bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unique proteome signatures in ICU patients with COVID-19 and delirium: an observational study
Authors: Edel Andreas , Sreekanth Jayanth , Kurth Florian , Ralser Markus , Demichev Vadim , Mülleder Michael , Blanc Eric , Spies Claudia 
Published: December 2024

AbstractBackgroundDelirium is common in COVID-19 intensive care unit (ICU) patients. Biomarkers for prediction, detection, and monitoring are missing. Unbiased omics analyses are warranted to gain a systems biology view on pathophysiology.MethodsThis prospective observational satellite study aims to investigate the proteome signatures of COVID-19 ICU patients, comparing those with delirium to those without. This study was conducted in ICUs of a university hospital between March 2020 and September 2021. ICU patients of legal age with a positive SARS-CoV-2 test were screened daily for oversedation and delirium. Blood samples were taken thrice a week. 457 samples were analyzed using data-independent acquisition mass spectrometry to determine protein levels. A mixed-effects logistic regression model was developed to identify proteins significantly influenced by delirium, accounting for sex and age as confounders. This model also aimed to determine proteins that were either up- or downregulated in association with delirium. Additionally, an enrichment analysis was conducted to examine the biological pathways linked to these delirium-associated proteins.ResultsOut of 360 ICU patients, 69 were analyzed for protein profiling. Out of these 69 patients, 42 patients (60.9%) had delirium on ICU admission, and 27 (39.1%) did not. Based on the multivariate model, the analysis of 204 proteins unfolded 125 (61.3%) to be differentially expressed. In total, 80.8% (n=101) of these 125 proteins were associated with delirium. Of these, 10 proteins were uniquely associated with delirium and were not significant in the multivariate model (SERPING1, SERPINA7, HP, TGFBI, CD5L, IGHV3-7, IGHV1-46, IGHV3-15, IGHV3-23, and “IGHV4-34;IGHV4-38-2”). In the univariate model for delirium, six out of 111 significant proteins showed increased expression with a log2FC > 0.5: PIGR, MST1, LBP, CRP, SAA1, and “SAA1;SAA2”; while three showed decreased expression with a log2FC < - 0.5: HP, PPBP, and “HP;HPR”. The enrichment analysis of delirium-influenced proteins revealed three significant pathways: “Network map of SARS-CoV-2 signaling” (M42569/WP5115), “Acute inflammatory response” (M10617), and “Regulation of defense response” (M15277).ConclusionWe identified a unique proteomic signature in COVID-19 ICU patients with delirium, including up- and downregulated proteins. These findings may provide potential biomarker candidates for the assessment of delirium risk and its underlying causes. These findings could be a further step towards the development of personalized, causative treatments for delirium and its monitoring in the ICU.Trial registrationThe study was retrospectively registered in the German Clinical Trials Register on May 13, 2020 (DRKS00021688).
Hearing in Two Closely RelatedPeromyscusSpecies (Peromyscus maniculatusandP. leucopus)
Authors: Joseph Luberson , New Emily Margaret , Joseph Desi Marie , Woodley Tamara Chenell , Franco Vanessa Yamileth , Li Ben-Zheng , Wogan Guinevere OU , McCullagh Elizabeth A. 
Published: December 2024

ABSTRACTThe genusPeromyscushas been extensively used as a model for ecological, behavioral, and evolutionary investigations. We used auditory brainstem responses (ABRs), craniofacial morphology, and pinna measurements to compare characteristics that impact hearing in two wild-caught species,P. leucopus P. maniculatus. We observed significant statistical differences in craniofacial and pinna attributes between species withP. leucopusoverall exhibiting larger features thanP. maniculatus. ABR recordings indicated that both species showed similar best frequency thresholds between 8-24 kHz. We found significant effects of intensity on amplitude ratio of wave I and IV forP. maniculatus, but notP. leucopusand effects of wave number on slope of the latency-intensity function with higher wave IV and shorter wave I slope of latency intensity function inP. leucopus. Finally, the data showed significant differences in latency shift of the DN1 component of the BIC in relation to ITD between species, while no significant differences were observed across relative DN1 amplitude. This study supports the used ofP. leucopusandP. maniculatusas future model species for auditory research.
Mitochondrial DNA mutations in human oocytes undergo frequency-dependent selection but do not increase with age
Authors: Arbeithuber Barbara , Anthony Kate , Higgins Bonnie , Oppelt Peter , Shebl Omar , Tiemann-Boege Irene , Chiaromonte Francesca , Ebner Thomas , Makova Kateryna D. 
Published: December 2024

SummaryMitochondria, cellular powerhouses, harbor DNA (mtDNA) inherited from the mothers. MtDNA mutations can cause diseases, yet whether they increase with age in human germline cells—oocytes—remains understudied. Here, using highly accurate duplex sequencing of full-length mtDNA, we detectedde novomutations in single oocytes, blood, and saliva in women between 20 and 42 years of age. We found that, with age, mutations increased in blood and saliva but not in oocytes. In oocytes, mutations with high allele frequencies (≥1%) were less prevalent in coding than non-coding regions, whereas mutations with low allele frequencies (<1%) were more uniformly distributed along mtDNA, suggesting frequency-dependent purifying selection. In somatic tissues, mutations caused elevated amino acid changes in protein-coding regions, suggesting positive or destructive selection. Thus, mtDNA in human oocytes is protected against accumulation of mutations having functional consequences and with aging. These findings are particularly timely as humans tend to reproduce later in life.Graphical abstract
Deciphering the tumor-infiltrating CD73+ regulatory γδ T cell ecosystem associated with poor survival of patients with ovarian cancer
Authors: Chabab Ghita , Michaud Henri-Alexandre , Dejou Cécile , Chauvin Maeva , Chépeaux Laure-Agnès , Glasson Yaël , Boissière Florence , Lenain Marion , Dumé Anne-Sophie , Sarrant Pauline , Chemin Gabriel , Wajda Pauline , Dubois Bertrand , MacManus Anna , Colombo Pierre-Emmanuel , Fabbro Michel , Bonnefoy Nathalie , Lafont Virginie 
Published: December 2024

AbstractThe ability of tumor cells to overcome immune surveillance is an essential step in tumor development and progression. Among the immune cells playing a role in tumor control, γδ T cells contribute to the immune response against many tumor types through their direct cytotoxic activity against cancer cells and their capacity to regulate the functions of other immune cells. However, their presence in the tumor microenvironment is also associated with poor prognosis, suggesting that γδ T cells may also have pro-tumor activities. We previously described a regulatory γδ T-cell subset that expresses CD73 and produces IL-10, IL-8 and adenosine. Here, we report a higher CD73+ γδ T cell density in the tumor microenvironment of ovarian cancer samples from patients with short-term than long-term survival. Starting from this original observation, we investigated their neighborhood and described a specific ecosystem according to their pro-tumor functions.
Multi-omics analysis and genome-scale metabolic reconstruction of cattleBos taurusfor optimal production of cultured meat
Authors: Lee Junkyu , Kim Jaehyun , Bae Hyun Won , Kim Minji , Jung Byung Kwon , Kim Juyeon , Lee SungGun , Kim Hyun Uk 
Published: December 2024

AbstractWith the growing urgency of addressing climate change, cultured meat has gained significant attention as a sustainable alternative to conventional meat production.Bos taurus, a key cattle species, is considered as a potential source of cultured meat. However, much remains to be understood about the biology ofB. taurusmuscle cells. In this study, bovine satellite cells (BSCs) derived from the semimembranosus muscle of Korean Hanwoo cattle were subjected to multi-omics profiling and genome-scale metabolic reconstruction. First, differential gene expression and gene set enrichment analyses, based on RNA-seq data, identified key pathways associated with muscle cell proliferation (e.g., ‘Cell cycle’ and ‘RNA polymerase’) and differentiation (e.g., ‘Cytoskeleton in muscle cells’ and ‘Tryptophan metabolism’). Next, using the human1 GEM as a template, we constructed the firstB. taurus-specific genome-scale metabolic model (GEM), named BtaSBML2986, which comprises 2,986 genes, 13,278 reactions, and 8,652 metabolites. Muscle cells were cultured under six distinct conditions, and biomass predictions generated using BtaSBML2986 were validated against experimental growth rates. This integrated approach also provided insights into core pathways such as glycolysis and the TCA cycle. BtaSBML2986 represents a significant step forward in understandingB. taurusmuscle metabolism and will serve as a valuable tool for advancing cultured meat research and optimizing culture processes.
Deregulation of epigenetic factor, KDM6A, is involved during Candida albicans mediated delayed wound healing
Authors: Ghoshal Ankita , Shah Awantika , Balaji Kithiganahalli Narayanaswamy 
Published: December 2024

AbstractDeregulation of wound healing process leads to chronic non-healing wounds. Opportunistic fungal pathogens likeCandida albicansis known to colonize open wounds leading to delayed, insufficient, or disorganized healing. In our study, we investigate the regulatory mechanisms orchestrating thisC. albicansmediated delay of wound healing and underscore a critical role for the transcription factor c-AMP Response Element Binding Protein (CREB) in regulating pro-inflammatory cytokines and genes implicated in wound healing. Parallelly, we found the epigenetic factor, KDM6A (Ubiquitously Transcribed tetratricopeptide repeat on chromosome X, also known as UTX) to be downregulated upon infection and modulating expression of metalloproteinases duringC. albicansgoverned wound healing impairment. Mechanistically, we observed enhanced recruitment of EZH2, a methyl transferase, over the promoters of KDM6A during infection, hence, governing its expression. Our findings, therefore, underscore a role of KDM6A and CREB inC. albicansmediated delayed wound healing.
Lipid Flipping, O-antigen Shielding, and Water Dynamics Revealed by 100-200 µs Coarse-Grained Simulations ofE. coliOuter Membrane Proteins
Authors: Kalenkiewicz Andrew , Elcock Adrian H. 
Published: December 2024

AbstractGram-negative (GN) bacterial infections are a major global health concern, with antibiotic-resistant strains representing a growing problem. The outer membrane (OM) of GN bacteria is the primary interface between the cell and its environment, and it plays a crucial role in regulating how GN bacteria interact with a host’s immune system and with antimicrobial drugs. Consequently, understanding the structural details of the GN OM is an essential step toward addressing the pressing threat of GN organisms. One way to gain insights into complex molecular structures like the GN OM is to use coarse-grained molecular dynamics (MD) simulations. In this work, we use theMartini3coarse-grained force field to model and simulate ten different OM proteins (OMPs) fromE. coliembedded in four different OM models that each contain lipopolysaccharides (LPS) with different O-antigen lengths. We extensively assess OMP-phospholipid interactions and demonstrate that TolC, in particular, shows a strong preference for binding cardiolipin. We also uncover a phenomenon that, to our knowledge, has not been previously described in the simulation literature—i.e., the ability of OMPs to serve as sites of phospholipid flipping from the OM inner leaflet to the outer leaflet. Finally, we show that longer LPS O-antigen chains occlude OMPs, and we provide a detailed characterization of water and ion movement throughout our simulations.
Trophic level associated gut length divergence evolved under sexual conflict in Lake Malawi cichlids
Authors: Carmona Baez Aldo , Ciccotto Patrick J. , Moore Emily C. , Peterson Erin N. , Lamm Melissa S. , Roberts Natalie B. , Coyle Kaitlin P. , Barker M. Kaitlyn , Dickson Ethan , Cass Amanda N. , Pereira Guilherme S. , Zeng Zhao-Bang , Guerrero Rafael F. , Roberts Reade B. 
Published: December 2024

AbstractVariation in gastrointestinal morphology is associated with dietary specialization across the animal kingdom. Gut length generally correlates with trophic level, and increased gut length in herbivores is a classic example of adaptation to cope with diets with lower nutrient content and a higher proportion of refractory material. However, the genetic basis of gut length variation remains largely unstudied, partly due to the inaccessibility and plasticity of the gut tissue, as well as the lack of dietary diversity within traditional model organisms relative to that observed among species belonging to different trophic levels. Here, we confirm the genetic basis of gut length variation among recently evolved Lake Malawi cichlid fish species with different dietary adaptations. We then produce interspecific, inter-trophic-level hybrids to map evolved differences in intestinal length in an F2 mapping cross betweenMetriaclima mbenjii, an omnivore with a relatively long gut, andAulonocara koningsi, a carnivore with a relatively short gut. We identify numerous candidate quantitative trait loci for evolved differences in intestinal length. These quantitative trait loci are predominantly sex-specific, supporting an evolutionary history of sexual conflicts for the gut. We also identify epistatic interactions potentially associated with canalization and the maintenance of cryptic variation in the cichlid adaptive radiation. Overall, our results suggest a complex, polygenic evolution of gut length variation associated with trophic level differences among cichlids, as well as conflicts and interactions that may be involved in evolutionary processes underlying other traits in cichlids.SummaryThis study examines the genetic basis of gut length variation in Lake Malawi cichlids, which exhibit different dietary adaptations. It highlights how cichlids recapitulate a broad taxonomic trend: gut length correlates with trophic level, with herbivores and omnivores having longer intestines than carnivores. By creating hybrids ofMetriaclima mbenjii(omnivore) andAulonocara koningsi(carnivore), we identify several quantitative trait loci and epistatic interactions underlying gut length differences. These genetic associations are predominantly sex-specific, suggesting historical sexual conflicts. The results indicate complex, polygenic evolution of gut morphology in these fish, and suggest evolutionary interactions and processes shaping dietary traits across species.
Cryo-EM of PMEL Amyloids Reveals Pathogenic Mechanism of Pigment Dispersion Syndrome
Authors: Yanagisawa Haruaki , Arai Harumi , Miyazawa Hideyuki , Kikkawa Masahide , Oda Toshiyuki 
Published: December 2024

AbstractPMEL amyloids provide a vital scaffold for melanin deposition in melanosomes, playing a central role in pigmentation. Despite their importance, the high-resolution structure of PMEL amyloids has remained elusive. Here, we determined near-atomic resolution structures of wild-type PMEL amyloids using cryo-electron microscopy, revealing two distinct polymorphic forms with unique structural features. We further examined the pathogenic G175S mutation linked to pigment dispersion syndrome (PDS). Structural analysis showed that the G175S mutation introduces an additional hydrogen bond, stabilizing a novel fibril conformation. In vitro assays demonstrated a fourfold increase in polymerization efficiency for the G175S mutant compared to the wild-type. This enhanced polymerization correlated with a ∼70% increase in secreted amyloids in G175S-expressing cells without detectable changes in melanosome morphology or number. These findings suggest that the G175S mutation promotes amyloidogenesis within melanosomes, increasing amyloid load and contributing to PDS pathophysiology. This study provides insights into the molecular basis of PMEL amyloid formation in both physiological and pathological contexts, offering new perspectives on their structural diversity and dysregulation in pigmentation disorders.
Large MAF Transcription Factors Reawaken Evolutionarily Dormant Fast-Glycolytic Type IIb Myofibers in Human Skeletal Muscle
Authors: Sadaki Shunya , Tsuji Ryosuke , Hayashi Takuto , Watanabe Masato , Iwai Ryoto , Wenchao Gu , Semenova Ekaterina A. , Sultanov Rinat I. , Zhelankin Andrey V. , Generozov Edward V. , Ahmetov Ildus I. , Sakakibara Iori , Ojima Koichi , Sakurai Hidetoshi , Muratani Masafumi , Kudo Takashi , Takahashi Satoru , Fujita Ryo 
Published: December 2024

AbstractSmall mammals rely on type IIb myofibers, expressing the fastest myosin IIb (encoded byMYH4), for rapid muscle contraction. In contrast, larger mammals, including humans, show reduced or absentMYH4expression and type IIb myofibers, favoring slower-contracting myofibers. The evolutionary mechanisms underlying this shift remain unclear. Here, we identify large MAF transcription factors (MAFA, MAFB, MAF) as key regulators ofMYH4expression in large mammals, including human and bovine. Overexpression of large MAFs induces MYH4 expression and enhances glycolytic capacity in human myotubes, supported by RNA-seq and metabolic flux analyses. RNA-seq of human muscle biopsies reveals a positive correlation betweenMAFA,MAF, andMYH4expression, with these genes elevated in power-trained individuals. These findings reveal a conserved mechanism across mammals, showing that large MAFs can induce type IIb myofibers even in humans, with potential applications for enhancing athletic performance and addressing age-related muscle weakness associated with the loss of fast-twitch myofibers.
Distribution of Time Documented as Spent on Observation Unit Disposition Process
Authors: Edmond Farrah , Algarin Mojica Nicole , Horowitz Samantha , Ng Htet , Bacchus Matthew , Harharsh Tarek , Richman Mark 
Published: December 2024

AbstractIntroductionEmergency Department (ED) Observation Units (OUs) are increasingly-common. Centers for Medicare and Medicaid Services (CMS) reimbursement policies incentivize documenting longer times spent on the disposition/discharge process (≥31 minutes). In addition, there is a well-recognized phenomenon of “terminal digit preference (ending times in 0 or 5). The Long Island Jewish Medical Center (LIJ) ED’s OU disposition process is performed by physician assistants (PAs). This study investigates the distribution of times documented by OU PAs as being spent on disposition and whether those times indicate terminal digit preference.MethodsDocumentation for discharge times of 102 patients dispositioned from the LIJ ED OU were captured, along with the PA involved. Students T-test was used to compare percentages. Statistical significance was set a priori at p <0.05.ResultsSeven PAs entered discharge times for 102 patients. No times were documented as <31 minutes. Time documented by PAs demonstrated significant clustering (ie, each PA was very consistent in the amount of time they documented). Nearly 50% of times were documented as “35 minutes.” Almost the entire remainder of times (46.1%) were documented as exactly 31 minutes or within 2 minutes of that (ie, 31, 32, or 33 minutes). Slightly over 50% of times documented ended in a “0” or a “5,” statistically-significantly greater than the expected 20% (p <0.0001).DiscussionDocumentation of most times being at or just slightly greater than 31 minutes suggests that documentation may reflect CMS’s reimbursement incentives. Over half of times documented ended in 0 or 5, indicating “terminal digit preference.” Further research is needed to confirm these findings and analyze the impact of CMS policy changes on in healthcare documentation.
Resolving inter- and intra-patient heterogeneity inNPM1-mutated AML at single-cell resolution
Authors: Karakaslar E Onur , Argiro Eva M , Struckman Nadine E , Shirali Ramin HZ , Severens Jeppe F , Honders M Willy , Kloet Susan L , Veelken Hendrik , Reinders Marcel JT , Griffioen Marieke , van den Akker Erik B 
Published: December 2024

ABSTRACTNPM1-mutated AML is one of the largest entities in international classification systems of myeloid neoplasms, which are based on integrating morphologic and clinical data with genomic data. Previous research, however, indicates that bulk transcriptomics-based subtyping may improve prognostication and therapy guidance. Here, we characterized the heterogeneity inNPM1-mutated AML by performing single-cell RNA-sequencing and spectral flow cytometry on 16 AML belonging to three distinct subtypes previously identified by bulk transcriptomics. Using single-cell expression profiling we generated a comprehensive atlas ofNPM1-mutated AML, collectively reconstituting complete myelopoiesis. The threeNPM1-mutated transcriptional subtypes showed consistent differences in the proportions of myeloid cell clusters with distinct patterns in lineage commitment and maturational arrest. In all samples, malignant cells were detected across different myeloid cell clusters, indicating thatNPM1-mutated AML are heavily skewed but not fully arrested in myelopoiesis. Same-sample multi-color spectral flow cytometry recapitulated these skewing patterns, indicating that the threeNPM1-mutated subtypes can be consistently identified across platforms. Moreover, our analyses highlighted differences in the abundance of rare hematopoietic stem cells suggesting that skewing occurs early in myelopoiesis. To conclude, by harnessing single-cell RNA-sequencing and spectral flow cytometry, we provide a detailed description of three distinct and reproducible patterns in lineage skewing inNPM1-mutated AML that may have potential relevance for prognosis and treatment of patients withNPM1-mutated AML.KEY MESSAGESNPM1-mutated AML shows strong intra- and interpatient heterogeneity with malignant cells skewed rather than fully arrested at different maturation stages in myelopoiesis.Single-cell RNA sequencing and spectral flow cytometry revealed recurrent patterns in proportions of malignant myeloid cells with distinct patterns in lineage commitment and maturational arrest.GRAPHICAL ABSTRACT
Investigating the pathogenicity of the recessiveHNF1Ap.A251T variant in monogenic diabetes using iPSC-derived beta-like cells
Authors: Cherkaoui Ines , Du Qian , Egli Dieter M. , Dion Camille , Leitch Harry G. , Sachedina Dilshad , Misra Shivani , Rutter Guy A. 
Published: December 2024

AbstractMonogenic diabetes, formerly called Maturity-Onset Diabetes of the Young (MODY), involves single-gene mutations, typically with dominant inheritance, and has been associated with variants in 14 genes. Among these,HNF1Amutations are the most common, and their diagnosis allows the use of alternative therapies, including sulfonylureas. In an earlier study, we described a variant displaying recessive transmission, p.A251T (Misra, S et al,Diabetes Care, 2020). Initial functional studies revealed only a modest impact on protein function. We extend these earlierin vitrostudies to demonstrate that beta-like cells derived from pluripotent stem cells from variant carriers show impaired differentiation into insulin-positive cells, whereas differentiation into alpha cells is significantly enhanced. Additionally, mutant cells showed impaired glucose-stimulated insulin secretion but partially preserved responsiveness to treatment with sulfonylureas. Our study provides proof of principle for the utility of using patient-derived stem cells as a platform to assess the pathogenicity ofHNF1Avariants, and to explore potential treatment strategies.