bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modeling Microbial Regulatory Feedback in Organic Matter Decomposition Identifies Copiotrophic Traits as Key Drivers of Positive Priming
Authors: Ahamed Firnaaz , Stegen James C. , Graham Emily B. , Scheibe Timothy D. , Song Hyun-Seob 
Published: August 2024

AbstractMicrobial priming, characterized by significant changes in organic matter (OM) decomposition rates due to minor external treatments with the addition of labile OM, exerts a significant impact on biogeochemical cycles in ecosystems. Priming can take many forms, including positive priming (increased OM decomposition rates), negative priming (decreased OM decomposition rates), and everything in between. Currently, we lack generalizable frameworks that can mechanistically explain these diverse patterns of priming, making it challenging to identify its governing factors. In this work, we theorized priming to result from a biogeochemical feedback loop regulated by microorganisms optimizing the balance between cost and benefit towards maximizing their growth rates, i.e., the cost of exoenzyme synthesis for decomposing complex OM and the benefits of energy acquisition from microbial growth on labile OM. Accordingly, we examined the impacts of microbial growth traits and interactions on priming employing a cybernetic approach, which specializes in predicting complex microbial growth patterns through a regulatory feedback loop. Using the cybernetic model, we simulated the occurrence of priming driven by microorganisms in the following four distinct settings: copiotrophic degraders independently, oligotrophic degraders independently, a consortium of copiotrophic degraders and oligotrophic non-degraders, and a consortium of oligotrophic degraders and copiotrophic non-degraders. Comprehensive Monte Carlo simulations using these four models revealed several critical aspects of priming, including: (1) positive priming is a dominant phenomenon in general, while negative priming can also occur sporadically under specific parameter settings, (2) positive priming is more frequently observed in microbial systems with copiotrophic degraders than with oligotrophic degraders, (3) the presence of copiotrophic non-degraders suppresses positive priming, while the presence of oligotrophic non-degraders promotes positive priming, and (4) the evolution of priming over time is also influenced by microbial growth traits and interactions. Most strikingly, all four models predicted a dramatic positive priming effect triggered by the addition of a small amount (i.e., less than 10%) of labile organic matter, with no notable changes observed beyond this point. Together with other findings summarized above, this might represent a key feature of microbial priming that might be commonly observed across microbial systems with diverse growth traits as supported by literature data. Overall, this work combining new theories and models significantly enhances our understanding of priming by providing model-generated and empirically-testable hypotheses on the mechanisms governing priming.
Adversarial learning enables unbiased organism-wide cross-species alignment of single-cell RNA data at scale
Authors: Díaz-Mejía Juan Javier , Williams Elias , Innes Brendan , Focsa Octavian , Mendonca Dylan , Singh Swechha , Nixon Allison , Schuster Ronen , Buechler Matthew B. , Hinz Boris , Cooper Sam 
Published: August 2024

AbstractToday’s single-cell RNA (scRNA) datasets remain siloed, due to significant challenges associated with their integration at scale. Moreover, most scRNA analysis tools that operate at scale leverage supervised techniques that are insufficient for cell-type identification and discovery. Here, we demonstrate that the alignment of scRNA data using unsupervised models is accurate at an organism-wide scale and between species. To do this, we show adversarial training of a deep-learning model we term batch-adversarial single-cell variational inference (BA-scVI) can be employed to align standardized benchmark datasets comprising dozens of scRNA studies spanning tissues in humans and mice. In the aligned space, we analyze cell types that span tissues in both species and find prevalent complement expressing macrophages and fibroblasts. We provide access to the tools presented via an online interface for atlas exploration and reference-based drag-and-drop alignment of new data.
Nonequilibrium phases of a biomolecular condensate facilitated by enzyme activity
Authors: Coupe Sebastian , Fakhri Nikta 
Published: August 2024

AbstractBiomolecular condensates represent a frontier in cellular organization, existing as dynamic materials driven out of equilibrium by active cellular processes. Here we explore active mechanisms of condensate regulation by examining the interplay between DEAD-box helicase activity and RNA base-pairing interactions within ribonucleoprotein condensates. We demonstrate how the ATP-dependent activity of DEAD-box helicases—a key class of enzymes in condensate regulation—acts as a nonequilibrium driver of condensate properties through the continuous remodeling of RNA interactions. By combining the LAF-1 DEAD-box helicase with a designer RNA hairpin concatemer, we unveil a complex landscape of dynamic behaviors, including time-dependent alterations in RNA partitioning, evolving condensate morphologies, and shifting condensate dynamics. Importantly, we reveal an antagonistic relationship between RNA secondary structure and helicase activity which promotes condensate homogeneity via a nonequilibrium steady state. By elucidating these nonequilibrium mechanisms, we gain a deeper understanding of cellular organization and expand the potential for active synthetic condensate systems.
Local Synthesis of Reticulon-1C Lessens the Outgrowth of Injured Axons by Controlling Spastin Activity
Authors: Luarte Alejandro , Gallardo Javiera , Corvalán Daniela , Chakraborty Ankush , Gouveia-Roque Cláudio , Bertin Francisca , Contreras Carlos , Ramírez Juan Pablo , Weber Andrè , Acevedo Waldo , Zuschratter Werner , Herrera-Molina Rodrigo , Wyneken Úrsula , Paula-Lima Andrea , Adasme-Rocha Tatiana , Figueroa Antonia , González Carolina , González-Billault Christian , Hengst Ulrich , Couve Andrés 
Published: August 2024

AbstractThe regenerative potential of developing cortical axons following injury depends on intrinsic mechanisms, such as axon-autonomous protein synthesis, that are still not fully understood. An emerging factor in this regenerative process is the bi-directional interplay between microtubule dynamics and structural proteins of the axonal endoplasmic reticulum. Therefore, we hypothesize that locally synthesized structural proteins of the endoplasmic reticulum may regulate microtubule dynamics and the outgrowth of injured cortical axons. This hypothesis is supported by RNA data-mining, which identified Reticulon-1 as the sole ER-shaping protein consistently present in axonal transcriptomes and found it to be downregulated following cortical axon injury. Using compartmentalized microfluidic chambers, we demonstrate that local knockdown of Reticulon-1 mRNA enhances outgrowth while reducing the distal tubulin levels of injured cortical axons. Additionally, live cell imaging shows injury-induced reductions in microtubule growth rate and length, which are fully restored by axonal Reticulon-1 knockdown. Interestingly, axonal inhibition of the microtubule-severing protein Spastin fully prevents the effects of local Reticulon-1 knockdown on outgrowth and tubulin levels, while not affecting microtubule dynamics. Furthermore, we provide evidence supporting that the Reticulon-1C isoform is locally synthesized in injured axons and associates with Spastin to inhibit its severing activity. Our findings reveal a novel injury-dependent mechanism in which a locally synthesized ER-shaping protein lessens microtubule dynamics and the outgrowth of cortical axons.
Identification of a novel resistance gene which provides insight into Vip3Aa mode of action inHelicoverpa armigera
Authors: Bachler Andreas , Padovan Amanda , Anderson Craig J. , Wei Yiyun , Wu Yidong , Pearce Stephen , Downes Sharon , James Bill , Tessnow Ashley , Sword Gregory A. , Williams Michelle , Tay Wee Tek , Gordon Karl H. J. , Walsh Tom K. 
Published: August 2024

AbstractThe global reliance onBacillus thuringiensis(Bt) proteins for controlling lepidopteran pests in cotton, corn, and soybean crops underscores the critical need to understand resistance mechanisms. Vip3Aa, one of the most widely deployed and currently effective Bt proteins in genetically modified crops, plays a pivotal role in pest management. This study identifies the molecular basis of Vip3Aa resistance in AustralianHelicoverpa armigerathrough genetic crosses, and integrated genomic and transcriptomic analyses. We identified a previously uncharacterized gene, LOC110373801 (designatedHaVipR1), as a crucial determinant of Vip3Aa resistance in two field-derived resistant lines. Functional validation using CRISPR-Cas9 knockout in susceptible lines confirmed the gene’s role in conferring resistance.Despite extensive laboratory selection of Vip3Aa-resistant colonies in Lepidoptera, the biochemical mechanisms underlying resistance have remained elusive. Our research demonstrates thatHaVipR1-mediated resistance operates independently of known resistance genes, including midgut-specific chitin synthase and the transcription factor SfMyb.The identification ofHaVipR1offers further insights into the Vip3Aa mechanism of action. This discovery is vital for devising strategies to counteract resistance and sustain the efficacy of Bt crops. Future research should focus on elucidating the biochemical pathways involvingHaVipR1and investigating its interactions with other resistance mechanisms. Our findings underscore the utility of analysing field-derived resistant lines in providing biologically relevant insights and stress the necessity for comprehensive management strategies to maintain agricultural productivity.Significance StatementThis is the first identification of a specific gene inHelicoverpa armigerawhich mediates resistance to theBacillus thuringiensis(Bt) protein Vip3Aa. We identify that this gene is disrupted in two different ways in separate field-derived resistant lines, one being a large transposable element insertion in the first intron of theHaVipR1gene, confirmed using long-read sequencing. Disruption of this gene using CRISPR-Cas9 knockout in a susceptibleH. armigeraline confers Vip3A resistance. The identification of a specific gene is important for molecular monitoring and management ofH. armigeraas well as other global pests of concern likeSpodoptera frugiperda. These findings also offer insights for researchers aiming to understand how Vip3Aa functions, as the action pathway remains unclear.
Avoided and avoidable deaths with the use of COVID-19 convalescent plasma in Italy during the first two years of pandemic
Authors: Franchini Massimo , Casadevall Arturo , Dragotakes Quigly , Focosi Daniele 
Published: August 2024

AbstractItaly was the first western country to be hit by the COVID-19 pandemic and suffered nearly 200,000 deaths so far during the four years of the pandemic. In March 2020, Italy first deployed COVID-19 convalescent plasma (CCP) to treat hospitalized patients. Despite this initial effort, the proportion of COVID-19 patients treated with CCP during the first two years of the pandemic (2020-2021) was very low (approximately 2% of individuals hospitalized for COVID-19). In this study, we estimated the number of actual inpatient lives saved by CCP treatment in Italy using national mortality data, and CCP mortality reduction data from meta-analyses of randomized controlled trials and real-world data. We also estimated the potential number of lives saved if CCP had been deployed to 100% of hospitalized patients or used in 15% to 75% of outpatients. According to these models, CCP usage in 2020-2021 saved between 385-1304 lives, but this number would have increased to 17,751-60,079 if 100% of inpatients had been transfused with CCP. Similarly, broader (15-75%) usage in outpatients could have prevented 21,187-190,689 hospitalizations (desaturating hospitals) and 6,144-81,926 deaths. These data have important implications for convalescent plasma use in future infectious disease emergencies.
Early Detection of Mental Health Crises through AI-Powered Social Media Analysis: A Prospective Observational Study
Authors: Mansoor Masab A. , Ansari Kashif 
Published: August 2024

AbstractBackgroundEarly detection of mental health crises is crucial for timely intervention and improved outcomes. This study explores the potential of artificial intelligence (AI) in analyzing social media data to identify early signs of mental health crises.MethodsWe developed a multi-modal deep learning model integrating natural language processing and temporal analysis techniques. The model was trained on a diverse dataset of 996,452 social media posts in multiple languages (English, Spanish, Mandarin, and Arabic) collected from Twitter, Reddit, and Facebook over a 12-month period. Performance was evaluated using standard metrics and validated against expert psychiatric assessment.ResultsThe AI model demonstrated high accuracy (89.3%) in detecting early signs of mental health crises, with an average lead time of 7.2 days before human expert identification. Performance was consistent across languages (F1 scores: 0.827-0.872) and platforms (F1 scores: 0.839-0.863). Key digital markers included linguistic patterns, behavioral changes, and temporal trends. The model showed varying accuracy for different crisis types: depressive episodes (91.2%), manic episodes (88.7%), suicidal ideation (93.5%), and anxiety crises (87.3%).ConclusionsAI-powered analysis of social media data shows promise for early detection of mental health crises across diverse linguistic and cultural contexts. However, ethical challenges including privacy concerns, potential stigmatization, and cultural biases need careful consideration. Future research should focus on longitudinal outcome studies, ethical integration with existing mental health services, and development of personalized, culturally-sensitive models.
A biofilm-tropicPseudomonas aeruginosabacteriophage uses the exopolysaccharide Psl as receptor
Authors: Walton Brenna , Abbondante Serena , Marshall Michaela Ellen , Dobruchowska Justyna M. , Alvi Amani , Gallagher Larry A. , Vallikat Nikhil , Zhang Zhemin , Wozniak Daniel J. , Yu Edward W. , Boons Geert-Jan , Pearlman Eric , Rietsch Arne 
Published: August 2024

AbstractBacteria in nature can exist in multicellular communities called biofilms. Biofilms also form in the course of many infections.Pseudomonas aeruginosainfections frequently involve biofilms, which contribute materially to the difficulty to treat these infections with antibiotic therapy. Many biofilm-related characteristics are controlled by the second messenger, cyclic-di-GMP, which is upregulated on surface contact. Among these factors is the exopolysaccharide Psl, which is a critically important component of the biofilm matrix. Here we describe the discovery of aP. aeruginosabacteriophage, which we have called Clew-1, that directly binds to and uses Psl as a receptor. While this phage does not efficiently infect planktonically growing bacteria, it can disruptP. aeruginosabiofilms and replicate in biofilm bacteria. We further demonstrate that the Clew-1 can reduce the bacterial burden in a mouse model ofP. aeruginosakeratitis, which is characterized by the formation of a biofilm on the cornea. Due to its reliance on Psl for infection, Clew-1 does not actually form plaques on wild-type bacteria under standardin vitroconditions. This argues that our standard isolation procedures likely exclude bacteriophage that are adapted to using biofilm markers for infection. Importantly, the manner in which we isolated Clew-1 can be easily extended to other strains ofP. aeruginosaand indeed other bacterial species, which will fuel the discovery of other biofilm-tropic bacteriophage and expand their therapeutic use.
Multi-Targeted Effects of Novel Cycloastragenol Derivatives: Enhancing NRF2, Proteostasis, and Telomerase Pathways with p53 Modulation to Delay Replicative Senescence
Authors: Yilmaz Sinem , Bedir Erdal , Ballar Kirmizibayrak Petek 
Published: August 2024

AbstractAging is a complex, multifactorial process driven by various cellular and molecular mechanisms, including telomere shortening, oxidative stress, and the decline of proteostasis, all of which contribute to replicative senescence and age-related diseases. Cycloastragenol (CA), a triterpenoid saponin derived fromAstragalus membranaceus, has shown potential for its ability to activate telomerase, suggesting therapeutic benefits in delaying cellular aging. In this study, we explored the effects of novelCAderivatives, obtained through biotransformation as telomerase activators, on the NRF2/proteasome/telomerase axis and their potential to delay replicative senescence in human primary epidermal keratinocytes (HEKn).Our findings reveal that theseCAderivatives significantly enhance NRF2 nuclear activity, leading to the upregulation of key cytoprotective enzymes essential for mitigating oxidative stress. Notably, these derivatives exhibited efficacy at much lower concentrations compared toCA, demonstrating their potential for enhanced therapeutic application. The derivatives also markedly increased proteasome activity, particularly in the β1 and β5 subunits, thereby preserving proteostasis—a critical factor in preventing the accumulation of damaged proteins associated with aging. Furthermore, continuous treatment with these derivatives sustained stimulatory effects, which was evidenced by increased NRF2, proteasome, and hTERT protein levels even in senescent cells and extended cellular lifespan.Additionally, we explored the impact ofCAderivatives on p53-mediated pathways, demonstrating that these compounds effectively modulate the p53/p21 axis, reducing cell cycle arrest and promoting cellular proliferation. Moreover, the derivatives exhibited neuroprotective properties by attenuating glutamate-induced excitotoxicity, further underscoring their potential as multi-targeted anti-aging agents. In conclusion, our study provides strong evidence that novelCAderivatives act on multiple fronts to enhance NRF2 activity, maintain proteostasis, and modulate telomerase and p53 pathways, most at lower doses compared toCA. These actions collectively contribute to the delay of replicative senescence and the promotion of cellular longevity, positioningCAderivatives as potent candidates for developing multi-targeted anti-aging therapies that address the complex interplay of aging-related cellular processes.HighlightsTelomerase-activeCAderivatives enhance NRF2 activity and proteasome activity, leading to cytoprotection at lower doses thanCA.CAderivatives modulate the p53 pathway and cell cycle, prolonging cellular lifespan and delaying replicative senescence.CAderivatives protect cells against glutamate-excitotoxicity along with decreased p53 protein levels.
Attentional priority and limbic activity favor gains over losses
Authors: Hu Kesong , Rosa Eve De , Anderson Adam K 
Published: August 2024

AbstractProspect theory has suggested that decisions reflect a bias toward avoidance of loss compared to equivalent gains. In our study we examine whether a similar bias is found in decisions regarding whether a loss associated stimulus or a gain associated stimulus is given priority in perception. We find that for most people, gains are given priority over loss in the decision of which of the two stimuli occurs first. We also ask whether gains are reflected in greater activity in limbic systems related to emotion. In an fMRI study, we find that most people show greater emotional response to gains, not losses. We consider how these findings might be related to risk aversion in studies of decision making.
A fast-acting inhibitor of blood-stageP. falciparumwith mechanism distinct from artemisinin and chloroquine
Authors: Kabeche Stephanie , Meister Thomas , Yeh Ellen 
Published: August 2024

ABSTRACTArtemisinins are first-line treatment for malaria, prized for their extremely fast reduction of parasite load in patients. New fast-acting antimalarial compounds are urgently needed to counter artemisinin resistance, but the fast parasite reduction observed with artemisinins is rare among antimalarial compounds. Here we show that MMV1580853 has a very fastin vitrokilling rate, comparable to that of dihydroartemisinin. Near-complete parasite growth inhibition was observed within 1 hour of treatment with MMV1580853 and dihydroartemisinin, while chloroquine, another fast-acting antimalarial, showed partial growth inhibition after 1h. MMV1580853 was reported to inhibit prenyltransferases, but its fast killing rate is inconsistent with this mechanism-of-action and we were unable to validate any of 3 annotatedP. falciparumprenyltransferases as MMV1580853 targets. MMV1580853 also did not phenocopy the inhibition phenotype of either chloroquine or dihydroartemisinin. These results indicate that MMV1580853 has a distinct mechanism-of-action leading to a very fast killing rate. MMV1580853 compound development and investigation of its mechanism-of-action will be critical avenues in the search for drugs matching the remarkable clinical efficacy of artemisinin.
E. coliphylogeny drives co-amoxiclav resistance through variable expression ofblaTEM-1
Authors: Matlock William , Rodger Gillian , Pritchard Emma , Colpus Matthew , Kapel Natalia , Barrett Lucinda , Morgan Marcus , Oakley Sarah , Hopkins Katie L. , Roohi Aysha , Karageorgopoulos Drosos , Avison Matthew B. , Walker A. Sarah , Lipworth Samuel , Stoesser Nicole 
Published: August 2024

AbstractCo-amoxiclav resistance inE. coliis a clinically important phenotype associated with increased mortality. The class A beta-lactamaseblaTEM-1is often carried by co- amoxiclav-resistant pathogens, but exhibits high phenotypic heterogeneity, making genotype-phenotype predictions challenging. We present a curated dataset ofn=377E. coliisolates representing all 8 known phylogroups, where the only acquired beta- lactamase isblaTEM-1. For all isolates, we generate hybrid assemblies and co-amoxiclav MICs, and for a subset (n=67/377),blaTEM-1qPCR expression data. First, we test whether certainE. colilineages are intrinsically better or worse at expressingblaTEM-1, for example, due to lineage differences in regulatory systems, which are challenging to directly quantify. Using genotypic features of the isolates (blaTEM-1promoter variants and copy number), we develop a hierarchical Bayesian model forblaTEM-1expression that controls for phylogeny. We establish thatblaTEM-1expression intrinsically varies across the phylogeny, with some lineages (e.g. phylogroups B1 and C, ST12) better at expression than others (e.g. phylogroups E and F, ST372). Next, we test whether phylogenetic variation in expression influences the resistance of the isolates. With a second model, we use genotypic features (blaTEM-1promoter variants, copy number, duplications;ampCpromoter variants; efflux pump AcrF presence) to predict isolate MIC, again controlling for phylogeny. Lastly, we use a third model to demonstrate that the phylogenetic influence onblaTEM-1expression causally drives the variation in co- amoxiclav MIC. This underscores the importance of incorporating phylogeny into genotype-phenotype predictions, and the study of resistance more generally.