bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prostate-derived circulating microRNAs add prognostic value to prostate cancer risk calculators
Authors: Zenner Morgan L. , Kirkpatrick Brenna , Leonardo Trevor R. , Schlicht Michael J. , Saldana Alejandra Cavazos , Loitz Candice , Valyi-Nagy Klara , Maienschein-Cline Mark , Gann Peter H. , Abern Michael , Nonn Larisa 
Published: May 2023

AbstractProstate cancer is the second leading cause of malignancy-related deaths among American men. Active surveillance is a safe option for many men with less aggressive disease, yet definitively determining low-risk cancer is challenging with biopsy alone. Herein, we sought to identify prostate-derived microRNAs in patient sera and serum extracellular vesicles, and determine if those microRNAs improve upon the current clinical risk calculators for prostate cancer prognosis before and after biopsy. Prostate-derived intracellular and extracellular vesicle-contained microRNAs were identified by small RNA sequencing of prostate cancer patient explants and primary cells. Abundant microRNAs were included in a custom microRNA PCR panel that was queried in whole serum and serum extracellular vesicles from a diverse cohort of men diagnosed with prostate cancer. The levels of these circulating microRNAs significantly differed between indolent and aggressive disease and improved the area under the curve for pretreatment nomograms of prostate cancer disease risk. The microRNAs within the extracellular vesicles had improved prognostic value compared to the microRNAs in the whole serum. In summary, quantifying microRNAs circulating in extracellular vesicles is a clinically feasible assay that may provide additional information for assessing prostate cancer risk stratification.
Streamlined intravital imaging approach for long-term monitoring of epithelial cell dynamics on an inverted confocal microscope
Authors: Hamersky Michael , Tekale Khushi , Winfree L. Matthew , Rowan Matthew JM , Seldin Lindsey 
Published: May 2023

ABSTRACTUnderstanding normal and aberrant in vivo cell behaviors is necessary to develop clinical interventions to thwart disease initiation and progression. It is therefore critical to optimize imaging approaches that facilitate the observation of cell dynamics in situ, where tissue structure and composition remains unperturbed. The epidermis is the body’s outermost barrier as well as the source of the most prevalent human cancers, namely cutaneous skin carcinomas. The accessibility of skin tissue presents a unique opportunity to monitor epithelial and dermal cell behaviors in intact animals using noninvasive intravital microscopy. Nevertheless, this sophisticated imaging approach has primarily been achieved using upright multiphoton microscopy, which represents a significant barrier-for-entry for most investigators. In this study, we present a custom-designed 3D-printed microscope stage insert suitable for use with inverted confocal microscopes that streamlines long-term intravital imaging of ear skin in live transgenic mice. We believe this invention, which may be readily customized to image other organ systems, will prove invaluable to the cell biology community by significantly enhancing the accessibility of intravital microscopy. This technological advancement is critical to bolster our understanding of live cell dynamics in both normal and disease contexts.
The E3 ubiquitin ligase Itch regulates death receptor and cholesterol trafficking to affect TRAIL-mediated apoptosis
Authors: Holloway James , Turkington Richard C. , Longley Daniel B. , Evergren Emma 
Published: May 2023

ABSTRACTThe activation of apoptosis signalling by TRAIL (TNF-related apoptosis-inducing ligand) through receptor binding is a fundamental mechanism of cell death induction and is often perturbed in cancer cells to enhance their cell survival and treatment resistance. Ubiquitination plays an important role in the regulation of TRAIL-mediated apoptosis, and here we investigate the role of the E3 ubiquitin ligase Itch in TRAIL-mediated apoptosis in oesophageal cancer cells. Knockdown of Itch expression resulted in resistance to TRAIL-induced apoptosis, caspase-8 activation, Bid cleavage and also promoted cisplatin resistance. Whilst the assembly of the death-inducing signalling complex (DISC) at the plasma membrane was not perturbed relative to the control, the TRAIL-R2 receptor was mis-localised in the Itch-knockdown cells. Further, we observed significant mitochondrial widening with an increased cholesterol content. An inhibitor of cholesterol trafficking, U18666A, was able to replicate some of the effects of Itch knockdown, including protection from TRAIL-induced apoptosis, reduced caspase-8 activation, Bid cleavage and Cisplatin resistance. This study highlights the importance of Itch in regulating the crosstalk between mitochondrial cholesterol and TRAIL-induced apoptosis.
dsRNA-based viromics: A novel tool unveiled hidden soil viral diversity and richness
Authors: Poursalavati A. , Larafa A. , Fall M.L. 
Published: May 2023

AbstractViruses play a crucial role in agroecosystem functioning. However, few studies have examined the diversity of the soil virome, especially when it comes to RNA viruses. Despite the great progress in viral metagenomics and metatranscriptomics (metaviromics) toward RNA viruses characterization, soil RNA viruses’ ecology is embryonic compared to DNA viruses. We currently lack a wet lab. method to accurately unhide the true soil viral diversity. To overcome this limitation, we developed dsRNA-based methods capitalizing on our expertise in soil RNA extraction and dsRNA extraction ported from studies of phyllosphere viral diversity. This proposed method detected both RNA and DNA viruses and is proven to capture a greater soil virus diversity than existing methods, virion-associated nucleic enrichment, and metaviromics. Indeed, using this method we detected 284 novel RNA-dependent RNA polymerases and expanded the diversity ofBirnaviridaeandRetroviridaeviral families to agricultural soil, which, to our knowledge, have never been reported in such ecosystem. The dsRNA-based method is cost-effective in terms of affordability and requirements for data processing, facilitating large-scale and high-throughput soil sample processing to unlock the potential of the soil virome and its impact on biogeochemical processes (e.g. carbon and nutrient cycling). This method can also benefit future studies of viruses in complex environments, for example, to characterize RNA viruses in the human gut or aquatic environment where RNA viruses are less studied mainly because of technical limitations.
Changing awareness and sources of tobacco and e-cigarettes among children in Great Britain
Authors: Parnham Jennie C. , Vrinten Charlotte , Cheeseman Hazel , Bunce Laura , Hopkinson Nicholas S , Filippidis Filippos T , Laverty Anthony A. 
Published: May 2023

ABSTRACTIntroductionIt is illegal in the UK to sell tobacco or nicotine e-cigarettes to people under the age of 18 years, as is displaying tobacco cigarettes at the point of sale. This paper examined changes in exposure to display of these products in shops and sources of these products among adolescent users over time.MethodsData from representative repeated online cross-sectional surveys of youth in Great Britain (11-18 years) were used (2018-2022; n=12,445). Outcome measures included noticing product displays and sources of e-cigarettes and tobacco cigarettes. Logistic regressions examined the associations of these outcome variables over time and with sociodemographic variables.ResultsOf 12,040 participants with complete data, 10.1% used some form of nicotine product (4.2% cigarettes, 2.9% e-cigarettes, 3.0% both) at least occasionally. The likelihood of noticing tobacco cigarettes on display fell over time for both supermarkets (2018: 67.1% to 2022: 58.5%) and small shops (2018: 81.3% to 2022: 66.3%), but the likelihood of noticing e-cigarettes in supermarkets rose (2018: 57.4% to 2022: 66.5%). Sources of tobacco cigarettes did not differ over time, but e-cigarette users were more likely to get their e-cigarettes from small shops in 2022 (51.2%) vs. 2019 (34.2%) (Odds ratio 2.02; 95%CI 1.24, 3.29).ConclusionThis study provides evidence that current policies to limit awareness of and access to both tobacco and e-cigarettes among adolescents in the UK may not be effective. UK policy on the advertising, promotion and sale of both tobacco and e-cigarettes need to be reinforced to deter use among children.
Bile acid fitness determinants of aBacteroides fragilisisolate from a human pouchitis patient
Authors: Fiebig Aretha , Schnizlein Matthew K. , Pena-Rivera Selymar , Trigodet Florian , Dubey Abhishek Anil , Hennessy Miette , Basu Anindita , Pott Sebastian , Dalal Sushila , Rubin David , Sogin Mitchell L. , Eren A. Murat , Chang Eugene B. , Crosson Sean 
Published: May 2023

AbstractBacteroides fragiliscomprises 1-5% of the gut microbiota in healthy humans but can expand to >50% of the population in ulcerative colitis (UC) patients experiencing inflammation. The mechanisms underlying such microbial blooms are poorly understood, but the gut of UC patients has physicochemical features that differ from healthy patients and likely impact microbial physiology. For example, levels of the secondary bile acid deoxycholate (DC) are highly reduced in the ileoanal J-pouch of UC colectomy patients. We isolated aB. fragilisstrain from a UC patient with pouch inflammation (i.e. pouchitis) and developed it as a genetic model system to identify genes and pathways that are regulated by DC and that impactB. fragilisfitness in DC and crude bile. Treatment ofB. fragiliswith a physiologically relevant concentration of DC reduced cell growth and remodeled transcription of one-quarter of the genome. DC strongly induced expression of chaperones and select transcriptional regulators and efflux systems and downregulated protein synthesis genes. Using a barcoded collection of ≈50,000 unique insertional mutants, we further definedB. fragilisgenes that contribute to fitness in media containing DC or crude bile. Genes impacting cell envelope functions including cardiolipin synthesis, cell surface glycosylation, and systems implicated in sodium-dependent bioenergetics were major bile acid fitness factors. As expected, there was limited overlap between transcriptionally regulated genes and genes that impacted fitness in bile when disrupted. Our study provides a genome-scale view of aB. fragilisbile response and genetic determinants of its fitness in DC and crude bile.ImportanceThe Gram-negative bacterium,Bacteroides fragilis, is a common member of the human gut microbiota that colonizes multiple host niches and can influence human physiology through a variety of mechanisms. Identification of genes that enableB. fragilisto grow across a range of host environments has been impeded in part by the relatively limited genetic tractability of this species. We have developed a high-throughput genetic resource for aB. fragilisstrain isolated from a UC pouchitis patient. Bile acids limit microbial growth and are altered in abundance in UC pouches, whereB. fragilisoften blooms. Using this resource, we uncovered pathways and processes that impactB. fragilisfitness in bile and that may contribute to population expansions during bouts of gut inflammation.
A unified neural representation model for spatial and semantic computations
Authors: Haga Tatsuya , Oseki Yohei , Fukai Tomoki 
Published: May 2023

AbstractHippocampus and entorhinal cortex encode spaces by spatially local and hexagonal grid activity patterns (place cells and grid cells), respectively. In addition, the same brain regions also implicate neural representations for non-spatial, semantic concepts (concept cells). These observations suggest that neurocomputational mechanisms for spatial knowledge and semantic concepts are related in the brain. However, the exact relationship remains to be understood. Here we show a mathematical correspondence between a value function for goal-directed spatial navigation and an information measure for word embedding models in natural language processing. Based on this relationship, we integrate spatial and semantic computations into a neural representation model called as “disentangled successor information” (DSI). DSI generates biologically plausible neural representations: spatial representations like place cells and grid cells, and concept-specific word representations which resemble concept cells. Furthermore, with DSI representations, we can perform inferences of spatial contexts and words by a common computational framework based on simple arithmetic operations. This computation can be biologically interpreted by partial modulations of cell assemblies of non-grid cells and concept cells. Our model offers a theoretical connection of spatial and semantic computations and suggests possible computational roles of hippocampal and entorhinal neural representations.
Chemical protein unfolding - A simple cooperative model
Authors: Seelig Joachim , Seelig Anna 
Published: May 2023

AbstractChemical unfolding with guanidineHCl or urea is a common method to study the conformational stability of proteins. The analysis of unfolding isotherms is usually performed with an empirical linear extrapolation method (LEM). The method contradicts however, common expectations. A large positive free energy is assigned to the native protein which is usually considered to be a minimum of the free energy. Here we present a multistate cooperative model, which addresses specifically the binding of the denaturant to the protein and the cooperativity of the protein unfolding equilibrium. The model is based on a molecular statistical-mechanical partition function of the ensemble but simple solutions for the calculation of the binding isotherm and the associated free energy are presented. The model is applied to 23 published unfolding isotherms of small and large proteins. For a given denaturant, the binding constant depends on temperature and pH, but shows little protein specificity. Chemical unfolding is less cooperative than thermal unfolding. The cooperativity parameter σ is two orders of magnitude larger than that of thermal unfolding. The multistate cooperative model predicts a zero free energy for the native protein, which becomes strongly negative beyond the midpoint concentration of unfolding. The free energy to unfold a cooperative unit corresponds exactly to the diffusive energy of the denaturant concentration gradient necessary for unfolding. The temperature dependence of unfolding isotherms yields the denaturant-induced unfolding entropy and, in turn, the unfolding enthalpy. The multistate cooperative model provides molecular insight, is as simple to apply as the LEM, but avoids the conceptual difficulties of the latter.
Temporal dynamics of gut microbiomes in non-industrialized urban Amazonia
Authors: Schaan Ana Paula , Vidal Amanda , Zhang An-Ni , Poyet Mathilde , Alm Eric J , Groussin Mathieu , Ribeiro-dos-Santos Ândrea 
Published: May 2023

ABSTRACTBackgroundIncreasing levels of industrialization have been associated with changes in gut microbiome structure and loss of features thought to be crucial for maintaining gut ecological balance. The stability of gut microbial communities over time within individuals seems to be largely affected by this transition but has been overlooked among transitioning populations from low to middle-income countries. Here, we used shotgun sequencing to characterize the temporal dynamics of gut microbiomes of 24 individuals living in an urban non-industrialized lifestyle in the Brazilian Amazon and contextualized our data with 165 matching longitudinal samples from an urban industrialized and a rural non-industrialized population.ResultsWe show that gut microbiome composition and diversity have greater variability over time among non-industrialized individuals when compared to industrialized counterparts and that taxa may present diverse temporal dynamics across human populations. Enterotype classifications show community types are generally stable over time despite shifts in microbiome structure. Further, by tracking genomes over time, we show that levels of bacterial population replacements are more frequent among Amazonian individuals and non-synonymous variants accumulate in genes associated with degradation of host dietary polysaccharides.ConclusionsOur results suggest that the stability of gut microbiomes is influenced by levels of industrialization and that tracking microbial population dynamics is important to understand how the microbiome will adapt to these transitions.
L. pneumophilaresists its self-harming metabolite HGA via secreted factors and collective peroxide scavenging
Authors: Holland Mische , Farinella Danielle N. , Cruz-Lorenzo Emily , Laubscher Madelyn I. , Doakes Darian A. , Ramos Maria A. , Kubota Nanami , Levin Tera C. 
Published: May 2023

AbstractMany pathogenic bacteria, includingLegionella pneumophila, infect humans from environmental reservoirs. To survive in these reservoirs, bacteria must withstand microbe-on-microbe competition. We previously discovered thatL. pneumophilacan compete with neighboring bacteria via an antimicrobial metabolite called homogentisic acid (HGA) (Levin, Goldspiel, and Malik 2019). Curiously,L. pneumophilastrains that secrete HGA are not wholly immune to its effects: low-density bacteria are strongly inhibited by HGA whereas high-density cells are tolerant. How do these bacteria tolerate HGA and avoid self-harm during interbacterial competition? Here, we find that HGA toxicity occurs via the production of toxic hydroperoxides and multiple factors facilitate high-density tolerance. First, HGA only becomes fully toxic after >1 hour of oxidation. While this manifests as a delay in killing within well-mixed liquid cultures, in a biofilm environment, this could provide time for HGA to diffuse away before becoming toxic. Second, HGA generates quantities of hydroperoxides that can be collectively scavenged by high-density, but not low-density cells. And third, high-density cells produce one or more secreted factors that are transiently protective from HGA. In combination, we propose that the bacteria are able to deploy HGA to generate a pool of reactive oxygen species surrounding their own biofilms, while maintaining non-toxic conditions within them. Overall, these findings help to explain how broadly toxic molecules can be used as inter-bacterial weapons. They also provide insights about why some of our current decontamination methods to controlL. pneumophilaare ineffective, leading to recurrent disease outbreaks.
Guild and Niche Determination Enable Targeted Alteration of the Microbiome
Authors: Moyne Oriane , Al-Bassam Mahmoud , Lieng Chloe , Thiruppathy Deepan , Norton Grant J. , Kumar Manish , Haddad Eli , Zaramela Livia S. , Zengler Karsten 
Published: May 2023

AbstractMicrobiome science has greatly contributed to our understanding of microbial life and its essential roles for the environment and human health1–5. However, the nature of microbial interactions and how microbial communities respond to perturbations remains poorly understood, resulting in an often descriptive and correlation-based approach to microbiome research6–8. Achieving causal and predictive microbiome science would require direct functional measurements in complex communities to better understand the metabolic role of each member and its interactions with others. In this study we present a new approach that integrates transcription and translation measurements to predict competition and substrate preferences within microbial communities, consequently enabling the selective manipulation of the microbiome. By performing metatranscriptomic (metaRNA-Seq) and metatranslatomic (metaRibo-Seq) analysis in complex samples, we classified microbes into functional groups (i.e. guilds) and demonstrated that members of the same guild are competitors. Furthermore, we predicted preferred substrates based on importer proteins, which specifically benefited selected microbes in the community (i.e. their niche) and simultaneously impaired their competitors. We demonstrated the scalability of microbial guild and niche determination to natural samples and its ability to successfully manipulate microorganisms in complex microbiomes. Thus, the approach enhances the design of pre- and probiotic interventions to selectively alter members within microbial communities, advances our understanding of microbial interactions, and paves the way for establishing causality in microbiome science.
Gene expression genetics of the striatum of Diversity Outbred mice
Authors: Philip Vivek M. , He Hao , Saul Michael C. , Dickson Price E. , Bubier Jason A. , Chesler Elissa J. 
Published: May 2023

AbstractBrain transcriptional variation is a heritable trait that mediates complex behaviors, including addiction. Expression quantitative trait locus (eQTL) mapping reveals genomic regions harboring genetic variants that influence transcript abundance. In this study, we profiled transcript abundance in the striatum of 386 Diversity Outbred (J:DO) mice of both sexes using RNA-Seq. All mice were characterized using a behavioral battery of widely-used exploratory and risk-taking assays prior to transcriptional profiling. We performed eQTL mapping, incorporated the results into a browser-based eQTL viewer, and deposited co-expression network members in GeneWeaver. The eQTL viewer allows researchers to query specific genes to obtain allelic effect plots, analyze SNP associations, assess gene expression correlations, and apply mediation analysis to evaluate whether the regulatory variant is acting through the expression of another gene. GeneWeaver allows multi-species comparison of gene sets using statistical and combinatorial tools. This data resource allows users to find genetic variants that regulate differentially expressed transcripts and place them in the context of other studies of striatal gene expression and function in addiction-related behavior.
The Origin Recognition Complex requires chromatin tethering by a hypervariable intrinsically disordered region that is functionally conserved from sponge to man
Authors: Adiji Olubu A. , McConnell Brendan S. , Parker Matthew W. 
Published: May 2023

ABSTRACTThe first step towards eukaryotic genome duplication is loading of the replicative helicase, the Mcm2-7 complex, onto chromatin. This so-called “licensing” step is executed by the Pre-Replication Complex (Pre-RC) whose assembly on chromatin is nucleated by the DNA-binding activity of the Origin Recognition Complex (ORC). It is thought that metazoan ORC, like the yeast complex, is recruited directly to chromatin by its ATP-dependent DNA binding and encirclement activity. However, we have previously shown that this DNA binding mode is dispensable for chromatin recruitment of fly ORC, raising the question of how metazoan ORC binds chromosomes. We show here that the intrinsically disordered region (IDR) of fly Orc1 is both necessary and sufficient for recruitment of ORC to chromosomesin vivoand demonstrate that this activity is regulated by IDR phosphorylation.In vitrostudies show that the IDR alone binds DNA and this bestows the ORC holocomplex with a high-affinityATP-independentDNA binding mode. Interestingly, we find that Orc1 IDRs have diverged so markedly across metazoans that they are unrecognizable as orthologs and yet we find that these compositionally homologous sequences retain DNA and chromatin binding activity down to basal metazoans. Altogether, these data suggest that chromatin is recalcitrant to ORC’s ATP-dependent DNA binding activity and we propose that this necessitates IDR-dependent chromatin tethering which poises ORC to opportunistically encircle nucleosome free regions as they become available. This work reveals a novel step in metazoan replication licensing and expands our understanding of disordered protein homology and evolution by stretching the relationship between primary structure and function.