bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Exploratory Multi-Session Study of Learning High-Dimensional Body-Machine Interfacing for Assistive Robot Control
Authors: Lee Jongmin M. , Gebrekristos Temesgen , De Santis Dalia , Nejati-Javaremi Mahdieh , Gopinath Deepak , Parikh Biraj , Mussa-Ivaldi Ferdinando A. , Argall Brenna D. 
Published: April 2023

AbstractIndividuals who suffer from severe paralysis often lose the capacity to perform fundamental body movements and everyday activities. Empowering these individuals with the ability to operate robotic arms, in high-dimensions, helps to maximize both functional utility and human agency. However, high-dimensional robot teleoperation currently lacks accessibility due to the challenge in capturing high-dimensional control signals from the human, especially in the face of motor impairments. Body-machine interfacing is a viable option that offers the necessary high-dimensional motion capture, and it moreover is noninvasive, affordable, and promotes movement and motor recovery. Nevertheless, to what extent body-machine interfacing is able to scale to high-dimensional robot control, and whether it is feasible for humans to learn, remains an open question. In this exploratory multi-session study, we demonstrate the feasibility of human learning to operate a body-machine interface to control a complex, assistive robotic arm in reaching and Activities of Daily Living tasks. Our results suggest the manner of control space mapping, from interface to robot, to play a critical role in the evolution of human learning.
Context-Aware Amino Acid Embedding Advances Analysis of TCR-Epitope Interactions
Authors: Zhang Pengfei , Bang Seojin , Cai Michael , Lee Heewook 
Published: April 2023

AbstractAccurate prediction of binding interaction between T cell receptors (TCRs) and host cells is fundamental to understanding the regulation of the adaptive immune system as well as to developing data-driven approaches for personalized immunotherapy. While several machine learning models have been developed for this prediction task, the question of how to specifically embed TCR sequences into numeric representations remains largely unexplored compared to protein sequences in general. Here, we investigate whether the embedding models designed for protein sequences, and the most widely used BLOSUM-based embedding techniques are suitable for TCR analysis. Additionally, we present our context-aware amino acid embedding models (catELMo) designed explicitly for TCR analysis and trained on 4M unlabeled TCR sequences with no supervision. We validate the effectiveness ofcatELMoin both supervised and unsupervised scenarios by stacking the simplest models on top of our learned embeddings. For the supervised task, we choose the binding affinity prediction problem of TCR and epitope sequences and demonstrate notably significant performance gains (up by at least 14% AUC) compared to existing embedding models as well as the state-of-the-art methods. Additionally, we also show that our learned embeddings reduce more than 93% annotation cost while achieving comparable results to the state-of-the-art methods. In TCR clustering task (unsupervised),catELMoidentifies TCR clusters that are more homogeneous and complete about their binding epitopes. Altogether, ourcatELMotrained without any explicit supervision interprets TCR sequences better and negates the need for complex deep neural network architectures in downstream tasks.
Surface-guided computing to analyze subcellular morphology and membrane-associated signals in 3D
Authors: Zhou Felix Y. , Weems Andrew , Gihana Gabriel M. , Chen Bingying , Chang Bo-Jui , Driscoll Meghan , Danuser Gaudenz 
Published: April 2023

AbstractSignal transduction and cell function are governed by the spatiotemporal organization of membrane-associated molecules. Despite significant advances in visualizing molecular distributions by 3D light microscopy, cell biologists still have limited quantitative understanding of the processes implicated in the regulation of molecular signals at the whole cell scale. In particular, complex and transient cell surface morphologies challenge the complete sampling of cell geometry, membrane-associated molecular concentration and activity and the computing of meaningful parameters such as the cofluctuation between morphology and signals. Here, we introduce u-Unwrap3D, a framework to remap arbitrarily complex 3D cell surfaces and membrane-associated signals into equivalent lower dimensional representations. The mappings are bidirectional, allowing the application of image processing operations in the data representation best suited for the task and to subsequently present the results in any of the other representations, including the original 3D cell surface. Leveraging this surface-guided computing paradigm, we track segmented surface motifs in 2D to quantify the recruitment of Septin polymers by blebbing events; we quantify actin enrichment in peripheral ruffles; and we measure the speed of ruffle movement along topographically complex cell surfaces. Thus, u-Unwrap3D provides access to spatiotemporal analyses of cell biological parameters on unconstrained 3D surface geometries and signals.
SARS-CoV-2 selectively induces the expression of unproductive splicing isoforms of interferon, class I MHC and splicing machinery genes
Authors: Lüscher Dias Thomaz , Mamede Costa Andrade da Conceição Izabela , Toledo Nayara Evelin de , Queiroz Lúcio Rezende , Castro Ícaro , Polidoro Alves Barbosa Rafael , Del-Bem Luiz Eduardo , Nakaya Helder , Franco Glória Regina 
Published: April 2023

AbstractSplicing is a highly conserved, intricate mechanism intimately linked to transcription elongation, serving as a pivotal regulator of gene expression. Alternative splicing may generate specific transcripts incapable of undergoing translation into proteins, designated as unproductive. A plethora of respiratory viruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), strategically manipulate the host’s splicing machinery to circumvent antiviral responses. During the infection, SARS-CoV-2 effectively suppresses interferon (IFN) expression, leading to B cell and CD8+ T cell leukopenia, while simultaneously increasing the presence of macrophages and neutrophils in patients with severe COVID-19. In this study, we integrated publicly available omics datasets to systematically analyze transcripts at the isoform level and delineate the nascent-peptide translatome landscapes of SARS-CoV-2-infected human cells. Our findings reveal a hitherto uncharacterized mechanism whereby SARS-CoV-2 infection induces the predominant expression of unproductive splicing isoforms in key IFN signaling genes, interferon-stimulated genes (ISGs), class I MHC genes, and splicing machinery genes, including IRF7, OAS3, HLA-B, and HNRNPH1. In stark contrast, cytokine and chemokine genes, such as IL6, CXCL8, and TNF, predominantly express productive (protein-coding) splicing isoforms in response to SARS-CoV-2 infection. We postulate that SARS-CoV-2 employs a previously unreported tactic of exploiting the host splicing machinery to bolster viral replication and subvert the immune response by selectively upregulating unproductive splicing isoforms from antigen presentation and antiviral response genes. Our study sheds new light on the molecular interplay between SARS-CoV-2 and the host immune system, offering a foundation for the development of novel therapeutic strategies to combat COVID-19.
An assessment of the human Sortilin1 protein network, its expression and targetability using small molecules
Authors: Kumar Arun HS 
Published: April 2023

AbstractBackgroundSortilin1 (SORT1) is a ubiquitously expressed transporter involved in sorting or clearing proteins and is pathologically linked to tissue fibrosis and calcification. Targeting SORT1 may have potential clinical efficacy in controlling or reversing cardiovascular fibrosis and/or calcification. Hence this study assessed the protein-protein network of human SORT1 and its targetability using small molecule nutra/pharmaceuticals.Material and methodsNetwork proteins of SORT1 in homo sapiens was identified using the String database, and the affinity of the protein-protein interaction of this network was analysed using Chimera software. The tissue specific expression profile of SORT1 was evaluated and assessed for enrichment in different cell types including the immune cells. A library of in-house small molecules and currently used therapeutics for cardiovascular diseases were screened using AutoDock vina to assess targetability of human SORT1. Concentration affinity (CA) ratio of the small molecules was estimated to assess the clinical feasibility of targeting SORT1.ResultsIGF2R, NTRK2, GRN and GGA1 were identified as high affinity interaction networks of SORT1. Of these high affinity interactions, IGF2R and GRN can be considered as relevant networks in regulating tissue fibrosis or microcalcification process due to their influence on T-cell activation, inflammation, wound repair, and tissue remodelling process. The tissue cell type enrichment indicated major expression of SORT1 in adipocytes, specialised epithelial cells, monocytes, cardiomyocytes, and thyroid glandular cells. The binding pocket analysis of human SORT1 showed twelve potential drug interaction sites with varying binding score (0.86 to 5.83) and probability of interaction (0.004 to 0.304). Five of the drug interaction sites were observed to be targetable at therapeutically feasible concentration of the small molecules evaluated. Empagliflozin, sitagliptin and lycopene showed superior affinity and CA ratio compared to established inhibitors of SORT1.ConclusionIGF2R and GRN are relevant networks of SORT1 regulating tissue fibrosis or microcalcification process. SORT1 can be targeted using currently approved small molecule therapeutics (empagliflozin and sitagliptin) or widely used nutraceutical (Lycopene) which should be evaluated in a randomised clinical trial to assess the efficacy to reduce cardiac/vascular microcalcification process.
Binucleated human hepatocytes arise through loss of membrane anchorage to the midbody during endomitosis
Authors: Darmasaputra Gabriella , Chuva de Sousa Lopes Susana M. , Clevers Hans , Galli Matilde 
Published: April 2023

AbstractMany plant and animal cells transition from canonical to non-canonical cell cycles during development, resulting in the formation of polyploid cells. Two types of non-canonical cell cycles exist: endoreplication, where cells increase their DNA content without entering M phase, and endomitosis, where cells enter M phase but exit prematurely. Although endoreplication has been extensively studied in plants and insects, much less is known on the regulation of endomitosis, which is the most common mode of polyploidization in mammals. In this study, we use fetal-derived human hepatocyte organoids (Hep-Org), to investigate how human hepatocytes initiate and execute endomitosis. We find that cells in endomitosis M phase have normal mitotic timings, but lose membrane anchorage to the midbody during cytokinesis, resulting in regression of the cytokinetic furrow and formation of binucleate cells. Using immunofluorescence, we find that three cortical anchoring proteins, RacGAP1, anillin, and citron kinase (CIT-K), lose their association with the cell cortex during cytokinetic regression. Moreover, reduction of WNT activity by withdrawal of CHIR99021, a GSK3 inhibitor, from the culturing medium increases the percentage of binucleated cells in Hep-Orgs. This effect is lost in organoids with mutations in the atypical E2F proteins, E2F7 and E2F8, which have been implicated in binucleation of rodent hepatocytes. Together, our results identify how human hepatocytes inhibit cell division in endomitosis, and highlight an evolutionary recurrent mechanism to initiate non-canonical cell cycles in mammals.
Origin and early divergence of tandem duplicated sorbitol transporter genes in Rosaceae: insights from evolutionary analysis of the SOT gene family in Angiosperms
Authors: Yang Fan , Luo Jiawei , Guo Wenmeng , Zhang Yuxin , Liu Yunxiao , Yu Ze , Sun Yaqiang , Li Mingjun , Ma Fengwang , Zhao Tao 
Published: April 2023

AbstractSorbitol is a critical photosynthate and storage substance in the Rosaceae family. Sorbitol transporters (SOTs) play a vital role in facilitating sorbitol allocation from source to sink organs and sugar accumulation in sink organs. Despite observing gene duplications in the SOT gene family, the origin and evolutionary process of these duplications are unclear, due to the complicated interplay of whole genome duplications and tandem duplications. Here, we investigated the synteny relationships of all detected Polyol/Monosaccharide Transporter (PLT) genes in 61 angiosperm genomes and SOT genes in major representative Rosaceae genomes. Combining phylogenetic analysis, we elucidated the lineage-specific expansion and syntenic conservation of PLTs and SOTs across different plant lineages. We found that Rosaceae SOTs, as PLT family members, originated from a pair of PLT tandem duplicating genes belonging to Class III-A. Additionally, lineage-specific and synergistic duplications in Amygdaloideae had contributed to the expansion of SOTs in Rosaceae plants. Overall, our findings provide insights into the genomic origins, duplication, and divergence of SOT gene family members, which are fundamental for further functional characterizations of each member.
A transferrin receptor 1-targeted PNA-peptide conjugate inhibits microRNA-21 expression in cardiac and other mouse tissues
Authors: Zhang Genwei , Antilla Sarah , Li Chengxi , Loas Andrei , Nielsen Thomas E. , Pentelute Bradley L. 
Published: April 2023

ABSTRACTMicroRNAs (miRNAs) are implicated in the onset and progression of a variety of diseases. Modulating the expression of specific miRNAs is a possible option for therapeutic intervention. A promising strategy is the use of antisense oligonucleotides (ASOs) to inhibit miRNAs. Targeting ASOs to specific tissues can potentially lower the dosage and improve clinical outcomes by alleviating systemic toxicity. We leverage here automated peptide nucleic acid (PNA) synthesis technology to manufacture an anti-miRNA oligonucleotide (antagomir) covalently attached to a 12-mer peptide that binds to transferrin receptor 1. Our PNA-peptide conjugate is active in cells and animals, effectively inhibiting the expression of miRNA-21 both in cultured mouse cardiomyocytes and different mouse organs (heart, liver, kidney, lung, and spleen), while remaining well-tolerated in animals up to the highest tested dose of 30 mg/kg. Conjugating the targeting ligand to the PNA antagomir significantly improved inhibition of miRNA-21 in the heart by over 50% relative to the PNA alone. Given the modulation of biodistribution observed with our PNA-peptide conjugate, we anticipate this antagomir platform to serve as a starting point for pre-clinical development studies.Table of Contents EntrySynopsisConjugating T12, a peptide targeting transferrin receptor 1 (TfR1), to a peptide nucleic acid (PNA) oligonucleotide targeting microRNA-21 increases delivery of the PNA-T12 conjugate to cardiac tissue relative to PNA alone.
An integrated single-cell transcriptome landscape of postnatal mouse hypothalamus
Authors: Junaid Muhammad , Choe Han Kyoung , Kondoh Kunio , Lee Eun Jeong , Lim Su Bin 
Published: April 2023

SummaryThe neural stem cells (NSCs) in the hypothalamus are relatively more narrowly defined than in other neurogenic regions of the postnatal brain. By leveraging single-cell RNA sequencing (scRNA-seq) data, we generated an integrated reference dataset comprising 296,282 cells from postnatal hypothalamic regions and the adjacent region, bed nucleus of the stria terminalis (BNST), and identified 30 hypothalamic neuronal and non-neuronal cell populations. The analyses of their gene expression pattern, and specific differentiation trajectories reveal the presence of NSCs and intermediate progenitor cells (IPCs) that show a continuum of activation and differentiation processes in the hypothalamus after birth. Through comparative analyses of the integrated dataset with our lab-generated Connect-seq data obtained from the whole hypothalamus, we further assessed the technical validity of the dataset presented in this study. Our large-scale unified scRNA-seq dataset with harmonized cell-level metadata can serve as a valuable resource for investigating cell type-specific gene expression and cellular differentiation trajectories in the postnatal mouse hypothalamus.
WITHDRAWN: Dual targeting of mitochondrial Lon peptidase 1 and chymotrypsin-like protease by small molecule BT317, as potential therapeutics in malignant astrocytomas
Authors: Douglas Christopher , Jain Shashi , Lomeli Naomi , Di Kaijun , Nandwana Nitesh Kumar , Mohammed Adil Shareef , Vu Thao , Pham James , Lepe Javier , Kenney Maria Cristina , Das Bhaskar , Bota Daniela A. 
Published: April 2023

Withdrawal StatementThe authors have withdrawn their manuscript owing to massive revision and data validation. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
The Genetic Architecture of Multimodal Human Brain Age
Authors: Wen Junhao , Zhao Bingxin , Yang Zhijian , Erus Guray , Skampardoni Ioanna , Mamourian Elizabeth , Cui Yuhan , Hwang Gyujoon , Bao Jingxuan , Boquet-Pujadas Aleix , Zhou Zhen , Veturi Yogasudha , Ritchie Marylyn D. , Shou Haochang , Thompson Paul M. , Shen Li , Toga Arthur W. , Davatzikos Christos 
Published: April 2023

AbstractThe complex biological mechanisms underlying human brain aging remain incompletely understood, involving multiple body organs and chronic diseases. In this study, we used multimodal magnetic resonance imaging and artificial intelligence to examine the genetic architecture of the brain age gap (BAG) derived from gray matter volume (GM-BAG,N=31,557 European ancestry), white matter microstructure (WM-BAG,N=31,674), and functional connectivity (FC-BAG,N=32,017). We identified sixteen genomic loci that reached genome-wide significance (P-value<5×10−8). A gene-drug-disease network highlighted genes linked to GM-BAG for treating neurodegenerative and neuropsychiatric disorders and WM-BAG genes for cancer therapy. GM-BAG showed the highest heritability enrichment for genetic variants in conserved regions, whereas WM-BAG exhibited the highest heritability enrichment in the 5’ untranslated regions; oligodendrocytes and astrocytes, but not neurons, showed significant heritability enrichment in WM and FC-BAG, respectively. Mendelian randomization identified potential causal effects of several exposure variables on brain aging, such as type 2 diabetes on GM-BAG (odds ratio=1.05 [1.01, 1.09], P-value=1.96×10−2) and AD on WM-BAG (odds ratio=1.04 [1.02, 1.05], P-value=7.18×10−5). Overall, our results provide valuable insights into the genetics of human brain aging, with clinical implications for potential lifestyle and therapeutic interventions. All results are publicly available at the MEDICINE knowledge portal:https://labs.loni.usc.edu/medicine.
Spatial and temporal regulation of Wnt signaling pathway members in the development of butterfly eyespots
Authors: Banerjee Tirtha Das , Murugesan Suriya Narayanan , Monteiro Antόnia 
Published: April 2023

AbstractWnt signaling is involved in the differentiation of eyespot color patterns on the wings of butterflies, but the identity and spatio-temporal regulation of specific Wnt pathway members remains unclear. Here we explore the localization and function of armadillo/β-catenin dependent (canonical) and armadillo/β- catenin independent (non-canonical) Wnt signaling in eyespot development inBicyclus anynanaby localizing Armadillo (Arm), the expression of all sevenwntligand and fourfrizzledreceptor transcripts present in the genome of this species, and testing the function ofarmandfrizzled4using CRISPR-Cas9. During mid to late larval wing development, Arm protein was present in cells at the center of the future eyespots, the foci, and the wing margin, butwntsexpressed on the wing,wnt1(wingless),wnt6, andwnt10showed expression only some distance away from the foci, along the wing margin. The receptorfrizzled9was expressed in the wing margin and in finger-like projections leading to the foci during early larval wing development, overlapping in expression with Arm. At the same time, the receptorfrizzled4showed a novel expression pattern, anti-localized with Arm, where it is likely transducing non-canonical Wnt signaling. In the early pupal stage,wnt1was newly expressed in the foci, as previously shown, along with Arm. In addition,frizzled4andfrizzled9-mediated Wnt signaling is likely repressing the expression offrizzled2, as these receptors have anti-colocalized expression domains. Arm had a conserved expression in three other nymphalid butterflies, and functional knockouts ofarmandfrizzled4inB. anynanashowed that both genes are essential for the differentiation of eyespots. These results show that distinct Wnt signaling pathways are essential for eyespot development in butterflies and are likely interacting to control their active domains.
Compilation of all known protein changes in the human Alzheimer’s disease brain
Authors: Askenazi Manor , Kavanagh Tomas , Pires Geoffrey , Ueberheide Beatrix , Wisniewski Thomas , Drummond Eleanor 
Published: April 2023

AbstractProteomic studies of human Alzheimer’s disease brain tissue have exceptional potential to identify protein changes that drive disease and to identify new drug targets. Here, we detail a combined analysis of 38 published Alzheimer’s disease proteomic studies, generating a comprehensive map of protein changes in human brain tissue across thirteen brain regions, three disease stages (preclinical Alzheimer’s disease, mild cognitive impairment, advanced Alzheimer’s disease), and proteins enriched in amyloid plaques, neurofibrillary tangles, and cerebral amyloid angiopathy. Our dataset is compiled into a user-friendly, searchable database called NeuroPro. Our combined analysis included 18,119 reported protein differences in human Alzheimer’s disease brain tissue, which mapped to 5,311 total altered proteins. Proteomic studies were remarkably consistent. 848 proteins were consistently altered in ≥5 studies, many of which are understudied in the Alzheimer’s field. Comparison of protein changes in early-stage and advanced Alzheimer’s disease revealed significant synapse, vesicle, and lysosomal changes early in disease, but widespread mitochondrial changes only in advanced Alzheimer’s disease. Comparison of vulnerable and resistant brain regions suggested that protein changes in resistant regions in advanced Alzheimer’s disease are similar to those in vulnerable regions in early-stage Alzheimer’s disease, indicating a temporal progression of protein dysfunction during Alzheimer’s disease advancement. We conclude that NeuroPro is a powerful new resource that provides new insights into human Alzheimer’s disease brain protein changes and highlights novel proteins of particular interest that may mechanistically drive Alzheimer’s disease.