bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-Source Graph Synthesis (MUGS) for Pediatric Knowledge Graphs from Electronic Health Records
Authors: Li Mengyan , Li Xiaoou , Pan Kevin , Geva Alon , Yang Doris , Sweet Sara Morini , Bonzel Clara-Lea , Panickan Vidul Ayakulangara , Xiong Xin , Mandl Kenneth , Cai Tianxi 
Published: January 2024

AbstractThe wealth of valuable real-world medical data found within Electronic Health Record (EHR) systems is particularly significant in the field of pediatrics, where conventional clinical studies face notably high barriers. However, constructing accurate knowledge graphs from pediatric EHR data is challenging due to its limited content density compared to EHR data for the general population. Additionally, knowledge graphs built from EHR data primarily covering adult patients may not suit the unique biomedical characteristics of pediatric patients. In this research, we introduce a graph transfer learning approach aimed at constructing precise pediatric knowledge graphs. We present MUlti-source Graph Synthesis (MUGS), an algorithm designed to create embeddings for pediatric EHR codes by leveraging information from three distinct sources: (1) pediatric EHR data, (2) EHR data from the general population, and (3) existing hierarchical medical ontology knowledge shared across different patient populations. We break down these code embeddings into shared and unshared components, facilitating the adaptive and robust capture of varying levels of heterogeneity across different medical sites through meticulous hyperparameter tuning. We assessed the quality of these code embeddings in recognizing established relationships among pediatric codes, as curated from credible online sources, pediatric physicians, or GPT. Furthermore, we developed a web API for visualizing pediatric knowledge graphs generated using MUGS embeddings and devised a phenotyping algorithm to identify patients with characteristics similar to a given profile, with a specific focus on pediatric pulmonary hypertension (PH). The MUGS-generated embeddings demonstrated resilience against negative transfer and exhibited superior performance across all three tasks when compared to pediatric-only approaches, multi-site pooling, and semantic-based methods. MUGS embeddings open up new avenues for evidence-based pediatric research utilizing EHR data.
Emotion-related impulsivity is related to orbitofrontal cortical sulcation
Authors: Hastings William L. , Willbrand Ethan H. , Elliott Matthew V. , Johnson Sheri L. , Weiner Kevin S. 
Published: January 2024

AbstractBackgroundEmotion-related impulsivity (ERI) describes the trait-like tendency toward poor self-control when experiencing strong emotions. ERI has been shown to be elevated across psychiatric disorders and predictive of the onset and worsening of psychiatric syndromes. Recent work has correlated ERI scores with the neuroanatomy of the orbitofrontal cortex (OFC). Informed by a growing body of research indicating that the morphology of cortical folds (sulci) can produce insights into behavioral outcomes, the present study modeled the association between ERI and the sulcal morphology of OFC at a finer scale than previously conducted.MethodsAnalyses were conducted in a transdiagnostic sample of 118 individuals with a broad range of psychiatric syndromes. We first manually defined over 2000 sulci across the 118 participants. We then implemented a model-based LASSO regression to relate OFC sulcal morphology to ERI and test whether effects were specific to ERI as compared to non-emotion-related impulsivity.ResultsThe LASSO regression revealed bilateral associations of ERI with the depth of eight OFC sulci. These effects were specific to ERI and were not observed in non-emotion-related impulsivity. In addition, we identified a new transverse component of the olfactory sulcus in every hemisphere that is dissociable from the longitudinal component based on anatomical features and correlation with behavior, which could serve as a new transdiagnostic biomarker.ConclusionsThe results of this data-driven investigation provide greater neuroanatomical and neurodevelopmental specificity on how OFC is related to ERI. As such, findings link neuroanatomical characteristics to a trait that is highly predictive of psychopathology.
Recombinant venom proteins in insect seminal fluid reduces female lifespan
Authors: Beach Samuel J. , Maselko Maciej 
Published: January 2024

AbstractThe emergence of insecticide resistance has increased the need for alternative pest management tools1,2Numerous genetic biocontrol approaches, which involve the release of genetically modified organisms to control pest populations, are in various stages of development to provide highly targeted pest control3-7. However, all current mating-based genetic biocontrol technologies function by releasing engineered males which skew sex-ratios or reduce offspring viability in subsequent generations. This allows mated females continue to cause harm (e.g. transmit disease). Here, we demonstrate the first example ofintragenerational genetic biocontrol, wherein mating with engineered males reduces female lifespan. The toxic male technique (TMT) involves the heterologous expression of insecticidal proteins within the male reproductive tract that are transferred to females via mating. We demonstrate TMT inDrosophila melanogastermales, which reduce the median lifespan of mated females by 37 - 59% compared to controls mated to wild type males. Agent-based models ofAedes aegyptipredict that compared to existing genetic biocontrol technologies, even modest levels of mated female mortality could allow TMT to suppress a female population substantially faster, which is likely to result in reduced disease burdens. TMT presents a novel approach for combatting outbreaks of disease vectors and agricultural pests.Graphical Abstract
OmniNA: A foundation model for nucleotide sequences
Authors: Shen Xilin , Li Xiangchun 
Published: January 2024

AbstractFoundation models have demonstrated exceptional efficacy across diverse downstream tasks. However, within the realms of genomics and transcriptomics, a notable gap persists in the availability of models that afford a comprehensive understanding of nucleotide sequence principles across various species. Here, we present OmniNA, a foundation generative model designed for comprehensive nucleotide sequence learning. The model was pre-trained on 91.7 million nucleotide sequences and the corresponding annotations encompassing 1076.2 billion bases and 197 million words spanning a multitude of species. We demonstrated OmniNA gains the capacity to understand the semantics of the nucleotide sequence and textual annotations by analyzing the learned representation of the pre-trained model. OmniNA can be fine-tuned to align multiple nucleotide learning tasks with natural language paradigms. We demonstrate OmniNA-1.7B surpasses or rivals state-of-the art methods in 17 nucleotide tasks, encompassing nucleotide sequences detection and species classification. The model’s understanding of nucleotide grammars enhances its capability to reveal the mutation effect of nucleotide sequence on DNA and RNA processing. We hereby release the OmniNA-1.7B model as an open-source contribution to the research community. This foundation model signifies a step toward advancing our comprehension of nucleotide sequences across diverse species and holds substantial promise to facilitating genomics and transcriptomics research.
The Alzheimer’s Aβ peptide forms biomolecular condensates that trigger amyloid aggregation
Authors: Šneiderienė Greta , Díaz Alicia González , Adhikari Sourav Das , Wei Jiapeng , Michaels Thomas , Šneideris Tomas , Linse Sara , Vendruscolo Michele , Garai Kanchan , Knowles Tuomas P. J. 
Published: January 2024

AbstractThe onset and development of Alzheimer’s disease (AD) is linked to the accumulation of pathological aggregates formed from the normally monomeric amyloid-β peptide within the central nervous system. These Aβ aggregates are increasingly successfully targeted with clinical therapies, but the fundamental molecular steps that trigger the initial nucleation event leading to the conversion of monomeric Aβ peptide into pathological aggregates remain unknown. Here we show that the Aβ peptide can form biomolecular condensates on lipid bilayers both in molecular assays and in living cells. Our results reveal that these Aβ condensates can significantly accelerate the primary nucleation step in the amyloid conversion cascade that leads to the formation of amyloid aggregates and plaque. We show that Aβ condensates contain phospholipids, are intrinsically heterogenous, and are prone to undergo a liquid-to-solid transition leading to the formation amyloid fibrils. These findings uncover the liquid-liquid phase separation behaviour of the Aβ peptide, and reveal a new molecular step very early in the amyloid-β aggregation cascade that can form the basis for novel therapeutic intervention strategies.Significance statementThe hallmark of Alzheimer’s disease is the abnormal buildup of the normally soluble amyloid β protein aggregates in the central nervous system. While the molecular mechanisms at the late stages of the amyloid β aggregation cascade are well understood, the initial steps remained elusive until now. Our current study demonstrates that amyloid β undergoes liquid-liquid phase separation on lipid surfaces, which triggers primary nucleation and initiates the amyloid β aggregation cascade. This newly identified step in the molecular mechanism of Alzheimer’s disease represents a promising target for the development of alternative innovative therapeutic strategies.
Comparative pangenome analysis of major pneumococcal genotypes from India
Authors: Murthy Peela Sreeram Chandra , Sistla Sujatha 
Published: January 2024

AbstractBackgroundPneumococcal genomes are highly dynamic with varying core genome sizes. The genotype classification system, Global Pneumococcal Sequence Clusters, identified patterns within genotype and antibiotic resistance. Few genotypes like GPSC10 are frequently associated with antimicrobial resistance and high rates of non-vaccine serotypes.ObjectiveTo identify and annotate the differences in the core genomes of major GPSC in India, and construct and analyse the Indian Pneumococcal Pangenome (IPPG).MethodsUsing existing dataset from the Global Pneumococcal Sequencing Project, 618 strains were included. The most frequent GPSCs: GPSC1, GOSC2, GPSC8, GPSC9 and GPSC10 were analyzed separately. Pangenomes were constructed using Panaroo with tuning the family threshold parameter. Differences in protein clusters were identified using Orthovenn3 webserver. Functional annotations were performed by eggNOG, Uniprot and STRING database searches.ResultsThe IPPG core genome size (1615 genes) was similar to those reported previously, with similar distribution of metabolic categories across the five GPSC types. The GPSC10 (1619 genes) and GPSC1 (1909 genes) had the lowest and highest core genome sizes respectively, and these core genomes possessed genes encoding for macrolide and tetracycline resistance. Virulence genes ply, psaA, pce (cbpE), pavA, nanB, lytA, and hysA are detected among all the core genomes.ConclusionsThere is a genotype specific variation within the core genomes of major GPSCs in India. The presence of antibiotic resistance genes among GPSC1 and GPSC10 core genomes explain widespread drug resistance due to these genotypes. The core virulence genes identified among all the genotypes indicate conserved pathogenesis mechanisms, and can be targets for vaccine development or therapy.
Different vaccine platforms result in distinct antibody responses to the same antigen in haemodialysis patients
Authors: Wall Nadya , Lamerton Rachel , Ashford Fiona , Perez-Toledo Marisol , Jasiulewicz Aleksandra , Banham Gemma D , Newby Maddy L , Faustini Sian , Richter Alex , Selvaskandan Haresh , Billany Roseanne E , Adenwalla Sherna , Henderson Ian R , Crispin Max , Graham-Brown Matthew , Harper Lorraine , Cunningham Adam F 
Published: January 2024

AbstractGeneralised immune dysfunction in chronic kidney disease, especially in patients requiring haemodialysis (HD), significantly enhances the risk of severe infections. Moreover, vaccine-induced immunity is typically reduced in HD populations, but the full mechanisms behind this remain unclear. The SARS-CoV-2 pandemic provided an opportunity to examine the magnitude and functionality of antibody responses in HD patients to a previously unencountered antigen, Spike (S)-glycoprotein, after vaccination with different vaccine platforms (viral vector (VV); mRNA (mRV)). Here, we compared total and functional anti-S antibody responses (cross-variant neutralisation and complement binding) in 187 HD patients and 43 healthy controls 21-28 days after serial immunisation. After 2 doses of the same vaccine, HD patients had anti-S antibody levels and complement binding capacity comparable to controls. However, 2 doses of mRV induced greater polyfunctional antibody responses than VV, yet previous SARS-CoV-2 infection or an mRV boost after 2 doses of VV significantly enhanced antibody functionality in HD patients. Therefore, HD patients can generate near-normal, functional antigen-specific antibody responses following serial vaccination to a novel antigen, suggesting largely intact B cell memory. Encouragingly, exploiting immunological memory by using mRNA vaccines and boosting may improve the success of vaccination strategies in this vulnerable patient population.
Targeted CRISPR-Cas9 screening identifies transcription factor network controlling murine haemato-endothelial fate commitment
Authors: Teske Michael , Wertheimer Tobias , Butz Stefan , Zwicky Pascale , Mallona Izaskun , Elling Ulrich , Lancrin Christophe , Becher Burkhard , Grosso Ana Rita , Baubec Tuncay , Schmolka Nina 
Published: January 2024

AbstractHaematopoiesis is a tightly coordinated process that forms and maintains all blood cells. During development blood generation begins in the yolk sac with the differentiation of haemato-endothelial mesoderm giving rise to haematopoietic progenitors. Which molecular regulators are crucial for haemato-endothelial mesoderm formation remains unclear and has not been studied in an unbiased way. Here we employ a mouse embryonic stem cell model that recapitulates embryonic blood development and perform targeted CRISPR-Cas9 knock out screens focusing on transcription factors and chromatin regulators. Focusing on the transition of primitive towards haematoendothelial mesoderm we identified the known master regulator Etv2 and novel transcription factors including Smad1, Ldb1, Six4 and Zbtb7b acting as crucial drivers or repressors of mesodermal commitment. Our transcriptome analysis highlights that each factor has a precise impact on the gene expression signature of the developing mesoderm resulting in the formation of mesodermal subsets with a defined lineage differentiation bias. Our study reveals novel molecular pathways governing mesodermal development crucial to allow endothelial and haematopoietic lineage specification.
Mitochondrial ncRNA LDL-805 declines in alveolar epithelial type 2 cells of chronic obstructive pulmonary disease patients
Authors: Mathuram Theodore L. , Su Yafei , Bard Jonathan E. , Perry Noa A. , Chen Chien Wen , Warren Marisa T. , Linden Phillip A. , Perry Yaron , Hatzoglou Maria , Wu Yun , Blumental-Perry Anna 
Published: January 2024

AbstractRationaleWe showed that levels of a murine mitochondrial noncoding RNA,mito-ncR-LDL805, increase in alveolar epithelial type 2 cells exposed to extracts from cigarette smoke. The transcripts translocate to the nucleus, upregulating nucleus-encoded mitochondrial genes and mitochondrial bioenergetics. This response is lost after chronic exposure to smoke in a mouse model of chronic obstructive pulmonary disease.ObjectivesTo determine ifmito-ncR-LDL805plays a role in human disease, this study aimed to (i) identify the human homologue, (ii) test if the smoke-induced response occurs in human cells, (ii) determine causality between the subcellular localization of the transcript and increased mitochondrial bioenergetics, and (iii) analyzemito-ncR-LDL805transcript levels in samples from patients with chronic obstructive pulmonary disease.MethodsLevels and subcellular localization of the human homologue identified from an RNA transcript library were assessed in human alveolar epithelial type 2 cells exposed to smoke extract. Lipid nanoparticles were used for nucleus-targeted delivery ofmito-ncR-LDL805transcripts. Analyses includedin situhybridization, quantitative PCR, cell growth, and Seahorse mitochondrial bioenergetics assays.Measurements and Main ResultsThe levels of human homologue transiently increased and the transcripts translocated to the nuclei in human cells exposed to smoke extract. Targeted nuclear delivery of transcripts increased mitochondrial bioenergetics. Alveolar cells from humans with chronic obstructive pulmonary disease had reduced levels of themito-ncR-LDL805.Conclusionsmito-ncR-LDL805mediates mitochondrial bioenergetics in murine and human alveolar epithelial type 2 cells in response to cigarette smoke exposure, but this response is likely lost in diseases associated with chronic smoking, such as chronic obstructive pulmonary disease, due to its diminished levels.ImpactThis study describes a novel mechanism by which epithelial cells in the lungs adapt to the mitochondrial stress triggered by exposure to cigarette smoke. We show that a noncoding RNA in mitochondria is upregulated and translocated to the nuclei of alveolar epithelial type 2 cells to trigger expression of genes that restore mitochondrial bioenergetics. Mitochondria function and levels of the noncoding RNA decrease under conditions that lead to chronic obstructive pulmonary disease, suggesting that the mitochondrial noncoding RNA can serve as potential therapeutic target to restore function to halt disease progression.
Quantifying spectral information about source separation in multisource odour plumes
Authors: Tootoonian Sina , True Aaron C. , Crimaldi John P. , Schaefer Andreas T. 
Published: January 2024

AbstractOdours released by objects in natural environments can contain information about their spatial locations. In particular, the correlation of odour concentration fields produced by two spatially separated sources contains information about the distance between the sources. Mice are able to distinguish correlated and anti-correlated odour fluctuations at frequencies up to 40 Hz. Can this high-frequency acuity support odour source localization? Here we answer this question by quantifying the spatial information about source separation contained in the spectral constituents of correlations. We used computational fluid dynamics simulations of multisource plumes in two-dimensional chaotic flow environments to generate temporally complex, covarying odour concentration fields. By relating the correlation of these fields to the spectral decompositions of the associated odour concentration timeseries, and making simplifying assumptions about the statistics of these decompositions, we derived analytic expressions for the Fisher information contained in the spectral components of the correlations about source separation. We computed the Fisher information for a broad range of frequencies and source separations and found that high frequencies were more informative than low frequencies when sources were close relative to the sizes of the large eddies in the flow. We observed a qualitatively similar effect in an independent set of simulations with different geometry, but not for surrogate data with a similar power spectrum to our simulations but in which all frequencies werea prioriequally informative. Our work suggests that the high-frequency acuity of the murine olfactory system may support high-resolution spatial localization of odour sources. We also provide a model of the distribution of the spectral components of correlations that is accurate over a broad range of frequencies and source separations. More broadly, our work establishes an approach for the quantification of the spatial information in odour concentration timeseries.
Blood immunophenotyping identifies distinct kidney histopathology and outcomes in patients with lupus nephritis
Authors: Horisberger Alice , Griffith Alec , Keegan Joshua , Arazi Arnon , Pulford John , Murzin Ekaterina , Howard Kaitlyn , Hancock Brandon , Fava Andrea , Sasaki Takanori , Ghosh Tusharkanti , Inamo Jun , Beuschel Rebecca , Cao Ye , Preisinger Katie , Gutierrez-Arcelus Maria , Eisenhaure Thomas M. , Guthridge Joel , Hoover Paul J. , Dall’Era Maria , Wofsy David , Kamen Diane L. , Kalunian Kenneth C. , Furie Richard , Belmont Michael , Izmirly Peter , Clancy Robert , Hildeman David , Woodle E. Steve , Apruzzese William , McMahon Maureen A. , Grossman Jennifer , Barnas Jennifer L. , Payan-Schober Fernanda , Ishimori Mariko , Weisman Michael , Kretzler Matthias , Berthier Celine C. , Hodgin Jeffrey B. , Demeke Dawit S. , Putterman Chaim ,   Accelerating Medicines Partnership: RA/SLE Network, Brenner Michael B. , Anolik Jennifer H. , Raychaudhuri Soumya , Hacohen Nir , James Judith A. , Davidson Anne , Petri Michelle A. , Buyon Jill P. , Diamond Betty , Zhang Fan , Lederer James A. , Rao Deepak A. 
Published: January 2024

AbstractLupus nephritis (LN) is a frequent manifestation of systemic lupus erythematosus, and fewer than half of patients achieve complete renal response with standard immunosuppressants. Identifying non-invasive, blood-based pathologic immune alterations associated with renal injury could aid therapeutic decisions. Here, we used mass cytometry immunophenotyping of peripheral blood mononuclear cells in 145 patients with biopsy-proven LN and 40 healthy controls to evaluate the heterogeneity of immune activation in patients with LN and to identify correlates of renal parameters and treatment response. Unbiased analysis identified 3 immunologically distinct groups of patients with LN that were associated with different patterns of histopathology, renal cell infiltrates, urine proteomic profiles, and treatment response at one year. Patients with enriched circulating granzyme B+T cells at baseline showed more severe disease and increased numbers of activated CD8 T cells in the kidney, yet they had the highest likelihood of treatment response. A second group characterized primarily by a high type I interferon signature had a lower likelihood of response to therapy, while a third group appeared immunologically inactive by immunophenotyping at enrollment but with chronic renal injuries. Main immune profiles could be distilled down to 5 simple cytometric parameters that recapitulate several of the associations, highlighting the potential for blood immune profiling to translate to clinically useful non-invasive metrics to assess immune-mediated disease in LN.