bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitochondrial proteins encoded by the 22q11.2 neurodevelopmental locus regulate neural stem and progenitor cell proliferation
Authors: Campbell Philip D. , Lee Isaiah , Thyme Summer , Granato Michael 
Published: October 2023

AbstractMicrodeletion of a 3Mb region encompassing 45 protein-coding genes at chromosome 22q11.2 (22q11.2DS) predisposes individuals to multiple neurodevelopmental disorders and is one of the greatest genetic risk factors for schizophrenia. Defective mitochondrial function has been hypothesized to contribute to 22q11.2DS pathogenesis; however, which of the six mitochondrial genes contribute to neurodevelopmental phenotypes and their underlying mechanisms remain unresolved. To systematically test 22q11.2DS genes for functional roles in neurodevelopment and behavior, we generated genetic mutants for each of the 37 conserved zebrafish orthologs and performed high throughput behavioral phenotyping using seven behavioral assays. Through this unbiased approach, we identified five single-gene mutants with partially overlapping behavioral phenotypes. Two of these genes,mrpl40andprodha, encode for mitochondrial proteins and, similar to what we observed inmrpl40andprodhamutants, pharmacologic inhibition of mitochondrial function during development results in microcephaly. Single mutant analysis shows that bothmrpl40andprodhamutants display aberrant neural stem and progenitor cell proliferation, with each gene regulating distinct cell populations. Finally, double mutants for bothmrpl40andprodhadisplay aggravated behavioral phenotypes and neural stem and progenitor cell analysis reveals a previously unrecognized partially redundant role formrpl40andprodhain regulating radial glia-like cell proliferation. Combined, our results demonstrate a critical role for mitochondrial function in neural stem and progenitor cell populations in the developing vertebrate brain and provide compelling evidence that mitochondrial dysfunction during neurodevelopment is linked to brain volume and behavioral phenotypes observed in models of 22q11.2DS.
Whole-genome sequencing analysis of suicide deaths integrating brain-regulatory eQTLs data to identify risk loci and genes
Authors: Han Seonggyun , DiBlasi Emily , Monson Eric T. , Shabalin Andrey , Ferris Elliott , Chen Danli , Fraser Alison , Yu Zhe , Staley Michael , Callor W. Brandon , Christensen Erik D. , Crockett David K. , Li Qingqin S. , Willour Virginia , Bakian Amanda V. , Keeshin Brooks , Docherty Anna R. , Eilbeck Karen , Coon Hilary 
Published: October 2023

AbstractRecent large-scale genome-wide association studies (GWAS) have started to identify potential genetic risk loci associated with risk of suicide; however, a large portion of suicide-associated genetic factors affecting gene expression remain elusive. Dysregulated gene expression, not assessed by GWAS, may play a significant role in increasing the risk of suicide death. We performed the first comprehensive genomic association analysis prioritizing brain expression quantitative trait loci (eQTLs) within regulatory regions in suicide deaths from the Utah Suicide Genetic Risk Study (USGRS). 440,324 brain-regulatory eQTLs were obtained by integrating brain eQTLs, histone modification ChIP-seq, ATAC-seq, DNase-seq, and Hi-C results from publicly available data. Subsequent genomic analyses were conducted in whole-genome sequencing (WGS) data from 986 suicide deaths of non-Finnish European (NFE) ancestry and 415 ancestrally matched controls. Additional independent USGRS suicide deaths with genotyping array data (n = 4657) and controls from the Genome Aggregation Database were explored for WGS result replication. One significant eQTL locus, rs926308 (p = 3.24e−06), was identified. The rs926308-T is associated with lower expression of RFPL3S, a gene important for neocortex development and implicated in arousal. Gene-based analyses performed using Sherlock Bayesian statistical integrative analysis also detected 20 genes with expression changes that may contribute to suicide risk. From analyzing publicly available transcriptomic data, ten of these genes have previous evidence of differential expression in suicide death or in psychiatric disorders that may be associated with suicide, including schizophrenia and autism (ZNF501, ZNF502, CNN3, IGF1R, KLHL36, NBL1, PDCD6IP, SNX19, BCAP29, and ARSA). Electronic health records (EHR) data was further merged to evaluate if there were clinically relevant subsets of suicide deaths associated with genetic variants. In summary, our study identified one risk locus and ten genes associated with suicide risk via gene expression, providing new insight into possible genetic and molecular mechanisms leading to suicide.
The role of TXNIP in cancer: a fine balance between redox, metabolic, and immunological tumor control
Authors: Deng Jinhai , Pan Teng , Liu Zaoqu , McCarthy Caitlin , Vicencio Jose M. , Cao Lulu , Alfano Giovanna , Suwaidan Ali Abdulnabi , Yin Mingzhu , Beatson Richard , Ng Tony 
Published: October 2023

AbstractThioredoxin-interacting protein (TXNIP) is commonly considered a master regulator of cellular oxidation, regulating the expression and function of Thioredoxin (Trx). Recent work has identified that TXNIP has a far wider range of additional roles: from regulating glucose and lipid metabolism, to cell cycle arrest and inflammation. Its expression is increased by stressors commonly found in neoplastic cells and the wider tumor microenvironment (TME), and, as such, TXNIP has been extensively studied in cancers. In this review, we evaluate the current literature regarding the regulation and the function of TXNIP, highlighting its emerging role in modulating signaling between different cell types within the TME. We then assess current and future translational opportunities and the associated challenges in this area. An improved understanding of the functions and mechanisms of TXNIP in cancers may enhance its suitability as a therapeutic target.
Integration of 3D-printed cerebral cortical tissue into an ex vivo lesioned brain slice
Authors: Jin Yongcheng , Mikhailova Ellina , Lei Ming , Cowley Sally A. , Sun Tianyi , Yang Xingyun , Zhang Yujia , Liu Kaili , Catarino da Silva Daniel , Campos Soares Luana , Bandiera Sara , Szele Francis G. , Molnár Zoltán , Zhou Linna , Bayley Hagan 
Published: October 2023

AbstractEngineering human tissue with diverse cell types and architectures remains challenging. The cerebral cortex, which has a layered cellular architecture composed of layer-specific neurons organised into vertical columns, delivers higher cognition through intricately wired neural circuits. However, current tissue engineering approaches cannot produce such structures. Here, we use a droplet printing technique to fabricate tissues comprising simplified cerebral cortical columns. Human induced pluripotent stem cells are differentiated into upper- and deep-layer neural progenitors, which are then printed to form cerebral cortical tissues with a two-layer organization. The tissues show layer-specific biomarker expression and develop a structurally integrated network of processes. Implantation of the printed cortical tissues into ex vivo mouse brain explants results in substantial structural implant-host integration across the tissue boundaries as demonstrated by the projection of processes and the migration of neurons, and leads to the appearance of correlated Ca2+ oscillations across the interface. The presented approach might be used for the evaluation of drugs and nutrients that promote tissue integration. Importantly, our methodology offers a technical reservoir for future personalized implantation treatments that use 3D tissues derived from a patient’s own induced pluripotent stem cells.
Nanoparticle display of prefusion coronavirus spike elicits S1-focused cross-reactive antibody response against diverse coronavirus subgenera
Authors: Hutchinson Geoffrey B. , Abiona Olubukola M. , Ziwawo Cynthia T. , Werner Anne P. , Ellis Daniel , Tsybovsky Yaroslav , Leist Sarah R. , Palandjian Charis , West Ande , Fritch Ethan J. , Wang Nianshuang , Wrapp Daniel , Boyoglu-Barnum Seyhan , Ueda George , Baker David , Kanekiyo Masaru , McLellan Jason S. , Baric Ralph S. , King Neil P. , Graham Barney S. , Corbett-Helaire Kizzmekia S. 
Published: October 2023

AbstractMultivalent antigen display is a fast-growing area of interest toward broadly protective vaccines. Current nanoparticle-based vaccine candidates demonstrate the ability to confer antibody-mediated immunity against divergent strains of notably mutable viruses. In coronaviruses, this work is predominantly aimed at targeting conserved epitopes of the receptor binding domain. However, targeting conserved non-RBD epitopes could limit the potential for antigenic escape. To explore new potential targets, we engineered protein nanoparticles displaying coronavirus prefusion-stabilized spike (CoV_S-2P) trimers derived from MERS-CoV, SARS-CoV-1, SARS-CoV-2, hCoV-HKU1, and hCoV-OC43 and assessed their immunogenicity in female mice. Monotypic SARS-1 nanoparticles elicit cross-neutralizing antibodies against MERS-CoV and protect against MERS-CoV challenge. MERS and SARS nanoparticles elicit S1-focused antibodies, revealing a conserved site on the S N-terminal domain. Moreover, mosaic nanoparticles co-displaying distinct CoV_S-2P trimers elicit antibody responses to distant cross-group antigens and protect male and female mice against MERS-CoV challenge. Our findings will inform further efforts toward the development of pan-coronavirus vaccines.
Structure of the ceramide-bound SPOTS complex
Authors: Schäfer Jan-Hannes , Körner Carolin , Esch Bianca M. , Limar Sergej , Parey Kristian , Walter Stefan , Januliene Dovile , Moeller Arne , Fröhlich Florian 
Published: October 2023

AbstractSphingolipids are structural membrane components that also function in cellular stress responses. The serine palmitoyltransferase (SPT) catalyzes the rate-limiting step in sphingolipid biogenesis. Its activity is tightly regulated through multiple binding partners, including Tsc3, Orm proteins, ceramides, and the phosphatidylinositol-4-phosphate (PI4P) phosphatase Sac1. The structural organization and regulatory mechanisms of this complex are not yet understood. Here, we report the high-resolution cryo-EM structures of the yeast SPT in complex with Tsc3 and Orm1 (SPOT) as dimers and monomers and a monomeric complex further carrying Sac1 (SPOTS). In all complexes, the tight interaction of the downstream metabolite ceramide and Orm1 reveals the ceramide-dependent inhibition. Additionally, observation of ceramide and ergosterol binding suggests a co-regulation of sphingolipid biogenesis and sterol metabolism within the SPOTS complex.
Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress
Authors: Wang Wenjun , Tan Junyang , Liu Xiaomin , Guo Wenqi , Li Mengmeng , Liu Xinjie , Liu Yanyan , Dai Wenyu , Hu Liubing , Wang Yimin , Lu Qiuxia , Lee Wen Xing , Tang Hong-Wen , Zhou Qinghua 
Published: October 2023

AbstractEndonuclease G (ENDOG), a nuclear-encoded mitochondrial intermembrane space protein, is well known to be translocated into the nucleus during apoptosis. Recent studies have shown that ENDOG might enter the mitochondrial matrix to regulate mitochondrial genome cleavage and replication. However, little is known about the role of ENDOG in the cytosol. Our previous work showed that cytoplasmic ENDOG competitively binds with 14-3-3γ, which released TSC2 to repress mTORC1 signaling and induce autophagy. Here, we demonstrate that cytoplasmic ENDOG could also release Rictor from 14-3-3γ to activate the mTORC2-AKT-ACLY axis, resulting in acetyl-CoA production. Importantly, we observe that ENDOG could translocate to the ER, bind with Bip, and release IRE1a/PERK to activate the endoplasmic reticulum stress response, promoting lipid synthesis. Taken together, we demonstrate that loss of ENDOG suppresses acetyl-CoA production and lipid synthesis, along with reducing endoplasmic reticulum stress, which eventually alleviates high-fat diet-induced nonalcoholic fatty liver disease in female mice.
Visualizing moiré ferroelectricity via plasmons and nano-photocurrent in graphene/twisted-WSe2 structures
Authors: Zhang Shuai , Liu Yang , Sun Zhiyuan , Chen Xinzhong , Li Baichang , Moore S. L. , Liu Song , Wang Zhiying , Rossi S. E. , Jing Ran , Fonseca Jordan , Yang Birui , Shao Yinming , Huang Chun-Ying , Handa Taketo , Xiong Lin , Fu Matthew , Pan Tsai-Chun , Halbertal Dorri , Xu Xinyi , Zheng Wenjun , Schuck P. J. , Pasupathy A. N. , Dean C. R. , Zhu Xiaoyang , Cobden David H. , Xu Xiaodong , Liu Mengkun , Fogler M. M. , Hone James C. , Basov D. N. 
Published: October 2023

AbstractFerroelectricity, a spontaneous and reversible electric polarization, is found in certain classes of van der Waals (vdW) materials. The discovery of ferroelectricity in twisted vdW layers provides new opportunities to engineer spatially dependent electric and optical properties associated with the configuration of moiré superlattice domains and the network of domain walls. Here, we employ near-field infrared nano-imaging and nano-photocurrent measurements to study ferroelectricity in minimally twisted WSe2. The ferroelectric domains are visualized through the imaging of the plasmonic response in a graphene monolayer adjacent to the moiré WSe2 bilayers. Specifically, we find that the ferroelectric polarization in moiré domains is imprinted on the plasmonic response of the graphene. Complementary nano-photocurrent measurements demonstrate that the optoelectronic properties of graphene are also modulated by the proximal ferroelectric domains. Our approach represents an alternative strategy for studying moiré ferroelectricity at native length scales and opens promising prospects for (opto)electronic devices.
Myoglobin-loaded gadolinium nanotexaphyrins for oxygen synergy and imaging-guided radiosensitization therapy
Authors: Ma Xiaotu , Liang Xiaolong , Yao Meinan , Gao Yu , Luo Qi , Li Xiaoda , Yu Yue , Sun Yining , Cheng Miffy H. Y. , Chen Juan , Zheng Gang , Shi Jiyun , Wang Fan 
Published: October 2023

AbstractGadolinium (Gd3+)-coordinated texaphyrin (Gd-Tex) is a promising radiosensitizer that entered clinical trials, but temporarily fails largely due to insufficient radiosensitization efficacy. Little attention has been given to using nanovesicles to improve its efficacy. Herein, Gd-Tex is transformed into building blocks “Gd-Tex-lipids” to self-assemble nanovesicles called Gd-nanotexaphyrins (Gd-NTs), realizing high density packing of Gd-Tex in a single nanovesicle and achieving high Gd-Tex accumulation in tumors. To elucidate the impact of O2 concentration on Gd-Tex radiosensitization, myoglobin (Mb) is loaded into Gd-NTs (Mb@Gd-NTs), resulting in efficient relief of tumor hypoxia and significant enhancement of Gd-Tex radiosensitization, eventually inducing the obvious long-term antitumor immune memory to inhibit tumor recurrence. In addition to Gd3+, the versatile Mb@Gd-NTs can also chelate 177Lu3+ (Mb@177Lu/Gd-NTs), enabling SPECT/MRI dual-modality imaging for accurately monitoring drug delivery in real-time. This “one-for-all” nanoplatform with the capability of chelating various trivalent metal ions exhibits broad clinical application prospects in imaging-guided radiosensitization therapy.
PAM-flexible genome editing with an engineered chimeric Cas9
Authors: Zhao Lin , Koseki Sabrina R. T. , Silverstein Rachel A. , Amrani Nadia , Peng Christina , Kramme Christian , Savic Natasha , Pacesa Martin , Rodríguez Tomás C. , Stan Teodora , Tysinger Emma , Hong Lauren , Yudistyra Vivian , Ponnapati Manvitha R. , Jacobson Joseph M. , Church George M. , Jakimo Noah , Truant Ray , Jinek Martin , Kleinstiver Benjamin P. , Sontheimer Erik J. , Chatterjee Pranam 
Published: October 2023

AbstractCRISPR enzymes require a defined protospacer adjacent motif (PAM) flanking a guide RNA-programmed target site, limiting their sequence accessibility for robust genome editing applications. In this study, we recombine the PAM-interacting domain of SpRY, a broad-targeting Cas9 possessing an NRN > NYN (R = A or G, Y = C or T) PAM preference, with the N-terminus of Sc + +, a Cas9 with simultaneously broad, efficient, and accurate NNG editing capabilities, to generate a chimeric enzyme with highly flexible PAM preference: SpRYc. We demonstrate that SpRYc leverages properties of both enzymes to specifically edit diverse PAMs and disease-related loci for potential therapeutic applications. In total, the approaches to generate SpRYc, coupled with its robust flexibility, highlight the power of integrative protein design for Cas9 engineering and motivate downstream editing applications that require precise genomic positioning.
Intermolecular interactions underlie protein/peptide phase separation irrespective of sequence and structure at crowded milieu
Authors: Poudyal Manisha , Patel Komal , Gadhe Laxmikant , Sawner Ajay Singh , Kadu Pradeep , Datta Debalina , Mukherjee Semanti , Ray Soumik , Navalkar Ambuja , Maiti Siddhartha , Chatterjee Debdeep , Devi Jyoti , Bera Riya , Gahlot Nitisha , Joseph Jennifer , Padinhateeri Ranjith , Maji Samir K. 
Published: October 2023

AbstractLiquid-liquid phase separation (LLPS) has emerged as a crucial biological phenomenon underlying the sequestration of macromolecules (such as proteins and nucleic acids) into membraneless organelles in cells. Unstructured and intrinsically disordered domains are known to facilitate multivalent interactions driving protein LLPS. We hypothesized that LLPS could be an intrinsic property of proteins/polypeptides but with distinct phase regimes irrespective of their sequence and structure. To examine this, we studied many (a total of 23) proteins/polypeptides with different structures and sequences for LLPS study in the presence and absence of molecular crowder, polyethylene glycol (PEG-8000). We showed that all proteins and even highly charged polypeptides (under study) can undergo liquid condensate formation, however with different phase regimes and intermolecular interactions. We further demonstrated that electrostatic, hydrophobic, and H-bonding or a combination of such intermolecular interactions plays a crucial role in individual protein/peptide LLPS.
TerC proteins function during protein secretion to metalate exoenzymes
Authors: He Bixi , Sachla Ankita J. , Helmann John D. 
Published: October 2023

AbstractCytosolic metalloenzymes acquire metals from buffered intracellular pools. How exported metalloenzymes are appropriately metalated is less clear. We provide evidence that TerC family proteins function in metalation of enzymes during export through the general secretion (Sec-dependent) pathway. Bacillus subtilis strains lacking MeeF(YceF) and MeeY(YkoY) have a reduced capacity for protein export and a greatly reduced level of manganese (Mn) in the secreted proteome. MeeF and MeeY copurify with proteins of the general secretory pathway, and in their absence the FtsH membrane protease is essential for viability. MeeF and MeeY are also required for efficient function of the Mn2+-dependent lipoteichoic acid synthase (LtaS), a membrane-localized enzyme with an extracytoplasmic active site. Thus, MeeF and MeeY, representative of the widely conserved TerC family of membrane transporters, function in the co-translocational metalation of Mn2+-dependent membrane and extracellular enzymes.
Alternative splicing in lung influences COVID-19 severity and respiratory diseases
Authors: Nakanishi Tomoko , Willett Julian , Farjoun Yossi , Allen Richard J. , Guillen-Guio Beatriz , Adra Darin , Zhou Sirui , Richards J. Brent 
Published: October 2023

AbstractAlternative splicing generates functional diversity in isoforms, impacting immune response to infection. Here, we evaluate the causal role of alternative splicing in COVID-19 severity and susceptibility by applying two-sample Mendelian randomization to cis-splicing quantitative trait loci and the results from COVID-19 Host Genetics Initiative. We identify that alternative splicing in lung, rather than total expression of OAS1, ATP11A, DPP9 and NPNT, is associated with COVID-19 severity. MUC1 and PMF1 splicing is associated with COVID-19 susceptibility. Colocalization analyses support a shared genetic mechanism between COVID-19 severity with idiopathic pulmonary fibrosis at the ATP11A and DPP9 loci, and with chronic obstructive lung diseases at the NPNT locus. Last, we show that ATP11A, DPP9, NPNT, and MUC1 are highly expressed in lung alveolar epithelial cells, both in COVID-19 uninfected and infected samples. These findings clarify the importance of alternative splicing in lung for COVID-19 and respiratory diseases, providing isoform-based targets for drug discovery.
Global land subsidence mapping reveals widespread loss of aquifer storage capacity
Authors: Hasan Md Fahim , Smith Ryan , Vajedian Sanaz , Pommerenke Rahel , Majumdar Sayantan 
Published: October 2023

AbstractGroundwater overdraft gives rise to multiple adverse impacts including land subsidence and permanent groundwater storage loss. Existing methods are unable to characterize groundwater storage loss at the global scale with sufficient resolution to be relevant for local studies. Here we explore the interrelation between groundwater stress, aquifer depletion, and land subsidence using remote sensing and model-based datasets with a machine learning approach. The developed model predicts global land subsidence magnitude at high spatial resolution (~2 km), provides a first-order estimate of aquifer storage loss due to consolidation of ~17 km3/year globally, and quantifies key drivers of subsidence. Roughly 73% of the mapped subsidence occurs over cropland and urban areas, highlighting the need for sustainable groundwater management practices over these areas. The results of this study aid in assessing the spatial extents of subsidence in known subsiding areas, and in locating unknown groundwater stressed regions.
Open-loop analog programmable electrochemical memory array
Authors: Chen Peng , Liu Fenghao , Lin Peng , Li Peihong , Xiao Yu , Zhang Bihua , Pan Gang 
Published: October 2023

AbstractEmerging memories have been developed as new physical infrastructures for hosting neural networks owing to their low-power analog computing characteristics. However, accurately and efficiently programming devices in an analog-valued array is still largely limited by the intrinsic physical non-idealities of the devices, thus hampering their applications in in-situ training of neural networks. Here, we demonstrate a passive electrochemical memory (ECRAM) array with many important characteristics necessary for accurate analog programming. Different image patterns can be open-loop and serially programmed into our ECRAM array, achieving high programming accuracies without any feedback adjustments. The excellent open-loop analog programmability has led us to in-situ train a bilayer neural network and reached software-like classification accuracy of 99.4% to detect poisonous mushrooms. The training capability is further studied in simulation for large-scale neural networks such as VGG-8. Our results present a new solution for implementing learning functions in an artificial intelligence hardware using emerging memories.