bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bio-engineering a common probiotic to exploit colonic inflammation promotes reliable efficacy in translational models of colitis
Authors: Verdugo-Meza Andrea , Gill Sandeep K. , Godovannyi Artem , Adur Malavika K. , Barnett Jacqueline A. , Estaki Mehrbod , Ye Jiayu , Haskey Natasha , Mehain Hannah , Josephson Jessica K. , Ishida Ray , Ghesquiere Chanel , Sly Laura M. , Gibson Deanna L. 
Published: October 2024

AbstractThe intricate balance between the gut microbiome and host health inspires innovations in drug development. Commensal bacteria provide a multi-targeted approach ideal for treating complex medical conditions, like inflammatory bowel disease (IBD). These bacteria are self-replicating factories with broad targets that promote balanced intestinal inflammation, mucosal barrier function, and eubiosis. Yet, the lack of superiority to gold-standard treatments and their clinical inconsistency makes most probiotics unreliable for disease treatments. Intestinal inflammation, a driving factor in many diseases, often overwhelms commensal bacteria, which lack the stress-resistance mechanisms necessary to withstand host immune defenses. To address this, we introduced a persistence platform BioPersist™ intoE. coliNissle 1917. We hypothesized that a bio-engineered probiotic, or genetically engineered microbial medicine (GEMM™), designed to persist during inflammation would enhance probiotic bioavailability during colitis, leading to sustained therapeutic outcomes. We evaluated BioPersist in multiple translational colitis models such as in mice and pigs. BioPersist delayed the onset and reduced the severity of both chronic and acute colitis, proving more effective than 5-aminosalicylate. BioPersist thrived during inflammation promoting tolerogenic immune responses that limited infiltrating leukocyte activity and decreased TNF-α from resident myeloid cells in the mesentery. The persistence feature of BioPersist allowed the probiotic to overcome the damaging inflammatory response, eliciting mucosal healing evident by the increase in microbially-derived butyric acid. Based on these preclinical results, BioPersist may be a novel therapeutic option for both human and veterinary applications that sustains efficacy during colitis.One Sentence SummaryAdding a persistence feature to a probiotic enhances its efficacy for colitis treatment, enhancing future human and veterinary therapeutic applications.
Gut microbial metabolic flux disorder in hypertension
Authors: Lai Wenkai , Zhang Yuchen , Wang Meiling , Lai Shirong , Liu Qing , Luo Qi , Zou Quan , Yang Fenglong 
Published: October 2024

ABSTRACTHypertension is a major risk factor for cardiovascular diseases such as stroke and heart failure. Recent studies have shown that changes in the composition and function of the gut microbiota are closely related to the onset and development of hypertension. However, the individual differences in gut microbiota species make it difficult for traditional analysis methods to effectively reveal the pathogenic mechanisms of hypertension. In contrast, the inter-individual variability in gut microbial metabolites is much smaller, allowing for better cross-individual comparisons and reducing confounding factors in analysis. The interactions between gut microbiota and metabolites are highly complex, and network analysis can systematically capture this complexity. In this study Flux Balance Analysis (FBA) was utilized to predict the metabolic flux of gut microbiota and constructed cross-feeding networks. Random Forest and XGBoost models were employed to identify metabolites associated with hypertension. A differential microbial correlation network was used to analyze important metabolically related microbial sub-networks, and ultimately, the metabolic abnormalities and metabolite-related pathways were analyzed at the network level using the metabolite correlation network and cross-feeding networks. It was observed that the interaction patterns among 25 species—collectively referred to as the KEPR guild, with the most abundant genera being Eubacterium, Ruminococcus, Klebsiella, and Parabacteroides—changed, leading to alterations in 12 metabolites, such as choline (chol), 1-butanol (btoh), trimethylamine (tma), cytidine (cytd), and betaine (glyb) etc. Choline can be oxidized to form betaine, thereby affecting host blood pressure. Abnormalities in siroheme and methanethiol may result in reduced secretion of hydrogen sulfide by microbes, which in turn impacts blood pressure regulation mechanisms. The changes in these 12 metabolites may also enhance the degradation of mucin-type O-glycans and reduce butyrate metabolic activity, weakening the protective ability of intestinal epithelial cells. This may lead to inflammation and oxidative stress, exacerbating endothelial cell damage and consequently resulting in endothelial dysfunction and increased blood pressure. The findings of this study provide new insights into the pathogenic mechanisms of hypertension and offer potential targets for clinical intervention.
Structural basis of TMPRSS11D specificity and autocleavage activation
Authors: Fraser Bryan J. , Wilson Ryan P. , Ilyassov Olzhas , Lac Jackie , Dong Aiping , Li Yen-Yen , Seitova Alma , Li Yanjun , Hejazi Zahra , Kenney Tristan M.G. , Penn Linda Z. , Edwards Aled , Morin Gregg B. , Bénard François , Arrowsmith Cheryl H. 
Published: October 2024

AbstractTransmembrane Protease, Serine-2 (TMPRSS2) and TMPRSS11D are human proteases that enable SARS-CoV-2 and Influenza A/B virus infections, but their biochemical mechanisms for facilitating viral cell entry remain unclear. We demonstrate these proteases can spontaneously and efficiently cleave their own zymogen activation motifs, thereby activating their wider protease activity on other cellular substrates. We determined TMPRSS11D co-crystal structures in complexes with a native TMPRSS11D zymogen activation motif and with an engineered activation motif, providing insights into TMPRSS11D autocleavage activation and revealing unique regions of its substrate binding cleft. We further show that a protease inhibitor that underwent clinical trials for TMPRSS2-targeted COVID-19 therapy, nafamostat mesylate, was rapidly cleaved by TMPRSS11D and converted to low activity derivatives. These insights into human protease viral tropism and into liabilities with existing human serine protease inhibition strategies will guide future drug discovery campaigns for these targets.
SOX10 and microRNAs: decoding their interplay in regulating melanoma plasticity
Authors: Lai Xin , Luan Chunyan , Zhang Zhesi , Wessely Anja , Heppt Markus V. , Berking Carola , Vera Julio 
Published: October 2024

AbstractRecent studies show that the dysregulation of the transcription factor SOX10 is essential for development and progression of melanoma. MicroRNAs (miRNAs) can regulate the expression of transcription factors at the post-transcriptional level. The interactions between SOX10 and its targeting miRNAs form network motifs such as feedforward and feedback loops. Such motifs can result in non-linear dynamics in gene expression levels, therefore playing a crucial role in regulating tumor proliferation and metastasis as well as tumor’s responses to therapies. Here, we reviewed and discussed the intricate interplay between SOX10 and miRNAs in melanoma biology including melanogenesis, phenotype switch, and therapy resistance. Additionally, we investigated the gene regulatory interactions in melanoma, identifying crucial network motifs that involve both SOX10 and miRNAs. We also analyzed the expression levels of the components within these motifs. From a control theory perspective, we explained how these dynamics are linked to the phenotypic plasticity of melanoma cells. In summary, we underscored the importance of employing a data-driven network biology approach to elucidate the complex regulatory mechanisms and identify driver network motifs within the melanoma network. This methodology facilitates a deeper understanding of the regulation of SOX10 by miRNAs in melanoma. The insight gained could potentially contribute to the development of miRNA-based treatments for SOX10, thereby enhancing the clinical management of this malignancy.
Suspended and sinking particle-associated microbiomes exhibit distinct lifestyles in the Elbe estuary
Authors: Tobias-Hünefeldt Sven P. , Woodhouse Jason N. , Ruscheweyh Hans-Joachim , Sunagawa Shinichi , Russnak Vanessa , Streit Wolfgang R. , Grossart Hans-Peter 
Published: October 2024

AbstractEstuaries are important components of the global carbon cycle; exchanging carbon between aquatic, atmospheric, and terrestrial environments, representing important loci for blue carbon storage and greenhouse gas emissions. Estuarine particles are especially important due to their microbial transformation and vertical/horizontal transport. We used metagenomes and metatranscriptomes to assess changes in microbial community composition and functions across the Elbe estuary over one year, linking changes to dissolved and particulate organic matter. We will be the first to link microbial activity derived from molecular data to particulate and dissolved organic carbon characteristics. There were no microbial species responses to the measured physicochemical and dissolved/particulate organic matter parameters, however Weighted Correlation Network Analyses showed significant spatial microbiome differences linked to the estuarine salinity profile. Meanwhile, suspended and sinking particle fractions did not show any community wide differences, but individual gene analyses revealed clear microbial lifestyle differences. Sinking particle-associated transcripts highly expressed competition and stress-responses genes, while suspended particle-associated transcripts favoured energy acquisition and growth. Transcription patterns further indicate that suspended particles may represent a mitigating influence on methane release via methanotrophy, while both suspended and sinking particles produce methane through the same gene complex. This notion suggests that increased sinking particle abundance, such as under high turbidity conditions, leads to increased methane production. Our findings further imply that urban activities such as dredging may have a high impact on greenhouse gas emissions, and higher suspended-sinking particle ratios may alleviate aquatic-atmospheric methane exchanges. Future studies should explore in detail the underlying mechanisms and controlling variables, in particular when taking predicted global changes into account.
Acute and chronic pesticide exposure trigger fundamentally different molecular responses in bumble bee brains
Authors: Witwicka Alicja , López-Osorio Federico , Arce Andres , Gill Richard J , Wurm Yannick 
Published: October 2024

AbstractBeneficial wild insects including pollinators encounter various pesticide exposure conditions, from brief high concentrations to continuous low-level exposure. To effectively assess the environmental risks of pesticides, it is critical to understand how different exposure patterns influence their effects. Unfortunately, this knowledge remains limited. To clarify whether different exposure schemes disrupt the physiology of pollinators in similar manners, we exposed bumble bees to acute and chronic treatments of three different pesticides: Acetamiprid, clothianidin, and sulfoxaflor. Gene expression profiling enabled us to compare the effects of these treatments on the brain in a high-resolution manner. There were two main surprises: First, acute and chronic exposure schemes affected largely non-overlapping sets of genes. Second, different pesticides under the same exposure scheme showed more comparable effects than the same pesticide under different exposure schemes. Acute exposure caused up-regulation of stress response mechanisms causing distinct regulatory changes, rather than amplifying the effects of prolonged low-dose exposure that affected predominantly immunity and energy metabolism. These findings show that the mode of exposure critically determines the effects of pesticides. Our results signal the need for safety testing practices to better consider mode-of-exposure dependent effects and suggest that transcriptomics can support such improvements.
Identification of potential sepsis therapeutic drugs using a zebrafish rapid screening approach
Authors: Widder Mark , Carbaugh Chance , van der Schalie William , Miller Ronald , Brennan Linda , Moore Ashley , Campbell Robert , Akers Kevin , Ressner Roseanne , Martin Monica , Madejczyk Michael , Dancy Blair , Lee Patricia , Lanteri Charlotte 
Published: October 2024

AbstractIn the military, combat wound infections can progress rapidly to life-threatening sepsis. Discovery of effective small molecule drugs to prevent and/or treat sepsis is a priority. To identify potential sepsis drug candidates, we used an optimized larval zebrafish model of endotoxicity/sepsis (Philip et al., 2017) to screen commercial libraries of U.S. Food and Drug Administration (FDA)- approved drugs and other active pharmaceutical ingredients (API) known to affect pathways implicated in the initiation and progression of sepsis in humans (i.e., inflammation, mitochondrial dysfunction, coagulation, and apoptosis). We induced endotoxicity in 3- and 5-day post fertilization larval zebrafish (characterized by mortality and tail fin edema (vascular leakage)) by immersion exposure toPseudomonas aeruginosa60 μg/mL lipopolysaccharide (LPS) for 24 hours, then screened for the rescue potential of 644 selected drugs simultaneously with LPS at 10 μM. After LPS exposure, we used a neurobehavioral assay (light-dark test) to further evaluate rescue from endotoxicity and to determine possible off-target drug side effects. We identified 29 drugs with > 60% rescue of tail edema and mortality. Three drugs (Ketanserin, Tegaserod, and Brexpiprazole) produced 100% rescue and did not differ from the controls in the light-dark test, suggesting a lack of off-target neurobehavioral effects. Further testing of these three drugs at a nearly 100% lethal concentration ofKlebsiella pneumoniaeLPS (45 μg/mL) showed 100% rescue from mortality and 88%-100% mitigation against tail edema. The success of the three identified drugs in a zebrafish endotoxicity/sepsis model warrants further evaluation in mammalian sepsis models.
Four cell wall-degrading enzymes ofXanthomonas campestrispv.campestrisdetermine bacterial escape from hydathodes to the leaf vasculature
Authors: Paauw Misha , Giesbers Marcel , Pfeilmeier Sebastian , van den Burg Harrold A. 
Published: October 2024

AbstractTo colonize plants, pathogenic bacteria modulate the biology of the host employing different bacterial secretion systems. For example, the type II secretion system (T2SS) releases toxins, proteases, lipases and carbohydrate-degrading enzymes into the extracellular environment to promote tissue softening and soft rot. In this way, the T2SS promotes virulence of phytopathogenic Gram-negative bacteria. However, the role of the T2SS and its substrates for vascular disease remains enigmatic. Here, we show that the Xps-T2SS allowsXanthomonas campestrispv.campestris(Xcc) to breach the tissue barrier between hydathodes– the initial bacterial entry point – and xylem thereby gaining access to the leaf vasculature. Yet, Xps-T2SS was dispensable for bacterial multiplication in the leaf apoplast or inside the hydathode cavity suggesting a role beyond plant defense suppression or nutrient acquisition. Using comparative genomics, four plant cell wall-degrading enzymes (CWDEs) were found to be associated with vascular pathogenesis. Testing gene knockout combinations of those enzymes revealed that virulence of only the quadruple CWDE mutant was down to the level of thexps-T2SS mutant. Our results thus demonstrate that the Xps-T2SS and a set of CWDEs that is likely secreted by this system allow Xcc to break this tissue barrier enabling long-distance mobility of Xcc inside the host plant. We thus expand our understanding on how certain bacterial pathogens have specialized towards vascular pathogens.
UniScore, a unified and universal measure for peptide identification by multiple search engines
Authors: Tabata Tsuyoshi , Yoshizawa Akiyasu C. , Ogata Kosuke , Chang Chih-Hsiang , Araki Norie , Sugiyama Naoyuki , Ishihama Yasushi 
Published: October 2024

AbstractWe propose UniScore as a metric for integrating and standardizing the outputs of multiple search engines in the analysis of data-dependent acquisition (DDA) data from LC/MS/MS-based bottom-up proteomics. UniScore is calculated from the annotation information attached to the product ions alone by matching the amino acid sequences of candidate peptides suggested by the search engine with the product ion spectrum. The acceptance criteria are controlled independently of the score values by using the false discovery rate based on the target-decoy approach. Compared to other rescoring methods that use deep learning-based spectral prediction, larger amounts of data can be processed using minimal computing resources. When applied to large-scale global proteome data and phosphoproteome data, the UniScore approach outperformed each of the conventional single search engines examined (Comet, X! Tandem, Mascot and MaxQuant). Furthermore, UniScore could also be directly applied to peptide matching in chimeric spectra without any additional filters.
Shaping tiny worlds: Paternal microbiota manipulation influences offspring microbial colonization and development in a sex role-reversed pipefish
Authors: Wagner Kim-Sara , Salasc Frédéric , Marten Silke-Mareike , Roth Olivia 
Published: October 2024

AbstractMicrobes are acquired through vertical and environmental horizontal transmission. Vertical transmission is directly linked to reproductive success and entails early transmission, facilitating coexistence of host and microbes over generations. The multiple potentially interacting routes of vertical transmission are challenging to be disentangled in conventional sex-role species, as they are mostly intermingled on the maternal side, i.e., through egg production, pregnancy, birth and postnatal care. The evolution of male pregnancy in syngnathids (pipefishes and seahorses) offers an opportunity to separate vertical microbial provisioning through the egg (maternal) from provisioning through pregnancy (paternal). We experimentally evaluated the existence and role of paternal microbiota provisioning through male pregnancy on offspring development and microbial colonization. Male pipefish were exposed to antibiotics, and subsequently recolonized with bacteria of paternal, maternal, and environmental origin (spike treatment). After pregnancy, the microbiome (16s rRNA) of developing offspring was repeatedly ribotyped. Paternal antibiotic and spike treatments influenced the microbial composition of the brood pouch and offspring microbiome development. Paternal spike treatment gave offspring a kickstart in life by reducing pregnancy duration and inducing offspring survival. Expanding on how distinct vertical microbial transmission routes shape offspring microbiome will foster our understanding of the holobiont function in health and disease.
DNA methylation clocks struggle to distinguish inflammaging from healthy aging, but feature rectification improves coherence and enhances detection of inflammaging
Authors: Skinner Colin M. , Conboy Michael J. , Conboy Irina M. 
Published: October 2024

AbstractBiological age estimation from DNA methylation and determination of relevant biomarkers is an active research problem which has predominantly been tackled with black-box penalized regression. Machine learning is used to select a small subset of features from hundreds of thousands CpG probes and to increase generalizability typically lacking with ordinary least-squares regression. Here, we show that such feature selection lacks biological interpretability and relevance in the clocks of the first- and next-generations, and clarify the logic by which these clocks systematically exclude biomarkers of aging and disease. Moreover, in contrast to the assumption that regularized linear regression is needed to prevent overfitting, we demonstrate that hypothesis-driven selection of biologically relevant features in conjunction with ordinary least squares regression yields accurate, well-calibrated, generalizable clocks with high interpretability. We further demonstrate that the interplay of disease-related shifts of predictor values and their corresponding weights, which we term feature shifts, contributes to the lack of resolution between health and disease in conventional linear models. Lastly, we introduce a method of feature rectification, which aligns these shifts to improve the distinction of age predictions for healthy people vs. patients with various diseases.Key FindingsThere is no apparent biological significance of the CpGs selected by first- and next-generation clocksThe range of residuals for first- and next-generation clock predications on healthy samples is very large; for all models tested, a prediction error of +/-10-20 years is within the 95% range of variation for healthy controls and does not signify age accelerationThere is no significant shift in the mean of residuals for patient populations relative to healthy populations for most studied first- and next-generation clocks. For those with significance, the effect size is very small.Hypothesis-driven feature pre-selection, coupled with modified forward step-wise selection yields age predictors on par with first and next-generation clocks. EN/ML is not needed.Disease-related shifts at different CpG probes, along with learned model weights, can be either positive or negative; their combination leads to de-coherence effect in linear models.Model coherence can be induced by rectifying features to have only positive shifts in patient samples; this provides a better resolution between health and disease in DNAm age models, and expectedly, introduces more non-linearity to the input data.