bluuebunny/crossref_metadata_2025_split huggingface dataset:
TIAM1 signaling drives prostatic budding and branching phenotypes and is a potential therapeutic target for BPH
Authors: Khedmatgozar Hamed , Dutta Sayanika , Dominguez Michael , Latour Daniel , Johnson Melanie , Fokar Mohamed , Warraich Irfan , de Riese Werner , Haynes Allan , Matusik Robert J. , Brandi Luis , Nandana Srinivas , Tripathi Manisha 
Published: February 2024

AbstractBenign prostatic hyperplasia (BPH) is the most prevalent urologic disease in men aged over 50 years. However, the molecular mechanisms that drive BPH pathophysiology remain elusive. In this study, we integrated bioinformatic and experimental analyses of human BPH to identify TIAM1-RAC1 signaling pathway as a promising candidate for a molecular-based approach for BPH therapy. First, elevated TIAM1 expression in a BPH transcriptomic signature that was generated from the analysis of RNA-seq data from three independent BPH patient cohorts was validated at the protein level in a fourth patient cohort. Additional bioinformatic analyses of the BPH transcriptomic signature pointed to TIAM1-RAC1 pathway as the potential lead therapeutic pathway; and NSC23766 - a small molecule inhibitor of TIAM1 signaling - as a developmental lead compound for BPH therapy. Next, a proof-of-concept pharmacological approach of TIAM1-RAC1 inhibition in human prostatic cells using NSC23766 resulted in attenuated organoid budding and branching - a developmental program associated with prostatic nodule formation and BPH pathogenesis. Finally, shRNA-based genetic knock-down of TIAM1 in human prostatic cells led to a reduction in budding and branching phenotypes thereby phenocopying the effects of NSC23766. Together, our observations implicate elevated TIAM1 as a driver of budding and branching in BPH, and our studies pave the way for TIAM1-RAC1 based targeted approach for the treatment of the disease.
Characterisation of behaviours relevant to apathy syndrome in the aged male rat
Authors: Jackson Megan G , Lightman Stafford L , Robinson Emma S J 
Published: February 2024

AbstractApathy is a complex psychiatric syndrome characterised by motivational deficit, emotional blunting and cognitive changes. It occurs alongside a broad range of neurological disorders, but also occurs in otherwise healthy ageing. Despite its clinical prevalence, apathy does not yet have a designated treatment strategy. Generation of a translational animal model of apathy syndrome would facilitate the development of novel treatments. Given the multidimensional nature of apathy, a model cannot be achieved with a single behavioural test. Using a battery of behavioural tests we investigated whether aged rats exhibit behavioural deficits across different domains relevant to apathy.Using the effort for reward and progressive ratio tasks we found that aged rats (21-27 months) show intact reward motivation. Using the novelty supressed feeding test and position-based object exploration we found aged rats showed increased anxiety-like behaviour inconsistent with emotional blunting. The sucrose preference test and reward learning assay showed intact reward sensitivity and reward-related cognition in aged rats. However, using a bowl-digging version of the probabilistic reversal learning task, we found a deficit in cognitive flexibility in aged rats that did not translate across to a touchscreen version of the task.While these data reveal important changes in cognitive flexibility and anxiety associated with ageing, aged rats do not show deficits across other behavioural domains relevant to apathy. This suggests that aged rats are not a suitable model for age-related apathy syndrome. These findings contrast with previous work in mice, revealing important species differences in behaviours relevant to apathy syndrome in ageing.
Tunable Macroscopic Alignment of Self-Assembling Peptide Nanofibers
Authors: Farsheed Adam C. , Zevallos-Delgado Christian , Yu Le Tracy , Saeidifard Sajede , Swain Joseph W.R. , Makhoul Jonathan T. , Thomas Adam J. , Cole Carson C. , Huitron Eric Garcia , Grande-Allen K. Jane , Singh Manmohan , Larin Kirill V. , Hartgerink Jeffrey D. 
Published: February 2024

AbstractFibrous proteins that comprise the extracellular matrix (ECM) guide cellular growth and tissue organization. A lack of synthetic strategies able to generate aligned, ECM-mimetic biomaterials has hampered bottom-up tissue engineering of anisotropic tissues and led to a limited understanding of cell-matrix interactions. Here, we present a facile extrusion-based fabrication method to produce anisotropic, nanofibrous hydrogels using self-assembling peptides. The application of shear force coinciding with ion-triggered gelation is used to kinetically trap supramolecular nanofibers into aligned, hierarchical structures. We establish how modest changes in phosphate buffer concentration during peptide self-assembly can be used to tune their alignment and packing. In addition, increases in the nanostructural anisotropy of fabricated hydrogels are found to enhance their strength and stiffness under hydrated conditions. To demonstrate their utility as an ECM-mimetic biomaterial, aligned nanofibrous hydrogels are used to guide directional spreading of multiple cell types, but strikingly, increased matrix alignment is not always correlated with increased cellular alignment. Nanoscale observations reveal differences in cell-matrix interactions between variably aligned scaffolds and implicate the need for mechanical coupling for cells to understand nanofibrous alignment cues. In total, innovations in the supramolecular engineering of self-assembling peptides allow us to generate a gradient of anisotropic nanofibrous hydrogels, which are used to better understand directed cell growth.
Lipidomics of homeoviscous adaptation to low temperatures inStaphylococcus aureusutilizing exogenous straight-chain unsaturated fatty acids over biosynthesized endogenous branched-chain fatty acids
Authors: Barbarek Shannon C. , Shah Ritika , Paul Sharanya , Alvarado Gloria , Appala Keerthi , Henderson Emma C. , Strandquist Evan T. , Pokorny Antje , Singh Vineet K. , Gatto Craig , Dahl Jan-Ulrik , Hines Kelly M. , Wilkinson Brian J. 
Published: February 2024

ABSTRACTIt is well established thatStaphylococcus aureuscan incorporate exogenous straight-chain unsaturated fatty acids (SCUFAs) into membrane phospho- and glyco-lipids from various sources in supplemented culture media, and when growingin vivoin an infection. Given the enhancement of membrane fluidity when oleic acid (C18:1Δ9) is incorporated into lipids, we were prompted to examine the effect of medium supplementation with C18:1Δ9 on growth at low temperatures. C18:1Δ9 supported the growth of a cold-sensitive, branched-chain fatty acid (BCFA)-deficient mutant at 12°C. Interestingly, we found similar results in the BCFA-sufficient parental strain. We show that incorporation of C18:1Δ9 and its elongation product C20:1Δ9 into membrane lipids was required for growth stimulation and relied on a functional FakAB incorporation system. Lipidomics analysis of the phosphatidylglycerol (PG) and diglycosyldiacylglycerol (DGDG) lipid classes revealed major impacts of C18:1Δ9 and temperature on lipid species. Growth at 12°C in the presence of C18:1Δ9 also led to increased production of the carotenoid pigment staphyloxanthin; however, this was not an obligatory requirement for cold adaptation. Enhancement of growth by C18:1Δ9 is an example of homeoviscous adaptation to low temperatures utilizing an exogenous fatty acid. This may be significant in the growth ofS. aureusat low temperatures in foods that commonly contain C18:1Δ9 and other SCUFAs in various forms.IMPORTANCEWe show thatS. aureuscan use its known ability to incorporate exogenous fatty acids to enhance its growth at low temperatures. Individual species of phosphatidylglycerols and diglycosyldiacylglycerol bearing one or two degrees of unsaturation derived from incorporation of C18:1Δ9 at 12°C are described for the first time. In addition, enhanced production of the carotenoid staphyloxanthin occurs at low temperatures. The studies describe a biochemical reality underlying in membrane biophysics. This is an example of homeoviscous adaptation to low temperatures utilizing exogenous fatty acids over the regulation of the biosynthesis of endogenous fatty acids. The studies have likely relevance to food safety in that unsaturated fatty acids may enhance growth ofS. aureusin the food environment.
Online early supportive psychological intervention for bereaved families during COVID-19: Lessons Learned and Implementation Challenges
Authors: Hashemzadeh Mona , Jamaloo Samira , Shahmohamadi Elnaz , Rahmani Anahita , Damavandi Gilda Rajabi , Mousavi Mehri Seyed , Sotoudeh Hossein Gharaati , Artounian Valentin 
Published: February 2024

AbstractAs the COVID-19 pandemic has created complex conditions and the horrific loss of numerous lives, grieving the loss of loved ones in close families can be extremely difficult. To reduce the suffering of the loss and prevent the development of complicated grief, it is necessary to provide bereavement care as soon as possible. Therefore, we quickly developed a complete online program that included supportive psychotherapeutic interventions and psychiatric counseling. The structure of all services is the main emphasis of the study, which also emphasizes the quantitative components and the unique characteristics of the interventions. Based on the lesson learned, we discussed the difficulties experienced in putting into practice an internet-based preventive service.
Predicting Donor Selection and Multi-Organ Transplantation within Organ Procurement Organizations Using Machine Learning
Authors: Tanchip Chelsea , Noaeen Mohammad , Kazari Kamyar , Shakeri Zahra 
Published: February 2024

AbstractOrgan procurement organizations (OPOs) play a crucial role in the field of organ transplantation, serving as key intermediaries in the process of organ donation. However, despite their vital function, there exists a pressing issue of transparency within the organ allocation process. This opacity not only impedes the overall effectiveness of OPOs but also raises ethical and societal concerns regarding organ distribution. This study utilizes the recently published ORCHID dataset, containing 133,101 records of organ donor referrals, to understand organ procurement and donor selection strategies in OPOs using machine learning (ML). We developed seven ML classification models to predict donor selection and the likelihood of at least four organs being suitable for transplantation, in line with established definitions of multi-organ transplantation. The models demonstrated variable recall values for donor selection, ranging between 0.62 and 0.80, while achieving consistently high performance across other evaluation metrics, notably with AUC values exceeding 0.95. Particularly in the context of multi-organ transplant predictions, the models exhibited remarkable effectiveness, with recall values spanning from 0.88 to 0.98 and AUC metrics consistently above 0.97. Administrative milestones and particular organ transplants were identified as key determinants in the organ allocation process. This study’s findings suggest significant opportunities to improve organ allocation strategies by focusing on the optimization of administrative practices, highlighting their substantial impact on transplantation success rates.
Pesticide chemical leads inhibiting protein-protein interactions
Authors: Ben Shushan Rotem Shelly , Cohen Elad , Ben Naim Noam , Amram Eytan , Gressel Jonathan , Peleg Dotan , Dotan Nesly , Bloch Itai , Gal Maayan 
Published: February 2024

AbstractPesticides, especially herbicides, have revolutionized agriculture by providing energy-efficient solutions for pest control that replaces labor-intensive cultivation methods. However, the widespread evolution of pesticide resistance poses a significant challenge to current agriculture. Most pesticides function by binding to specific pockets on target enzymes, enabling a single mutation to confer resistance. An alternative approach is the disruption of protein-protein interactions (PPI), thus for resistance to occur, it requires complementary mutations on both interacting partners. Despite extensive efforts, no herbicides with new modes of action have been commercialized for decades. Thus, we focused on the discovery and design of small molecule inhibitors that target the interface of the PPI complex of O-acetylserine sulfhydrylase (OASS) and serine acetyltransferase (SAT), key plant enzymes involved in the biosynthesis of the essential amino acid cysteine. Using in silico filtering techniques on a virtual library of 30 million small molecules, we identified initial hits capable of binding OASS and interfering with its interaction with a peptide derived from SAT. Subsequently, we conducted chemical optimizations to evaluate biophysical enzyme disruption, followed by cellular and in-planta activity in plants. These new compounds described herein can serve as promising starting points for further optimization as herbicides acting on a new mode of action.
Upregulation of the AMPK-FOXO1-PDK4 pathway is a primary mechanism of pyruvate dehydrogenase activity reduction and leads to increased glucose uptake in tafazzin-deficient cells
Authors: Liang Zhuqing , Ralph-Epps Tyler , Schmidtke Michael W. , Lazcano Pablo , Denis Simone W. , Balážová Mária , Chakkour Mohamed , Hazime Sanaa , Ren Mindong , Schlame Michael , Houtkooper Riekelt H. , Greenberg Miriam L. 
Published: February 2024

AbstractBarth syndrome (BTHS) is a rare disorder caused by mutations in theTAFAZZINgene. Previous studies from both patients and model systems have established metabolic dysregulation as a core component of BTHS pathology. In particular, features such as lactic acidosis, pyruvate dehydrogenase (PDH) deficiency, and aberrant fatty acid and glucose oxidation have been identified. However, the lack of a mechanistic understanding of what causes these conditions in the context of BTHS remains a significant knowledge gap, and this has hindered the development of effective therapeutic strategies for treating the associated metabolic problems.In the current study, we utilized tafazzin-knockout C2C12 mouse myoblasts (TAZ-KO) and cardiac and skeletal muscle tissue from tafazzin-knockout mice to identify an upstream mechanism underlying impaired PDH activity in BTHS. This mechanism centers around robust upregulation of pyruvate dehydrogenase kinase 4 (PDK4), resulting from hyperactivation of AMP-activated protein kinase (AMPK) and subsequent transcriptional upregulation by forkhead box protein O1 (FOXO1). Upregulation of PDK4 in tafazzin-deficient cells causes direct phospho-inhibition of PDH activity accompanied by increased glucose uptake and elevated intracellular glucose concentration. Collectively, our findings provide a novel mechanistic framework whereby impaired tafazzin function ultimately results in robust PDK4 upregulation, leading to impaired PDH activity and likely linked to dysregulated metabolic substrate utilization. This mechanism may underlie previously reported findings of BTHS-associated metabolic dysregulation.
Bundle Analytics based Data Harmonization for Multi-Site Diffusion MRI Tractometry
Authors: Chandio Bramsh Qamar , Villalon-Reina Julio E. , Nir Talia M. , Thomopoulos Sophia I. , Feng Yixue , Benavidez Sebastian , Jahanshad Neda , Harezlak Jaroslaw , Garyfallidis Eleftherios , Thompson Paul M. 
Published: February 2024

AbstractThe neural pathways of the living human brain can be tracked using diffusion MRI-based tractometry. Alongtract statistical analysis of microstructural metrics can reveal the effects of neurological and psychiatric diseases with 3D spatial precision. To maximize statistical power to detect disease effects and factors that influence them, data from multiple sites and scanners must often be combined, yet scanning protocols and hardware may vary widely. For simple scalar metrics, data harmonization methods - such as ComBat and its variants - allow modeling of disease effects on derived brain metrics, while adjusting for effects of scanning site or protocol. Here, we extend this method to pointwise segment analyses of 3D fiber bundles by integrating ComBat into the BUndle ANalytics (BUAN) tractometry pipeline. In a study of the effects of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) on 38 white matter tracts, we merge data from 7 different scanning protocols used in the Alzheimer’s Disease Neuroimaging Initiative, which vary in voxel size and angular resolution. By incorporating ComBat harmonization, we model site- and scanner-specific effects, ensuring the reliability and comparability of results by mitigating confounding variables. We also evaluate choices that arise in extending batch adjustment to tracts, such as the regions used to estimate the correction. We also compare the approach to the simpler approach of modeling the site as a random effect. To the best of our knowledge, this is one of the first applications to adapt harmonization to 3D tractometry.
PerturBase: a comprehensive database for single-cell perturbation data analysis and visualization
Authors: Wei Zhiting , Si Duanmiao , Duan Bin , Gao Yicheng , Yu Qian , Guo Ling , Liu Qi 
Published: February 2024

AbstractSingle-cell perturbation sequencing techniques (scPerturbation), represented by single cell genetic perturbation sequencing (e.g., Perturb-seq) and single cell chemical perturbation sequencing (e.g., sci-Plex), result from the integration of single-cell toolkits with conventional bulk screening methods. These innovative sequencing techniques empower researchers to dissect perturbation functions and mechanisms in complex biological systems at an unprecedented resolution. Despite these advancements, a notable gap exists in the availability of a dedicated database for exploring and querying scPerturbation data. To address this gap and facilitate seamless data sharing for researchers, we present PerturBase—the first and most comprehensive database designed for the analysis and visualization of scPerturbation data (http://www.perturbase.cn/). PerturBase consolidates 122 datasets from 46 publicly accessible research studies, covering 115 single-modal and 7 multi-modal datasets that include 24254 genetic and 230 chemical perturbations from about 6 million cells. The database provides insights through various software-analyzed results, encompassing quality control, denoising, differential expression gene analysis, perturbation function analysis, and correlation characterization between perturbations. All datasets and in-depth analyses are presented in user-friendly, easy-to-browse pages and can be visualized through intuitive tables and various image formats. In summary, PerturBase stands as a pioneering high-content database, intended for searching, visualizing, and analyzing scPerturbation datasets, contributing to an enhanced understanding of perturbation functions and mechanisms.Graphical abstract
Realizing the Potential of Social Determinants Data: A Scoping Review of Approaches for Screening, Linkage, Extraction, Analysis and Interventions
Authors: Li Chenyu , Mowery Danielle L. , Ma Xiaomeng , Yang Rui , Vurgun Ugurcan , Hwang Sy , Donnelly Hayoung Kim , Bandhey Harsh , Akhtar Zohaib , Senathirajah Yalini , Sadhu Eugene Mathew , Getzen Emily , Freda Philip J , Long Qi , Becich Michael J. 
Published: February 2024

BackgroundSocial determinants of health (SDoH) like socioeconomics and neighborhoods strongly influence outcomes, yet standardized SDoH data is lacking in electronic health records (EHR), limiting research and care quality.MethodsWe searched PubMed using keywords “SDOH” and “EHR”, underwent title/abstract and full-text screening. Included records were analyzed under five domains: 1) SDoH screening and assessment approaches, 2) SDoH data collection and documentation, 3) Use of natural language processing (NLP) for extracting SDoH, 4) SDoH data and health outcomes, and 5) SDoH-driven interventions.ResultsWe identified 685 articles, of which 324 underwent full review. Key findings include tailored screening instruments implemented across settings, census and claims data linkage providing contextual SDoH profiles, rule-based and neural network systems extracting SDoH from notes using NLP, connections found between SDoH data and healthcare utilization/chronic disease control, and integrated care management programs executed. However, considerable variability persists across data sources, tools, and outcomes.DiscussionDespite progress identifying patient social needs, further development of standards, predictive models, and coordinated interventions is critical to fulfill the potential of SDoH-EHR integration. Additional database searches could strengthen this scoping review. Ultimately widespread capture, analysis, and translation of multidimensional SDoH data into clinical care is essential for promoting health equity.
Investigating the apical notch, apical dominance and meristem re-emergence inMarchantia polymorpha
Authors: Marron Alan O. 
Published: February 2024

AbstractMeristems are the growth centres of plants. Across all plant groups, the phytohormone auxin controls meristem maintenance and mediates regeneration of new meristems if existing ones are damaged. The Marchantia gemma is an experimentally tractable system featuring two meristematic regions (apical notches). I used laser ablation to precisely manipulate the apical notches, finding that the first apical cell layer is indispensable for meristem maintenance. Within this, a contiguous quorum of cells is required for meristem maintenance, depending on the other apical notch’s integrity. Apical notches remodel in response to damage, demonstrating that the apical cell layer acts as a communicating population rather than containing one master-controller Apical Cell and subordinate subapical cells. I show communication between notches and regenerating meristems, with heterogeneity across the gemma tissue for carrying this communication signal. The apical dominance signal represses cell division and requires both sources and sinks, features of auxin-mediated communication. I present a model of Marchantia meristem organization, involving intra-, inter- and extra-meristem communication. This provides a framework for further study of meristem communication, formation and maintenance in Marchantia and a better understanding of plant meristems as a whole.Significance StatementMeristems are important as the growth centres of plants. Understanding how meristems function and regenerate, and how existing meristems repress the emergence of new growth centres (apical dominance) is central to understanding how plants develop. Meristems in the model plant Marchantia display regenerative and dominance behaviour typical of plant meristems. Using laser ablation microscopy, I show that meristematic cells act a population and find evidence for communication within and between meristems, including during regeneration. Only certain regions of the plant transmit these signals, and normal meristem dynamics requires tissues acting as signal sources and sinks; features characteristic of the hormone auxin. I present a model for Marchantia meristem organization and regeneration, providing a framework for the study of meristems generally.