment. Additionally, senior management’s academic experience positively correlates with both current and future market returns and company value.

Originality/value
This study contributes to the development of top management team building and corporate governance practices. Additionally, it furnishes investors with valuable insights into assessing the risk level of companies through the characteristics of their top management teams, thereby facilitating informed investment decision-making and improving capital market resource allocation efficiency.
Pace Control Systems: investigating people issues
Authors: Gulia Aditya , Pandey Jatin 
Published: November 2024

Learning outcomes
After completion of the case study, the students will be able to understand lead and lag indicators, understand job performance and its linkage with job satisfaction, calculate the cost of turnover and design solutions to the problem of attrition and low satisfaction.

Case overview/synopsis
Pace Control Gears was a small-scale enterprise based out of Sonipat, India. It was an entrepreneurial venture by Rajesh Kumar, who had set Pace in 2010 to manufacture low-voltage electrical apparatus. Recently, Pace had begun to experience issues with quality control that were largely the result of human error. The company was facing a drop in satisfaction levels and higher attrition levels among the employees. Kumar had to find a solution quickly to address the problem, as it had direct implications for the company’s margins and the assurance of quality that it was associated with in the market.

Complexity academic level
This case study is suited to undergraduate and postgraduate courses in human resource management and general management.

Supplementary materials
Teaching notes are available for educators only.

Subject code
CSS 6: Human Resources Management.
Examining the mediating role of organizational pride on the relationship of human values and work outcomes of facilities managers
Authors: Ling Florence Yean Yng , Ng Yong Jun , Zhai Wujuan 
Published: November 2024

Purpose
This study aims to explore the relationship between facilities managers’ human values, organizational pride and work outcomes, with the aim of discovering ways to boost their work outcomes.

Design/methodology/approach
A two-pronged research design comprising an online survey followed by in-depth interviews was adopted. Partial least square structural equation modeling (PLS-SEM) was used to model the data.

Findings
All 18 human values and 7 organizational pride emotions are present to a significant extent in facilities managers. The PLS-SEM showed that human values positively affect work outcomes of facilities managers significantly. In addition, work outcomes are further boosted when organizational pride is present.

Research limitations/implications
The degree of human values that an individual possesses may not be easily measured using a five-point Likert scale as there might be social desirability bias.

Practical implications
The implication is that organizations should select and hire facilities managers with high human values and introduce programs and initiatives to improve facilities managers’ organizational pride as these lead to higher work outcomes. Some recommendations on how to achieve these are provided.

Originality/value
The findings extend existing knowledge by empirically showing the mediating influence of organizational pride on the relationship between human values and facilities managers’ work outcomes. When organizational pride is present, work outcomes of facilities managers is boosted.