bluuebunny/crossref_metadata_2025_split huggingface dataset:
Obesity and atypical depression symptoms: findings from Mendelian randomization in two European cohorts
Authors: Pistis Giorgio , Milaneschi Yuri , Vandeleur Caroline L. , Lasserre Aurélie M. , Penninx Brenda W.J.H. , Lamers Femke , Boomsma Dorret I. , Hottenga Jouke-Jan , Marques-Vidal Pedro , Vollenweider Peter , Waeber Gérard , Aubry Jean-Michel , Preisig Martin , Kutalik Zoltán 
Published: February 2021

AbstractStudies considering the causal role of body mass index (BMI) for the predisposition of major depressive disorder (MDD) based on a Mendelian Randomization (MR) approach have shown contradictory results. These inconsistent findings may be attributable to the heterogeneity of MDD; in fact, several studies have documented associations between BMI and mainly the atypical subtype of MDD. Using a MR approach, we investigated the potential causal role of obesity in both the atypical subtype and its five specific symptoms assessed according to the Statistical Manual of Mental Disorders (DSM), in two large European cohorts, CoLaus|PsyCoLaus (n = 3350, 1461 cases and 1889 controls) and NESDA|NTR (n = 4139, 1182 cases and 2957 controls). We first tested general obesity measured by BMI and then the body fat distribution measured by waist-to-hip ratio (WHR). Results suggested that BMI is potentially causally related to the symptom increase in appetite, for which inverse variance weighted, simple median and weighted median MR regression estimated slopes were 0.68 (SE = 0.23,p = 0.004), 0.77 (SE = 0.37,p = 0.036), and 1.11 (SE = 0.39,p = 0.004). No causal effect of BMI or WHR was found on the risk of the atypical subtype or for any of the other atypical symptoms. Our findings show that higher obesity is likely causal for the specific symptom of increase in appetite in depressed participants and reiterate the need to study depression at the granular level of its symptoms to further elucidate potential causal relationships and gain additional insight into its biological underpinnings.
In the nose or on the tongue? Contrasting motivational effects of oral and intranasal oxytocin on arousal and reward during social processing
Authors: Kou Juan , Lan Chunmei , Zhang Yingying , Wang Qianqian , Zhou Feng , Zhao Zhongbo , Montag Christian , Yao Shuxia , Becker Benjamin , Kendrick Keith M. 
Published: February 2021

AbstractIntranasal oxytocin exerts wide-ranging effects on socioemotional behavior and is proposed as a potential therapeutic intervention in psychiatric disorders. However, following intranasal administration, oxytocin could penetrate directly into the brain or influence its activity via increased peripheral concentrations crossing the blood–brain barrier or influencing vagal projections. In the current randomized, placebo-controlled, pharmaco-imaging clinical trial we investigated effects of 24IU oral (lingual) oxytocin spray, restricting it to peripherally mediated blood-borne and vagal effects, on responses to face emotions in 80 male subjects and compared them with 138 subjects treated intranasally with 24IU. Oral, but not intranasal oxytocin administration increased both arousal ratings for faces and associated brain reward responses, the latter being partially mediated by blood concentration changes. Furthermore, while oral oxytocin increased amygdala and arousal responses to face emotions, after intranasal administration they were decreased. Thus, oxytocin can produce markedly contrasting motivational effects in relation to socioemotional cues when it influences brain function via different routes. These findings have important implications for future therapeutic use since administering oxytocin orally may be both easier and have potentially stronger beneficial effects by enhancing responses to emotional cues and increasing their associated reward.
Inhibition of long non-coding RNA XIST upregulates microRNA-149-3p to repress ovarian cancer cell progression
Authors: Jiang Rong , Zhang Hongyu , Zhou Jinhua , Wang Juan , Xu Yuejuan , Zhang He , Gu Yanzheng , Fu Fengqing , Shen Yu , Zhang Guangbo , Feng Lanlan , Zhang Xueguang , Chen Youguo , Shen Fangrong 
Published: February 2021

AbstractLong non-coding RNAs (lncRNAs) and microRNAs (miRNAs) play critical roles in human diseases. We aimed to clarify the role of lncRNA X-inactive specific transcript (XIST)/miR-149-3p/forkhead box P3 (FOXP3) axis in ovarian cancer (OC) cell growth. XIST, miR-149-3p and FOXP3 expression in OC tissues and cell lines was assessed, and the predictive role of XIST in prognosis of OC patients was analyzed. The OC cell lines were screened and accordingly treated with silenced/overexpressed XIST plasmid or miR-149-3p mimic/inhibitor, and then the proliferation, invasion, migration, colony formation ability, apoptosis, and cell cycle distribution of OC cells were measured. Effect of altered XIST and miR-149-3p on tumor growth in vivo was observed. Online website prediction and dual luciferase reporter gene were implemented to detect the targeting relationship of lncRNA XIST, miR-149-3p, and FOXP3. XIST and FOXP3 were upregulated, whereas miR-149-3p was downregulated in OC tissues and cells. High XIST expression indicated a poor prognosis of OC. Inhibition of XIST or elevation of miR-149-3p repressed proliferation, invasion, migration, and colony formation ability, and promoted apoptosis and cell cycle arrest of HO-8910 cells. In SKOV3 cells upon treatment of overexpressed XIST or reduction of miR-149-3p, there exhibited an opposite tendency. Based on online website prediction, dual luciferase reporter gene, and RNA pull-down assays, we found that there was a negative relationship between XIST and miR-149-3p, and miR-149-3p downregulated FOXP3 expression. This study highlights that knockdown of XIST elevates miR-149-3p expression to suppress malignant behaviors of OC cells, thereby inhibiting OC development.
The interplay of UBE2T and Mule in regulating Wnt/β-catenin activation to promote hepatocellular carcinoma progression
Authors: Ho Nicole Pui Yu , Leung Carmen Oi Ning , Wong Tin Lok , Lau Eunice Yuen Ting , Lei Martina Mang Leng , Mok Etienne Ho Kit , Leung Hoi Wing , Tong Man , Ng Irene Oi Lin , Yun Jing Ping , Ma Stephanie , Lee Terence Kin Wah 
Published: February 2021

AbstractEmerging evidence indicates the role of cancer stem cells (CSCs) in tumor relapse and therapeutic resistance in patients with hepatocellular carcinoma (HCC). To identify novel targets against liver CSCs, an integrative analysis of publicly available datasets involving HCC clinical and stemness-related data was employed to select genes that play crucial roles in HCC via regulation of liver CSCs. We revealed an enrichment of an interstrand cross-link repair pathway, in which ubiquitin-conjugating enzyme E2 T (UBE2T) was the most significantly upregulated. Consistently, our data showed that UBE2T was upregulated in enriched liver CSC populations. Clinically, UBE2T overexpression in HCC was further confirmed at mRNA and protein levels and was correlated with advanced tumor stage and poor patient survival. UBE2T was found to be critically involved in the regulation of liver CSCs, as evidenced by increases in self-renewal, drug resistance, tumorigenicity, and metastasis abilities. Mule, an E3 ubiquitin ligase, was identified to be the direct protein binding partner of UBE2T. Rather than the canonical role of acting as a mediator to transfer ubiquitin to E3 ligases, UBE2T is surprisingly able to physically bind and regulate the protein expression of Mule via ubiquitination. Mule was found to directly degrade β-catenin protein, and UBE2T was found to mediate liver CSC functions through direct regulation of Mule-mediated β-catenin degradation; this effect was abolished when the E2 activity of UBE2T was impaired. In conclusion, we revealed a novel UBE2T/Mule/β-catenin signaling cascade that is involved in the regulation of liver CSCs, which provides an attractive potential therapeutic target for HCC.
Osteomodulin positively regulates osteogenesis through interaction with BMP2
Authors: Lin Wenzhen , Zhu Xiaohan , Gao Li , Mao Mengying , Gao Daming , Huang Zhengwei 
Published: February 2021

AbstractOsteomodulin (OMD), a member of the small leucine-rich proteoglycan family, distributes in mineralized tissues and is positively regulated by bone morphogenetic protein 2 (BMP2). However, the exact function of OMD during mineralization and its association with BMP2 remain poorly understood. Herein, the expression pattern of OMD during osteogenesis was investigated in human dental pulp stem cells. Silencing OMD gene significantly suppressed the alkaline phosphatase activity, mineralized nodule formation and osteogenesis-associated gene transcription. Besides, OMD could enhance BMP2-induced expression of SP7 and RUNX2 with concentration dependence in vitro. Rat mandibular bone defect model revealed that scaffolds injected with the combination of OMD and suboptimal BMP2 exhibited more mature and abundant mineralized bone than that treated with OMD or suboptimal BMP2 alone. Mechanistically, OMD could bind to BMP2 via its terminal leucine-rich repeats and formed complexes with BMP2 and its membrane receptors, thus promoting BMP/SMAD signal transduction. In addition, OMD was a putative target gene of SMAD4, which plays a pivotal role in this pathway. Collectively, these data elucidate that OMD may act as a positive coordinator in osteogenesis through BMP2/SMADs signaling.
Double-targeting CDCA8 and E2F1 inhibits the growth and migration of malignant glioma
Authors: Wang Xiaoxiong , Wang Heping , Xu Jiajun , Hou Xu , Zhan Haoqiang , Zhen Yunbo 
Published: February 2021

AbstractHigh-grade glioma is the most common and aggressive primary brain tumor in adults with poor therapeutic efficiency and survival prognosis. Cell division cycle associated 8 (CDCA8) has been well known as a cell cycle regulator and tumor promotor in various malignant tumors. However, its biological role in glioma still remains unclear. Our results showed that high level of CDCA8 was significantly correlated with advanced WHO grade and poor overall survival and disease-free survival prognosis. In vitro and in vivo investigations demonstrated that CDCA8 promoted the glioma malignancy by promoting cell proliferation, cell migration, and inhibiting cell apoptosis. Moreover, we found its synergetic biological protein—E2F1 by the gene microarray chip. In this study, we revealed that CDCA8 synergized with E2F1 facilitated the proliferation and migration of glioma. In conclusion, our study provides a novel promising therapeutic targets and prognostic biomarkers for malignant glioma treatment.
The N-terminal BRCT domain determines MCPH1 function in brain development and fertility
Authors: Liu Xiaoqian , Schneble-Löhnert Nadine , Kristofova Martina , Qing Xiaobing , Labisch Jan , Hofmann Susanne , Ehrenberg Sandra , Sannai Mara , Jörß Tjard , Ori Alessandro , Godmann Maren , Wang Zhao-Qi 
Published: February 2021

AbstractMCPH1 is a causal gene for the neurodevelopmental disorder, human primary microcephaly (MCPH1, OMIM251200). Most pathogenic mutations are located in the N-terminal region of the gene, which encodes a BRCT domain, suggesting an important function of this domain in brain size determination. To investigate the specific function of the N-terminal BRCT domain in vivo, we generated a mouse model lacking the N’-BRCT domain of MCPH1 (referred as Mcph1-ΔBR1). These mutant mice are viable, but exhibit reduced brain size, with a thinner cortex due to a reduction of neuroprogenitor populations and premature neurogenic differentiation. Mcph1-ΔBR1 mice (both male and female) are infertile; however, almost all female mutants develop ovary tumours. Mcph1-ΔBR1 MEF cells exhibit a defect in DNA damage response and DNA repair, and show the premature chromosome condensation (PCC) phenotype, a hallmark of MCPH1 patient cells and also Mcph1 knockout cells. In comparison with Mcph1 complete knockout mice, Mcph1-ΔBR1 mice faithfully reproduce all phenotypes, indicating an essential role of the N-terminal BRCT domain for the physiological function of MCPH1 in the control of brain size and gonad development as well as in multiple cellular processes.
The ATPase Pontin is a key cell cycle regulator by amplifying E2F1 transcription response in glioma
Authors: Wang Run , Li Xuebing , Sun Cuiyun , Yu Lin , Hua Dan , Shi Cuijuan , Wang Qian , Rao Chun , Luo Wenjun , Jiang Zhendong , Zhou Xuexia , Yu Shizhu 
Published: February 2021

AbstractPontin (RUVBL1) is a highly conserved ATPase of the AAA + (ATPases Associated with various cellular Activities) superfamily and is implicated in various biological processes crucial for oncogenesis. Its overexpression is observed in multiple human cancers, whereas the relevance of Pontin to gliomagenesis remains obscure. To gain insights into Pontin involvement in glioma, we performed bioinformatics analyses of Pontin co-expressed genes, Pontin-affected genes, and carried out experimental studies. The results verified that Pontin was upregulated in gliomas. Its higher levels might predict the worse prognosis of glioma patients. The Pontin co-expressed genes were functionally enriched in cell cycle progression and RNA processing. In the nucleus, Pontin promoted cell growth via facilitating cell cycle progression. Using RNA-seq, we found that Pontin knockdown resulted in altered expression of multiple genes, among which the E2F1 targets accounted for a large proportion. Mechanistic studies found that Pontin interacted with E2F1 and markedly amplified the E2F1 transcription response in an ATPase domain-dependent manner. By analyzing the RNA-seq data, we also found that Pontin could impact on the alternative splicing (AS). Both differential expressed genes and AS events affected by Pontin were associated with cell cycle regulation. Taken together, our findings provide novel insights of the importance of Pontin in gliomagenesis by regulating cell cycle and AS, and shed light on the possible application of Pontin as an antineoplastic target in glioma.
Role of microRNA-335 carried by bone marrow mesenchymal stem cells-derived extracellular vesicles in bone fracture recovery
Authors: Hu Haifeng , Wang Dong , Li Lihong , Yin Haiyang , He Guoyu , Zhang Yonghong 
Published: February 2021

AbstractMesenchymal stem cells (MSCs) have the potential to reduce healing time and treat nonunion in fracture patients. In this study, bone marrow MSCs-derived extracellular vesicles (B-EVs) were firstly extracted and identified. CD9−/− and normal mice were enrolled for the establishment of fracture models and then injected with B-EVs. Osteoblast differentiation and fracture recovery were estimated. The levels of osteoblast-related genes were detected, and differentially expressed microRNAs (miRs) in B-EVs-treated normal fracture mice were screened and verified. The downstream mechanisms of miR were predicted and assessed. The loss-of functions of miR-335 in B-EV and gain-of-functions of VapB were performed in animal and cell experiments to evaluate their roles in bone fracture. Collectively, B-EVs promoted bone fracture recovery and osteoblast differentiation by releasing miR-335. miR-335 downregulation in B-EVs impaired B-EV functions in fracture recovery and osteoblast differentiation. miR-335 could target VapB, and VapB overexpression reversed the effects of B-EVs on osteoblast differentiation. B-EV treatment activated the Wnt/β-catenin pathway in fracture mice and osteoblasts-like cells. Taken together, the study suggested that B-EVs carry miR-335 to promote bone fracture recovery via VapB and the Wnt/β-catenin pathway. This study may offer insights into bone fracture treatment.
HNRNPD interacts with ZHX2 regulating the vasculogenic mimicry formation of glioma cells via linc00707/miR-651-3p/SP2 axis
Authors: Yu Sifei , Ruan Xuelei , Liu Xiaobai , Zhang Fangfang , Wang Di , Liu Yunhui , Yang Chunqing , Shao Lianqi , Liu Qianshuo , Zhu Lu , Lin Yang , Xue Yixue 
Published: February 2021

AbstractStudies have found that RNA-binding proteins (RBPs) are dysfunctional and play a significant regulatory role in the development of glioma. Based on The Cancer Genome Atlas database and the previous studies, we selected heterogeneous nuclear ribonucleoprotein (HNRNPD) as the research candidate and sought its downstream targeted genes. In the present study, HNRNPD, linc00707, and specific protein 2 (SP2) were highly expressed, while zinc fingers and homeboxes 2 (ZHX2) and miR-651-3p were remarkedly downregulated in glioma tissues and cells. HNRNPD, linc00707, and SP2 knockdown or ZHX2 and miR-651-3p overexpression suppressed glioma cells proliferation, migration, and invasion and vasculogenic mimicry (VM) formation. Knockdown of HNRNPD increased the stability of ZHX2 mRNA. ZHX2 bound to the promoter region of linc00707 and negatively regulate its expression. Linc00707 could bind with miR-651-3p, while miR-651-3p bound to the 3′ untranslated region (3′UTR) of SP2 mRNA to negatively regulate its expression. The transcription factor SP2 directly bound to the promoter regions of the VM formation-related proteins MMP2, MMP9, and VE-cadherin, playing a role in promoting transcription in order to regulate the VM formation ability of glioma cells.
Targeting Aurora B kinase with Tanshinone IIA suppresses tumor growth and overcomes radioresistance
Authors: Li Ming , Liu Haidan , Zhao Qin , Han Shuangze , Zhou Li , Liu Wenbin , Li Wei , Gao Feng 
Published: February 2021

AbstractAurora B kinase is aberrantly overexpressed in various tumors and shown to be a promising target for anti-cancer therapy. In human oral squamous cell carcinoma (OSCC), the high protein level of Aurora B is required for maintaining of malignant phenotypes, including in vitro cell growth, colony formation, and in vivo tumor development. By molecular modeling screening of 74 commercially available natural products, we identified that Tanshinone IIA (Tan IIA), as a potential Aurora B kinase inhibitor. The in silico docking study indicates that Tan IIA docks into the ATP-binding pocket of Aurora B, which is further confirmed by in vitro kinase assay, ex vivo pull-down, and ATP competitive binding assay. Tan IIA exhibited a significant anti-tumor effect on OSCC cells both in vitro and in vivo, including reduction of Aurora B and histone H3 phosphorylation, induction of G2/M cell cycle arrest, increase the population of polyploid cells, and promotion of apoptosis. The in vivo mouse model revealed that Tan IIA delayed tumor growth of OSCC cells. Tan IIA alone or in combination with radiation overcame radioresistance in OSCC xenograft tumors. Taken together, our data indicate that Tan IIA is an Aurora B kinase inhibitor with therapeutic potentials for cancer treatment.
Loss-of-function of p53 isoform Δ113p53 accelerates brain aging in zebrafish
Authors: Zhao Ting , Ye Shengfan , Tang Zimu , Guo Liwei , Ma Zhipeng , Zhang Yuxi , Yang Chun , Peng Jinrong , Chen Jun 
Published: February 2021

AbstractReactive oxygen species (ROS) stress has been demonstrated as potentially critical for induction and maintenance of cellular senescence, and been considered as a contributing factor in aging and in various neurological disorders including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). In response to low-level ROS stress, the expression of Δ133p53, a human p53 isoform, is upregulated to promote cell survival and protect cells from senescence by enhancing the expression of antioxidant genes. In normal conditions, the basal expression of Δ133p53 prevents human fibroblasts, T lymphocytes, and astrocytes from replicative senescence. It has been also found that brain tissues from AD and ALS patients showed decreased Δ133p53 expression. However, it is uncharacterized if Δ133p53 plays a role in brain aging. Here, we report that zebrafish Δ113p53, an ortholog of human Δ133p53, mainly expressed in some of the radial glial cells along the telencephalon ventricular zone in a full-length p53-dependent manner. EDU-labeling and cell lineage tracing showed thatΔ113p53-positive cells underwent cell proliferation to contribute to the neuron renewal process. Importantly,Δ113p53M/Mmutant telencephalon possessed less proliferation cells and more senescent cells compared to wild-type (WT) zebrafish telencephalon since 9-months old, which was associated with decreased antioxidant genes expression and increased level of ROS in the mutant telencephalon. More interestingly, unlike the mutant fish at 5-months old with cognition ability,Δ113p53M/Mzebrafish, but not WT zebrafish, lost their learning and memory ability at 19-months old. The results demonstrate thatΔ113p53protects the brain from aging by its antioxidant function. Our finding provides evidence at the organism level to show that depletion of Δ113p53/Δ133p53 may result in long-term ROS stress, and finally lead to age-related diseases, such as AD and ALS in humans.
Origins of human genetics. A personal perspective
Authors: Passarge Eberhard 
Published: February 2021

AbstractGenetics evolved as a field of science after 1900 with new theories being derived from experiments obtained in fruit flies, bacteria, and viruses. This personal account suggests that the origins of human genetics can best be traced to the years 1949 to 1959. Several genetic scientific advances in genetics in 1949 yielded results directly relating to humans for the first time, except for a few earlier observations. In 1949 the first textbook of human genetics was published, the American Journal of Human Genetics was founded, and in the previous year the American Society of Human Genetics. In 1940 in Britain a textbook entitledIntroduction to Medical Geneticsserved as a foundation for introducing genetic aspects into medicine. The introduction of new methods for analyzing chromosomes and new biochemical assays using cultured cells in 1959 and subsequent years revealed that many human diseases, including cancer, have genetic causes. It became possible to arrive at a precise cause-related genetic diagnosis. As a result the risk of occurrence or re-occurrence of a disease within a family could be assessed correctly. Genetic counseling as a new concept became a basis for improved patient care. Taken together the advances in medically orientated genetic research and patient care since 1949 have resulted in human genetics being both, a basic medical and a basic biological science. Prior to 1949 genetics was not generally viewed in a medical context. Although monogenic human diseases were recognized in 1902, their occurrence and distribution were considered mainly at the population level.
More accurate quantification of model-to-model agreement in externally forced climatic responses over the coming century
Authors: Maher Nicola , Power Scott B. , Marotzke Jochem 
Published: February 2021

AbstractSeparating how model-to-model differences in the forced response (UMD) and internal variability (UIV) contribute to the uncertainty in climate projections is important, but challenging. ReducingUMDincreases confidence in projections, whileUIVcharacterises the range of possible futures that might occur purely by chance. Separating these uncertainties is limited in traditional multi-model ensembles because most models have only a small number of realisations; furthermore, some models are not independent. Here, we use six largely independent single model initial-condition large ensembles to separate the contributions ofUMDandUIVin projecting 21st-century changes of temperature, precipitation, and their temporal variability under strong forcing (RCP8.5). We provide a method that produces similar results using traditional multi-model archives. WhileUMDis larger thanUIVfor both temperature and precipitation changes,UIVis larger thanUMDfor the changes in temporal variability of both temperature and precipitation, between 20° and 80° latitude in both hemispheres. Over large regions and for all variables considered here except temporal temperature variability, models agree on the sign of the forced response whereas they disagree widely on the magnitude. Our separation method can readily be extended to other climate variables.