Miracle-dz/UniFAR-FTUs huggingface dataset:
Carbamazepine Enhances Adipogenesis by Inhibiting Wnt/β-Catenin Expression

Carbamazepine is a drug that is widely used in the treatment of epilepsy and bipolar disorder. The prevalence of obesity in patients treated with carbamazepine has been frequently reported. However, whether carbamazepine affects adipogenesis, one of the critical steps in the development of obesity, remains unclear. Here, we show that carbamazepine increased the expression levels of peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein β (C/EBPβ), and fatty acid synthase (FASN) in 3T3-L1 cells. Notably, carbamazepine inhibited the expression levels of β-catenin, a negative regulator of adipogenesis, leading to enhanced adipogenesis. Conversely, β-catenin overexpression abolished the effect of carbamazepine on adipogenic gene expression. However, depletion of β-catenin further enhanced PPARγ expression. In addition, carbamazepine reduced β-catenin expression by lowering the levels of phospho-low density lipoprotein receptor-related protein 6 (p-LRP6) and phospho-glycogen synthase kinase 3β (p-GSK3β) in Wnt/β-catenin signaling. Moreover, carbamazepine reduced Wnt mRNA expression and decreased the promoter activities of TCF, the target of β-catenin during adipogenesis. These results suggest that carbamazepine enhances adipogenesis by suppressing Wnt/β-catenin expression, indicating its potential effects on obesity-related metabolism.
Nonzero-Sum Game Reinforcement Learning for Performance Optimization in Large-Scale Industrial Processes

This article presents a novel technique to achieve plant-wide performance optimization for large-scale unknown industrial processes by integrating the reinforcement learning method with the multiagent game theory. A main advantage of this technique is that plant-wide optimal performance is achieved by a distributed approach where multiple agents solve simplified local nonzero-sum optimization problems so that a global Nash equilibrium is reached. To this end, first, the plant-wide performance optimization problem is reformulated by decomposition into local optimization subproblems for each production index in a multiagent framework. Then, the nonzero-sum graphical game theory is utilized to compute the operational indices for each unit process with the purpose of reaching the global Nash equilibrium, resulting in production indices following their prescribed target values. The stability and the global Nash equilibrium of this multiagent graphical game solution are rigorously proved. The reinforcement learning methods are then developed for each agent to solve the nonzero-sum graphical game problem using data measurements available in the system in real time. The plant dynamics do not have to be known. Finally, the emulation results are given to show the effectiveness of the proposed automated decision algorithm by using measured data from a large mineral processing plant in Gansu Province, China.
Conversion of coastal wetlands, riparian wetlands, and peatlands increases greenhouse gas emissions: A global meta‐analysis

Land‐use/land‐cover change (LULCC) often results in degradation of natural wetlands and affects the dynamics of greenhouse gases (GHGs). However, the magnitude of changes in GHG emissions from wetlands undergoing various LULCC types remains unclear. We conducted a global meta‐analysis with a database of 209 sites to examine the effects of LULCC types of constructed wetlands (CWs), croplands (CLs), aquaculture ponds (APs), drained wetlands (DWs), and pastures (PASs) on the variability in CO2, CH4, and N2O emissions from the natural coastal wetlands, riparian wetlands, and peatlands. Our results showed that the natural wetlands were net sinks of atmospheric CO2 and net sources of CH4 and N2O, exhibiting the capacity to mitigate greenhouse effects due to negative comprehensive global warming potentials (GWPs; −0.9 to −8.7 t CO2‐eq ha−1 year−1). Relative to the natural wetlands, all LULCC types (except CWs from coastal wetlands) decreased the net CO2 uptake by 69.7%−456.6%, due to a higher increase in ecosystem respiration relative to slight changes in gross primary production. The CWs and APs significantly increased the CH4 emissions compared to those of the coastal wetlands. All LULCC types associated with the riparian wetlands significantly decreased the CH4 emissions. When the peatlands were converted to the PASs, the CH4 emissions significantly increased. The CLs, as well as DWs from peatlands, significantly increased the N2O emissions in the natural wetlands. As a result, all LULCC types (except PASs from riparian wetlands) led to remarkably higher GWPs by 65.4%−2,948.8%, compared to those of the natural wetlands. The variability in GHG fluxes with LULCC was mainly sensitive to changes in soil water content, water table, salinity, soil nitrogen content, soil pH, and bulk density. This study highlights the significant role of LULCC in increasing comprehensive GHG emissions from global natural wetlands, and our results are useful for improving future models and manipulative experiments.
Genistein‐3′‐sodium sulphonate protects against lipopolysaccharide‐induced lung vascular endothelial cell apoptosis and acute lung injury via BCL‐2 signalling

Under septic conditions, Lipopolysaccharide (LPS)‐induced apoptosis of lung vascular endothelial cells (ECs) triggers and aggravates acute lung injury (ALI), which so far has no effective therapeutic options. Genistein‐3′‐sodium sulphonate (GSS) is a derivative of native soy isoflavone, which has neuro‐protective effects through its anti‐apoptotic property. However, whether GSS protects against sepsis‐induced lung vascular endothelial cell apoptosis and ALI has not been determined. In this study, we found that LPS‐induced Myd88/NF‐κB/BCL‐2 signalling pathway activation and subsequent EC apoptosis were effectively down‐regulated by GSS in vitro. Furthermore, GSS not only reversed the sepsis‐induced BCL‐2 changes in expression in mouse lungs but also blocked sepsis‐associated lung vascular barrier disruption and ALI in vivo. Taken together, our results demonstrated that GSS might be a promising candidate for sepsis‐induced ALI via its regulating effects on Myd88/NF‐κB/BCL‐2 signalling in lung ECs.
The Effects of Population Tuning and Trial-by-Trial Variability on Information Encoding and Behavior

Identifying the features of population responses that are relevant to the amount of information encoded by neuronal populations is a crucial step toward understanding population coding. Statistical features, such as tuning properties, individual and shared response variability, and global activity modulations, could all affect the amount of information encoded and modulate behavioral performance. We show that two features in particular affect information: the modulation of population responses across conditions (population signal) and the inverse population covariability along the modulation axis (projected precision). We demonstrate that fluctuations of these two quantities are correlated with fluctuations of behavioral performance in various tasks and brain regions consistently across 4 monkeys (1 female and 1 male Macaca mulatta; and 2 male Macaca fascicularis). In contrast, fluctuations in mean correlations among neurons and global activity have negligible or inconsistent effects on the amount of information encoded and behavioral performance. We also show that differential correlations reduce the amount of information encoded in finite populations by reducing projected precision. Our results are consistent with predictions of a model that optimally decodes population responses to produce behavior. SIGNIFICANCE STATEMENT The last two or three decades of research have seen hot debates about what features of population tuning and trial-by-trial variability influence the information carried by a population of neurons, with some camps arguing, for instance, that mean pairwise correlations or global fluctuations are important while other camps report opposite results. In this study, we identify the most important features of neural population responses that determine the amount of encoded information and behavioral performance by combining analytic calculations with a novel nonparametric method that allows us to isolate the effects of different statistical features. We tested our hypothesis on 4 macaques, three decision-making tasks, and two brain areas. The predictions of our theory were in agreement with the experimental data.
Mutation That Promotes Activation of Trypsinogen Increases Severity of Secretagogue-Induced Pancreatitis in Mice.

BACKGROUND & AIMS Mutations in the human serine protease 1 gene (PRSS1), which encodes cationic trypsinogen, can accelerate its autoactivation and cause hereditary or sporadic chronic pancreatitis. Disruption of the locus that encodes cationic trypsinogen in mice (T7) causes loss of expression of the protein, but only partially decreases the severity of secretagogue-induced acute pancreatitis and has no effect on chronic pancreatitis. We investigated whether trypsinogen becomes pathogenic only when it is activated by mutation METHODS: We generated mice with knock-in of the p.K24R mutation (called T7K24R mice), which is analogous to human PRSS1 mutation p.K23R. We gave T7K24R and C57BL/6N (control) mice repeated injections of cerulein to induce pancreatitis. Plasma amylase activity, pancreatic edema, and myeloperoxidase content in pancreas and lungs and were quantified. We expressed mutant and full-length forms of PRSS1 in Escherichia coli and compared their autoactivation RESULTS: The p.K24R mutation increased autoactivation of T7 5-fold. T7K24R mice developed no spontaneous pancreatitis. T7K24R mice given cerulein injections had increased pancreatic activation of trypsinogen and edema, infiltration of lung and pancreas by inflammatory cells, and plasma amylase activity compared with control mice given cerulein injections. Injection of cerulein for 2 days induced progressive pancreatitis in T7K24R mice, but not in control mice, with typical features of chronic pancreatitis CONCLUSIONS: Introduction of a mutation into mice that is analogous to the p.K23R mutation in PRSS1 increases pancreatic activation of trypsinogen during secretagogue-induced pancreatitis. Higher pancreatic activity of trypsin increases the severity of pancreatitis even though loss of trypsin activity does not prevent pancreatitis in mice.
Neglected Tropical Diseases as a ‘litmus test’ for Universal Health Coverage? Understanding who is left behind and why in Mass Drug Administration: Lessons from four country contexts

Introduction Individuals and communities affected by NTDs are often the poorest and most marginalised; ensuring a gender and equity lens is centre stage will be critical for the NTD community to reach elimination goals and inform Universal Health Coverage (UHC). NTDs amenable to preventive chemotherapy have been described as a ‘litmus test’ for UHC due to the high mass drug administration (MDA) coverage rates needed to be effective and their model of community engagement. However, until now highly aggregated coverage data may have masked inequities in availability, accessibility and acceptability of medicines, slowing down the equitable achievement of elimination goals. Methods We conducted qualitative programmatic analysis across different country contexts through the novel application of the Tanahashi Coverage Framework enhanced by gendered intersectional theory to interrogate different components of programme coverage: availability, accessibility, acceptability, contact and effective. Drawing on communities and health implementers perspectives (using focus groups, interviews, and participatory methods) from varying levels of the health system, across four African country contexts (Cameroon, Ghana, Liberia and Nigeria), we show who is left behind and provide recommendations for programmes to respond. Findings We have unmasked inequities in programme delivery that repeatedly leave vulnerable populations underserved in relation to the prevention and treatment of PC NTDs across all components of coverage explored within the Tanahashi framework. Inequities are influenced by health systems challenges and limitations, due to lack of consideration of gender, power and equity issues. Effective treatment for individuals and communities is shaped by individual identities and the intersecting axes of inequity that converge to shape these positions including gender, age, disability, and geography. Health systems are inherently social and gendered thus they become mediators in managing the impact that social and structural processes have on individual health outcomes. Significance To our knowledge this is the only paper which has combined a comprehensive equity framework with intersectional feminist theory, to establish a fuller understanding of who is left behind and why in MDA across countries and contexts. Ensuring the most vulnerable have continued access to future treatment options will contribute to the progressive realisation of UHC, allowing the NTD community to continue to support their vision of being a true ‘litmus test’.
Donor-site Morbidity after Retromolar Bone Harvesting Using a Standardised Press Fit Cylinder Protocol

Precise fitting and immobilisation of bone transplants at the recipient site is of utmost importance for the healing process. With the help of the standardised Osseo Transfer System, the recipient site is adjusted to the graft, rather than vice versa as it is typically done. The aim of this study was to analyse donor-site morbidity after harvesting cylindrical bone grafts from the retromolar region using the Osseo Transfer System. The patient satisfaction with the surgical procedures was also evaluated. All patients treated with this standardised reconstruction method between 2006 and 2013 at the Department of Cranio-Maxillofacial Surgery, University Hospital Giessen, were included in this study. Complications were recorded and evaluated. Bone graft success and patient satisfaction were documented with a questionnaire, and then confirmed by clinical and radiological follow-up examinations. Fifty-four patients were treated and 64 harvested cylindrical autologous bone grafts were transplanted. In all cases, dental implants could be inserted after bone healing. One patient lost an implant, associated with failure of the bone graft. Six patients who were examined continued to show neurological disorders in locally limited areas. No complete or long-term damage of the inferior alveolar nerve occurred. More than 94% (n = 52) of the patients were ‘very satisfied’ or ‘satisfied’ with the results and would recommend this surgical treatment to other patients. The standardised Osseo Transfer was an effective treatment option for small and mid-sized alveolar ridge augmentations. A low donor-site morbidity rate and a high transplant success rate were verified. The Osseo Transfer System demonstrated to be a reliable surgical technique without major complications. We highly recommend this surgical augmentation procedure as a surgical treatment for local bone defects.
Links between Cognitive Status and Trace Element Levels in Hair for an Environmentally Exposed Population: A Case Study in the Surroundings of the Estarreja Industrial Area

In the present study, trace elements (TE) levels were evaluated in scalp hair along the continuum from healthy subjects (HS) to patients suffering from subjective memory concerns (SMC), and/or mild cognitive impairment (MCI), and those with already installed dementia (DEM) in order to: (i) assess the effects of environmental and lifestyle factors on TE concentrations and (ii) evaluate the analyzed elements as possible diagnostic biomarkers for the disease. The study involved 79 mainly permanent residents, >55 years old, from the city of Estarreja (northern Portugal), a former industrial area. The health status of the participants was assessed by means of a complete socio-demographic questionnaire and through cognitive screening tests, namely the Mini-Mental State Examination (MMSE). The test scores were categorized and used in the statistical analysis. Hair samples were collected and analyzed by inductively coupled plasma-mass spectrometry (ICP-MS) ICP-MS for selected TE. Dementia appears to be associated with higher age, the female gender, lower education level, and longer residence time in the study area. In addition, most of the participants diagnosed with dementia frequently consume home-grown foodstuffs, some irrigated with contaminated well water. The calculation of the TE enrichment factors of soil samples collected in kitchen gardens/small farms in the vicinity of the Estarreja Chemical Complex (ECC) reinforces the degree of Hg soil contamination in the area, due to anthropogenic sources that can be a source for the population Hg exposure route among others. Mercury levels in hair differed significantly between the four individual groups (HS, SMC, MCI, and DEM), increasing from healthy to dementia participants. Improved diagnostic results can be obtained using hair TE signatures coupled with MMSE scores. This strategy may prove useful for predictive diagnosis in population screening for cognitive impairment.
Alternative mechanical heart valves for the developing world

Due to the prevalence of rheumatic heart disease in the developing world, mechanical heart valves in the younger patient population remain the prostheses of choice if repair is not feasible. Despite their durability, mechanical valves are burdened by coagulation and thromboembolism. Modern design tools can be utilized during the design process of mechanical valves, which allow a more systematic design approach and more detailed analysis of the blood flow through and around valves. These tools include computer-aided design, manufacturing, and engineering, such as computational fluid dynamics and finite element analysis, modern manufacturing techniques such as additive manufacturing, and sophisticated in-vitro and in-vivo tests. Following this systematic approach, a poppet valve was redesigned and the results demonstrate the benefits of the method. More organized flow patterns and fewer complex fluid structures were observed. The alternative trileaflet valve design has also been identified as a potential solution and, if a similar design approach is adopted, it could lead to the development of an improved mechanical heart valve in the future. It is imperative that researchers in developing countries continue their search for a mechanical heart valve with a reduced thromboembolic risk, requiring less or no anticoagulation.
Platelet vesicles are potent inflammatory mediators in red blood cell products and washing reduces the inflammatory phenotype

Studies suggest that washing red cell concentrates (RCCs) to remove soluble mediators and/or inflammatory components, such as extracellular vesicles (EVs), may lead to better clinical outcomes. This study tested the hypothesis that non‐red blood cell (RBC) generated vesicles in RCC are potent inflammatory mediators in vitro and washing RCCs can reduce these vesicles and subsequently decrease the inflammatory activity of RCCs.
Chimeric Antigen Receptor (CAR) T Cells Targeting the CD19 Antigen for the Treatment of Pediatric Relapsed B Cell ALL

T cells can be genetically modified to target tumor antigens through the expression of a chimeric antigen receptor (CAR). CAR T cells targeting the CD19 antigen is a novel therapeutic approach for patients with relapsed B cell acute lymphoblastic leukemia (B-ALL). We have previously demonstrated that CAR T cells have a significant clinical benefit in adult patients with relapsed B-ALL. The primary objective of this study ([NCT01860937][1]) is to extend the use and test the safety of CD19 specific CAR T cells in children with relapsed CD19+ B-ALL. To date, 11 pediatric patients with very high risk (VHR) or relapsed B-ALL have been enrolled on protocol with a median age of 13 years (range 2-23 years) at time of T cell collection. We have treated 4 pediatric patients with relapsed B-ALL (ages 13, 14, 19, and 22 years) using patient derived T cells expressing a CD19 specific CAR (19-28z). Complete response (complete remission or complete remission with incomplete count recovery) occurred in 2/4 (50%) patients. Severe cytokine release syndrome (sCRS) defined by fever for ≥3 consecutive days, elevated serum cytokine levels, and one clinical sign of toxicity (hypotension, hypoxia, neurologic disorder including altered mental status, obtundation, and/or seizure) occurred in both patients who responded to CAR T cells. Morphologic disease (≥5% bone marrow blasts) at time of treatment was present in three patients including both patients with sCRS. Systemic immunosuppressants (corticosteroids or anti-IL6 receptor antibody tocilizumab) abrogated clinical symptoms of sCRS. Elevated serum cytokines of IFN-g (>20 fold), fractalkine (>20 fold), Flt-3L (>55 fold), IL-5 (>15 fold), IL-6 (>100 fold), and IL-10 (>15 fold) were demonstrated in patients with sCRS. Monitoring of bone marrow demonstrated peak 19-28z CAR T-cell detection within 1-2 weeks following infusion with gradual contracture over 2-3 months. These early results demonstrate the feasibility and significant clinical impact of this approach in patients with relapsed B-ALL. To more rapidly generate statistically relevant data, demonstrate the “exportability” of this technology between academic institutions, and offer this therapeutic option to a broader number of pediatric patients with chemo-refractory B-ALL our trial will expand into a phase I multicenter clinical trial with a collaborating institution. Subsequent cohorts of patients will receive 19-28z CAR T cells and will be evaluated for toxicity, persistence of CAR T cells, and for anti-leukemic efficacy. Disclosures Off Label Use: CAR T cells for relapsed B-ALL. Riviere: Juno Therapeutics: Consultancy, Scientific co-founder and Stock holder Other. Boulad: Genzyme Sanofi: Trials partially funded by Genzyme Sanofi Other. Sadelain: Juno Therapeutics: Consultancy, Scientific co-founder and Stock holder Other. Brentjens: Juno Therapeutics: Consultancy, Scientific co-founder and Stock holder Other. [1]: /lookup/external-ref? link_type=CLINTRIALGOV&access_num=NCT01860937&atom=%2Fbloodjournal%2F124%2F21%2F3716.atom