bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hair glucocorticoids are associated with childhood adversity, depressive symptoms and reduced global and lobar grey matter in Generation Scotland
Authors: Green Claire , Stolicyn Aleks , Harris Mathew A. , Shen Xueyi , Romaniuk Liana , Barbu Miruna C. , Hawkins Emma L. , Wardlaw Joanna M. , Steele J. Douglas , Waiter Gordon D. , Sandu Anca-Larisa , Campbell Archie , Porteous David J. , Seckl Jonathan R. , Lawrie Stephen M. , Reynolds Rebecca M. , Cavanagh Jonathan , McIntosh Andrew M. , Whalley Heather C. 
Published: October 2021

AbstractHypothalamic–pituitary–adrenal (HPA) axis dysregulation has been commonly reported in major depressive disorder (MDD), but with considerable heterogeneity of results; potentially due to the predominant use of acute measures of an inherently variable/phasic system. Chronic longer-term measures of HPA-axis activity have yet to be systematically examined in MDD, particularly in relation to brain phenotypes, and in the context of early-life/contemporaneous stress. Here, we utilise a temporally stable measure of cumulative HPA-axis function (hair glucocorticoids) to investigate associations between cortisol, cortisone and total glucocorticoids with concurrent measures of (i) lifetime-MDD case/control status and current symptom severity, (ii) early/current-life stress and (iii) structural neuroimaging phenotypes, in N = 993 individuals from Generation Scotland (mean age = 59.1 yrs). Increased levels of hair cortisol were significantly associated with reduced global and lobar brain volumes with reductions in the frontal, temporal and cingulate regions (βrange = −0.057 to −0.104, all PFDR < 0.05). Increased levels of hair cortisone were significantly associated with MDD (lifetime-MDD status, current symptoms, and severity; βrange = 0.071 to 0.115, all PFDR = < 0.05), with early-life adversity (β = 0.083, P = 0.017), and with reduced global and regional brain volumes (global: β = −0.059, P = 0.043; nucleus accumbens: β = −0.075, PFDR = 0.044). Associations with total glucocorticoids followed a similar pattern to the cortisol findings. In this large community-based sample, elevated glucocorticoids were significantly associated with MDD, with early, but not later-life stress, and with reduced global and regional brain phenotypes. These findings provide important foundations for future mechanistic studies to formally explore causal relationships between early adversity, chronic rather than acute measures of glucocorticoids, and neurobiological associations relevant to the aetiology of MDD.
Childhood urbanicity interacts with polygenic risk for depression to affect stress-related medial prefrontal function
Authors: Zhang Xiao , Yan Hao , Yu Hao , Zhao Xin , Shah Shefali , Dong Zheng , Yang Guang , Zhang Xiaoxi , Muse Timothy , Li Jing , Jiang Sisi , Liao Jinmin , Zhang Yuyanan , Chen Qiang , Weinberger Daniel R. , Yue Weihua , Zhang Dai , Tan Hao Yang 
Published: October 2021

AbstractUrbanization is increasing globally, and is associated with stress and increased mental health risks, including for depression. However, it remains unclear, especially at the level of brain function, how urbanicity, social threat stressors, and psychiatric risk may be linked. Here, we aim to define the structural and functional MRI neural correlates of social stress, childhood urbanicity, and their putative mechanistic relevance to depressive illness risk, in terms of behavioral traits and genetics. We studied a sample of healthy adults with divergent urban and rural childhoods. We examined childhood urbanicity effects on brain structure as suggested by MRI, and its functional relevance to depression risk, through interactions between urbanicity and trait anxiety-depression, as well as between urbanicity and polygenic risk for depression, during stress-related medial prefrontal cortex (mPFC) engagement. Subjects with divergent rural and urban childhoods were similar in adult socioeconomic status and were genetically homogeneous. Urban childhood was associated with relatively reduced mPFC gray matter volumes as suggested by MRI. MPFC engagement under social status threat correlated with the higher trait anxiety-depression in subjects with urban childhoods, but not in their rural counterparts, implicating an exaggerated physiological response to the threat context with urbanicity, in association with behavioral risk for depression. Stress-associated mPFC engagement also interacted with polygenic risk for depression, significantly predicting a differential mPFC response in individuals with urban but not rural childhoods. Developmental urbanicity, therefore, appears to interact with genetic and behavioral risk for depression on the mPFC neural response to a threat context.
FBXW11 contributes to stem-cell-like features and liver metastasis through regulating HIC1-mediated SIRT1 transcription in colorectal cancer
Authors: Yao Jing , Yang Jun , Yang Zhe , Wang Xin-Ping , Yang Tong , Ji Bing , Zhang Zheng-Yun 
Published: October 2021

AbstractColorectal tumorigenesis is a heterogeneous disease driven by multiple genetic and epigenetic alterations. F-box and WD repeat domain containing 11 (FBXW11) is a member of the F-box protein family that regulates the ubiquitination of key factors associated with tumor growth and aggressiveness. Our study aimed to explore the role of FBXW11 in the development and metastasis of colorectal cancer (CRC). FBXW11 was overexpressed in colorectal tumor tissues and its overexpression was associated with a poor prognosis of CRC patients. The upregulation of FBXW11 not only promoted cell proliferation, invasion, and migration, but also contributed to maintaining stem-cell features in colorectal tumor cells. Further analysis revealed that FBXW11 targeted hypermethylated in cancer 1 (HIC1) and reduced its stability in CRC cells through ubiquitination. Moreover, the expression of sirtuin 1 (SIRT1), a deacetylase in tumor cells was upregulated by FBXW11 via regulating HIC1 expression. The mouse xenograft models of CRC confirmed that FBXW11 knockdown impeded colorectal tumor growth and liver metastasis in vivo. In summary, our study identified FBXW11 as an oncogenic factor that contributed to stem-cell-like properties and liver metastasis in CRC via regulating HIC1-mediated SIRT1 expression. These results provide a rationale for the development of FBXW11-targeting drugs for CRC patients.
Roles and action mechanisms of WNT4 in cell differentiation and human diseases: a review
Authors: Zhang Quanlong , Pan Yan , Ji Jingjing , Xu Yuxin , Zhang Qiaoyan , Qin Luping 
Published: October 2021

AbstractWNT family member 4 (WNT4), which belongs to the conserved WNT protein family, plays an important role in the development and differentiation of many cell types during the embryonic development and adult homeostasis. Increasing evidence has shown that WNT4 is a special ligand that not only activates the β-catenin independent pathway but also acts on β-catenin signaling based on different cellular processes. This article is a summary of the current knowledge about the expression, regulation, and function of WNT4 ligands and their signal pathways in cell differentiation and human disease processes. WNT4 is a promoter in osteogenic differentiation in bone marrow stromal cells (BMSCs) by participating in bone homeostasis regulation in osteoporotic diseases. Non-canonical WNT4 signaling is necessary for metabolic maturation of pancreatic β-cell. WNT4 is also necessary for decidual cell differentiation and decidualization, which plays an important role in preeclampsia. WNT4 promotes neuronal differentiation of neural stem cell and dendritic cell (DC) into conventional type 1 DC (cDC1). Besides, WNT4 mediates myofibroblast differentiation in the skin, kidney, lung, and liver during scarring or fibrosis. On the negative side, WNT4 is highly expressed in cancer tissues, playing a pro-carcinogenic role in many cancer types. This review provides an overview of the progress in elucidating the role of WNT4 signaling pathway components in cell differentiation in adults, which may provide useful clues for the diagnosis, prevention, and therapy of human diseases.
SIRT2-mediated deacetylation and deubiquitination of C/EBPβ prevents ethanol-induced liver injury
Authors: Zhang Yingting , Long Xidai , Ruan Xin , Wei Qian , Zhang Lin , Wo Lulu , Huang Dongdong , Lin Longshuai , Wang Difei , Xia Li , Zhao Qinghua , Liu Junling , Zhao Qian , He Ming 
Published: October 2021

AbstractProtein acetylation has emerged to play pivotal roles in alcoholic liver disease (ALD). Sirutin 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase involved in the regulation of aging, metabolism, and stress. However, the role of SIRT2 in ALD remains unclear. Here, we report that the SIRT2-mediated deacetylation–deubiquitination switch of CCAAT/enhancer-binding protein beta (C/EBPβ) prevents ALD. Our results showed that hepatic SIRT2 protein expression was negatively correlated with the severity of alcoholic liver injury in ALD patients. Liver-specific SIRT2 deficiency sensitized mice to ALD, whereas transgenic SIRT2 overexpression in hepatocytes significantly prevented ethanol-induced liver injury via normalization of hepatic steatosis, lipid peroxidation, and hepatocyte apoptosis. Mechanistically, we identified C/EBPβ as a critical substrate of SIRT2 implicated in ALD. SIRT2-mediated deacetylation at lysines 102 and 211 decreased C/EBPβ ubiquitination, resulting in enhanced protein stability and subsequently increased transcription of C/EBPβ-target gene LCN2. Importantly, hepatic deacetylated C/EBPβ and LCN2 compensation reversed SIRT2 deletion-induced ALD aggravation in mice. Furthermore, C/EBPβ protein expression was positively correlated with SIRT2 and LCN2 expression in the livers of ALD patients and was inversely correlated with ALD development. Therefore, activating SIRT2-C/EBPβ-LCN2 signaling pathway is a potential therapy for ALD.
Thousands of Qatari genomes inform human migration history and improve imputation of Arab haplotypes
Authors: Razali Rozaimi Mohamad , Rodriguez-Flores Juan , Ghorbani Mohammadmersad , Naeem Haroon , Aamer Waleed , Aliyev Elbay , Jubran Ali ,   Qatar Genome Program Research Consortium,   Qatar Genome Project Management, Ismail Said I. , Al-Muftah Wadha , Badji Radja , Mbarek Hamdi , Darwish Dima , Fadl Tasnim , Yasin Heba , Ennaifar Maryem , Abdellatif Rania , Alkuwari Fatima , Alvi Muhammad , Al-Sarraj Yasser , Saad Chadi , Althani Asmaa ,   Biobank and Sample Preparation, Fethnou Eleni , Qafoud Fatima , Alkhayat Eiman , Afifi Nahla ,   Sequencing and Genotyping group, Tomei Sara , Liu Wei , Lorenz Stephan ,   Applied Bioinformatics Core, Syed Najeeb , Almabrazi Hakeem , Vempalli Fazulur Rehaman , Temanni Ramzi ,   Data Management and Computing Infrastructure group, Saqri Tariq Abu , Khatib Mohammedhusen , Hamza Mehshad , Zaid Tariq Abu , El Khouly Ahmed , Pathare Tushar , Poolat Shafeeq , Al-Ali Rashid ,   Consortium Lead Principal Investigators (in alphabetical order), Albagha Omar , Al-Khodor Souhaila , Alshafai Mashael , Badii Ramin , Chouchane Lotfi , Estivill Xavier , Fakhro Khalid A. , Mokrab Younes , Puthen Jithesh V. , Suhre Karsten , Tatari Zohreh , Clark Andrew G. , Fakhro Khalid A. , Mokrab Younes 
Published: October 2021

AbstractArab populations are largely understudied, notably their genetic structure and history. Here we present an in-depth analysis of 6,218 whole genomes from Qatar, revealing extensive diversity as well as genetic ancestries representing the main founding Arab genealogical lineages of Qahtanite (Peninsular Arabs) and Adnanite (General Arabs and West Eurasian Arabs). We find that Peninsular Arabs are the closest relatives of ancient hunter-gatherers and Neolithic farmers from the Levant, and that founder Arab populations experienced multiple splitting events 12–20 kya, consistent with the aridification of Arabia and farming in the Levant, giving rise to settler and nomadic communities. In terms of recent genetic flow, we show that these ancestries contributed significantly to European, South Asian as well as South American populations, likely as a result of Islamic expansion over the past 1400 years. Notably, we characterize a large cohort of men with the ChrY J1a2b haplogroup (n = 1,491), identifying 29 unique sub-haplogroups. Finally, we leverage genotype novelty to build a reference panel of 12,432 haplotypes, demonstrating improved genotype imputation for both rare and common alleles in Arabs and the wider Middle East.
Emergence and melting of active vortex crystals
Authors: James Martin , Suchla Dominik Anton , Dunkel Jörn , Wilczek Michael 
Published: October 2021

AbstractMelting of two-dimensional (2D) equilibrium crystals is a complex phenomenon characterized by the sequential loss of positional and orientational order. In contrast to passive systems, active crystals can self-assemble and melt into an active fluid by virtue of their intrinsic motility and inherent non-equilibrium stresses. Currently, the non-equilibrium physics of active crystallization and melting processes is not well understood. Here, we establish the emergence and investigate the melting of self-organized vortex crystals in 2D active fluids using a generalized Toner-Tu theory. Performing extensive hydrodynamic simulations, we find rich transition scenarios. On small domains, we identify a hysteretic transition as well as a transition featuring temporal coexistence of active vortex lattices and active turbulence, both of which can be controlled by self-propulsion and active stresses. On large domains, an active vortex crystal with solid order forms within the parameter range corresponding to active vortex lattices. The melting of this crystal proceeds through an intermediate hexatic phase. Generally, these results highlight the differences and similarities between crystalline phases in active fluids and their equilibrium counterparts.
Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease
Authors: Schmidt Amand F. , Hunt Nicholas B. , Gordillo-Marañón Maria , Charoen Pimphen , Drenos Fotios , Kivimaki Mika , Lawlor Deborah A. , Giambartolomei Claudia , Papacosta Olia , Chaturvedi Nishi , Bis Joshua C. , O’Donnell Christopher J. , Wannamethee Goya , Wong Andrew , Price Jackie F. , Hughes Alun D. , Gaunt Tom R. , Franceschini Nora , Mook-Kanamori Dennis O. , Zwierzyna Magdalena , Sofat Reecha , Hingorani Aroon D. , Finan Chris 
Published: October 2021

AbstractDevelopment of cholesteryl ester transfer protein (CETP) inhibitors for coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and drug target Mendelian randomization of CETP protein concentration, comparing this to Mendelian randomization of proprotein convertase subtilisin/kexin type 9 (PCSK9). We show that previous failures of CETP inhibitors are likely compound related, as illustrated by significant degrees of between-compound heterogeneity in effects on lipids, blood pressure, and clinical outcomes observed in trials. On-target CETP inhibition, assessed through Mendelian randomization, is expected to reduce the risk of CHD, heart failure, diabetes, and chronic kidney disease, while increasing the risk of age-related macular degeneration. In contrast, lower PCSK9 concentration is anticipated to decrease the risk of CHD, heart failure, atrial fibrillation, chronic kidney disease, multiple sclerosis, and stroke, while potentially increasing the risk of Alzheimer’s disease and asthma. Due to distinct effects on lipoprotein metabolite profiles, joint inhibition of CETP and PCSK9 may provide added benefit. In conclusion, we provide genetic evidence that CETP is an effective target for CHD prevention but with a potential on-target adverse effect on age-related macular degeneration.
Bioengineered 3D models of human pancreatic cancer recapitulate in vivo tumour biology
Authors: Osuna de la Peña David , Trabulo Sara Maria David , Collin Estelle , Liu Ying , Sharma Shreya , Tatari Marianthi , Behrens Diana , Erkan Mert , Lawlor Rita T. , Scarpa Aldo , Heeschen Christopher , Mata Alvaro , Loessner Daniela 
Published: October 2021

AbstractPatient-derived in vivo models of human cancer have become a reality, yet their turnaround time is inadequate for clinical applications. Therefore, tailored ex vivo models that faithfully recapitulate in vivo tumour biology are urgently needed. These may especially benefit the management of pancreatic ductal adenocarcinoma (PDAC), where therapy failure has been ascribed to its high cancer stem cell (CSC) content and high density of stromal cells and extracellular matrix (ECM). To date, these features are only partially reproduced ex vivo using organoid and sphere cultures. We have now developed a more comprehensive and highly tuneable ex vivo model of PDAC based on the 3D co-assembly of peptide amphiphiles (PAs) with custom ECM components (PA-ECM). These cultures maintain patient-specific transcriptional profiles and exhibit CSC functionality, including strong in vivo tumourigenicity. User-defined modification of the system enables control over niche-dependent phenotypes such as epithelial-to-mesenchymal transition and matrix deposition. Indeed, proteomic analysis of these cultures reveals improved matrisome recapitulation compared to organoids. Most importantly, patient-specific in vivo drug responses are better reproduced in self-assembled cultures than in other models. These findings support the use of tuneable self-assembling platforms in cancer research and pave the way for future precision medicine approaches.
Brain adiponectin signaling controls peripheral insulin response in Drosophila
Authors: Arquier Nathalie , Bjordal Marianne , Hammann Philippe , Kuhn Lauriane , Léopold Pierre 
Published: October 2021

AbstractThe brain plays a key role in energy homeostasis, detecting nutrients, metabolites and circulating hormones from peripheral organs and integrating this information to control food intake and energy expenditure. Here, we show that a group of neurons in the Drosophila larval brain expresses the adiponectin receptor (AdipoR) and controls systemic growth and metabolism through insulin signaling. We identify glucose-regulated protein 78 (Grp78) as a circulating antagonist of AdipoR function produced by fat cells in response to dietary sugar. We further show that central AdipoR signaling inhibits peripheral Juvenile Hormone (JH) response, promoting insulin signaling. In conclusion, we identify a neuroendocrine axis whereby AdipoR-positive neurons control systemic insulin response.
Global syndromes induced by changes in solutes of the world’s large rivers
Authors: Wu Jiang , Xu Nan , Wang Yichu , Zhang Wei , Borthwick Alistair G. L. , Ni Jinren 
Published: October 2021

AbstractSolute-induced river syndromes have grown in intensity in recent years. Here we investigate seven such river syndromes (salinization, mineralization, desalinization, acidification, alkalization, hardening, and softening) associated with global trends in major solutes (Ca2+, Mg2+, Na+, K+, SO42−, Cl−, HCO3−) and dissolved silica in the world’s large rivers (basin areas ≥ 1000 km2). A comprehensive dataset from 600 gauge stations in 149 large rivers reveals nine binary patterns of co-varying trends in runoff and solute concentration. Solute-induced river syndromes are associated with remarkable increases in total dissolved solids (68%), chloride (81%), sodium (86%) and sulfate (142%) fluxes from rivers to oceans worldwide. The syndromes are most prevalent in temperate regions (30~50°N and 30~40°S based on the available data) where severe rock weathering and active human interferences such as urbanization and agricultural irrigation are concentrated. This study highlights the urgency to protect river health from extreme changes in solute contents.
The pupil responds spontaneously to perceived numerosity
Authors: Castaldi Elisa , Pomè Antonella , Cicchini Guido Marco , Burr David , Binda Paola 
Published: October 2021

AbstractAlthough luminance is the main determinant of pupil size, the amplitude of the pupillary light response is also modulated by stimulus appearance and attention. Here we ask whether perceived numerosity modulates the pupillary light response. Participants passively observed arrays of black or white dots of matched physical luminance but different physical or illusory numerosity. In half the patterns, pairs of dots were connected by lines to create dumbbell-like shapes, inducing an illusory underestimation of perceived numerosity; in the other half, connectors were either displaced or removed. Constriction to white arrays and dilation to black were stronger for patterns with higher perceived numerosity, either physical or illusory, with the strength of the pupillary light response scaling with the perceived numerosity of the arrays. Our results show that even without an explicit task, numerosity modulates a simple automatic reflex, suggesting that numerosity is a spontaneously encoded visual feature.
Breast Cancer Consensus Subtypes: A system for subtyping breast cancer tumors based on gene expression
Authors: Horr Christina , Buechler Steven A. 
Published: October 2021

AbstractBreast cancer is heterogeneous in prognoses and drug responses. To organize breast cancers by gene expression independent of statistical methodology, we identified the Breast Cancer Consensus Subtypes (BCCS) as the consensus groupings of six different subtyping methods. Our classification software identified seven BCCS subtypes in a study cohort of publicly available data (n = 5950) including METABRIC, TCGA-BRCA, and data assayed by Affymetrix arrays. All samples were fresh-frozen from primary tumors. The estrogen receptor-positive (ER+) BCCS subtypes were: PCS1 (18%) good prognosis, stromal infiltration; PCS2 (15%) poor prognosis, highly proliferative; PCS3 (13%) poor prognosis, highly proliferative, activated IFN-gamma signaling, cytotoxic lymphocyte infiltration, high tumor mutation burden; PCS4 (18%) good prognosis, hormone response genes highly expressed. The ER− BCCS subtypes were: NCS1 (11%) basal; NCS2 (10%) elevated androgen response; NCS3 (5%) cytotoxic lymphocyte infiltration; unclassified tumors (9%). HER2+ tumors were heterogeneous with respect to BCCS.
Visualizing temperature-dependent phase stability in high entropy alloys
Authors: Evans Daniel , Chen Jiadong , Bokas George , Chen Wei , Hautier Geoffroy , Sun Wenhao 
Published: October 2021

AbstractHigh entropy alloys (HEAs) contain near equimolar amounts of five or more elements and are a compelling space for materials design. In the design of HEAs, great emphasis is placed on identifying thermodynamic conditions for single-phase and multi-phase stability regions, but this process is hindered by the difficulty of navigating stability relationships in high-component spaces. Traditional phase diagrams use barycentric coordinates to represent composition axes, which require (N – 1) spatial dimensions to represent an N-component system, meaning that HEA systems with N > 4 components cannot be readily visualized. Here, we propose forgoing barycentric composition axes in favor of two energy axes: a formation-energy axis and a ‘reaction energy’ axis. These Inverse Hull Webs offer an information-dense 2D representation that successfully captures complex phase stability relationships in N ≥ 5 component systems. We use our proposed diagrams to visualize the transition of HEA solid-solutions from high-temperature stability to metastability upon quenching, and identify important thermodynamic features that are correlated with the persistence or decomposition of metastable HEAs.