bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tying the Knot: In Silico Design of Foldable Lasso Peptides
Authors: Nguyen John D. M. , da Hora Gabriel C. A. , Mifflin Marcus C. , Roberts Andrew G. , Swanson Jessica M. J. 
Published: January 2025

ABSTRACTLasso peptides are a unique class of natural products with distinctively threaded structures, conferring exceptional stability against thermal and proteolytic degradation. Despite their promising biotechnological and pharmaceutical applications, reported attempts to prepare them by chemical synthesis result in forming the nonthreaded branched-cyclic isomer, rather than the desired lassoed structure. This is likely due to the entropic challenge of folding a short, threaded motif prior to chemically mediated cyclization. Accordingly, this study aims to better understand and enhance the relative stability of pre-lasso conformations—the essential precursor to lasso peptide formation—through sequence optimization, chemical modification, and disulfide incorporation. Using Rosetta fixed backbone design, optimal sequences for several class II lasso peptides are identified. Enhanced sampling with well-tempered metadynamics confirmed that designed sequences derived from the lasso structures of rubrivinodin and microcin J25 exhibit a notable improvement in pre-lasso stability relative to the competing nonthreaded conformations. Chemical modifications to the isopeptide bond-forming residues of microcin J25 further increase the probability of pre-lasso formation, highlighting the beneficial role of non-canonical amino acid residues. Counterintuitively, the introduction of a disulfide cross-link decreased pre-lasso stability. Although cross-linking inherently constrains the peptide structure, decreasing the entropic dominance of unfolded phase space, it hinders the requisite wrapping of the N-terminal end around the tail to adopt the pre-lasso conformation. However, combining chemical modifications with the disulfide cross-link results in further pre-lasso stabilization, indicating that the ring modifications counteract the constraints and provide a cooperative benefit with cross-linking. These findings lay the groundwork for further design efforts to enable synthetic access to the lasso peptide scaffold.SIGNIFICANCELasso peptides are a unique class of ribosomally synthesized and post-translationally modified natural products with diverse biological activities and potential for therapeutic applications. Although direct synthesis would facilitate therapeutic design, it has not yet been possible to fold these short sequences to their threaded architecture without the help of biosynthetic enzyme stabilization. Our work explores strategies to enhance the stability of the pre-lasso structure, the essential precursor tode novolasso peptide formation. We find that sequence design, incorporating non-canonical amino acid residues, and design-guided cross-linking can augment stability to increase the likelihood of lasso motif accessibility. This work presents several strategies for the continued design of foldable lasso peptides.
A logratio approach to the analysis of autosomal genotype frequencies across multiple samples
Authors: Graffelman Jan 
Published: January 2025

AbstractJohn Aitchison has shown that the logratio principal component analysis of multiple samples of a biallelic polymorphism can evidentiate the Hardy-Weinberg law. This article extends Aitchison’s work to multiallelic polymorphisms showing how the Hardy-Weinberg law manifests itself in a logratio based statistical analysis of larger genotypic compositions. Some fundamental relationships between allelic and genotypic compositions are derived, and the close relationships between the logratio principal component analysis of allelic and genotypic compositions and the corresponding compositional biplots are established. We perform simulations and practical genetic data analysis to explore the implications of Hardy-Weinberg equilibrium for the logratio principal component analysis of genotypic compositions. A general multiallelic compositional measure for disequilibrium is presented, and shown to relate to the classical inbreeding coefficient. The proposed compositional analysis is illustrated with biallelic glyoxalase genotypes and multiallelic forensic STRs from the 1,000 Genomes project.
Mouse Single-Cell Long-Read Splicing Atlas by Ouro-Seq
Authors: An Hyunsu , Choi Sin Young , Yi Jawoon , Lim Chaemin , Shin So-I , Oh Sera , Lee Rosalind H. , Park Jihwan 
Published: January 2025

ABSTRACTAlternative splicing creates cellular and phenotypic diversity; thus, characterizing splicing patterns across diverse cell types is essential for a comprehensive understanding of these cell types. However, existing full-length single-cell RNA-sequencing methods suffer from multiple technical limitations, such as the pervasive presence of reverse transcription artifacts across genes. Here, we introduce Ouro-Seq, a novel single-cell long-read sequencing framework with a versatile artifact removal mechanism for characterizing full-length mRNA species expressed by individual cells. We also developed a computational pipeline that identifies genuine full-length cDNAs and normalizes full-length mRNA size distributions for integration. Using Ouro-Seq, we constructed the Mouse Single-Cell Long-Read Splicing Atlas by collecting full-length transcriptomes of 103,304 nuclei or cells from 12 major organs and tissues of adult mice. Our atlas comprehensively characterizes alternative splicing, alternative promoter usage, and alternative polyadenylation events across cell types, revealing previously unappreciated functional heterogeneity among individual cells. Different cell types exhibit largely distinct expression patterns of various isoforms, corresponding to their specific morphologies and biological functions. Our splicing atlas and generalized long-read frameworks will empower researchers to fully interpret biological variation across full-length transcriptomes of single cells.
Immune cell mitochondrial phenotypes are largely preserved in mitochondrial diseases and do not reflect disease severity
Authors: Liu Cynthia C. , Kurade Mangesh , Monzel Anna S. , Kelly Catherine , Juster Robert-Paul , Trumpff Caroline , Hirano Michio , Picard Martin 
Published: January 2025

ABSTRACTObjectiveTo profile immune cell mitochondrial phenotypes in mitochondrial diseases (MitoD) and evaluate how those phenotypes relate to disease manifestations or biomarkers.MethodsWe profiled mitochondrial content and oxidative phosphorylation (OxPhos) enzymatic activities in isolated monocytes, lymphocytes, neutrophils, platelets, and mixed peripheral blood mononuclear cells (PBMCs) from 37 individuals with MitoD (m.3243A>G, n=23; single, large-scale mitochondrial DNA (mtDNA) deletions, n=14) and 68 healthy women and men from the Mitochondrial Stress, Brain Imaging, and Epigenetics (MiSBIE) study.ResultsWe first confirm and quantify robust cell type differences in mitochondrial content, activities of OxPhos complexes I, II, and IV, and the mitochondrial respiratory capacity (MRC) index. In relation to MitoD, neither mitochondrial content nor OxPhos capacity were consistently affected, other than a mild monocyte-specific reduction in complex I (partially mtDNA encoded) relative to complex II (entirely nDNA encoded), consistent with the mtDNA defects examined. Relative to the large differences in cell type-specific mitochondrial phenotypes, differences in MitoD relative to controls were generally small (<25%) across mitochondrial measures. The MitoD biomarkers GDF15 and FGF21, as well as clinical disease severity measures, were most strongly related to mitochondrial abnormalities in platelets, and most weakly related to mitochondrial OxPhos capacity in lymphocytes, which are known to eliminate mtDNA defects. Finally, comparing PBMCs collected in the morning/fasted state to the afternoon/fed state following a stressful experience, we report significant time-dependent changes in mitochondrial biology over the time scale of hours.ConclusionsOverall, these results demonstrate that the dynamic and cell-type specific mitochondrial phenotypes are preserved in mitochondrial diseases and are generally unrelated to the severity of MitoD symptoms.
Impacts of species introductions on the trait diversity of interacting avian frugivores and fleshy-fruited plants depend on native trait diversity
Authors: Nowak Larissa , Fricke Evan C. , Traveset Anna , Donoso Isabel 
Published: January 2025

AbstractIntroductions of non-native species to native ecological communities by humans are major drivers of global biodiversity change. At the same time, biotic interactions, such as those between avian frugivores and fleshy-fruited plants, build the backbone of ecosystems. Hence, studying how species introductions influence interacting species of both trophic levels is essential to understand possible functional consequences of global change.Here, we take a trait-based approach, focusing on species traits that influence their biotic interactions and related ecosystem functioning, and explore how species introductions affect the diversity of such functional traits within and across assemblages of interacting fleshy-fruited plants and frugivorous birds at several locations across the globe.Specifically, we calculate differences in trait diversity and mean trait values, and compare beta trait diversity with and without introduced species, for 25 frugivorous bird and 62 fleshy-fruited plant assemblages.Introduced species tended to increase bird and plant trait diversity in assemblages with low native trait diversity but decreased it in assemblages with higher native trait diversity. In bird assemblages, species introductions shifted mean values towards larger birds with wider bills and more pointed wings. In plant assemblages, mean trait values showed variable changes: fruit length increased and plant height decreased.Comparisons between assemblages revealed that introduced species reduced the beta trait diversity of both frugivorous birds and fleshy-fruited plants, suggesting biotic homogenisation in terms of their functional traits.Changes in trait diversity underscore that species introductions can have functional consequences for biotic interactions and related ecosystem functions, potentially affecting the availability of interaction partners with matching traits and the provisioning of seed dispersal.
A universal spectrum annotator for complex peptidoforms in mass spectrometry-based proteomics
Authors: Schulte Douwe , Leuvenink Rien , Jager Shelley , Heck Albert J. R. , Snijder Joost 
Published: January 2025

AbstractAccurate and comprehensive peptide spectrum annotation is a crucial step to interpret mass spectrometry-based proteomics data. While peak assignment in peptide fragmentation spectra is central to a broad range of proteomics applications, current tools tend to be specialized to a specific task. Here we present a more comprehensive tool, the Annotator, which unifies spectrum annotation for bottom-up, middle-down, top-down, cross-linked, and glycopeptide fragmentation mass spectra, from all fragmentation methods, including all ion types: a/b/c, x/y/z, d/v/w, and immonium ions. The Annotator integrates all known post-translational modifications from common databases and additionally allows for the definition of custom modifications and diagnostic fragment ions. The underlying library used for the theoretical fragmentation and matching is based on the unified peptidoform notation ProForma 2.0 and made available as a Rust library (rustyms) with Python bindings. This enables spectrum annotation of diverse and complex peptidoforms across the broad range of mass spectrometry-based proteomics applications.
Decoding cellular transcriptional regulatory networks governing wheat inflorescence development
Authors: Liu Xuemei , Lin Xuelei , Kang Jingmin , Long Katie A. , Yue Jingjing , Chen Chuan , Wang Dongzhi , Lister Ashleigh , Macaulay Iain C. , Liu Xin , Uauy Cristobal , Xiao Jun 
Published: January 2025

AbstractWheat inflorescence architecture, particularly spikelet and floret development, is critical for grain yield. To decode the cellular transcriptional regulatory network (cTRN) underlying wheat inflorescence development, we integrated multiple single-cell omics technologies to construct a spatiotemporal atlas of transcriptional and chromatin accessibility dynamics. This comprehensive analysis identified 20 cell types, 7,211 cell type-specific genes and 152,333 cell type-specific accessible chromatin regions (csACRs) in the wheat inflorescence. Trajectory analysis identified two sub-clusters of proliferating cells as the origins of spikelet and floret formation, deviating from the traditional developmental model. Key transcription factors and hormone-related genes in the cTRN, along with the csACRs, providing new targets for modulating wheat inflorescence architecture. Our findings provide a high-resolution resource for crop inflorescence research and establish a paradigm for applying spatiotemporal single-cell omics analysis to plant biology.
Evaluation of nutritional factors, cytokines, liver parameters and survival of patients with liver cirrhosis and hepatocellular carcinoma: a cross-sectional study
Authors: Faria Iara Carvalho , Monici Leonardo Trevisan , Pavan Célia Regina , Almeida Jazon Romilson de Souza , Faria Sérgio Henrique Dias Marques , Sevá-Pereira Tiago 
Published: January 2025

AbstractHepatocellular carcinoma (HCC) is the leading cause of mortality among cirrhotic patients, often linked to advanced liver disease. This cross-sectional study evaluated the nutritional factors, cytokine profiles, liver function parameters, and survival of patients with liver cirrhosis (LC) and HCC. Forty-seven patients were grouped as LC (n=21) or LC with HCC (n=26). Nutritional status was assessed through anthropometry, bioelectrical impedance analysis, and dietary recall, while cytokine levels (IL-6, IL-10, TNF-α) and biochemical markers (AST, ALT, albumin, prealbumin) were analyzed. Survival data were evaluated using Kaplan-Meier curves and Cox regression. HCC patients exhibited higher IL-6 levels, correlating with advanced disease stages (p=0.035). IL-10 levels were elevated in early-stage HCC (BCLC A) compared to BCLC B (p=0.006). AST and ALT levels were significantly higher in HCC patients, reflecting greater hepatocyte damage. Survival analysis revealed a median of 756 days, with shorter survival in HCC patients (p=0.0172). Nutritional parameters did not significantly correlate with survival outcomes, though most patients were eutrophic or overweight. This study highlights the roles of IL-6 and IL-10 as potential biomarkers in HCC progression and provides critical insights into the biochemical and nutritional profiles associated with LC and HCC. These findings may inform future therapeutic interventions.
Diagnostic Accuracy of a Smartphone-Enabled Urinary Albumin-to-Creatinine Ratio Test for Detecting Chronic Kidney Disease Among At-Risk Populations
Authors: Jeddah Danielle , Bevins Nicholas B , Ronen Matan , Tangri Navdeep 
Published: January 2025

AbstractObjectiveTo evaluate the diagnostic accuracy of the FDA-cleared Minuteful Kidney Test (MKT), a home-based semi-quantitative urine albumin-to-creatinine ratio (uACR) test, compared to the Beckman Coulter AU 480 analyzer, a standard laboratory quantitative method, for detecting albuminuria in individuals with or at risk for chronic kidney disease (CKD).MethodsUrine samples were obtained from individuals with risk factors for kidney damage. Each sample was analyzed for uACR using both the MKT and the laboratory standard method. Albuminuria was classified according to KDIGO guidelines: A1 (uACR ≤30 mg/g, “Normal to mildly increased”), A2 (uACR 30-300 mg/g, “Moderately increased”), and A3 (uACR ≥300 mg/g, “Severely increased”). Sensitivity, specificity, PPV, and NPV of MKT were calculated against the laboratory standard.ResultsOut of 615 collected urine samples, 555 met inclusion criteria. Albuminuria (uACR ≥30 mg/g) was detected in 24.9% of samples using the laboratory method (95% CI, 21.3–28.5%). The MKT demonstrated a sensitivity of 96.4%, specificity of 84.2%, NPV of 98.6%, and PPV of 66.8%. The test accurately categorized 85.6% of samples into the KDIGO albuminuria categories A1, A2, and A3, accurately identifying 100% of laboratory-confirmed A3 samples as abnormal.ConclusionsThe Minuteful Kidney Test shows high sensitivity, exceeding the guideline-required threshold (>85%, P<0.001), and robust specificity for detecting albuminuria in high-risk populations. This device offers potential to improve CKD screening and management and facilitate early intervention in primary care and community settings, where accurate rule-out capabilities are essential.
Evidence Suggesting Prolonged Neuroinflammation in a Subset of Children after Moderate/Severe TBI: A UCLA RAPBI Study
Authors: McCabe Courtney , Dennis Emily L , Lindsey Hannah M , Babikian Talin , Bickart Kevin , Giza Christopher C , Asarnow Robert F 
Published: January 2025

AbstractTraumatic brain injury (TBI) presents a public health concern as a leading cause of death and disability in children. Pediatric populations are particularly vulnerable to adverse outcomes following TBI due to periods of rapid growth, synaptic pruning, and myelination. Pediatric patients with moderate-severe TBI (msTBI) and healthy controls were evaluated from the post-acute (2-5 months) to chronic phase (13-19 months) of recovery using diffusion magnetic resonance imaging (dMRI) and interhemispheric transfer time (IHTT), which is an event-related potential measure the speed of information transfer across the corpus callosum. We previously identified two subgroups of patients based on IHTT, with one group showing a significantly slower IHTT (TBI-slow), poorer cognitive performance, and progressive structural damage. In contrast, the other group (TBI-normal) did not differ from controls on IHTT or cognitive performance and showed relative structural recovery over time. Here, we examined group differences in restricted diffusion imaging (RDI), which is a dMRI metric sensitive to inflammation. Comparing TBI-slow, TBI-normal, and controls on RDI cross-sectionally, dMRI connectometry analysis revealed higher RDI across the white matter in the TBI-slow group compared to both the control and TBI-normal groups.Longitudinal analyses indicated that while both TBI groups exhibited a decrease in RDI over time, suggesting resolution of neuroinflammation and recovery, the decreases in the TBI-slow group were smaller. The differences in RDI between TBI-slow and TBI-normal suggest that inflammation may play a key role in the prolonged recovery, including brain structure, cognitive performance, and symptom reports, of pediatric patients with msTBI.
Clinical and bacterial determinants of unfavorable tuberculosis treatment outcomes: an observational study in Georgia
Authors: Goig Galo A. , Loiseau Chloé , Maghradze Nino , Mchedlishvili Kakha , Avaliani Teona , Tsutsunava Ana , Brites Daniela , Kalkan Sevda , Borrell Sonia , Aspindzelashvili Rusudan , Avaliani Zaza , Kipiani Maia , Tukvadze Nestani , Jugheli Levan , Gagneux Sebastien 
Published: January 2025

AbstractTuberculosis (TB) remains a major public health concern. Improving TB control programmes and treatment success rates requires a deeper understanding of the factors that determine disease presentation and patient treatment outcomes. While the demographic and clinical factors influencing treatment outcomes are well documented, the role of bacterial genetics remains limited. In this study, we analyzed theMycobacterium tuberculosiscomplex (MTBC) genomes and the associated clinical data from 4,536 TB patients in the country of Georgia covering a period of 13 years. Multivariable modelling confirmed the role of known demographic and clinical factors such as sex, age, body mass index (BMI) and comorbidities in determining treatment outcomes, as well as the efficacy of novel TB treatments containing bedaquiline. In addition, we found that some bacterial variables, including the MTBC lineage, the specific mutations conferring resistance to rifampicin and fluoroquinolones, as well as a high bacterial burden were associated with unfavorable outcomes. GWAS analyses revealed no genetic mutations in the bacteria other than known drug resistance-conferring mutations to be associated with treatment outcomes. However, we found that mutations in the bacterial genesufDwere linked to cavitary disease. Additionally, we observed that mutations insufD,mutations conferring resistance to rifampicin and fitness compensatory mutations were associated with the bacterial burden within patients. We conclude that both patient and bacterial factors determine disease presentation and clinical outcomes in TB.
Partner military deployment and war conditions increase perinatal depression and decrease postpartum mother-infant bonding
Authors: Allouche-Kam Hadas , Chan Sabrina J , Arora Isha Hemant , Pham Christina T. , Reuveni Inbal , Sheiner Eyal , Dekel Sharon 
Published: January 2025

AbstractThe pregnancy and postpartum period represents a time of potentially heightened psychological vulnerability with implications for the offspring. Knowledge of the mental health of perinatal women exposed to armed conflict when their partner is in military deployment is scarce. This matched-control, survey-based study included a sample of 429 women recruited during the first months of the Israel-Hamas War who were pregnant or within six months postpartum. Women reporting partner in military deployment (n=250) were matched on background factors to women whose partner was no longer deployed (n=179). We found that nearly 44% of pregnant women with partner deployed endorsed depression symptoms at a clinical level. This group was more than two times as likely to endorse depression symptoms than matched controls. Postpartum women with partner deployed had significantly lower levels of mother-infant bonding than the matched group of partners not deployed. Mediation models revealed that social support mediated the relationship between study group and these maternal outcomes. Our findings suggest that war-exposed spouses of partners who are deployed are at increased risk for psychiatric morbidity and problems with attachment to the infant. Attention to optimizing social support in perinatal population is warranted during times of war and other large-scale traumas.
Immune and Mutational Profile of Gene-Edited Low-Immunogenic Human Primary Cholangiocyte Organoids
Authors: Petrus-Reurer Sandra , Baez-Ortega Adrian , Lei Winnie , Kumaran Girishkumar , Williamson James , Jones Julia , Trajkovski Daniel , Lawson Andrew R.J. , Mahbubani Krishnaa T. , Brodie Cara , Lehner Paul , Bottomley Matthew J. , Martincorena Inigo , Saeb-Parsy Kourosh 
Published: January 2025

ABSTRACTPrimary human cells cultured in organoid format have great promise as potential regenerative cellular therapies. However, their immunogenicity and mutational profile remain unresolved, impeding effective long-term translation to the clinic. In this study we report, for the first time, the generation of human leukocyte antigen (HLA)-I and HLA-II knock-out expandable human primary cholangiocyte organoids (PCOs) using CRISPR-Cas9 as a potential ‘universal’ low-immunogenic therapy for bile duct disorders. HLA-edited PCOs (ePCOs) displayed the same phenotypical and functional characteristics as parental un-edited PCOs. Despite minimal off-target edits, single-molecule DNA-sequencing demonstrated that ePCOs and PCOs acquire substantial mutations in culture at similar rates but without evident selection for cancer-driver mutations. ePCOs induced reduced T cell-mediated immunity and a donor-dependent NK cell cytotoxicityin vitroand evaded cytotoxic responses with increased graft survival in humanized micein vivo. Our findings have important implications for assessment of safety and immunogenicity of organoid cellular therapies.