bluuebunny/crossref_metadata_2025_split huggingface dataset:
USP39 promotes hepatocellular carcinogenesis through regulating alternative splicing in cooperation with SRSF6/HNRNPC
Authors: Zheng Jingyi , Wu Shasha , Tang Mao , Xi Shaoyan , Wang Yanchen , Ren Jun , Luo Hao , Hu Pengchao , Sun Liangzhan , Du Yuyang , Yang Hui , Wang Fenfen , Gao Han , Dai Ziwei , Ou Xijun , Li Yan 
Published: October 2023

AbstractAbnormal alternative splicing (AS) caused by alterations in spliceosomal factors is implicated in cancers. Standard models posit that splice site selection is mainly determined by early spliceosomal U1 and U2 snRNPs. Whether and how other mid/late-acting spliceosome components such as USP39 modulate tumorigenic splice site choice remains largely elusive. We observed that hepatocyte-specific overexpression of USP39 promoted hepatocarcinogenesis and potently regulated splice site selection in transgenic mice. In human liver cancer cells, USP39 promoted tumor proliferation in a spliceosome-dependent manner. USP39 depletion deregulated hundreds of AS events, including the oncogenic splice-switching of KANK2. Mechanistically, we developed a novel RBP-motif enrichment analysis and found that USP39 modulated exon inclusion/exclusion by interacting with SRSF6/HNRNPC in both humans and mice. Our data represented a paradigm for the control of splice site selection by mid/late-acting spliceosome proteins and their interacting RBPs. USP39 and possibly other mid/late-acting spliceosome proteins may represent potential prognostic biomarkers and targets for cancer therapy.
The immune response to SARS-CoV-2 in people with HIV
Authors: Höft Maxine A. , Burgers Wendy A. , Riou Catherine 
Published: October 2023

AbstractThis review examines the intersection of the HIV and SARS-CoV-2 pandemics. People with HIV (PWH) are a heterogeneous group that differ in their degree of immune suppression, immune reconstitution, and viral control. While COVID-19 in those with well-controlled HIV infection poses no greater risk than that for HIV-uninfected individuals, people with advanced HIV disease are more vulnerable to poor COVID-19 outcomes. COVID-19 vaccines are effective and well tolerated in the majority of PWH, though reduced vaccine efficacy, breakthrough infections and faster waning of vaccine effectiveness have been demonstrated in PWH. This is likely a result of suboptimal humoral and cellular immune responses after vaccination. People with advanced HIV may also experience prolonged infection that may give rise to new epidemiologically significant variants, but initiation or resumption of antiretroviral therapy (ART) can effectively clear persistent infection. COVID-19 vaccine guidelines reflect these increased risks and recommend prioritization for vaccination and additional booster doses for PWH who are moderately to severely immunocompromised. We recommend continued research and monitoring of PWH with SARS-CoV-2 infection, especially in areas with a high HIV burden.
Neuropathologist-level integrated classification of adult-type diffuse gliomas using deep learning from whole-slide pathological images
Authors: Wang Weiwei , Zhao Yuanshen , Teng Lianghong , Yan Jing , Guo Yang , Qiu Yuning , Ji Yuchen , Yu Bin , Pei Dongling , Duan Wenchao , Wang Minkai , Wang Li , Duan Jingxian , Sun Qiuchang , Wang Shengnan , Duan Huanli , Sun Chen , Guo Yu , Luo Lin , Guo Zhixuan , Guan Fangzhan , Wang Zilong , Xing Aoqi , Liu Zhongyi , Zhang Hongyan , Cui Li , Zhang Lan , Jiang Guozhong , Yan Dongming , Liu Xianzhi , Zheng Hairong , Liang Dong , Li Wencai , Li Zhi-Cheng , Zhang Zhenyu 
Published: October 2023

AbstractCurrent diagnosis of glioma types requires combining both histological features and molecular characteristics, which is an expensive and time-consuming procedure. Determining the tumor types directly from whole-slide images (WSIs) is of great value for glioma diagnosis. This study presents an integrated diagnosis model for automatic classification of diffuse gliomas from annotation-free standard WSIs. Our model is developed on a training cohort (n = 1362) and a validation cohort (n = 340), and tested on an internal testing cohort (n = 289) and two external cohorts (n = 305 and 328, respectively). The model can learn imaging features containing both pathological morphology and underlying biological clues to achieve the integrated diagnosis. Our model achieves high performance with area under receiver operator curve all above 0.90 in classifying major tumor types, in identifying tumor grades within type, and especially in distinguishing tumor genotypes with shared histological features. This integrated diagnosis model has the potential to be used in clinical scenarios for automated and unbiased classification of adult-type diffuse gliomas.
Single-cell multi-omics analysis identifies two distinct phenotypes of newly-onset microscopic polyangiitis
Authors: Nishide Masayuki , Nishimura Kei , Matsushita Hiroaki , Edahiro Ryuya , Inukai Sachi , Shimagami Hiroshi , Kawada Shoji , Kato Yasuhiro , Kawasaki Takahiro , Tsujimoto Kohei , Kamon Hokuto , Omiya Ryusuke , Okada Yukinori , Hattori Kunihiro , Narazaki Masashi , Kumanogoh Atsushi 
Published: October 2023

AbstractThe immunological basis of the clinical heterogeneity in autoimmune vasculitis remains poorly understood. In this study, we conduct single-cell transcriptome analyses on peripheral blood mononuclear cells (PBMCs) from newly-onset patients with microscopic polyangiitis (MPA). Increased proportions of activated CD14+ monocytes and CD14+ monocytes expressing interferon signature genes (ISGs) are distinctive features of MPA. Patient-specific analysis further classifies MPA into two groups. The MPA-MONO group is characterized by a high proportion of activated CD14+ monocytes, which persist before and after immunosuppressive therapy. These patients are clinically defined by increased monocyte ratio in the total PBMC count and have a high relapse rate. The MPA-IFN group is characterized by a high proportion of ISG+ CD14+ monocytes. These patients are clinically defined by high serum interferon-alpha concentrations and show good response to immunosuppressive therapy. Our findings identify the immunological phenotypes of MPA and provide clinical insights for personalized treatment and accurate prognostic prediction.
Electrically programmable magnetic coupling in an Ising network exploiting solid-state ionic gating
Authors: Yun Chao , Liang Zhongyu , Hrabec Aleš , Liu Zhentao , Huang Mantao , Wang Leran , Xiao Yifei , Fang Yikun , Li Wei , Yang Wenyun , Hou Yanglong , Yang Jinbo , Heyderman Laura J. , Gambardella Pietro , Luo Zhaochu 
Published: October 2023

AbstractTwo-dimensional arrays of magnetically coupled nanomagnets provide a mesoscopic platform for exploring collective phenomena as well as realizing a broad range of spintronic devices. In particular, the magnetic coupling plays a critical role in determining the nature of the cooperative behavior and providing new functionalities in nanomagnet-based devices. Here, we create coupled Ising-like nanomagnets in which the coupling between adjacent nanomagnetic regions can be reversibly converted between parallel and antiparallel through solid-state ionic gating. This is achieved with the voltage-control of the magnetic anisotropy in a nanosized region where the symmetric exchange interaction favors parallel alignment and the antisymmetric exchange interaction, namely the Dzyaloshinskii-Moriya interaction, favors antiparallel alignment of the nanomagnet magnetizations. Applying this concept to a two-dimensional lattice, we demonstrate a voltage-controlled phase transition in artificial spin ices. Furthermore, we achieve an addressable control of the individual couplings and realize an electrically programmable Ising network, which opens up new avenues to design nanomagnet-based logic devices and neuromorphic computers.
A clock-dependent brake for rhythmic arousal in the dorsomedial hypothalamus
Authors: Liu Qiang , Bell Benjamin J. , Kim Dong Won , Lee Sang Soo , Keles Mehmet F. , Liu Qili , Blum Ian D. , Wang Annette A. , Blank Elijah J. , Xiong Jiali , Bedont Joseph L. , Chang Anna J. , Issa Habon , Cohen Jeremiah Y. , Blackshaw Seth , Wu Mark N. 
Published: October 2023

AbstractCircadian clocks generate rhythms of arousal, but the underlying molecular and cellular mechanisms remain unclear. In Drosophila, the clock output molecule WIDE AWAKE (WAKE) labels rhythmic neural networks and cyclically regulates sleep and arousal. Here, we show, in a male mouse model, that mWAKE/ANKFN1 labels a subpopulation of dorsomedial hypothalamus (DMH) neurons involved in rhythmic arousal and acts in the DMH to reduce arousal at night. In vivo Ca2+ imaging reveals elevated DMHmWAKE activity during wakefulness and rapid eye movement (REM) sleep, while patch-clamp recordings show that DMHmWAKE neurons fire more frequently at night. Chemogenetic manipulations demonstrate that DMHmWAKE neurons are necessary and sufficient for arousal. Single-cell profiling coupled with optogenetic activation experiments suggest that GABAergic DMHmWAKE neurons promote arousal. Surprisingly, our data suggest that mWAKE acts as a clock-dependent brake on arousal during the night, when mice are normally active. mWAKE levels peak at night under clock control, and loss of mWAKE leads to hyperarousal and greater DMHmWAKE neuronal excitability specifically at night. These results suggest that the clock does not solely promote arousal during an animal’s active period, but instead uses opposing processes to produce appropriate levels of arousal in a time-dependent manner.
C9orf72-catalyzed GTP loading of Rab39A enables HOPS-mediated membrane tethering and fusion in mammalian autophagy
Authors: Zhang Shen , Tong Mindan , Zheng Denghao , Huang Huiying , Li Linsen , Ungermann Christian , Pan Yi , Luo Hanyan , Lei Ming , Tang Zaiming , Fu Wan , Chen She , Liu Xiaoxia , Zhong Qing 
Published: October 2023

AbstractThe multi-subunit homotypic fusion and vacuole protein sorting (HOPS) membrane-tethering complex is required for autophagosome-lysosome fusion in mammals, yet reconstituting the mammalian HOPS complex remains a challenge. Here we propose a “hook-up” model for mammalian HOPS complex assembly, which requires two HOPS sub-complexes docking on membranes via membrane-associated Rabs. We identify Rab39A as a key small GTPase that recruits HOPS onto autophagic vesicles. Proper pairing with Rab2 and Rab39A enables HOPS complex assembly between proteoliposomes for its tethering function, facilitating efficient membrane fusion. GTP loading of Rab39A is important for the recruitment of HOPS to autophagic membranes. Activation of Rab39A is catalyzed by C9orf72, a guanine exchange factor associated with amyotrophic lateral sclerosis and familial frontotemporal dementia. Constitutive activation of Rab39A can rescue autophagy defects caused by C9orf72 depletion. These results therefore reveal a crucial role for the C9orf72-Rab39A-HOPS axis in autophagosome-lysosome fusion.
Catalytic 4-exo-dig carbocyclization for the construction of furan-fused cyclobutanones and synthetic applications
Authors: Hong Kemiao , Zhou Yi , Yuan Haoxuan , Zhang Zhijing , Huang Jingjing , Dong Shanliang , Hu Wenhao , Yu Zhi-Xiang , Xu Xinfang 
Published: October 2023

AbstractCyclobutanone is a strained motif with broad applications, while direct assembly of the aromatic ring fused cyclobutanones beyond benzocyclobutenone (BCB) skeletons remains challenging. Herein, we report a Rh-catalyzed formal [3+2] annulation of diazo group tethered alkynes involving a 4-exo-dig carbocyclization process, providing a straightforward access to furan-fused cyclobutanones. DFT calculations disclose that, by comparison to the competitive 5-endo-dig process, 4-exo-dig carbocyclization is mainly due to lower angle strain of the key sp-hybridized vinyl cationic transition state in the cyclization step. Using less reactive catalysts Rh2(carboxylate)4 is critical for high selectivity, which is explained as catalyst-substrate hydrogen bonding interaction. This method is proved successful to direct access previously inaccessible and unknown furan-fused cyclobutanone scaffolds, which can participate in a variety of post-functionalization reactions as versatile synthetic blocks. In addition, preliminary antitumor activity study of these products indicates that some molecules exhibite significant anticancer potency against different human cancer cell lines.
Structure of full-length cobalamin-dependent methionine synthase and cofactor loading captured in crystallo
Authors: Mendoza Johnny , Purchal Meredith , Yamada Kazuhiro , Koutmos Markos 
Published: October 2023

AbstractCobalamin-dependent methionine synthase (MS) is a key enzyme in methionine and folate one-carbon metabolism. MS is a large multi-domain protein capable of binding and activating three substrates: homocysteine, folate, and S-adenosylmethionine for methylation. Achieving three chemically distinct methylations necessitates significant domain rearrangements to facilitate substrate access to the cobalamin cofactor at the right time. The distinct conformations required for each reaction have eluded structural characterization as its inherently dynamic nature renders structural studies difficult. Here, we use a thermophilic MS homolog (tMS) as a functional MS model. Its exceptional stability enabled characterization of MS in the absence of cobalamin, marking the only studies of a cobalamin-binding protein in its apoenzyme state. More importantly, we report the high-resolution full-length MS structure, ending a multi-decade quest. We also capture cobalamin loading in crystallo, providing structural insights into holoenzyme formation. Our work paves the way for unraveling how MS orchestrates large-scale domain rearrangements crucial for achieving challenging chemistries.
Tripartite motif containing 26 prevents steatohepatitis progression by suppressing C/EBPδ signalling activation
Authors: Xu Minxuan , Tan Jun , Liu Xin , Han Li , Ge Chenxu , Zhang Yujie , Luo Fufang , Wang Zhongqin , Xue Xiaoqin , Xiong Liangyin , Wang Xin , Zhang Qinqin , Wang Xiaoxin , Tian Qin , Zhang Shuguang , Meng Qingkun , Dai Xianling , Kuang Qin , Li Qiang , Lou Deshuai , Hu Linfeng , Liu Xi , Kuang Gang , Luo Jing , Chang Chunxiao , Wang Bochu , Chai Jie , Shi Shengbin , Han Lianyi 
Published: October 2023

AbstractCurrently potential preclinical drugs for the treatment of nonalcoholic steatohepatitis (NASH) and NASH-related pathopoiesis have failed to achieve expected therapeutic efficacy due to the complexity of the pathogenic mechanisms. Here we show Tripartite motif containing 26 (TRIM26) as a critical endogenous suppressor of CCAAT/enhancer binding protein delta (C/EBPδ), and we also confirm that TRIM26 is an C/EBPδ-interacting partner protein that catalyses the ubiquitination degradation of C/EBPδ in hepatocytes. Hepatocyte-specific loss of Trim26 disrupts liver metabolic homeostasis, followed by glucose metabolic disorder, lipid accumulation, increased hepatic inflammation, and fibrosis, and dramatically facilitates NASH-related phenotype progression. Inversely, transgenic Trim26 overexpression attenuates the NASH-associated phenotype in a rodent or rabbit model. We provide mechanistic evidence that, in response to metabolic insults, TRIM26 directly interacts with C/EBPδ and promotes its ubiquitin proteasome degradation. Taken together, our present findings identify TRIM26 as a key suppressor over the course of NASH development.
Multiple reaction pathway on alkaline earth imide supported catalysts for efficient ammonia synthesis
Authors: Li Zichuang , Lu Yangfan , Li Jiang , Xu Miao , Qi Yanpeng , Park Sang-Won , Kitano Masaaki , Hosono Hideo , Chen Jie-Sheng , Ye Tian-Nan 
Published: October 2023

AbstractThe tunability of reaction pathways is required for exploring efficient and low cost catalysts for ammonia synthesis. There is an obstacle by the limitations arising from scaling relation for this purpose. Here, we demonstrate that the alkali earth imides (AeNH) combined with transition metal (TM = Fe, Co and Ni) catalysts can overcome this difficulty by utilizing functionalities arising from concerted role of active defects on the support surface and loaded transition metals. These catalysts enable ammonia production through multiple reaction pathways. The reaction rate of Co/SrNH is as high as 1686.7 mmol·gCo−1·h−1 and the TOFs reaches above 500 h−1 at 400 °C and 0.9 MPa, outperforming other reported Co-based catalysts as well as the benchmark Cs-Ru/MgO catalyst and industrial wüstite-based Fe catalyst under the same reaction conditions. Experimental and theoretical results show that the synergistic effect of nitrogen affinity of 3d TMs and in-situ formed NH2− vacancy of alkali earth imides regulate the reaction pathways of the ammonia production, resulting in distinct catalytic performance different from 3d TMs. It was thus demonstrated that the appropriate combination of metal and support is essential for controlling the reaction pathway and realizing highly active and low cost catalysts for ammonia synthesis.
Asymmetric gating of a human hetero-pentameric glycine receptor
Authors: Liu Xiaofen , Wang Weiwei 
Published: October 2023

AbstractHetero-pentameric Cys-loop receptors constitute a major type of neurotransmitter receptors that enable signal transmission and processing in the nervous system. Despite intense investigations into their working mechanism and pharmaceutical potentials, how neurotransmitters activate these receptors remains unclear due to the lack of high-resolution structural information in the activated open state. Here we report near-atomic resolution structures resolved in digitonin consistent with all principle functional states of the human α1β GlyR, which is a major Cys-loop receptor that mediates inhibitory neurotransmission in the central nervous system of adults. Glycine binding induces cooperative and symmetric structural rearrangements in the neurotransmitter-binding extracellular domain but asymmetrical pore dilation in the transmembrane domain. Symmetric response in the extracellular domain is consistent with electrophysiological data showing cooperative glycine activation and contribution from both α1 and β subunits. A set of functionally essential but differentially charged amino acid residues in the transmembrane domain of the α1 and β subunits explains asymmetric activation. These findings provide a foundation for understanding how the gating of the Cys-loop receptor family members diverges to accommodate specific physiological environments.
Enhanced multi-year predictability after El Niño and La Niña events
Authors: Liu Yiling , Donat Markus. G. , England Matthew. H. , Alexander Lisa. V. , Hirsch Annette L. , Delgado-Torres Carlos 
Published: October 2023

AbstractSeveral aspects of regional climate including near-surface temperature and precipitation are predictable on interannual to decadal time scales. Despite indications that some climate states may provide higher predictability than others, previous studies analysing decadal predictions typically sample a variety of initial conditions. Here we assess multi-year predictability conditional on the phase of the El Niño–Southern Oscillation (ENSO) at the time of prediction initialisation. We find that predictions starting with El Niño or La Niña conditions exhibit higher skill in predicting near-surface air temperature and precipitation multiple years in advance, compared to predictions initialised from neutral ENSO conditions. This holds true in idealised prediction experiments with the Community Climate System Model Version 4 and to a lesser extent also real-world predictions using the Community Earth System Model and a multi-model ensemble of hindcasts contributed to the Coupled Model Intercomparison Project Phase 6 Decadal Climate Prediction Project. This enhanced predictability following ENSO events is related to phase transitions as part of the ENSO cycle, and related global teleconnections. Our results indicate that certain initial states provide increased predictability, revealing windows of opportunity for more skillful multi-year predictions.
Revealing invisible cell phenotypes with conditional generative modeling
Authors: Lamiable Alexis , Champetier Tiphaine , Leonardi Francesco , Cohen Ethan , Sommer Peter , Hardy David , Argy Nicolas , Massougbodji Achille , Del Nery Elaine , Cottrell Gilles , Kwon Yong-Jun , Genovesio Auguste 
Published: October 2023

AbstractBiological sciences, drug discovery and medicine rely heavily on cell phenotype perturbation and microscope observation. However, most cellular phenotypic changes are subtle and thus hidden from us by natural cell variability: two cells in the same condition already look different. In this study, we show that conditional generative models can be used to transform an image of cells from any one condition to another, thus canceling cell variability. We visually and quantitatively validate that the principle of synthetic cell perturbation works on discernible cases. We then illustrate its effectiveness in displaying otherwise invisible cell phenotypes triggered by blood cells under parasite infection, or by the presence of a disease-causing pathological mutation in differentiated neurons derived from iPSCs, or by low concentration drug treatments. The proposed approach, easy to use and robust, opens the door to more accessible discovery of biological and disease biomarkers.
SARS-CoV-2 infection of human lung epithelial cells induces TMPRSS-mediated acute fibrin deposition
Authors: Erickson Rachel , Huang Chang , Allen Cameron , Ireland Joanna , Roth Gwynne , Zou Zhongcheng , Lu Jinghua , Lafont Bernard A. P. , Garza Nicole L. , Brumbaugh Beniah , Zhao Ming , Suzuki Motoshi , Olano Lisa , Brzostowski Joseph , Fischer Elizabeth R. , Twigg Homer L. , Johnson Reed F. , Sun Peter D. 
Published: October 2023

AbstractSevere COVID-associated lung injury is a major confounding factor of hospitalizations and death with no effective treatments. Here, we describe a non-classical fibrin clotting mechanism mediated by SARS-CoV-2 infected primary lung but not other susceptible epithelial cells. This infection-induced fibrin formation is observed in all variants of SARS-CoV-2 infections, and requires thrombin but is independent of tissue factor and other classical plasma coagulation factors. While prothrombin and fibrinogen levels are elevated in acute COVID BALF samples, fibrin clotting occurs only with the presence of viral infected but not uninfected lung epithelial cells. We suggest a viral-induced coagulation mechanism, in which prothrombin is activated by infection-induced transmembrane serine proteases, such as ST14 and TMPRSS11D, on NHBE cells. Our finding reveals the inefficiency of current plasma targeted anticoagulation therapy and suggests the need to develop a viral-induced ARDS animal model for treating respiratory airways with thrombin inhibitors.
Integrated reconstructive spectrometer with programmable photonic circuits
Authors: Yao Chunhui , Xu Kangning , Zhang Wanlu , Chen Minjia , Cheng Qixiang , Penty Richard 
Published: October 2023

AbstractOptical spectroscopic sensors are a powerful tool to reveal light-matter interactions in many fields. Miniaturizing the currently bulky spectrometers has become imperative for the wide range of applications that demand in situ or even in vitro characterization systems, a field that is growing rapidly. In this paper, we propose a novel integrated reconstructive spectrometer with programmable photonic circuits by simply using a few engineered MZI elements. This design effectively creates an exponentially scalable number of uncorrelated sampling channels over an ultra-broad bandwidth without incurring additional hardware costs, enabling ultra-high resolution down to single-digit picometers. Experimentally, we implement an on-chip spectrometer with a 6-stage cascaded MZI structure and demonstrate <10 pm resolution with >200 nm bandwidth using only 729 sampling channels. This achieves a bandwidth-to-resolution ratio of over 20,000, which is, to our best knowledge, about one order of magnitude greater than any reported miniaturized spectrometers to date.