bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epidrug Screening Identifies Type I PRMT Inhibitors as Modulators of Lysosomal Exocytosis and Drug Sensitivity in Cancers
Authors: Sergi Baris , Yuksel-Catal Neslihan , Ozcan Selahattin Can , Syed Hamzah , Duvvuri Umamaheswar , Kiselyov Kirill , Acilan Ceyda 
Published: August 2024

AbstractEpigenetic changes drive differential gene expression, contributing to oncogenic transformation and drug resistance. Lysosomes are crucial in cell signaling and the sequestration of toxins and chemotherapeutic agents. This sequestration followed by expulsion through lysosomal exocytosis is a factor in drug resistance. The epigenetic regulation of lysosomal exocytosis remains poorly understood. Our research focuses on this regulation, hypothesizing that epigenetic modifier drugs (epidrugs) capable of inhibiting lysosomal exocytosis and could serve as potential therapeutics. Additionally, we investigate their potential synergy with drugs known to be sequestered in lysosomes.To examine this concept, we screened approximately 150 epigenetic drugs targeting various reader, writer, or eraser proteins. These drugs were assessed for their combined cytotoxic effects with cisplatin, their impact on lysosomal exocytosis, and on lysosomal biogenesis. Our findings reveal that among the epidrugs showing synergy with cisplatin and further reducing cell viability in combination, two type I PRMT inhibitors, MS023 and GSK3368715, inhibited lysosomal exocytosis. Notably, neither of these drugs altered the expression of the CLEAR lysosomal biogenesis network of genes, suggesting the involvement of novel regulators in lysosomal functions. To explore the specific components of the trafficking machinery affected by PRMT inhibitors, we conducted an RNA-seq analysis, uncovering several differentially expressed genes (DEGs). In addition to previously described functions such as methylation activity, or DNA repair; these DEGs included those involved in vesicular trafficking, lysosomal enzyme activity and lysosome dynamics, offering potential insights into the mechanism of reduced exocytosis and identifying a novel mode for its regulation. Additionally, both inhibitors exhibited synergy with other drugs known to be sequestered in lysosomes, such as carboplatin, oxaliplatin, sunitinib, and doxorubicin, indicating that inhibition of lysosomal exocytosis may be a common phenomenon for such drugs. These findings underscore the potential of Type I PRMT inhibitors as therapeutic agents in cancer treatment. Consistently, analysis on the publicly available patient data revealed that lower levels of type I PRMTs (PRMT1 and 6) were associated with better patient response to these drugs, further suggesting their potential as drug candidates for combination therapy to enhance chemotherapy efficacy and improve cancer patient survival rates.
SIRT5-mediated GLS and GDH desuccinylation attenuates autophagy in MAC-T cells induced by ammonia
Authors: Yang Hanlin , Gao Shikai , Lu Guangyang , He Junhui , Dong Jinru , Zhang Xinyi , Liu Luya , Zhong Kai , Zha Guangming , Han Liqiang , Guo Shuang , Li Heping , Wang Yueying 
Published: August 2024

AbstractOur previous research revealed that NH3regulated autophagy dependent on SIRT5 in MAC-T cells. Interestingly, SIRT5 reduced the content of NH3and glutamate by inhibiting GLS activity, ADP/ATP value also declined. In this study, SIRT5 interacted with endogenous GLS and GDH, and had no effect on endogenous GLS and GDH expression. SIRT5 declined significantly the succinylation levels of GLS and GDH, and further reduced the enzymatic activity of GLS and GDH. SIRT5 declined the glutamine metabolism, which attenuated ammonia release in MAC-T cells, accompanying with cellular autophagy decline, reducing the formation of autophagosome. Deletion of SIRT5 increased the content of NH3and glutamate, as well as promotes autophagy, which could be alleviated by SIRT5 overexpression. SIRT5 KO was associated with increased succinylation and activity of GLS and GDH, as well as autophagy response in MAC-T cells. Furthermore, SIRT5 promoted the maintenance of mitochondria homeostasis. Mechanistically, SIRT5 modulated the succinylation levels and enzymatic activities of GLS and GDH in mitochondria and promoted the maintenance of mitochondria homeostasis, further attenuating ammonia-stimulated autophagy in MAC-T cells.HighlightsSIRT5 catalyzed lysine desuccinylation of GLS and GDH.GLS and GDH enzymatic activity were enhanced by lysine succinylation.GLS and GDH were required for SIRT5 to regulate ammonia-induced cellular autophagy.SIRT5 promoted the maintenance of mitochondrial homeostasis
Foraging niche partitioning of threeMyotisbat species and marine fish consumption byMyotis pilosusin a subtropical East Asian region
Authors: Wei Xiaodong , Poon Emily Shui Kei , Chung John Chun Ting , Chan David Tsz Chung , Shek Chung Tong , Tsui Wing Chi , Zhao Huabin , Sin Simon Yung Wa 
Published: August 2024

AbstractMost bats are insectivorous, but some species have evolved the ability to prey on fish. Although piscivory has been confirmed in the Rickett’s big-footed myotis (Myotis pilosus), the extent of piscivory of other cohabitingMyotisspecies is uncertain. This study aims to explore the dietary niches and fish consumption of threeMyotisspecies in a subtropical East Asian region, and specifically the fish diet ofM. pilosus. Our findings reveal, for the first time, thatM. pilosusconsumes marine fishes, in contrast to previous research conducted in inland regions that suggested year-round consumption of cyprinids in freshwater habitats. We also observed seasonal variation in the diets ofM. pilosus. It predominately hunted wide-banded hardyhead silverside, sailfin flying fish, and shorthead anchovy during the wet season, while mainly preying upon mullets during the dry months. In more inland areas,M. pilosuswas found to primarily feed on invasive freshwater poeciliids. Furthermore,M. pilosusconsumed more fish during the dry season, while there was a greater consumption of insects during the wet months. Most notably among our findings is the consumption of fish by two individuals of Horsfield’s myotis (M. horsfieldii), indicating that the species is potentially piscivorous. We revealed that bothM. horsfieldiiandM. pilosusconsumed water striders, suggesting that foraging of aquatic insects could be driving the evolution of fishing behavior. Our findings have also shed light on the flexibility of foraging behavior in piscivorous bats.
Advanced Echocardiographic Assessment in Transthyretin Amyloidosis: Early Phenotype Markers in Mutation Carriers
Authors: Capeline Lorena Squassante , Mancuso Frederico José Neves , Oishi Gardênia Silva Lobo , Uellendahl Marly , Naylor Fernando , Oliveira Acary Souza Bulle , Moises Valdir Ambrósio 
Published: August 2024

AbstractBackgroundTransthyretin cardiac amyloidosis (ATTR-CA) is a life-threatening heart condition due to mutations in the transthyretin (TTR) gene. This study aimed to investigate ventricular global longitudinal strain (GLS) and global circumferential strain (GCS) alongside traditional echocardiographic measures in TTR carries with preserved ejection fraction (EF).MethodsIndividuals with a family history of ATTR-CA, positive genetic testing for TTR, no clinical cardiac involvement and preserved EF were matched with healthy controls.ResultsSixty-five patients were included: 31 TTR+ and 34 controls. No significant differences in chamber dimensions or EF were observed between groups. However, septal velocities were markedly lower in TTR+ than controls (9 [7;12] cm/s vs. 12 [10;13] cm/s, p=0.003). Additionally, both GCS and GLS were significantly reduced in the TTR+ group compared to controls (-21 ±4% vs. -28 ±4%, p<0.001 and -19 ±3% vs. -25 ±2%, p<0.001, respectively). Furthermore, right ventricular strain showed a similar trend, being lower in the TTR+ group compared to controls (-18 ±4% vs. -25 ±5%, p<0.005). Logistic regression analysis identified GLS (OR = 2.46; 95% CI 1.30-4.62) and E/e’ mean ratio (OR = 2.04; 95% CI 1.09-3.91) as independent predictors of positive genetic testing for TTR.ConclusionAsymptomatic individuals with a family history of ATTR-CA and positive genetic testing for TTR, despite preserved EF, exhibit lower GLS and GCS compared to controls. GLS and the E/e’ ratio were identified as independent predictors of positive genetic testing for TTR.
Role of Artificial Intelligence-Powered Conversational Agents (Chatbots) in Musculoskeletal Disorders: A Scoping Review Protocol
Authors: González Aroca Joaquín , Vergara-Merino Laura , Escobar Liquitay Camila Micaela , Farías A Humberto , Olivares Arancibia Jorge , Puelles Álvaro 
Published: August 2024

AbstractIntroductionMusculoskeletal disorders (MSDs) represent a significant global health burden, leading to substantial disability and socioeconomic impact. With the rise of artificial intelligence (AI), particularly large language models-driven conversational agents (chatbots), there is potential to enhance the management of MSDs. However, the application of AI-powered chatbots in this population has not been comprehensively synthesized.ObjectiveTo explore the current and potential use of AI-powered chatbots in the management of MSDs. The review will map out the targeted diseases, the purposes of chatbot interventions, the clinical tools or frameworks utilized in training these systems, and the evaluated outcomes in clinical settings.MethodsThis scoping review will follow the PRISMA-ScR guidelines, with a comprehensive search across multiple databases including Medline (Ovid MEDLINE), Embase (Ovid), ISI Web of Science (wos; clarivate) and ClinicalTrials.gov. Studies involving adults with MSDs, regardless of publication status, language, or year, will be included. The scoping review will exclude studies using non-AI chatbots or human health coaches. Data extraction and synthesis will focus on demographic characteristics, chatbot methods, outcomes, and thematic analysis.Ethics and disseminationFormal ethical approval is not required as this study involves neither human participants nor unpublished secondary data. Findings of the scoping review will be disseminated through professional networks, conference presentations and publication in a scientific journal.Strengths and limitations of this studyWe developed a search strategy with high sensitivity to retrieve studiesThis scoping review will not exclude studies by publication status, language, or year of publication.
An equity-focused comparison of the COVID-19 vaccine rollout plans across six Canadian provinces
Authors: Sobers Mercedes , Atukorale Vajini , Mauer-Vakil Dane , Bashir Kainat , Ouedraogo Mariame , Dharma Christoffer , Ataullahjan Anushka , Fadel Shaza A. , Allin Sara 
Published: August 2024

AbstractObjectivesThis study examined how six Canadian provinces (Alberta, British Columbia, Manitoba, Nova Scotia, Ontario, Quebec) adapted guidelines from the National Advisory Committee on Immunization to prioritize COVID-19 vaccines equitably for five key populations at high risk: Black communities; First Nations, Inuit, and Métis populations; non-medical essential workers; individuals experiencing homelessness; and individuals with disabilities. The objective was to compare timelines, justifications, and contextual factors that influenced provincial prioritization for early vaccine access.MethodsA mixed-methods approach was used to investigate how provinces operationalized equity in their vaccine rollout plans. Environmental scans (December 2020 – May 2021) gathered data on prioritization and distribution from provincial reports and media articles. Key informant interviews (December 2021 – April 2022) with provincial experts provided context on decision-making and justifications for prioritizing key populations. Data analysis employed the “Reach” component of the RE-AIM framework, with qualitative analysis of interviews following an interpretive descriptive approach.ResultsProvinces used age-, risk-, and health status-based approaches to select priority populations. While all provinces consulted the National Advisory Committee on Immunization guidelines and various ethical frameworks to guide their decisions, deviations occurred due to local contexts. First Nations, Inuit, and Métis populations were prioritized earliest in all provinces, while Black communities received the least prioritization. Key subgroups, such as urban First Nations, Inuit, and Métis, unsheltered homeless individuals, and homebound disabled persons, were often overlooked. Factors that emerged as key drivers of priority population selection were data availability, population size, and geography.ConclusionsThis study fills gaps in the literature by highlighting key contextual factors unique to each province that drove provincial justifications for their prioritization decisions. We provide several examples of the importance of data availability and early community-led partnerships when designing a successful mass vaccination rollout.
A theoretical framework to quantify the tradeoff between individual and population benefits of expanded antibiotic use
Authors: LaPrete Cormac R. , Ahmed Sharia M. , Toth Damon J.A. , Reimer Jody R. , Vaughn Valerie M. , Adler Frederick R. , Keegan Lindsay T. 
Published: August 2024

AbstractThe use of antibiotics during a disease outbreak presents a critical tradeoff between immediate treatment benefits to the individual and the long-term risk to the population. Typically, the extensive use of antibiotics has been thought to increase selective pressures, leading to resistance. This study explores scenarios where expanded antibiotic treatment can be advantageous for both individual and population health. We develop a mathematical framework to assess the impacts on outbreak dynamics of choosing to treat moderate infections not treated under current guidelines, focusing on cholera as a case study. We derive conditions under which treating moderate infections can sufficiently decrease transmission and reduce the total number of antibiotic doses administered. We identify two critical thresholds: the Outbreak Prevention Threshold (OPT), where expanded treatment reduces the reproductive number below 1 and halts transmission, and the Dose Utilization Threshold (DUT), where expanded treatment results in fewer total antibiotic doses used than under current guidelines. For cholera, we find that treating moderate infections can feasibly stop an outbreak when the untreated reproductive number is less than 1.424 and will result in fewer does used compared to current guidelines when the untreated reproductive number is less than 1.533. These findings demonstrate that conditions exist under which expanding treatment to include moderate infections can reduce disease spread and the selective pressure for antibiotic resistance. These findings extend to other pathogens and outbreak scenarios, suggesting potential targets for optimized treatment strategies that balance public health benefits and antibiotic stewardship.
Patients’ Experience and Satisfaction towards Virtual Health Care during the COVID-19 Pandemic in Southern Region of Saudi Arabia
Authors: Shati Ayed A. , Alamri Hasan S. , Al-Garni Abdulaziz M. , Mahmood Syed E. , Alsamghan Awad S. 
Published: August 2024

AbstractBackgroundHealthcare providers can use these virtual platforms for delivering medical advice and prescriptions of medications to patients. This study was aimed to explore the patient’s experiences and level of satisfaction regarding virtual health care received during the COVID-19 pandemic. This study also assessed the before and during lockdown sleep quality in these participants.Design and MethodsThe current study included 522 participants from Saudi Arabia. Virtual healthcare satisfaction questionnaire was implemented to record the data on patient experience toward the virtual health care during COVID-19 pandemic.ResultsPatients’ opinions regarding virtual health care received during the COVID-19 pandemic era are summarized using the “five-point Likert scale”. The mean score of all the five statements is 4.15, reflecting 83% level of satisfaction of participants towards virtual health care. Among participants, mostly agreed that they were able to communicate adequately with doctors, the picture and sound quality of the virtual appointment were good, their privacy was respected during the consultation, they were comfortable during history taking and exams that were done, and the doctor explained solutions including prescribing medicine and/or providing advice. However, there was no significant association found between the type of specialty attended or patient demographic factors and level of satisfaction. Results of subjective sleep parameters assessed before and during lock down are depicted. Results of t-test showed that the mean scores of all the components namely sleep duration (P<0.001); sleep disturbances (P<0.001), sleep latency (P<0.001), daytime dysfunction (P<0.001), habitual sleep efficiency (P<0.001), and subjective sleep quality (P<0.001) significantly differed between two assessment levels. Mean scores of all the components shifted towards higher values, representing worsening of sleep quality during the COVID-19 pandemic lock down.ConclusionsFindings support and conclude that virtual health care system can be adopted in clinical settings.
Prevalence of Problematic Papers in Non-Coding RNA Research
Authors: Lou Ying , Zhou Zhengyi , Shen Zhesi , Li Menghui 
Published: August 2024

AbstractThis study examines the prevalence of problematic papers in the rapidly growing field of non-coding RNA (ncRNA) research. Analysis of 153,826 ncRNA papers during 2000-2023 reveals that around 1.79% have been retracted and an additional 5.68% have raised concerns on PubPeer. The number of problematic papers has steadily increased, peaking in 2019 when the concerning and retraction rates reached nearly 10.8% and 3.7%, respectively. These unreliable papers have been widely disseminated, accumulating hundreds of thousands of citations in academic literature, patents, clinical trials, and policy documents, posing a significant threat to research integrity and public health. The main issues identified include image manipulation, data falsification, fake peer reviews, and ethical lapses. The findings call for urgent, comprehensive scrutiny of ncRNA publications and broader reforms to address systemic problems driving the proliferation of problematic research.
Thermodynamic versus kinetic basis for the high conformational stability of nanobodies for therapeutic applications
Authors: Gómez-Mulas Atanasio , Salido Eduardo , Pey Angel L. 
Published: August 2024

AbstractSingle domain nanobodies (NB) are powerful tools for biotechnological and therapeutic applications. They strongly bind to their targets and are very stable. Early studies showed that NB unfolding is reversible and can be analyzed by equilibrium thermodynamics whereas more recent studies focused on their kinetic stability in very harsh conditions, far from storage or physiological temperatures (4-37°C). Here we reinforce the thermodynamic view in which a simple two-state denaturation model is applicable. We found that thermal stability of NB actually reflect thermodynamic stabilities in wide range of temperatures (18-100°C). We also modeled their structure observing subtle differences. We expect that our approach will be helpful to improve our capacity to enhance structure-function-stability relationships of NB.
Characterizing microbubble-mediated permeabilization in a vessel-on-a-chip model
Authors: Meijlink Bram , Collado Lara Gonzalo , Bishard Kristina , Conboy James P. , Langeveld Simone A.G. , Koenderink Gijsje H. , van der Steen Antonius F.W. , de Jong Nico , Beekers Inés , Trietsch Sebastiaan J. , Kooiman Klazina 
Published: August 2024

ABSTRACTDrug transport from blood to extravascular tissue can locally be achieved by increasing the vascular permeability through ultrasound-activated microbubbles. However, the mechanism remains unknown, including whether short and long cycles of ultrasound induce the same onset rate, spatial distribution, and amount of vascular permeability increase. Accurate models are necessary for insights into the mechanism so a microvessel-on-a-chip is developed with a membrane-free extravascular space. Using these microvessels-on-a-chip, we show distinct differences between 2 MHz ultrasound treatments with 10 or 1000 cycles. The onset rate is slower for 10 than 1000 cycles, while both cycle lengths increase the permeability in spot-wise patterns without affecting cell viability. Significantly less vascular permeability increase and sonoporation are induced for 10 versus 1000 cycles at 750 kPa (i.e., highest studied peak negative acoustic pressure (PNP)). The PNP threshold for vascular permeability increases is 750 versus 550 kPa for 10 versus 1000 cycles, while this is 750 versus 220 kPa for sonoporation. Vascular permeability increases do not correlate with αvβ3-targeted microbubble behavior, while sonoporation correlates with αvβ3-targeted microbubble clustering. In conclusion, the further mechanistic unraveling of vascular permeability increase by ultrasound-activated microbubbles in a developed microvessel-on-a-chip model aids safe and efficient development of microbubble-mediated drug transport.
EdgeHOG: fine-grained ancestral gene order inference at tree-of-life scale
Authors: Bernard Charles , Nevers Yannis , Karampudi Naga Bhushana Rao , Gilbert Kimberly J. , Train Clément , Vesztrocy Alex Warwick , Glover Natasha , Altenhoff Adrian , Dessimoz Christophe 
Published: August 2024

AbstractAncestral genomes are essential for studying the diversification of life from the last universal common ancestor to modern organisms. Methods have been proposed to infer ancestral gene order, but they lack scalability, limiting the depth to which gene neighborhood evolution can be traced back. We introduce edgeHOG, a tool designed for accurate ancestral gene order inference with linear time complexity. Validated on various benchmarks, edgeHOG was applied to the entire OMA orthology database, encompassing 2,845 extant genomes across all domains of life. This represents the first tree-of-life scale inference, resulting in 1,133 ancestral genomes. In particular, we reconstructed ancestral contigs for the last common ancestor of eukaryotes, dating back around 1.8 billion years, and observed significant functional association among neighboring genes. The method also dates gene adjacencies, revealing conserved histone clusters and rapid sex chromosome rearrangements, enabling computational inference of these features.
Characterization of a High-Affinity Copper Transporter in the White-Nose Syndrome Causing Fungal PathogenPseudogymnoascus destructans
Authors: Friudenberg Alyssa D. , Anne Saika , Peterson Ryan L. 
Published: August 2024

AbstractCopper is an essential micronutrient and the ability to scavenge tightly bound or trace levels of copper ions at the host-pathogen interface is vital for fungal proliferation in animal hosts. Recent studies suggest that trace metal ion acquisition is critical for the establishment and propagation ofPseudogymnoascus destructans, the fungal pathogen responsible for white-nose syndrome (WNS), on their bat host. However, little is known about these metal acquisition pathways inP. destructans. In this study, we report the characterization of theP. destructanshigh-affinity copper transporter VC83_00191 (PdCTR1a), which is implicated as a virulence factor associated with the WNS disease state. UsingSaccharomyces cerevisiaeas a recombinant expression host, we find thatPdCTR1a localizes to the cell surface plasma membrane and can efficiently traffic Cu-ions into the yeast cytoplasm. Complementary studies in the nativeP. destructansfungus provide evidence thatPdCTR1a transcripts and protein levels are dictated by Cu-bioavailability in the growth media. Our study demonstrates thatPdCTR1a is a functional high-affinity copper transporter and is relevant to Cu-homeostasis pathways inP. destructans.