bluuebunny/crossref_metadata_2025_split huggingface dataset:
Within-person changes in objectively measured activity levels as a predictor of brain atrophy in multiple sclerosis
Authors: Fitzgerald Kathryn C. , Sanjayan Muraleetharan , Dewey Blake , Niyogi Pratim Guha , Rjeily Nicole Bou , Fadlallah Yasser , Delaney Alice , Lee Alexandra Zambriczki , Duncan Safiya , Wyche Chelsea , Moni Ela , Calabresi Peter A. , Zipunnikov Vadim , Mowry Ellen M. 
Published: January 2025

AbstractObjectiveThe evaluate the association between changes in accelerometry-derived activity patterns and brain atrophy in people with multiple sclerosis (PwMS).MethodsWe included PwMS aged ≥40 years with approximately annual brain MRI who wore GT9X Actigraph accelerometers every three months over two years. Functional principal components analysis (fPCA) summarized overall activity and timing. Additional indices included total and 2-hour specific activity, sedentary time, and circadian rhythm parameters. Whole brain segmentation used SLANT-CRUISE. Generalized estimating equations quantifying between- and within-person effects modeled associations between accelerometry changes and MRI outcomes, adjusting for demographic and clinical factors.ResultsWe included 233 PwMS (mean age: 54.4 years, SD: 8.6, 30% male) who wore accelerometers an average of 6.3 times over 58 days across two years. fPCA showed within-person increases in the first fPC, representing low nighttime and high morning activity, were associated with slower brain atrophy (per 1 SD increase: 0.24%; 95% CI: 0.10, 0.40; p=0.0009). Similarly, a 10% increase in 8:00–10:00 AM activity was associated with 0.49% higher whole brain volume (95% CI: 0.19, 0.79; p=0.001) over time, while increased nighttime activity (0:00–2:00) was linked to −0.28% brain volume loss (95% CI: −0.48, −0.08; p=0.007). Higher moderate-to-vigorous activity and daytime activity were associated with greater brain volume preservation longitudinally.InterpretationChanges in activity patterns, particularly increased nighttime activity and reduced morning activity, are linked to brain atrophy in PwMS. Accelerometry offers a scalable, sensitive method for tracking MS progression and may be beneficial as a recruitment or outcome measure in trials.
CLINICAL VALIDATION OF SWAASA®ARTIFICIAL INTELLIGENCE PLATFORM USING COUGH SOUNDS FOR SCREENING AND DIAGNOSIS OF RESPIRATORY DISEASES
Authors: Thangakunam Balamugesh , Chandy Sujith Thomas , Rudraraju Gowrisree , Sripada Narayana Rao , Govindaraj Jayanthy , Gottipulla Charishma , Mamidgi Baswaraj , Palreddy Shubha Deepti , Bhoge Nikhil kumar Reddy , Narreddy Harsha Vardhan Reddy , Prasanna Samuel P , Christopher Devasahayam Jesudas , Jain Manmohan , Yechuri Venkat 
Published: January 2025

AbstractIntroductionAnalysis of cough sounds have the potential to give a clue regarding the underlying respiratory disease. The SaaS® platform using artificial intelligence technology can analyze the cough sounds.MethodsPatients (age >= 18 years) presenting to our departments with respiratory symptoms were prospectively recruited into the study. Patients cough sound was recorded by a mobile device in which the Swaasa software was installed. Spirometry was done and patients’ clinical diagnosis is taken as reference standard for comparison. Polychotomous variables were analyzed in binary form as normal and abnormal. Multi-class outcomes were defined as obstructive, restrictive, or normal spirometry, mild-moderate-severe impairment of spirometry values or disease conditions like asthma, COPD, ILD, Bronchiectasis.ResultsWe recruited 2179 patients with respiratory diseases and 827 normal individuals. Sixty-two percent of them were males. The Swaasa platform has 90% accuracy in distinguishing cough from normal individuals and patients as well as distinguishing normal from abnormal spirometry. The performance was consistent across demographic parameters such as age, gender, and BMI. Its accuracy in differentiating into various severity subtypes of spirometry as well as disease types can be improved further.ConclusionSwaasa®commends an elevated level of precision in classifying normal and abnormal conditions across demographic subgroups indicating its promise as a screening tool. While the accuracy measures emphasize further refinement to ensure consistent high performance across disease scenarios and severity levels, the study shows Swaasa®’s reasonable potential in identification of specific respiratory diseases and their severity.
Validation of an AI for Skin Diseases in Korea and Global Usage Statistics
Authors: Han Seung Seog , Cho Soo Ick , Chang Sung Eun , Kim Seong Hwan , Na Jung-Im 
Published: January 2025

BackgroundTo address the diversity of skin conditions and the low prevalence of skin cancers, we curated a large dataset and collected real-world data, to evaluate the real-world performance.MethodsWe evaluated a neural network model using the NIA dataset (70 diseases; 152,443 images from 92,004 cases from 9 hospitals). The NIA dataset was used to calculate the algorithm’s sensitivity for detecting skin cancer. Global usage statistics (1,690,849 queries) were analyzed to estimate the algorithm’s specificity for malignancy predictions, assuming all predictions were false positives.A global reader test (61,066 questionnaires) was performed using the SNU dataset (80 diseases; 240 images).ResultsFor malignancy diagnosis (NIA dataset), the sensitivity of the algorithm was 78.2% based on the three predicted differentials. In global usage statistics, among predictions for tumorous conditions, the malignancy prediction rates from the three differentials were 12.0% in Korea and 10.0% globally. The algorithm’s predictions for benign tumors were most prevalent in Asia (55.5%), Oceania (46.8%), and Europe (46.5%), while predictions for infectious diseases were more common in Africa (17.1%)In the reader test (SNU dataset), sensitivity / specificity of the algorithm (87.5% / 91.0%) outperformed those of participants (Korea = 56.9% / 87.2%, global = 55.5% / 84.3%).ConclusionFor skin cancer diagnosis in Korea, the sensitivity and specificity of the algorithm were estimated to be 78.2% and 88.0%. Further research on appropriate indications is required for screening use, taking overdiagnosis into consideration.
mRNA lipid nanoparticle-incorporated nanofiber-hydrogel composite generates a local immunostimulatory niche for cancer immunotherapy
Authors: Zhu Yining , Yao Zhi-Cheng , Li Shuyi , Ma Jingyao , Wei Christine , Yu Di , Stelzel Jessica L. , Ni Bobby Y.X. , Miao Yang , Van Batavia Kyra , Lu Xiaoya , Lin Jinghan , Dai Yifan , Kong Jiayuan , Shen Ruochen , Goodier Kailei D. , Liu Xiang , Cheng Leonardo , Vuong Ivan , Howard Gregory P. , Livingston Natalie K. , Choy Joseph , Schneck Jonathan P. , Doloff Joshua C. , Reddy Sashank K. , Hickey John W. , Mao Hai-Quan 
Published: January 2025

ABSTRACTHydrogel materials have emerged as versatile platforms for various biomedical applications. Notably, the engineered nanofiber-hydrogel composite (NHC) has proven effective in mimicking the soft tissue extracellular matrix, facilitating substantial recruitment of host immune cells and the formation of a local immunostimulatory microenvironment. Leveraging this feature, here we report an mRNA lipid nanoparticle (LNP)-incorporated NHC microgel matrix, termed LiNx, by incorporating LNPs loaded with mRNA encoding tumour antigens. Harnessing the potent transfection efficiency of LNPs in antigen-presenting cells (APCs), LiNx demonstrates remarkable immune cell recruitment, antigen expression and presentation, and cellular interaction. These attributes collectively create an immunostimulating milieu and yield a potent immune response achievable with a single dose, comparable to the conventional three-dose LNP immunization regimen. Further investigations reveal that the LiNx not only generates heightened Th1 and Th2 responses but also elicits a distinctive Type 17 T helper cell-mediated response pivotal for bolstering antitumour efficacy. Our findings elucidate the mechanism underlying LiNx’s role in potentiating antigen-specific immune responses, presenting a new strategy for cancer immunotherapy.
ZUGC-RNA degradation generates immunosuppressor to evade immune responses in eukaryotes
Authors: Gao Shuliang , Chen Mengting , Wich Douglas , Bloomer Hanan , Qu Zhiyuan , Guan Huiwen , Xu Qiaobing 
Published: January 2025

AbstractAmong the hundreds of modified nucleosides identified in terrestrial life, 2-amino-6-aminopurine (Z) is widely recognized as a prominent modified purine. Recently, RNA written with the ZUGC alphabet shows significant potential in RNA therapeutics as a synthetic biosystem. Here, we demonstrate that ZUGC-RNA can evade immune recognition in eukaryotes, independent of factors such as RNA length, sequence, 5’-triphosphate, modified uridine, and secondary structure. Notably, we discovered that both the degradation of ZUGC-RNA and metabolites of Z-nucleotides can function as immunosuppressors, silencing TLR7 sensing to block immune responses. This mechanism differs from that of pseudo-uridine (Ψ) modified RNA currently in use. ZUGC-RNAs also demonstrate broad applicability across multiple neural cell types. Our findings provide valuable insights for developing more tolerable RNA-based drugs and designing immunomodulators targeting TLR7. In addition to the potential prebiotic relevance of Z, our finding not only contributes to understanding the RNA world hypothesis but also provides new insights into the exploration of the origin of life.
FLIM Imaging of mCherryTYG Deciphers pH Dynamics and Lifestyles ofSalmonellaTyphimurium
Authors: Singh Moirangthem Kiran , Fernandez Marion , Dilawari Rahul , Zangoui Parisa , Kenney Linda J. 
Published: January 2025

ABSTRACTIntracellular pH regulation is fundamental to bacterial adaptation, virulence, and survival in diverse environments.SalmonellaTyphimurium, a key human pathogen, exploits host and environmental pH cues to transition between planktonic, biofilm, and virulence-associated states. However, precise tools to monitor bacterial pH dynamics at subcellular resolution have been limited. Herein, we report the development and application of mCherryTYG, a genetically encoded pH-sensitive fluorophore optimized for fluorescence lifetime imaging (FLIM), enabling robust and high-resolution pH measurements across diverse conditions. mCherryTYG demonstrated exceptional sensitivity across a broad pH range (5.5–8.5) with consistent lifetime responses, and was unaffected by temperature, buffer composition, or ionic strength. Using FLIM, we characterized the pH dynamics ofSalmonellaacrossin vitro, host, and biofilm contexts. Under acidic stressin vitro,Salmonellamaintained a uniform intracellular pH (∼6.04), providing clarity on previously debated heterogeneity. In infections of HeLa cells,Salmonellaexisted in distinct pH environments: acidic vacuolar pH (∼5.89) and neutral cytoplasmic pH (∼7.10). During the late infection stage, ∼17% of the bacterial population retained an acidic pH. Biofilm studies revealed stratified pH profiles, with acidic pH near the bottom and neutral pH at the surface, mirroring patterns observed in other pathogens. In heterologous host models, pH gradients shaped bacterial adaptation strategies. InC. elegans,Salmonellaexperienced a progressive pH gradient from neutral pH (∼7.10) in the anterior lumen to acidic pH (∼6.45) in the posterior. Similarly, in zebrafish,Salmonellaencountered acidic lysosome-rich enterocytes (∼5.84) and neutral regions (∼7.33) in the anterior gut. This study establishes mCherryTYG-FLIM as a transformative tool for studying bacterial pH regulation, revealing pH as a critical modulator ofSalmonellalifestyle transitions: virulence, and persistence. Our findings provide new insights into host-microbe interactions and present pH as a promising target for therapeutic interventions against bacterial infections.
Loss of tumor cell MHC Class II drives insensitivity of BRAF-mutant anaplastic thyroid cancers to MAPK inhibitors
Authors: Tiedje Vera , Greenberg Jillian , Qin Tianyue , Im Soo-Yeon , Krishnamoorthy Gnana P. , Boucai Laura , Xu Bin , French Jena D. , Sherman Eric J , Ho Alan L , de Stanchina Elisa , Socci Nicholas D. , Jin Jian , Ghossein Ronald , Knauf Jeffrey A. , Koche Richard P , Fagin James A. 
Published: January 2025

AbstractCancer cells present neoantigens dominantly through MHC class I (MHCI) to drive tumor rejection through cytotoxic CD8+ T-cells. There is growing recognition that a subset of tumors express MHC class II (MHCII), causing recognition of antigens by TCRs of CD4+ T-cells that contribute to the anti-tumor response. We find that mouse BrafV600E-driven anaplastic thyroid cancers (ATC) respond markedly to the RAF + MEK inhibitors dabrafenib and trametinib (dab/tram) and that this is associated with upregulation of MhcII in cancer cells and increased CD4+ T-cell infiltration. A subset of recurrent tumors lose MhcII expression due to silencing ofCiita, the master transcriptional regulator of MhcII, despite preserved interferon gamma signal transduction, which can be rescued by EZH2 inhibition. Orthotopically-implanted Ciita-/-and H2-Ab1-/-ATC cells into immune competent mice become unresponsive to the MAPK inhibitors. Moreover, depletion of CD4+, but not CD8+ T-cells, also abrogates response to dab/tram. These findings implicate MHCII-driven CD4+ T cell activation as a key determinant of the response of Braf-mutant ATCs to MAPK inhibition.
An oligo walk to identify siRNAs against the circular Tau 12->7 RNA
Authors: Welden Justin R. , Margvelani Giorgi , Miaro Megan , Mathews David , Rodgers David W. , Stamm Stefan 
Published: January 2025

AbstractCircular RNAs are associated with numerous diseases and recent evidence shows that they can be translated into proteins after undergoing RNA modification. Circular RNAs differ from their ‘linear’ mRNA counterparts in their backsplice site, allowing selective targeting using RNA interference, which however limits the options to place the siRNA. We tested all possible siRNAs against the backsplice site of the circTau 12->7 RNA after it was subjected to adenosine to inosine RNA editing, a modification that promotes translation of the circRNA. Most siRNAs reduced the circRNA and protein abundance, which however did not correlate. We identified an siRNA with an IC50 of 750 pmol efficacy on protein expression. This circRNA fulfilled six of the eight criteria for siRNAs targeting mRNAs. Thus, modified circRNAs expressing protein can be targeted with siRNAs, but their optimal sequence needs to be determined empirically.
Combining Directed Evolution with Machine Learning Enables Accurate Genotype-to-Phenotype Predictions
Authors: Howard Alexander J. , Rim Ellen Y. , Garrett Oscar D. , Shim Yejin , Notwell James H. , Ronald Pamela C. 
Published: January 2025

AbstractLinking sequence variation to phenotypic effects is critical for efficient exploitation of large genomic datasets. Here we present a novel approach combining directed evolution with protein language modeling to characterize naturally-evolved variants of a rice immune receptor. Using high-throughput directed evolution, we engineered the rice immune receptorPik-1to bind and recognize the fungal proteins Avr-PikC and Avr-PikF, which evade detection by currently characterizedPik-1alleles. A protein language model was fine-tuned on this data to correlate sequence variation with ligand binding behavior. This modeling was then used to characterizePik-1variants found in the 3,000 Rice Genomes Project dataset. Two variants scored highly for binding against Avr-PikC, andin vitroanalyses confirmed their improved ligand binding over the wild-typePik-1receptor. Overall, this machine learning approach identified promising sources of disease resistance in rice and shows potential utility for exploring the phenotypic variation of other proteins of interest.
Unconventionally primed type 1 follicular helper T cells are required for long-lived IgA plasma cell development following mucosal viral infection
Authors: Haniuda Kei , Edner Natalie M. , Makita Yuko , Watts Tania H. , Wu Gregory F. , Dileepan Thamotharampillai , Gommerman Jennifer L. 
Published: January 2025

AbstractAlthough IgA+long-lived plasma cells (LLPCs) generated following mucosal viral infection provide durable protection against reinfection, little is known about their generation. Here, we show that oral RV infection induces gut-resident LLPCs that produce highly mutated protective IgA. Unlike RV-specific IgG+LLPCs, IgA+LLPCs were generated independently of MHCII expression by dendritic cells – rather MHCII expression by B cells was both necessary and sufficient. B cell MHCII was also sufficient to induce a unique population of T-bet+follicular helper T (TFH1) cells which were crucial for RV-specific IgA+LLPC accumulation in the gut via IFNγ- and CXCR3-dependent mechanisms. Similar to RV infection, TFH1 cells were required for influenza-specific IgA response. However, unlike RV infection, B cell MHCII was not sufficient to induce influenza-specific IgA+LLPCs, suggesting the operation of mucosal site-specific priming mechanisms. Collectively, our data reveal that unconventionally primed TFH1 cells support IgA responses to mucosal viral infections.
Designing biochemical circuits with tree search
Authors: Bhamidipati Pranav S. , Thomson Matthew 
Published: January 2025

AbstractDiscovering biochemical circuits that exhibit a desired behavior is an outstanding problem in biological engineering. The traditional approach of enumerating every possible circuit topology becomes intractable for circuits with more than four components due to combinatorial scaling of the search space. Here, we use Monte Carlo Tree Search (MCTS), a reinforcement learning (RL) algorithm, to optimize circuit topology for a target phenotype by approaching circuit design as a sequence of assembly decisions. Our RL-based design framework, which we call CircuiTree, efficiently and comprehensively finds robust designs for three-component oscillators by prioritizing sparsity. CircuiTree can also infer candidate network motifs from its search results, producing similar results to enumeration. Using parallel MCTS, we scale this workflow up to five components and find that highly fault-tolerant designs use a novel strategy, which we call motif multiplexing. Multiplexed circuits contain many overlapping network motifs that each activate in different mutational scenarios. The evolutionary robustness of multiplexing may explain the ubiquity of multiple sub-oscillators in circadian clock circuits. Overall, CircuiTree provides the first scalable computational platform for designing biochemical circuits.
Accelerated Adaptation of SARS-CoV-2 Variants in Mice Lacking IFITM3 Preserves Distinct Tropism and Pathogenesis
Authors: Denz Parker J. , Papa Jonathan L. , McFadden Matthew I. , Rao Prerana R. , Roettger Jack , Forero Adriana , Yount Jacob S. 
Published: January 2025

ABSTRACTHere we investigated whether interferon induced transmembrane protein 3 (IFITM3), a key antiviral protein deficient in certain human populations, affects interspecies adaptation of SARS-CoV-2. We found that SARS-CoV-2 Beta and Omicron variants passaged through IFITM3-deficient versus wild type mice exhibit enhanced replication and pathogenesis in this new host species. Enhancements associated with amino acid substitutions in the viral genome, suggesting that IFITM3 limits accumulation of adaptive mutations. Mouse-adapted viruses enabled comparative studies of variants in mice. Beta caused lung dysfunction and altered cilia-associated gene programs, consistent with broad viral antigen distribution in lungs. Omicron, which shows low pathogenicity and upper respiratory tract preference in humans, replicated to high nasal titers while showing restrained spatial distribution in lungs and diminished lung inflammatory responses compared to Beta. Our findings demonstrate that IFITM3 deficiency accelerates coronavirus adaptation and reveal that intrinsic SARS-CoV-2 variant traits shape tropism, immunity, and pathogenesis across hosts.HIGHLIGHTSIFITM3 is a critical barrier to SARS-CoV-2 adaptation in new host speciesMouse-adapted SARS-CoV-2 strains enable comparative pathologyOmicron favors nose and large airways, leading to mild lung pathologyBeta exhibits broad lung replication, driving severe inflammation and dysfunction
The Host DHX29 RNA Helicase Regulates HCMV Immediate Early Protein Synthesis
Authors: Lenarcic Erik M. , Moorman Nathaniel J. 
Published: January 2025

AbstractThe dead box helicase DHX29 plays a critical role in the translation of mRNAs containing complex RNA secondary structure in their 5’ untranslated regions. The human cytomegalovirus (HCMV) genome has a high GC content, suggesting the 5’UTRs of viral mRNAs may contain significant secondary structure and require DHX29 for their efficient translation initiation. We found that depleting DHX29 from primary human fibroblasts prior to infection reduced viral mRNA and protein levels and decreased HCMV replication. The defect in HCMV replication correlated with decreased expression of the HCMV immediate early proteins IE1 and IE2, which are necessary for the establishment of lytic infection. Analysis of polysome associated mRNAs revealed that the defect in IE1 and IE2 expression is due to decreased mRNA translation efficiency. We found that DHX29 depletion led to reduced levels of the eIF4F translation initiation complex, resulting from decreased translation of the eIF4G mRNA. However, in line with our previous results showing a minimal role for the eIF4F complex in HCMV mRNA translation, we found that depleting eIF4G prior to infection did not impact IE1 and IE2 translation. Together our results define a new role for DHX29 in regulating eIF4F-dependent translation and identify a critical role for DHX29 in the translation of HCMV mRNAs.SignificanceExpression of the HCMV immediate early proteins IE1 and IE2 is critical for the establishment of lytic replication and the reactivation of latent HCMV infections. Defining the mechanisms controlling HCMV IE1 and IE2 protein expression has the potential to identify new strategies for therapeutic interventions that can limit HCMV disease in immune naïve and immune compromised individuals. Our finding that the cellular DHX29 helicase is necessary for the efficient translation of mRNAs encoding IE1 and IE2 suggests that therapies that inhibit DHX29 could potentially be useful in treating HCMV disease and adds to the growing body of literature suggesting DHX29 activity is a disease driver in multiple indications including viral disease, inflammation and cancer.
Zmap: an intelligent region-allocation method to map single-cell into spatial data
Authors: Cai Quanyou , Lin Lihui , Liu Xin , Chen Jiekai 
Published: January 2025

ABSTRACTIntegration of single-cell and spatial transcriptome represents as a fundamental strategy to enhance spatial data quality. However, existing methods for mapping single-cell data to spatial coordinates struggle with large-scale datasets comprising millions of cells. Here, we introduce Zmap, an intelligent region-allocation method inspired by the region-of-interest (ROI) concept from image processing. By using gradient descent, Zmap allocates cells to structured spatial regions that matching the most significant biological information, optimizing the integration of data and improving speed and accuracy. Zmap excels in integrating data even in the presence of various sequencing artifacts, such as cell segmentation errors and imbalanced cell-type representations. Zmap outperforms state-of-the-art methods by 10 to 1000 times in speed, and it is the only approach capable of integrating datasets containing millions of cells in a single run. As a result, Zmap uncovers originally hidden gene expression patterns in the brain section, offers new insights into organogenesis and tumor microenvironments, all with exceptional efficiency and accuracy.