bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying common disease trajectories of Alzheimer’s disease with electronic health records
Authors: Fu Mingzhou , Chang Timothy S. 
Published: July 2024

AbstractBackgroundsAlzheimer’s disease (AD), a leading cause of dementia, poses a growing global public health challenge. While recent studies have identified AD risk factors, they often focus on specific comorbidities, neglecting the complex interrelations and temporal dynamics. Our study addresses this by analyzing AD progression through longitudinal trajectories, utilizing clinical diagnoses over time. Using machine learning and network analysis, we created a computational framework to identify common AD progression patterns.MethodsWe analyzed patient diagnoses from UC Health Data Warehouse’s Electronic Health Records, coded with the International Classification of Diseases, version 10 (ICD-10). Using the Fine and Gray model to detect significant temporal risk factors between diagnoses, we examined associations between diagnosis pairs and refined the patients’ diagnostic trajectories, delineating all possible trajectory combinations. These refined trajectories were compared using Dynamic Time Warping and grouped into clusters with hierarchical clustering. We investigated common AD trajectories through network analysis and compared patient demographics, symptoms, and AD manifestations across clusters. The Greedy Equivalence Search algorithm was used to infer causal relationships within these trajectories. We rigorously evaluated these trajectories through association tests and comparison to controls,ResultsOur analysis included 24,473 eligible AD patients, which was filtered to include 5,762 patients with 6,794 unique AD progression trajectories. We identified four trajectory clusters: 1) a mental health cluster (e.g., anxiety disorder → depressive episode) (N_patient = 1,448); 2) an encephalopathy cluster (e.g., hypertension → other disorders of brain) (N_patient = 3,223); 3) a neurodegenerative disease cluster (e.g., transient cerebral ischemic attacks → other degenerative disease of nervous system) (N_patient = 1,502); and 4) a vascular disease cluster (e.g. hypertension → other cerebrovascular diseases) (N_patient = 1,446). Significant differences were observed in demographics, symptoms, and AD features across clusters. Causal analysis indicated that 26.2% of the identified trajectory connections were causal. We also observed patients with risk trajectories faced higher risks of AD compared to those without the trajectory or with only a single risk factor.ConclusionWe uncovered AD diagnosis trajectories, incorporating temporal aspects and causal relationships. These insights improve our understanding of AD development and AD subtypes, and can enhance risk assessment. Our findings can significantly benefit patient care and medical research by moving toward earlier and more accurate diagnoses, along with personalized treatment, such as medical risk factors management and lifestyle modifications.
Polyamines sustain epithelial regeneration in aged intestines by modulating protein homeostasis
Authors: Minetti Alberto , Omrani Omid , Brenner Christiane , Allies Gabriele , Imada Shinya , Rösler Jonas , Khawaled Saleh , Cansiz Feyza , Meckelmann Sven W. , Gebert Nadja , Heinze Ivonne , Lu Jing , Spengler Katrin , Rasa Mahdi , Heller Regine , Yilmaz Omer , Tasdogan Alpaslan , Neri Francesco , Ori Alessandro 
Published: July 2024

AbstractAging hampers the regenerative potential of intestinal epithelium across species including humans, yet the underlying causes remain elusive. Here, using proteomic and metabolomic profiling of intestinal tissues together with functional assays, we characterized the temporal dynamics of regeneration following injury induced by 5-fluorouracil, a commonly used chemotherapeutic agent. Comparison of regeneration dynamics in mice of different ages revealed the emergence of a proteostasis stress signature and increased levels of polyamines following injury exclusively in old epithelia. Mechanistically, we show that delayed regeneration is an intrinsic feature of aged epithelial cells that display reduced protein synthesis and accumulation of ubiquitylated proteins. Notably, dietary restriction followed by re-feeding prior to injury increases polyamine pathway activation, enhances protein synthesis, and restores the regenerative capacity of aged intestines. Our findings highlight promising epithelial targets for interventions aimed at tackling the decline in tissue repair mechanisms associated with aging.
Multiome Perturb-seq unlocks scalable discovery of integrated perturbation effects on the transcriptome and epigenome
Authors: Metzner Eli , Southard Kaden M. , Norman Thomas M. 
Published: July 2024

SUMMARYSingle-cell CRISPR screens link genetic perturbations to transcriptional states, but high-throughput methods connecting these induced changes to their regulatory foundations are limited. Here we introduce Multiome Perturb-seq, extending single-cell CRISPR screens to simultaneously measure perturbation-induced changes in gene expression and chromatin accessibility. We apply Multiome Perturb-seq in a CRISPRi screen of 13 chromatin remodelers in human RPE-1 cells, achieving efficient assignment of sgRNA identities to single nuclei via an improved method for capturing barcode transcripts from nuclear RNA. We organize expression and accessibility measurements into coherent programs describing the integrated effects of perturbations on cell state, finding thatARID1AandSUZ12knockdowns induce programs enriched for developmental features. Pseudotime analysis of perturbations connects accessibility changes to changes in gene expression, highlighting the value of multimodal profiling. Overall, our method provides a scalable and simply implemented system to dissect the regulatory logic underpinning cell state.
The acquisition of additional control over quorum sensing regulation buffers noise in microbial growth dynamics
Authors: Fondi Marco , Riccardi Christopher , Patti Francesca Di , Coscione Francesca , Mengoni Alessio , Perrin Elena 
Published: July 2024

ABSTRACTQuorum sensing (QS) is a cell-to-cell communication system used by bacteria to act collectively. Often, bacteria possess more than one QS regulatory module that form complex regulatory networks. Presumably, these configurations have evolved through the integration of novel transcription factors into the native regulatory systems. The selective advantages provided by these alternative configurations on QS-related phenotypes is poorly predictable only based on their underlying network structure. Here we show that the acquisition of extra regulatory modules of QS has important consequences on the overall regulation of microbial growth dynamics by significantly reducing the variability in the final size of the population inBurkholderia. We mapped the distribution of horizontally transferred QS modules in extant bacterial genomes, finding that these tend to add up to already-present modules in the majority of cases, 63.32%. We then selected a strain harboring two intertwined QS modules and,using mathematical modelling, we predicted an intrinsic ability of the newly acquired module to buffer noise in growth dynamics. We experimentally validated this prediction choosing one strain possessing both systems, deleting one of the two and measuring key growth parameters and QS synthase expression. We extended such considerations on two other strains naturally implementing the two versions of the QS regulation studied herein. Finally, using transcriptomics, we show that the de-regulation of metabolism likely plays a key role in differentiating the two configurations. Our results shed light on the role of additional control over QS regulation and illuminate on the possible phenotypes that may arise after HGT events.
Characterisation of human hair follicle development
Authors: Sudderick Zoe R. , Glover James D. , Batho-Samblas Cameron , Shih Barbara Bo-Ju , Headon Denis J. 
Published: July 2024

AbstractHumans have a characteristic distribution of hair across the body. Visible, relatively long and thick terminal hair fibres are present on the scalp and eyebrows in childhood, and are stimulated to grow on other parts of the body, such as the beard and armpits, by hormones during puberty. The short and fine vellus hairs, in contrast, are not readily visible and cover most of the body, including the face. Here we report quantification of the timing and characteristics of hair follicle development in human embryogenesis, from gestational weeks 8 to 19, and compare this to mouse hair follicle development. We find that human hair follicles develop first on the head, where we identify several distinct initiation sites, followed by the torso. Although terminal and vellus hair follicles have clear differences in the adult, both hair types initially develop from placodes and dermal condensates of similar size. Once their development is initiated, we find that human hair follicles grow and mature at the same rate, regardless of anatomical location, but have different density at different body sites. These findings suggest that regional hair differences in human skin, such as the distinction between scalp and forehead, are largely caused by processes acting after the initial hair follicle morphogenesis. Efforts to understand the evolution of human ‘hairlessness’ should, therefore, focus on genetic and cellular events that take place after hair follicle morphogenesis. Finally, we compared human skin appendages, including eccrine sweat glands, with those in mouse. We found that molecular markers, such as EDA, EDAR, SOX2 and WNT pathway components, are broadly similar in expression between both species, although specific differences do exist. Together with comparison of morphology and gene expression, these results support the use of embryonic mouse primary hair follicles as a model for human hair follicle development.
Cell-free expression of Nipah virus transmembrane proteins for proteoliposome vaccine design
Authors: Hu Vivian T. , Ezzatpour Shahrzad , Selivanovitch Ekaterina , Carter Jordan , Sahler Julie , Adeleke Richard Ayomide , August Avery , Aguilar Hector C. , Daniel Susan , Kamat Neha P. 
Published: July 2024

AbstractMembrane proteins expressed on the surface of enveloped viruses are potent antigens in a vaccine, yet are difficult to produce and present due to their instability without a lipid scaffold. Current vaccination strategies that incorporate viral membrane proteins, such as live attenuated viruses, inactivated viruses, or extracellular vesicles, have limitations including lengthy production time, poor immunogenicity, extensive processing steps, and/or poor stability. Cell-free protein synthesis of viral membrane proteins offers a rapid, one-step method to assemble vaccine nanoparticles via cotranslational folding of membrane proteins into nanoscale liposomes. Here, we develop a vaccine candidate for the deadly Nipah virus (NiV), a highly lethal virus listed by the World Health Organization as a priority pathogen, by cell-free expressing two full-length Nipah virus membrane proteins. We demonstrate that both NiV fusion protein (NiV F) and NiV glycoprotein (NiV G) can be expressed and cotranslationally integrated into liposomes and that they fold into their native conformation. We find the removal of a signal peptide sequence and alteration of liposome lipid composition improves viral membrane protein incorporation. Furthermore, a lipid adjuvant, monophosphoryl lipid A (MPLA), can be readily added to liposomes without disrupting protein-vesicle loading or protein folding conformations. Finally, we demonstrate that our generated liposomal formulations lead to enhanced humoral responses in mice compared to empty and single-protein controls. This work establishes a platform to quickly assemble and present membrane antigens as multivalent vaccines that will enable a rapid response to the broad range of emerging pathogenic threats.
In-vitro Metabolite Identification for MEDI7219, an Oral GLP-1 Peptide, using LC-MS/MS with CID and EAD Fragmentation
Authors: Liu Kate , Huang Yue , Wang Taoqing , Mu Ruipeng , Rosenbaum Anton I. 
Published: July 2024

AbstractOral peptide therapeutics typically suffer from short half-lives as they are readily degraded by digestive enzymes. Systematic peptide engineering along with formulation optimization led to the development of a clinical candidate MEDI7219, an orally-bioavailable GLP-1 peptide, that is much more stable than wild type GLP-1 or semaglutide. In this study, we elucidated peptide biotransformation products using in vitro pancreatin assay that employed both collision-induced dissociation (CID) and electron-activated dissociation (EAD) LC-MS/MS methods. Using this approach, we have confidently identified a total of 13 metabolites. Relative quantification of these metabolites over time showed sequential cleavage pattern as peptides were further digested to smaller fragments. These 13 metabolites mapped to 8 cleavage sites on MEDI7219 structure. Most of these cleavage sites can be explained by the specificity of digestive enzymes, e.g. ,trypsin, pepsin and elastase. α-methyl-L-phenylalanine appeared to be well protected from chymotrypsin and pepsin digestion since no cleavage peptides ending with α-methyl-L-phenylalanine were observed. These study results expand upon previously published stability data and provide new insights on potential GLP1 proteolytic liabilities for future engineering. Furthermore, this study exemplifies the application of pancreatin in vitro system methodology as a valuable tool for understanding metabolism of oral peptide therapeuticsin vitro. Additionally, orthogonal MS fragmentation modes offered improved confidence in identification for peptide unknown metabolites.Significance StatementIn vitro metabolite identification of oral GLP1 peptide that uncovers potential proteolytic hotspots that can inform future oral peptide engineering.
Comparative Genomic Analysis ofCampylobacter rectusand Closely Related Species
Authors: Hughes Lago Casey , Blackburn Dana , Kinder Pavlicek Meghan , Threadgill Deborah S. 
Published: July 2024

ABSTRACTCampylobacter rectusis a gram-negative, anaerobic bacterium strongly associated with periodontitis. It also causes various extraoral infections and is linked to adverse pregnancy outcomes in humans and murine models.C. rectusand related oralCampylobactershave been termed “emergingCampylobacterspecies” because infections by these organisms are likely underreported. Previously, no comparative methods have been used to analyze more than singleC. rectusstrains and until recently, very fewC. rectusgenomes have been publicly available. More sequenced genomes and comparative analyses are needed to study the genomic features and pathogenicity of this species. We sequenced eight newC. rectusstrains and used comparative methods to identify regions of interest. An emphasis was put on the type III flagellar secretion system (T3SS), type IV secretion system (T4SS), and type VI secretion system (T6SS) because these protein complexes are important for pathogenesis in otherCampylobacterspecies. RAST, BV-BRC, and other bioinformatics tools were used to assemble, annotate, and compare these regions in the genomes. The pan-genome ofC. rectusconsists of 2670 genes with core and accessory genomes of 1429 and 1241 genes, respectively. All isolates analyzed in this study have T3SS and T6SS hallmark proteins, while five of the isolates are missing a T4SS system. Twenty-one prophage clusters were identified across the panel of isolates, including four that appear intact. Overall, significant genomic islands were found, suggesting regions in the genomes that underwent horizontal gene transfer. Additionally, the high frequency of CRISPR arrays and other repetitive elements has led to genome rearrangements across the strains, including in areas adjacent to secretion system gene clusters. This study describes the substantial diversity present amongC. rectusisolates and highlights tools/assays that have been developed to permit functional genomic studies. Additionally, we have expanded the studies onC. showaeT4SS since we have two newC. showaegenomes to report. We also demonstrate that unlikeC. rectus,C showaedoes not demonstrate evidence of intact T6SS except for the strain CAM. The only strain of sequencedC. massilensishas neither T4SS or T6SS.
Multi-omics Analysis of Umbilical Cord Hematopoietic Stem Cells from a Multi-ethnic Cohort of Hawaii Reveals the Intergenerational Effect of Maternal Pre-Pregnancy Obesity and Risk Prediction for Cancers
Authors: Du Yuheng , Benny Paula A. , Shao Yuchen , Schlueter Ryan J. , Gurary Alexandra , Lum-Jones Annette , Lassiter Cameron B , AlAkwaa Fadhl M. , Tiirikainen Maarit , Towner Dena , Ward W. Steven , Garmire Lana X 
Published: July 2024

AbstractBackgroundMaternal obesity is a health concern that may predispose newborns to a high risk of medical problems later in life. To understand the intergenerational effect of maternal obesity, we hypothesized that the maternal obesity effect is mediated by epigenetic changes in the CD34+/CD38−/Lin− hematopoietic stem cells (uHSCs) in the offspring. Towards this, we conducted a DNA methylation centric multi-omics study. We measured the DNA methylation and gene expression in the CD34+/CD38−/Lin− uHSCs and metabolomics of the cord blood, all from a multi-ethnic cohort (n=72) from Kapiolani Medical Center for Women and Children in Honolulu, Hawaii (collected between 2016 and 2018).ResultsDifferential methylation (DM) analysis unveiled a global hypermethylation pattern in the maternal pre-pregnancy obese group (BH adjusted p<0.05), after adjusting for major clinical confounders. KEGG pathway enrichment, WGCNA, and PPI analyses revealed hypermethylated CpG sites were involved in critical biological processes, including cell cycle, protein synthesis, immune signaling, and lipid metabolism. Utilizing Shannon entropy on uHSCs methylation, we discerned notably higher quiescence of uHSCs impacted by maternal obesity. Additionally, the integration of multi-omics data-including methylation, gene expression, and metabolomics-provided further evidence of dysfunctions in adipogenesis, erythropoietin production, cell differentiation, and DNA repair, aligning with the findings at the epigenetic level. Furthermore, we trained a random forest classifier using the CpG sites in the genes of the top pathways associated with maternal obesity, and applied it to predict cancer vs. adjacent normal labels from samples in 14 Cancer Genome Atlas (TCGA) cancer types. Five of 14 cancers showed balanced accuracy of 0.6 or higher: LUSC (0.87), PAAD (0.83), KIRC (0.71), KIRP (0.63) and BRCA (0.60).ConclusionsThis study revealed the significant correlation between pre-pregnancy maternal obesity and multi-omics level molecular changes in the uHSCs of offspring, particularly in DNA methylation. Moreover, these maternal obesity epigenetic markers in uHSCs may predispose offspring to higher risks in certain cancers.
Conserved perception of host and non-host signals via the a-pheromone receptor Ste3 inColletotrichum graminicola
Authors: Rudolph Anina Yasmin , Schunke Carolin , Nordzieke Daniela Elisabeth 
Published: July 2024

AbstractUnderstanding the interactions between fungal plant pathogens and host roots is crucial for developing effective disease management strategies. This study investigates the molecular mechanisms underpinning the chemotropic responses of the maize anthracnose fungusColletotrichum graminicolato maize root exudates. We identify the 7-transmembrane G-protein coupled receptor (GPCR) CgSte3 as a key player in sensing both plant-derived class III peroxidases and diterpenoids. Activation of CgSte3 initiates signaling through the Cell Wall Integrity Mitogen-Activated Protein Kinase (CWI MAPK) pathway, facilitating the pathogen’s growth towards plant defense molecules. The NADPH oxidase CgNox2 is crucial for peroxidase sensing but not for diterpenoid detection. These findings reveal that CgSte3 and CWI MAPK pathways are central toC. graminicola’sability to hijack plant defense signals, highlighting potential targets for controlling maize anthracnose.
An anomalous 3’-terminal phosphorothioated mismatch bypass activity and its application as a binary molecular switch
Authors: Kumar Shrawan , Gariya Hira Singh , Sharma Chandrika , Parveen Saba , Nair Vandana K , Sengupta Mrittika , Ghosh Souradyuti 
Published: July 2024

AbstractPhosphorothioated (PST) oligonucleotides are increasingly being used in RNA silencing, antisense, and biosensing applications. However, the possibilities and consequences of their desultory interactions with other possible nucleic acids and DNA polymerases inside the cell remain inadequately characterized. In this study, we report the discovery of an unusual terminal mismatch bypass activity involving 3′-PST containing DNA primers and certain strand displacement DNA polymerases. Using rolling circle DNA amplification, we have identified that strand displacement DNA polymerases such as phi29 and BST large fragment (LF) can bypass 3′-terminal PST mismatches upto 1 – 20 nt length. Next, we explore the length and sequence dependence of this unusual attribute, incubation in near-ambient and 60 – 65°C temperatures, and measures to blockade or modulate this mismatch bypass activity to create a binary fully nucleic acid-based and non-photocontrolled molecular switch (the first of its kind). After proposing possible underlying mechanisms for this activity, we discuss its potential consequences and applications.
Development of antisense tools to studyBodo saltansand its intracellular symbiont
Authors: Ahrar Mastaneh , Glenn Lorna , Held Marie , Jackson Andrew , Kus Krzysztof , Hurst Gregory D.D. , Chrostek Ewa 
Published: July 2024

AbstractObligate symbioses are common in nature and present a particular challenge for functional genetic analysis. In many cases, the host is a non-model species with poor tools for genetic manipulation and the symbiont cannot be cultured or its gene expression manipulated to investigate function. Here we investigated the potential for using antisense inhibition to analyse host and symbiont gene function within an obligate aquatic symbiosis. We focused on the kinetoplastid hostBodo saltansand its bacterial symbiont, CandidatusBodocaedibacter vickermanii, a member ofRickettsiales. We conclude that antisense inhibition is not feasible in theB. saltansand its symbiont, as the holobiont feeds on the antisense molecules – and increases in numbers – upon treatment with the antisense construct. Although our approach has proven unsuccessful, we have developed an array of protocols which can be used to study the biology of this microeukaryote and its microbial associates.
p53 protein abundance is a therapeutic window across TP53 mutant cancers and is targetable with proximity inducing small molecules
Authors: Sadagopan Ananthan , Garaffo Nicholas , Chang Heng-Jui , Schreiber Stuart L. , Meyerson Matthew , Gibson William J. 
Published: July 2024

AbstractTP53mutant cancers are associated with approximately half of cancer deaths. The most common mechanism of p53 inactivation involves missense mutations. Such mutations inTP53result in a robust upregulation of the p53 protein. Here, we demonstrate an induced proximity approach to selectively killTP53mutant cells. This approach uses the increased abundance of p53 protein inTP53mutant cancer cells to concentrate toxic molecules in these cells. We demonstrate the first generalizable strategy using a small molecule to selectively killTP53mutant cells. This molecule binds the Y220C mutant of p53 and concentrates a PLK1 inhibitor in cells harboringTP53Y220C mutations. Together, these data demonstrate that the abundance of p53 protein provides a therapeutic window forTP53missense mutant cancers that can be translated into a cell death signal using proximity-inducing small molecules.