bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathological oligodendrocyte precursor cells revealed in human schizophrenic brains and trigger schizophrenia-like behaviors and synaptic defects in genetic animal model
Authors: Yu Guangdan , Su Yixun , Guo Chen , Yi Chenju , Yu Bin , Chen Hui , Cui Yihui , Wang Xiaorui , Wang Yuxin , Chen Xiaoying , Wang Shouyu , Wang Qi , Chen Xianjun , Hu Xuelian , Mei Feng , Verkhratsky Alexei , Xiao Lan , Niu Jianqin 
Published: September 2022

AbstractAlthough the link of white matter to pathophysiology of schizophrenia is documented, loss of myelin is not detected in patients at the early stages of the disease, suggesting that pathological evolution of schizophrenia may occur before significant myelin loss. Disrupted-in-schizophrenia-1 (DISC1) protein is highly expressed in oligodendrocyte precursor cells (OPCs) and regulates their maturation. Recently, DISC1-Δ3, a major DISC1 variant that lacks exon 3, has been identified in schizophrenia patients, although its pathological significance remains unknown. In this study, we detected in schizophrenia patients a previously unidentified pathological phenotype of OPCs exhibiting excessive branching. We replicated this phenotype by generating a mouse strain expressing DISC1-Δ3 gene in OPCs. We further demonstrated that pathological OPCs, rather than myelin defects, drive the onset of schizophrenic phenotype by hyperactivating OPCs’ Wnt/β-catenin pathway, which consequently upregulates Wnt Inhibitory Factor 1 (Wif1), leading to the aberrant synaptic formation and neuronal activity. Suppressing Wif1 in OPCs rescues synaptic loss and behavioral disorders in DISC1-Δ3 mice. Our findings reveal the pathogenetic role of OPC-specific DISC1-Δ3 variant in the onset of schizophrenia and highlight the therapeutic potential of Wif1 as an alternative target for the treatment of this disease.
Efficacy of psychotropic medications on suicide and self-injury: a meta-analysis of randomized controlled trials
Authors: Huang Xieyining , Harris Lauren M. , Funsch Kensie M. , Fox Kathryn R. , Ribeiro Jessica D. 
Published: September 2022

AbstractUsing psychotropic medications to treat and prevent self-injurious thoughts and behaviors (SITBs) has become increasingly popular, but conclusive evidence supporting the efficacy this approach remains elusive. To empirically examine whether psychotropic medications are efficacious treatments for SITBs, the present meta-analysis comprehensively summarizes all published randomized controlled trials (RCTs) that have reported the causal effects of psychotropic medications on suicide and self-injury. A total of 251 papers from 718 unique RCTs were included. A frequentist pairwise approach was adopted for meta-analyses. Potential effect modifiers were examined via met regressions and potential biases were evaluated through sensitivity analyses. On average, medications yielded an 8% reduction in SITB frequency and a reduction of 0.2 standard deviations in symptoms and severity. Findings were largely consistent across potential effect modifiers, and significant evidence of publication bias was not detected. Only one medication class (i.e., antipsychotics) and two specific medications (i.e., citalopram, ketamine) produced larger-than-average treatment effects. Psychostimulants and typical antipsychotics may produce iatrogenic effects. Less than 4% of included studies required individuals to exhibit SITBs, and nearly half of analyzed effects were drawn from studies that excluded individuals on the basis of SITB risk. Taken together, findings suggest that psychotropic medications produce small treatment effects on SITBs; however, these findings should be considered in light of the methodological constraints of the existing literature, including the lack of studies intentionally including individuals with SITBs. It is critical for future RCTs to prioritize including individuals with existing SITBs to further clarify treatment effects in self-injurious and suicidal populations. Additional research is needed to better understand the treatment mechanisms of psychotropic medications and identify the causal processes underlying SITBs.
MIIP functions as a novel ligand for ITGB3 to inhibit angiogenesis and tumorigenesis of triple-negative breast cancer
Authors: Gao Yujing , Fang Yujie , Huang Yongli , Ma Rui , Chen Xixi , Wang Fang , Pei Xiuying , Gao Yuanqi , Chen Xuehua , Liu Xinrui , Shan Jingxuan , Li Pu 
Published: September 2022

AbstractMigration and invasion inhibitory protein (MIIP) has been identified as a tumor suppressor in various cancer types. Although MIIP is reported to exert tumor suppressive functions by repressing proliferation and metastasis of cancer cells, the detailed mechanism is poorly understood. In the present study, we found MIIP is a favorable indicator of prognosis in triple-negative breast cancer. MIIP could inhibit tumor angiogenesis, proliferation, and metastasis of triple-negative breast cancer cells in vivo and in vitro. Mechanistically, MIIP directly interacted with ITGB3 and suppressed its downstream signaling. As a result, β-catenin was reduced due to elevated ubiquitin-mediated degradation, leading to downregulated VEGFA production and epithelial mesenchymal transition. More importantly, we found RGD motif is essential for MIIP binding with ITGB3 and executing efficient tumor-suppressing effect. Our findings unravel a novel mechanism by which MIIP suppresses tumorigenesis in triple-negative breast cancer, and MIIP is thus a promising molecular biomarker or therapeutic target for the disease.
LncRNA SNHG1 regulates neuroblastoma cell fate via interactions with HDAC1/2
Authors: Hsu Chia-Lang , Yin Chieh-Fan , Chang Yi-Wen , Fan Ya-Chih , Lin Shih-Han , Wu Yu-Ching , Huang Hsuan-Cheng , Juan Hsueh-Fen 
Published: September 2022

AbstractThe small nucleolar RNA host gene 1 (SNHG1) is a novel oncogenic long non-coding RNA (lncRNA) aberrantly expressed in different tumor types. We previously found highly expressed SNHG1 was associated with poor prognosis and MYCN status in neuroblastoma (NB). However, the molecular mechanisms of SNHG1 in NB are still unclear. Here, we disrupted endogenous SNHG1 in the MYCN-amplified NB cell line SK-N-BE(2)C using the CRISPR/Cas9 system and demonstrated the proliferation and colony formation ability of SNHG1-knowndown cells were suppressed. The transcriptome analysis and functional assays of SNHG1-knockdown cells revealed SNHG1 was involved in various biological processes including cell growth, migration, apoptosis, cell cycle, and reactive oxygen species (ROS). Interestingly, the expression of core regulatory circuitry (CRC) transcription factors in MYCN-amplified NB, including PHOX2B, HAND2, GATA3, ISL1, TBX1, and MYCN, were decreased in SNHG1-knockdown cells. The chromatin-immunoprecipitation sequencing (ChIP-seq) and transposase-accessible chromatin using sequencing (ATAC-seq) analyses showed that chromatin status of these CRC members was altered, which might stem from interactions between SNHG1 and HDAC1/2. These findings demonstrate that SNHG1 plays a crucial role in maintaining NB identity via chromatin regulation and reveal the function of the lncRNA SNHG1 in NB.
Evolutionary origin of vertebrate OCT4/POU5 functions in supporting pluripotency
Authors: Sukparangsi Woranop , Morganti Elena , Lowndes Molly , Mayeur Hélène , Weisser Melanie , Hammachi Fella , Peradziryi Hanna , Roske Fabian , Hölzenspies Jurriaan , Livigni Alessandra , Godard Benoit Gilbert , Sugahara Fumiaki , Kuratani Shigeru , Montoya Guillermo , Frankenberg Stephen R. , Mazan Sylvie , Brickman Joshua M. 
Published: September 2022

AbstractThe support of pluripotent cells over time is an essential feature of development. In eutherian embryos, pluripotency is maintained from naïve states in peri-implantation to primed pluripotency at gastrulation. To understand how these states emerged, we reconstruct the evolutionary trajectory of the Pou5 gene family, which contains the central pluripotency factor OCT4. By coupling evolutionary sequence analysis with functional studies in mouse embryonic stem cells, we find that the ability of POU5 proteins to support pluripotency originated in the gnathostome lineage, prior to the generation of two paralogues, Pou5f1 and Pou5f3 via gene duplication. In osteichthyans, retaining both genes, the paralogues differ in their support of naïve and primed pluripotency. The specialization of these duplicates enables the diversification of function in self-renewal and differentiation. By integrating sequence evolution, cell phenotypes, developmental contexts and structural modelling, we pinpoint OCT4 regions sufficient for naïve pluripotency and describe their adaptation over evolutionary time.
Preclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration
Authors: Jiang Ying , Alam John J. , Gomperts Stephen N. , Maruff Paul , Lemstra Afina W. , Germann Ursula A. , Stavrides Philip H. , Darji Sandipkumar , Malampati Sandeep , Peddy James , Bleiwas Cynthia , Pawlik Monika , Pensalfini Anna , Yang Dun-Sheng , Subbanna Shivakumar , Basavarajappa Balapal S. , Smiley John F. , Gardner Amanda , Blackburn Kelly , Chu Hui-May , Prins Niels D. , Teunissen Charlotte E. , Harrison John E. , Scheltens Philip , Nixon Ralph A. 
Published: September 2022

AbstractThe endosome-associated GTPase Rab5 is a central player in the molecular mechanisms leading to degeneration of basal forebrain cholinergic neurons (BFCN), a long-standing target for drug development. As p38α is a Rab5 activator, we hypothesized that inhibition of this kinase holds potential as an approach to treat diseases associated with BFCN loss. Herein, we report that neflamapimod (oral small molecule p38α inhibitor) reduces Rab5 activity, reverses endosomal pathology, and restores the numbers and morphology of BFCNs in a mouse model that develops BFCN degeneration. We also report on the results of an exploratory (hypothesis-generating) phase 2a randomized double-blind 16-week placebo-controlled clinical trial (Clinical trial registration: NCT04001517/EudraCT #2019-001566-15) of neflamapimod in mild-to-moderate dementia with Lewy bodies (DLB), a disease in which BFCN degeneration is an important driver of disease expression. A total of 91 participants, all receiving background cholinesterase inhibitor therapy, were randomized 1:1 between neflamapimod 40 mg or matching placebo capsules (taken orally twice-daily if weight <80 kg or thrice-daily if weight >80 kg). Neflamapimod does not show an effect in the clinical study on the primary endpoint, a cognitive-test battery. On two secondary endpoints, a measure of functional mobility and a dementia rating-scale, improvements were seen that are consistent with an effect on BFCN function. Neflamapimod treatment is well-tolerated with no study drug associated treatment discontinuations. The combined preclinical and clinical observations inform on the validity of the Rab5-based pathogenic model of cholinergic degeneration and provide a foundation for confirmatory (hypothesis-testing) clinical evaluation of neflamapimod in DLB.
The role of renewables for rapid transitioning of the power sector across states in India
Authors: Gulagi Ashish , Ram Manish , Bogdanov Dmitrii , Sarin Sandeep , Mensah Theophilus Nii Odai , Breyer Christian 
Published: September 2022

AbstractRecent events like heatwaves and abnormal rainfall are a glimpse of the devastating effects of human induced climate change. No country is immune to its effects, but a developing country like India is particularly vulnerable. This research, for the individual states of India, explores the technical feasibility and economic viability of a renewable transition pathway for the power sector. Based on the assumptions of this study, we show that a renewables-based power system by 2050 is lower in cost than the current coal dominated system, has zero greenhouse gas emissions and provides reliable electricity to around 1.7 billion people. Electricity generation will be based on solar PV, wind energy, and hydropower, while batteries and multi-fuel reciprocating internal combustion engines based on synthetic fuels provide the required flexibility to the power system. This transition would address multiple imperatives: affordability, accessibility, and sustainability without compromising economic growth.
Reaction-based fluorogenic probes for detecting protein cysteine oxidation in living cells
Authors: Ferreira Renan B. , Fu Ling , Jung Youngeun , Yang Jing , Carroll Kate S. 
Published: September 2022

Abstract‘Turn-on’ fluorescence probes for detecting H2O2 in cells are established, but equivalent tools to monitor the products of its reaction with protein cysteines have not been reported. Here we describe fluorogenic probes for detecting sulfenic acid, a redox modification inextricably linked to H2O2 signaling and oxidative stress. The reagents exhibit excellent cell permeability, rapid reactivity, and high selectivity with minimal cytotoxicity. We develop a high-throughput assay for measuring S-sulfenation in cells and use it to screen a curated kinase inhibitor library. We reveal a positive association between S-sulfenation and inhibition of TK, AGC, and CMGC kinase group members including GSK3, a promising target for neurological disorders. Proteomic mapping of GSK3 inhibitor-treated cells shows that S-sulfenation sites localize to the regulatory cysteines of antioxidant enzymes. Our studies highlight the ability of kinase inhibitors to modulate the cysteine sulfenome and should find broad application in the rapidly growing field of redox medicine.
Resolving molecular diffusion and aggregation of antibody proteins with megahertz X-ray free-electron laser pulses
Authors: Reiser Mario , Girelli Anita , Ragulskaya Anastasia , Das Sudipta , Berkowicz Sharon , Bin Maddalena , Ladd-Parada Marjorie , Filianina Mariia , Poggemann Hanna-Friederike , Begam Nafisa , Akhundzadeh Mohammad Sayed , Timmermann Sonja , Randolph Lisa , Chushkin Yuriy , Seydel Tilo , Boesenberg Ulrike , Hallmann Jörg , Möller Johannes , Rodriguez-Fernandez Angel , Rosca Robert , Schaffer Robert , Scholz Markus , Shayduk Roman , Zozulya Alexey , Madsen Anders , Schreiber Frank , Zhang Fajun , Perakis Fivos , Gutt Christian 
Published: September 2022

AbstractX-ray free-electron lasers (XFELs) with megahertz repetition rate can provide novel insights into structural dynamics of biological macromolecule solutions. However, very high dose rates can lead to beam-induced dynamics and structural changes due to radiation damage. Here, we probe the dynamics of dense antibody protein (Ig-PEG) solutions using megahertz X-ray photon correlation spectroscopy (MHz-XPCS) at the European XFEL. By varying the total dose and dose rate, we identify a regime for measuring the motion of proteins in their first coordination shell, quantify XFEL-induced effects such as driven motion, and map out the extent of agglomeration dynamics. The results indicate that for average dose rates below 1.06 kGy μs−1 in a time window up to 10 μs, it is possible to capture the protein dynamics before the onset of beam induced aggregation. We refer to this approach as correlation before aggregation and demonstrate that MHz-XPCS bridges an important spatio-temporal gap in measurement techniques for biological samples.
Insular cortical circuits as an executive gateway to decipher threat or extinction memory via distinct subcortical pathways
Authors: Wang Qi , Zhu Jia-Jie , Wang Lizhao , Kan Yan-Peng , Liu Yan-Mei , Wu Yan-Jiao , Gu Xue , Yi Xin , Lin Ze-Jie , Wang Qin , Lu Jian-Fei , Jiang Qin , Li Ying , Liu Ming-Gang , Xu Nan-Jie , Zhu Michael X. , Wang Lu-Yang , Zhang Siyu , Li Wei-Guang , Xu Tian-Le 
Published: September 2022

AbstractThreat and extinction memories are crucial for organisms’ survival in changing environments. These memories are believed to be encoded by separate ensembles of neurons in the brain, but their whereabouts remain elusive. Using an auditory fear-conditioning and extinction paradigm in male mice, here we discovered that two distinct projection neuron subpopulations in physical proximity within the insular cortex (IC), targeting the central amygdala (CeA) and nucleus accumbens (NAc), respectively, to encode fear and extinction memories. Reciprocal intracortical inhibition of these two IC subpopulations gates the emergence of either fear or extinction memory. Using rabies-virus-assisted tracing, we found IC-NAc projection neurons to be preferentially innervated by intercortical inputs from the orbitofrontal cortex (OFC), specifically enhancing extinction to override fear memory. These results demonstrate that IC serves as an operation node harboring distinct projection neurons that decipher fear or extinction memory under the top-down executive control from OFC.
Characterizing DNA methylation signatures of retinoblastoma using aqueous humor liquid biopsy
Authors: Li Hong-Tao , Xu Liya , Weisenberger Daniel J. , Li Meng , Zhou Wanding , Peng Chen-Ching , Stachelek Kevin , Cobrinik David , Liang Gangning , Berry Jesse L. 
Published: September 2022

AbstractRetinoblastoma (RB) is a cancer that forms in the developing retina of babies and toddlers. The goal of therapy is to cure the tumor, save the eye and maximize vision. However, it is difficult to predict which eyes are likely to respond to therapy. Predictive molecular biomarkers are needed to guide prognosis and optimize treatment decisions. Direct tumor biopsy is not an option for this cancer; however, the aqueous humor (AH) is an alternate source of tumor-derived cell-free DNA (cfDNA). Here we show that DNA methylation profiling of the AH is a valid method to identify the methylation status of RB tumors. We identify 294 genes directly regulated by methylation that are implicated in p53 tumor suppressor (RB1, p53, p21, and p16) and oncogenic (E2F) pathways. Finally, we use AH to characterize molecular subtypes that can potentially be used to predict the likelihood of treatment success for retinoblastoma patients.
Mechanism driven design of trimer Ni1Sb2 site delivering superior hydrogenation selectivity to ethylene
Authors: Ge Xiaohu , Dou Mingying , Cao Yueqiang , Liu Xi , Yuwen Qiang , Zhang Jing , Qian Gang , Gong Xueqing , Zhou Xinggui , Chen Liwei , Yuan Weikang , Duan Xuezhi 
Published: September 2022

AbstractMechanism driven catalyst design with atomically uniform ensemble sites is an important yet challenging issue in heterogeneous catalysis associated with breaking the activity-selectivity trade-off. Herein, a trimer Ni1Sb2 site in NiSb intermetallic featuring superior selectivity is elaborated for acetylene semi-hydrogenation via a theoretical guidance with a precise synthesis strategy. The trimer Ni1Sb2 site in NiSb intermetallic is predicted to endow acetylene reactant with an adequately but not excessively strong σ-adsorption mode while ethylene product with a weak π-adsorption one, where such compromise delivers higher ethylene formation rate. An in-situ trapping of molten Sb by Ni strategy is developed to realize the construction of Ni1Sb2 site in the intermetallic P63/mmc NiSb catalysts. Such catalyst exhibits ethylene selectivity up to 93.2% at 100% of acetylene conversion, significantly prevailing over the referred Ni catalyst. These insights shed new lights on rational catalyst design by taming active sites to energetically match targeted reaction pathway.
Neural probe system for behavioral neuropharmacology by bi-directional wireless drug delivery and electrophysiology in socially interacting mice
Authors: Yoon Yousang , Shin Hyogeun , Byun Donghak , Woo Jiwan , Cho Yakdol , Choi Nakwon , Cho Il-Joo 
Published: September 2022

AbstractAssessing the neurological and behavioral effects of drugs is important in developing pharmacological treatments, as well as understanding the mechanisms associated with neurological disorders. Herein, we present a miniaturized, wireless neural probe system with the capability of delivering drugs for the real-time investigation of the effects of the drugs on both behavioral and neural activities in socially interacting mice. We demonstrate wireless drug delivery and simultaneous monitoring of the resulting neural, behavioral changes, as well as the dose-dependent and repeatable responses to drugs. Furthermore, in pairs of mice, we use a food competition assay in which social interaction was modulated by the delivery of the drug, and the resulting changes in their neural activities are analyzed. During modulated food competition by drug injection, we observe changes in neural activity in mPFC region of a participating mouse over time. Our system may provide new opportunities for the development of studying the effects of drugs on behaviour and neural activity.
60 million years of glaciation in the Transantarctic Mountains
Authors: Barr Iestyn D. , Spagnolo Matteo , Rea Brice R. , Bingham Robert G. , Oien Rachel P. , Adamson Kathryn , Ely Jeremy C. , Mullan Donal J. , Pellitero Ramón , Tomkins Matt D. 
Published: September 2022

AbstractThe Antarctic continent reached its current polar location ~83 Ma and became shrouded by ice sheets ~34 Ma, coincident with dramatic global cooling at the Eocene-Oligocene boundary. However, it is not known whether the first Antarctic glaciers formed immediately prior to this or were present significantly earlier. Here we show that mountain glaciers were likely present in the Transantarctic Mountains during the Late Palaeocene (~60–56 Ma) and middle Eocene (~48–40 Ma). Temperate (warm-based) glaciers were prevalent during the Late Eocene (~40–34 Ma) and, in reduced numbers, during the Oligocene (~34–23 Ma), before larger, likely cold-based, ice masses (including ice sheets) dominated. Some temperate mountain glaciers were present during the Miocene Climatic Optimum (~15 Ma), before a widespread switch to cold-based glaciation. Our findings highlight the longevity of glaciation in Antarctica and suggest that glaciers were present even during the Early-Cenozoic greenhouse world.
The natural history and genetic diversity of Haemophilus influenzae infecting the airways of adults with cystic fibrosis
Authors: Izydorczyk Conrad , Waddell Barbara J. , Weyant Robert B. , Surette Michael G. , Somayaji Ranjani , Rabin Harvey R. , Conly John M. , Church Deirdre L. , Parkins Michael D. 
Published: September 2022

AbstractHaemophilus influenzae is a Gram-negative pathobiont, frequently recovered from the airways of persons with cystic fibrosis (pwCF). Previous studies of H. influenzae infection dynamics and transmission in CF predominantly used molecular methods, lacking resolution. In this retrospective cohort study, representative yearly H. influenzae isolates from all pwCF attending the Calgary Adult CF Clinic with H. influenzae positive sputum cultures between 2002 and 2016 were typed by pulsed-field gel electrophoresis. Isolates with shared pulsotypes common to ≥ 2 pwCF were sequenced by Illumina MiSeq. Phylogenetic and pangenomic analyses were used to assess genetic relatedness within shared pulsotypes, and epidemiological investigations were performed to assess potential for healthcare associated transmission. H. influenzae infection was observed to be common (33% of patients followed) and dynamic in pwCF. Most infected pwCF exhibited serial infections with new pulsotypes (75% of pwCF with ≥ 2 positive cultures), with up to four distinct pulsotypes identified from individual patients. Prolonged infection by a single pulsotype was only rarely observed. Intra-patient genetic diversity was observed at the single-nucleotide polymorphism and gene content levels. Seven shared pulsotypes encompassing 39% of pwCF with H. influenzae infection were identified, but there was no evidence, within our sampling scheme, of direct patient-to-patient infection transmission.