bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systemic inflammation and lymphocyte activation precede rheumatoid arthritis
Authors: He Ziyuan , Glass Marla C. , Venkatesan Pravina , Feser Marie L. , Lazaro Leander , Okada Lauren Y. , Tran Nhung T. T. , He Yudong D. , Rachid Zaim Samir , Bennett Christy E. , Ravisankar Padmapriyadarshini , Dornisch Elisabeth M. , Arishi Najeeb A. , Asamoah Ashley G. , Barzideh Saman , Becker Lynne A. , Bemis Elizabeth A. , Buckner Jane H. , Collora Christopher E. , Criley Megan A. L. , Demoruelle M. Kristen , Fleischer Chelsie L. , Garber Jessica , Genge Palak C. , Gong Qiuyu , Graybuck Lucas T. , Gustafson Claire E. , Hattel Brian C. , Hernandez Veronica , Heubeck Alexander T. , Kawelo Erin K. , Krishnan Upaasana , Kuan Emma L. , Kuhn Kristine A. , LaFrance Christian M. , Lee Kevin J. , Li Ruoxin , Lord Cara , Mettey Regina R. , Moss Laura , Musgrove Blessing , Nguyen Kathryn , Ochoa Andrea , Parthasarathy Vaishnavi , Pebworth Mark-Phillip , Pedrick Chong , Peng Tao , Phalen Cole G. , Reading Julian , Roll Charles R. , Seifert Jennifer A. , Siedschlag Marguerite D. , Speake Cate , Striebich Christopher C. , Stuckey Tyanna J. , Swanson Elliott G. , Takada Hideto , Thai Tylor , Thomson Zachary J. , Trieu Nguyen , Tsaltskan Vlad , Wang Wei , Weiss Morgan D. A. , Westermann Amy , Zhang Fan , Boyle David L. , Goldrath Ananda W. , Bumol Thomas F. , Li Xiao-jun , Holers V. Michael , Skene Peter J. , Savage Adam K. , Firestein Gary S. , Deane Kevin D. , Torgerson Troy R. , Gillespie Mark A. 
Published: October 2024

AbstractSome autoimmune diseases, including rheumatoid arthritis (RA), are preceded by a critical subclinical phase of disease activity. Proactive clinical management is hampered by a lack of biological understanding of this subclinical ‘at-risk’ state and the changes underlying disease development. In a cross-sectional and longitudinal multi-omics study of peripheral immunity in the autoantibody-positive at-risk for RA period, we identified systemic inflammation, proinflammatory-skewed B cells, expanded Tfh17-like cells, epigenetic bias in naive T cells, TNF+IL1B+ monocytes resembling a synovial macrophage population, and CD4 T cell transcriptional features resembling those suppressed by abatacept (CTLA4-Ig) in RA patients. Our findings characterize pathogenesis prior to clinical diagnosis and suggest the at-risk state exhibits substantial immune alterations that could potentially be targeted for early intervention to delay or prevent autoimmunity. We provide a suite of tools athttps://apps.allenimmunology.org/aifi/insights/ra-progression/to facilitate exploration and enhance accessibility of this extensive dataset.One Sentence SummaryACPA+ at-risk individuals show RA-like inflammation and multi-compartment immune dysregulation during transition to clinically active RA
Predicting Immunogenic CD4+ T Cell Epitopes in Bacteria Using Antigen and Peptide Features
Authors: Marrama Daniel , Battey Hannah , Khaledian Ehdieh , Müller Miriam , Panda Sudhasini , da Silva Antunes Ricardo , Sette Alessandro , Arlehamn Cecilia S. Lindestam , Peters Bjoern 
Published: October 2024

AbstractBackgroundT cell epitope prediction methods have been broadly utilized to facilitate epitope discovery in infectious agents and help design reagents, diagnostics, and vaccines. Current prediction methods are mainly focused on peptide presentation by MHC molecules, which is a necessary but not sufficient requirement for an epitope. For complex pathogens such as bacteria, it would be desirable to make such predictions more specific to limit the number of candidates that have to be experimentally tested.ObjectiveTo develop a machine learning-based prediction model that integrates both peptide-level and antigen-level features to improve the specificity of CD4+ T cell epitope predictions for bacteria.MethodsWe used a dataset of 20,216 peptides fromMycobacterium tuberculosis(Mtb), tested for T cell recognition in Mtb-infected participants, that led to the discovery of n = 144 peptide epitopes. For each peptide, we calculated six peptide-level features (e.g. MHC class II binding predictions and conservation scores) and six antigen-level features (e.g. including RNA expression levels and subcellular localization scores). Three machine learning algorithms—Random Forest, Gradient Boosting, and XGBoost—were trained using stratified, 5-fold cross-validation and combined into an ensemble model. Experimental validation was performed onStreptococcus pneumoniaepeptides, using ex vivo IFNγ assays to confirm the predictive performance.ResultsThe ensemble model achieved an ROC-AUC of 0.91 in predicting immunogenic peptides in theMycobacterium tuberculosis(Mtb) dataset. Gene expression and conservation were identified as the most impactful features, followed by MHC class II binding predictions. When validated on an independentBordetella pertussisdataset, the model demonstrated accurate predictive capability, especially for peptides with broad recognition in the participant cohort (ROC-AUC up to 0.82). Prospectively applying the model toStreptococcus pneumoniae, we synthesized peptides predicted by our ensemble model to be immunogenic or non-immunogenic. Ex vivo testing with PBMCs from healthy participants showed that peptides predicted to be immunogenic elicited significantly higher IFNγ responses than non-immunogenic peptides, validating the model.ConclusionsOur machine learning approach, integrating both peptide and antigen features, effectively predicts immunogenic CD4+ T cell epitopes across different bacterial pathogens. This method enhances epitope selection efficiency, aiding vaccine development and immunological research by reducing the need for extensive experimental screening.
Chemoenzymatic Synthesis Planning Guided by Reaction Type Score
Authors: Li Hongxiang , Liu Xuan , Jiang Guangde , Zhao Huimin 
Published: October 2024

ABSTRACTThanks to the growing interests in computer-aided synthesis planning (CASP), a wide variety of retrosynthesis and retrobiosynthesis tools have been developed in the past decades. However, synthesis planning tools for multi-step chemoenzymatic reactions are still rare despite the widespread use of enzymatic reactions in chemical synthesis. Herein we report a reaction type score (RTscore)-guided chemoenzymatic synthesis planning (RTS-CESP) strategy. Briefly, the RTscore is trained using a text-based convolutional neural network (TextCNN) to distinguish synthesis reactions from decomposition reactions and evaluate synthesis efficiency. Once multiple chemical synthesis routes are generated by a retrosynthesis tool for a target molecule, RTscore is used to rank them and find the step(s) that can be replaced by enzymatic reactions to improve synthesis efficiency. As proof of concept, RTS-CESP was applied to 10 molecules with known chemoenzymatic synthesis routes in literature and was able to predict all of them with six being the top-ranked routes. Moreover, RTS-CESP was employed for 1000 molecules in the boutique database and was able to predict the chemoenzymatic synthesis routes for 554 molecules, outperforming ASKCOS, a state-of-the-art chemoenzymatic synthesis planning tool. Finally, RTS-CESP was used to design a new chemoenzymatic synthesis route for the FDA-approved drug Alclofenac, which was shorter than literature-reported route and have been experimentally validated.
Ice and air: Visualisation of freeze-thaw embolism and freezing spread in youngL. tulipiferaleaves
Authors: Johnson Kate M. , Scherer Muriel , Gerber Dominic , Style Robert W. , Dufresne Eric R. , Brodersen Craig R. 
Published: October 2024

AbstractSpring freezing is an unforgiving stress for young leaves, often leading to death, with consequences for tree productivity and survival. While both the plant water transport system and living tissues are vulnerable to freezing, we do not know whether damage to one or both of these systems causes death in leaves exposed to freezing. Whole saplings ofLiriodendron tulipiferawere exposed to freezing and thawing trajectories designed to mimic natural spring freezes. We monitored the formation of freeze-thaw xylem embolism and damage to photosynthetic tissues to reveal a predictable progression of ice formation across the leaf surface that is strongly influenced by leaf vein architecture, notably the presence or absence of bundle sheath extensions. Our data also show that freeze-thaw embolism occurs only in the largest vein orders where mean vessel diameter exceeds 30µm. With evidence of both freeze-thaw embolism and damage to photosynthetic tissue, we conclude that this dual-mode lethality may be common among other wide-vesseled angiosperm-leaves, potentially playing a role in limiting geographic distributions, and show that bundle sheath extensions may stall or even prevent freezing spread.HighlightBoth ice and air lead likely lead to death in youngL.tulipferaleaves exposed to freezing, with the spread of both governed by physical characteristics of these leaves.
DNA methylation memory of pancreatic acinar-ductal metaplasia transition state altering Kras-downstream PI3K and Rho GTPase signaling in the absence of Kras mutation
Authors: Lo Emily K.W. , Idrizi Adrian , Tryggvadottir Rakel , Zhou Weiqiang , Hou Wenpin , Ji Hongkai , Cahan Patrick , Feinberg Andrew P. 
Published: October 2024

AbstractA critical area of recent cancer research is the emergence of transition states between normal and cancer that exhibit increased cell plasticity which underlies tumor cell heterogeneity. Pancreatic ductal adenocarcinoma (PDAC) can arise from the combination of a transition state termed acinar-to-ductal metaplasia (ADM) and a gain-of-function mutation in the proto-oncogeneKRAS. During ADM, digestive enzyme-producing acinar cells acquire a transient ductal epithelium-like phenotype while maintaining their geographical acinar organization. One route of ADM initiation is the overexpression of theKrüppel-like factor 4gene (KLF4) in the absence of oncogenic driver mutations. Here, we asked to what extent cells acquire and retain an epigenetic memory of the ADM transition state in the absence of oncogene mutation. We identified differential DNA methylation at Kras-downstreamPI3KandRho/Rac/Cdc42GTPase pathway genes during ADM, as well as a corresponding gene expression increase in these pathways. Importantly, differential methylation persisted after gene expression returned to normal. Caerulein exposure, which induces widespread digestive system changes in addition to ADM, showed similar changes in DNA methylation in ADM cells. Regions of differential methylation were enriched for motifs of KLF and AP-1 family transcription factors, as were those of human pancreatic intraepithelial neoplasia (PanIN) samples, demonstrating the relevance of this epigenetic transition state memory in human carcinogenesis. Finally, single-cell spatial transcriptomics revealed that these ADM transition cells were enriched for PI3K pathway and AP1 family members, linking epigenetic memory to cancer cell plasticity even in the absence of oncogene mutation.
In-depth investigation of genome to refine QTL positions for spontaneous sex-reversal in XX rainbow trout
Authors: Dehaullon Audrey , Fraslin Clémence , Bestin Anastasia , Poncet Charles , Guiguen Yann , Quillet Edwige , Phocas Florence 
Published: October 2024

AbstractSex determination is a flexible process in fish, controlled by genetics or environmental factors or a combination of both depending on the species. Revealing the underlying molecular mechanisms may have important implications for research on reproductive development in vertebrates, as well as sex-ratio control and selective breeding in fish. Phenotypic sex in rainbow trout is primarily controlled by a XX/XY male heterogametic sex determination system. Unexpectedly in genetically XX all-female farmed populations, a small proportion of males or intersex individuals are regularly observed. This spontaneous masculinisation is a highly heritable trait, controlled by minor sex-modifier genes that remain unknown, although several QTL regions were detected in previous studies. In this work we used genome-based approaches and various statistical methods to investigate these QTL regions. We validated in six different French farmed populations DNA markers we had previously identified in a different commercial population on chromosomes Omy1, Omy12 and Omy20. We also identified functional candidate genes located that may be involved in spontaneous masculinisation by reducing germ cell proliferation and repressing oogenesis of XX-rainbow trout in the absence of the master sex determining gene. In particular,syndig1,tlx1andhellson Omy1, as well askhdrbs2andcsmd1on Omy20 deserve further investigation as potential sex-modifier genes to precise their functional roles as well as their interaction with rearing temperature. Those findings could be used to produce all-female populations that are preferred by farmers due to a delayed maturation of females and higher susceptibility of male trout to diseases.
Light activatespsbAtranslation in plants by relieving inhibition of translation factor HCF173 by thepsbAORF incis
Authors: Williams-Carrier Rosalind , Chotewutmontri Prakitchai , Perkel Sarah , Rojas Margarita , Belcher Susan , Barkan Alice 
Published: October 2024

AbstractThe D1 reaction center protein of photosystem II is subject to photooxidative damage. Photodamaged D1 must be replaced with newly synthesized D1 to maintain photosynthesis. In plant chloroplasts, D1 synthesis is coupled to D1 photodamage via regulated translation initiation onpsbAmRNA, which encodes D1. Mechanisms underlying this coupling are unclear. We show by analysis of reporter constructs in tobacco that thepsbAtranslational activators HCF173 and HCF244 activate viacis-elements in thepsbAUTRs and that the 5’ UTR sequence bound by HCF173 is essential forpsbAexpression. However, thepsbAUTRs are not sufficient to program light-regulated translation. Instead, thepsbAopen reading frame acts incisto repress translation initiation, and D1 photodamage relieves this repression. A truncated HCF173 mutant conditions constitutively highpsbAribosome occupancy in the dark, implicating HCF173 as a mediator of the repressive signal. We propose a model that is informed by structures of the Complex I assembly factor CIA30/NDUFAF1 positing that D1 photodamage relieves a repressive cotranslational interaction between nascent D1 and HCF173’s CIA30 domain, and that the D1 assembly factor HCF136 promotes this interaction. These findings elucidate a translational rheostat that maintains photosynthesis in the face of inevitable photosystem II photodamage.
In silico design of a multi-epitope vaccine against tick-borne encephalitis virus via immunoinformatic analysis
Authors: Wang Bingjie 
Published: October 2024

AbstractTick-borne encephalitis virus (TBEV) is a serious pathogen that poses a significant threat to humans, causing encephalitis that can result in lifelong sequelae. In this study, we focused on the complete proteomes of the five current TBEV subtypes to identify dominant epitopes. Immunoinformatics tools were employed to screen for LBL, HTL, and CTL epitopes. These epitopes were then linked using various linkers and combined with adjuvants and histidine tag. The vaccine underwent a series of physicochemical property analyses, including secondary structure prediction, three-dimensional structure prediction, molecular docking, molecular dynamics simulation, immune simulation, and in silico cloning. The results indicate that the vaccine is highly conserved, strongly immunogenic, stable, non-allergenic, and non-toxic. Molecular docking and molecular dynamics simulation demonstrate that the vaccine can form a stable binding complex with TLR3. Immune simulation analysis shows that the vaccine effectively stimulates both cellular and humoral immune responses, accompanied by an increase in cytokine titers. Furthermore, through codon optimization and in silico cloning, the vaccine can be stably and effectively expressed in theEscherichia colisystem. As an effective candidate for TBEV vaccination, the multi-epitope vaccine developed in this study has promising application prospects and provides a new approach for the research, development, and improvement of vaccines targeting TBEV.
Deficient QPRT drives trans-Golgi NAD+hyperinflation and pathological protein secretion in rheumatoid arthritis
Authors: Njunge Lucy Wanjiru , Liu Kaijing , Xiong Chenghe , Chen Liuqing , He Qifei , Wang Pei , Huang Guan , Li Yong , Abhulimen Peace Osebhue , Cheng Wenxiang , Yu Qiuliyang 
Published: October 2024

AbstractAberrant protein secretion is a central driver of tissue inflammation and destruction in rheumatoid arthritis (RA). While RA fibroblast-like synoviocytes (FLSs) exhibit prominent endoplasmic reticulum (ER) and Golgi, the mechanism underlying their excessive protein secretion is not fully understood. Here, we identified the deficiency ofde novoNAD+synthesis enzyme, quinolinate phosphoribosyltransferase (QPRT), as a significant abnormality in RA synovium. QPRT loss counterintuitively inflates NAD+in the trans-Golgi network (TGN) while decreasing NAD+in the cytoplasm, ER and cis/medial-Golgi. QPRT knockdown promoted Golgi membrane expansion and epithelial-to-mesenchymal-transition (EMT)-associated secretome production in RA FLSs by suppressing TGN-residing PARP12, resulting in mTORC1-mediated protein translation and Golgi expansion. Furthermore, QPRT gene therapy restored NAD+balance, corrected Golgi dysfunction, reduced cytokine production, and improved RA severity in mouse models. These findings underscore QPRT’s role in coordinating protein secretion and the regulatory dynamics of compartmentalized NAD+, proposing QPRT targeting as a therapeutic strategy for inflammatory, secretory and Golgi-related diseases.
Correlation Between Enzymatic and Non-Enzymatic Genes inAcinetobacter baumanniiIsolates
Authors: Rahi Alya Amer , Al-Hasnawy Huda H. 
Published: October 2024

AbstractsBackgroundAcinetobacter baumanniiis a multidrug-resistant bacterium responsible for severe infections, particularly in hospital settings. Its resistance is driven by enzymatic genes such as those encoding beta-lactamases and carbapenemases, which degrade antibiotics, and non-enzymatic genes that modify mechanisms like efflux pumps and membrane permeability, further enhancing its defence against treatments. Together, these factors allowA. baumanniito thrive in clinical environments, complicating infection management.ObjectiveThis study aimed to explore the relationships between beta-lactamases, carbapenemases, efflux pumps, and membrane permeability changes, to understand their collective contribution toA. baumannii’smultidrug resistance.Materials and MethodsAmong 300 clinical isolates from urine, blood, wounds, and burns, 25 (8.33%) were identified asA. baumannii. These included 8% from urine, 12% from blood, and 40% each from wound and burn swabs. all specimens were taken from patients who have different symptoms in hospital of Al-Hilla Teaching Hospital/ Babylon. The research was carried out through the period January and June 2024. Bacterial identification was conducted using the VITEK-2 system and HI-Chromoagar®A. baumannii. Enzymatic genes were detected using conventional PCR, while non-enzymatic genes were analyzed via RT-qPCR.ResultsMolecular analysis revealed the presence of beta-lactamase (blaOXA-51, blaOXA-23) and metallo-beta-lactamase genes (blaVIM, blaIMP), with high antibiotic resistance rates. Gene expression analysis highlighted efflux pump upregulation (adeB) and altered permeability (CarO), reinforcing multidrug resistance mechanisms.ConclusionThe combined action of enzymatic and non-enzymatic resistance genes inA. baumanniipresents a significant treatment challenge, necessitating multi-target therapeutic approaches.
Disruption of molecular interactions between G3BP1 stress granule host protein and nucleocapsid (NTD-N) protein impedes SARS-CoV-2 virus replication
Authors: Dhaka Preeti , Singh Ankur , Nehul Sanketkumar , Choudhary Shweta , Panda Prasan Kumar , Sharma Gaurav Kumar , Kumar Pravindra , Tomar Shailly 
Published: October 2024

ABSTRACTThe Ras GTPase-activating protein SH3-domain-binding protein 1 (G3BP1) serves as a formidable barrier to viral replication by generating stress granules (SGs) in response to viral infections. Interestingly, viruses, including SARS-CoV-2, have evolved defensive mechanisms to hijack SG proteins like G3BP1 for the dissipation of SGs that lead to the evasion of host’s immune responses. Previous research has demonstrated that the interaction between the NTF2-like domain of G3BP1 (G3BP1NTF-2) and the intrinsically disordered N-terminal domain (NTD-N1-25) of the N protein plays a crucial role in regulating viral replication and pathogenicity. Interestingly, the current study identified an additional upstream stretch of residues (128KDGIIWVATEG138) (N128-138) within the N-terminal domain of the N protein (NTD-N41-174) that also forms molecular contacts with the G3BP1 protein, as revealed throughin silicoanalysis, site-directed mutagenesis and biochemical analysis. Remarkably, WIN-62577, and fluspirilene, the small molecules targeting the conserved peptide binding pocket in G3BP1NTF-2,not only disrupted the protein-protein interactions (PPIs) between the NTD-N41-174and G3BP1NTF-2but also exhibited significant antiviral efficacy against SARS-CoV-2 replication with EC50values of ∼1.8 µM and ∼1.3 µM, respectively. The findings of this study, validated by biophysical thermodynamics and biochemical investigations, advance the potential of developing therapeutics targeting the SG host protein against SARS-CoV-2, which may also serve as a broad-spectrum antiviral target.
A multi-subunit autophagic capture complex facilitates degradation of ER stalled MHC-I in pancreatic cancer
Authors: Berquez Marine , Li Alexander L. , Luy Matthew A. , Venida Anthony C. , O’Loughlin Thomas , Rademaker Gilles , Barpanda Abhilash , Hu Jingjie , Yano Julian , Wiita Arun , Gilbert Luke A. , Bruno Peter M. , Perera Rushika M. 
Published: October 2024

AbstractPancreatic ductal adenocarcinoma (PDA) evades immune detection partly via autophagic capture and lysosomal degradation of major histocompatibility complex class I (MHC-I). Why MHC-I is susceptible to capture via autophagy remains unclear. By synchronizing exit of proteins from the endoplasmic reticulum (ER), we show that PDAC cells display prolonged retention of MHC-I in the ER and fail to efficiently route it to the plasma membrane. A capture-complex composed of NBR1 and the ER-phagy receptor TEX264 facilitates targeting of MHC-I for autophagic degradation, and suppression of either receptor is sufficient to increase total levels and re-route MHC-I to the plasma membrane. Binding of MHC-I to the capture complex is linked to antigen presentation efficiency, as inhibiting antigen loading via knockdown of TAP1 or beta 2-Microglobulin led to increased binding between MHC-I and the TEX264-NBR1 capture complex. Conversely, expression of ER directed high affinity antigenic peptides led to increased MHC-I at the cell surface and reduced lysosomal degradation. A genome-wide CRISPRi screen identified NFXL1, as an ER-resident E3 ligase that binds to MHC-I and mediates its autophagic capture. High levels of NFXL1 are negatively correlated with MHC-I protein expression and predicts poor patient prognosis. These data highlight an ER resident capture complex tasked with sequestration and degradation of non-conformational MHC-I in PDAC cells, and targeting this complex has the potential to increase PDAC immunogenicity.