bluuebunny/crossref_metadata_2025_split huggingface dataset:
Profiling extremophile bacterial communities recovered from a mining tailing against soil ecosystems through comparative genome-resolved metagenomics and evolutionary analysis
Authors: Rojas Moises A. , Serrano Gladis , Torres Jorge , Ortega Jaime , Gálvez Gabriel , Vilches Emilio , Parra Valentina , Reyes-Jara Angélica , Maracaja-Coutinho Vinicius , Pizarro Lorena , Latorre Mauricio , Di Genova Alex 
Published: August 2024

AbstractMicrobial communities inhabiting mining environments harbor a diverse array of bacteria with specialized metabolic capacities adapted to extreme conditions. Here, we utilized comparative genome-resolved metagenomics of a high-quality Illumina-sequenced sample from the Cauquenes copper tailing in central Chile. We investigate the metabolic roles and evolutionary behaviors of the resident microorganisms, focusing on capacities related to copper, iron, and sulfur metabolism. We recovered 44 medium and high-quality metagenome-assembled genomes (MAGs), primarily classified belonging to phylumActinobacteriota(21),Proteobacteria(10), andAcidobacteriota(6). These MAGs were compared to the Global Soil MAGs project (SMAG catalog), which includes bacteria from conventional or natural ecosystems, to uncover specialized properties of mining bacteria. Notably, we discovered a new phylum,Nitrospirota_A, and provided insights into the unexplored taxonomic classifications at the lowest ranks such as genus and species. Functional potential analysis revealed that the mining community has enhanced molecular capabilities associated with sulfur and copper metabolism. Evolutionary analysis revealed that mining genes involved in targeted metabolism are under strong negative selection, indicating conservative evolutionary pressure within the mining environment. In particular, it was possible to identify a MAG from the genusAcidithrixwith a global dN/dS ratio greater than 1, suggesting positive selection. Additionally, core proteins essential for bacterial survival, such as flagellar motors, cell cycle regulators, and biogenesis proteins, were also under positive selection. The latter points to the need for enhanced mobility in these microorganisms to locate resources efficiently. We demonstrate that copper mining communities are diverse and possess a significant metabolic repertoire under extreme conditions in sulfur and copper proteins. Those specialized genes appear to be in a conservative state rather than undergoing adaptive evolution. This study enhances our understanding of extremophile mining microbiomes, highlighting their high variability in classification, metabolic functions, evolution, and adaptation, which can be leveraged for further biotechnological applications.
Integer topological defects provide a new way to quantify and classify cell sheets
Authors: Zhao Zihui , Li He , Yao Yisong , Zhao Yongfeng , Serra Francesca , Kawaguchi Kyogo , Zhang Hepeng , Chaté Hugues , Sano Masaki 
Published: August 2024

AbstractSheets of confluent cells are often considered as active nematics, with accumulation attopological defects and escape fromdefects being widely recognized. However, collective dynamics surrounding integer-charge defects remain poorly understood, despite its biological importance. By using microfabricated patterns, we induce diverse+1topological defects (aster, spirals, and target) within monolayers of neural progenitor cells. Remarkably, cells are consistently attracted to the core of+1defects regardless of their type, challenging existing theories and the conventional extensile/contractile dichotomy. We trace back the origin of this accumulation behavior to previously overlooked nonlinear active forces using a combination of experiments and a continuous theory derived from a cell-level model. Our findings demonstrate that+1topological defects can reveal key features of active nematic systems and offer a new way to characterize and classify cell layers.
Mosquitoes reared in distinct insectaries within an institution in close spatial proximity possess significantly divergent microbiomes
Authors: Brettell Laura E. , Hoque Ananya F. , Joseph Tara S. , Dhokiya Vishaal , Hornett Emily A. , Hughes Grant L. , Heinz Eva 
Published: August 2024

AbstractThe microbiome affects important aspects of mosquito biology and differences in microbial composition can affect the outcomes of laboratory studies. To determine how the biotic and abiotic conditions in an insectary affect the composition of the bacterial microbiome of mosquitoes we reared mosquitoes from a single cohort of eggs from one genetically homogeneous inbredAedes aegypticolony, which were split into three batches, and transferred to each of three different insectaries located within the Liverpool School of Tropical Medicine. Using three replicate trays per insectary, we assessed and compared the bacterial microbiome composition as mosquitoes developed from these eggs. We also characterised the microbiome of the mosquitoes’ food sources, measured environmental conditions over time in each climate-controlled insectary, and recorded development and survival of mosquitoes. While mosquito development was overall similar between all three insectaries, we saw differences in microbiome composition between mosquitoes from each insectary. Furthermore, bacterial input via food sources, potentially followed by selective pressure of temperature stability and range, did affect the microbiome composition. At both adult and larval stages, specific members of the mosquito microbiome were associated with particular insectaries; and the insectary with less stable and cooler conditions resulted in slower pupation rate and higher diversity of the larval microbiome. Tray and cage effects were also seen in all insectaries, with different bacterial taxa implicated between insectaries. These results highlight the necessity of considering the variability and effects of different microbiome composition even in experiments carried out in a laboratory environment starting with eggs from one batch; and highlights the impact of even minor inconsistencies in rearing conditions due to variation of temperature and humidity.
SNAP-tag2: faster and brighter protein labeling
Authors: Kühn Stefanie , Nasufovic Veselin , Wilhelm Jonas , Kompa Julian , de Lange Eline M.F. , Lin Yin-Hsi , Egoldt Cornelia , Fischer Jonas , Lennoi Artem , Tarnawski Miroslaw , Reinstein Jochen , Vlijm Rifka , Hiblot Julien , Johnsson Kai 
Published: August 2024

AbstractSNAP-tag is a powerful tool for labeling proteins with synthetic fluorophores in bioimaging. However, its utility in live-cell applications can be constrained by its relatively slow labeling kinetics and the limited cell permeability of its substrates. Here we introduce new labeling substrates and an engineered SNAP-tag for faster labelingin vitroand in live cells. SNAP-tag2 presents a second-order rate constant with rhodamine substrates that approaches 107s-1M-1, a 100-fold improvement over the corresponding SNAP-tag-substrate pairs. When labeled with highly fluorogenic dyes, SNAP-tag2 also shows a 5-fold increase in fluorescence brightness relative to currently used SNAP-tag. The increased labeling kinetics and brightness of SNAP-tag2 translates into a greatly improved performance in various live-cell (super-resolution) imaging applications.
Credible set is sensitive to imputation quality and missing variants
Authors: Liang Yanyu ,   23andMe Research Team, Auton Adam , Wang Xin 
Published: August 2024

AbstractBayesian fine-mapping to obtain credible sets has been widely applied post GWAS to pinpoint causal variants. The calculation of credible sets generally assumes that all variants have been equally well genotyped, which is often not the case when a GWAS has been run on imputed data. In this work, we investigate the behavior of credible sets in imputed datasets utilizing ‘held out’ genotyped variants to measure accuracy. We show, via simulation, that: i) the coverage of credible sets decreases when using imputed variants in GWAS; ii) rare causal variants often fail to be tagged in credible sets when they are not present in the GWAS variant set. We develop a reweighting approach to take imputation quality into account during fine-mapping that only requires summary statistics, and demonstrate the approach with real data.
Segregated basal ganglia output pathways correspond to genetically divergent neuronal subclasses
Authors: Mendelsohn Alana I. , Nikoobakht Laudan , Bikoff Jay B. , Costa Rui M. 
Published: August 2024

SUMMARYThe basal ganglia control multiple sensorimotor behaviors though anatomically segregated and topographically organized subcircuits with outputs to specific downstream circuits. However, it is unclear how the anatomical organization of basal ganglia output circuits relates to the molecular diversity of cell types. Here, we demonstrate that the major output nucleus of the basal ganglia, the substantia nigra pars reticulata (SNr) is comprised of transcriptomically distinct subclasses that reflect its distinct progenitor lineages. We show that these subclasses are topographically organized within SNr, project to distinct targets in the midbrain and hindbrain, and receive inputs from different striatal subregions. Finally, we show that these mouse subclasses are also identifiable in human SNr neurons, suggesting that the genetic organization of SNr is evolutionarily conserved. These findings provide a unifying logic for how the developmental specification of diverse SNr neurons relates to the anatomical organization of basal ganglia circuits controlling specialized downstream brain regions.
Toward the Clinical Translation of Safe Intravenous Long Circulating Iodinated Lipid Nanoemulsion Contrast Agents for CT Imaging
Authors: Attia Mohamed F. , Marasco Ryan N. , Kwain Samuel , Foxx Charity , Whitehead Daniel C. , Kabanov Alexander , Lee Yueh Z. 
Published: August 2024

AbstractCurrent clinical small molecule x-ray CT agents are effective but pose risks such as nephrotoxicity, short blood circulation time, limiting scan durations, potential thyroid impact, and immune responses. These challenges drive the development of kidney-safe x-ray nanoparticle (NP)-based contrast agents (CAs), though translation to clinical practice is hindered by chemical complexities and potential toxicity. We have engineered an intravenous, injectable, and safe blood pool NP-based CT CAs at a clinical-equivalent dose of ∼300 mgI/kg (∼2 mL/kg), ideal for vascular and hepatic imaging which are limited by clinical agents. Our iodinated lipid nanodroplet emulsions (ILNEs) contrast agent offers high x-ray attenuation thus improved contrast enhancement, extended stability, and exceptional batch-to-batch consistency. It also boasts a straightforward and scalable manufacturing process with minimal protein interaction, prolonged blood residency (∼4h), and hepatic clearance within 3 days, avoiding nephrotoxicity. Studies in vitro, in mice, and 16.6kg porcine animal model studies confirm its safety, cytocompatibility, and absence of tissue damage. Blood, and thyroid-stimulating hormone (TSH) analyses, and kidney and liver function tests, also support further toxicity evaluations for clinical translation.
Single-turnover kinetic analysis of non-LTR retrotransposition defines the mechanism and rate constants governing each step
Authors: Dangerfield Tyler L. , Zhou Jun , Eickbush Thomas , Johnson Kenneth A. 
Published: August 2024

AbstractSite specific retrotransposon-mediated gene therapy has the potential to revolutionize medicine by allowing insertion of large gene cargos. Despite decades of effort, the reaction sequence remains to be fully elucidated limiting the ability to engineer improved activity for gene insertion. Here we provide a kinetic/mechanistic framework for R2 non-LTR retrotransposition. Single turnover measurements and global data fitting defined the rate constants for each step in the pathway involving 1st-strand DNA cleavage to provide a DNA primer, reverse transcription to copy the RNA, 2nd-strand DNA cleavage to provide the second primer, and 2nd-strand synthesis to make duplex cDNA. Sequence analysis of the cDNA confirms accurate replication of the 1400 nt RNA used in this study. This represents the only complete analysis of the reaction sequence and first observation of 2nd-strand synthesisin vitro. We provide a kinetic framework to understand non-LTR retrotransposition, which provide a basis to engineer improved activity.
Headache-specific Hyperexcitation Sensitises and Habituates on different Time Scales: An Event Related Potential study of Pattern-Glare
Authors: Dogan Cihan , Miller Claire E. , Jefferis Tom , Saranti Margarita , Tempesta Austyn J. , Schofield Andrew J. , Palaniappan Ramaswamy , Bowman Howard 
Published: August 2024

AbstractCortical hyperexcitability is a key pathophysiological feature in several neurological disorders, including migraine, epilepsy, tinnitus, and Alzheimer’s disease. We examined the temporal characteristics of Evoked Related Potentials (ERPs) in a healthy population using the Pattern Glare Test, a diagnostic tool used to assess patients with sensitivity to cortical hyperexcitability. During the experiment, participants recorded state measures with this study focussing on susceptibility to migraine. We investigated two timeframes: habituation over the course of the experiment and sensitization over the course of stimulus presentation. We found evidence of hyperexcitability in the visual cortex, for the clinically aggravating stimuli (medium). Participants who reported a higher state measure exhibited a higher degree of habituation and sensitization, which was dependent on susceptibility to migraine. These findings suggest that the same experimental paradigm and analysis should be performed on a clinically diagnosed population.
Gene expression responses of CF airway epithelial cells exposed to elexacaftor/tezacaftor/ivacaftor (ETI) suggest benefits beyond improved CFTR channel function
Authors: Hampton Thomas H. , Barnaby Roxanna , Roche Carolyn , Nymon Amanda , Fukutani Kiyoshi Ferreira , MacKenzie Todd A. , Stanton Bruce A. 
Published: August 2024

AbstractThe combination of elexacaftor/tezacaftor/ivacaftor (ETI, Trikafta) reverses the primary defect in Cystic Fibrosis (CF) by improving CFTR mediated Cl-and HCO3-secretion by airway epithelial cells (AEC), leading to improved lung function and less frequent exacerbations and hospitalizations. However, studies have shown that CFTR modulators like ivacaftor, a component of ETI, has numerous effects on CF cells beyond improved CFTR channel function. Because little is known about the effect of ETI on CF AEC gene expression we exposed primary human AEC to ETI for 48 hours and interrogated the transcriptome by RNA-seq and qPCR. ETI increased defensin gene expression (DEFB1) an observation consistent with reports of decreased bacterial burden in the lungs of people with CF (pwCF). ETI also decreasedMMP10andMMP12gene expression, suggesting that ETI may reduce proteolytic induced lung destruction in CF. ETI also reduced the expression of the stress response gene heme oxygenase (HMOX1). qPCR analysis confirmedDEFB1, HMOX1, MMP10andMMP12gene expression results observed by RNA-seq. Gene pathway analysis revealed that ETI decreased inflammatory signaling, cellular proliferation and MHC Class II antigen presentation. Collectively, these findings suggest that the clinical observation that ETI reduces lung infections in pwCF is related in part to drug induced increases inDEFB1, and that ETI may reduce lung damage by reducingMMP10andMMP12gene expression, which is predicted to reduce matrix metalloprotease activity. Moreover, pathway analysis also identified several genes responsible for the ETI induced reduction in inflammation observed in people with CF.New and NoteworthyGene expression responses by CF AEC exposed to ETI suggest that in addition to improving CFTR channel function, ETI is likely to increase resistance to bacterial infection by increasing levels of beta defensin 1 (hBD-1). ETI may also reduce lung damage by suppressing MMP10, and reduce airway inflammation by repressing proinflammatory cytokine secretion by AEC cells.
Structural basis for carbohydrate recognition by the Gal/GalNAc lectin ofEntamoeba histolytica
Authors: Gérard Samuel F. , Redfield Christina , Higgins Matthew K. 
Published: August 2024

SummaryIntestinal amoebiasis is caused byEntamoeba histolytica,one of the deadliest human-infective parasites. Central to its pathogenicity is its binding to mucosal carbohydrates, which precedes tissue damage by trogocytosis. Carbohydrate binding is mediated by a single adhesin, the galactose/N-acetylgalactosamine (Gal/GalNAc) lectin, which is the leading vaccine candidate for amoebiasis. We present the structure of the native heterodimeric lectin, revealing an ordered core containing the light chain and the N-terminal region of the heavy chain. Structures in the presence of ligand show that the Gal/GalNAc binding site is in the light chain. An elongated arm emerges from the heavy chain, which adopts multiple positions. This arm contains the epitope for a monoclonal antibody which blocks binding to target cells, located unexpectedly away from the Gal/GalNAc binding site. This study reveals the molecular basis for sugar binding by theEntamoeba histolyticaGal/GalNAc lectin and will guide future vaccine development against amoebiasis.
Neuroendocrine differentiation (ND) in sensitivity of neuroendocrine tumor (NET) cells to ONC201/TIC10 cancer therapeutic
Authors: Ding Elizabeth , Pinho-Schwermann Maximillian , Zhang Shengliang , Purcell Connor , El-Deiry Wafik S. 
Published: August 2024

AbstractProstate cancer (PCa) neuroendocrine tumor (NET)-like cells with low or absent androgen receptor (AR) signaling cause hormone therapy resistance and poor prognosis. Small cell lung carcinoma (SCLC), a high-grade NET, presents with metastasis early and has poor survival. ONC201/TIC10 is a first-in-class cancer therapeutic with clinical activity in diffuse gliomas and neuroendocrine tumors. We hypothesized that markers of neuroendocrine differentiation, activation of the integrated stress response (ISR) and the TRAIL pathway, as well as the expression of ClpP, contribute to neuroendocrine tumor cell death and sensitivity to ONC201. We show that PCa and SCLC cell lines (N=6) are sensitive to ONC201, regardless of the extent of neuroendocrine differentiation. Endogenous levels of some NET markers (CgA, FoxO1, ENO2, PGP9.5, SOX2) are present in a spectrum in PCa and SCLC cell lines. Overexpression of neural transcription factor BRN2 in DU145 PCa cells does not increase expression of NET differentiation markers FoxO1, ENO2, PGP9.5, and CgA at 48 hours. However, the transient BRN2 overexpression showed slight decreases in some NET markers on the spectrum while maintaining sensitivity of PCa cells to ONC201 before any phenotypic change related to NET differentiation. Our results show that ONC201 has preclinical activity against PCa including those without NET markers or in PCa cells with transient overexpression of neural transcription factor BRN2. Our results have relevance to activity of ONC201 in PCa where most castrate-resistant androgen-independent cancers are not therapy resistant due to NET differentiation. Importantly, NET differentiation does not promote resistance to ONC201 supporting further clinical investigations across the spectrum of PCa.
Dietary zinc restriction mimics protein restriction and extends lifespan inDrosophila
Authors: Kosakamoto Hina , Aikawa Hide , Kitazawa Souto , Sakuma Chisako , Okada Rina , Miura Masayuki , Obata Fumiaki 
Published: August 2024

AbstractDietary restriction extends lifespan in model organisms, mainly through dietary amino acids. Compared to macronutrients, the effect of dietary micronutrients on organismal lifespan has not been intensively investigated. Here, using a synthetic diet, we test whether restriction of each micronutrient, including vitamins and minerals, affects lifespan and fecundity in adultDrosophila. While restriction of many of these micronutrients have either negative or no impact on lifespan, zinc (Zn) restriction alone can increase it. Dietary Zn restriction (ZnR) decreases fecundity, increases starvation resistance, and promotes preference for feeding amino acids, in adult females, phenocopying dietary amino acid restriction. Our study demonstrates that dietary intake of trace elements has profound impacts on physiology and lifespan, and that limiting dietary zinc may be a strategy to improve the healthspan of animals.
A Hybrid Type I and II Polyketide Synthases Yields Distinct Aromatic Polyketides
Authors: Zhao Li Ya , Shi Jing , Xu Zhao Yang , Sun Jia Lin , Yan Zhang Yuan , Tong Zhi Wu , Tan Ren Xiang , Jiao Rui Hua , Ge Hui Ming 
Published: August 2024

ABSTRACTBacterial aromatic polyketides are compounds with multiple aromatic rings synthesized by bacterial type II polyketide synthases (PKSs), some of which have been developed into clinical drugs. Compounds containing aromatic polyketides synthesized by a hybrid type I and type II PKSs are extremely rare. Here, we report the discovery of a gene cluster encoding both modular type I PKS, type II PKS and KAS III through extensive bioinformatics analysis, leading to the characterization of the hybrid polyketide, spirocycline A. The structure of spirocycline A is unprecedented among all aromatic polyketides, featuring a unique starter unit, four spirocycles, and forming a dimer. Biosynthetic studies indicate that the starter unit of this molecule is synthesized by type I PKS in collaboration with twotrans-acting ketoreductase (KR) and enoylreductase (ER). It is then transferred by KAS III to the type II PKS system, which then synthesizes the tricyclic aromatic polyketide backbone. The subsequent formation of the spirocycle and dimerization is carried out by four redox enzymes encoded in the gene cluster. Overall, the discovery of spirocycline A provides a new approach for identifying novel aromatic polyketides and offers potential enzymatic tools for the bioengineering of these hybrid polyketides.Table of Contents
AI-Generated Hallmarks of Aging and Cancer: A Computational Approach Using Causal Emergence and Dependency Networks
Authors: Xiong Jianghui 
Published: August 2024

AbstractThis study introduces “hallmarks engineering,” a computational approach to generate quantifiable hallmarks of aging and cancer. We evaluated these hallmarks using genome-wide DNA methylation data from ten age-related diseases. Causal emergence analysis revealed that hallmark-level features show stronger disease associations than individual genes, with improvements up to 9.7 orders of magnitude. Hallmark-based models achieved comparable predictive performance with fewer predictors compared to regular pathway-based models. Dependency network analysis uncovered regulatory networks with power-law distributions and identified top-level “super-regulators” such as genomic stability. Notably, the inclusion of neurodegenerative and cancer hallmarks enhanced representation for their respective disease categories. Our findings suggest that top-down modeling using computationally generated hallmarks may reveal common mechanisms across multiple diseases, offering a promising approach for modeling multimorbidity.