bluuebunny/crossref_metadata_2025 huggingface dataset:
Group Financial Statements
Authors: Winfield Jimmy , Graham Mark , Miller Taryn
Published: October 2023

This chapter explores group financial statements. Compared to the company financial statements, the group financial statements facilitate a more meaningful evaluation of the parent company's shareholders' investment because they provide a consolidated report of the effects of the economic activities of the entire group. Subsidiaries (those businesses over which the parent has control) are consolidated. This involves reporting 100% of the assets and liabilities of the subsidiary in the group statement of financial position. Similarly, the group statement of comprehensive income reports 100% of each item of income and expense from the subsidiary's statement of comprehensive income. The chapter then considers the concept of goodwill, which describes a range of reasons the business might be worth more to the acquirer than the fair value of its identifiable net assets. It also looks at the equity accounting of associates and joint ventures, as well as the group statement of cash flows.
Double-Entry Bookkeeping 2: Books of Prime Entry, Accounting Systems and other Double-Entry Applications
Authors: Scott Peter
Published: October 2023

This chapter considers various different accounting systems. It illustrates the process that is used to record transactions on a daily basis in an accounting system. The chapter discusses three different systems: sales system, purchases system, and payroll system. The chapter provides the details on the process and relevant information entered in each accounting system. The final part of the chapter talks about other double-entry applications.
Ratio Analysis 2: Liquidity, Working Capital and Long-Term Financial Stability
Authors: Scott Peter
Published: October 2023

This chapter focuses on liquidity ratios and the related analysis provided by working capital ratios. In addition, the chapter considers how an entity's capital structure contributes to an assessment of that entity's long-term financial stability. Then, it looks at the key ratios in the assessment of entities' capital structures and considers how to evaluate organizations' ability to survive with high levels of borrowings. Throughout the chapter, calculations for various liquidity ratios are illustrated.
Extracellular vesicles altered by a per- and polyfluoroalkyl substance mixture:in vitrodose-dependent release, chemical content, and microRNA signatures involved in liver health
Authors: Carberry Celeste K , Bangma Jacqueline , Koval Lauren , Keshava Deepak , Hartwell Hadley J , Sokolsky Marina , Fry Rebecca C , Rager Julia E
Published: October 2023

Per- and polyfluoroalkyl substances (PFAS) have emerged as high-priority contaminants due to their ubiquity and pervasiveness in the environment. Numerous PFAS co-occur across sources of drinking water, including areas in North Carolina (NC) where some detected concentrations are above the Environmental Protection Agency’s health advisory levels. Although evidence demonstrates that PFAS exposure induces harmful effects in the liver, the involvement of extracellular vesicles (EVs) as potential mediators of these effects has yet to be evaluated. This study set out to evaluate the hypothesis that PFAS mixtures induce dose-dependent release of EVs from liver cells, with exposures causing differential loading of microRNAs (miRNAs) and PFAS chemical signatures. To test this hypothesis, a defined PFAS mixture was prioritized utilizing data collected by the NC PFAS Testing Network. This mixture contained 3 substances, perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorohexanoic acid (PFHxA), selected based upon co-occurrence patterns and the inclusion of both short-chain (PFHxA) and long-chain (PFOA and PFOS) substances. HepG2 liver cells were exposed to equimolar PFAS, and secreted EVs were isolated from conditioned media and characterized for count and molecular content. Exposures induced a dose-dependent release of EVs carrying miRNAs that were differentially loaded upon exposure. These altered miRNA signatures were predicted to target mRNA pathways involved in hepatic fibrosis and cancer. Chemical concentrations of PFOS, PFOA, and PFHxA were also detected in both parent HepG2 cells and their released EVs, specifically within a 15-fold range after normalizing for protein content. This study therefore established EVs as novel biological responders and measurable endpoints for evaluating PFAS-induced toxicity.
Reconciling Incongruencies
Authors: Boni Rebecca L. , Dingley Catherine
Published: October 2023

This grounded theory study explored the processes and actions enacted by oncology nurses to enhance professional quality of life and the related meaning, facilitators, and barriers. Oncology nurses described a process by which they continually Reconcile Incongruencies. This process involves 4 categories: Accepting the Context of Oncology Nursing, Bettering the World, Pursuing a Calling, and Being Valued. External facilitators and barriers, self-driven actions to maintain, and consequences of professional quality of life were also revealed. The findings from this study offer an operational definition, a foundation for instrument development, and the consequences of oncology nurses' professional quality of life.
Homeostatic Modulation of CD4+ T Cell Subsets Using the Chinese Medicine Jianpi Qushi Heluo Formula During the Alleviation of Primary Membranous Nephropathy
Authors: Zeng Qin , Wang Xinhui , Chen Jiemei , Yan Lei , Zhu Haibo , Liang Ying
Published: October 2023

Background:

Compelling evidence suggests that the immune system plays a key role in the development and progression of primary membranous nephropathy (pMN). The Jianpi Qushi Heluo Formula (JQHF) is an empirical and effective traditional Chinese medicine prescription used for the clinical treatment of pMN in China. However, it remains unclear whether JQHF treatment affects the peripheral immune system of patients with pMN.

Methods:

Twenty-five patients with pMN and 10 healthy controls (HC) were enrolled. Patients with pMN were treated with JQHF for 6 months. Circulating CD4+ T cell subsets and associated chemokines were analyzed using flow cytometry among both HC and pMN before and after 6 months of JQHF treatment.

Results:

Patients with pMN treated with JQHF achieved 60% clinical remission and a significant reduction in 24-hour urinary protein excretion (24hUTP). Compared to HC, Th1 cells increased, Treg cells decreased, and Th1/Th2, Th1/Treg, and Th17/Treg cells increased in the pMN (P = 0.011, P = 0.035, P = 0.001, P = 0.026, P = 0.038, respectively). JQHF treatment significantly improved cellular immune imbalance in patients with pMN. Patients with pMN showed increased levels of peripheral blood C-X-C motif chemokine ligand 9 (CXCL9), CXCL10, and C-C motif ligand 20 (CCL20), but no significant difference was observed compared with HC. JQHF treatment significantly reduced CXCL10 levels (P = 0.0071). Moreover, 24hUTP was strongly and positively correlated with Th1 cell and CXCL10 levels (P = 0.0438 and P = 0.0211, respectively). Total serum protein levels were strongly and positively correlated with Tregs (P = 0.0816). Th1 cells also strongly and positively correlated with CXCL10 levels (P = 0.0012).

Conclusion:

Our findings suggest an imbalance in the immune differentiation of peripheral blood CD4+ T cells in patients with pMN. JQHF treatment had a pronounced effect on pMN, which may be mediated by the improvement of homeostatic modulation of CD4+ T cell subsets.
Multimodal approaches for inequality in kidney care: turning social determinants of health into opportunities
Authors: Purtell Louise , Bennett Paul , Bonner Ann
Published: October 2023

Purpose of review

Kidney disease is associated with major health and economic burdens worldwide, disproportionately carried by people in low and middle socio-demographic index quintile countries and in underprivileged communities. Social determinants such as education, income and living and working conditions strongly influence kidney health outcomes. This review synthesised recent research into multimodal interventions to promote kidney health equity that focus on the social determinants of health.

Recent findings

Inequity in kidney healthcare commonly arises from nationality, race, sex, food insecurity, healthcare access and environmental conditions, and affects kidney health outcomes such as chronic kidney disease progression, dialysis and transplant access, morbidity and mortality. Multimodal approaches to addressing this inequity were identified, targeted to: patients, families and caregivers (nutrition, peer support, financial status, patient education and employment); healthcare teams (workforce, healthcare clinician education); health systems (data coding, technology); communities (community engagement); and health policy (clinical guidelines, policy, environment and research).

The engagement of diverse patients, families, caregivers and communities in healthcare research and implementation, as well as clinical care delivery, is vital to counteracting the deleterious effects of social determinants of kidney health.
Platelet mechanosensing as key to understanding platelet function
Authors: Schoen Ingmar , Kenny Martin , Patil Smita
Published: October 2023

Purpose of review

This review highlights how the perception of platelet function is evolving based on recent insights into platelet mechanobiology.

Recent findings

The mechanosensitive ion channel Piezo1 mediates activation of free-flowing platelets under conditions of flow acceleration through mechanisms independent of adhesion receptors and classical activation pathways. Interference with the initiation of platelet migration or with the phenotypic switch of migrating platelets to a procoagulant state aggravates inflammatory bleeding. Mechanosensing of biochemical and biophysical microenvironmental cues during thrombus formation feed into platelet contractile force generation. Measurements of single platelet contraction and bulk clot retraction show promise to identify individuals at risk for hemorrhage.

New findings unravel novel mechanotransduction pathways and effector functions in platelets, establishing mechanobiology as a pivotal component of platelet function. These insights highlight limitations of existing treatments and offer new potential therapeutic approaches and diagnostic avenues based on mechanobiological principles. Further extensive research is required to distinguish between core hemostatic and pathological mechanisms influenced by platelet mechanosensing.
Machine Learning Strategies for Improved Phenotype Prediction in Underrepresented Populations
Authors: Bonet David , Levin May , Montserrat Daniel Mas , Ioannidis Alexander G.
Published: October 2023

Precision medicine models often perform better for populations of European ancestry due to the over-representation of this group in the genomic datasets and large-scale biobanks from which the models are constructed. As a result, prediction models may misrepresent or provide less accurate treatment recommendations for underrepresented populations, contributing to health disparities. This study introduces an adaptable machine learning toolkit that integrates multiple existing methodologies and novel techniques to enhance the prediction accuracy for underrepresented populations in genomic datasets. By leveraging machine learning techniques, including gradient boosting and automated methods, coupled with novel population-conditional re-sampling techniques, our method significantly improves the phenotypic prediction from single nucleotide polymorphism (SNP) data for diverse populations. We evaluate our approach using the UK Biobank, which is composed primarily of British individuals with European ancestry, and a minority representation of groups with Asian and African ancestry. Performance metrics demonstrate substantial improvements in phenotype prediction for underrepresented groups, achieving prediction accuracy comparable to that of the majority group. This approach represents a significant step towards improving prediction accuracy amidst current dataset diversity challenges. By integrating a tailored pipeline, our approach fosters more equitable validity and utility of statistical genetics methods, paving the way for more inclusive models and outcomes.
CellContrast: Reconstructing Spatial Relationships in Single-Cell RNA Sequencing Data via Deep Contrastive Learning
Authors: Li Shumin , Ma Jiajun , Zhao Tianyi , Jia Yuran , Liu Bo , Luo Ruibang , Huang Yuanhua
Published: October 2023

A vast amount of single-cell RNA-seq (SC) data has been accumulated via various studies and consortiums, but the lack of spatial information limits its analysis of complex biological activities. To bridge this gap, we introduce cellContrast, a computational method for reconstructing spatial relationships among SC cells from spatial transcriptomics (ST) reference. By adopting a contrastive learning framework and training with ST data, cellContrast projects gene expressions into a hidden space where proximate cells share similar representation values. We performed extensive benchmarking on diverse platforms, including SeqFISH, Stereo-Seq, 10X Visium, and MERSCOPE, on mouse embryo and human breast cells. The results reveal that cellContrast substantially outperforms other related methods, facilitating accurate spatial reconstruction of SC. We further demonstrate cellContrast’s utility by applying it to cell-type co-localization and cell-cell communication analysis with real-world SC samples, proving the recovered cell locations empower novel discoveries and mitigate potential false positives.
TheR1441C-LRRK2mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner
Authors: Wallings Rebecca L. , McFarland Karen , Staley Hannah A. , Neighbarger Noelle , Schaake Susen , Brüggemann Norbert , Zittel Simone , Usnich Tatiana , Klein Christine , Sammler Esther M , Tansey Malú Gámez
Published: October 2023

Considering age is the greatest risk factor for many neurodegenerative diseases, aging, in particular aging of the immune system, is the most underappreciated and understudied contributing factor in the neurodegeneration field. Genetic variation around theLRRK2gene affects risk of both familial and sporadic Parkinson’s disease (PD). The leucine-rich repeat kinase 2 (LRRK2) protein has been implicated in peripheral immune signaling, however, the effects of an aging immune system on LRRK2 function have been neglected to be considered. We demonstrate here that theR1441Cmutation induces a hyper-responsive phenotype in macrophages from young female mice, characterized by increased effector functions, including stimulation-dependent antigen presentation, cytokine release, phagocytosis, and lysosomal function. This is followed by age-acquired immune cell exhaustion in a Lrrk2-kinase-dependent manner. Immune-exhausted macrophages exhibit suppressed antigen presentation and hypophagocytosis, which is also demonstrated in myeloid cells fromR1441CandY1699C-PD patients. Our novel findings thatLRRK2mutations confer immunological advantage at a young age but may predispose the carrier to age-acquired immune cell exhaustion have significant implications for LRRK2 biology and therapeutic development. Indeed, LRRK2 has become an appealing target in PD, but our findings suggest that more research is required to understand the cell-type specific consequences and optimal timing of LRRK2-targeting therapeutics.

One Sentence Summary

TheR1441C-LRRK2mutation causes an age-acquired immune cell exhaustion in macrophages in a sex-dependent manner
Assessing the Population Consequences of Disturbance and Climate Change for the Pacific Walrus
Authors: Johnson Devin L. , Eisaguirre Joseph M. , Taylor Rebecca L. , Garlich-Miller Joel L.
Published: October 2023

Climate change and anthropogenic disturbance are increasingly affecting wildlife at a global scale. Predicting how varying types and degrees of disturbance may interact to influence population dynamics is a key management challenge. Population Consequences of Disturbance (PCoD) models provide a framework to link effects of anthropogenic disturbance on an individual’s behavior and physiology to population-level changes. Bioenergetic models often constitute the basis of these frameworks, wherein an individual’s daily energy balance is simulated over the course of its lifetime, allowing many individuals to be subjected to different environmental conditions and ultimately simulate population-level vital rates under varying degrees of disturbance. In the present study, we develop a Pacific walrus (Odobenus rosmarus divergens) PCoD model to encompass the population-level effects of both anthropogenic disturbance and climate change. Pacific walruses are an Arctic/subarctic ice-associated pinniped. As the Arctic has become increasingly ice-free with climate change, walruses spend more time on land-based (rather than ice-based) haulouts from which they must expend more energy to reach foraging areas, and where they have a greater risk of predation and disturbance-based mortalities. Concurrently, sea ice loss is increasing the anthropogenic footprint in Arctic regions (e.g., fisheries, shipping, energy exploration) which creates additional disturbance. We developed a bioenergetic Dynamic Energy Budget (DEB) model for the Pacific walrus and applied it to four scenarios (ranging from optimistic-pessimistic) which incorporate different global sea ice model projections along with varying degrees of anthropogenic disturbance. All scenarios indicated a decline in Pacific walrus carrying capacity and population growth rate (and thus overall abundance) to the end of the 21stcentury, but demonstrated that the intensity of that decline could be mitigated by global efforts to reduce carbon emissions (i.e., lessening the rate of sea ice loss) and local management and conservation efforts to protect sensitive habitat areas. In summary, we introduced a flexible PCoD modelling framework in a novel context which will prove useful to researchers studying walruses and other species similarly threatened by rapid environmental change.
A comparative study of algorithms detecting differential rhythmicity in transcriptomic data
Authors: Miao Lin , Weidemann Douglas E. , Ngo Katherine , Unruh Benjamin A. , Kojima Shihoko
Published: October 2023

Rhythmic transcripts play pivotal roles in driving the daily oscillations of various biological processes. Genetic or environmental disruptions can lead to alterations in the rhythmicity of transcripts, ultimately impacting downstream circadian outputs, including metabolic processes and even behavior. To statistically compare the differences in transcript rhythms between two or more conditions, several algorithms have been developed to analyze circadian transcriptomic data, each with distinct features. In this study, we compared the performance of seven algorithms that were specifically designed to detect differential rhythmicity. We found that even when applying the same statistical threshold, these algorithms yielded varying numbers of differentially rhythmic transcripts. Nevertheless, the set of transcripts commonly identified as differentially rhythmic exhibited substantial overlap among algorithms. Furthermore, the phase and amplitude differences calculated by these algorithms displayed significant correlations. In summary, our study highlights a high degree of similarity in the results produced by these algorithms. Furthermore, when selecting an algorithm for analysis, it is crucial to ensure the compatibility of input data with the specific requirements of the chosen algorithm and to assess whether the algorithm’s output fits the needs of the user.
Prior heat stress increases pathogen susceptibility in the model cnidarianExaptasia diaphana
Authors: Diaz de Villegas Sofia C. , Borbee Erin M. , Abdelbaki Peyton Y. , Fuess Lauren E.
Published: October 2023

Anthropogenic climate change has significantly altered terrestrial and marine ecosystems globally, often in the form of climate-related events such as thermal anomalies and disease outbreaks. Although the isolated effects of these stressors have been well documented, a growing body of literature suggests that stressors often interact, resulting in complex effects on ecosystems, including coral reefs where sequential associations between heat stress and disease have had profound impacts. Here we used the model cnidarianExaiptasia diaphanato investigate mechanisms linking prior heat stress to increased disease susceptibility. We examined anemone pathogen susceptibility and physiology (symbiosis, immunity, and energetics) following recovery from heat stress. We observed significantly increased pathogen susceptibility in anemones previously exposed to heat stress. Notably, prior heat stress reduced anemone energetic reserves (carbohydrate concentration), and activity of multiple immune components. Minimal effects of prior heat stress on symbiont density were observed. Together, results suggest changes in energetic availability might have the strongest effect on pathogen susceptibility and immunity following heat stress. The results presented here provide critical insight regarding the interplay between heat stress recovery and pathogen susceptibility in cnidarians and are an important first step towards understanding temporal associations between these stressors.
A role for theC. elegansArgonaute protein CSR-1b isoform in small nuclear RNA 3’ processing
Authors: Waddell Brandon M. , Wu Cheng-Wei
Published: October 2023

The Integrator is a multi-subunit protein complex that catalyzes the maturation of snRNA transcripts via 3’ cleavage, a step required for snRNA incorporation with snRNP for spliceosome biogenesis. Here we developed a GFP basedin vivosnRNA misprocessing reporter as a readout of Integrator function and performed a genome-wide RNAi screen for Integrator regulators. We found that loss of the Argonaute encodingcsr-1gene resulted in widespread 3’ misprocessing of snRNA transcripts that is accompanied by a significant increase in alternative splicing. Loss ofcsr-1down-regulates the germline expression of Integrator subunit-4 and is accompanied by a reduced protein translation efficiency of multiple Integrator catalytic and non-catalytic subunits. Through isoform analysis, we identify thatcsr-1bis specifically required for snRNA processing and this is dependent on its catalytic slicer activity. Moreover, mRNA-sequencing revealed high similarity in the transcriptome profile betweencsr-1and Integrator subunit knockdown via RNAi. Together, our findings revealcsr-1bas a new regulator of the Integrator complex and implicate a novel role of this Argonaute protein in snRNA 3’ processing.
GUANinE v1.0: Benchmark Datasets for Genomic AI Sequence-to-Function Models
Authors: Robson Eyes S , Ioannidis Nilah M.
Published: October 2023

Computational genomics increasingly relies on machine learning methods for genome interpretation, and the recent adoption of neural sequence-to-function models highlights the need for rigorous model specification and controlled evaluation, problems familiar to other fields of AI. Research strategies that have greatly benefited other fields -- including benchmarking, auditing, and algorithmic fairness --- are also needed to advance the field of genomic AI and to facilitate model development. Here we propose a genomic AI benchmark, GUANinE, for evaluating model generalization across a number of distinct genomic tasks. Compared to existing task formulations in computational genomics, GUANinE is large-scale, de-noised, and suitable for evaluating pretrained models. GUANinE v1.0 primarily focuses on functional genomics tasks such as functional element annotation and gene expression prediction, and it also draws upon connections to evolutionary biology through sequence conservation tasks. The current GUANinE tasks provide insight into the performance of existing genomic AI models and non-neural baselines, with opportunities to be refined, revisited, and broadened as the field matures. Finally, the GUANinE benchmark allows us to evaluate new self-supervised T5 models and explore the tradeoffs between tokenization and model performance, while showcasing the potential for self-supervision to complement existing pretraining procedures.
Distinct resource utilization by introduced man-made grouper hybrid: an overlooked anthropogenic impact from a longstanding religious practise
Authors: Chung Arthur , Schunter Celia
Published: October 2023

Anthropogenic activities, such as non-native aquaculture species introduction have been considerably altering trophic interactions in marine ecosystems. The hybrid grouper (TGGG), an aquaculture product originated from artificial F1 crossbreed betweenEpinephelus fuscoguttatusandE. lanceolatus, have been released in the wild through religious activities, raising concerns about this man-made introduced species. The carnivorous diet, together with large body size inherited from the parental species have made TGGG a candidate that could pose significant impacts to the marine ecosystem. Yet, little is known about the diet composition of TGGG upon release into the natural environment, and any dietary overlap or partition with closely related endemic species. Here, we deploy gut content DNA metabarcoding to determine the prey richness and dietary niche of wild caught TGGG and compare with four native grouper species (Epinephelus awoara, E. bleekeri, E. coioides and E. quoyanus). The TGGG exhibited six unique prey taxa with teleosts being the major taxa preyed upon followed by crustaceans and cephalopods and displayed significant lower mean number of pray taxa compared to other groupers. The TGGG exhibits a significantly different diet composition, possibly indicating a diet transitioning and acquiring new feeding behavior. This study provides a comprehensive analysis with high taxonomic resolution on the diet of artificial hybrids in the wild, suggesting possibility of introduction success if release events persist. Finally, these findings provide new information on how local trophic dynamics are impacted by under-investigated release of animals through religious practices.
Endocisternal interfaces for minimally invasive neural stimulation and recording of the brain and spinal cord
Authors: Chen Joshua C. , Dhuliyawalla Abdeali , Garcia Robert , Robledo Ariadna , Woods Joshua E. , Alrashdan Fatima , O’Leary Sean , Crosby Scott , Felicella Michelle M , Wakhloo Ajay K. , Karas Patrick , Goodman Wayne , Sheth Sameer A. , Sheth Sunil A. , Robinson Jacob T. , Kan Peter
Published: October 2023

Minimally invasive neural interfaces can be used to diagnose, manage, and treat many disorders with substantially reduced risks of surgical complications. Endovascular neural interfaces implanted in the veins or arteries is one approach, but it requires prescriptions of anti-thrombotic medication and are likely not explantable after endothelialization. More critically, the approach is limited by the small size and location of blood vessels, such that many important cortical, subcortical, spinal targets cannot be reached. Here, we demonstrate a chronic endocisternal neural interface that approaches brain and spinal cord targets through inner and outer cerebral spinal fluid (CSF) spaces. These spaces surround the nervous system and lack the tortuosity of the circulatory system, giving us access to the entire brain convexity, deep brain structures within the ventricles, and the spinal cord from the spinal subarachnoid space. Combined with miniature magnetoelectric-powered bioelectronics, the entire wireless system is deployable through a percutaneous procedure. The flexible catheter electrodes can be freely navigated throughout the body from the spinal to cranial subarachnoid space, and from the cranial subarachnoid space to the ventricles. We show in a large animal model that we can also reposition the recording and stimulation electrodes or explant the neural interface after chronic implantation. This enables applications in therapies that require transient or permanent brain/machine interface such as stroke rehabilitation and epilepsy monitoring and opens a new class of minimally invasive endocisternal bioelectronics.
Force-field perturbations and muscle vibration strengthen stability-related foot placement responses during steady-state gait
Authors: van Leeuwen A.M. , Bruijn S.M. , Dean J.C.
Published: October 2023

Mediolateral gait stability can be maintained by coordinating our foot placement with respect to the center-of-mass (CoM) kinematic state. Neurological impairments can reduce the degree of foot placement control. For individuals with such impairments, interventions that could improve foot placement control could thus contribute to improved gait stability. In this study we aimed to better understand two potential interventions, by investigating their effect in neurologically intact individuals. The degree of foot placement control can be quantified based on a foot placement model, in which the CoM position and velocity during swing predict subsequent foot placement. Previously, perturbing foot placement with a force-field resulted in an enhanced degree of foot placement control as an after-effect. Moreover, muscle vibration enhanced the degree of foot placement control through sensory augmentation whilst the vibration was applied. Here, we replicated these two findings and further investigated whether Q1) sensory augmentation leads to an after-effect and Q2) whether combining sensory augmentation with force-field perturbations leads to a larger after-effect, as compared to force-field perturbations only. In addition, we evaluated several potential contributors to the degree of foot placement control, by considering foot placement errors, CoM variability and the CoM position gain (βpos) of the foot placement model, next to the R2measure as the degree of foot placement control. Sensory augmentation led to a higher degree of foot placement control as an after-effect (Q1). However, combining sensory augmentation and force-field perturbations did not lead to a larger after-effect, as compared to following force-field perturbations only (Q2). Furthermore, we showed that, the improved degree of foot placement control following force-field perturbations and during/following muscle vibration, did not reflect diminished foot placement errors. Rather, participants demonstrated a stronger active response (higher βpos) as well as higher CoM variability.
Single cell transcriptomic profiling identifies tumor-acquired and therapy-resistant cell states in pediatric rhabdomyosarcoma
Authors: Danielli Sara G , Wei Yun , Dyer Michael A , Stewart Elizabeth , Wachtel Marco , Schäfer Beat W , Patel Anand G , Langenau David M
Published: October 2023

Rhabdomyosarcoma (RMS) is a pediatric tumor that resembles undifferentiated muscle cells; yet the extent to which cell state heterogeneity and molecular features are shared with human development have not been fully ascribed. Here, we report a single-cell/nucleus RNA sequencing atlas derived from 72 datasets that includes patient tumors, patient-derived xenografts, primaryin vitrocultures, and established cell lines. We report four dominant muscle-lineage cell states in RMS: progenitors, proliferative, differentiated, and ground cells. We stratify these RMS cells along the continuum of human muscle development and show that RMS cells share expression patterns with fetal/embryonal myogenic precursors rather than postnatal satellite cells. Indeed, fusion-negative RMS (FN-RMS) have a discrete stem cell hierarchy that faithfully recapitulates fetal muscle development. We also identify therapy-resistant FN-RMS progenitor cells that share transcriptomic similarity with bipotent skeletal mesenchymal cells, while a subset of fusion-positive (FP) RMS have tumor-acquired cells states, including a neuronal cell state, that are not found in development. Chemotherapy induced upregulation of progenitor signatures in FN-RMS while the neuronal gene programs were retained after therapy in FP-RMS. Taken together, this work identifies new cell state heterogeneity including unique treatment-resistant and tumor-acquired cell states that differ across RMS subtypes.
Gendered hiring and attrition on the path to parity for academic faculty
Authors: LaBerge Nicholas , Wapman K. Hunter , Clauset Aaron , Larremore Daniel B.
Published: October 2023

Despite long-running efforts to increase gender diversity among tenured and tenure track faculty in the U.S., women remain underrepresented in most academic fields, sometimes dramatically so. Here we quantify the relative importance of faculty hiring and faculty attrition for both past and future faculty gender diversity using comprehensive data on the training and employment of 268,769 tenured and tenure-track faculty rostered at 12,112 U.S. PhD-granting departments, spanning 111 academic fields between 2011–2020. Over this time, we find that hiring had a far greater impact on women’s representation among faculty than attrition in the majority (90.1%) of academic fields, even as academia loses a higher share of women faculty relative to men at every career stage. Finally, we model the impact of five specific policy interventions on women’s representation, and project that eliminating attrition differences between women and men only leads to a marginal increase in women’s overall representation—in most fields, successful interventions will need to make substantial and sustained changes to hiring in order to reach gender parity.
Pervasive biases in proxy GWAS based on parental history of Alzheimer’s disease
Authors: Wu Yuchang , Sun Zhongxuan , Zheng Qinwen , Miao Jiacheng , Dorn Stephen , Mukherjee Shubhabrata , Fletcher Jason M. , Lu Qiongshi
Published: October 2023

Almost every recent Alzheimer’s disease (AD) genome-wide association study (GWAS) has performed meta-analysis to combine studies with clinical diagnosis of AD with studies that use proxy phenotypes based on parental disease history. Here, we report major limitations in current GWAS-by-proxy (GWAX) practices due to uncorrected survival bias and non-random participation of parental illness survey, which cause substantial discrepancies between AD GWAS and GWAX results. We demonstrate that current AD GWAX provide highly misleading genetic correlations between AD risk and higher education which subsequently affects a variety of genetic epidemiologic applications involving AD and cognition. Our study sheds important light on the design and analysis of mid-aged biobank cohorts and underscores the need for caution when interpreting genetic association results based on proxy-reported parental disease history.
Commissureless acts as a substrate adapter in a conserved Nedd4 E3 ubiquitin ligase pathway to promote axon growth across the midline
Authors: Sullivan Kelly G. , Bashaw Greg J.
Published: October 2023

In both vertebrates and invertebrates, commissural neurons prevent premature responsiveness to the midline repellant Slit by downregulating surface levels of its receptor Roundabout1 (Robo1). InDrosophila, Commissureless (Comm) plays a critical role in this process; however, there is conflicting data on the underlying molecular mechanism. Here, we demonstrate that the conserved PY motifs in the cytoplasmic domain of Comm are required allow the ubiquitination and lysosomal degradation of Robo1. Disruption of these motifs prevents Comm from localizing to Lamp1 positive late endosomes and to promote axon growth across the midlinein vivo. In addition, we conclusively demonstrate a role for Nedd4 in midline crossing. Genetic analysis shows thatnedd4mutations result in midline crossing defects in the Drosophila embryonic nerve cord, which can be rescued by introduction of exogenous Nedd4. Biochemical evidence shows that Nedd4 incorporates into a three-member complex with Comm and Robo1 in a PY motif-dependent manner. Finally, we present genetic evidence that Nedd4 acts with Comm in the embryonic nerve cord to downregulate Robo1 levels. Taken together, these findings demonstrate that Comm promotes midline crossing in the nerve cord by facilitating Robo1 ubiquitination by Nedd4, ultimately leading to its degradation.
Enterocytozoon hepatopenaeiProliferate inProcambarus clarkii: A Warning for Crayfish and Shrimp Aquaculture
Authors: Ling Bingxin , Wu Yujiao , Yu Qing , Wang Chunxia , Hu Mengjiao , Meng Xianzhi , Long Mengxian , Pan Guoqing , Xiang Zhonghuai , Zhou Zeyang , Chen Jie
Published: October 2023

The pacific whiteleg shrimp (Litopenaeus vannamei) and the crayfish (Procambarus clarkii) are the most productive aquatic animals in the world. The prevalence of the microsporidiumEnterocytozoon hepatopenaei(EHP), an intracellular spore-forming unicellular parasite which leading retarded growth ofL. vannamei, has caused severe economic losses in most shrimp farming country. In this study, we found that the wildP. clarkii, living in shrimp ponds with EHP outbreak, excreted white faeces after temporary laboratory culture. The hepatopancreas (HP) of symptomatic crayfish exhibited a lighter color and severely atrophied. H&E-stain showed tissue lesions in both hepatopancreas and intestine, and clustered microsporidian spores were filled in the cytoplasm of the cells. PCR usingEHPptp2and two microsporidian-universal primers sets demonstrated the existence of EHP in the hepatopancreas, intestine and the white feces ofP. clarkii. The EHP loads of 103-104copies ofEHPptp2/50 ng HPgDNA were detected by qPCR. Developing stages and mature spores of EHP were observed in hepatopancreas ofP. clarkiithrough indirect-immunofluorescence assay (IFA) and transmission electron microscopy (TEM). Considering the large-scale cultivation ofL. vannameiandP. clarkii, overlap farming areas between these two species as well as the ability of crayfish to crawl on land and water, our finding indicates the potential role ofP. clarkiiin the transmission of EHP, and it is an early warning for crayfish and shrimp farming.
V-pipe 3.0: a sustainable pipeline for within-sample viral genetic diversity estimation
Authors: Fuhrmann Lara , Jablonski Kim Philipp , Topolsky Ivan , Batavia Aashil A , Borgsmüller Nico , Icer Baykal Pelin , Carrara Matteo , Chen Chaoran , Dondi Arthur , Dragan Monica , Dreifuss David , John Anika , Langer Benjamin , Okoniewski Michal , du Plessis Louis , Schmitt Uwe , Singer Franziska , Stadler Tanja , Beerenwinkel Niko
Published: October 2023

The large amount and diversity of viral genomic datasets generated by next-generation sequencing technologies poses a set of challenges for computational data analysis workflows, including rigorous quality control, adaptation to higher sample coverage, and tailored steps for specific applications. Here, we present V-pipe 3.0, a computational pipeline designed for analyzing next-generation sequencing data of short viral genomes. It is developed to enable reproducible, scalable, adaptable, and transparent inference of genetic diversity of viral samples. By presenting two large-scale data analysis projects, we demonstrate the effectiveness of V-pipe 3.0 in supporting sustainable viral genomic data science.
An inducible ESCRT-III inhibition tool to control HIV-1 budding
Authors: Wang Haiyan , Gallet Benoit , Moriscot Christine , Pezet Mylène , Chatellard Christine , Kleman Jean-Philippe , Göttlinger Heinrich , Weissenhorn Winfried , Boscheron Cécile
Published: October 2023

HIV-1 budding as well as many other cellular processes require the Endosomal Sorting Complex Required for Transport (ESCRT) machinery. Understanding the architecture of the native ESCRT-III complex at HIV-1 budding sites is limited due to spatial resolution and transient ESCRT-III recruitment. Here, we developed a drug-inducible transient HIV-1 budding inhibitory tool to enhance the ESCRT-III lifetime at budding sites. We generated auto-cleavable CHMP2A, CHMP3, and CHMP4B fusion proteins with the hepatitis C virus NS3 protease. We characterized the CHMP-NS3 fusion proteins in the absence and presence of protease inhibitor Glecaprevir with regard to expression, stability, localization and HIV-1 Gag VLP budding. Immunoblotting experiments revealed rapid and stable accumulation of CHMP-NS3 fusion proteins with variable modification of Gag VLP budding upon drug administration. Notably, CHMP2A-NS3 and CHMP4B-NS3 fusion proteins substantially decrease VLP release while CHMP3-NS3 exerted a minor effect and synergized with CHMP2A-NS3. Localization studies demonstrated the re-localization of CHMP-NS3 fusion proteins to the plasma membrane, endosomes, and Gag VLP budding sites. Through the combined use of transmission electron microscopy and video-microscopy, we unveiled drug-dependent accumulation of CHMP2A-NS3 and CHMP4B-NS3, causing a delay in HIV-1 Gag-VLP release. Our findings provide novel insight into the functional consequences of inhibiting ESCRT-III during HIV-1 budding and establish new tools to decipher the role of ESCRT-III at HIV-1 budding sites and other ESCRT-catalyzed cellular processes.
A Tetravalent Dengue Virus-like Particle Vaccine Induces High levels of Neutralizing Antibodies and Inhibits Dengue Replication in Non-Human Primates
Authors: Thoresen Daniel , Matsuda Kenta , Urakami Akane , Tun Mya Myat Ngwe , Nomura Takushi , Moi Meng Ling , Watanabe Yuri , Ishikawa Momoko , Hau Trang Thi Thu , Yamamoto Hiroyuki , Suzaki Yuriko , Ami Yasushi , Smith Jonathan F , Matano Tetsuro , Morita Kouichi , Akahata Wataru
Published: October 2023

Dengue virus (DENV) represents a significant global health burden, with 50% of the world’s population at risk of infection, and there is an urgent need for next-generation vaccines. Virus-like particle (VLP)-based vaccines, which mimic the antigenic structure of the authentic virus but lack the viral genome, are an attractive approach. Here we describe a dengue VLP (DENVLP) vaccine which generates a robust and long-lasting neutralizing antibody response against all four DENV serotypes in non-human primates. Importantly, DENVLP vaccination produced no ADE response against any of four DENV serotypes. Finally, we demonstrate in a non-human primate challenge model that DENVLP vaccination substantially reduces viral replication. We also transfer the purified IgG from the immunized monkeys into immunodeficient mice, where they protect against subsequent lethal dengue virus challenge, indicating a humoral mechanism of protection. These results indicate that a DENVLP vaccine is a safe and effective vaccine candidate.

One Sentence Summary:Immunization of non-human primates with a tetravalent dengue VLP vaccine induces high levels of neutralizing antibodies and reduces the severity of infection for all four dengue serotypes.
Listeria monocytogenesutilizes glutathione and limited inorganic sulfur compounds as a source of essential L-cysteine
Authors: Berude John C. , Kennouche Paul , Reniere Michelle L. , Portnoy Daniel A.
Published: October 2023

Listeria monocytogenes(Lm) is a Gram-positive facultative intracellular pathogen that leads a biphasic lifecycle, transitioning its metabolism and selectively inducing virulence genes when it encounters mammalian hosts. Virulence gene expression is controlled by the master virulence regulator PrfA, which is allosterically activated by host- and bacterially-derived glutathione (GSH). The amino acid L-cysteine is the rate-limiting substrate for GSH synthesis in bacteria and is essential for bacterial growth. Unlike many bacteria,Lmis auxotrophic for L-cysteine and must import exogenous cysteine for growth and virulence. GSH is enriched in the host cytoplasm, and previous work suggests thatLmutilizes exogenous GSH for PrfA activation. Despite these observations, the import mechanism(s) for GSH remains elusive. Analysis of known GSH importers predicted a homologous importer inLmcomprised of the Ctp ABC transporter and the OppDF ATPases of the Opp oligopeptide importer. Here, we demonstrated that the Ctp complex is a high-affinity GSH/GSSG importer that is required forLmgrowth at physiologically relevant concentrations. Further, we demonstrated that OppDF are required for GSH/GSSG import in an Opp-independent manner. These data support a model where Ctp and OppDF form a unique complex for GSH/GSSG import that supports growth and pathogenesis. Additionally, we show thatLmutilizes the inorganic sulfur sources thiosulfate and H2S for growth in a CysK-dependent manner in the absence of other L-cysteine sources. These findings suggest a pathoadaptive role for partial cysteine auxotrophy inLm, where locally high GSH/GSSG or inorganic sulfur concentrations may signal arrival to distinct host niches.
Managing environmental sustainability in customer experience processes: A multi-stakeholder analysis within the food delivery ecosystem
Authors: Calza Francesco , Sorrentino Annarita , Tutore Ilaria
Published: October 2023

Purpose

This paper aims to determine how environmental sustainability (ES) can be integrated into the customer experience (CX). In order to accomplish this, the paper uses a customer journey (CJ) perspective. Speculatively, the paper analyses the experiential stakeholder ecosystem beyond the CJ to verify the obstacles to the implementation of ES.

Design/methodology/approach

This paper uses a qualitative analysis of in-depth interviews with multiple stakeholders within the food delivery ecosystem. The multi-stakeholder analysis allows the authors to explore the problem not only from an operational point of view but also from a strategic point of view since in the delivery of a service the value for the end customer is the result of the efforts of several players.

Findings

The results shed light on the importance attributed to ES by the players that make up the food delivery ecosystem. The findings emphasise the importance of an ecosystemic view amongst stakeholders to achieve ES.

Originality/value

This research extends the scarce and embryonic literature on a sustainable CX by applying a CJ perspective, by revealing how and with which touchpoints it is possible to be environmentally sustainable in the design of the CX.
Research on fatigue life prediction model for 2A70-T6 aluminum alloy at different strain ratios
Authors: Wei Yaobing , Li Yanan , Liu Jianhui , Wang Gai , Guo Yanlei , Pan Xuemei
Published: October 2023

Purpose

In practical engineering, oil filters often work under asymmetric cyclic loading. In order to improve the prediction accuracy of fatigue life of the oil filters under asymmetric cyclic loading, the effect of strain ratio and low cycle fatigue plastic deformation on fatigue life need to be considered. This paper aims to discuss the aforementioned objective.

Design/methodology/approach

First, strain-controlled fatigue tests with strain ratios of 0, 0.5 and −1 were carried out on the oil filter material 2A70-T6 aluminum alloy, and the test data were used to obtain strain fatigue life curves at three strain ratios. Then, based on the idea of the constant life curve method, the average value of the ratio of the strain amplitude corresponding to different strain ratios under the same partial life was defined as the strain ratio factor. Finally, the elastic-plastic factor was modified by the strain ratio factor, and a new fatigue life prediction model considering the effect of strain ratio was proposed.

Findings

The proposed model was validated, respectively, by fatigue test data of 2A70-T6 aluminum alloy, 2124-T851 aluminum alloy and oil filter and the results of the proposed model were compared with the Coffin–Manson equation, Morrow model and Smith–Watson–Topper (SWT) model, showing that the proposed model had higher applicability and accuracy.

Originality/value

In this work, a strain ratio factor is established based on the idea of the constant life curve method, and the strain ratio factor is used to modify the introduced elastic-plastic factor, and then a new fatigue life prediction model considering the influence of strain ratio and low cycle fatigue plastic deformation on material fatigue damage accumulation is proposed. The results show that the prediction results of the proposed model are in good agreement with the experimental data, and the proposed model has good fatigue life prediction ability considering the influence of strain ratio and lays a foundation for the fatigue life prediction of the oil filter.