bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient-specific iPSC-derived cardiomyocytes reveal aberrant activation of Wnt/β-catenin signaling in SCN5A-related Brugada syndrome
Authors: Cai Dongsheng , Wang Xiaochen , Sun Yaxun , Fan Hangping , Zhou Jingjun , Yang Zongkuai , Qiu Hangyuan , Wang Jue , Su Jun , Gong Tingyu , Jiang Chenyang , Liang Ping 
Published: September 2023

Abstract
Background
Mutations in the cardiac sodium channel gene SCN5A cause Brugada syndrome (BrS), an arrhythmic disorder that is a leading cause of sudden death and lacks effective treatment. An association between SCN5A and Wnt/β-catenin signaling has been recently established. However, the role of Wnt/β-catenin signaling in BrS and underlying mechanisms remains unknown.

Methods
Three healthy control subjects and one BrS patient carrying a novel frameshift mutation (T1788fs) in the SCN5A gene were recruited in this study. Control and BrS patient-specific induced pluripotent stem cells (iPSCs) were generated from skin fibroblasts using nonintegrated Sendai virus. All iPSCs were differentiated into cardiomyocytes using monolayer-based differentiation protocol. Action potentials and sodium currents were recorded from control and BrS iPSC-derived cardiomyocytes (iPSC-CMs) by single-cell patch clamp.

Results
BrS iPSC-CMs exhibited increased burden of arrhythmias and abnormal action potential profile featured by slower depolarization, decreased action potential amplitude, and increased beating interval variation. Moreover, BrS iPSC-CMs showed cardiac sodium channel (Nav1.5) loss-of-function as compared to control iPSC-CMs. Interestingly, the electrophysiological abnormalities and Nav1.5 loss-of-function observed in BrS iPSC-CMs were accompanied by aberrant activation of Wnt/β-catenin signaling. Notably, inhibition of Wnt/β-catenin significantly rescued Nav1.5 defects and arrhythmic phenotype in BrS iPSC-CMs. Mechanistically, SCN5A-encoded Nav1.5 interacts with β-catenin, and reduced expression of Nav1.5 leads to re-localization of β-catenin in BrS iPSC-CMs, which aberrantly activates Wnt/β-catenin signaling to suppress SCN5A transcription.

Conclusions
Our findings suggest that aberrant activation of Wnt/β-catenin signaling contributes to the pathogenesis of SCN5A-related BrS and point to Wnt/β-catenin as a potential therapeutic target.
In vitro-generated human muscle reserve cells are heterogeneous for Pax7 with distinct molecular states and metabolic profiles
Authors: Bouche Axelle , Borner Benoit , Richard Chloé , Grand Ysaline , Hannouche Didier , Laumonier Thomas 
Published: September 2023

Abstract
Background
The capacity of skeletal muscles to regenerate relies on Pax7+ muscle stem cells (MuSC). While in vitro-amplified MuSC are activated and lose part of their regenerative capacity, in vitro-generated human muscle reserve cells (MuRC) are very similar to quiescent MuSC with properties required for their use in cell-based therapies.

Methods
In the present study, we investigated the heterogeneity of human MuRC and characterized their molecular signature and metabolic profile.

Results
We observed that Notch signaling is active and essential for the generation of quiescent human Pax7+ MuRC in vitro. We also revealed, by immunofluorescence and flow cytometry, two distinct subpopulations of MuRC distinguished by their relative Pax7 expression. After 48 h in differentiation medium (DM), the Pax7High subpopulation represented 35% of the total MuRC pool and this percentage increased to 61% after 96 h in DM. Transcriptomic analysis revealed that Pax7High MuRC were less primed for myogenic differentiation as compared to Pax7Low MuRC and displayed a metabolic shift from glycolysis toward fatty acid oxidation. The bioenergetic profile of human MuRC displayed a 1.5-fold decrease in glycolysis, basal respiration and ATP-linked respiration as compared to myoblasts. We also observed that AMPKα1 expression was significantly upregulated in human MuRC that correlated with an increased phosphorylation of acetyl-CoA carboxylase (ACC). Finally, we showed that fatty acid uptake was increased in MuRC as compared to myoblasts, whereas no changes were observed for glucose uptake.

Conclusions
Overall, these data reveal that the quiescent MuRC pool is heterogeneous for Pax7 with a Pax7High subpopulation being in a deeper quiescent state, less committed to differentiation and displaying a reduced metabolic activity. Altogether, our data suggest that human Pax7High MuRC may constitute an appropriate stem cell source for potential therapeutic applications in skeletal muscle diseases.
Mesenchymal stem cells in synovial fluid increase in number in response to synovitis and display more tissue-reparative phenotypes in osteoarthritis
Authors: Furuoka Hideto , Endo Kentaro , Sekiya Ichiro 
Published: September 2023

Abstract
Background
Synovial fluid mesenchymal stem cells (SF-MSCs) originate in the synovium and contribute to the endogenous repair of damaged intra-articular tissues. Here, we clarified the relationship between their numbers and joint structural changes during osteoarthritis (OA) progression and investigated whether SF-MSCs had phenotypes favorable for tissue repair, even in an OA environment.

Methods
Partial medial meniscectomy (pMx) and sham surgery were performed on both knees of rats. SF and knee joints were collected from intact rats and from rats at 2, 4, and 6 weeks after surgery. SF was cultured for 1 week to calculate the numbers of colony-forming cells and colony areas. Joint structural changes were evaluated histologically to investigate their correlation with the numbers and areas of colonies. RNA sequencing was performed for SF-MSCs from intact knees and knees 4 weeks after the pMx and sham surgery.

Results
Colony-forming cell numbers and colony areas were greater in the pMx group than in the intact and sham groups and peaked at 2 and 4 weeks, respectively. Synovitis scores showed the strongest correlation with colony numbers (R = 0.583) and areas (R = 0.456). RNA sequencing revealed higher expression of genes related to extracellular matrix binding, TGF-β signaling, and superoxide dismutase activity in SF-MSCs in the pMx group than in the sham group.

Conclusion
The number of SF-MSCs was most closely correlated with the severity of synovitis in this rat OA model. Tissue-reparative gene expression patterns were observed in SF-MSCs from OA knees, but not from knees without intra-articular tissue damage.
A large carbon sink induced by the implementation of the largest afforestation program on Earth
Authors: Zhu Jiaojun , Sun Yirong , Zheng Xiao , Yang Kai , Wang G. Geoff , Xia Chaozong , Sun Tao , Zhang Jinxin 
Published: September 2023

Abstract
Background
Three-North Afforestation Program (TNAP) in China is the largest ecological restoration project on Earth (ongoing from 1978 to 2050), harboring a huge area of newly planted forests, which provides a wealth of goods and ecosystem services that benefit society at levels ranging from region to East Asia. This project-induced carbon (C) sink has been expected to be large, but its size and location remain uncertain.

Results
In this study, we investigated the changes in the C stocks of biomass, soil C and the C accumulation benefited from the ecological effects in the project areas from 1978 to 2017 within the Three-North regions (4.069 × 106 km2), and evaluated its project-induced C sequestration. Using a combination of remote sensing images, field observations and national forest inventory data, we estimated a total ecosystem sink of 47.06 Tg C per year (1 Tg = 1012 g) increased by the TNAP implementation. Importantly, we first found that the C sink via the ecological effects of this project could contribute to a high proportion up to 15.94%, indicating a critical role of ecological effects in shaping the distribution of C stocks in the protective forests. This finding suggests that it is necessary to explicitly consider carbon sequestration benefited from the ecological effects when estimating C sink and parameterizing C models of the restoration projects in China and globally.

Conclusions
Our results update the estimates of C pools in the world's largest ecological restoration project area, demonstrating that this project has substantially contributed to mitigating the climate change.
Drug policies’ sensitivity towards women, pregnancy, and motherhood: a content analysis of national policy and programs from nine countries and their adherence to international guidelines
Authors: Ghosh Abhishek , Jerkovic Dijana , Ignjatova Liljana Aleksandar , Bruguera Carla , Ibrahim Dalia I. , Okulicz-Kozaryn Katarzyna , Maphisa J. Maphisa , Martinelli Thomas F. , Neto Ana , Canedo Joana , Gordon Rebecca 
Published: September 2023

Abstract
Background and objectives
Substance use in women is associated with unique psycho-social and physical vulnerabilities and poses complex challenges during pregnancy and motherhood. Gender-sensitive drug policy which considers the needs of women and their children could address these concerns. The objectives of this study were: (1) to systematically explore national-level drug policies’ sensitivity and responsiveness to women, pregnant women, and children; and (2) to examine the adherence of drug policies with international guidelines for gender sensitivity in drug policy.

Methods
The research team was diverse professional backgrounds and nine countries. A summative content analysis of national drug policy documents, action plans, and strategies was performed. Specific documents focusing on women, pregnancy, and children were analysed. Specific themes and how frequently they appeared in the documents were identified. This quantification was an attempt to explore usage indicating the relative focus of the policies. A thematic map was developed to understand how national-level drug policies conceive and address specific concerns related to women who use drugs. We adapted the UNODC checklist for gender mainstreaming to assess policies’ adherence to international guidelines.

Results
Twenty published documents from nine countries were reviewed. The common themes that emerged for women, pregnancy, and children were needs assessment, prevention, treatment, training, supply reduction, and collaboration and coordination. Custody of children was a unique theme for pregnant women. Specific psycho-social concerns and social reintegration were special themes for women, whereas legislation, harm reduction, research, and resource allocation were children-specific additional themes. For women-specific content analysis, special issues/concerns in women with drug misuse, need assessment, and prevention were the three most frequent themes; for the children-specific policies, prevention, training, and treatment comprised the three most occurring themes. For pregnant women/pregnancy, prevention, treatment, and child custody were the highest occurring themes. According to ratings of the countries’ policies, there is limited adherence to international guidelines which ensure activities are in sync with the specific needs of women, pregnant women and their children.

Conclusion
Our analysis should help policymakers revise, update and adapt national policies to ensure they are gender-responsive and address the needs of women, pregnant women and their children.
How effective are protected areas for reducing threats to biodiversity? A systematic review protocol
Authors: Pulido-Chadid Katherine , Virtanen Elina , Geldmann Jonas 
Published: September 2023

Abstract
Background
Protected areas (PAs) have become one of the most important instruments to preserve nature and, when effective, can significantly reduce human pressure and derived threats to biodiversity. However, evidence suggests that despite the growing number and coverage of PAs worldwide, biodiversity trends continue to deteriorate, and human pressure increases outside and inside PAs. While many studies have focused on the effectiveness of PAs in maintaining ecological features, less attention has been given to the threat reduction potential of PAs, despite threats being one of the main factors leading to the need to conserve biodiversity. It is therefore essential to understand PAs' role in addressing threats. In this paper, we describe the protocol for conducting a systematic review to explore and review the evidence surrounding the effectiveness of PAs as an intervention to reduce threats to biodiversity. We will examine the role of PAs in addressing several types of threats. Thus, our primary research question is: How effective are protected areas for reducing threats to biodiversity?

Methods
This protocol follows the Collaboration for Environmental Evidence guidelines for evidence synthesis and complies with the ROSES (Reporting Standards for Systematic Evidence Synthesis) reporting framework. We will use a comprehensive search, covering databases such as Web of Science—core collection and Scopus and organizational websites to capture relevant grey literature. Our search terms and strategies aim to find studies assessing change of threats given in PAs at any scale and ecosystem type capturing literature in English. Independent reviewers will screen search results at the title—abstract, and full text levels. In order to evaluate the relevance of the evidence, we will use the Collaboration for Environmental Evidence Critical Appraisal Tool. The results will be presented as a narrative synthesis supported by quantitative data. Additionally, a meta-analysis, if possible, will be performed.
External validation of semi-automated surveillance algorithms for deep surgical site infections after colorectal surgery in an independent country
Authors: van der Werff Suzanne D. , Verberk Janneke D.M. , Buchli Christian , van Mourik Maaike S.M. , Nauclér Pontus 
Published: September 2023

Abstract
Background
Automated surveillance methods that re-use electronic health record data are considered an attractive alternative to traditional manual surveillance. However, surveillance algorithms need to be thoroughly validated before being implemented in a clinical setting. With semi-automated surveillance patients are classified as low or high probability of having developed infection, and only high probability patients subsequently undergo manual record review. The aim of this study was to externally validate two existing semi-automated surveillance algorithms for deep SSI after colorectal surgery, developed on Spanish and Dutch data, in a Swedish setting.

Methods
The algorithms were validated in 225 randomly selected surgeries from Karolinska University Hospital from the period January 1, 2015 until August 31, 2020. Both algorithms were based on (re)admission and discharge data, mortality, reoperations, radiology orders, and antibiotic prescriptions, while one additionally used microbiology cultures. SSI was based on ECDC definitions. Sensitivity, specificity, positive predictive value, negative predictive value, and workload reduction were assessed compared to manual surveillance.

Results
Both algorithms performed well, yet the algorithm not relying on microbiological culture data had highest sensitivity (97.6, 95%CI: 87.4–99.6), which was comparable to previously published results. The latter algorithm aligned best with clinical practice and would lead to 57% records less to review.

Conclusions
The results highlight the importance of thorough validation before implementation in other clinical settings than in which algorithms were originally developed: the algorithm excluding microbiology cultures had highest sensitivity in this new setting and has the potential to support large-scale semi-automated surveillance of SSI after colorectal surgery.
High-energy blunt pelvic ring injury incidence and polytrauma caseload in a single level I trauma center during COVID-19 related pseudo-lockdown measures: a retrospective cohort study based on a prospective registry
Authors: Morello Vanessa , Zingg Matthieu , Andereggen Elisabeth , Ansorge Alexandre , Valisena Silvia , Gamulin Axel 
Published: September 2023

Abstract
Background
Pelvic ring injuries are potentially lethal lesions associated with polytrauma patients and need an efficient trauma team for their management. The purpose of this study was to evaluate the incidence of high-energy blunt pelvic ring injuries and the absolute number of polytrauma patients in a single level I trauma center during the 2020 pseudo-lockdown period related to the Coronavirus pandemic, and to compare it with corresponding periods in 2014–2019 in order to better understand the need of organized and dedicated personnel and infrastructures.

Methods
This retrospective cohort study was based on data prospectively recorded into the institutional Severely Injured Patients’ Registry. Data were obtained for each year period (January 1st to December 31st) and corresponding pseudo-lockdown period (March 16th to June 19th). High-energy blunt pelvic ring injuries inclusion criteria were: (1) Registry entry between January 1st, 2014 and December 31st, 2020; (2) age ≥ 16 years old; and (3) pelvic ring injury presence. Corresponding exclusion criteria were: (1) death before admission; (2) transfer from another institution > 24 h after trauma; (3) penetrating, blast, burn and electrical injuries, drownings; (4) patients living outside the defined institution’s catchment area; and (5) any document attesting the patient’s will to not participate in any study. Polytrauma patients inclusion criteria were: (1) Registry entry between January 1st, 2014 and December 31st, 2020; (2) age ≥ 16 years old; and (3) Injury Severity Score ≥ 16. Corresponding exclusion criteria were: (1) death before admission; (2) transfer from another institution > 24 h after trauma; and (3) any document attesting the patient’s will to not participate in any study. Categorical variables were reported using proportions and continuous variables using medians and interquartile ranges. Because data were exhaustive for the authors’ level I trauma center, no inferential statistics were computed.

Results
The incidence of high-energy blunt pelvic ring injuries and the absolute number of polytrauma patients remained within range of previous years despite pseudo-lockdown measures.

Conclusions
These observations bring better knowledge about pseudo-lockdown’s impact on trauma and may help for future health strategy planning by pointing out the importance of maintaining the activity of level I trauma centers in terms of personnel and infrastructures.
Ochratoxin A induces abnormal tryptophan metabolism in the intestine and liver to activate AMPK signaling pathway
Authors: Ma Weiqing , Fu Yang , Zhu Shanshan , Xia Daiyang , Zhai Shuangshuang , Xiao Deqin , Zhu Yongwen , Dione Michel , Ben Lukuyu , Yang Lin , Wang Wence 
Published: September 2023

Abstract
Background
Ochratoxin A (OTA) is a mycotoxin widely present in raw food and feed materials and is mainly produced by Aspergillus ochraceus and Penicillium verrucosum. Our previous study showed that OTA principally induces liver inflammation by causing intestinal flora disorder, especially Bacteroides plebeius (B. plebeius) overgrowth. However, whether OTA or B. plebeius alteration leads to abnormal tryptophan-related metabolism in the intestine and liver is largely unknown. This study aimed to elucidate the metabolic changes in the intestine and liver induced by OTA and the tryptophan-related metabolic pathway in the liver.

Materials and methods
A total of 30 healthy 1-day-old male Cherry Valley ducks were randomly divided into 2 groups. The control group was given 0.1 mol/L NaHCO3 solution, and the OTA group was given 235 μg/kg body weight OTA for 14 consecutive days. Tryptophan metabolites were determined by intestinal chyme metabolomics and liver tryptophan-targeted metabolomics. AMPK-related signaling pathway factors were analyzed by Western blotting and mRNA expression.

Results
Metabolomic analysis of the intestinal chyme showed that OTA treatment resulted in a decrease in intestinal nicotinuric acid levels, the downstream product of tryptophan metabolism, which were significantly negatively correlated with B. plebeius abundance. In contrast, OTA induced a significant increase in indole-3-acetamide levels, which were positively correlated with B. plebeius abundance. Simultaneously, OTA decreased the levels of ATP, NAD+ and dipeptidase in the liver. Liver tryptophan metabolomics analysis showed that OTA inhibited the kynurenine metabolic pathway and reduced the levels of kynurenine, anthranilic acid and nicotinic acid. Moreover, OTA increased the phosphorylation of AMPK protein and decreased the phosphorylation of mTOR protein.

Conclusion
OTA decreased the level of nicotinuric acid in the intestinal tract, which was negatively correlated with B. plebeius abundance. The abnormal metabolism of tryptophan led to a deficiency of NAD+ and ATP in the liver, which in turn activated the AMPK signaling pathway. Our results provide new insights into the toxic mechanism of OTA, and tryptophan metabolism might be a target for prevention and treatment.

Graphical Abstract
Integrins and their potential roles in mammalian pregnancy
Authors: Johnson Gregory A. , Burghardt Robert C. , Bazer Fuller W. , Seo Heewon , Cain Joe W. 
Published: September 2023

AbstractIntegrins are a highly complex family of receptors that, when expressed on the surface of cells, can mediate reciprocal cell-to-cell and cell-to-extracellular matrix (ECM) interactions leading to assembly of integrin adhesion complexes (IACs) that initiate many signaling functions both at the membrane and deeper within the cytoplasm to coordinate processes including cell adhesion, migration, proliferation, survival, differentiation, and metabolism. All metazoan organisms possess integrins, and it is generally agreed that integrins were associated with the evolution of multicellularity, being essential for the association of cells with their neighbors and surroundings, during embryonic development and many aspects of cellular and molecular biology. Integrins have important roles in many aspects of embryonic development, normal physiology, and disease processes with a multitude of functions discovered and elucidated for integrins that directly influence many areas of biology and medicine, including mammalian pregnancy, in particular implantation of the blastocyst to the uterine wall, subsequent placentation and conceptus (embryo/fetus and associated placental membranes) development. This review provides a succinct overview of integrin structure, ligand binding, and signaling followed with a concise overview of embryonic development, implantation, and early placentation in pigs, sheep, humans, and mice as an example for rodents. A brief timeline of the initial localization of integrin subunits to the uterine luminal epithelium (LE) and conceptus trophoblast is then presented, followed by sequential summaries of integrin expression and function during gestation in pigs, sheep, humans, and rodents. As appropriate for this journal, summaries of integrin expression and function during gestation in pigs and sheep are in depth, whereas summaries for humans and rodents are brief. Because similar models to those illustrated in Fig. 1, 2, 3, 4, 5 and 6 are present throughout the scientific literature, the illustrations in this manuscript are drafted as Viking imagery for entertainment purposes.