bluuebunny/crossref_metadata_2025_split huggingface dataset:
Do environmental risk factors for the development of psychosis distribute differently across dimensionally assessed psychotic experiences?
Authors: Cosgrave Jan , Purple Ross J. , Haines Ross , Porcheret Kate , van Heugten-van der Kloet Dalena , Johns Louise , Alexander Iona , Goodwin Guy M. , Foster Russell G. , Wulff Katharina 
Published: April 2021

AbstractPsychotic experiences (PE) are associated with poorer functioning, higher distress and the onset of serious mental illness. Environmental exposures (e.g. childhood abuse) are associated with the development of PE. However, which specific exposures convey risk for each type or dimension of PE has rarely been explored. The Oxford Wellbeing Life and Sleep (OWLS) survey includes 22 environmental risk factors for psychosis and was designed to examine how environmental risks are associated with specific dimensions of PE. Multivariate logistic regression models were fit using these risk factors to predict six dimensions of PE (perceptual abnormalities, persecutory ideation, bizarre ideas, cognitive disorganisation, delusional mood and negative symptoms). Models were built using only 70% of the data, and then fit to the remaining data to assess their generalisability and quality. 1789 (27.2% men; mean age = 27.6; SD = 10.9) survey responses were analysed. The risk factors predictive of the most PE were anxiety, social withdrawal during childhood and trauma. Cannabis and depression predicted three dimensions with both predicting bizarre ideas and persecutory ideation. Psychological abuse and sleep quality each predicted two dimensions (persecutory ideation and delusional mood). Risk factors predicting one PE dimension were age (predicting cognitive disorganisation), physical abuse (bizarre ideas), bullying and gender (persecutory ideation); and circadian phase (delusional mood). These results lend support for a continuum of psychosis, suggesting environmental risks for psychotic disorders also increase the risk of assorted dimensions of PE. Furthermore, it advocates the use of dimensional approaches when examining environmental exposures for PE given that environmental risks distribute differently across dimensions.
Utilization of machine learning for identifying symptom severity military-related PTSD subtypes and their biological correlates
Authors: Siegel Carole E. , Laska Eugene M. , Lin Ziqiang , Xu Mu , Abu-Amara Duna , Jeffers Michelle K. , Qian Meng , Milton Nicholas , Flory Janine D. , Hammamieh Rasha , Daigle Bernie J. , Gautam Aarti , Dean Kelsey R. , Reus Victor I. , Wolkowitz Owen M. , Mellon Synthia H. , Ressler Kerry J. , Yehuda Rachel , Wang Kai , Hood Leroy , Doyle Francis J. , Jett Marti , Marmar Charles R. 
Published: April 2021

AbstractWe sought to find clinical subtypes of posttraumatic stress disorder (PTSD) in veterans 6–10 years post-trauma exposure based on current symptom assessments and to examine whether blood biomarkers could differentiate them. Samples were males deployed to Iraq and Afghanistan studied by the PTSD Systems Biology Consortium: a discovery sample of 74 PTSD cases and 71 healthy controls (HC), and a validation sample of 26 PTSD cases and 36 HC. A machine learning method, random forests (RF), in conjunction with a clustering method, partitioning around medoids, were used to identify subtypes derived from 16 self-report and clinician assessment scales, including the clinician-administered PTSD scale for DSM-IV (CAPS). Two subtypes were identified, designated S1 and S2, differing on mean current CAPS total scores: S2 = 75.6 (sd 14.6) and S1 = 54.3 (sd 6.6). S2 had greater symptom severity scores than both S1 and HC on all scale items. The mean first principal component score derived from clinical summary scales was three times higher in S2 than in S1. Distinct RFs were grown to classify S1 and S2 vs. HCs and vs. each other on multi-omic blood markers feature classes of current medical comorbidities, neurocognitive functioning, demographics, pre-military trauma, and psychiatric history. Among these classes, in each RF intergroup comparison of S1, S2, and HC, multi-omic biomarkers yielded the highest AUC-ROCs (0.819–0.922); other classes added little to further discrimination of the subtypes. Among the top five biomarkers in each of these RFs were methylation, micro RNA, and lactate markers, suggesting their biological role in symptom severity.
Contribution of growth hormone secretagogue receptor (GHSR) signaling in the ventral tegmental area (VTA) to the regulation of social motivation in male mice
Authors: Park Su-Bin , King Samantha , MacDonald David , Wilson Anne , MacKay Harry , Woodside Barbara , Abizaid Alfonso 
Published: April 2021

AbstractMost psychiatric disorders are characterized by deficits in the ability to interact socially with others. Ghrelin, a hormone normally associated with the regulation of glucose utilization and appetite, is also implicated in the modulation of motivated behaviors including those associated with food and sex rewards. Here we hypothesized that deficits in ghrelin receptor (growth hormone secretagogue receptor; GHSR) signaling are also associated with deficits in social motivation in male mice. To test this hypothesis, we compared social motivation in male mice lacking GHSR or mice treated with the GHSR antagonist JMV2959 with that of WT or vehicle-treated mice. GHSR signaling in dopamine cells of the ventral tegmental area (VTA) has been implicated in the control of sexual behavior, thus we further hypothesized that GHSR signaling in the VTA is important for social motivation. Thus, we conducted studies where we delivered JMV2959 to block GHSR in the VTA of mice, and studies where we rescued the expression of GHSR in the VTA of GHSR knockout (KO) mice. Mice lacking GHSR or injected with JMV2959 peripherally for 3 consecutive days displayed lower social motivation as reflected by a longer latency to approach a novel conspecific and shorter interaction time compared to WT or vehicle-treated controls. Furthermore, intra-VTA infusion of JMV2959 resulted in longer latencies to approach a novel conspecific, whereas GHSR KO mice with partial rescue of the GHSR showed decreased latencies to begin a novel social interaction. Together, these data suggest that GHSR in the VTA facilitate social approach in male mice, and GHSR-signaling deficits within the VTA result in reduced motivation to interact socially.
Drug-resistant cancer cell-derived exosomal EphA2 promotes breast cancer metastasis via the EphA2-Ephrin A1 reverse signaling
Authors: Gao Zicong , Han Xingxing , Zhu Yuying , Zhang He , Tian Ran , Wang Zhiyong , Cui Yanfen , Wang Zhaosong , Niu Ruifang , Zhang Fei 
Published: April 2021

AbstractTumor metastasis induced by drug resistance is a major challenge in successful cancer treatment. Nevertheless, the mechanisms underlying the pro-invasive and metastatic ability of drug resistance remain elusive. Exosome-mediated intercellular communications between cancer cells and stromal cells in tumor microenvironment are required for cancer initiation and progression. Recent reports have shown that communications between cancer cells also promote tumor aggression. However, little attention has been regarded on this aspect. Herein, we demonstrated that drug-resistant cell-derived exosomes promoted the invasion of sensitive breast cancer cells. Quantitative proteomic analysis showed that EphA2 was rich in exosomes from drug-resistant cells. Exosomal EphA2 conferred the invasive/metastatic phenotype transfer from drug-resistant cells to sensitive cells. Moreover, exosomal EphA2 activated ERK1/2 signaling through the ligand Ephrin A1-dependent reverse pathway rather than the forward pathway, thereby promoting breast cancer progression. Our findings indicate the key functional role of exosomal EphA2 in the transmission of aggressive phenotype between cancer cells that do not rely on direct cell–cell contact. Our study also suggests that the increase of EphA2 in drug-resistant cell-derived exosomes may be an important mechanism of chemotherapy/drug resistance-induced breast cancer progression.
DDRGK1, a crucial player of ufmylation system, is indispensable for autophagic degradation by regulating lysosomal function
Authors: Cao Yan , Li Rongyang , Shen Ming , Li Chengyu , Zou Yan , Jiang Qiang , Liu Shuo , Lu Chunwan , Li Honglin , Liu Honglin , Cai Yafei 
Published: April 2021

AbstractDDRGK domain-containing protein 1 (DDRGK1) is an important component of the newly discovered ufmylation system and its absence has been reported to induce extensive endoplasmic reticulum (ER) stress. Recently, emerging evidence indicates that the ufmylation system is correlated with autophagy, although the exact mechanism remains largely unknown. To explore the regulation mechanism of DDRGK1 on autophagy, in this study, we established an immortalized mouse embryonic fibroblast (MEF) cell lines harvested from the DDRGK1F/F:ROSA26-CreERT2 mice, in which DDRGK1 depletion can be induced by 4-hydroxytamoxifen (4-OHT) treatment. Here, we show that DDRGK1 deficiency in MEFs has a dual effect on autophagy, which leads to a significant accumulation of autophagosomes. On one hand, it promotes autophagy induction by impairing mTOR signaling; on the other hand, it blocks autophagy degradation by inhibiting autophagosome–lysosome fusion. This dual effect of DDRGK1 depletion on autophagy ultimately aggravates apoptosis in MEFs. Further studies reveal that DDRGK1 loss is correlated with suppressed lysosomal function, including impaired Cathepsin D (CTSD) expression, aberrant lysosomal pH, and v-ATPase accumulation, which might be a potential trigger for impairment in autophagy process. Hence, this study confirms a crucial role of DDRGK1 as an autophagy regulator by controlling lysosomal function. It may provide a theoretical basis for the treatment strategies of various physiological diseases caused by DDRGK1 deficiency.
TAZ is required for chondrogenesis and skeletal development
Authors: Li Yang , Yang Shuting , Qin Ling , Yang Shuying 
Published: April 2021

AbstractChondrogenesis is a major contributor to skeletal development and maintenance, as well as bone repair. Transcriptional coactivator with PDZ-binding motif (TAZ) is a key regulator of osteogenesis and adipogenesis, but how TAZ regulates chondrogenesis and skeletal development remains undefined. Here, we found that TAZ expression is gradually increased during chondrogenic differentiation. Deletion of TAZ in chondrocyte lineage impaired articular and growth plate, as well as the bone development in TAZ-deficient mice. Consistently, loss of TAZ impaired fracture healing. Mechanistically, we found that ectopic expression of TAZ markedly promoted chondroprogenitor proliferation, while deletion of TAZ impaired chondrocyte proliferation and differentiation. TAZ associated with Sox5 to regulate the expression and stability of Sox5 and downstream chondrocyte marker genes’ expression. In addition, overexpression of TAZ enhanced Col10a1 expression and promoted chondrocyte maturation, which was blocked by deletion of TAZ. Overall, our findings demonstrated that TAZ is required for skeletal development and joint maintenance that provided new insights into therapeutic strategies for fracture healing, heterotopic ossification, osteoarthritis, and other bone diseases.
A central circadian oscillator confers defense heterosis in hybrids without growth vigor costs
Authors: Yang Li , Liu Pengtao , Wang Xuncheng , Jia Aolin , Ren Diqiu , Tang Yaru , Tang Yaqi , Deng Xing Wang , He Guangming 
Published: April 2021

AbstractPlant immunity frequently incurs growth penalties, which known as the trade-off between immunity and growth. Heterosis, the phenotypic superiority of a hybrid over its parents, has been demonstrated for many traits but rarely for disease resistance. Here, we report that the central circadian oscillator, CCA1, confers heterosis for bacterial defense in hybrids without growth vigor costs, and it even significantly enhances the growth heterosis of hybrids under pathogen infection. The genetic perturbation of CCA1 abrogated heterosis for both defense and growth in hybrids. Upon pathogen attack, the expression of CCA1 in F1 hybrids is precisely modulated at different time points during the day by its rhythmic histone modifications. Before dawn of the first infection day, epigenetic activation of CCA1 promotes an elevation of salicylic acid accumulation in hybrids, enabling heterosis for defense. During the middle of every infection day, diurnal epigenetic repression of CCA1 leads to rhythmically increased chlorophyll synthesis and starch metabolism in hybrids, effectively eliminating the immunity-growth heterosis trade-offs in hybrids.
ARIH1 signaling promotes anti-tumor immunity by targeting PD-L1 for proteasomal degradation
Authors: Wu Youqian , Zhang Chao , Liu Xiaolan , He Zhengfu , Shan Bing , Zeng Qingxin , Zhao Qingwei , Zhu Huaying , Liao Hongwei , Cen Xufeng , Xu Xiaoyan , Zhang Mengmeng , Hou Tingjun , Wang Zhe , Yan Huanhuan , Yang Shuying , Sun Yaqin , Chen Yanying , Wu Ronghai , Xie Tingxue , Chen Wei , Najafov Ayaz , Ying Songmin , Xia Hongguang 
Published: April 2021

AbstractCancer expression of PD-L1 suppresses anti-tumor immunity. PD-L1 has emerged as a remarkable therapeutic target. However, the regulation of PD-L1 degradation is not understood. Here, we identify several compounds as inducers of PD-L1 degradation using a high-throughput drug screen. We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283. We identify ARIH1 as the E3 ubiquitin ligase responsible for targeting PD-L1 to degradation. Overexpression of ARIH1 suppresses tumor growth and promotes cytotoxic T cell activation in wild-type, but not in immunocompromised mice, highlighting the role of ARIH1 in anti-tumor immunity. Moreover, combining EGFR inhibitor ES-072 with anti-CTLA4 immunotherapy results in an additive effect on both tumor growth and cytotoxic T cell activation. Our results delineate a mechanism of PD-L1 degradation and cancer escape from immunity via EGFR-GSK3α-ARIH1 signaling and suggest GSK3α and ARIH1 might be potential drug targets to boost anti-tumor immunity and enhance immunotherapies.
Chromatic micromaps in primary visual cortex
Authors: Chatterjee Soumya , Ohki Kenichi , Reid R. Clay 
Published: April 2021

AbstractThe clustering of neurons with similar response properties is a conspicuous feature of neocortex. In primary visual cortex (V1), maps of several properties like orientation preference are well described, but the functional architecture of color, central to visual perception in trichromatic primates, is not. Here we used two-photon calcium imaging in macaques to examine the fine structure of chromatic representation and found that neurons responsive to spatially uniform, chromatic stimuli form unambiguous clusters that coincide with blobs. Further, these responsive groups have marked substructure, segregating into smaller ensembles or micromaps with distinct chromatic signatures that appear columnar in upper layer 2/3. Spatially structured chromatic stimuli revealed maps built on the same micromap framework but with larger subdomains that go well beyond blobs. We conclude that V1 has an architecture for color representation that switches between blobs and a combined blob/interblob system based on the spatial content of the visual scene.
Suppression of pancreatic ductal adenocarcinoma growth and metastasis by fibrillar collagens produced selectively by tumor cells
Authors: Tian Chenxi , Huang Ying , Clauser Karl R. , Rickelt Steffen , Lau Allison N. , Carr Steven A. , Vander Heiden Matthew G. , Hynes Richard O. 
Published: April 2021

AbstractPancreatic ductal adenocarcinoma (PDAC) has a collagen-rich dense extracellular matrix (ECM) that promotes malignancy of cancer cells and presents a barrier for drug delivery. Data analysis of our published mass spectrometry (MS)-based studies on enriched ECM from samples of progressive PDAC stages reveal that the C-terminal prodomains of fibrillar collagens are partially uncleaved in PDAC ECM, suggesting reduced procollagen C-proteinase activity. We further show that the enzyme responsible for procollagen C-proteinase activity, bone morphogenetic protein1 (BMP1), selectively suppresses tumor growth and metastasis in cells expressing high levels of COL1A1. Although BMP1, as a secreted proteinase, promotes fibrillar collagen deposition from both cancer cells and stromal cells, only cancer-cell-derived procollagen cleavage and deposition suppresses tumor malignancy. These studies reveal a role for cancer-cell-derived fibrillar collagen in selectively restraining tumor growth and suggest stratification of patients based on their tumor epithelial collagen I expression when considering treatments related to perturbation of fibrillar collagens.
Optimized photochemistry enables efficient analysis of dynamic RNA structuromes and interactomes in genetic and infectious diseases
Authors: Zhang Minjie , Li Kongpan , Bai Jianhui , Velema Willem A. , Yu Chengqing , van Damme Ryan , Lee Wilson H. , Corpuz Maia L. , Chen Jian-Fu , Lu Zhipeng 
Published: April 2021

AbstractDirect determination of RNA structures and interactions in living cells is critical for understanding their functions in normal physiology and disease states. Here, we present PARIS2, a dramatically improved method for RNA duplex determination in vivo with >4000-fold higher efficiency than previous methods. PARIS2 captures ribosome binding sites on mRNAs, reporting translation status on a transcriptome scale. Applying PARIS2 to the U8 snoRNA mutated in the neurological disorder LCC, we discover a network of dynamic RNA structures and interactions which are destabilized by patient mutations. We report the first whole genome structure of enterovirus D68, an RNA virus that causes polio-like symptoms, revealing highly dynamic conformations altered by antiviral drugs and different pathogenic strains. We also discover a replication-associated asymmetry on the (+) and (−) strands of the viral genome. This study establishes a powerful technology for efficient interrogation of the RNA structurome and interactome in human diseases.
Selectivity of mRNA degradation by autophagy in yeast
Authors: Makino Shiho , Kawamata Tomoko , Iwasaki Shintaro , Ohsumi Yoshinori 
Published: April 2021

AbstractSynthesis and degradation of cellular constituents must be balanced to maintain cellular homeostasis, especially during adaptation to environmental stress. The role of autophagy in the degradation of proteins and organelles is well-characterized. However, autophagy-mediated RNA degradation in response to stress and the potential preference of specific RNAs to undergo autophagy-mediated degradation have not been examined. In this study, we demonstrate selective mRNA degradation by rapamycin-induced autophagy in yeast. Profiling of mRNAs from the vacuole reveals that subsets of mRNAs, such as those encoding amino acid biosynthesis and ribosomal proteins, are preferentially delivered to the vacuole by autophagy for degradation. We also reveal that autophagy-mediated mRNA degradation is tightly coupled with translation by ribosomes. Genome-wide ribosome profiling suggested a high correspondence between ribosome association and targeting to the vacuole. We propose that autophagy-mediated mRNA degradation is a unique and previously-unappreciated function of autophagy that affords post-transcriptional gene regulation.
Ultra-strong polymeric hollow fiber membranes for saline dewatering and desalination
Authors: Liang Can Zeng , Askari Mohammad , Choong Looh Tchuin , Chung Tai-Shung 
Published: April 2021

AbstractOsmotically assisted reverse osmosis (OARO) has become an emerging membrane technology to tackle the limitations of a reverse osmosis (RO) process for water desalination. A strong membrane that can withstand a high hydraulic pressure is crucial for the OARO process. Here, we develop ultra-strong polymeric thin film composite (TFC) hollow fiber membranes with exceptionally high hydraulic burst pressures of up to 110 bar, while maintaining high pure water permeance of around 3 litre/(m2 h bar) and a NaCl rejection of about 98%. The ultra-strong TFC hollow fiber membranes are achieved mainly by tuning the concentration of the host polymer in spinning dopes and engineering the fiber dimension and morphology. The optimal TFC membranes display promising water permeance under the OR and OARO operation modes. This work may shed new light on the fabrication of ultra-strong TFC hollow fiber membranes for water treatments and desalination.
Immunogenicity and efficacy of mRNA COVID-19 vaccine MRT5500 in preclinical animal models
Authors: Kalnin Kirill V. , Plitnik Timothy , Kishko Michael , Zhang Jinrong , Zhang Donghui , Beauvais Adrien , Anosova Natalie G. , Tibbitts Tim , DiNapoli Josh , Ulinski Gregory , Piepenhagen Peter , Cummings Sheila M. , Bangari Dinesh S. , Ryan Susan , Huang Po-Wei D. , Huleatt James , Vincent Deanne , Fries Katherine , Karve Shrirang , Goldman Rebecca , Gopani Hardip , Dias Anusha , Tran Khang , Zacharia Minnie , Gu Xiaobo , Boeglin Lianne , Abysalh Jonathan , Vargas Jorel , Beaulieu Angela , Shah Monic , Jeannotte Travis , Gillis Kimberly , Chivukula Sudha , Swearingen Ron , Landolfi Victoria , Fu Tong-Ming , DeRosa Frank , Casimiro Danilo 
Published: April 2021

AbstractEmergency use authorization of COVID vaccines has brought hope to mitigate pandemic of coronavirus disease 2019 (COVID-19). However, there remains a need for additional effective vaccines to meet the global demand and address the potential new viral variants. mRNA technologies offer an expeditious path alternative to traditional vaccine approaches. Here we describe the efforts to utilize an mRNA platform for rational design and evaluations of mRNA vaccine candidates based on the spike (S) glycoprotein of SARS-CoV-2. Several mRNA constructs of S-protein, including wild type, a pre-fusion stabilized mutant (2P), a furin cleavage-site mutant (GSAS) and a double mutant form (2P/GSAS), as well as others, were tested in animal models for their capacity to elicit neutralizing antibodies (nAbs). The lead 2P/GSAS candidate was further assessed in dose-ranging studies in mice and Cynomolgus macaques, and for efficacy in a Syrian golden hamster model. The selected 2P/GSAS vaccine formulation, designated MRT5500, elicited potent nAbs as measured in neutralization assays in all three preclinical models and more importantly, protected against SARS-CoV-2-induced weight loss and lung pathology in hamsters. In addition, MRT5500 elicited TH1-biased responses in both mouse and non-human primate (NHP), thus alleviating a hypothetical concern of potential vaccine-associated enhanced respiratory diseases known associated with TH2-biased responses. These data position MRT5500 as a viable vaccine candidate for entering clinical development.