bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing the reliability and validity of pictorial-assisted 24-hour recall for measuring hand hygiene and child faeces disposal: a cross-sectional study in Malawi
Authors: Rizk Olivier , Bick Sarah , White Blessings , Chidziwisano Kondwani , Dreibelbis Robert
Published: August 2024

Whilst improving hygiene and sanitation behaviours is key to cost-effective and sustainable WASH interventions, measuring behaviour change remains a challenge. This study assessed the validity and reliability of pictorial 24-hour recall (P24hR), a novel method using unprompted recall of past activities through pictures, compared to structured observation for measuring handwashing with soap (HWWS) and safe child faeces disposal in rural Malawi. Data were collected from 88 individuals across 74 households in Chiradzulu district using both methods over a two-day period, with the recall period of the P24hR corresponding to the period of structured observation completed the previous day. Results showed poor agreement between P24hR and observations in detection of hygiene opportunities and behaviours. P24hR under-reported handwashing opportunities when frequency was high and over-reported them when frequency was low. The 95% limits of agreement for handwashing opportunities estimated through Bland-Altman analysis (-7.62 to 4.89) were unacceptably wide given median 5 opportunities observed per participant. P24hR also over-reported HWWS and safe child faeces disposal, and kappa statistics indicated agreement no better than by chance. Structured observation remains the preferred method for measuring hygiene behaviours despite its known limitations, including potential reactivity bias.
A new preprocedural predictive risk model for post-endoscopic retrograde cholangiopancreatography pancreatitis: The SuPER model
Authors: Sugimoto Mitsuru , Takagi Tadayuki , Suzuki Tomohiro , Shimizu Hiroshi , Shibukawa Goro , Nakajima Yuki , Takeda Yutaro , Noguchi Yuki , Kobayashi Reiko , Imamura Hidemichi , Asama Hiroyuki , Konno Naoki , Waragai Yuichi , Akatsuka Hidenobu , Suzuki Rei , Hikichi Takuto , Ohira Hiromasa
Published: August 2024

Background

Post–endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is a severe and deadly adverse event following ERCP. The ideal method for predicting PEP risk before ERCP has yet to be identified. We aimed to establish a simple PEP risk score model (SuPER model: Support for PEP Reduction) that can be applied before ERCP.

Methods

This multicenter study enrolled 2074 patients who underwent ERCP. Among them, 1037 patients each were randomly assigned to the development and validation cohorts. In the development cohort, the risk score model for predicting PEP was established via logistic regression analysis. In the validation cohort, the performance of the model was assessed.

Results

In the development cohort, five PEP risk factors that could be identified before ERCP were extracted and assigned weights according to their respective regression coefficients: -2 points for pancreatic calcification, 1 point for female sex, and 2 points for intraductal papillary mucinous neoplasm, a native papilla of Vater, or the pancreatic duct procedures (treated as “planned pancreatic duct procedures” for calculating the score before ERCP). The PEP occurrence rate was 0% among low-risk patients (≤ 0 points), 5.5% among moderate-risk patients (1 to 3 points), and 20.2% among high-risk patients (4 to 7 points). In the validation cohort, the C statistic of the risk score model was 0.71 (95% CI 0.64–0.78), which was considered acceptable. The PEP risk classification (low, moderate, and high) was a significant predictive factor for PEP that was independent of intraprocedural PEP risk factors (precut sphincterotomy and inadvertent pancreatic duct cannulation) (OR 4.2, 95% CI 2.8–6.3;P< 0.01).

Conclusions

The PEP risk score allows an estimation of the risk of PEP prior to ERCP, regardless of whether the patient has undergone pancreatic duct procedures. This simple risk model, consisting of only five items, may aid in predicting and explaining the risk of PEP before ERCP and in preventing PEP by allowing selection of the appropriate expert endoscopist and useful PEP prophylaxes.
Health-related quality of life in Long COVID: Mapping the condition-specific C19-YRSm measure onto the EQ-5D-5L
Authors: Smith Adam B. , Greenwood Darren C. , Williams Paul , Kwon Joseph , Petrou Stavros , Horton Mike , Osborne Thomas , Milne Ruairidh ,   LOCOMOTION Consortium, Sivan Manoj
Published: August 2024

Background

Long Covid (LC) is a clinical syndrome of persistent, fluctuating symptoms subsequent to COVID-19 infection with a prevalence global estimate of many millions of cases. LC has significant detrimental effects on health-related quality of life (HRQoL), activities of daily living (ADL), and work productivity. Condition-specific patient-reported outcome measures (PROMs), such as the modified Covid-19 Yorkshire Rehabilitation Scale (C19-YRSm), have been developed to capture the impact of LC. However, these do not provide health utility data required for cost-utility analyses of LC interventions. The aim of this study was therefore to derive a mapping algorithm for the C19-YRSm to enable health utilities to be generated from this PROM.

Methods

Data were collected from a large study evaluating LC services in the UK. A total of 1434 people with LC had completed both the C19-YRSm and the EQ-5D-5L on the same day. The EQ-5D-5L responses were then converted to EQ-5D-3L utility scores. Correlation and linear regression analyses were applied to determine items from the C19-YRSm and covariates for inclusion in the algorithm. Model fit, mean differences across the range of EQ-5D-3L scores (−0.59 to 1), and Bland-Altman plots were used to evaluate the algorithm. Responsiveness (standardised response mean; SRM) of the mapped utilities was also investigated on a subset of participants with repeat assessments (N=85).

Results

There was a strong level of association between 8 items and 2 domains on the C19-YRSm with the EQ-5D single-item dimensions. These related to joint pain, muscle pain, anxiety, depression, walking/moving around, personal care, ADL, and social role, as well as Overall Health and Other Symptoms. Model fit was good (R2= 0.7). The mean difference between the actual and mapped scores was < 0.10 for the range from 0 to 1 indicating a good degree of targeting for positive values of the EQ-5D-3L. The SRM for the mapped EQ-5D-3L health utilities (based on the C19-YRSm) was 0.37 compared to 0.17 for the observed EQ-5D-3L utility scores, suggesting the mapped EQ-5D-3L is more responsive to change.

Conclusions

We have developed a simple, responsive, and robust mapping algorithm to enable EQ-5D-3L health utilities to be generated from 10 items of the C19-YRSm. This mapping algorithm will facilitate economic evaluations of interventions, treatment, and management of people with LC, as well as further helping to describe and characterise patients with LC irrespective of any treatment and interventions.
Post Traumatic Stress Disorder in Patients with Traumatic Spinal Cord Injury
Authors: Haq Mahdi , Rashad Nabhan
Published: August 2024

Introduction

Post traumatic stress disorder (PTSD) is a psychiatric disorder that may develop after exposure to a traumatic event. Patients of traumatic spinal cord injuries are at risk of developing PTSD, and diagnosing this disorder and recognizing risk factors is important for effective treatment.

Objective

To determine the prevalence of PTSD in post-traumatic spinal cord injury patients and correlate the presence of PTSD to factors such as age, cause of injury, and level of injury.

Methods

A descriptive cross sectional study was conducted at Paraplegic Center in Peshawar, Pakistan. The Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) was used to assess the presence of post-traumatic stress disorder in patients at the Paraplegic Center. The study was carried out from 20 December 2014 to 20 February 2015 on a convenience sample of 51 patients. The criterion for inclusion in the study was to have a traumatic spinal cord injury, while the exclusion criterion was to have a spinal cord injury that was non-traumatic in nature.

Results

Out of 51 patients, 31% met the diagnostic criteria for PTSD. The age group of 15-24 years had a 27% prevalence of PTSD, while the age groups of 25-34 years and 35-44 years had a PTSD prevalence of 42% and 40% respectively. Patients who had fallen from a height had the highest prevalence of PTSD – 41%, as compared to patients who had other causes of traumatic spinal cord injury. Patients with a lumbar spinal lesion had a PTSD prevalence of 44%, whereas patients with a cervical and thoracic spinal lesion had a PTSD prevalence of 33% and 25% respectively.

Conclusion

The study shows that the middle age groups had a higher prevalence of PTSD, and patients who had fallen from a height had the highest prevalence of PTSD. Lumbar spinal lesion patients had a higher prevalence of PTSD than patients who had spinal lesions at the cervical or thoracic level.
Genome-wide association studies on malaria in Sub-Saharan Africa: a scoping review
Authors: Akoth Morine , Odhiambo John , Omolo Bernard
Published: August 2024

Background

Malaria remains one of the leading causes of death in Sub-Saharan Africa (SSA). The scoping review mapped evidence in research on existing studies on malaria genome-wide association studies (GWAS) in SSA.

Methods

A scoping review was conducted to investigate the extent of malaria studies in SSA under GWAS. The review followed the methodology for scoping reviews developed by Arksey and O’Malley, including identification of research problems, searching for relevant studies, selecting studies, charting data, collating, summarizing, and reporting the findings. Data from relevant studies were collected and synthesized using Excel and Zotero software. The data collected included information on the author, the years of study, the countries of study, the research areas of interest, and the study designs used.

Results

Of an initial pool of over 2000 articles retrieved from four databases, namely Google Scholar, PubMed, Scopus, and Web of Science, 569 were retained. After applying the inclusion-exclusion criteria, 99 articles were found to be relevant. Most of these studies (n=25, 60%) used a case-control study design, while the rest used cross-sectional, cohort, longitudinal, family-based, and retrospective designs. These studies were conducted between 2000 and 2023, with a significant increase observed in 2011. Most studies were carried out in Kenya (n = 25), Gambia (n = 17), Cameroon (n = 15), Ghana (n = 12), and Tanzania (n=11), primarily exploring genetic variants associated with malaria susceptibility, resistance, and severity.

Conclusion

Many case-control studies in Kenya and Gambia reported genetic variants in malaria susceptibility, resistance, and severity. Few articles were systematic reviews and scoping reviews. GWAS on malaria is scarce in SSA and even fewer studies are model-based. Consequently, there is a pressing need for more genome-wide research on malaria in SSA.
Integrating feature importance techniques and causal inference to enhance early detection of heart disease
Authors: Arzanipour Atousa
Published: August 2024

Heart disease remains a leading cause of mortality worldwide, necessitating robust methods for its early detection and intervention. This study employs a comprehensive approach to identify and analyze critical features contributing to heart disease. Using a dataset of 270 patients, three well-known feature importance techniques—Boruta, Information Gain, and Lasso Regression—are applied to determine the top five features for heart disease detection. Following the identification of these key features, the g-computation method, a causal inference technique, is utilized to explore the causal relationships between these features and the presence of heart disease. The findings provide valuable insights into not only the features that are highly correlated with chronic heart disease but also those that have a direct causal impact on the classification of patients. This integrated approach enhances the understanding of heart disease etiology and can inform more effective diagnostic and therapeutic strategies.
Adult renal tubular organoids can be produced from different human individuals in a completely same protocol
Authors: Mori Makiko , Mori Yutaro , Yuki Nakao , Mandai Shintaro , Fujiki Tamami , Kikuchi Hiroaki , Ando Fumiaki , Susa Koichiro , Mori Takayasu , Waseda Yuma , Yoshida Soichiro , Fujii Yasuhisa , Sohara Eisei , Uchida Shinichi
Published: August 2024

Introduction

Organoids are miniature organs produced by newly emerging technologies. Kidney organoids originated from human inducible pluripotent stem cells (iPSCs) were developed to recapitulate renal diseases. However, producing iPSC kidney organoids from multiple individuals at the same time and in a uniform condition is still impossible. Here, we report adult renal tubular organoids, “tubuloids”, established from primary renal epithelial cells from multiple human individuals in a uniform manner.

Methods

Kidneys obtained from patients due to the surgery for malignancy were minced into small pieces, and primary renal epithelial tubule cells are cultured. 4 patients had normal kidney function and 4 had mild chronic kidney disease (CKD). Growth factors were added to the primary cultured cells at the same time and Matrigel was added to these 8 lines.

Results

Primary cultured renal epithelial cells from normal kidneys showed a large number of fine, swollen epithelial appearance. On the other hand, primary cultured kidney epithelial cells from mild CKD kidneys were smaller and slightly elongated than those of normal kidneys. The growth speed was faster in normal kidney cells than in mild CKD cells. At the beginning of the three-dimensionalization (day 0), normal renal tubuloids grew faster than mild CKD tubuloids. The difference in size between normal tubuloids and mild CKD ones became less noticeable on day 5. Both types of tubuloids reached almost same size on day 10. All 8 strains are of different human origin, and uniform tubuloids could be produced at the same time and in a uniform protocol.

Conclusion

In terms of pathological models, the differences between mouse models and humans cannot be ignored, and there is a great need for a more human-like model of human pathology from both medical and research perspectives. Our renal tubular organoids can be produced in a uniform manner at the same time. It is expected to be used as a new type of convenient human pathological model.
An aberrant protamine ratio is associated with decreased H4ac levels in murine and human sperm
Authors: Kruse Alexander , Schneider Simon , Merges Gina Esther , Fröbius Andreas Christian , Forné Ignasi , Imhof Axel , Schorle Hubert , Steger Klaus
Published: August 2024

Protamine 2 (Prm2/PRM2), together with Protamine 1 (Prm1/PRM1), constitute the two protamines found in both murine and human sperm. During spermiogenesis in haploid male germ cells, chromatin undergoes significant condensation, a phase in which most histones are replaced by a species-specific ratio of these two protamines. Altered PRM1/PRM2 ratios are associated with subfertility and infertility in both male mice and men. Notably, during histone-to-protamine exchange a small fraction of histones remains (ranging from 1% to 15%) bound to DNA. The regulatory roles of these residual histones, governed by post-translational modifications (PTMs), play a pivotal role in spermatogenesis, particularly in chromatin remodeling and epigenetic regulation of genes during sperm differentiation or even in early embryogenesis.

In this study, utilizing aPrm2-deficient mouse model and conducting an analysis of sperm samples from men exhibiting either normozoospermia or atypical spermiograms, we observed alterations in the methylation and acetylation profiles of histones H3 and H4. Subsequent in-depth analysis revealed that discrepancies in protamine ratios do not significantly influence the post-translational modifications (PTMs) of histones in testicular sperm. In epididymal sperm these altered protamine ratios are associated with a reduction in the acetylation levels of histone H4 (H4ac), a phenomenon consistent across both murine and human samples. In particular, H4K5ac and H4K12ac were identified as the two modifications that appear to decrease as a result of reducedPrm2/PRM2levels. Our findings reveal that Protamine 2 is necessary for the maintenance of specific histone PTMs, such as acetylation, which is essential for proper spermatogenesis and particularly for chromatin remodeling.
Brain-like border ownership signals support prediction of natural videos
Authors: Ye Zeyuan , Wessel Ralf , Franken Tom P.
Published: August 2024

To make sense of visual scenes, the brain must segment foreground from background. This is thought to be facilitated by neurons in the primate visual system that encode border ownership (BOS), i.e. whether a local border is part of an object on one or the other side of the border. It is unclear how these signals emerge in neural networks without a teaching signal of what is foreground and background. In this study, we investigated whether BOS signals exist in PredNet, a self-supervised artificial neural network trained to predict the next image frame of natural video sequences. We found that a significant number of units in PredNet are selective for BOS. Moreover these units share several other properties with the BOS neurons in the brain, including robustness to scene variations that constitute common object transformations in natural videos, and hysteresis of BOS signals. Finally, we performed ablation experiments and found that BOS units contribute more to prediction than non-BOS units for videos with moving objects. Our findings indicate that BOS units are especially useful to predict future input in natural videos, even when networks are not required to segment foreground from background. This suggests that BOS neurons in the brain might be the result of evolutionary or developmental pressure to predict future input in natural, complex dynamic visual environments.
Translation efficiency covariation across cell types is a conserved organizing principle of mammalian transcriptomes
Authors: Liu Yue , Rao Shilpa , Hoskins Ian , Geng Michael , Zhao Qiuxia , Chacko Jonathan , Ghatpande Vighnesh , Qi Kangsheng , Persyn Logan , Wang Jun , Zheng Dinghai , Zhong Yochen , Park Dayea , Cenik Elif Sarinay , Agarwal Vikram , Ozadam Hakan , Cenik Can
Published: August 2024

Characterization of shared patterns of RNA expression between genes across conditions has led to the discovery of regulatory networks and novel biological functions. However, it is unclear if such coordination extends to translation, a critical step in gene expression. Here, we uniformly analyzed 3,819 ribosome profiling datasets from 117 human and 94 mouse tissues and cell lines. We introduce the concept ofTranslation Efficiency Covariation(TEC), identifying coordinated translation patterns across cell types. We nominate potential mechanisms driving shared patterns of translation regulation. TEC is conserved across human and mouse cells and helps uncover gene functions. Moreover, our observations indicate that proteins that physically interact are highly enriched for positive covariation at both translational and transcriptional levels. Our findings establish translational covariation as a conserved organizing principle of mammalian transcriptomes.
Ultra-low photodamage three-photon microscopy assisted by neural network for monitoring regenerative myogenesis
Authors: Li Yifei , Li Keying , He Mubin , Liang Chenlin , Xie Xin , Qian Jun
Published: August 2024

Three-photon microscopy (3PM) enables high-resolution three-dimensional (3D) imaging in deeply situated and highly scattering biological specimens, facilitating precise characterization of biological morphology and cellular-level physiologyin vivo. However, the use of fluorescent probes with relatively low three-photon absorption cross-sections necessitates high-peak-power lasers for excitation, which poses inherent risks of light-induced damage. Additionally, the low repetition frequency of these lasers prolongs scanning time per pixel, hampering imaging speed and exacerbating the potential for photodamage. Such limitations hinder the application of 3PM in studying vulnerable tissues, including muscle regeneration. To address this critical issue, we developed the Multi-Scale Attention Denoising Network (MSAD-Net), a precise and versatile denoising network suitable for diverse structures and varying noise levels. Our network enables the use of lower excitation power (1/4-1/2 of the common power) and shorter scanning time (1/6-1/4 of the common time) in 3PM while preserving image quality and tissue integrity. It achieves an impressive structural similarity index (SSIM) of up to 0.9932 and an incredibly fast inference time of just 80 milliseconds per frame which ensured both high fidelity and practicality for downstream applications. By utilizing MSAD-Net-assisted imaging, we comprehensively characterize the biological morphology and functionality of muscle regeneration processes through deepin vivofive-channel imaging under extremely low excitation power and short scanning time, while maintaining a high signal-to-background ratio (SBR) and excellent axial spatial resolution. Furthermore, we conducted high axial-resolution dynamic imaging of vascular microcirculation, macrophages, and ghost fibers. Our findings provide a deeper understanding of the mechanisms underlying muscle regeneration at the cellular and tissue levels.
A Self-Assembling Immune-Featured Osteosarcoma Patient/PDX Derived Organoid Model and Biobank for Personalized Immune Therapy
Authors: Mu Haoran , Tao Yining , Wang Jinzeng , He Xin , Zhang Qi , Chen Weixi , Yao Bing , Ding Sen , Yang Xiyu , Zhang Liyuan , Wang Hongsheng , Zuo Dongqing , Shen Jiakang , Sun Mengxiong , Wang Haoyu , Jiao Ming , Jin Xinmeng , Jin Yinhui , Liang Youzhi , Gong Yuyan , Mao Winfred , Liu Qian , Wang Zhuoying , Lv Yu , Xu Jing , Zhang Tao , Yang Yuqin , Lin Jun , Asward Fred J. , Joseph James D. , Li Mingxi , Cai Zhengdong , Sun Wei , Yang Liu , Hua Yingqi
Published: August 2024

Osteosarcoma (OS) exhibit intra- and inter-heterogeneity, complicating the exploration of effective therapeutic strategies. Traditionalin vitroandin vivomodels are limited in inheriting biological and genomic heterogeneities of OS patients, even in inheriting the features on tumor microenvironment. The prolonged generation time of current models makes the drug development of OS slow and is not suitable to clinically rapid timing. Here, we introduce methods for generating and biobanking patient/PDX-derived osteosarcoma organoids (OS PD(X)Os) that recapitulate the histological, biological and genomic features of their paired OS patients. OS PD(X)Os can be generated quickly with high reliabilityin vitroor transplanted to immunodeficient mice. We further demonstrate an immune-featured OS PD(X)O (named iOS) model and its method for testing personalized chemotherapy response, personalized immune therapeutic strategy and target drug development, such as a novel PRMT5MTAinhibitor ARPN2169 on MTAP-deleted OS. Our studies show that iOS models maintain many typical features of OS and could be rapidly employed to investigate patient-specific therapeutic strategies. Additionally, our biobank establishes a rich resource for basic, translational and even clinical OS researches.
Exploiting functional regions in the viral RNA genome as druggable entities
Authors: Luo Dehua , Zheng Yingge , Huang Zhiyuan , Wen Zi , Guo Lijun , Deng Yingxiang , Li Qingling , Bai Yuqing , Haider Shozeb , Wei Dengguo
Published: August 2024

RNA-targeting compounds or small interfering RNAs (siRNAs) offer a potent means for controlling viral infections. An essential prerequisite to their design depends on identifying conserved and functional viral RNA structures in cells. Techniques that probe RNA structuresin situhave been developed recently including SHAPE-MaP, which has been helpful in analyzing the secondary structures of RNA. In this study, we report on the application of SHAPE-MaP to the Porcine Epidemic Diarrhoea Virus (PEDV) RNA genome to categorize different functional regions including potential quadruplex forming sequence and target sites of small interfering RNA (siRNA). Our results show that these structures can be exploited to inhibit viral proliferation and that SHAPE-MaP is an effective method to the identification of secondary structures in RNA genomes.
Continuous emergence of phototaxis inDictyostelium discoideum
Authors: Genettais Damien , Bernard Charles , Geoffroy Felix , Nizak Clément , Adiba Sandrine
Published: August 2024

The evolutionary transition from uni- to multicellularity is associated with new properties resulting from collective cell behavior. The social amoebaDictyostelium discoideumalternating between individual cells and multicellular forms of varying size provides a powerful biological system to characterize such emergent properties. Multicellular forms coined slugs have long been described as chemotactic towards cAMP, and also as phototactic. While chemotaxis is also well-documented at the single-cell level, which merely explains slug chemotaxis, we asked whether slug phototaxis is an emergent property of multicellularity. For this, we developed an automated microscopy setup to quantify and compare the migration trajectories of single cells and slugs moving in the dark or illuminated with lateral light. We find that single cells, either extracted from phototactic slugs or taken prior to multicellular aggregation, are not phototactic, implying that slug phototaxis results from interactions between cells that lack this property. Further, by analysing slugs composed of a varying number of cells, we find that phototaxis efficiency increases continuously with slug size. Cell-cell interactions combined with self-organization are thus key elements for this property to emerge.
AmygdalaGo-BOLT3D: A boundary learning transformer for tracing human amygdala
Authors: Dong Bo , Zhou Quan , Gao Peng , Wei Jintao , Xiao Jiale , Wang Wei , Liang Peipeng , Lin Danhua , He Hongjian , Zuo Xi-Nian
Published: August 2024

Automated amygdala segmentation is one of the most common tasks in human neuroscience research. However, due to the small volume of the human amygdala, especially in developing brains, the precision and consistency of the segmentation results are often affected by individual differences and inconsistencies in data distribution. To address these challenges, we propose an algorithm for learning boundary contrast of 427 manually traced amygdalae in children and adolescents to generate a transformer, AmygdalaGo-BOLT3D, for automatic segmentation of human amygdala. This method focuses on the boundary to effectively address the issue of false positive recognition and inaccurate edges due to small amygdala volume. Firstly, AmygdalaGo-BOLT3D develops a basic architecture for an adaptive cooperation network with multiple granularities. Secondly, AmygdalaGo-BOLT3D builds the self-attention-based consistency module to address generalizability problems arising from individual differences and inconsistent data distributions. Third, AmygdalaGo-BOLT3D adapts the original sample-mask model for the amygdala scene, which consists of three parts, namely a lightweight volumetric feature encoder, a 3D cue encoder, and a volume mask decoder, to improve the generalized segmentation of the model. Finally, AmygdalaGo-BOLT3D implements a boundary contrastive learning framework that utilizes the interaction mechanism between a prior cue and the embedded magnetic resonance images to achieve effective integration between the two. Experimental results demonstrate that predictions of the overall structure and boundaries of the human amygdala exhibit highly improved precision and help maintain stability in multiple age groups and imaging centers. This verifies the stability and generalization of the algorithm designed for multiple tasks. AmygdalaGo-BOLT3D has been deployed for the community (GITHUB LINK) to provide an open science foundation for its applications in population neuroscience.
Early life challenge enhances cortisol regulation in zebrafish larvae
Authors: Castillo-Ramírez Luis A. , Herget Ulrich , Ryu Soojin , De Marco Rodrigo J.
Published: August 2024

The hypothalamic-pituitary-adrenal (HPA) axis in mammals and the hypothalamic-pituitary-interrenal (HPI) axis in fish are open systems that adapt to the environment during development. Little is known about how this adaptation begins and regulates early stress responses. We used larval zebrafish to examine the impact of prolonged forced swimming at 5 days post-fertilization (dpf), termed early-life challenge (ELC), on cortisol responses, neuropeptide expression in the nucleus preopticus (NPO), and gene transcript levels. At 6 dpf, ELC-exposed larvae showed normal baseline cortisol but reduced reactivity to an initial stressor. Conversely, they showed increased reactivity to a second stressor within the 30-minute refractory period, when cortisol responses are typically suppressed. ELC larvae had fewer corticotropin-releasing hormone (crh), arginine vasopressin (avp), and oxytocin (oxt)-positive cells in the NPO, with reduced crh and avp co-expression. Gene expression analysis revealed upregulation of genes related to cortisol metabolism (hsd11b2,cyp11c1), steroidogenesis (star), and stress modulation (crh,avp,oxt). These results suggest that early environmental challenge initiates adaptive plasticity in the HPI axis, tuning cortisol regulation to balance responsiveness and protection during repeated stress. Future studies should explore the broader physiological effects of prolonged forced swimming and its long-term impact on cortisol regulation and stress-related circuits.

This study explores how early-life challenges in zebrafish affect stress responses and hormone regulation, offering insights into developmental adaptability and stress management mechanisms.
Efficient modular system identification provides a high-resolution assay of temporal processing and reveals the multilevel effects of attention along the human auditory pathway
Authors: Singh Ravinderjit , Bharadwaj Hari
Published: August 2024

Human studies of auditory temporal processing and the effects therein of aging, hearing loss, musicianship, and other auditory processing disorders have conventionally employed brainstem evoked potentials (e.g., FFRs/EFRs targeting specific modulation frequencies). Studies of temporal processing in forebrain structures are fewer and are often restricted to the 40 Hz steady-state response. One factor contributing to the limited investigation is the lack of a fast and reliable method to characterize temporal processing non-invasively in humans over a wide range of modulation frequencies. Here, we use a system-identification approach where white noise, modulated using an extended maximum-length sequence (em-seq), is employed to target stimulus energy toward a modulation-frequency range of interest and efficiently obtain a robust auditory modulation-temporal response function or ‘mod-TRF’. The mod-TRF can capture activity from sources in the early processing pathway (5-7 ms latency), middle-latency region (MLR), and late latency region (LLR). The mod-TRF is a high-resolution, modular assay of the temporal modulation transfer function (tMTF) in that the distinct neural components contributing to the tMTF can be separated on the basis of their latency, modulation frequency band, and scalp topography. This decomposition provides the insight that the seemingly random individual variation in the shape of the tMTF can be understood as arising from individual differences in the weighting and latency of similar underlying neural sources in the composite scalp response. We measured the mod-TRF under different states of attention and found a reduction in latency or enhancement of amplitude of the response from specific sources. Surprisingly, we found that attention effects can extend to the earliest parts of the processing pathway (5ms) in highly demanding tasks. Taken together, the mod-TRF is a promising tool for dissecting auditory temporal processing and obtain further insight into a variety of phenomenon such as aging, hearing loss, and neural pathology.
Rapid depletion and super-resolution microscopy reveal an unexpected role of the nuclear-speckle protein SRSF5 in paraspeckle assembly and dynamics during cellular stress
Authors: Arnold Benjamin , Kessler Laurell , Okuda Ellen Kazumi , Riegger Ricarda J. , Cañás Maria Clara Hernández , Zebrowska Ewelina , Bakisoglu Cem , Nagasse Helder Y. , Stanek David , Dormann Dorothee , Zarnack Kathi , Heilemann Mike , Müller-McNicoll Michaela
Published: August 2024

Nuclear speckles (NS) and paraspeckles (PS) are adjacent condensates with distinct protein composition, with serine-arginine-rich splicing factors (SRSFs) concentrated in NS. Surprisingly, we find that SRSF5 is present in both. Combining super-resolution imaging, proximity proteomics and iCLIP, we show that SRSF5 binds with PS core proteins to the PS-scaffold RNANEAT1and locates between PS spheres. Acute SRSF5 depletion results in reduced PS with differently packagedNEAT1. Under stress, SRSF5’s association with PS increases, and without SRSF5, PS cluster assembly is impaired. Interfering with binding to purine-rich RNAs even causes PS-NS fusion. In an intriguing over-compensation, longer SRSF5 depletion reduces TDP-43 levels via premature polyadenylation, leading toNEAT1isoform switching and more PS. We propose that SRSF5 forms a stress-specific PS shell and acts as a glue for PS clusters. Additionally, we uncover SRSF5 as a novel regulator of TDP-43 and demonstrate how acute depletion distinguishes direct from compensatory effects.

Highlights

NS protein SRSF5 associates with PS shells and enriches between PS spheres

SRSF5 binds the PS-scaffold RNANEAT1and ensures properNEAT1packaging

SRSF5 association with PS increases under stress and promotes cluster formation

Interfering with binding to purine-rich RNAs causes the fusion of PS and NS

Acute SRSF5 depletion reveals compensatory effects on PS assembly and dynamics

SRSF5 regulates TDP-43 levels via premature polyadenylation
Immunotherapeutic strategy to prevent progression and complications of acute rheumatic fever
Authors: Rafeek Rukshan Ahamed Mohamed , Ketheesan Natkunam , Good Michael F. , Pandey Manisha , Lepletier Ailin
Published: August 2024

Acute rheumatic fever (ARF) is an autoimmune disease triggered by antibodies and T-cells targeting the Group A streptococcal (GAS, Strep A) bacterium, often leading to rheumatic heart disease (RHD). Long-term antibiotic therapy is recognized as a cornerstone of public health programs to prevent reinfection and progression of ARF. However, better tools to slow disease progression, and mitigate its lifelong consequences are required. Evidence obtained in a preclinical model suggests that this can be achieved. Using the rat autoimmune valvulitis model, we explored the potential of low-dose interleukin 2 (LD-IL-2) as an immunotherapeutic intervention. In this model injection of recombinant Strep A M5 protein (rM5) to Lewis rats induce autoimmune complications, cardiac tissue inflammation and conduction abnormalities. In animals injected with rM5 and treated with LD-IL-2, no cardiac functional or histological changes were observed. LD-IL-2 therapy effectively reduced the production of cross-reactive antibodies against cardiac tissue and induced a significant increase in classical regulatory T-cells (Treg) and CD8+Tregs in the mediastinal (heart-draining) lymph nodes. These novel findings suggest LD-IL-2 will be an effective immunotherapeutic agent for treating ARF/RHD.
Quantifying the impact of a broadly protective sarbecovirus vaccine in a future SARS-X pandemic
Authors: Whittaker Charles , Barnsley Gregory , Olivera Mesa Daniela , Laydon Daniel J , Tan Chee Wah , Zhu Feng , Johnson Rob , Doohan Patrick , Nedjati-Gilani Gemma , Winskill Peter , Hogan Alexandra B. , Deol Arminder , Mukandavire Christinah , Hauck Katharina , Lye David Chien Boon , Wang Lin-Fa , Watson Oliver J. , Ghani Azra C
Published: August 2024

COVID-19 has underscored the need for more timely access to vaccines during future pandemics. This has motivated development of broad-spectrum vaccines providing protection against viral families, which could be stockpiled ahead of an outbreak and deployed rapidly following detection. We use mathematical modelling to evaluate the utility of a broadly protective sarbecovirus vaccine (BPSV) during a hypothetical SARS-X outbreak, including ring-vaccination, spatial targeting and mass vaccination of high-risk populations. Our results show BPSV ring- or spatially-targeted vaccination strategies are unlikely to contain a SARS-CoV-2-like virus but could contain or slow the spread of a SARS-CoV-1-like virus. Vaccination of high-risk populations with the BPSV ahead of a virus-specific vaccine (VSV) becoming available could substantially reduce mortality. For a 250-day VSV development timeline, BPSV availability reduced infection-related deaths in our model by 54% on average, though exact impact depended on the non-pharmaceutical intervention (NPI) scenario considered. We further show that BPSV availability enables shorter and less stringent NPIs to be imposed whilst limiting disease burden to that observed in the VSV-only scenario, though results are sensitive to vaccine properties (e.g. efficacy), health system capabilities (e.g. vaccination rollout speed) and the assumed timeline to VSV availability. Our modelling suggests that availability of a BPSV for those aged 60+ years could have averted 40-65% of COVID-19 deaths during the pandemic’s first year, with exact impact depending on the size of the maintained stockpile. Our work highlights significant potential impact of a BPSV, but that achieving this depends on investment into health systems enabling rapid and equitable access during future SARS-X pandemics.
Lack of Epistatic Interaction ofSNCAwithAPOEin Synucleinopathies
Authors: Saini Prabhjyot , Yu Eric , Estiar Mehrdad A. , Krohn Lynne , Mufti Kheireddin , Rudakou Uladzislau , Ruskey Jennifer A. , Asayesh Farnaz , Laurent Sandra B. , Spiegelman Dan , Arnulf Isabelle , Montplaisir Jacques Y. , Gagnon Jean-François , Desautels Alex , Dauvilliers Yves , Gigli Gian Luigi , Valente Mariarosaria , Janes Francesco , Bernardini Andrea , Sonka Karel , Kemlink David , Oertel Wolfgang , Kaivola Karri , Janzen Annette , Plazzi Giuseppe , Antelmi Elena , Biscarini Francesco , Figorilli Michela , Puligheddu Monica , Mollenhauer Brit , Trenkwalder Claudia , Sixel-Döring Friederike , De Cock Valérie Cochen , Monaca Christelle Charley , Heidbreder Anna , Ferini-Strambi Luigi , Dijkstra Femke , Viaene Mineke , Abril Beatriz , Boeve Bradley F. , Postuma Ronald B. , Rouleau Guy A. , Anselmi Victoria , Ibrahim Abubaker , Stefani Ambra , Högl Birgit , Hu Michele T.M. , Scholz Sonja W. , Gan-Or Ziv
Published: August 2024

Two recent studies suggested that theAPOEε4 haplotype was associated with increased α-synuclein pathology in cell and mouse models. Genetic variants in theSNCAregion have strong association with Parkinson’s disease (PD), Dementia with Lewy Bodies (DLB), and idiopathic REM Sleep Behavior Disorder (iRBD), whileAPOEis a genetic risk determinant for only DLB. To determine if genetic-level interactions betweenSNCAandAPOEexists that can explain the protein-level association, we investigated the genotypic interaction ofAPOEandSNCAin cohorts of PD, DLB, and iRBD. We analyzed genome-wide association study (GWAS) data from 5,229 PD patients and 5,480 controls, 2,610 DLB patients and 1,920 controls, and 1,055 iRBD patients and 3,667 controls. We used logistic regression interaction models across all 3 cohorts independently between the 1) top GWAS signals ofSNCASNPs andAPOEhaplotypes, 2) SNP x SNP and 3-way SNP interaction across the entire coding region plus 200kb flanking each gene. No significant interactions were found to be associated with any of the synucleinopathies after correction for multiple testing. Our results do not support a role for genetic interactions betweenAPOEandSNCAacross PD, DLB, and iRBD. Since the tested genetic variants affect the expression and function of these proteins, it is likely that any interactions between them does not affect the risk of PD, DLB and iRBD.
Intestinal Parasites among Primary School Children in Aden, Yemen
Authors: Gubran Ali N. M. , Al-Haidary Naif Mohammed , Bajubair Marwa Faisal M. , Algibary Afrah Mohsen Ali , Ali Manal Galeb Mhmad , Ali Marwa Fuad Othman
Published: August 2024

Background

Intestinal parasite infection is a significant public health problem worldwide. This study aimed to determine the prevalence of intestinal parasites among primary school children, identify the most common types of parasites, and identify the risk factors contributing to infection in Aden, Yemen.

Methodology/Principal Findings

An analytical cross-sectional study was conducted on 201 school children in Aden, Yemen. Stool specimens were collected and tested using direct methods (saline and iodine preparations) and sedimentation concentration techniques. Data analysis was performed using SPSS (Version 21) with p ≤ 0.05 considered statistically significant. The overall prevalence of intestinal parasites was 47.3%; 35.8% had a single parasite and 11.5% had multiple parasites. Higher rates were observed among female schoolchildren (51.2%), children whose mothers had primary education (51.3%), secondary education (50%), housewives (48.5%), and children aged >9 years (50%). The most predominant parasite was Entamoeba histolytica/dispar (36.3%). There was no significant association between the identified risk factors and intestinal parasitic infections.

Conclusions/Significance

The prevalence rate of intestinal parasites is high in Aden, Yemen, with Entamoeba histolytica/dispar being the most dominant parasite. The highest rates were found among female schoolchildren, those whose mothers were housewives with primary or secondary education, and children aged >9 years.

Author Summary

Intestinal parasite infections are a major health issue in many parts of the world, especially in developing countries like Yemen. This study investigated the prevalence of these infections among primary school children in Aden, Yemen. By analyzing stool samples from 201 children, we found that nearly half were infected with at least one type of parasite. The most common parasite was Entamoeba histolytica/dispar, affecting more than a third of the children. We also discovered that certain groups of children were more likely to be infected, such as older children, girls, and those whose mothers had lower levels of education or were housewives. Understanding these patterns can help in developing targeted interventions to reduce the spread of these infections and improve children’s health and educational outcomes.
TIDAL – Tool to Implement Developmental Analysis of Longitudinal data
Authors: Kwong Alex S. F. , Edmondson-Stait Amelia , Xu Eileen , Thompson Ellen J. , Parker Richard M. A. , Elhakeem Ahmed , Romaniuk Liana , Pearson Rebecca M. , Tilling Kate , Eley Thalia C. , McIntosh Andrew M , Whalley Heather C.
Published: August 2024

Motivation

Growth curve modelling is one method used to model trajectories of traits and behaviours over time. However, accessing, analysing and interpreting trajectories requires statistical expertise, thereby creating potential barriers for users to implement and understand longitudinal traits. TIDAL is a user-friendly research tool designed to facilitate trajectory modelling by improving access, analysis and interpretation of trajectory and longitudinal data.

Implementation

TIDAL is available in two formats: an R package and an online Shiny application. The R package can be used offline, negating the need to upload potentially sensitive data.

General features

TIDAL includes all the main steps of trajectory analysis including: 1) data preparation, (converting data from wide to long format); 2) data exploration, via basic plots and descriptive information; 3) analysis of trajectories using mixed effects modelling, interpretation of results, visualisation of trajectories, and extraction of key features (scores at different ages; area under the curve); and 4) interactions to derive population specific trajectories, combined with all the above. TIDAL is built with a simple graphical interface to guide users through each step. R syntax accompanies each step.

Availability

Both versions of TIDAL can be found here: [https://tidal-modelling.github.io/].
Results of the Protein Engineering Tournament: An Open Science Benchmark for Protein Modeling and Design
Authors: Armer Chase , Kane Hassan , Cortade Dana L. , Redestig Henning , Estell David A. , Yusuf Adil , Rollins Nathan , Spinner Hansen , Marks Debora , Brunette TJ , Kelly Peter J. , DeBenedictis Erika
Published: August 2024

The grand challenge of protein engineering is the development of computational models to characterize and generate protein sequences for arbitrary functions. Progress is limited by lack of 1) benchmarking opportunities, 2) large protein function datasets, and 3) access to experimental protein characterization. We introduce the Protein Engineering Tournament—a fully-remote competition designed to foster the development and evaluation of computational approaches in protein engineering. The tournament consists of anin silicoround, predicting biophysical properties from protein sequences, followed by anin vitroround where novel protein sequences are designed, expressed and characterized using automated methods. Upon completion, all datasets, experimental protocols, and methods are made publicly available. We detail the structure and outcomes of a pilot Tournament involving seven protein design teams, powered by six multi-objective datasets, with experimental characterization by our partner, International Flavors and Fragrances. Forthcoming Protein Engineering Tournaments aim to mobilize the scientific community towards transparent evaluation of progress in the field.

Graphical Abstract
A posture subspace in primary motor cortex
Authors: Marino Patrick J. , Bahureksa Lindsay , Fernández Fisac Carmen , Oby Emily R. , Smoulder Adam L. , Motiwala Asma , Degenhart Alan D. , Grigsby Erinn M. , Joiner Wilsaan M. , Chase Steven M. , Yu Byron M. , Batista Aaron P.
Published: August 2024

To generate movements, the brain must combine information about movement goal and body posture. Motor cortex (M1) is a key node for the convergence of these information streams. How are posture and goal information organized within M1’s activity to permit the flexible generation of movement commands? To answer this question, we recorded M1 activity while monkeys performed a variety of tasks with the forearm in a range of postures. We found that posture- and goal-related components of neural population activity were separable and resided in nearly orthogonal subspaces. The posture subspace was stable across tasks. Within each task, neural trajectories for each goal had similar shapes across postures. Our results reveal a simpler organization of posture information in M1 than previously recognized. The compartmentalization of posture and goal information might allow the two to be flexibly combined in the service of our broad repertoire of actions.