bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel indole-mediated potassium ion import system confers a survival advantage to the Xanthomonadaceae family
Authors: Zhu Yuxiang , Han Yong , Liu Guanglei , Bian Zeran , Yan Xiayi , Li Yaoyao , Long Hongan , Yu Guanshuo , Wang Yan 
Published: March 2022

Abstract
Interspecific and intraspecific communication systems of microorganisms are involved in the regulation of various stress responses in microbial communities. Although the significance of signaling molecules in the ubiquitous family Xanthomonadaceae has been reported, the role bacterial communications play and their internal mechanisms are largely unknown. Here, we use Lysobacter enzymogenes, a member of Xanthomonadaceae, to identify a novel potassium ion import system, LeKdpXFABC. This import system participates in the indole-mediated interspecies signaling pathway and matters in environmental adaptation. Compared with the previously reported kdpFABC of Escherichia coli, LekdpXFABC contains a novel indispensable gene LekdpX and is directly regulated by the indole-related two-component system QseC/B. QseC autophosphorylation is involved in this process. The operon LekdpXFABC widely exists in Xanthomonadaceae. Moreover, indole promotes antimicrobial product production at the early exponential phase. Further analyses show that indole enhances potassium ion adsorption on the cell surface by upregulating the production of O-antigenic polysaccharides. Finally, we confirm that LeKdpXFABC mediation by indole is subject to the intraspecific signaling molecules DSFs, of which the biosynthesis genes always exist together with LekdpXFABC. Therefore, as a new idea, the signal collaborative strategy of indole and DSFs might ensure the persistent fitness advantage of Xanthomonadaceae in variable environments.
Validation of a new instrument to guide and support insanity evaluations: the defendant’s insanity assessment support scale (DIASS)
Authors: Parmigiani Giovanna , Mandarelli Gabriele , Roma Paolo , Ferracuti Stefano 
Published: March 2022

AbstractThe insanity defense represents one of the most controversial and debated evaluations performed by forensic psychiatrists and psychologists. Despite the variation among different jurisdictions, in Western countries, the legal standards for insanity often rely on the presence of cognitive and/or volitional impairment of the defendant at the time of the crime. We developed the defendant’s insanity assessment support scale (DIASS) based on a wide view of competent decision-making, which reflects core issues relevant to legal insanity in many jurisdictions. To assess the characteristics of the DIASS we asked 40 forensic experts (16% women; years of experience = 20.6 ± 12.9) to evaluate 10 real-life derived forensic cases with the DIASS; cases included defendants’ psychiatric symptom severity, evaluated through the 24-itemBrief Psychiatric Rating Scale (BPRS). Exploratory factor analysis by principal axis factoring was conducted, which disclosed a two-factor solution explaining 57.6% of the total variance. The DIASS showed a good internal consistency (Cronbach’s alpha = 0.86), and substantial inter-rater reliability (Cohen’s kappa = 0.72). The capacities analyzed through the DIASS were mainly affected by mania/excitement and psychotic dimensions in nonresponsible and with substantially diminished responsibility defendants, while by hostility and negative symptoms in responsible defendants. The DIASS proved to be an effective psychometric tool to guide and structure insanity defense evaluations, in order to improve their consistency and reliability.
Progranulin improves neural development via the PI3K/Akt/GSK-3β pathway in the cerebellum of a VPA-induced rat model of ASD
Authors: Wang Lili , Chen Jianhui , Hu Yuling , Liao Ailing , Zheng Wenxia , Wang Xiaoqing , Lan Junying , Shen Jingjing , Wang Shali , Yang Feng , Wang Yan , Li Yingbo , Chen Di 
Published: March 2022

AbstractAutism spectrum disorder (ASD) is a neurodevelopmental disease featuring social interaction deficits and repetitive/stereotyped behaviours; the prevalence of this disorder has continuously increased. Progranulin (PGRN) is a neurotrophic factor that promotes neuronal survival and differentiation. However, there have not been sufficient studies investigating its effect in animal models of autism. This study investigated the effects of PGRN on autistic phenotypes in rats treated with valproic acid (VPA) and assessed the underlying molecular mechanisms. PGRN was significantly downregulated in the cerebellum at postnatal day 14 (PND14) and PND35 in VPA-exposed rats, which simultaneously showed defective social preference, increased repetitive behaviours, and uncoordinated movements. When human recombinant PGRN (r-PGRN) was injected into the cerebellum of newborn ASD model rats (PND10 and PND17), some of the behavioural defects were alleviated. r-PGRN supplementation also reduced cerebellar neuronal apoptosis and rescued synapse formation in ASD rats. Mechanistically, we confirmed that PGRN protects neurodevelopment via the PI3K/Akt/GSK-3β pathway in the cerebellum of a rat ASD model. Moreover, we found that prosaposin (PSAP) promoted the internalisation and neurotrophic activity of PGRN. These results experimentally demonstrate the therapeutic effects of PGRN on a rat model of ASD for the first time and provide a novel therapeutic strategy for autism.
m6A demethylase ALKBH5 promotes tumor cell proliferation by destabilizing IGF2BPs target genes and worsens the prognosis of patients with non-small-cell lung cancer
Authors: Tsuchiya Kazuo , Yoshimura Katsuhiro , Iwashita Yuji , Inoue Yusuke , Ohta Tsutomu , Watanabe Hirofumi , Yamada Hidetaka , Kawase Akikazu , Tanahashi Masayuki , Ogawa Hiroshi , Funai Kazuhito , Shinmura Kazuya , Suda Takafumi , Sugimura Haruhiko 
Published: March 2022

AbstractThe modification of N6-methyladenosine (m6A) in RNA and its eraser ALKBH5, an m6A demethylase, play an important role across various steps of human carcinogenesis. However, the involvement of ALKBH5 in non-small-cell lung cancer (NSCLC) development remains to be completely elucidated. The current study revealed that the expression of ALKBH5 was increased in NSCLC and increased expression of ALKBH5 worsened the prognosis of patients with NSCLC. In vitro study revealed that ALKBH5 knockdown suppressed cell proliferation ability of PC9 and A549 cells and promoted G1 arrest and increased the number of apoptotic cells. Furthermore, ALKBH5 overexpression increased the cell proliferation ability of the immortalized cell lines. Microarray analysis and western blotting revealed that the expression of CDKN1A (p21) or TIMP3 was increased by ALKBH5 knockdown. These alterations were offset by a double knockdown of both ALKBH5 and one of the IGF2BPs. The decline of mRNAs was, at least partly, owing to the destabilization of these mRNAs by one of the IGF2BPs. In conclusions, the ALKBH5–IGF2BPs axis promotes cell proliferation and tumorigenicity, which in turn causes the unfavorable prognosis of NSCLC.
MiR-323a regulates ErbB3/EGFR and blocks gefitinib resistance acquisition in colorectal cancer
Authors: Zhang Yuanzhou , Liang Shunshun , Xiao Bowen , Hu Jingying , Pang Yechun , Liu Yuling , Yang Juan , Ao Junpin , Wei Lin , Luo Xiaoying 
Published: March 2022

AbstractThe rapid onset of resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) limits its clinical utility in colorectal cancer (CRC) patients, and pan-erb-b2 receptor tyrosine kinase (ErbB) treatment strategy may be the alternative solution. The aim of this study was to develop a possible microRNA multi-ErbB treatment strategy to overcome EGFR-TKI resistance. We detect the receptor tyrosine kinase activity in gefitinib-resistant colorectal cancer cells, ErbB3/EGFR is significantly activated and provides a potential multi-ErbB treatment target. MiR-323a-3p, a tumor suppressor, could target both ErbB3 and EGFR directly. Apoptosis is the miR-323a-3p inducing main biological process by functional enrichment analysis, and The EGFR and ErbB signaling are the miR-323a-3p inducing main pathway by KEGG analysis. MiR-323a-3p promotes CRC cells apoptosis by targeting ErbB3-phosphoinositide 3‐kinases (PI3K)/PKB protein kinase (Akt)/glycogen synthase kinase 3 beta (GSK3β)/EGFR-extracellular regulated MAP kinase (Erk1/2) signaling directly. And miR-323a-3p, as a multi-ErbBs inhibitor, increase gefitinib sensitivity of the primary cell culture from combination miR-323a-3p and gefitinib treated subcutaneous tumors. MiR-323a-3p reverses ErbB3/EGFR signaling activation in gefitinib-resistant CRC cell lines and blocks acquired gefitinib resistance.
Ferroptosis, a new target for treatment of renal injury and fibrosis in a 5/6 nephrectomy-induced CKD rat model
Authors: Wang Jingyu , Wang Yaqing , Liu Yi , Cai Xintian , Huang Xin , Fu Wenjing , Wang Lei , Qiu Lihua , Li Junying , Sun Li 
Published: March 2022

AbstractFerroptosis is a non-traditional form of regulated cell death, characterized by iron overload and lipid peroxidation. Exploration of ferroptosis in chronic kidney disease (CKD) has been extremely limited to date. In this study, we established a rat model of CKD by 5/6 nephrectomy, treated CKD rats with the ferroptosis inducer, cisplatin (CDDP), and the ferroptosis inhibitor, deferoxamine mesylate (DFO), and observed the resulting pathologic changes (injury markers and fibrosis) and ferroptotic biochemical indices. Kidney iron deposition, lipid peroxidation, mitochondrial defects, ferroptosis marker induction, and TUNEL staining positivity were detected in CKD group rats. Further, treatment with CDDP or DFO influenced renal injury and fibrosis by affecting ferroptosis, rather than apoptosis, and ferroptosis occurs in the remnant kidney due to disordered iron metabolism. In conclusion, our study shows for the first time that 5/6 nephrectomy induces ferroptosis in the remnant kidney and clarifies the underlying pathogenesis. Moreover, we demonstrate that ferroptosis is involved in CKD progression and represents a therapeutic target in chronic kidney injury and renal fibrosis.
Gene-lifestyle interactions in the genomics of human complex traits
Authors: Laville Vincent , Majarian Timothy , Sung Yun J. , Schwander Karen , Feitosa Mary F. , Chasman Daniel I. , Bentley Amy R. , Rotimi Charles N. , Cupples L. Adrienne , de Vries Paul S. , Brown Michael R. , Morrison Alanna C. , Kraja Aldi T. , Province Mike , Gu C. Charles , Gauderman W. James ,   the CHARGE Gene-Lifestyle Interactions Working Group, Laville Vincent , Majarian Timothy , Sung Yun J. , Schwander Karen , Feitosa Mary F. , Chasman Daniel I. , Bentley Amy R. , Rotimi Charles N. , Cupples L. Adrienne , de Vries Paul S. , Brown Michael R. , Morrison Alanna C. , Kraja Aldi T. , Province Mike , Gu C. Charles , Gauderman W. James , Rao D. C. , Manning Alisa K. , Aschard Hugues , Rao D. C. , Manning Alisa K. , Aschard Hugues 
Published: March 2022

AbstractThe role and biological significance of gene-environment interactions in human traits and diseases remain poorly understood. To address these questions, the CHARGE Gene-Lifestyle Interactions Working Group conducted series of genome-wide interaction studies (GWIS) involving up to 610,475 individuals across four ancestries for three lipids and four blood pressure traits, while accounting for interaction effects with drinking and smoking exposures. Here we used GWIS summary statistics from these studies to decipher potential differences in genetic associations and G×E interactions across phenotype-exposure-ancestry combinations, and to derive insights on the potential mechanistic underlying G×E through in-silico functional analyses. Our analyses show first that interaction effects likely contribute to the commonly reported ancestry-specific genetic effect in complex traits, and second, that some phenotype-exposures pairs are more likely to benefit from a greater detection power when accounting for interactions. It also highlighted modest correlation between marginal and interaction effects, providing material for future methodological development and biological discussions. We also estimated contributions to phenotypic variance, including in particular the genetic heritability conditional on the exposure, and heritability partitioned across a range of functional annotations and cell types. In these analyses, we found multiple instances of potential heterogeneity of functional partitions between exposed and unexposed individuals, providing new evidence for likely exposure-specific genetic pathways. Finally, along this work, we identified potential biases in methods used to jointly meta-analyze genetic and interaction effects. We performed simulations to characterize these limitations and to provide the community with guidelines for future G×E studies.
Machine learning–based observation-constrained projections reveal elevated global socioeconomic risks from wildfire
Authors: Yu Yan , Mao Jiafu , Wullschleger Stan D. , Chen Anping , Shi Xiaoying , Wang Yaoping , Hoffman Forrest M. , Zhang Yulong , Pierce Eric 
Published: March 2022

AbstractReliable projections of wildfire and associated socioeconomic risks are crucial for the development of efficient and effective adaptation and mitigation strategies. The lack of or limited observational constraints for modeling outputs impairs the credibility of wildfire projections. Here, we present a machine learning framework to constrain the future fire carbon emissions simulated by 13 Earth system models from the Coupled Model Intercomparison Project phase 6 (CMIP6), using historical, observed joint states of fire-relevant variables. During the twenty-first century, the observation-constrained ensemble indicates a weaker increase in global fire carbon emissions but higher increase in global wildfire exposure in population, gross domestic production, and agricultural area, compared with the default ensemble. Such elevated socioeconomic risks are primarily caused by the compound regional enhancement of future wildfire activity and socioeconomic development in the western and central African countries, necessitating an emergent strategic preparedness to wildfires in these countries.
Spelling interface using intracortical signals in a completely locked-in patient enabled via auditory neurofeedback training
Authors: Chaudhary Ujwal , Vlachos Ioannis , Zimmermann Jonas B. , Espinosa Arnau , Tonin Alessandro , Jaramillo-Gonzalez Andres , Khalili-Ardali Majid , Topka Helge , Lehmberg Jens , Friehs Gerhard M. , Woodtli Alain , Donoghue John P. , Birbaumer Niels 
Published: March 2022

AbstractPatients with amyotrophic lateral sclerosis (ALS) can lose all muscle-based routes of communication as motor neuron degeneration progresses, and ultimately, they may be left without any means of communication. While others have evaluated communication in people with remaining muscle control, to the best of our knowledge, it is not known whether neural-based communication remains possible in a completely locked-in state. Here, we implanted two 64 microelectrode arrays in the supplementary and primary motor cortex of a patient in a completely locked-in state with ALS. The patient modulated neural firing rates based on auditory feedback and he used this strategy to select letters one at a time to form words and phrases to communicate his needs and experiences. This case study provides evidence that brain-based volitional communication is possible even in a completely locked-in state.
Decoding internally generated transitions of conscious contents in the prefrontal cortex without subjective reports
Authors: Kapoor Vishal , Dwarakanath Abhilash , Safavi Shervin , Werner Joachim , Besserve Michel , Panagiotaropoulos Theofanis I. , Logothetis Nikos K. 
Published: March 2022

AbstractA major debate about the neural correlates of conscious perception concerns its cortical organization, namely, whether it includes the prefrontal cortex (PFC), which mediates executive functions, or it is constrained within posterior cortices. It has been suggested that PFC activity during paradigms investigating conscious perception is conflated with post-perceptual processes associated with reporting the contents of consciousness or feedforward signals originating from exogenous stimulus manipulations and relayed via posterior cortical areas. We addressed this debate by simultaneously probing neuronal populations in the rhesus macaque (Macaca mulatta) PFC during a no-report paradigm, capable of instigating internally generated transitions in conscious perception, without changes in visual stimulation. We find that feature-selective prefrontal neurons are modulated concomitantly with subjective perception and perceptual suppression of their preferred stimulus during both externally induced and internally generated changes in conscious perception. Importantly, this enables reliable single-trial, population decoding of conscious contents. Control experiments confirm significant decoding of stimulus contents, even when oculomotor responses, used for inferring perception, are suppressed. These findings suggest that internally generated changes in the contents of conscious visual perception are reliably reflected within the activity of prefrontal populations in the absence of volitional reports or changes in sensory input.
S6K1-mediated phosphorylation of PDK1 impairs AKT kinase activity and oncogenic functions
Authors: Jiang Qiwei , Zhang Xiaomei , Dai Xiaoming , Han Shiyao , Wu Xueji , Wang Lei , Wei Wenyi , Zhang Ning , Xie Wei , Guo Jianping 
Published: March 2022

AbstractFunctioning as a master kinase, 3-phosphoinositide-dependent protein kinase 1 (PDK1) plays a fundamental role in phosphorylating and activating protein kinases A, B and C (AGC) family kinases, including AKT. However, upstream regulation of PDK1 remains largely elusive. Here we report that ribosomal protein S6 kinase beta 1 (S6K1), a member of AGC kinases and downstream target of mechanistic target of rapamycin complex 1 (mTORC1), directly phosphorylates PDK1 at its pleckstrin homology (PH) domain, and impairs PDK1 interaction with and activation of AKT. Mechanistically, S6K1-mediated phosphorylation of PDK1 augments its interaction with 14-3-3 adaptor protein and homo-dimerization, subsequently dissociating PDK1 from phosphatidylinositol 3,4,5 triphosphate (PIP3) and retarding its interaction with AKT. Pathologically, tumor patient-associated PDK1 mutations, either attenuating S6K1-mediated PDK1 phosphorylation or impairing PDK1 interaction with 14-3-3, result in elevated AKT kinase activity and oncogenic functions. Taken together, our findings not only unravel a delicate feedback regulation of AKT signaling via S6K1-mediated PDK1 phosphorylation, but also highlight the potential strategy to combat mutant PDK1-driven cancers.
Multiplexed action-outcome representation by striatal striosome-matrix compartments detected with a mouse cost-benefit foraging task
Authors: Bloem Bernard , Huda Rafiq , Amemori Ken-ichi , Abate Alex S. , Krishna Gayathri , Wilson Anna L. , Carter Cody W. , Sur Mriganka , Graybiel Ann M. 
Published: March 2022

AbstractLearning about positive and negative outcomes of actions is crucial for survival and underpinned by conserved circuits including the striatum. How associations between actions and outcomes are formed is not fully understood, particularly when the outcomes have mixed positive and negative features. We developed a novel foraging (‘bandit’) task requiring mice to maximize rewards while minimizing punishments. By 2-photon Ca++imaging, we monitored activity of visually identified anterodorsal striatal striosomal and matrix neurons. We found that action-outcome associations for reward and punishment were encoded in parallel in partially overlapping populations. Single neurons could, for one action, encode outcomes of opposing valence. Striosome compartments consistently exhibited stronger representations of reinforcement outcomes than matrix, especially for high reward or punishment prediction errors. These findings demonstrate multiplexing of action-outcome contingencies by single identified striatal neurons and suggest that striosomal neurons are particularly important in action-outcome learning.
Single-cell transcriptomics identifies potential cells of origin of MYC rhabdoid tumors
Authors: Graf Monika , Interlandi Marta , Moreno Natalia , Holdhof Dörthe , Göbel Carolin , Melcher Viktoria , Mertins Julius , Albert Thomas K. , Kastrati Dennis , Alfert Amelie , Holsten Till , de Faria Flavia , Meisterernst Michael , Rossig Claudia , Warmuth-Metz Monika , Nowak Johannes , Meyer zu Hörste Gerd , Mayère Chloe , Nef Serge , Johann Pascal , Frühwald Michael C. , Dugas Martin , Schüller Ulrich , Kerl Kornelius 
Published: March 2022

AbstractRhabdoid tumors (RT) are rare and highly aggressive pediatric neoplasms. Their epigenetically-driven intertumoral heterogeneity is well described; however, the cellular origin of RT remains an enigma. Here, we establish and characterize different genetically engineered mouse models driven under the control of distinct promoters and being active in early progenitor cell types with diverse embryonic onsets. From all models only Sox2-positive progenitor cells give rise to murine RT. Using single-cell analyses, we identify distinct cells of origin for the SHH and MYC subgroups of RT, rooting in early stages of embryogenesis. Intra- and extracranial MYC tumors harbor common genetic programs and potentially originate from fetal primordial germ cells (PGCs). Using PGC specific Smarcb1 knockout mouse models we validate that MYC RT originate from these progenitor cells. We uncover an epigenetic imbalance in MYC tumors compared to PGCs being sustained by epigenetically-driven subpopulations. Importantly, treatments with the DNA demethylating agent decitabine successfully impair tumor growth in vitro and in vivo. In summary, our work sheds light on the origin of RT and supports the clinical relevance of DNA methyltransferase inhibitors against this disease.
A deep-learning approach for online cell identification and trace extraction in functional two-photon calcium imaging
Authors: Sità Luca , Brondi Marco , Lagomarsino de Leon Roig Pedro , Curreli Sebastiano , Panniello Mariangela , Vecchia Dania , Fellin Tommaso 
Published: March 2022

AbstractIn vivo two-photon calcium imaging is a powerful approach in neuroscience. However, processing two-photon calcium imaging data is computationally intensive and time-consuming, making online frame-by-frame analysis challenging. This is especially true for large field-of-view (FOV) imaging. Here, we present CITE-On (Cell Identification and Trace Extraction Online), a convolutional neural network-based algorithm for fast automatic cell identification, segmentation, identity tracking, and trace extraction in two-photon calcium imaging data. CITE-On processes thousands of cells online, including during mesoscopic two-photon imaging, and extracts functional measurements from most neurons in the FOV. Applied to publicly available datasets, the offline version of CITE-On achieves performance similar to that of state-of-the-art methods for offline analysis. Moreover, CITE-On generalizes across calcium indicators, brain regions, and acquisition parameters in anesthetized and awake head-fixed mice. CITE-On represents a powerful tool to speed up image analysis and facilitate closed-loop approaches, for example in combined all-optical imaging and manipulation experiments.