bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microbiota-dependent early life programming of gastrointestinal motility
Authors: Frith Mary E. , Kashyap Purna C. , Linden David R. , Theriault Betty , Chang Eugene B. 
Published: November 2023

SummaryGastrointestinal microbes modulate peristalsis and stimulate the enteric nervous system (ENS), whose development, as in the central nervous system (CNS), continues into the murine postweaning period. Given that adult CNS function depends on stimuli received during critical periods of postnatal development, we hypothesized that adult ENS function, namely motility, depends on microbial stimuli during similar critical periods. We gave fecal microbiota transplantation (FMT) to germ-free mice at weaning or as adults and found that only the mice given FMT at weaning recovered normal transit, while those given FMT as adults showed limited improvements. RNAseq of colonic muscularis propria revealed enrichments in neuron developmental pathways in mice exposed to gut microbes earlier in life, while mice exposed later – or not at all – showed exaggerated expression of inflammatory pathways. These findings highlight a microbiota-dependent sensitive period in ENS development, pointing to potential roles of the early life microbiome in later life dysmotility.
Hypermetabolic state is associated with circadian rhythm disruption in mouse and human cancer cells
Authors: Iascone Daniel Maxim , Zhang Xue , Bafford Patricia , Mesaros Clementina , Sela Yogev , Hofbauer Samuel , Zhang Shirley L. , Cook Kieona , Pivarshev Pavel , Stanger Ben Z. , Anderson Stewart , Dang Chi V. , Sehgal Amita 
Published: November 2023

AbstractCrosstalk between cellular metabolism and circadian rhythms is a fundamental building block of multicellular life, and disruption of this reciprocal communication could be relevant to degenerative disease, including cancer. Here, we investigated whether maintenance of circadian rhythms depends upon specific metabolic pathways, particularly in the context of cancer. We found that in adult mouse fibroblasts, ATP levels were a major contributor to overall levels of a clock gene luciferase reporter, although not necessarily to the strength of circadian cycling. In contrast, we identified significant metabolic control of circadian function in anin vitromouse model of pancreatic adenocarcinoma. Metabolic profiling of a library of congenic tumor cell clones revealed significant differences in levels of lactate, pyruvate, ATP, and other crucial metabolites that we used to identify candidate clones with which to generate circadian reporter lines. Despite the shared genetic background of the clones, we observed diverse circadian profiles among these lines that varied with their metabolic phenotype: the most hypometabolic line had the strongest circadian rhythms while the most hypermetabolic line had the weakest rhythms. Treatment of these tumor cell lines with bezafibrate, a peroxisome proliferator-activated receptor (PPAR) agonist shown to increase OxPhos, decreased the amplitude of circadian oscillation in a subset of tumor cell lines. Strikingly, treatment with the Complex I antagonist rotenone enhanced circadian rhythms only in the tumor cell line in which glycolysis was also low, thereby establishing a hypometabolic state. We further analyzed metabolic and circadian phenotypes across a panel of human patient-derived melanoma cell lines and observed a significant negative association between metabolic activity and circadian cycling strength. Together, these findings suggest that metabolic heterogeneity in cancer directly contributes to circadian function, and that high levels of glycolysis or OxPhos independently disrupt circadian rhythms in these cells.
Cholinergic Modulation of Neurovascular Coupling and Neuroimaging Signals
Authors: Brezzo Gaia , Berwick Jason , Martin Chris J 
Published: November 2023

AbstractThe use of non-invasive functional neuroimaging methods to discriminate levels or patterns of brain activity between different groups, across different time points, or in response to drug treatment, depends on an understanding of neurovascular coupling relationships and how they themselves are affected by the factors of interest. For instance, Alzheimer’s disease (AD) features cerebral blood flow (CBF) and neurovascular unit changes as well as being characterised by a cholinergic dysfunction which impacts upon CBF regulation. The present study investigated the acute neurovascular effects of cholinergic agonist and antagonist treatment in a rat model utilising a multimodal measurement approach. Drugs were administered to rats during concurrent imaging of cortical CBF and recording of local field potential responses to somatosensory stimulation. Analysis of concurrent neuronal and vascular measures revealed a pronounced loss of neurovascular coupling following treatment with the cholinergic antagonist scopolamine. Separate analysis of CBF and neuronal responses reveal an interaction effect of stimulus input and drug treatment for both cholinergic agonist and antagonist treatment, as well as an augmentation of both neuronal and haemodynamic response magnitudes after treatment with the clinically prescribed cholinergic agonist donepezil. These findings have implications for the use and interpretation of functional neuroimaging data acquired in individuals with disease-related or pharmacological manipulations of cholinergic function.
Tick bite-induced Alpha-Gal Syndrome and Immunologic Responses in an Alpha-Gal Deficient Murine Model
Authors: Sharma Surendra Raj , Choudhary Shailesh K. , Vorobiov Julia , Commins Scott P. , Karim Shahid 
Published: November 2023

AbstractIntroductionAlpha-Gal Syndrome (AGS) is a delayed allergic reaction due to specific IgE antibodies targeting galactose-α-1,3-galactose (α-gal), a carbohydrate found in red meat. This condition has gained significant attention globally due to its increasing prevalence, with more than 450,000 cases estimated in the United States alone. Previous research has established a connection between AGS and tick bites, which sensitize individuals to α-gal antigens and elevate the levels of α-gal specific IgE. However, the precise mechanism by which tick bites influence the host’s immune system and contribute to the development of AGS remains poorly understood. This study investigates various factors related to ticks and the host associated with the development of AGS following a tick bite, using mice with a targeted disruption of alpha-1,3-galactosyltransferase (AGKO) as a model organism.MethodsLone-star tick (Amblyomma americanum) and gulf-coast tick (Amblyomma maculatum) nymphs were used to sensitize AGKO mice, followed by pork meat challenge. Tick bite site biopsies from sensitized and non-sensitized mice were subjected to mRNA gene expression analysis to assess the host immune response. Antibody responses in sensitized mice were also determined.ResultsOur results showed a significant increase in the titer of total IgE, IgG1, and α-gal IgG1 antibodies in the lone-star tick-sensitized AGKO mice compared to the gulf-coast tick-sensitized mice. Pork challenge inAm. americanum-sensitized mice led to a decline in body temperature after the meat challenge. Gene expression analysis revealed thatAm. americanumbites direct mouse immunity toward Th2 and facilitate host sensitization to the α-gal antigen, whileAm. maculatumdid not.ConclusionThis study supports the hypothesis that specific tick species may increase the risk of developing α-gal-specific IgE and hypersensitivity reactions or AGS, thereby providing opportunities for future research on the mechanistic role of tick and host-related factors in AGS development.
An Artificial Intelligence-Assisted Digital Microfluidic System for Multistate Droplet Control
Authors: Guo Kun-Lun , Song Ze-Rui , Zhou Jia-Le , Shen Bin , Yan Bing-Yong , Gu Zhen , Wang Hui-Feng 
Published: November 2023

AbstractDigital microfluidics (DMF) is a versatile technique for parallel and field-programmable control of individual droplets. Given the high freedom in droplet manipulation, it is essential to establish self-adaptive and intelligent control methods for DMF systems with informed of the transient state of droplets and their interactions. However, most related studies focus on the localization and shape recognition of droplets. Here, we develop an AI-assisted DMF framework named “μDropAI” for multistate droplet control based on droplet morphology. Semantic segmentation model is integrated into our custom-designed DMF system to recognize the droplet states and their interactions for feedback control with a state machine. The proposed model has a strong generalization ability and can recognize droplets of different colors and shapes with an error rate of less than 0.63%. It enables control of droplets without user intervene. The proposed system will inspire the development of semantic-driven DMF systems which can interface with artificial general intelligence (AGl) models for fully automatic control.
A new take on missing value imputation for bottom-up label-free LC-MS/MS proteomics
Authors: Etourneau Lucas , Fancello Laura , Wieczorek Samuel , Varoquaux Nelle , Burger Thomas 
Published: November 2023

AbstractLabel-free bottom-up proteomics using mass spectrometry and liquid chromatography has long established as one of the most popular high-throughput analysis workflow for proteome characterization. However, it produces data hindered by complex and heterogeneous missing values, which imputation has long remained problematic. To cope with this, we introduce Pirat, an algorithm that harnesses this challenge following an unprecedented approach. Notably, it models the instrument limit by estimating a global censoring mechanism from the data available. Moreover, it leverages the correlations between enzymatic cleavage products (i.e., peptides or precursor ions), while offering a natural way to integrate complementary transcriptomic information, when available. Our benchmarking on several datasets covering a variety of experimental designs (number of samples, acquisition mode, missingness patterns, etc.) and using a variety of metrics (differential analysis ground truth or imputation errors) shows that Pirat outperforms all pre-existing imputation methods. These results pinpoint the potential of Pirat as an advanced tool for imputation in proteomic data analysis, and more generally underscore the worthiness of improving imputation by explicitly modeling the correlation structures either grounded to the analytical pipeline or to the molecular biology central dogma governing multiple omic approaches.
Reconciling land sharing and sparing: a conceptual model for land use
Authors: Junod Marco Fioratti , Borchers Nicolas , Reid Brian J. , Sims Ian , Miller Anthony J. 
Published: November 2023

AbstractSince the introduction of the terms in the early 2000s, the land sharing versus land sparing dichotomy has sparked considerable discussion stemming from the relationship between food production and ecological function. The theory underpinning these approaches straddles disciplinary and ideological boundaries and is frequently outlined within a general economy versus ecology background. Both strategies have come up with competing models on the relationship linking agricultural production and ecological function.The present work introduces a conceptual synthesis to unify alternative models under a single coherent framework. A generalized model linking agricultural production with ecological function that can harmonize these conflicting views is presented. In addition, a conceptual shift of paradigm is suggested to approach the issue, moving from yield targets to preservation thresholds.This article provides the theoretical means to identify the environmental and policy conditions under which land sharing strategies, based on low inputs and low impact per unit of cultivated land, can compete with land sparing approaches for the combined goals of biodiversity preservation and food safety.
Are most human specific proteins encoded by long non-coding RNA ?
Authors: Sanejouand Yves-Henri 
Published: November 2023

AbstractBy looking for a lack of homologues in a reference database of 27 well-annotated proteomes of primates and 52 well-annotated proteomes of other mammals, 170 putative human-specific proteins were identified. Among them, only 2 are known at the protein level and 23 at the transcript level, according to Uniprot. Though 21 of these 25 proteins are found encoded by an open reading frame of a long non-coding RNA, 60% of them are predicted to be at least 90% globular, with a single structural domain. However, there is a near complete lack of structural knowledge about these proteins, with no tridimensional structure presently available in the Protein Databank and a fair prediction for a single of them in the AlphaFold Protein Structure Database. Moreover, the knowledge about the function of these possibly key proteins remains scarce.
Ultrasonic reporters of calcium for deep tissue imaging of cellular signals
Authors: Jin Zhiyang , Lakshmanan Anupama , Zhang Ruby , Tran Teresa A. , Rabut Claire , Dutka Przemysław , Duan Mengtong , Hurt Robert C. , Malounda Dina , Yao Yuxing , Shapiro Mikhail G. 
Published: November 2023

ABSTRACTCalcium imaging has enabled major biological discoveries. However, the scattering of light by tissue limits the use of standard fluorescent calcium indicators in living animals. To address this limitation, we introduce the first genetically encoded ultrasonic reporter of calcium (URoC). Based on a unique class of air-filled protein nanostructures called gas vesicles, we engineered URoC to produce elevated nonlinear ultrasound signal upon binding to calcium ions. With URoC expressed in mammalian cells, we demonstrate noninvasive ultrasound imaging of calcium signalingin vivoduring drug-induced receptor activation. URoC brings the depth and resolution advantages of ultrasound to thein vivoimaging of dynamic cellular function and paves the way for acoustic biosensing of a broader variety of biological signals.
Anti-cancer compound screening identifies Aurora Kinase A inhibition as a means to favor CRISPR/Cas9 gene correction over knock-out
Authors: Wilbie Danny , Eising Selma , Amo-Addae Vicky , Walther Johanna , Bosman Esmeralda , de Jong Olivier G , Molenaar Jan J , Mastrobattista Enrico 
Published: November 2023

AbstractCRISPR gene therapy holds the potential to cure a variety of genetic diseases by targeting causative mutations and introducing double stranded DNA breaks, subsequently allowing the host DNA repair mechanisms to introduce mutations. One option to introduce precise gene corrections is via the homology-directed repair (HDR) pathway. HDR can introduce a range of desired mutations dictated by a DNA template which holds a corrected DNA sequence which is written into the targeted gene. The problem in utilizing this pathway is that CRISPR-induced double stranded DNA breaks are repaired more often through the non-homologous end joining (NHEJ) pathway, which does not use a designed template and introduces random DNA damage in the form of insertions and deletions at the cut site. Since HDR activation depends on many interconnected processes in the cell, we aimed to screen a small library of drug compounds in clinical use or clinical development for cancer, to steer the DNA repair process towards preferential HDR activation.We included compounds in our screen based on three relevant mechanisms in CRISPR gene editing: the cell cycle, DNA repair processing and chromosomal packing. We included forty compounds, based on these criteria, screened their toxicity and dosed them in sub-toxic concentrations in cells during genome editing. Of these forty compounds we identified nine potential hits to have an effect on preferential activation of the HDR pathway over NHEJ. Alisertib, rucaparib and belinostat revealed a significant and major effect on gene editing pathway selection in further validation.Alisertib, an Aurora kinase A inhibitor, showed a particularly strong effect towards improving HDR over NHEJ. We subsequently investigated this effect at the genetic level and in a murine hepatoma cell line, which corroborated the initial findings. Alisertib led to an over 4-fold increase in preferential gene correction over gene knock-out, at a dose of 0.3 micromolar. However, the observations that Aurora kinase A inhibitors show considerable cytotoxicity (<50% cell viability) and can induce morphological changes at this concentration pose a limitation for the direct use of these inhibitors as HDR enhancers. However these findings do implicate that the pathways mediated by Aurora kinase A strongly influence HDR outcomes, which warrants further investigation into the downstream pathways driving this effect.
GFETM: Genome Foundation-based Embedded Topic Model for scATAC-seq Modeling
Authors: Fan Yimin , Osakwe Adrien , Han Shi , Li Yu , Ding Jun , Li Yue 
Published: November 2023

AbstractSingle-cell Assay for Transposase-Accessible Chromatin with sequencing (scATAC-seq) has emerged as a powerful technique for investigating open chromatin landscapes at single-cell resolution. However, analyzing scATAC-seq data remain challenging due to its sparsity and noise. Genome Foundation Models (GFMs), pre-trained on massive DNA sequences, have proven effective at genome analysis. Given that open chromatin regions (OCRs) harbour salient sequence features, we hypothesize that leveraging GFMs’ sequence embeddings can improve the accuracy and generalizability of scATAC-seq modeling. Here, we introduce the Genome Foundation Embedded Topic Model (GFETM), an interpretable deep learning framework that combines GFMs with the Embedded Topic Model (ETM) for scATAC-seq data analysis. By integrating the DNA sequence embeddings extracted by a GFM from OCRs, GFETM demonstrates superior accuracy and generalizability and captures cell-state specific TF activity both with zero-shot inference and attention mechanism analysis. Finally, the topic mixtures inferred by GFETM reveal biologically meaningful epigenomic signatures of kidney diabetes.
Inference of the demographic histories and selective effects of human gut commensal microbiota over the course of human history
Authors: Mah Jonathan C. , Lohmueller Kirk E. , Garud Nandita 
Published: November 2023

ABSTRACTDespite the importance of gut commensal microbiota to human health, there is little knowledge about their evolutionary histories, including their population demographic histories and their distributions of fitness effects (DFE) of new mutations. Here, we infer the demographic histories and DFEs of 27 of the most highly prevalent and abundant commensal gut microbial species in North Americans over timescales exceeding human generations using a collection of lineages inferred from a panel of healthy hosts. We find overall reductions in genetic variation among commensal gut microbes sampled from a Western population relative to an African rural population. Additionally, some species in North American microbiomes display contractions in population size and others expansions, potentially occurring at several key historical moments in human history. DFEs across species vary from highly to mildly deleterious, with accessory genes experiencing more drift compared to core genes. Within genera, DFEs tend to be more congruent, reflective of underlying phylogenetic relationships. Taken together, these findings suggest that human commensal gut microbes have distinct evolutionary histories, possibly reflecting the unique roles of individual members of the microbiome.
Comparative mutant analyses reveal a novel mechanism of ARF regulation in land plants
Authors: Prigge Michael J. , Morffy Nicholas , de Neve Amber , Szutu Whitnie , Abraham-Juárez María Jazmín , Johnson Kjel , Do Nicole , Lavy Meirav , Hake Sarah , Strader Lucia , Estelle Mark , Richardson Annis E. 
Published: November 2023

AbstractA major challenge in plant biology is to understand how the plant hormone auxin regulates diverse transcriptional responses throughout development, in different environments, and in different species. The answer may lie in the specific complement of auxin signaling components in each cell. The balance between activators (class-A AUXIN RESPONSE FACTORS) and repressors (class-B ARFs) is particularly important. It is unclear how this balance is achieved. Through comparative analysis of novel, dominant mutants in maize and the mossPhyscomitrium patens, we have discovered a ∼500-million-year-old mechanism of class-B ARF protein level regulation, important in determining cell fate decisions across land plants. Thus, our results add a key piece to the puzzle of how auxin regulates plant development.
Examining models of modern human origins through the analysis of 43 fully sequenced human Y chromosomes
Authors: Huang Shi 
Published: November 2023

AbstractMolecular studies have yielded two primary models for understanding the uniparental DNA phylogenetic trees of modern humans: the Recent Out of Africa (ROA) and the Recent Out of East Asia (ROE) models. These models differ in their underlying assumptions, particularly in relation to early stem haplotypes, even though they share many haplotype relationships. Leveraging the wealth of new genetic variants within the male-specific region unveiled through the comprehensive sequencing of 43 diverse human Y chromosomes, we here investigated the presence of shared variants among different haplotypes to determine which model better aligns with the genetic data. We were able to corroborate the existence of stem haplotypes specific to the ROE model, but not those exclusive to the ROA model. We found that A0b and A1a shared the most variants with each other, aligning with the A00A1a clade of the ROE model. Also, stem haplotypes specific to the ROE model showed the expected relationships, with A00A1a closest to B, AB closest to E, E closest to B, A, and C, ABDE closest to C. Our findings also revealed extensive variant sharing independent of common ancestry, consistent with the maximum genetic diversity theory underlying the ROE model but challenging the neutral theory behind the ROA model. These new genetic data lend robust support to the ROE model as the more accurate representation of modern human origins.
A modular platform to display multiple hemagglutinin subtypes on a single immunogen
Authors: Lamson Dana Thornlow , Mohamed Faez Amokrane Nait , Vu Mya , Maurer Daniel P. , Ronsard Larance , Lingwood Daniel , Schmidt Aaron G. 
Published: November 2023

ABSTRACTNext-generation influenza vaccines aim to elicit cross-reactive humoral responses to multiple influenza subtypes. Such increased breadth would not only improve seasonal vaccines but may afford ‘universal’ protection against influenza subtypes including those with pandemic potential. Here, we describe a “beads-on-a-string” (BOAS) immunogen, that tandemly links up to eight distinct hemagglutinin (HA) head domains from circulating and non-circulating influenzas. These BOAS are immunogenic in the murine model and elicit comparable serum responses to each individual component. Notably, we also find that BOAS elicit cross-reactive, and neutralizing responses to influenza subtypes not included in the immunizing immunogen. Furthermore, BOAS conjugation to protein-based ferritin nanoparticles does not significantly augment serum responses suggesting that our BOAS platform is sufficient for eliciting cross-reactive responses without off-target effects induced by the nanoparticle scaffold. This mix-and-match immunogen design strategy is a robust platform for eliciting responses to multiple influenza subtypes via a single immunogen, and a potential platform for other viral glycoproteins.