bluuebunny/crossref_metadata_2025_split huggingface dataset:
Canagliflozin and iron metabolism in the CREDENCE trial
Authors: Koshino Akihiko , Heerspink Hiddo J L , Jongs Niels , Badve Sunil V , Arnott Clare , Neal Bruce , Jardine Meg , Mahaffey Kenneth W , Pollock Carol , Perkovic Vlado , Hansen Michael K , Bakker Stephan J L , Wada Takashi , Neuen Brendon L 
Published: September 2024

ABSTRACT

Background
Studies in patients with heart failure have indicated that sodium-glucose cotransporter 2 (SGLT2) inhibitors increase iron use and enhance erythropoiesis. In this post hoc analysis of the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, we evaluated the effects of canagliflozin on iron metabolism in patients with chronic kidney disease (CKD) and whether the effects of canagliflozin on hemoglobin and cardiorenal outcomes were modified by iron deficiency.

Methods
We measured serum iron, total iron binding capacity (TIBC), transferrin saturation (TSAT) and ferritin at baseline and 12 months. The effects of canagliflozin, relative to placebo, on iron markers were assessed with analysis of covariance. Interactions between baseline iron deficiency, defined as TSAT &lt;20%, and the effects of canagliflozin on hemoglobin and cardiorenal outcomes were evaluated with mixed effect models and Cox regression models, respectively.

Results
Of 4401 participants randomized in CREDENCE, 2416 (54.9%) had iron markers measured at baseline, of whom 924 (38.2%) were iron deficient. Canagliflozin, compared with placebo, increased TIBC by 2.1% [95% confidence interval (CI) 0.4, 3.8; P = .014] and decreased ferritin by 11.5% (95% CI 7.1, 15.7; P &lt; .001) with no clear effect on serum iron or TSAT. Canagliflozin increased hemoglobin over the trial duration by 7.3 g/L (95% CI 6.2, 8.5; P &lt; .001) and 6.7 g/L (95% CI 5.2, 8.2; P &lt; .001) in patients with and without iron deficiency, respectively (P for interaction = .38). The relative effect of canagliflozin on the primary outcome of doubling of serum creatinine, kidney failure or death due to cardiovascular disease or kidney failure (hazard ratio 0.70, 95% CI 0.56, 0.87) was consistent regardless of iron deficiency (P for interaction = .83), as were effects on other cardiovascular and mortality outcomes (all P for interactions ≥0.10).

Conclusion
Iron deficiency is highly prevalent in patients with type 2 diabetes and CKD. Canagliflozin increased TIBC and decreased ferritin in patients with type 2 diabetes and CKD, suggesting increased iron utilization, and improved hemoglobin levels and clinical outcomes regardless of iron deficiency.
Coronavirus pandemic derived demands and inclusive leadership on junior doctors’ well-being
Authors: Lin Y K , Lin B Y-J 
Published: September 2024

Abstract

Background
International studies have revealed that numerous challenges (e.g. job demands) and opportunities (e.g. job resources as protective factors) affect the well-being of healthcare workers.

Aims
Building on the job demands–resources theory, we explored how job-related demands and the role of inclusive leadership as a job resource influenced the well-being of junior doctors during the coronavirus disease 2019 (COVID-19) pandemic.

Methods
A cross-sectional web survey was conducted in July 2022 for 82 junior doctors who had experienced the 3-year COVID-19 pandemic. The survey captured their perceived physical, psychological and COVID-19-related job demands and the inclusive leadership behaviours exhibited by their clinical unit supervisors as job resources. Data were also collected on junior doctors’ experiences of burnout, compassion satisfaction and occupational commitment as variables of job outcomes. Hierarchical linear regression analysis was applied to explore the relationships between the variables.

Results
Physical and COVID-19-related job demands were associated with increased burnout among junior doctors. Inclusive leadership as a job resource was associated with junior doctors’ reduced burnout and increased compassion satisfaction and buffered the negative effects of psychological demands on their compassion satisfaction. Only COVID-19-related job demands were associated with junior doctors’ occupational commitment.

Conclusions
Our study highlights the critical effects of COVID-19-related job demands on junior doctors’ burnout and occupational commitment. Inclusive leadership behaviours exhibited by clinical unit supervisors are a valuable job resource, which can be incorporated as one of the competencies training for medical staff.
Denouncing the ‘One Voice’ Doctrine
Authors: Teo Marcus 
Published: September 2024

Abstract
The ‘one voice’ doctrine holds that the executive’s recognition of foreign states and governments is conclusive evidence of their status as such in English proceedings. However, the doctrine—properly understood as an irrebuttable presumption of status—is beset with theoretical and practical problems. Here, I argue that courts should abandon it, for three reasons: first, the doctrine is motivated by overbroad accounts of the executive’s foreign affairs prerogative; second, it suffers from inconsistencies on matters of scope, which its underlying justifications cannot resolve; and third, the doctrine creates conceptual incoherence, undermining the purpose of other doctrines which operate contingently upon it. In its place, courts should adopt an alternative rule, triggering a rebuttable presumption of status and attributing evidential weight to executive certificates, which avoids these problems while still serving the ‘one voice’ doctrine’s only legitimate purpose: helping courts reliably answer questions of status.
Light at the end of the tunnel: FRAP assays combined with super resolution microscopy confirm the presence of a tubular vacuole network in meristematic plant cells
Authors: Scheuring David , Minina Elena A , Krueger Falco , Lupanga Upendo , Krebs Melanie , Schumacher Karin 
Published: September 2024

Abstract
Plant vacuoles play key roles in cellular homeostasis, performing catabolic and storage functions, and regulating pH and ion balance. Despite their essential role, there is still no consensus on how vacuoles are established. A model proposing that the endoplasmic reticulum is the main contributor of membrane for growing vacuoles in meristematic cells has been challenged by a study proposing that plant vacuoles are formed de novo by homotypic fusion of multivesicular bodies (MVBs). Here, we use the Arabidopsis thaliana root as a model system to provide a systematic overview of successive vacuole biogenesis stages, starting from the youngest cells proximate to the quiescent center. We combine in vivo high- and super-resolution (STED) microscopy to demonstrate the presence of tubular and connected vacuolar structures in all meristematic cells. Using customized fluorescence recovery after photobleaching (FRAP) assays, we establish different modes of connectivity and demonstrate that thin, tubular vacuoles, as observed in cells near the quiescent center, form an interconnected network. Finally, we argue that a growing body of evidence indicates that vacuolar structures cannot originate from MVBs alone but receive membrane material from different sources simultaneously.
Analysing the scientific literature on policing approaches to disrupt child sexual exploitation
Authors: McVeigh Mary Jo , Heward-Belle Susan 
Published: September 2024

Abstract
Child sexual exploitation (CSE) is an insidious and far-reaching crime that harms children and young people in the short and long term and is a major area of concern for the Australasian police force. CSE frequently exists alongside other forms of criminal activity such as trafficking and gang-related activities. A major approach to combating CSE is the disruption of offenders’ activities. This article provides the result of a scoping review of the Australian and international literature to locate, analyse, and synthesize contemporary literature about disruptive policing tactics. The conceptual lens taken to review the literature was based on two research questions: (1) what police practices are utilized under the auspice of disruptive policing? and (2) how effective are disruptive policing tactics in preventing or protecting children and young people from CSE? Studies were included if they were in English, published between 2010 and 2023 in peer-reviewed journals or grey literature, and outlined disruptive police practices concerning CSE. The review found that although there is support for disruptive policing practices as a safeguarding tool to protect children and young people from perpetrators of CSE, there is a dearth of literature in this area. Australian police force youth liaison officers and Police Citizens Youth Clubs (PCYC) play a pivotal role in disrupting CSE. Effective disruptive activities are not the duty of the police force alone. Disrupting CSE requires a whole-of-government approach.
Research trends of computational toxicology: a bibliometric analysis
Authors: Yarmohammadi Fatemeh , Hayes A Wallace , Karimi Gholamreza 
Published: September 2024

Abstract
Background: Computational toxicology utilizes computer models and simulations to predict the toxicity of chemicals. Bibliometric studies evaluate the impact of scientific research in a specific field. Methods: A bibliometric analysis of the computational methods used in toxicity assessment was conducted on the Web of Science between 1977 and 2024 February 12. Results: Findings of this study showed that computational toxicology has evolved considerably over the years, moving towards more advanced computational methods, including machine learning, molecular docking, and deep learning. Artificial intelligence significantly enhances computational toxicology research by improving the accuracy and efficiency of toxicity predictions. Conclusion: Generally, the study highlighted a significant rise in research output in computational toxicology, with a growing interest in advanced methods and a notable focus on refining predictive models to optimize drug properties using tools like pkCSM for more precise predictions.
Single‐cell and spatial transcriptomics: Discovery of human placental development and disease
Authors: Tang Mi , Xiong Liling , Cai Jianghui , Fan Li , Huang Cheng , Zhang Shimao , Jin Ying , Luo Er‐dan , Xing ShaSha , Yang Xiao 
Published: September 2024

AbstractThe human placenta is a vital organ, encompassing many distinct cell types, that maintains the growth and development of the fetus and is essential for substance exchange, defense, synthesis, and immunity. Abnormalities in placental cells can lead to various pregnancy complications, but the mechanisms remain largely unclear. Single‐cell and spatial transcriptomics technologies have been developed in recent years to demonstrate placental cell heterogeneity and spatial molecular localization. Here, we review and summarize the current literature, demonstrating these technologies and showing the heterogeneity of various placenta cells and cell–cell communication of normal human placenta, as well as placenta‐related diseases, such as preeclampsia, gestational diabetes mellitus, advanced maternal age, recurrent pregnancy loss, and placenta accreta spectrum disorders. Meanwhile, current weaknesses and future direction were discussed.
Indole alleviates nonalcoholic fatty liver disease in an ACE2‐dependent manner
Authors: Gao Yuanyuan , Chen Qi , Yang Songtao , Cao Jie , Li Fangyu , Li Rui , Wu Zhuoying , Wang Ying , Yuan Li 
Published: September 2024

AbstractIndole is a microbial metabolite produced by the gut microbiota through the degradation of dietary tryptophan, known for its well‐established anti‐inflammatory and antioxidant properties. In this study, we collected fecal samples from mice fed a high‐fat diet (HFD) and those on a standard diet (SD), then conducted 16S rRNA sequencing to analyze their gut microbiota. The analysis revealed distinct differences in the dominant bacterial species between the two groups, with a significant decrease in indole‐producing probiotics in the HFD mice compared to the SD group. Then we administered oral indole treatment to male C57BL/6J mice with HFD‐induced NAFLD and observed a significant improvement in hepatic steatosis and inflammation. Notably, indole alleviated the HFD‐induced decline in serum Angiotensin‐(1–7) [Ang‐(1–7)] levels and Angiotensin‐Converting Enzyme 2 (ACE2) expression. To further investigate the role of indole and ACE2 in NAFLD, we conducted experiments using ACE2 knockout (ACE2KO) mice that were also induced with HFD‐induced NAFLD and treated with indole. Interestingly, the protective effects of indole were compromised in the absence of ACE2. In HepG2 cells, indole similarly stimulated ACE2 expression and, in an ACE2‐dependent manner, reduced ROS generation, maintained mitochondrial membrane potential stability, and increased SIRT3 expression. In summary, our results highlight the formation of a biologically active gut‐liver axis between the gut microbiota and the liver through the tryptophan metabolite indole, which mitigates NAFLD in an ACE2‐dependent manner. Elevating dietary tryptophan and increasing indole levels may represent an effective approach for preventing and treating NAFLD.
Brown adipose tissue‐derived exosomes improve polycystic ovary syndrome in mice via STAT3/GPX4 signaling pathway
Authors: Fang Yu‐Qing , Zhang Han‐Ke , Wei Qiong‐Qiong , Li Yan‐Hui 
Published: September 2024

AbstractPolycystic ovary syndrome (PCOS) is associated with impaired adipose tissue physiology. Elevated brown adipose tissue (BAT) mass or activity has shown potential in the treatment of PCOS. In this study, we aimed to investigate whether BAT‐derived exosomes (BAT‐Exos), as potential biomarkers of BAT activity, exert similar benefits as BAT in the treatment of PCOS. PCOS was induced in female C57BL/6J mice orally administered 1 mg/kg of letrozole for 21 days. Subsequently, the animals underwent transplantation with BAT or administered BAT‐Exos (200 μg) isolated from young healthy mice via the tail vein; healthy female mice were used as controls. The results indicate that BAT‐Exos treatment significantly reduced body weight and improved insulin resistance in PCOS mice. In addition, BAT‐Exos improved ovulation function by reversing the acyclicity of the estrous cycle, decreasing circulating luteinizing hormone and testosterone, recovering ovarian performance, and improving oocyte quality, leading to a higher pregnancy rate and litter size. Furthermore, western blotting revealed reduced expression of signal transducer and activator of transcription 3 (STAT3) and increased expression of glutathione peroxidase 4 (GPX4) in the ovaries of mice in the BAT‐Exos group. To further explore the role of the STAT3/GPX4 signaling pathway in PCOS mice, we treated the mice with an intraperitoneal injection of 5 mg/kg stattic, a STAT3 inhibitor. Consistent with BAT‐Exos treatment, the administration of stattic rescued letrozole‐induced PCOS phenotypes. These findings suggest that BAT‐Exos treatment might be a potential therapeutic strategy for PCOS and that the STAT3/GPX4 signaling pathway is a critical therapeutic target for PCOS.
Integrating various Experimental Information to Assist Protein Complex Structure Prediction by GRASP
Authors: Xie Yuhao , Zhang Chengwei , Li Shimian , Du Xinyu , Wang Min , Hu Yingtong , Liu Sirui , Gao Yi Qin 
Published: September 2024

AbstractProtein complex structures are essential for understanding of biological activities and drug development. Improving complex structure prediction accuracy of AI models for cases such as antigen-antibody complexes is expected to further enhance their applicability. Meanwhile, a large variety of experimental methods are used to provide structural insights for protein complexes, with only sparse or approximate knowledge obtained. A general tool is needed to integrate AI models with limited experimental information for high-throughput and accurate protein complex structure prediction. To efficiently and flexibly incorporate the different forms of experimental information, we introduce here GRASP. GRASP outperforms existing tools in handling both simulated and real-world experimental restraints including those obtained from XL, CL, CSP, and DMS. As an example, GRASP excels in predicting antigen-antibody complex structures, even surpassing AF3 when utilizing experimental DMS and CL restraints. In addition to accelerating the restrained modeling process, its ability to integrate multiple forms of restraints makes it capable of integrative modeling. We also showcase its potential in modeling protein structural interactome in the near-cellular condition based on large-scalein vivoXL data for mitchondria.
Tricuspid valve leaflet remodeling in sheep with biventricular heart failure: A comparison between leaflets
Authors: Kostelnik Colton J. , Meador William D. , Lin Chien-Yu , Mathur Mrudang , Malinowski Marcin , Jazwiec Tomasz , Malinowska Zuzanna , Piekarska Magda L. , Gaweda Boguslaw , Timek Tomasz A. , Rausch Manuel K. 
Published: September 2024

ABSTRACTTricuspid valve leaflets are dynamic tissues that can respond to altered biomechanical and hemodynamic loads. Each leaflet has unique structural and mechanical properties, leading to differential in vivo strains. We hypothesized that these intrinsic differences drive heterogeneous, disease-induced remodeling between the leaflets. Although we previously reported significant remodeling changes in the anterior leaflet, the responses among the other two leaflets have not been reported. Using a sheep model of biventricular heart failure, we compared the remodeling responses between all tricuspid leaflets. Our results show that the anterior leaflet underwent the most significant remodeling, while the septal and posterior leaflets exhibited similar but less pronounced changes. We found several between-leaflet differences in key structural and mechanical metrics that have been shown to contribute to valvular dysfunction. These findings underscore the need to consider leaflet-specific remodeling to fully understand tricuspid valve dysfunction and to develop targeted therapies for its treatment and more accurate computational models.STATEMENT OF SIGNIFICANCEOur study is significant as it advances our understanding of tricuspid valve remodeling by providing a comprehensive analysis of all three leaflets in a sheep model of biventricular heart failure. Unlike prior works that focused primarily on the anterior leaflet or generalized leaflet changes, we integrated morphological, histological, immunohistochemistry, biaxial mechanical testing, and two-photon microscopy to quantify differences between all three tricuspid valve leaflets (anterior, posterior, and septal) across multiple functional scales. This comprehensive approach highlights the unique remodeling response of each leaflet. Our findings offer critical insights for developing targeted therapeutic strategies and improving computational models of disease progression.GRAPHICAL ABSTRACT
Modification and Analysis of Context-Specific Genome-Scale Metabolic Models: Methane-Utilizing Microbial Chassis as a Case Study
Authors: Kulyashov M.A. , Hamilton R. , Afshin Y. , Kolmykov S.K. , Sokolova T.S. , Khlebodarova T.M. , Kalyuzhnaya M.G. , Akberdin I.R. 
Published: September 2024

AbstractContext-specific genome-scale model (CS-GSM) reconstruction is becoming an efficient strategy for integrating and cross-comparing experimental multi-scale data to explore the relationship between cellular genotypes, facilitating fundamental or applied research discoveries. However, the application of CS modeling for non-conventional microbes is still challenging. Here, we present a GUI interface that integrates COBRApy, EscherPy, and RIPTiDe Python-based tools within the BioUML platform and streamlines the reconstruction and interrogation of the CS genome-scale metabolic frameworks via Jupyter Notebook. The approach was tested using -omics data collected forMethylotuvimicrobium alcaliphilum20ZR, a prominent microbial chassis for methane capturing and valorization. We optimized the previously reconstructed whole genome-scale metabolic network by adjusting the flux distribution using gene expression data. The outputs of the automatically reconstructed CS metabolic network were comparable to manually optimizediIA409 models for Ca-growth conditions. However, the CS model questions the reversibility of the phosphoketolase pathway and suggested higher flux via primary oxidation pathways. The model also highlighted unresolved carbon partitioning between assimilatory and catabolic pathways at the formaldehyde-formate node. Only a very few genes and only one enzyme with a predicted function in C1-metabolism, a homolog of the formaldehyde oxidation enzyme (fae1-2), showed a significant change in expression in La-growth conditions. The CS-GSM predictions agreed with the experimental measurements under the assumption that the Fae1-2 is a part of tetrahydrofolate-linked pathway. The cellular roles of the tungsten (W)-dependent formate dehydrogenase (fdhAB) andfae-homologues (fae1-2,andfae3) were investigated via mutagenesis. The phenotype of the fdhABmutant followed the model prediction. Furthermore, more significant reduction of the biomass yield was observed during growth in La-supplemented media, confirming a higher flux through formate.M. alcaliphilum20ZRmutants lackingfae1-2did not display any significant defects in methane or methanol-dependent growth. However, contrary tofae,thefae1-2homolog failed to restore the formaldehyde activating enzyme function in complementation tests.Overall, the presented data suggest that the developed computational workflow supports the reconstruction and validation of CS-GSM networks of non-model microbes.
Therapeutic modulation of ROCK overcomes metabolic adaptation of cancer cells to OXPHOS inhibition and drives synergistic anti-tumor activity
Authors: Blazanin Nicholas , Liang Xiaobing , Mahmud Iqbal , Kim Eiru , Martinez Sara , Tan Lin , Chan Waikin , Anvar Nazanin Esmaeili , Ha Min Jin , Qudratullah Md , Minelli Rosalba , Peoples Michael , Lorenzi Philip , Hart Traver , Lissanu Yonathan 
Published: September 2024

SummaryGenomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex includingSMARCA4andARID1Ain non-small cell lung cancer. Previously, we and others have identified thatSMARCA4-mutant lung cancers are highly dependent on oxidative phosphorylation (OXPHOS). Despite initial excitements, therapeutics targeting metabolic pathways such as OXPHOS have largely been disappointing due to rapid adaptation of cancer cells to inhibition of single metabolic enzymes or pathways, suggesting novel combination strategies to overcome adaptive responses are urgently needed. Here, we performed a functional genomics screen using CRISPR-Cas9 library targeting genes with available FDA approved therapeutics and identified ROCK1/2 as a top hit that sensitizes cancer cells to OXPHOS inhibition. We validate these results by orthogonal genetic and pharmacologic approaches by demonstrating that KD025 (Belumosudil), an FDA approved ROCK inhibitor, has highly synergistic anti-cancer activity in vitro and in vivo in combination with OXPHOS inhibition. Mechanistically, we showed that this combination induced a rapid, profound energetic stress and cell cycle arrest that was in part due to ROCK inhibition-mediated suppression of the adaptive increase in glycolysis normally seen by OXPHOS inhibition. Furthermore, we applied global phosphoproteomics and kinase-motif enrichment analysis to uncover a dynamic regulatory kinome upon combination of OXPHOS and ROCK inhibition. Importantly, we found converging phosphorylation-dependent regulatory cross-talk by AMPK and ROCK kinases on key RHO GTPase signaling/ROCK-dependent substrates such as PPP1R12A, NUMA1 and PKMYT1 that are known regulators of cell cycle progression. Taken together, our study identified ROCK kinases as critical mediators of metabolic adaptation of cancer cells to OXPHOS inhibition and provides a strong rationale for pursuing ROCK inhibitors as novel combination partners to OXPHOS inhibitors in cancer treatment.