bluuebunny/crossref_metadata_2025_split huggingface dataset:
TUnA: An uncertainty aware transformer model for sequence-based protein-protein interaction prediction
Authors: Ko Young Su , Parkinson Jonathan , Liu Cong , Wang Wei 
Published: February 2024

AbstractProtein-protein interactions (PPIs) are important for many biological processes, but predicting them from sequence data remains challenging. Existing deep learning models often cannot generalize to proteins not present in the training set, and do not provide uncertainty estimates for their predictions. To address these limitations, we present TUnA, a Transformer-based uncertainty aware model for PPI prediction. TUnA uses ESM-2 embeddings with Transformer encoders and incorporates a Spectral-normalized Neural Gaussian Process. TUnA achieves state-of-the-art performance and, importantly, evaluates uncertainty for unseen sequences. We demonstrate that TUnA’s uncertainty estimates can effectively identify the most reliable predictions, significantly reducing false positives. This capability is crucial in bridging the gap between computational predictions and experimental validation.
The Generalized Haldane (GH) model of genetic drift resolving the many paradoxes of molecular evolution
Authors: Ruan Yongsen , Wang Xiaopei , Hou Mei , Huang Liying , Diao Wenjie , Tracy Miles , Xu Shuhua , Liufu Zhongqi , Wen Haijun , Wu Chung-I 
Published: February 2024

AbstractGenetic drift, the random changes in frequencies of neutral variants, is the fundamental force of molecular evolution. However, the standard Wright-Fisher (WF) model of random sampling in population of sizeNonly partially defines genetic drift with 1/Nor 1/Ne(Nebeing a function of varyingN’s). In parallel, JBS Haldane (1927) proposed the branching process for genetic drift, whereby each gene copy is transmitted toKdescendants with the mean and variance ofE(K) andV(K). WhereasNis externally imposed on the standard and modified WF models, the Haldane model can be generalized (hence, the GH model) for regulatingN’s internally as a function ofE(K). The determination ofN, as well as the broader definition of genetic drift based onV(K), enables the GH model to account for many paradoxes of molecular evolution. They include: i) Genetic drift may often become stronger asNbecomes larger; ii) The two sexes experience drift differently; iii) Genetic drift operates on advantageous mutations is independent ofN; iv) Irresolution and paradoxes emerge in multi-copy gene systems (viruses, mitochondria, etc.) whereby genetic drift happens within and between individuals. We show how a GH model can resolve these paradoxes that elude the WF models. By integrating their results, GH models may supplant the WF models of genetic drift for the ever more complex biological systems.
Unraveling the gut microbiota of Tibetan chickens: insights into highland adaptation and ecological advantages
Authors: Zeng Tao , Cao Yongqing , Yin Jianmei , Feng Peishi , Tian Yong , Sun Hanxue , Gu Tiantian , Zong Yibo , Ma Xueying , Zhao Zelong , Chen Li , Xu Wenwu , Han Wei , Lu Lizhi 
Published: February 2024

ABSTRACTTibetan animals have several unique advantages owing to the harsh ecological conditions under which they live. Tibetan mammals have been studied extensively. However, understanding of the advantages and underlying mechanisms of the representative high-latitude bird, the Tibetan chicken (Gallus gallus, TC), remains limited. The gut microbiota of animals has been conclusively shown to be closely related to both host health and host environmental adaptation. This study aimed to explore the relationships between the cecal microbiome and the advantages of TCs based on comparisons among three populations: native TCs residing on the plateau, domestic TCs living in the plain, and one native plain species. Metatranscriptomic sequencing revealed a significant enrichment of active Bacteroidetes but a loss of active Firmicutes in native TCs. Additionally, the upregulated expression of genes in the cecal microbiome of native TCs showed enriched pathways related to energy metabolism, glycan metabolism, and the immune response. Furthermore, the expression of genes involved in the biosynthesis of short-chain fatty acids (SCFAs) and secondary bile acids (SBAs) was upregulated in the cecal microbiome of native TCs. Data from targeted metabolomics further confirmed elevated levels of certain SCFAs and SBAs in the cecum of native TCs. Based on the multi-omics association analysis, we proposed that the higher ratio of active Bacteroidetes/Firmicutes may be attributed to the efficient energy metabolism and stronger immunological activity of native TCs. Our findings provide a better understanding of the interactions between gut microbiota and highland adaptation, and novel insights into the mechanisms by which Tibetan chickens adapt to the plateau hypoxic environment.IMPORTANCEThe composition and function of the active cecal microbiome were significantly different between the plateau Tibetan chicken population and the plain chicken population. Higher expression genes related to energy metabolism and immune response were found in the cecal microbiome of the plateau Tibetan chicken population. The cecal microbiome in the plateau Tibetan chicken population exhibited higher biosynthesis of short-chain fatty and secondary bile acids, resulting in higher cecal content of these metabolites. The active Bacteroidetes/Firmicutes ratio in the cecal microbiome may contribute to the high-altitude adaptive advantage of the plateau Tibetan chicken population.
Simple prerequisite of presequence for mitochondrial protein import in the unicellular red algaCyanidioschyzon merolae
Authors: Hirata Riko , Mogi Yuko , Takahashi Kohei , Nozaki Hisayoshi , Higashiyama Tetsuya , Yoshida Yamato 
Published: February 2024

AbstractMitochondrial biogenesis relies on hundreds of proteins which are derived from genes encoded in the nucleus. According to characteristic properties of N-terminal targeting peptides (TP) and multi-step authentication by the protein translocase called the TOM complex, nascent polypeptides satisfying the requirements are imported into mitochondria. However, it has not been investigated whether the eukaryotic cell with a simple proteome and a single mitochondrion in a cell has a similar or simpler complexity of presequence requirements for mitochondrial protein import as other eukaryotes with multiple mitochondria. Based on the amino acid compositions of putative mitochondrial TP sequences in the unicellular red algaCyanidioschyzon merolae, we designed the synthetic TP (synTP) and confirmed that synTP-fused mVenus were translocated into the mitochondrionin vivo. Through a series of experimental evaluations using modified synTPs, we showed that functional TP must have some basic residues, at least one, and compose the specific amino acid composition, but the physicochemical properties of net charge, hydrophobicity and hydrophobic moment are not strictly determined inC. merolae. Combined with the simple composition of the TOM complex inC. merolae, our results suggest that a regional positive charge in TP would be recognized and verified solely by TOM22 as a single-step authentication for mitochondrial protein import inC. merolae. The simple authentication mechanism indicates that theC. merolaecell, with its simple cell structure and genome, would not need to increase the cryptographic complexity of the lock-and-key for mitochondrial protein import.
Proteomic comparison of epidemic AustralianBordetella pertussisbiofilm cells
Authors: Suyama Hiroki , Luu Laurence Don Wai , Zhong Ling , Raftery Mark J. , Lan Ruiting 
Published: February 2024

AbstractBordetella pertussiscauses whooping cough, a severe respiratory infectious disease. Studies have compared the currently dominant single nucleotide polymorphism (SNP) cluster I (pertussis toxin promoter allele,ptxP3) and previously dominant SNP cluster II (ptxP1) strains as planktonic cells. Since biofilm formation is linked withB. pertussispathogenesisin vivo, this study compared the biofilm formation capabilities of representative strains of cluster I and cluster II. Confocal laser scanning microscopy found that the cluster I strain had a denser biofilm structure compared to the cluster II strain. Differences in protein expression of the biofilm cells were then compared using Tandem Mass Tagging (TMT) and high-resolution multiple reaction monitoring (MRM-hr). In total, 1453 proteins were identified of which 40 proteins had significant differential expression between the two strains in biofilm conditions. Of particular interest was a large increase in expression of energy metabolism proteins (cytochrome proteins PetABC and BP3650) in the cluster I strain. When the expression of these proteins was compared between 6 additional strains from each cluster, it was found that the protein expression varied between all strains. These findings suggest that there are large levels of individual proteomic diversity betweenB. pertussisstrains in biofilm conditions despite the highly conserved genome of the species. Overall, this study revealed visual differences in biofilm structure betweenB. pertussisstrains and highlighted strain specific variation in protein expression that dominate potential cluster specific changes that may be linked with the dominance of cluster I strains.ImportanceBordetella pertussiscauses whooping cough. The currently circulating cluster I strains have taken over previously dominant cluster II strains. It is important to understand the reasons behind the evolution to develop new strategies against the pathogen. Recent studies have shown thatB. pertussiscan form biofilms during infection. This study compared the biofilm formation capabilities of a cluster I and a cluster II strain and identified visual differences in the biofilms. The protein expression between these strains grown in biofilms were compared and proteins identified with varied expression were measured with additional strains from each cluster. It was found that despite the highly conserved genetics of the species, there was varied protein expression between the additional strains. This study highlights that strain specific variation in protein expression during biofilm conditions that may dominate the cluster specific changes that may be linked to the dominance of cluster I strains.
Fine-tuning BERT models to extract transcriptional regulatory interactions of bacteria from biomedical literature
Authors: Varela-Vega Alfredo , Posada-Reyes Ali-Berenice , Méndez-Cruz Carlos-Francisco 
Published: February 2024

AbstractCuration of biomedical literature has been the traditional approach to extract relevant biological knowledge; however, this is time-consuming and demanding. Recently, Large language models (LLMs) based on pre-trained transformers have addressed biomedical relation extraction tasks outperforming classical machine learning approaches. Nevertheless, LLMs have not been used for the extraction of transcriptional regulatory interactions between transcription factors and regulated elements (genes or operons) of bacteria, a first step to reconstruct a transcriptional regulatory network (TRN). These networks are incomplete or missing for many bacteria. We compared six state-of-the-art BERT architectures (BERT, BioBERT, BioLinkBERT, BioMegatron, BioRoBERTa, LUKE) for extracting this type of regulatory interactions. We fine-tuned 72 models to classify sentences in four categories:activator,repressor,regulator, andno relation. A dataset of 1562 sentences manually curated from literature ofEscherichia coliwas utilized. The best model of LUKE architecture obtained a relevant performance in the evaluation dataset (Precision: 0.8601, Recall: 0.8788, F1-Score Macro: 0.8685, MCC: 0.8163). An examination of model predictions revealed that the model learned different ways to express the regulatory effect. The model was applied to reconstruct a TRN ofSalmonellaTyphimurium using 264 complete articles. We were able to accurately reconstruct 82% of the network. A network analysis confirmed that the transcription factor PhoP regulated many genes (uppermost degree), some of them responsible for antimicrobial resistance. Our work is a starting point to address the limitations of curating regulatory interactions, especially for the reconstruction of TRNs of bacteria or diseases of biological interest.
Multilevel proteomic profiling of colorectal adenocarcinoma cell differentiation to characterize an intestinal epithelial model
Authors: Fekete Emily EF , Wang Angela , Creskey Marybeth , Cummings Sarah E , Lavoie Jessie R , Ning Zhibin , Li Jianjun , Figeys Daniel , Chen Rui , Zhang Xu 
Published: February 2024

AbstractEmergent advancements on the intestinal microbiome for human health and disease treatment necessitates well-defined intestinal cellular models to study and rapidly assess host, microbiome, and drug interactions. This study characterized molecular alterations during Caco-2 cell differentiation, an epithelial intestinal model, using quantitative multi-omic approaches. We demonstrated that both spontaneous and medium-induced cellular differentiations displayed similar protein and pathway changes, including the down-regulation of proteins related to translation and proliferation, and up-regulation of proteins related to cell adhesion, molecule binding and metabolic pathways. Acetyl-proteomics revealed decreased histone acetylation and increased acetylation in proteins associated with mitochondria functions in differentiated cells. Butyrate-containing differentiation medium accelerates differentiation, with earlier up-regulation of proteins related to differentiation and host-microbiome interactions. These results emphasize the controlled progression of Caco-2 differentiation toward a specialized intestinal epithelial-like cell. This further enhances their characterization, establishing their suitability for facilitating the effective evaluation of risk and quality in microbiome-directed therapeutics.
Gene Therapy Mediates Therapeutic Improvement in Cardiac Hypertrophy and Survival in a Murine Model ofMYBPC3-Associated Cardiomyopathy
Authors: Greer-Short Amara , Greenwood Anna , Leon Elena C. , Qureshi Tawny Neal , von Kraut Konor , Wong Justin , Reid Christopher A. , Cheng Ze , Easter Emilee , Yang Jin , Ho Jaclyn , Steltzer Stephanie , Budan Ana , Cho Marie , Feathers Charles , Chung Tae Won , Rodriguez Neshel , Jones Samantha , Alleyne-Levy Chris , Liu Jun , Jing Frank , Prince William S. , Lin JianMin , Ivey Kathryn N. , Tingley Whittemore G. , Hoey Timothy , Lombardi Laura M. 
Published: February 2024

AbstractBackgroundHypertrophic cardiomyopathy (HCM) affects an estimated 600,000 people in the U.S. and is the leading cause of sudden cardiac arrest in those under 18. Loss-of-function mutations inMyosin Binding Protein C3,MYBPC3, are the most common genetic cause of HCM. The majority ofMYBPC3mutations causative for HCM result in truncations. The sarcomeric pathophysiology of the majority of HCM patients withMYBPC3mutations appears to be due to haploinsufficiency, as the total amount of MYBPC3 protein incorporated into sarcomeres falls significantly below normal.MethodsA clear path for the treatment of haploinsufficiency is the restoration of the insufficient gene product; in this case wild-type MYBPC3. To achieve this, we engineered an AAV vector (TN-201) with superior properties for mediating cardiomyocyte-selective expression of MYBPC3 after systemic delivery.ResultsWe have demonstrated for the first time with AAV gene therapy the ability of both a mouse surrogate and TN-201, which encodes human MYBPC3 to reverse cardiac hypertrophy and systolic dysfunction and to improve diastolic dysfunction and survival in a symptomatic MYBPC3-deficient murine model of disease. Dose-ranging efficacy studies exhibited restoration of wild-type MYBPC3 protein levels and saturation of cardiac improvement at the clinically relevant dose of 3E13 vg/kg, outperforming a previously published construct. Further, we have established stable cardiac benefit for greater than one year post-injection, as well as reversal of cardiac dysfunction even in late-stage models of disease.ConclusionsOur data suggest that by restoring MYBPC3 to the sarcomere, TN-201 has the potential to slow and even reverse the course of the disease in patients withMYBPC3-associated HCM.
Interactive visualisation of raw nanopore signal data with Squigualiser
Authors: Samarakoon Hiruna , Liyanage Kisaru , Ferguson James M. , Parameswaran Sri , Gamaarachchi Hasindu , Deveson Ira W. 
Published: February 2024

ABSTRACTNanopore sequencing measures ionic current during the translocation of DNA, RNA or protein molecules through a nanoscale protein pore. This raw current signal data can be ‘basecalled’ into sequence information and has the potential to identify other diverse molecular features, such as base modifications, secondary structures, etc. Despite the unique properties and potential utility of nanopore signal data, there are currently limited options available for signal data visualisation. To address this, we have developedSquigualiser, a toolkit for intuitive, interactive visualisation of sequence-aligned signal data, which currently supports both DNA and RNA sequencing data from Oxford Nanopore Technologies (ONT) instruments. A series of methodological innovations enable efficient alignment of raw signal data to a reference genome/transcriptome with single-base resolution.Squigualisergenerates an interactive signal browser view (HTML file), in which the user can navigate across a genome/transcriptome region and customise the display. Multiple independent reads are integrated into a signal ‘pileup’ format and different datasets can be displayed as parallel tracks to facilitate their comparison.Squigualiserprovides the most sophisticated framework for nanopore signal data visualisation to date and will catalyse new advances in signal analysis. We provideSquigualiseras an open-source tool for the nanopore community:https://github.com/hiruna72/squigualiser
A pangenome analysis of ESKAPE bacteriophages: the underrepresentation may impact machine learning models
Authors: Lee Jeesu , Hunter Branden , Shim Hyunjin 
Published: February 2024

AbstractBacteriophages are the most prevalent biological entities in the biosphere. However, limitations in both medical relevance and sequencing technologies have led to a systematic underestimation of the genetic diversity within phages. This underrepresentation not only creates a significant gap in our understanding of phage roles across diverse biosystems but also introduces biases in computational models reliant on these data for training and testing. In this study, we focused on publicly available genomes of bacteriophages infecting high-priority ESKAPE pathogens to show the extent and impact of this underrepresentation. First, we demonstrate a stark underrepresentation of ESKAPE phage genomes within the public genome and protein databases. Next, a pangenome analysis of these ESKAPE phages reveals extensive sharing of core genes among phages infecting the same host. Furthermore, genome analyses and clustering highlight close nucleotide-level relationships among the ESKAPE phages, raising concerns about the limited diversity within current public databases. Lastly, we uncover a scarcity of unique lytic phages and phage proteins with antimicrobial activities against ESKAPE pathogens. This comprehensive analysis of the ESKAPE phages underscores the severity of underrepresentation and its potential implications. This lack of diversity in phage genomes may restrict the resurgence of phage therapy and cause biased outcomes in data-driven computational models due to incomplete and unbalanced biological datasets.
Phylogeny predicts tolerance in aquatic animals for only a minority of chemicals
Authors: Coleman Alice L. , Edmands Suzanne 
Published: February 2024

AbstractThere are substantial gaps in our empirical knowledge of the effects of chemical exposure on aquatic life that are unlikely to be filled by traditional laboratory toxicity testing alone. One possible alternative of generating new toxicity data is cross-species extrapolation (CSE), a statistical approach in which existing data are used to predict the effect of a chemical on untested species. Some CSE models use relatedness as a predictor of chemical sensitivity, but relatively little is known about how strongly shared evolutionary history influences sensitivity across all chemicals. To address this question, we conducted a survey of phylogenetic signal in the toxicity data from aquatic animal species for a large set of chemicals using a phylogeny inferred from taxonomy. Strong phylogenetic signal was present in just six of thirty-two toxicity datasets, and there were no clear shared properties among those datasets with strong signal. Strong signal was rare even among chemicals specifically developed to target insects, meaning that these chemicals may be equally lethal to non-target taxa, including chordates. When signal was strong, distinct patterns of sensitivity were evident in the data, which may be informative when assembling toxicity datasets for regulatory use. Although strong signal does not appear to manifest in aquatic toxicity data for most chemicals, we encourage additional phylogenetic evaluations of toxicity data in order to guide the selection of CSE tools and as a means to explore the patterns of chemical sensitivity across the broad diversity of life.
Circadian clocks in human cerebral organoids
Authors: Rzechorzek Nina M , Sutcliffe Magdalena A , Mihut Andrei , Baranes Koby , Karam Nuzli , Sánchez Daniel Lloyd-Davies , Peak-Chew Sew Y , Zeng Aiwei , Poulin Noah , Seinkmane Estere , Karim Kaiser , Proctor Christopher M , Kotter Mark , Lancaster Madeline A , Beale Andrew D 
Published: February 2024

SummaryCircadian rhythms result from cell-intrinsic timing mechanisms that impact health and disease1,2. To date, however, neural circadian research has largely focused on the hypothalamic circuitry of nocturnal rodents3. Whether circadian rhythms exist in human brain cells is unknown. Here we showbona fidecircadian rhythms in human neurons, glia, cerebral organoids, and cerebral organoid slices (ALI-COs)4–8. Human neural circadian rhythms are synchronised by physiological timing cues such as glucocorticoids and daily temperature cycles, and these rhythms are temperature-compensated across the range of normal human brain temperatures9. Astrocyte rhythms are phase-advanced relative to other cultures and they modulate neuronal clock responses to temperature shift. Cerebral organoid rhythms are more robust at physiological brain temperatures; the relative amplitude of these rhythms increases over time in culture and their resetting capacity recapitulates key neurodevelopmental transitions in glucocorticoid signalling10–14. Remarkably, organoid post-transcriptional bioluminescent clock reporter rhythms are retained even when those of their putative transcriptional drivers are indiscernible15, and electrophysiology recordings confirm circadian rhythms in functional activity of monocultures, organoids, and ALI-COs. Around one third of the cerebral organoid proteome and phosphoproteome are circadian-rhythmic, with temporal consolidation of disease-relevant neural processes. Finally, we show that human brain organoid rhythms can be modulated and disrupted by commonly used brain-permeant drugs and mistimed cortisol exposure, respectively. Our results demonstrate that human brain cells and tissues develop their own circadian oscillations and that canonical mechanisms of the circadian clockwork may be inadequate to explain these rhythmic phenomena. 2D and 3D human neural cultures represent complementary and tractable models for exploring the emergence, disruption, and mechanics of the circadian neural clockwork, with important implications for chronobiology, brain function, and brain health.