bluuebunny/crossref_metadata_2025_split huggingface dataset:
Short N-terminal disordered regions and the proline-rich domain are major regulators of phase transitions for full-length UBQLN1, UBQLN2 and UBQLN4
Authors: Dao Thuy P. , Rajendran Anitha , Galagedera Sarasi K. K. , Haws William , Castañeda Carlos A. 
Published: September 2023

AbstractHighly homologous ubiquitin-binding shuttle proteins UBQLN1, UBQLN2 and UBQLN4 differ in both their specific protein quality control functions and their propensities to localize to stress-induced condensates, cellular aggregates and aggresomes. We previously showed that UBQLN2 phase separatesin vitro, and that the phase separation propensities of UBQLN2 deletion constructs correlate with their ability to form condensates in cells. Here, we demonstrated that full-length UBQLN1, UBQLN2 and UBQLN4 exhibit distinct phase behaviorsin vitro. Strikingly, UBQLN4 phase separates at a much lower saturation concentration than UBQLN1. However, neither UBQLN1 nor UBQLN4 phase separates with a strong temperature dependence, unlike UBQLN2. We determined that the temperature-dependent phase behavior of UBQLN2 stems from its unique proline-rich (Pxx) region, which is absent in the other UBQLNs. We found that the short N-terminal disordered regions of UBQLN1, UBQLN2 and UBQLN4 inhibit UBQLN phase separation via electrostatics interactions. Charge variants of the N-terminal regions exhibit altered phase behaviors. Consistent with the sensitivity of UBQLN phase separation to the composition of the N-terminal regions, epitope tags placed on the N-termini of the UBQLNs tune phase separation. Overall, ourin vitroresults have important implications for studies of UBQLNs in cells, including the identification of phase separation as a potential mechanism to distinguish the cellular roles of UBQLNs, and the need to apply caution when using epitope tags to prevent experimental artifacts.Highlights1) Full-length UBQLN1, UBQLN2 and UBQLN4 all exhibit LCST phase transitions but to different degrees.2) The N-terminal region (N-terminal to the UBL) substantially regulates UBQLN phase separation.3) Removal of the disease-associated proline-rich (Pxx) region in UBQLN2 removes the strong temperature dependence of UBQLN2 phase separation.
Large Scale Comparative Deconvolution Analysis of the Canine and Human Osteosarcoma Tumor Microenvironment Uncovers Conserved Clinically Relevant Subtypes
Authors: Patkar Sushant , Mannheimer Josh , Harmon Stephanie , Mazcko Christina , Choyke Peter , Brown G Tom , Turkbey Baris , LeBlanc Amy , Beck Jessica 
Published: September 2023

AbstractOsteosarcoma is a relatively rare but aggressive cancer of the bones with a shortage of effective biomarkers. Although less common in humans, Osteosarcomas are fairly common in adult pet dogs and have been shown to share many similarities with their human analogs. In this work, we analyze bulk transcriptomic data of 213 primary and 100 metastatic Osteosarcoma samples from 210 pet dogs enrolled in nation-wide clinical trials to uncover three Tumor Microenvironment (TME)-based subtypes: Immune Enriched (IE), Immune Enriched Dense Extra-Cellular Matrix-like (IE-ECM) and Immune Desert (ID) with distinct cell type compositions, oncogenic pathway activity and chromosomal instability. Furthermore, leveraging bulk transcriptomic data of canine primary tumors and their matched metastases from different sites, we characterize how the Osteosarcoma TME evolves from primary to metastatic disease in a standard of care clinical setting and assess its overall impact on clinical outcomes of canines. Most importantly, we find that TME-based subtypes of canine Osteosarcomas are conserved in humans and predictive of progression free survival outcomes of human patients, independently of known prognostic biomarkers such as presence of metastatic disease at diagnosis and percent necrosis following chemotherapy. In summary, these results demonstrate the power of using canines to model the human Osteosarcoma TME and discover novel biomarkers for clinical translation.
Sympathetic Motor Neuron Dysfunction is a Missing Link in Age-Associated Sympathetic Overactivity
Authors: de la Cruz Lizbeth , Bui Derek , Moreno Claudia M. , Vivas Oscar 
Published: September 2023

AbstractOveractivity of the sympathetic nervous system is a hallmark of aging. The cellular mechanisms behind this overactivity remain poorly understood, with most attention paid to likely central nervous system components. In this work, we hypothesized that aging also affects the function of motor neurons in the peripheral sympathetic ganglia. To test this hypothesis, we compared the electrophysiological responses and ion-channel activity of neurons isolated from the superior cervical ganglia of young (12 weeks), middle-aged (64 weeks), and old (115 weeks) mice. These approaches showed that aging does impact the intrinsic properties of sympathetic motor neurons, increasing spontaneous and evoked firing responses. A reduction of M current emerged as a major contributor to age-related hyperexcitability. Thus, it is essential to consider the effect of aging on motor components of the sympathetic reflex as a crucial part of the mechanism involved in sympathetic overactivity.
Electrical Coupling between Parvalbumin Basket Cells is Reduced after Experimental Status Epilepticus
Authors: Yu Jiandong , Santhakumar Vijayalakshmi 
Published: September 2023

AbstractAcquired epilepsies, characterized by abnormal increase in hypersynchronous network activity, can be precipitated by various factors including brain injuries which cause neuronal loss and increases in network excitability. Electrical coupling between neurons, mediated by gap junctions, has been shown to enhance synchronous neuronal activity and promote excitotoxic neurodegeneration. Consequently, neuronal gap junctional coupling has been proposed to contribute to development of epilepsy. Parvalbumin expressing interneurons (PV-INs), noted for their roles in powerful perisomatic inhibition and network oscillations, have gap junctions formed exclusively by connexin 36 subunits which show changes in expression following seizures, and in human and experimental epilepsy. However, only a fraction of the connexin hemichannels form functional connections, leaving open the critical question of whether functional gap junctional coupling between neurons is altered during development of epilepsy. Using a pilocarpine induced status epilepticus (SE) model of acquired temporal lobe epilepsy in rat, this study examined changes in electrical coupling between PV-INs in the hippocampal dentate gyrus one week after SE. Contrary to expectations, SE selectively reduced the probability of electrical coupling between PV-INs without altering coupling coefficient. Both coupling frequency and coupling coefficient between non-parvalbumin interneurons remained unchanged after SE. The early and selective decrease in functional electrical coupling between dentate PV-INs after SE may represent a compensatory mechanism to limit excitotoxic damage of fast-spiking interneurons and network synchrony during epileptogenesis.
AutoMolDesigner for Antibiotic Discovery: An AI-based Open-source Software for Automated Design of Small-molecule Antibiotics
Authors: Shen Tao , Guo Jiale , Han Zunsheng , Zhang Gao , Liu Qingxin , Si Xinxin , Wang Dongmei , Wu Song , Xia Jie 
Published: September 2023

ABSTRACTDiscovery of small-molecule antibiotics with novel chemotypes serves as one of the essential strategies to address antibiotic resistance. Although a considerable number of computational tools committed to molecular design have been reported, there is a deficit in the holistic and efficient tool specifically developed for small-molecule antibiotic discovery. To address this issue, we report AutoMolDesigner, a computational modeling software dedicated to small-molecule antibiotic design. It is a generalized framework comprising two functional modules, i.e., generative deep learning-enabled molecular generation and automated machine learning based-antibacterial activity/property prediction, wherein individually trained models and curated datasets are out-of-the-box for whole cell-based antibiotic screening and design. It is open-source thus allows for the incorporation of new features for flexible use. Unlike most software programs based on Linux and command lines, this application equipped with Qt-based graphical user interface can be run on personal computers with multiple operating systems, making it much easier to use for experimental scientists. The software and related materials are freely available at GitHub (https://github.com/taoshen99/AutoMolDesigner) and Zenodo (https://zenodo.org/record/8366085).
Nucleotide Excision Repair of Aflatoxin-induced DNA Damage within the 3D Human Genome Organization
Authors: Wu Yiran , Adeel Muhammad Muzammal , Sancar Aziz , Li Wentao 
Published: September 2023

ABSTRACTAflatoxin B1 (AFB1), a potent mycotoxin, is one of the two primary risk factors that cause liver cancer. In the liver, the bioactivated AFB1 intercalates into the DNA double helix to form a bulky DNA adduct which will lead to mutation if left unrepaired. We have adapted the tXR-seq method to measure the nucleotide excision repair of AFB1-induced DNA adducts. We have found that transcription-coupled repair plays a major role in the damage removal process and the released excision products have a distinctive length distribution pattern. We further analyzed the impact of 3D genome organization on the repair of AFB1-induced DNA adducts. We have revealed that chromosomes close to the nuclear center and A compartments undergo expedited repair processes. Notably, we observed an accelerated repair around both TAD boundaries and loop anchors. These findings provide insights into the complex interplay between repair, transcription, and 3D genome organization, shedding light on the mechanisms underlying AFB1-induced liver cancer.TEASERGenome-wide mapping repair of AFB1-caused DNA damage by tXR-seq reveals 3D genome organization’s significant impact on the repair.
Inhibiting endothelial cell Mst1 attenuates acute lung injury in mice
Authors: Guo Zhi-Fu , Tongmuang Nopprarat , Li Chao , Zhang Chen , Hu Louis , Capreri Daniel , Zuo Mei-Xing , Summer Ross , Sun Jianxin 
Published: September 2023

AbstractBackgroundLung endothelium plays a pivotal role in the orchestration of inflammatory and injury responses to acute pulmonary insults. Mammalian sterile 20-like kinase 1 (Mst1), a mammalian homolog of Hippo, is a serine/threonine kinase that is ubiquitously expressed in many tissues and has been shown to play an important role in the regulation of apoptosis, inflammation, stress responses, and organ growth. While Mst1 exhibits high expression in the lung, its involvement in the endothelial response to pulmonary insults remains largely unexplored.MethodsMst1 activity was assessed in lung endothelium by western blot. Mst1 endothelial specific knockout mice and a pharmacological inhibitor were employed to assess the effects of Mst1 on homeostatic and lipopolysaccharide (LPS)-induced endothelial responses. Readouts for these studies included various assays, including NF-κB activation and levels of various inflammatory cytokines and adhesion molecules. The role of Mst1 in lung injury was evaluated in a LPS-induced murine model of acute lung injury (ALI).ResultsMst1 phosphorylation was significantly increased in lung endothelial cells after exposure to tumor necrosis factor (TNF)-alpha (TNF-α) and mouse lung tissues after LPS exposure. Overexpression of full length Mst1 or its kinase domain promoted nuclear factor kappaB (NF-κB) activation through promoting JNK and p38 activation, whereas dominant negative forms of Mst1 (DN-Mst1) attenuated endothelial responses to TNF-α and interleukin-1β. Consistent with this, targeted deletion of Mst1 in lung endothelium reduced lung injury to LPS in mice. Similarly, wild-type mice were protected from LPS-induced lung injury following treatment with a pharmacological inhibitor of Mst1/2.ConclusionsOur findings identified Mst1 kinase as a key regulator in the control of lung EC activation and suggest that therapeutic strategies aimed at inhibiting Mst1 activation might be effective in the prevention and treatment of lung injury to inflammatory insults.
Mechanism of ZNF143 in chromatin looping and 3D genome organization
Authors: Zhang Mo , Huang Haiyan , Li Jingwei , Wu Qiang 
Published: September 2023

SummaryThe transcription factor ZNF143 contains a central domain of seven zinc fingers in a tandem array and is involved in 3D genome construction; however, the mechanism by which ZNF143 functions in chromatin looping remains unclear. Here, we show that ZNF143 directionally recognizes a diverse range of genomic sites within enhancers and promoters and is required for chromatin looping between these sites. In addition, ZNF143 is located between CTCF and cohesin at numerous CTCF sites, and ZNF143 removal narrows the space between CTCF and cohesin. Moreover, genetic deletion of ZNF143, in conjunction with acute CTCF depletion, reveals that ZNF143 and CTCF collaborate to regulate higher-order chromatin organization. Thus, ZNF143 is recruited by CTCF to the CTCF sites to regulate TAD formation, whereas directional recognition of genomic DNA motifs directly by ZNF143 itself regulates promoter activity via chromatin looping.
IMpact of a Point-of care UltraSound Examination on the management of acute respiratory or circulatory failure patients in the emergency department: The IMPULSE before-and-after implementation study
Authors: Bieler Sandra , Tagan Damien , Grosgurin Olivier , Fumeaux Thierry 
Published: September 2023

SummaryBackgroundDespite its diagnostic accuracy, the clinical impact of the use of Point-of-care Ultrasound (POCUS) in the emergency department (ED) is not well described, especially when performed by junior in-training residents.Aim of the studyto assess the effect of a short, structured POCUS training program on the management of ED patients by in-training residents.MethodIMPULSE is a before-and-after implementation study, evaluating the impact of a structured POCUS training program for ED in-training residents on the management of patients admitted for acute respiratory and/or circulatory failure in a Swiss regional hospital. The training curriculum was organized in three stages and combined an on-line training course, an 8-hour practical hands-on session, and 10 supervised POCUS exams. The ED residents who successfully completed the curriculum participated in the study. Observed outcomes were time to ED diagnosis, rate of correct diagnosis made during the ED stay and time needed to reach it, time to prescribe an appropriate treatment, and hospital mortality. Standard statistical analyses were performed with the use of Chi-square and Mann-Whitney U tests as appropriate, completed by a Bayesian analysis, with a Bayes Factor (BF) > 3 considered as significant.ResultsSixty-nine patients were included before the training program implementation and 54 after. After implementation, the median time to ED diagnosis was 25 minutes (IQR 44) vs 30 minutes (IQR 56) before implementation, a difference that was significant (BF 9.6). The rate of correct diagnosis was higher (95 vs 52 %) (p<0.001) and the time to make this correct diagnosis was significantly shorter after implementation (25 minutes, IQR 45, vs 43, IQR 60) (BF 5.0). This had an impact on the median time to prescribe the appropriate therapy, with a trend toward a shorter delay (47 minutes, IQR 76, vs 70, IQR 100) (BF 2.0). Eventually, there was a significant difference in hospital mortality (13 % vs 5.5 %, BF 15.7).Conclusionthe IMPULSE study shows that the implementation of a short, structured POCUS training program for ED residents to use ultrasound for the initial evaluation of acute respiratory and circulatory failure patients has an impact on diagnostic accuracy, on time to make a correct diagnosis and to prescribe an appropriate therapy, and eventually possibly on hospital mortality. If these results are reproduced in other settings, POCUS use by ED residents after short, structured training curriculum could become the standard of care for these patients.
Evaluating Performance of Near-Term Influenza Forecasters Across Consecutive Seasons
Authors: Nagraj VP , Williams Desiree , Turner Stephen D. 
Published: September 2023

AbstractNear-term forecasting efforts for seasonal influenza (flu) aim to enable better public health preparedness before, during, and after each season. The FluSight initiative has fostered flu forecasting activities since 2013. In 2021-22, the organizers switched the primary target to incident weekly flu hospitalizations at state, territorial, and national levels in the United States. Here we studied the performance of contributors who submitted forecasts for this target during the 2021-22 and 2022-23 seasons. We found that forecasters generally did not perform consistently across locations within seasons. For the select group of forecasters who submitted to both seasons, the overall performance relative to one another was not always consistent either. However, several forecasters, including the FluSight ensemble, were among the top performers in both seasons.
Endemic means change as SARS-CoV-2 evolves
Authors: Otto Sarah P. , MacPherson Ailene , Colijn Caroline 
Published: September 2023

SummaryCOVID-19 has become endemic, with dynamics that reflect the waning of immunity and re-exposure, by contrast to the epidemic phase driven by exposure in immunologically naïve populations. Endemic does not, however, mean constant. Further evolution of SARS-CoV-2, as well as changes in behaviour and public health policy, continue to play a major role in the endemic load of disease and mortality. In this paper, we analyse evolutionary models to explore the impact that newly arising variants can have on the short-term and longer-term endemic load, characterizing how these impacts depend on the transmission and immunological properties of variants. We describe how evolutionary changes in the virus will increase the endemic load most for persistently immune-escape variants, by an intermediate amount for more transmissible variants, and least for transiently immune-escape variants. Balancing the tendency for evolution to favour variants that increase the endemic load, we explore the impact of vaccination strategies and non-pharmaceutical interventions (NPIs) that can counter these increases in the impact of disease. We end with some open questions about the future of COVID-19 as an endemic disease.
Factors associated with osteoarthritis in elderly people in Shanghai: A cross-sectional study
Authors: Liang Xueyao , Zheng Bo , Cao Xiyou , Xu Shuangfei , Zhang Qiongmei , Fei Qing , Lu Nanqian , Zhang Kai , Liu Qingchun , Han Ying , Hu Xiaoyin , Wang Weibing , Liu Bing , Li Mengfan , Wu Ying , Zhao Yefeng 
Published: September 2023

ABSTRACTBackgroundOsteoarthritis (OA) is a degenerative disease of mostly’ middle-aged and elderly people that contributes a high burden of disease in China and worldwide. However, many putative risk factors associated with OA in elderly populations remain substantially unclear.MethodsIn our cross-sectional study, 2177 residents of the Putuo District of Shanghai aged 40 years and above were recruited to complete a questionnaire that queried basic health information and assessed the prevalence of OA. A non-conditional and an ordinal logistic regression model was used to analyze the associations between putative risk factors and the severity of confirmed OA.ResultsAmong 2099 eligible participants, the average age was 65.21 years (41.4% were male), and 551 self-reported OA [prevalence = 26.25% (24.13, 28.51)]. The prevalence of knee OA were the most common (23.11%, 21.12 to 25.23). OA was associated with age ≥ 60 years (aOR = 1.56; 1.18, 2.07), overweight BMI (24∼27.9 kg/m2) (1.30; 1.02 to 1.65), female sex (1.66; 1.30 to 2.12), unmarried status (1.41; 1.03 to 1.90), a family history of OA (6.23; 4.17 to 9.38), two or more comorbidities (2.18; 1.52 to 3.11), and prior injury to any joint (12.02; 4.86 to 31.22).ConclusionsOld age, Female sex,family history and multiple comorbidities were significant contributors to promote the severity of OA. Appropriate prevention and treatment strategies must be developed to reduce the burden of the disease.
Incidence and Determinants of loss to follow-up of HIV pre-exposure prophylaxis among key and priority population groups in Addis Ababa health centers, Ethiopia retrospective cohort study
Authors: Aragaw Addisu , Taddse Fentaw 
Published: September 2023

ABSTRACTBackground- ‘loss of follow-up’ is a significant public health concern globally. Retention in preventive care among at-risk key and priority population groups is critical for the successful prevention of HIV acquisition. Loss to follow-up of individuals has countless negative impacts on HIV prevention outcomes. There is, however, limited information about the incidence and predictors of loss to follow-up in the study area. Thus, this study aimed to determine the incidence rate and predictors of loss to follow-up among Prep users.Method- A retrospective cohort study was undertaken using 240 PrEP users between May 2020, and May 26, 2022, at Addis Ababa selected health centers. All eligible clients who fulfilled the inclusion criteria were included in study.Results and discussionA total of 240 participants with a median age of 32.0 years (interquartile range [IQR]: 27.0 to 40.0) had a median time since initiation of PrEP 21.2 months (IQR: 6.5 to 22.1). Almost half 122 (50.8%) were married, single 58 (24.2%), divorced 10 (4.2%), and widowed 50 (20.8%). One third were female sex workers (33.3%), and the rest (66.7%) were sero-discordant couples. Most of the users were from ART clinics (60.8%) and (39.2%) were from PMTCT clinics Being male is associated with 1.77 times in risk of getting lost than female (ARR=1.77, 95% CI =1.12-2.79). those who had no adherence counseling was associated with 1.86 times in the chance of LTFU as compared to those who had have adherence counseling (ARR=1.863, 95% CI =1.184, 2.930, P-value=0.003). 86 (35.8%) experienced loss to follow-up and the overall incidence rate of loss to follow-up was 7.3 (95% CI: 4.3-12.6) per 100 person-years of observation (PYs). PrEP adherence strategies should be developed and designed as a holistic approach, acknowledging the contextual factors of key population groups.Conclusion- About 35.8% clients became LTFU of PrEP with overall incidence of 7.3(4.3-12.6) per 100 pys observation. Research preparedness involving key and priority population groups should be strengthened for HIV prevention intervention evaluations in Ethiopia.