bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic programming algorithms for fast and accurate cell lineage tree reconstruction from CRISPR-based lineage tracing data
Authors: Dai Junyan , Molloy Erin K. 
Published: November 2024

AbstractCRISPR-based lineage tracing, coupled with single-cell RNA sequencing, has emerged as a promising approach for studying cell transformations during development as well as disease progression. However, the high ratio of cells to CRISPR-induced mutations, combined with missing data from silencing or dropout, make cell lineage tree (CLT) reconstruction difficult. As a result, this computational problem has attracted significant attention in recent years, including the introduction of Star Homoplasy Parsimony (SHP) in 2023 to model the specific properties of CRISPR-induced mutations, along with the Startle family of methods based on integer linear programming (ILP) or heuristic search (NNI). Here, we present Star-CDP, the first dynamic programming algorithm for SHP. Star-CDP solves SHP within a constrained search space Σ defined by subsets of cells from which a solution CLT must draw its clades. When Σ is the power set, Star-CDP is an exact exponential algorithm with time complexityO(nm|Σ|2), wherenis the number of cells,mis the number of target sites, and |Σ |=O(2n). We show that it is possible to build clade constraints that are polynomially-sized and effective in practice. Motivated by the technological challenges in producing consistent phylogenetic signal across the tree during lineage tracing, we also present algorithms to efficiently count, sample, and build consensus trees from all solutions to the clade-constrained SHP problem. In simulations, Star-CDP’s strict consensus effectively reduced false positive branches while preserving many more true positives compared to the standard strict consensus implemented by PAUP*, a popular parsimony method from species phylogenetics. Likewise, Star-CDP’s strict consensus achieved the same or higher accuracy (f1-score) on all but one of the 15 model conditions tested, often outperforming leading the methods, Startle-ILP and Startle-NNI, while also scaling to larger data sets than Startle-ILP. Lastly, we analyzed lineage tracing data from the KP-Tracer mouse model of lung adenocarcinoma, finding that Star-CDP produced plausible CLTs, often lowering the number of migration and reseeding events needed to explain metastases compared to Startle. Our analysis also showed, for the first time, that strategies for preprocessing cells with missing data—specifically cell pruning and deduplicating techniques—can have a substantial impact on CLTs reconstructed with the same method, even changing relative performance across methods compared to previously published results. The same was true of postprocessing trees with LAML, a maximum likelihood method designed for mixed-type missing data. By exploring these different pipelines, we recovered the most plausible CLT for the largest KP-Tracer metastatic tumor, reducing the number of reseeding events from 42 to 10 without increasing the number of migrations. Star-CDP is available on Github:https://github.com/molloy-lab/Star-CDP.
Dynamic analysis of Q-fever transmission among cattle in the Tropical Savannah Grassland zone of Ghana
Authors: Otoo Dominic , Mensah Kennedy , Adjei Eugene , Danquah Baaba Abassawah , Adusei Hawa , Chuaya Razak G. 
Published: November 2024

AbstractLivestock morbidity and death from Q-fever have been high, endangering local farmers’ livelihoods and affecting food security in Ghana. It is essential to understand the transmission dynamics of Q-fever to protect both the health of the animals and the main source of income for the community. A non-linear ordinary differential equation incorporating a vaccinated compartment was formulated and analyzed to gain insights into the spread of Q-fever. Routh Hurwitz criterion and Lyapunov function were used respectively to analyze the local and global stability of the disease-free equilibrium (Q0). We analyzed the behavior of the model compartments and discovered that many key factors significantly influence the persistence or eradication of Q-fever. Increased vaccination rates decrease the susceptible livestock while increasing the vaccinated livestock, potentially reducing the risk of outbreaks and limiting the spread of infections. A higher recovery rate leads to a quicker recovery, which aids in epidemic control by boosting population immunity and reducing the infectious time. The infection level rises whenR0>1, indicating a typical transcritical bifurcation behavior, but this growth stays steady and does not result in unbounded advancement.Author summaryQ-fever presents considerable health hazards to livestock in Ghana’s Tropical Savannah Grassland, adversely affecting local farmers’ income and food security in regions such as North Tongu municipality. To elucidate the transmission dynamics of the disease and safeguard both animal health and the community’s principal economic resource, we proposed a mathematical model employing non-linear differential equations that incorporate a vaccine compartment. This model enables the evaluation of how parameters such as vaccination and recovery rates influence the transmission of Q-fever in livestock. Our findings indicate that increased vaccination rates may diminish the population of susceptible livestock, hence reducing the possibility of outbreaks. In addition, a rapid recovery rate not only diminishes the duration of infectiousness in livestock but also enhances herd immunity, assisting in the containment of possible epidemics. The proposed model indicates that asR0exceeds 1, the infection level rises, displaying transcritical bifurcation behavior. However, this rise stabilizes and prevents uncontrolled spread. These findings emphasize the value of vaccination and recovery techniques in controlling and possibly eliminating Q-fever in cattle, which would ultimately help Ghanaian farming communities remain sustainable.
Intramammary infection of bovine H5N1 influenza virus in ferrets leads to transmission and mortality in suckling neonates
Authors: Baker PH , Moyer M , Bai Y , Stafford LS , Kelvin AA , Lee C , Kenney SP , Langel SN 
Published: November 2024

AbstractThe spread of H5N1 clade 2.3.4.4b in dairy herds raises concerns about zoonotic transmission due to the high viral load in milk, a key point of contact between livestock and humans. H5N1 clade 2.3.4.4b exhibits tropism for the mammary gland, with milk from infected cows containing high levels of viral RNA and infectious virus. The virus’s ability to infect the mammary gland suggests potential risks of transmission to offspring through breastfeeding. Here, we show that mammary gland infection with bovine H5N1 influenza in lactating ferrets transmits virus and disease to suckling kits. Viral RNA titers significantly increased in milk over time and remained high in mammary gland tissue. Suckling kits had significantly increased viral RNA in the oral and nasal cavity, as well as in feces. However, viral detection in the dam nasal cavities was delayed, with only minimal virus present in the oral cavity. Lung viral RNA levels were low in dams but high in a sampled suckling kit. Additionally, we detected the expression of the H5N1 receptor, α2,3 sialic acid, in mammary tissue from both ferrets and humans. These data demonstrate that H5N1 clade 2.3.4.4b infection in lactating dams leads to mastitis-related disease and transmits to suckling pups, resulting in 100% mortality among the neonates.
Nucleosome condensate and linker DNA alter chromatin folding pathways and rates
Authors: Qiu Yunrui , Liu Shuming , Lin Xingcheng , Unarta Ilona Christy , Huang Xuhui , Zhang Bin 
Published: November 2024

AbstractChromatin organization is essential for DNA packaging and gene regulation in eukaryotic genomes. While significant progresses have been made, the exact atomistic arrangement of nucleosomes remains controversial. Using a well-calibrated residue-level coarse-grained model and advanced dynamics modeling techniques, particularly the non-Markovian dynamics model, we map the free energy landscape of tetra-nucleosome systems, identify both metastable conformations and intermediate states in folding pathways, and quantify the folding kinetics. Our findings show that chromatin with 10nbase pairs (bp) DNA linker lengths favor zigzag fibril structures. However, longer linker lengths destabilize this conformation. When the linker length is 10n+ 5 bp, chromatin loses unique conformations, favoring a dynamic ensemble of structures resembling folding intermediates. Embedding the tetra-nucleosome in a nucleosome condensate similarly shifts stability towards folding intermediates as a result of the competition of inter-nucleosomal contacts. These results suggest that chromatin organization observedin vivoarises from the unfolding of fibril structures due to nucleosome crowding and linker length variation. This perspective aids in unifying experimental studies to develop atomistic models for chromatin.SignificanceAtomic structures of chromatin have become increasingly accessible, largely through cryo-EM techniques. Nonetheless, these approaches often face limitations in addressing how intrinsicin vivofactors influence chromatin organization. We present a structural characterization of chromatin under the combined effects of nucleosome condensate crowding and linker DNA length variation—two criticalin vivofeatures that have remained challenging to capture experimentally. This work leverages a novel application of non-Markovian dynamical modeling, providing accurate mapping of chromatin folding kinetics and pathways. Our findings support a hypothesis thatin vivochromatin organization arises from folding intermediates advancing toward a stable fibril configuration, potentially resolving longstanding questions surrounding chromatin atomic structure.
Activation of hypothalamic-pontine-spinal pathway promotes locomotor initiation and functional recovery after spinal cord injury in mice
Authors: Ji Chengyue , Zhang Yunfan , Lin Zeyu , Zhao Ziqi , Jiao Zhuolei , Zheng Zhiyuan , Shi Xiaoxue , Wang Xiaofei , Li Ziyu , Yu Shuisheng , Qu Yun , Wei Yaxuan , Zheng Bowen , Shi Hanyu , Wang Qifang , Sandoval Alfredo , Chen Bo , Yu Xiao , Xu Xiaohong , Poo Mu-ming , Chen Juxiang , Cai Weihua , Li Yi 
Published: November 2024

SUMMARYThe hypothalamus is critical for regulating behaviors essential for survival and locomotion, but how it integrates internal needs and transmits locomotion commands to the spinal cord (SC) remains unclear. We found that glutamatergic neurons in lateral hypothalamic area (LHA) are essential for regulating motivated locomotor activity. Using single-neuron projectome analysis, trans-synaptic tracing, and optogenetic manipulation, we showed that LHA facilitates motivated locomotion during food seeking via pontine oral part (PnO) projection neurons, rather than direct SC projections or indirect stress signaling via medial septum and diagonal band. Activating PnO-SC projection neurons also initiated locomotion. Importantly, LHA-PnO projection neurons were crucial for regulating locomotor recovery following mouse spinal cord injury (SCI). Closed-loop deep brain stimulation (DBS) of LHA via gating by motor cortex signals markedly promoted long-term restoration of hindlimb motor functions after SCI. Thus, we have identified a hypothalamic-pontine- spinal pathway and the stimulation paradigm for potential therapeutic intervention after SCI.
Somatosensory high frequency oscillations across the human central nervous system
Authors: Bailey Emma , Nierula Birgit , Stephani Tilman , Nikulin Vadim , Eippert Falk 
Published: November 2024

AbstractSensory information processing in the central nervous system (CNS) requires both post-synaptic responses and spiking activity, with human electroencephalography (EEG) research largely focused on the former. However, EEG data also contain high-frequency oscillations (HFOs), which have been linked to cortical spike bursts in animal models, thus providing a non-invasive macroscopic marker of population spiking in humans. Here, we go beyond cortical processing and demonstrate that it is possible to simultaneously record HFOs to somatosensory stimulation across the entire human CNS – from spinal cord over subcortical to cortical processing stages. Using multivariate spatial filtering approaches in two independent datasets, we identify replicable and generalizable HFOs across the CNS and obtain a detailed characterization of these signals at each processing level. Finally, we provide evidence at the between- and within-individual level that low and high frequency electrophysiological responses represent at least partly independent information across the CNS. Taken together, our approach offers the first evidence that it is possible to detect and characterise HFOs simultaneously across the CNS, providing a unique non-invasive and multi-level window into human neurophysiology in health and disease.
Modality-Specific and Amodal Language Processing by Single Neurons
Authors: Lakretz Yair , Friedmann Naama , King Jean-Rémi , Mankin Emily , Rangel Anthony , Tankus Ariel , Dehaene Stanislas , Fried Itzhak 
Published: November 2024

AbstractAccording to psycholinguistic theories, during language processing, spoken and written words are first encoded along independent phonological and orthographic dimensions, then enter into modality-independent syntactic and semantic codes. Non-invasive brain imaging has isolated several cortical regions putatively associated with those processing stages, but lacks the resolution to identify the corresponding neural codes. Here, we describe the firing responses of over 1000 neurons, and mesoscale field potentials from over 1400 microwires and 1500 iEEG contacts in 21 awake neurosurgical patients with implanted electrodes during written and spoken sentence comprehension. Using forward modeling of temporal receptive fields, we determined which sensory or abstract dimensions are encoded. We observed a double dissociation between superior temporal neurons sensitive to phonemes and phonological features and previously unreported ventral occipito-temporal neurons sensitive to letters and orthographic features. We also discovered novel neurons, primarily located in middle temporal and inferior frontal areas, which are modality-independent and show responsiveness to higher linguistic features. Overall, these findings show how language processing can be linked to neural dynamics, across multiple brain regions at various resolutions and down to the level of single neurons.
Dynamic cytoplasmic fluidity during morphogenesis in a human fungal pathogen
Authors: Serrano A. , Puerner C. , Plumb E. , Chevalier L. , Elferich J. , Sinn L.R. , Grigorieff N. , Ralser M. , Delarue M. , Bassilana M. , Arkowitz R.A. 
Published: November 2024

AbstractThe molecular crowding of the cytoplasm impacts a range of cellular processes. Using a fluorescent microrheological probe (GEMs), we observed a striking decrease in molecular crowding during the yeast to filamentous growth transition in the human fungal pathogenCandida albicans. This decrease in crowding is due to a decrease in ribosome concentration that results in part from an inhibition of ribosome biogenesis, combined with an increase in cytoplasmic volume; leading to a dilution of the major cytoplasmic crowder. Moreover, our results suggest that inhibition of ribosome biogenesis is a trigger forC. albicansmorphogenesis.
Arv1 interacts with and regulates the first step of GPI biosynthesis inCandida albicans
Authors: Bharati Monika , Saini Harshita , Thakran Neha , Kumar Yatin , Yadav Usha , Shefali Shailja , Saun Sunyna , Anzar Aaisha , Komath Sneha Sudha 
Published: November 2024

AbstractThe ubiquitousARV1gene shows significant functional conservation across eukaryotes. In humans, it is implicated in early onset epileptic encephalopathy. Evidence suggests that the phenotypes manifested in affected patients are probably due to the deficiency in expression of cell surface GPI anchored proteins.S. cerevisiaeArv1 is proposed to be the elusive GPI flippase that delivers the GPI intermediate from the cytoplasmic face to the luminal side of the ER for further elaboration by the first mannosyltransferase of the pathway. Human and fungalARV1complementS. cerevisiae ARV1. Overexpressing some of the GPI-N-acetylglucosamine transferase (GPI-GnT) subunits rescues the null strain ofS. cerevisiae ARV1. In mammals and inT. bruceiArv1 co-immunoprecipitates with one or more subunits of the GPI-GnT. Based on these reports we hypothesized a cross-talk forARV1with the GPI biosynthetic pathway in the human pathogenic fungus,C. albicans. Using super resolution radial fluctuation (SRRF) analysis for co-localization, co-immunoprecipitation assays, and acceptor-photobleaching Förster resonance energy transfer (FRET) studies, we show thatC. albicansArv1 physically interacts with the GPI-GnT. It also transcriptionally regulates the expression of the GPI-GnT genes to control the GPI biosynthetic pathway via its very first step. Overexpression of one of the GPI-GnT subunits, CaGpi19, inC. albicans ARV1null strain rescues its cold-sensitive growth, azole sensitivity, cell wall phenotype and GPI-GnT activity. Thus, our results suggest extensive interactions between Arv1 and GPI biosynthesis inC. albicans.
Intraspecific Diversity ofStaphylococcus aureusPopulations Isolated from Cystic Fibrosis Respiratory Infections
Authors: Alexander Ashley M. , Loo Hui Qi , Askew Lauren , Raghuram Vishnu , Read Timothy D. , Goldberg Joanna B. 
Published: November 2024

AbstractChronic bacterial infections are often polymicrobial, comprising multiple bacterial species or variants of the same species. Because chronic infections may last for decades, they have the potential to generate high levels of intraspecific variation through within-host diversification over time, and the potential for superinfections to occur through the introduction of multiple pathogen populations to the ongoing infection. Traditional methods for identifying infective agents generally involve isolating one single colony from a given sample, usually after selecting for a specific pathogen or antibiotic resistance profile. Isolating a recognized virulent or difficult to treat pathogen is an important part of informing clinical treatment and correlative research; however, these reductive methods alone, do not provide researchers or healthcare providers with the potentially important perspective on the true pathogen population structure and dynamics over time. To begin to address this limitation, in this study, we compare findings onStaphylococcus aureussingle colonies versus and pools of colonies taken from fresh sputum samples from three patients with cystic fibrosis to isolates collected from the same sputum samples and processed by the clinical microbiology laboratory. Phenotypic and genotypic analysis of isolatedS. aureuspopulations revealed coexisting lineages in two of three sputum samples as well as population structures that were not reflected in the single colony isolates. Altogether, our observations presented here demonstrate that clinically relevant diversity can be missed with standard sampling methods when assessing chronic infections. More broadly, this work outlines the potential impact that comprehensive population-level sampling may have for both research efforts and more effective treatment practices.Data SummaryThe authors confirm all supporting data, code and protocols have been provided within the article.
Biocatalytic Tetrapeptide Macrocyclization by Cryptic Penicillin-binding Protein-type Thioesterases
Authors: Jeannette Paisley L. , Budimir Zachary L. , Johnson Lucas O. , Parkinson Elizabeth I. 
Published: November 2024

AbstractCyclic tetrapeptides (CTPs) are a diverse class of natural products with a broad range of biological activities. However, they are extremely challenging to synthesize due to the ring strain associated with their small ring size. While chemical methods have been developed to access CTPs, they generally require the presence of certain amino acids, limiting their substrate scopes. Herein, we report the first bioinformatics guided discovery of a thioesterase from a cryptic biosynthetic gene cluster for peptide cyclization. Specifically, we hypothesized that predicted Penicillin-binding type thioesterases (PBP-TEs) from cryptic nonribosomal peptide synthetase gene clusters containing four adenylation domains would catalyze tetrapeptide cyclization. We found that one of the predicted PBP-TEs, WP516, efficiently cyclizes a wide variety of tetrapeptide substrates. To date, it is only the second stand-alone enzyme capable of cyclizing tetrapeptides, and its substrate scope greatly surpasses that of the only other reported tetrapeptide cyclase Ulm16. AlphaFold modeling and covalent docking were used to rationalize the broad substrate scope of WP516 in comparison to other PBP-TEs. Overall, the bioinformatics guided workflow outlined in this paper, and the discovery of WP516, represent promising tools for the biocatalytic production of head-to-tail CTPs, as well as a more general strategy for discovery of enzymes for peptide cyclization.
Combining NeuroPainting with transcriptomics reveals cell-type-specific morphological and molecular signatures of the 22q11.2 deletion
Authors: Tegtmeyer Matthew , Liyanage Dhara , Han Yu , Hebert Kathryn B. , Pei Ruifan , Way Gregory P. , Ryder Pearl V. , Hawes Derek , Tromans-Coia Callum , Cimini Beth A. , Carpenter Anne E. , Singh Shantanu , Nehme Ralda 
Published: November 2024

AbstractNeuropsychiatric conditions pose substantial challenges for therapeutic development due to their complex and poorly understood underlying mechanisms. High-throughput, unbiased phenotypic assays present a promising path for advancing therapeutic discovery, especially within disease-relevant neural tissues. Here, we introduce NeuroPainting, a novel adaptation of the Cell Painting assay, optimized for high-dimensional morphological phenotyping of neural cell types, including neurons, neuronal progenitor cells, and astrocytes derived from human stem cells. Using NeuroPainting, we quantified cell structure and organelle behavior across various brain cell types, creating a public dataset of over 4,000 cellular traits. This extensive dataset not only sets a new benchmark for phenotypic screening in neuropsychiatric research but also serves as a gold standard for the research community, enabling comparisons and validation of results. We then applied NeuroPainting to identify morphological signatures associated with the 22q11.2 deletion, a major genetic risk factor for schizophrenia. We observed profound cell-type-specific effects of the 22q11.2 deletion, with significant alterations in mitochondrial structure, endoplasmic reticulum organization, and cytoskeletal dynamics, particularly in astrocytes. Transcriptomic analysis revealed reduced expression of cell adhesion genes in 22q11.2 deletion astrocytes, consistent with recent post-mortem findings. Integrating the RNA sequencing data and morphological profiles uncovered a novel biological link between altered expression of specific cell adhesion molecules and observed changes in mitochondrial morphology in 22q11.2 deletion astrocytes. These findings underscore the power of combined phenomic and transcriptomic analyses to reveal mechanistic insights associated with human genetic variants of neuropsychiatric conditions.