bluuebunny/crossref_metadata_2025_split huggingface dataset:
Network-based drug repurposing for schizophrenia
Authors: Truong Trang T. T. , Liu Zoe S. J. , Panizzutti Bruna , Kim Jee Hyun , Dean Olivia M. , Berk Michael , Walder Ken 
Published: February 2024

AbstractDespite recent progress, the challenges in drug discovery for schizophrenia persist. However, computational drug repurposing has gained popularity as it leverages the wealth of expanding biomedical databases. Network analyses provide a comprehensive understanding of transcription factor (TF) regulatory effects through gene regulatory networks, which capture the interactions between TFs and target genes by integrating various lines of evidence. Using the PANDA algorithm, we examined the topological variances in TF-gene regulatory networks between individuals with schizophrenia and healthy controls. This algorithm incorporates binding motifs, protein interactions, and gene co-expression data. To identify these differences, we subtracted the edge weights of the healthy control network from those of the schizophrenia network. The resulting differential network was then analysed using the CLUEreg tool in the GRAND database. This tool employs differential network signatures to identify drugs that potentially target the gene signature associated with the disease. Our analysis utilised a large RNA-seq dataset comprising 532 post-mortem brain samples from the CommonMind project. We constructed co-expression gene regulatory networks for both schizophrenia cases and healthy control subjects, incorporating 15,831 genes and 413 overlapping TFs. Through drug repurposing, we identified 18 promising candidates for repurposing as potential treatments for schizophrenia. The analysis of TF-gene regulatory networks revealed that the TFs in schizophrenia predominantly regulate pathways associated with energy metabolism, immune response, cell adhesion, and thyroid hormone signalling. These pathways represent significant targets for therapeutic intervention. The identified drug repurposing candidates likely act through TF-targeted pathways. These promising candidates, particularly those with preclinical evidence such as rimonabant and kaempferol, warrant further investigation into their potential mechanisms of action and efficacy in alleviating the symptoms of schizophrenia.
Clinical and imaging features of women with polygenic partial lipodystrophy: a case series
Authors: Loh Wann Jia , Yaligar Jadegoud , Hooper Amanda J. , Sadananthan Suresh Anand , Kway Yeshe , Lim Su Chi , Watts Gerald.F. , Velan Sambasivam Sendhil , Leow Melvin Khee Shing , Khoo Joan 
Published: February 2024

Abstract
Background
Familial partial lipodystrophy (FPLD) is an inherited disorder of white adipose tissue that causes premature cardiometabolic disease. There is no clear diagnostic criteria for FPLD, and this may explain the under-detection of this condition.

Aim
This pilot study aimed to describe the clinical features of women with FPLD and to explore the value of adipose tissue measurements that could be useful in diagnosis.

Methods
In 8 women with FPLD and 4 controls, skinfold measurements, DXA and whole-body MRI were undertaken.

Results
Whole genome sequencing was negative for monogenic metabolic causes, but polygenic scores for partial lipodystrophy were elevated in keeping with FPLD type 1. The mean age of diagnosis of DM was 31 years in the FPLD group. Compared with controls, the FPLD group had increased HOMA-IR (10.3 vs 2.9, p = 0.028) and lower mean thigh skinfold thickness (19.5 mm vs 48.2 mm, p = 0.008). The FPLD group had lower percentage of leg fat and an increased ratio of trunk to leg fat percentage on DXA. By MRI, the FPLD group had decreased subcutaneous adipose tissue (SAT) volume in the femoral and calf regions (p < 0.01); abdominal SAT, visceral adipose tissue, and femoral and calf muscle volumes were not different from controls.

Conclusion
Women with FPLD1 in Singapore have significant loss of adipose but not muscle tissue in lower limbs and have early onset of diabetes. Reduced thigh skinfold, and increased ratio of trunk to leg fat percentage on DXA are potentially clinically useful markers to identify FPLD1.
Genome-wide association study implicates the role of TBXAS1 in the pathogenesis of depressive symptoms among the Korean population
Authors: Park Kyungtaek , Do Ah Ra , Chung Yuree , Kim Min Ji , Rhee Sang Jin , Yoon Dae Hyun , Choi Seung Ho , Cho Sung Joon , Kim Han-Na , Ahn Yong Min , Won Sungho 
Published: February 2024

AbstractAlthough depression is an emerging disorder affecting many people worldwide, most genetic studies have been performed in European descent populations. Herein, a genome-wide association study (GWAS) was conducted in Korean population to elucidate the genomic loci associated with depressive symptoms. Two independent cohorts were used as discovery datasets, which consisted of 6474 (1484 cases and 4990 controls) and 1654 (557 cases and 1097 controls) Korean participants, respectively. The participants were divided into case and control groups based on the Beck Depression Inventory (BDI). Meta-analysis using the two cohorts revealed that rs6945590 was significantly associated with the risk of depressive symptoms [P = 2.83 × 10−8; odds ratio (OR) = 1.23; 95% confidence interval (CI): 1.15–1.33]. This association was validated in other independent cohorts which were another Korean cohort (258 cases and 1757 controls) and the East Asian study of the Psychiatric Genomics Consortium (PGC) (12,455 cases and 85,548 controls). The predicted expression levels of thromboxane A synthase 1 gene (TBXAS1), which encodes the enzyme thromboxane A synthase 1 and participates in the arachidonic acid (AA) cascade, was significantly decreased in the whole blood tissues of the participants with depressive symptoms. Furthermore, Mendelian randomization (MR) analysis showed a causal association between TBXAS1 expression and the risk of depressive symptoms. In conclusion, as the number of risk alleles (A) of rs6945590 increased, TBXAS1 expression decreased, which subsequently caused an increase in the risk of depressive symptoms.
Prefrontal cortical dopamine deficit may cause impaired glucose metabolism in schizophrenia
Authors: Wu Qiongqiong , Long Yujun , Peng Xingjie , Song Chuhan , Xiao Jingmei , Wang Xiaoyi , Liu Furu , Xie Peng , Yang Jinqing , Shi Zhe , Hu Zhonghua , McCaig Colin , St Clair David , Lang Bing , Wu Renrong 
Published: February 2024

AbstractThe brain neurotramsmitter dopamine may play an important role in modulating systemic glucose homeostasis. In seven hundred and four drug- naïve patients with first-episode schizophrenia, we provide robust evidence of positive associations between negative symptoms of schizophrenia and high fasting blood glucose. We then show that glucose metabolism and negative symptoms are improved when intermittent theta burst stimulation (iTBS) on prefrontal cortex (PFC) is performed in patients with predominantly negative symptoms of schizophrenia. These findings led us to hypothesize that the prefrontal cortical dopamine deficit, which is known to be associated with negative symptoms, may be responsible for abnormal glucose metabolism in schizophrenia. To explore this, we optogenetically and chemogenetically inhibited the ventral tegmental area (VTA)-medial prefrontal cortex (mPFC) dopamine projection in mice and found both procedures caused glucose intolerance. Moreover, microinjection of dopamine two receptor (D2R) neuron antagonists into mPFC in mice significantly impaired glucose tolerance. Finally, a transgenic mouse model of psychosis named Disc1tr exhibited depressive-like symptoms, impaired glucose homeostasis, and compared to wild type littermates reduced D2R expression in prefrontal cortex.
ISR inhibition reverses pancreatic β-cell failure in Wolfram syndrome models
Authors: Hu Rui , Chen Xiangyi , Su Qiang , Wang Zhaoyue , Wang Xushu , Gong Mengting , Xu Minglu , Le Rongrong , Gao Yawei , Dai Peng , Zhang Zhen-Ning , Shao Li , Li Weida 
Published: February 2024

AbstractPancreatic β-cell failure by WFS1 deficiency is manifested in individuals with wolfram syndrome (WS). The lack of a suitable human model in WS has impeded progress in the development of new treatments. Here, human pluripotent stem cell derived pancreatic islets (SC-islets) harboring WFS1 deficiency and mouse model of β cell specific Wfs1 knockout were applied to model β-cell failure in WS. We charted a high-resolution roadmap with single-cell RNA-seq (scRNA-seq) to investigate pathogenesis for WS β-cell failure, revealing two distinct cellular fates along pseudotime trajectory: maturation and stress branches. WFS1 deficiency disrupted β-cell fate trajectory toward maturation and directed it towards stress trajectory, ultimately leading to β-cell failure. Notably, further investigation of the stress trajectory identified activated integrated stress response (ISR) as a crucial mechanism underlying WS β-cell failure, characterized by aberrant eIF2 signaling in WFS1-deficient SC-islets, along with elevated expression of genes in regulating stress granule formation. Significantly, we demonstrated that ISRIB, an ISR inhibitor, efficiently reversed β-cell failure in WFS1-deficient SC-islets. We further validated therapeutic efficacy in vivo with β-cell specific Wfs1 knockout mice. Altogether, our study provides novel insights into WS pathogenesis and offers a strategy targeting ISR to treat WS diabetes.
Transcription factor ATMIN facilitates chemoresistance in nasopharyngeal carcinoma
Authors: Fang Xue-Liang , Li Qing-Jie , Lin Jia-Yi , Huang Cheng-Long , Huang Sheng-Yan , Tan Xi-Rong , He Shi-Wei , Zhu Xun-Hua , Li Jun-Yan , Gong Sha , Qiao Han , Li Ying-Qin , Liu Na , Ma Jun , Zhao Yin , Tang Ling-Long 
Published: February 2024

AbstractDespite that the docectaxel-cisplatin-5-fluorouracil (TPF) induction chemotherapy has greatly improved patients’ survival and became the first-line treatment for advanced nasopharyngeal carcinoma (NPC), not all patients could benefit from this therapy. The mechanism underlying the TPF chemoresistance remains unclear. Here, by analyzing gene-expression microarray data and survival of patients who received TPF chemotherapy, we identify transcription factor ATMIN as a chemoresistance gene in response to TPF chemotherapy in NPC. Mass spectrometry and Co-IP assays reveal that USP10 deubiquitinates and stabilizes ATMIN protein, resulting the high-ATMIN expression in NPC. Knockdown of ATMIN suppresses the cell proliferation and facilitates the docetaxel-sensitivity of NPC cells both in vitro and in vivo, while overexpression of ATMIN exerts the opposite effect. Mechanistically, ChIP-seq combined with RNA-seq analysis suggests that ATMIN is associated with the cell death signaling and identifies ten candidate target genes of ATMIN. We further confirm that ATMIN transcriptionally activates the downstream target gene LCK and stabilizes it to facilitate cell proliferation and docetaxel resistance. Taken together, our findings broaden the insight into the molecular mechanism of chemoresistance in NPC, and the USP10-ATMIN-LCK axis provides potential therapeutic targets for the management of NPC.
GITRL impairs hepatocyte repopulation by liver progenitor cells to aggravate inflammation and fibrosis by GITR+CD8+ T lymphocytes in CDE Mice
Authors: Li Li , He Yu , Liu Kai , Liu Lin , Shan Shan , Liu Helin , Ren Jiangbo , Sun Shujie , Wang Min , Jia Jidong , Wang Ping 
Published: February 2024

AbstractAs an alternative pathway for liver regeneration, liver progenitor cells and their derived ductular reaction cells increase during the progression of many chronic liver diseases. However, the mechanism underlying their hepatocyte repopulation after liver injury remains unknown. Here, we conducted progenitor cell lineage tracing in mice and found that fewer than 2% of hepatocytes were derived from liver progenitor cells after 9 weeks of injury with a choline-deficient diet supplemented with ethionine (CDE), and this percentage increased approximately three-fold after 3 weeks of recovery. We also found that the proportion of liver progenitor cells double positive for the ligand of glucocorticoid-induced tumour necrosis factor receptor (GITRL, also called Tnfsf18) and SRY-related HMG box transcription 9 (Sox9) among nonparenchymal cells increased time-dependently upon CDE injury and reduced after recovery. When GITRL was conditionally knocked out from hepatic progenitor cells, its expression in nonparenchymal cells was downregulated by approximately fifty percent, and hepatocyte repopulation increased by approximately three folds. Simultaneously, conditional knockout of GITRL reduced the proportion of liver-infiltrating CD8+ T lymphocytes and glucocorticoid-induced tumour necrosis factor receptor (GITR)-positive CD8+ T lymphocytes. Mechanistically, GITRL stimulated cell proliferation but suppressed the differentiation of liver progenitor organoids into hepatocytes, and CD8+ T cells further reduced their hepatocyte differentiation by downregulating the Wnt/β-catenin pathway. Therefore, GITRL expressed by liver progenitor cells impairs hepatocyte differentiation, thus hindering progenitor cell-mediated liver regeneration.
IL-8 activates fibroblasts to promote the invasion of HNSCC cells via STAT3-MMP1
Authors: Chen Yu , Huang Li , Gan Rui-Huan , Yuan Shuo , Lan Ting , Zheng Dali , Lu You-Guang 
Published: February 2024

AbstractMatrix metalloproteinase-1 (MMP1) has an aberrant expression relevant to various behaviors of cancers. As dominant components of the tumor stroma, fibroblasts constitute an important source of Matrix metalloproteinase (MMPs) including mainly MMP1. The impacts of MMP1 derived from fibroblasts in tumor microenvironment, however, is not well defined. In this study, we demonstrated a part of crosstalk between fibroblasts and cancer cells that enhanced the invasiveness of cancer cells, IL8-induced activation of STAT3 signaling pathway as a key promoter to elevated MMP1 level in fibroblasts that supports the migration and invasion of head and neck squamous cell carcinoma (HNSCC) cells by extracellular matrix degradation. Importantly, once exposed to the inhibitor of STAT3 phosphorylation (TPCA-1), the enhanced induction of HNSCC cells invasion triggered by fibroblasts was significantly impaired.
The impact of reproductive factors on the metabolic profile of females from menarche to menopause
Authors: Clayton Gemma L. , Borges Maria Carolina , Lawlor Deborah A. 
Published: February 2024

AbstractWe explore the relation between age at menarche, parity and age at natural menopause with 249 metabolic traits in over 65,000 UK Biobank women using multivariable regression, Mendelian randomization and negative control (parity only). Older age of menarche is related to a less atherogenic metabolic profile in multivariable regression and Mendelian randomization, which is largely attenuated when accounting for adult body mass index. In multivariable regression, higher parity relates to more particles and lipids in VLDL, which are not observed in male negative controls. In multivariable regression and Mendelian randomization, older age at natural menopause is related to lower concentrations of inflammation markers, but we observe inconsistent results for LDL-related traits due to chronological age-specific effects. For example, older age at menopause is related to lower LDL-cholesterol in younger women but slightly higher in older women. Our findings support a role of reproductive traits on later life metabolic profile and provide insights into identifying novel markers for the prevention of adverse cardiometabolic outcomes in women.
Implicit racial biases are lower in more populous more diverse and less segregated US cities
Authors: Stier Andrew J. , Sajjadi Sina , Karimi Fariba , Bettencourt Luís M. A. , Berman Marc G. 
Published: February 2024

AbstractImplicit biases - differential attitudes towards members of distinct groups - are pervasive in human societies and create inequities across many aspects of life. Recent research has revealed that implicit biases are generally driven by social contexts, but not whether they are systematically influenced by the ways that humans self-organize in cities. We leverage complex system modeling in the framework of urban scaling theory to predict differences in these biases between cities. Our model links spatial scales from city-wide infrastructure to individual psychology to predict that cities that are more populous, more diverse, and less segregated are less biased. We find empirical support for these predictions in U.S. cities with Implicit Association Test data spanning a decade from 2.7 million individuals and U.S. Census demographic data. Additionally, we find that changes in cities’ social environments precede changes in implicit biases at short time-scales, but this relationship is bi-directional at longer time-scales. We conclude that the social organization of cities may influence the strength of these biases.
Heavy-to-light electron transition enabling real-time spectra detection of charged particles by a biocompatible semiconductor
Authors: Zhao Dou , Gao Ruiling , Cheng Wei , Wen Mengyao , Zhang Xinlei , Yokota Tomoyuki , Sellin Paul , Yang Shengyuan A. , Shang Li , Zhou Chongjian , Someya Takao , Jie Wanqi , Xu Yadong 
Published: February 2024

AbstractThe current challenge of wearable/implantable personal dosimeters for medical diagnosis and radiotherapy applications is lack of suitable detector materials possessing both excellent detection performance and biocompatibility. Here, we report a solution-grown biocompatible organic single crystalline semiconductor (OSCS), 4-Hydroxyphenylacetic acid (4HPA), achieving real-time spectral detection of charged particles with single-particle sensitivity. Along in-plane direction, two-dimensional anisotropic 4HPA exhibits a large electron drift velocity of 5 × 105 cm s−1 at “radiation-mode” while maintaining a high resistivity of (1.28 ± 0.003) × 1012 Ω·cm at “dark-mode” due to influence of dense π-π overlaps and high-energy L1 level. Therefore, 4HPA detectors exhibit the record spectra detection of charged particles among their organic counterparts, with energy resolution of 36%, (μt)e of (4.91 ± 0.07) × 10−5 cm2 V−1, and detection time down to 3 ms. These detectors also show high X-ray detection sensitivity of 16,612 μC Gyabs−1 cm−3, detection of limit of 20 nGyair s−1, and long-term stability after 690 Gyair irradiation.
Learning nonequilibrium statistical mechanics and dynamical phase transitions
Authors: Tang Ying , Liu Jing , Zhang Jiang , Zhang Pan 
Published: February 2024

AbstractNonequilibrium statistical mechanics exhibit a variety of complex phenomena far from equilibrium. It inherits challenges of equilibrium, including accurately describing the joint distribution of a large number of configurations, and also poses new challenges as the distribution evolves over time. Characterizing dynamical phase transitions as an emergent behavior further requires tracking nonequilibrium systems under a control parameter. While a number of methods have been proposed, such as tensor networks for one-dimensional lattices, we lack a method for arbitrary time beyond the steady state and for higher dimensions. Here, we develop a general computational framework to study the time evolution of nonequilibrium systems in statistical mechanics by leveraging variational autoregressive networks, which offer an efficient computation on the dynamical partition function, a central quantity for discovering the phase transition. We apply the approach to prototype models of nonequilibrium statistical mechanics, including the kinetically constrained models of structural glasses up to three dimensions. The approach uncovers the active-inactive phase transition of spin flips, the dynamical phase diagram, as well as new scaling relations. The result highlights the potential of machine learning dynamical phase transitions in nonequilibrium systems.
Photo-thermal coupling to enhance CO2 hydrogenation toward CH4 over Ru/MnO/Mn3O4
Authors: Zhai Jianxin , Xia Zhanghui , Zhou Baowen , Wu Haihong , Xue Teng , Chen Xiao , Jiao Jiapeng , Jia Shuaiqiang , He Mingyuan , Han Buxing 
Published: February 2024

AbstractUpcycling of CO2 into fuels by virtually unlimited solar energy provides an ultimate solution for addressing the substantial challenges of energy crisis and climate change. In this work, we report an efficient nanostructured Ru/MnOx catalyst composed of well-defined Ru/MnO/Mn3O4 for photo-thermal catalytic CO2 hydrogenation to CH4, which is the result of a combination of external heating and irradiation. Remarkably, under relatively mild conditions of 200 °C, a considerable CH4 production rate of 166.7 mmol g−1 h−1 was achieved with a superior selectivity of 99.5% at CO2 conversion of 66.8%. The correlative spectroscopic and theoretical investigations suggest that the yield of CH4 is enhanced by coordinating photon energy with thermal energy to reduce the activation energy of reaction and promote formation of key intermediate COOH* species over the catalyst. This work opens up a new strategy for CO2 hydrogenation toward CH4.
Multicompartmental coacervate-based protocell by spontaneous droplet evaporation
Authors: Qi Cheng , Ma Xudong , Zeng Qi , Huang Zhangwei , Zhang Shanshan , Deng Xiaokang , Kong Tiantian , Liu Zhou 
Published: February 2024

AbstractHierarchical compartmentalization, a hallmark of both primitive and modern cells, enables the concentration and isolation of biomolecules, and facilitates spatial organization of biochemical reactions. Coacervate-based compartments can sequester and recruit a large variety of molecules, making it an attractive protocell model. In this work, we report the spontaneous formation of core-shell cell-sized coacervate-based compartments driven by spontaneous evaporation of a sessile droplet on a thin-oil-coated substrate. Our analysis reveals that such far-from-equilibrium architectures arise from multiple, coupled segregative and associative liquid-liquid phase separation, and are stabilized by stagnation points within the evaporating droplet. The formation of stagnation points results from convective capillary flows induced by the maximum evaporation rate at the liquid-liquid-air contact line. This work provides valuable insights into the spontaneous formation and maintenance of hierarchical compartments under non-equilibrium conditions, offering a glimpse into the real-life scenario.
Heat shock protein gp96 drives natural killer cell maturation and anti-tumor immunity by counteracting Trim28 to stabilize Eomes
Authors: Xu Yuxiu , Li Xin , Cheng Fang , Zhao Bao , Fang Min , Li Zihai , Meng Songdong 
Published: February 2024

AbstractThe maturation process of natural killer (NK) cells, which is regulated by multiple transcription factors, determines their functionality, but few checkpoints specifically targeting this process have been thoroughly studied. Here we show that NK-specific deficiency of glucose-regulated protein 94 (gp96) leads to decreased maturation of NK cells in mice. These gp96-deficient NK cells exhibit undermined activation, cytotoxicity and IFN-γ production upon stimulation, as well as weakened responses to IL-15 for NK cell maturation, in vitro. In vivo, NK-specific gp96-deficient mice show increased tumor growth. Mechanistically, we identify Eomes as the downstream transcription factor, with gp96 binding to Trim28 to prevent Trim28-mediated ubiquitination and degradation of Eomes. Our study thus suggests the gp96-Trim28-Eomes axis to be an important regulator for NK cell maturation and cancer surveillance in mice.