bluuebunny/crossref_metadata_2025 huggingface dataset:
The impacts of viral interaction on household transmission of respiratory viruses
Authors: Ibiebele Jessica C. , Godonou Elie-Tino , Callear Amy P. , Smith Matthew R. , Truscon Rachel , Johnson Emileigh , Eisenberg Marisa C. , Lauring Adam S. , Monto Arnold S. , Cobey Sarah , Martin Emily T.
Published: July 2024

The possibility of virus-virus interaction has been hypothesized at the population level, but there are limited data regarding the effects of viral interaction on transmission. This study used data from a prospective household cohort study to examine how viral interaction impacts transmission of influenza A virus (IAV), influenza B virus (IBV), and respiratory syncytial virus (RSV). We used two main predictors of transmission: coinfection in the index case and detection of a virus other than a primary virus of interest in the susceptible contact. Household- and individual-level analyses were conducted for IAV, IBV, and RSV. To estimate the risk of transmission within households with coinfected index cases, a household-level analysis was performed using multivariable regression with Poisson mixed effects models. To estimate an individual’s risk of transmission when multiple viruses co-circulated within their household, an individual-level analysis was performed using mixed-effects logistic regression models. Coinfection among index cases was associated with reduced transmission of IAV and RSV. Infection with a different virus among household contacts was associated with an increased risk of transmission of IAV and RSV. This study enhances the understanding of viral interaction by elucidating the potential impacts of interaction on virus transmission. These findings could have important implications for public health planning and prevention efforts.
The RpfB switch is a novel B12-sensing riboswitch regulating (non-replicating) persistence inMycobacterium tuberculosis
Authors: Kipkorir Terry , Polgar Peter , D’Halluin Alexandre , Gap-Gaupool Brindha , Makarov Vadim A. , Mukamolova Galina V. , Arnvig Kristine B.
Published: July 2024

Riboswitches are metabolite-sensing RNA elements that control a wide range of genes in bacteria. Most riboswitches identified to date are broadly conserved and control genes that are directly involved in the transport or biosynthesis of their cognate ligands. However, a minority of switches are restricted to a few species and in addition may bind less obvious ligands. One such switch controls the expression of theMycobacterium tuberculosis rpfBoperon, which is critical for resuscitation of dormant bacteria, ribosome maturation and reactivation of latent tuberculosis infection. The switch is restricted to pathogenic mycobacteria and until now, its ligand was unknown. However, in the current study, we identify the ligand as cobalamin or vitamin B12. Using in-line probing, we show that vitamin B12binds directly to the riboswitch RNA, and we predict a structure based on the cleavage pattern. Moreover, we show that B12suppresses the expression of anrpfB-lacZreporter fusion and crucially, that B12suppresses resuscitation ofM. tuberculosisfrom a state of non-replicating persistence. These findings demonstrate a pivotal role of crosstalk between a host-derived metabolite and a pathogen riboswitch in controllingM. tuberculosispersistence with potential for improved interventions.
The noncoding circular RNAcircHomer1regulates synaptic development and experience-dependent plasticity in mouse visual cortex
Authors: Jenks Kyle R. , Cai Ying , Nayan Marvin Eduarte , Tsimring Katya , Li Keji , Zepeda José C. , Heller Gregg R. , Delepine Chloe , Shih Jennifer , Yuan Shiyang , Zhu Yao , Wang Ye , Duan Yangyang , Fu Amy K. Y. , Ku Taeyun , Yun Dae Hee , Chung Kwanghun , Mellios Nikolaos , Sur Mriganka , Ip Jacque Pak Kan
Published: July 2024

Circular RNAs (circRNAs) are a class of closed-loop, single stranded RNAs whose expression is particularly enriched in the brain. Despite this enrichment and evidence that the expression of circRNAs are altered by synaptic development and in response to synaptic plasticityin vitro, the regulation by and function of the majority of circRNAs in experience-dependent plasticityin vivoremain unexplored. Here, we employed transcriptome-wide analysis comparing differential expression of both mRNAs and circRNAs in juvenile mouse primary visual cortex (V1) following monocular deprivation (MD), a model of experience-dependent developmental plasticity. Among the differentially expressed mRNAs and circRNAs following 3-day MD, the circular and the activity-dependent mRNA forms of theHomer1gene,circHomer1andHomer1arespectively, were of interest as their expression changed in opposite directions:circHomer1expression increased while the expression ofHomer1adecreased following 3-day MD. Knockdown ofcircHomer1delayed the depression of closed-eye responses normally observed after 3-day MD.circHomer1-knockdown also led to a reduction in average dendritic spine size prior to MD but critically there was no further reduction after 3-day MD, consistent with impaired structural plasticity.circHomer1-knockdown also prevented the reduction of surface AMPA receptors after 3-day MD. Synapse-localized puncta of the AMPA receptor endocytic protein Arc increased in volume after MD but were smaller incircHomer1-knockdown neurons, suggesting thatcircHomer1knockdown impairs experience-dependent AMPA receptor endocytosis. Thus, the expression of multiple circRNAs are regulated by experience-dependent developmental plasticity, and our findings highlight the essential role ofcircHomer1in V1 synaptic development and experience-dependent plasticity.

Significance Statement

Circular RNAs (circRNAs) are a class of closed-loop RNAs formed through back-splicing of exon and/or intron junctions. Initially considered as byproducts of aberrant RNA splicing with limited function, recent studies have implicated circRNAs in various neurological disorders. Despite their abundant expression in the brain, the role of circRNAs in experience-dependent plasticity remains poorly understood. We conducted anin vivotranscriptome analysis of circRNAs whose expression was regulated by experience-dependent plasticity in the mouse visual cortex and highlightcircHomer1, a circRNA derived from theHomer1gene, as a circRNA critical for synaptic development and experience-dependent plasticityin vivo.
Extracts of food and medicinal plants sold in Moroccan markets induce apoptosis-like inToxoplasma gondiitachyzoitesin vitro
Authors: Elkoraichi Ismail , Moiré Nathalie , Rais Samira , Dimier-Poisson Isabelle , Daoudi Fouad , Debierre-Grockiego Françoise
Published: July 2024

Treatment of congenital toxoplasmosis is potentially toxic and above all too expensive to be administered systematically in middle-income countries such as Morocco. There is therefore a real interest in discovering alternative treatments that would be financially accessible to all. In this context, plants used in traditional medicine and purchased in markets are good candidates. Aqueous extract ofAmmi visnagaseeds had no inhibitory effect againstT. gondiitachyzoites intracellular growthin vitroand induced a cytotoxic effect on host cells. In contrast, ethanolic extract ofA. visnagaseeds showed anti-Toxoplasmaeffect with low cytotoxicity, indicating the compounds extracted differed according to the solvent used. Aqueous extracts ofPunica granatumpeel andSyzygium aromaticumflower buds also showed anti-Toxoplasmaeffect with low cytotoxicity. All the extracts tested, with a greater effect from aqueous and ethanolic extracts ofA. visnagaseeds, induced apoptosis-like of extracellular tachyzoites, as determined by exposure of phosphatidylserine on tachyzoite surface and DNA fragmentation. Finally, the aqueous extracts ofA. visnagaseeds,P. granatumpeel andS. aromaticumflower buds exhibited antioxidant properties. Phytochemical analysis indicated that coumarins and sterols from the aqueous extract ofA. visnaga, saponins from the ethanolic extract ofA. visnaga, gallic tannins from the extract ofP. granatum, and phenols from the extract ofS. aromaticumwere certainly the main components responsible for the different effects observed. The results suggested that the seeds ofA. visnagaand the peel ofP. granatumare the two best candidates for possible preclinical studies on toxoplasmosis.
Evaluation of intercellular and extracellular synthesis of biogenic amines by the aquatic mossVesicularia dubyana
Authors: Belyshenko Alexander , Morgunova Maria , Malygina Ekaterina , Dmitrieva Maria , Imidoeva Natalia , Shelkovnikova Victoria , Telnova Tamara , Vlasova Anfisa , Vavilina Tatiana , Tretyakova Anastasia , Axenov-Gribanov Denis
Published: July 2024

Natural compounds of mosses are an understudied area of phytochemistry. Over the last 20 years, the amount of information on the chemistry of natural compounds in mosses has increased considerably, but is still underwhelming. Historically, only a few hundred natural products have been described for mosses, whereas the potential for bacteria or fungi is measured in hundreds of thousands of metabolites. Although metabolites with antimicrobial, antiviral, fungicidal, and cytotoxic activities have been discovered in mosses, only few studies have been devoted to compounds with neurogenic properties. In our study, the ability of the aquatic mossVesicularia dubyanato synthesize biogenic amines intercellularly and extracellularly has been evaluated.

Aquatic moss was grown in laboratory conditions, and methanol extraction of cell biomass and moss-environment medium was conducted. The presence of biogenic amines was confirmed by UHPLC-MS-MRM analysis.

The following compounds were revealed in the cellular biomass ofV. dubyana: histamine, kynurenine, kynurenic acid, tryptamine, and tyramine. Histamine was also detected in the moss-environment medium, indicating the extracellular synthesis of this natural compound. Methanol extracts of the studied moss showed low antibacterial and antioxidant activities. Thus, this study for the first time demonstrates biogenic amine synthesis by aquatic mosses.
Human ANP32A/B are SUMOylated and utilized by avian influenza virus NS2 protein to overcome species-specific restriction
Authors: Sun Liuke , Guo Xing , Yu Mengmeng , Wang Xue-Feng , Ren Huiling , Wang Xiaojun
Published: July 2024

Human ANP32A/B (huANP32A/B) poorly support the polymerase activity of avian influenza viruses (AIVs), thereby limiting interspecies transmission of AIVs from birds to humans. The SUMO-interacting motif (SIM) within NS2 promotes the adaptation of AIV polymerase to huANP32A/B via a yet undisclosed mechanism. Here we show that huANP32A/B are SUMOylated by the E3 SUMO ligase PIAS2α, and deSUMOylated by SENP1. SUMO modification of huANP32A/B results in the recruitment of NS2, thereby facilitating huANP32A/B-supported AIV polymerase activity. Such a SUMO-dependent recruitment of NS2 is mediated by its association with huANP32A/B via the SIM-SUMO interaction module, where K68/K153-SUMO in huANP32A or K68/K116-SUMO in huANP32B interacts with the NS2-SIM. The SIM-SUMO interactions between huANP32A/B and NS2 function to promote AIV polymerase activity by positively regulating AIV vRNP-huANP32A/B interactions and AIV vRNP assembly. Our study offers insights into the mechanism of NS2 SIM in facilitating AIVs adaptation to mammals.
Biased agonism of carvedilol in the beta1-adrenergic receptor is governed by conformational exclusion
Authors: Abiko Layara Akemi , Petrovic Ivana , Tatli Meltem , Desai Samit , Stahlberg Henning , Spang Anne , Grzesiek Stephan
Published: July 2024

G protein-coupled receptors (GPCRs) are the therapeutically most important family of receptors in the human genome. The selective activation of specific signaling pathways, termed biased signaling, is at the forefront of GPCR-targeted drug development (1). These pathways are governed by dynamic equilibria among multiple GPCR conformations modulated by orthosteric ligands (2). In this study, we elucidated the molecular mechanism underlying the biased signaling of carvedilol. This widely used beta-blocker is a heavily arrestin-biased agonist and at the same time, a G protein inverse agonist of beta-adrenergic receptors (betaARs) (3). Our solution NMR, cryo-electron microscopy, and biochemical data show that the inactive conformation induced by carvedilol prevents G protein binding but is recognized by arrestin. Arrestin binding to the receptor is independent of the type and presence of orthosteric ligands, with the only requirement that arrestin is activated by a receptor phosphopeptide, which does not need to be covalently linked to the receptor. Thus, arrestin-biased signaling appears governed by conformational exclusion of the G protein in agreement with the promiscuous recognition of GPCRs by arrestin. The provided molecular details reveal the mechanism of selective transducer activation by GPCRs and provide new opportunities for developing safer therapeutics.
A modular cell-free protein biosensor platform using split T7 RNA polymerase
Authors: McSweeney Megan A. , Patterson Alexandra T. , Loeffler Kathryn , Cuellar Lelo de Larrea Regina , McNerney Monica P. , Kane Ravi S. , Styczynski Mark P.
Published: July 2024

Conventional laboratory protein detection techniques are not suitable for point-of-care (POC) use because they require expensive equipment and laborious protocols, and existing POC assays suffer from long development timescales. Here, we describe a modular cell-free biosensing platform for generalizable protein detection that we call TLISA (T7 RNA polymerase-Linked ImmunoSensing Assay), designed for extreme flexibility and equipment-free use. TLISA uses a split T7 RNA polymerase fused to affinity domains against a protein. The target antigen drives polymerase reassembly, inducing reporter expression. We characterize the platform, then demonstrate its modularity by using 16 affinity domains against four different antigens with minimal protocol optimization. We show TLISA is suitable for POC use by sensing human biomarkers in serum and saliva with a colorimetric readout within one hour and by demonstrating functionality after lyophilization. Altogether, this technology could have potentially revolutionary impacts, enabling truly rapid, reconfigurable, equipment-free detection of virtually any protein.
High-throughput discovery of regulatory effector domains in human RNA-binding proteins
Authors: Thurm Abby R. , Finkel Yaara , Andrews Cecelia , Cai Xiangmeng S. , Benko Colette , Bintu Lacramioara
Published: July 2024

RNA regulation plays an integral role in tuning gene expression and is controlled by thousands of RNA-binding proteins (RBPs). We develop and use a high-throughput recruitment assay (HT-RNA-Recruit) to identify regulatory domains within human RBPs by recruiting over 30,000 protein tiles from 367 RBPs to a reporter mRNA. We discover over 100 unique RNA-regulatory effectors in 86 distinct RBPs, presenting evidence that RBPs contain functionally separable domains that dictate their post-transcriptional control of gene expression, and identify some with unique activity at 5’ or 3’UTRs. We identify some domains that downregulate gene expression both when recruited to DNA and RNA, and dissect their mechanisms of regulation. Finally, we build a synthetic RNA regulator that can stably maintain gene expression at desired levels that are predictable by a mathematical model. This work serves as a resource for human RNA-regulatory effectors and expands the synthetic repertoire of RNA-based genetic control tools.

Highlights

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HT-RNA-Recruit identifies hundreds of RNA-regulatory effectors in human proteins.

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Recruitment to 5’ and 3’ UTRs identifies regulatory domains unique to each position.

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Some protein domains have both transcriptional and post-transcriptional regulatory activity.

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We develop a synthetic RNA regulator and a mathematical model to describe its behavior.
Twinfilin is a non-processive depolymerase which synergizes with formin to dramatically accelerate actin filament uncapping by 300-fold
Authors: Reddy Vishal , Arya Ankita , Shekhar Shashank
Published: July 2024

Cellular actin networks assemble by actin filament elongation at barbed ends and are thought to disassemble primarily by depolymerization at filament pointed ends. Contrary to this conventional understanding of actin dynamics, twinfilin was recently shown to promote barbed-end depolymerization. Twinfilin has additionally been suggested to sequester monomers and cap as well as uncap filament barbed ends. As a result, the exact mechanisms by which twinfilin affects barbed-end dynamics remain controversial. Using multicolor single-molecule microscopy, we show that both mouse and yeast twinfilin are non-processive depolymerases that interact only transiently with barbed ends (~0.2-0.5 s). Each twinfilin binding event, on average, results in the removal of one or two actin subunits. At CP-capped barbed ends, twinfilin synergizes with formin to accelerate uncapping by up to ~320-fold. We find that uncapping by twinfilin, alone and together with formin, depends on the nucleotide state of the filament, with the two proteins causing a much more modest enhancement of uncapping of newly assembled filaments. Our study thus establishes twinfilin as a multifunctional barbed-end binding protein capable of non-processively depolymerizing, transiently capping, and synergizing with formin to rapidly uncap actin filament barbed ends.
Lactate-carried Mitochondrial Energy Overflow
Authors: Rauseo Daniela , Contreras-Baeza Yasna , Faurand Hugo , Cárcamo Nataly , Suárez Raibel , von Faber-Castell Alexandra , Silva Franco , Mora-González Valentina , Wyss Matthias T. , Baeza-Lehnert Felipe , Ruminot Iván , Alvarez-Navarro Carlos , Martín Alejandro San , Weber Bruno , Sandoval Pamela Y. , Barros L. Felipe
Published: July 2024

We addressed the question of mitochondrial lactate metabolism using genetically-encoded sensors. The organelle was found to contain a dynamic lactate pool that leads to dose- and time-dependent protein lactylation. In neurons, mitochondrial lactate reported blood lactate levels with high fidelity. The exchange of lactate across the inner mitochondrial membrane was found to be mediated by a high affinity H+-coupled transport system involving the mitochondrial pyruvate carrier MPC. Assessment of electron transport chain activity and determination of lactate flux showed that mitochondria are tonic lactate producers, a phenomenon driven by energization and stimulated by hypoxia. We conclude that an overflow mechanism caps the redox level of mitochondria, while saving energy in the form of lactate.

One Sentence Summary

Mitochondrial lactate production
Long-read sequencing transcriptome quantification with lr-kallisto
Authors: Loving Rebekah K. , Sullivan Delaney K. , Booeshagi A. Sina , Reese Fairlie , Rebboah Elisabeth , Sakr Jasmine , Rezaie Narges , Liang Heidi Y. , Filimban Ghassan , Kawauchi Shimako , Oakes Conrad , Trout Diane , Williams Brian A. , MacGregor Grant , Wold Barbara J. , Mortazavi Ali , Pachter Lior
Published: July 2024

RNA abundance quantification has become routine and affordable thanks to high-throughput “short-read” technologies that provide accurate molecule counts at the gene level. Similarly accurate and affordable quantification of definitive fulllength, transcript isoforms has remained a stubborn challenge, despite its obvious biological significance across a wide range of problems. “Long-read” sequencing platforms now produce data-types that can, in principle, drive routine definitive isoform quantification. However some particulars of contemporary long-read datatypes, together with isoform complexity and genetic variation, present bioinformatic challenges. We show here, using ONT data, that fast and accurate quantification of long-read data is possible and that it is improved by exome capture. To perform quantifications we developed lr-kallisto, which adapts the kallisto bulk and single-cell RNA-seq quantification methods for long-read technologies.
Clonal heterogeneity and antigenic stimulation shape persistence of the latent reservoir of HIV
Authors: Noceda Marco Garcia , Barton John P.
Published: July 2024

Drug treatment can control HIV-1 replication, but it cannot cure infection. This is because of a long-lived population of quiescent infected cells, known as the latent reservoir (LR), that can restart active replication even after decades of successful drug treatment. Many cells in the LR belong to highly expanded clones, but the processes underlying the clonal structure of the LR are unclear. Understanding the dynamics of the LR and the keys to its persistence is critical for developing an HIV-1 cure. Here we develop a quantitative model of LR dynamics that fits available patient data over time scales spanning from days to decades. We show that the interplay between antigenic stimulation and clonal heterogeneity shapes the dynamics of the LR. In particular, we find that large clones play a central role in long-term persistence, even though they rarely reactivate. Our results could inform the development of HIV-1 cure strategies.
Impact ofAPOE,Klothoand sex on cognitive decline with aging
Authors: Shibata Kengo , Chen Cheng , Tai Xin You , Manohar Sanjay G , Husain Masud
Published: July 2024

The effects ofAPOEandKlothogenes, both implicated in aging, on human cognition as a function of sex and age are yet to be definitively established. Here we showed in the largest cohort studied to date (N =320,861) thatAPOEhomozygous ε4 carriers had a greater decline in cognition with aging compared to ε3 carriers (ε4/ε3 & ε3/ε3) as well as smaller hippocampi and amygdala (N =37,976). Critically, sex and age differentially affected the decline in cognition. Younger (40 - 50 years) female homozygous ε4 carriers showed a cognitive advantage over female ε3 carriers, but this advantage was not present in males. By contrast,Klotho-VSheterozygosity did not affect cognition or brain volume, regardless ofAPOEgenotype, sex or age. These cognitive trajectories with aging demonstrate clear sex- dependent antagonistic pleiotropy effects ofAPOEε4, but no effects ofKlothogenotype on cognition and brain volume.
Still Not Sterile: Chlorhexidine gluconate treatment does not completely reduce skin microbial bioburden and promotes pathogen overabundance in patients undergoing elective surgeries
Authors: Townsend Elizabeth C. , Xu Kayla , De La Cruz Karinda , Huang Lynda , Sandstrom Shelby , Arend Delanie , Gromek Owen , Scarborough John , Huttenlocher Anna , Gibson Angela L.F. , Kalan Lindsay R.
Published: July 2024

Surgical site infections (SSI) continue to occur despite widespread adoption of surgical antiseptics. The effects of chlorhexidine gluconate (CHG)-based antiseptics on the skin microbiome also remains undefined due to confounding effects of CHG persistence on skin. Patients undergoing elective surgery were enrolled to characterize the immediate and long-term impact of pre-surgical preparation with CHG antiseptic on skin microbial communities. Due to the broad-spectrum antimicrobial activity of CHG and its propensity to bind extracellular DNA, methods to selectively identify live microorganisms are critical to this process and to fully elucidate the effectiveness of pre-surgical protocols and potential disruptions to the healthy skin microbiome. Swabs of the surgical site skin microbiome were collected at multiple timepoints before and after surgery. Microbial bioburden and community compositions were evaluated with viability qPCR and 16S ribosomal RNA gene profiling. Pre-operative CHG induced a measurable reduction in the viable microbial bioburden at the surgical site. On the day of surgery, surgical sites displayed a significant increase in the relative abundance of several SSI associated bacterial genera, including, Acinetobacter, Bacillus, Escherichia-Shigella,andPseudomonas, compared to baseline. Bacillusspecies isolated from subjects at baseline showed resistance to CHG with MICs exceeding 1000 µg/ml. Despite major shifts in the skin microbiome upon exposure to CHG, they were transient in the majority of individuals. Skin microbial community structure recovered by the post-surgical follow-up. In short, this study shows that pre-surgical application of CHG can significantly reduce viable skin microbial bioburden, however, complete sterility is not achieved. While CHG induces temporary shifts in the skin microbiome, including enrichment for potentially pathogenic taxa, the skin microbiome recovers back to near baseline. Collectively, these findings identify tangible avenues for improving antiseptic formulations and offer further support that the skin microbiome is viable, stable, and resilient to chemical perturbation.
Secreted exosomes induce filopodia formation
Authors: McAtee Caitlin , Patel Mikin , Hoshino Daisuke , Sung Bong Hwan , von Lersner Ariana , Shi Mingjian , Hong Nan Hyung , Young Anna , Krystofiak Evan , Zijlstra Andries , Weaver Alissa M.
Published: July 2024

Filopodia are dynamic adhesive cytoskeletal structures that are critical for directional sensing, polarization, cell-cell adhesion, and migration of diverse cell types. Filopodia are also critical for neuronal synapse formation. While dynamic rearrangement of the actin cytoskeleton is known to be critical for filopodia biogenesis, little is known about the upstream extracellular signals. Here, we identify secreted exosomes as potent regulators of filopodia formation. Inhibition of exosome secretion inhibited the formation and stabilization of filopodia in both cancer cells and neurons and inhibited subsequent synapse formation by neurons. Rescue experiments with purified small and large extracellular vesicles (EVs) identified exosome-enriched small EVs (SEVs) as having potent filopodia-inducing activity. Proteomic analyses of cancer cell-derived SEVs identified the TGF-β family coreceptor endoglin as a key SEV-enriched cargo that regulates filopodia. Cancer cell endoglin levels also affected filopodia-dependent behaviors, including metastasis of cancer cells in chick embryos and 3D migration in collagen gels. As neurons do not express endoglin, we performed a second proteomics experiment to identify SEV cargoes regulated by endoglin that might promote filopodia in both cell types. We discovered a single SEV cargo that was altered in endoglin-KD cancer SEVs, the transmembrane protein Thrombospondin Type 1 Domain Containing 7A (THSD7A). We further found that both cancer cell and neuronal SEVs carry THSD7A and that add-back of purified THSD7A is sufficient to rescue filopodia defects of both endoglin-KD cancer cells and exosome-inhibited neurons. We also find that THSD7A induces filopodia formation through activation of the Rho GTPase, Cdc42. These findings suggest a new model for filopodia formation, triggered by exosomes carrying THSD7A.
Rapalink-1 reveals novel mTOR-dependent genes and an agmatinergic axis-based metabolic feedback regulating mTOR activity and lifespan
Authors: Kumar Juhi , Rallis Charalampos
Published: July 2024

The mechanistic Target of Rapamycin, mTOR, is a conserved pro-ageing pathway with characterised inhibitors such as rapamycin, rapalogues and torins. Bi-steric third-generation inhibitors, such as rapalink-1 have been developed, however, their effects on organismal gene expression and lifespan have not been characterised. Here, we demonstrate that rapalink-1 affects fission yeast spatial and temporal growth and prolongs chronological lifespan with a distinct TORC1 selectivity profile. Endosome and vesicle-mediated transport and homeostasis processes related to autophagy and Pik3, the orthologue of human PI3K, render cells resistant to rapalink-1. Our study reveals mTOR-regulated genes with unknown roles in ageing including all fission yeast agmatinases, the enzymes that convert agmatine to putrescine and urea. Through genome-wide screens, we identify sensitive and resistant mutants to agmatine and putrescine. Genetic interactome assays for the agmatinase agm1 and further cell and molecular analyses, demonstrate that impairing the agmatinergic branch of arginine catabolism results in mTOR activity levels that are beneficial for growth but detrimental for chronological ageing. Our study reveals the anti-ageing action of agmatinases within a metabolic feedback circuit regulating mTOR activity levels and ageing and with possible implications to other systems, including human cells.
Meta-omics reveals role of photosynthesis in Microbially Induced Carbonate Precipitation at a CO2-rich Geyser
Authors: Violette Marlene , Hyland Ethan , Burgener Landon , Ghosh Adit , Montoya Brina , Kleiner Manuel
Published: July 2024

Microbially induced carbonate precipitation (MICP) is a natural process with potential biotechnological applications to address both carbon sequestration and sustainable construction needs. However, our understanding of the microbial processes involved in MICP is limited to a few well-researched pathways such as ureolytic hydrolysis. To expand our knowledge of MICP, we conducted an omics-based study on sedimentary communities from travertine around the CO2-driven Crystal Geyser near Green River, Utah. Using metagenomics and metaproteomics, we identified the community members and potential metabolic pathways involved in MICP. We found variations in microbial community composition between the two sites we sampled, but Rhodobacterales were consistently the most abundant order, including both chemoheterotrophs and anoxygenic phototrophs. We also identified several highly abundant genera of Cyanobacteriales. The dominance of these community members across both sites and the abundant presence of photosynthesis-related proteins suggest that photosynthesis could play a role in MICP at Crystal Geyser. We also found abundant bacterial proteins involved in phosphorous starvation response at both sites suggesting that P-limitation shapes both composition and function of the microbial community driving MICP. Our study emphasizes the possible involvement of photosynthesis in MICP processes at Crystal Geyser and suggests that P-limitation may either hinder or facilitate MICP within the community.
Standardizing and Scaffolding Healthcare AI-Chatbot Evaluation
Authors: Hua Yining , Xia Winna , Bates David W. , Hartstein George Luke , Kim Hyungjin Tom , Li Michael Lingzhi , Nelson Benjamin W. , Stromeyer Charles , King Darlene , Suh Jina , Zhou Li , Torous John
Published: July 2024

The rapid rise of healthcare chatbots, valued at $787.1 million in 2022 and projected to grow at 23.9% annually through 2030, underscores the need for robust evaluation frameworks. Despite their potential, the absence of standardized evaluation criteria and rapid AI advancements complicate assessments. This study addresses these challenges by developing the first comprehensive evaluation framework inspired by health app regulations and integrating insights from diverse stakeholders. Following PRISMA guidelines, we reviewed 11 existing frameworks, refining 271 questions into a structured framework encompassing three priority constructs, 18 second-level constructs, and 60 third-level constructs. Our framework emphasizes safety, privacy, trustworthiness, and usefulness, aligning with recent concerns about AI in healthcare. This adaptable framework aims to serve as the initial step in facilitating the responsible integration of chatbots into healthcare settings.
Epigenome-wide association study of pregnancy exposure to green space and placental DNA methylation
Authors: Aguilar-Lacasaña Sofía , Cosin-Tomas Marta , Raimbault Bruno , Gómez Laura , Sánchez Olga , Zanini Maria Julia , Capdevila Rosalia Pascal , Foraster Maria , Gascon Mireia , Rivas Ioar , Llurba Elisa , Gómez-Roig Maria Dolores , Sunyer Jordi , Vrijheid Martine , Bustamante Mariona , Dadvand Payam
Published: July 2024

Maternal exposure to green space during pregnancy has been associated with lower risk for adverse birth outcomes; however, the underlying biological mechanisms remain largely unknown. Epigenetic changes, such as DNA methylation (DNAm), might be one of the molecular mechanisms contributing to this association. The placenta is the key organ for foetal growth and development, but studies of prenatal green space exposure and placental DNAm are scarce and have not been conducted on a genome-wide scale. Here, we aimed to investigate the association between exposure to green space during pregnancy and epigenome-wide placental DNAm.

This study was conducted in 550 mother-child pairs from the Barcelona Life Study Cohort (BiSC), a population-based birth cohort in Spain (2018-2021). We comprehensively assessed green space exposure during pregnancy as (i) residential surrounding greenness (satellite-based Normalized Difference Vegetation Index (NDVI) in buffers of 100m, 300m and 500m), (ii) residential distance to the nearest major green space (meters), iii) use of green space (hours/week), and iv) visual access to greenery through home window (≥half of the view). Placental DNAm was measured with the EPIC array. To identify differentially methylated positions (DMPs), we fitted robust linear regression models adjusted for relevant covariates, while differentially methylated regions (DMRs) were identified using thedmrffmethod.

After Bonferroni (BN) correction, cg14852540, annotated toSLC25A10gene, was inversely associated with residential surrounding greenness within 500m buffer. Additionally, ten unique DMRs were associated with surrounding greenness within 300m and 500m, distance or visual access to green space. No associations were found for surrounding greenness within 100m or use of green space. Genes annotated to these loci are involved in transcriptional regulation, metabolism and mitochondrial respiration.

Overall, we identified associations between prenatal green space exposure and DNAm levels in placenta. Further research is needed to validate these results and understand the underlying biological pathways.
Meiosis-specific decoupling of the pericentromere from the kinetochore
Authors: Pan Bo , Bruno Melania , Macfarlan Todd S , Akera Takashi
Published: July 2024

The primary constriction site of the M-phase chromosome is an established marker for the kinetochore position, often used to determine the karyotype of each species. Underlying this observation is the concept that the kinetochore is spatially linked with the pericentromere where sister-chromatids are most tightly cohered. Here, we found an unconventional pericentromere specification with sister chromatids mainly cohered at a chromosome end, spatially separated from the kinetochore inPeromyscusmouse oocytes. This distal locus enriched cohesin protectors, such as the Chromosomal Passenger Complex (CPC) and PP2A, at a higher level compared to its centromere/kinetochore region, acting as the primary site for sister-chromatid cohesion. Chromosomes with the distal cohesion site exhibited enhanced cohesin protection at anaphase I compared to those without it, implying that these distal cohesion sites may have evolved to ensure sister-chromatid cohesion during meiosis. In contrast, mitotic cells enriched CPC only near the kinetochore and the distal locus was not cohered between sister chromatids, suggesting a meiosis-specific mechanism to protect cohesin at this distal locus. We found that this distal locus corresponds to an additional centromeric satellite block, located far apart from the centromeric satellite block that builds the kinetochore. SeveralPeromyscusspecies carry chromosomes with two such centromeric satellite blocks. Analyses on threePeromyscusspecies revealed that the internal satellite consistently assembles the kinetochore in both mitosis and meiosis, whereas the distal satellite selectively enriches cohesin protectors in meiosis to promote sister-chromatid cohesion at that site. Thus, our study demonstrates that pericentromere specification is remarkably flexible and can control chromosome segregation in a cell-type and context dependent manner.
AQuaRef: Machine learning accelerated quantum refinement of protein structures
Authors: Zubatyuk Roman , Biczysko Malgorzata , Ranasinghe Kavindri , Moriarty Nigel W. , Gokcan Hatice , Kruse Holger , Poon Billy K. , Adams Paul D. , Waller Mark P. , Roitberg Adrian E. , Isayev Olexandr , Afonine Pavel V.
Published: July 2024

Cryo-EM and X-ray crystallography provide crucial experimental data for obtaining atomic-detail models of biomacromolecules. Refining these models relies on library- based stereochemical restraints, which, in addition to being limited to known chemical entities, do not include meaningful noncovalent interactions relying solely on nonbonded repulsions. Quantum mechanical (QM) calculations could alleviate these issues but are too expensive for large molecules. We present a novel AI-enabled Quantum Refinement (AQuaRef) based on AIMNet2 neural network potential mimicking QM at substantially lower computational costs. By refining 41 cryo-EM and 30 X-ray structures, we show that this approach yields atomic models with superior geometric quality compared to standard techniques, while maintaining an equal or better fit to experimental data.
Trajectory of severe COVID anxiety and predictors for recovery in an 18-month cohort
Authors: King Jacob D , McQuaid Aisling , Barnicot Kirsten , Bassett Paul , Leeson Verity C , Di Simplicio Martina , Tyrer Peter , Tyrer Helen , Watt Richard G , Crawford Mike J
Published: July 2024

Background

People with severe COVID anxiety have significant fears of contagion, physiological symptoms of anxiety in response to a COVID stimuli, and employ safety behaviours which are often in excess of health guidelines and at the expense of other life priorities. The natural course of severe COVID anxiety is not known.

Methods

This prospective cohort study followed 285 people with severe COVID anxiety in United Kingdom over 18-months. Descriptive statistics and linear regression models identified factors associated with change in COVID anxiety.

Results

Most participants experienced major reductions in COVID anxiety over time (69.8% relative cohort mean decrease; p<0.001), but a quarter of people (23.7%, 95% CI 17.8 to 30.1) continued to worry about COVID every day. Increasing age, being from an ethnic background which conferred greater risk from COVID-19, and the persistence of high levels of health anxiety and depressive symptoms predicted significantly slower improvements in severe COVID anxiety adjusting for other clinical and demographic factors.

Conclusions

For most people severe COVID anxiety significantly improves with time. However established interventions treating depression or health anxiety, and targeting older people and people from at-risk minority groups who appear to recover at slower rates, might be clinically indicated in future pandemics.

Highlights

Most people with severe COVID anxiety reported large improvements in symptoms 18-months later.

Levels of co-occurring poor mental health and social functioning also improved for most people.

More than 1 in 10 continued to have severe COVID anxiety symptoms 18 months later.

Age, ethnic background, and high levels of health anxiety and depression predict slower improvements.

People with these risk characteristics could be considered for targeted support.
Association of polyunsaturated fatty acids with cholelithiasis risk and the role of plasma lipid mediators: insights from NHANES 2017-2020 and Mendelian randomization
Authors: Chen Yuxuan , Chen Wei , Qian Jin , Jin Xuanchen , Wang Congying , Zheng Yihu
Published: July 2024

Background & aims

Previous studies have suggested a potential link between polyunsaturated fatty acid (PUFA) intake and the risk of cholelithiasis. Omega-3 fatty acids, a key subfamily of PUFAs, have been identified in observational studies as playing a role in lipid regulation and potentially serving as a protective factor against cholelithiasis. In this study, we aim to investigate this association further by analyzing data from the 2017-2020 National Health and Nutrition Examination Survey (NHANES) and conducting Mendelian randomization (MR) analyses.

Methods

We employed weighted multivariate-adjusted logistic regression analyses to examine the association between PUFAs and cholelithiasis risk using data from NHANES 2017-2020. Additionally, a two-sample Mendelian randomization (MR) study was conducted utilizing pooled data from Genome-Wide Association Studies (GWAS) to establish the causal relationship between PUFAs and cholelithiasis. Following this, we performed two-step MR mediation analyses to investigate the mediating role of plasma lipids in the pathway, focusing on the strongly positive subfamily of PUFAs, Omega-3, in relation to plasma circulating lipids and cholelithiasis.

Results

Our observational study in NHANES included 7,527 participants. Weighted multivariate-adjusted logistic regression analyses initially revealed a negative association between PUFAs, their subclasses, and cholelithiasis. However, this association became nonsignificant after adjusting for multiple covariates. In contrast, MR analyses identified a significant negative association between PUFAs (OR=0.75 [95% CI, 0.58∼0.98]) and Omega-3 (OR=0.79 [95% CI, 0.7∼0.9]) and the risk of cholelithiasis. Specifically, Omega-3 was associated with a reduced risk of developing cholelithiasis (OR=0.77 [95% CI, 0.65∼0.91]), possibly due to the upregulation of LDL-C levels (Beta=0.24 [95% CI, 0.1∼0.38]). This upregulation of LDL-C subsequently lowered the risk of cholelithiasis (OR=0.77 [95% CI, 0.65∼0.91]), with the mediating effect of LDL-C accounting for 28% of the overall association.

Conclusions

Both cross-sectional observational analyses and Mendelian randomization (MR) analyses demonstrated a negative correlation between polyunsaturated fatty acids (PUFAs) and cholelithiasis. Omega-3 fatty acids seem to play a key role in this association by increasing plasma LDL-C levels, which in turn may help reduce the risk of cholelithiasis.
Age-Dependent Effects of UV Exposure and Xeroderma Pigmentosum Group A on DNA Damage, Repair Mechanisms, Genomic Instability, Cancer Risk, and Neurological Disorders
Authors: Danter WR
Published: July 2024

Background

Xeroderma pigmentosum, complementation group A (XPA), is a rare genetic disorder characterized by marked sensitivity to ultraviolet (UV) radiation, leading to increased risks of skin cancer, accelerated aging, and significant neurologic disorders. XPA prominently impacts DNA repair mechanisms, specifically nucleotide excision repair (NER), which is crucial for correcting UV-induced DNA damage.

Methods

This study utilized an advanced aiHumanoids platform to simulate the disease progression in individuals with XPA from birth to age 20 years. The virtual longitudinal study assessed the impacts of moderate and severe XPA under various UV exposure scenarios. The research included 25 age-matched wild-type controls to elucidate the comparative effects of XPA on DNA damage, genomic instability, cancer risk, and neurological outcomes.

Results

Using Wilcoxon sign rank p values and Cliff’s delta estimates of true effect size, the aiHumanoid simulations revealed significant differences in DNA repair efficiency between XPA affected and control groups, with pronounced deficits in XPA cohorts under UV exposure. Genomic instability and skin cancer risks were consistently elevated across all XPA simulations, particularly under UV stress. Neurological assessments indicated greater susceptibility to disorders in younger XPA subjects, with effects moderating somewhat with age.

Conclusion

The aiHumanoid platform provided novel insights into the progression of XPA, highlighting the severe impact of UV exposure on individuals with this condition. These findings advocate for early intervention strategies and underscore the necessity for rigorous protective measures against UV radiation, especially in younger populations. This research contributes to our further understanding of XPA, potentially guiding future therapeutic developments including early stage virtual drug trials and preventive approaches personalized to individual risk profiles.
Cell State-Specific Cytoplasmic Material Properties Control Spindle Architecture and Scaling
Authors: Kletter Tobias , Muñoz Omar , Reusch Sebastian , Biswas Abin , Halavatyi Aliaksandr , Neumann Beate , Kuropka Benno , Zaburdaev Vasily , Reber Simone
Published: July 2024

Mitotic spindles are dynamically intertwined with the cytoplasm they assemble in. How the physicochemical properties of the cytoplasm affect spindle architecture and size remains largely unknown. Using quantitative biochemistry in combination with adaptive feedback microscopy, we investigated mitotic cell and spindle morphology during neural differentiation of embryonic stem cells. While tubulin biochemistry and microtubule dynamics remained unchanged, spindles changed their scaling behaviour: in differentiating cells, spindles were significantly smaller than those in equally-sized undifferentiated stem cells. Integrating quantitative phase imaging, biophysical perturbations and theory, we found that as cells differentiated, their cytoplasm became more dilute. The concomitant decrease in free tubulin activated CPAP (centrosomal P4.1-associated protein) to enhance the centrosomal nucleation capacity. As a consequence, in differentiating cells, microtubule mass shifted towards spindle poles at the expense of the spindle bulk, explaining the differentiation-associated switch in spindle architecture. This study shows that cell state-specific cytoplasmic density tunes mitotic spindle architecture. Thus, we reveal physical properties of the cytoplasm as a major determinant in organelle size control.
SUMO promotes DNA repair protein collaboration to support alternative telomere lengthening in the absence of PML
Authors: Zhao Rongwei , Xu Meng , Yu Xiaoyang , Wondisford Anne R. , Lackner Rachel M. , Salsman Jayme , Dellaire Graham , Chenoweth David M. , O'Sullivan Roderick J. , Zhao Xiaolan , Zhang Huaiying
Published: July 2024

The alternative lengthening of telomeres (ALT) pathway maintains telomere length in a significant fraction of cancers that are associated with poor clinical outcomes. A better understanding of ALT mechanisms is therefore necessary for developing new treatment strategies for ALT cancers. SUMO modification of telomere proteins contributes to the formation of ALT telomere-associated PML bodies (APBs), in which telomeres are clustered and DNA repair proteins are enriched to promote homology-directed telomere DNA synthesis in ALT. However, it is still unknown whether—and if so, how—SUMO supports ALT beyond APB formation. Here, we show that SUMO condensates that contain DNA repair proteins enable telomere maintenance in the absence of APBs. In PML knockout ALT cell lines that lack APBs, we found that SUMOylation is required for manifesting ALT features independent of PML and APBs. Chemically induced telomere targeting of SUMO produces condensate formation and ALT features in PML-null cells. This effect requires both SUMOylation and interactions between SUMO and SUMO interaction motifs (SIMs). Mechanistically, SUMO-induced effects are associated with the accumulation of DNA repair proteins, including Rad52, Rad51AP1, RPA, and BLM, at telomeres. Furthermore, Rad52 can undergo phase separation, enrich SUMO at telomeres, and promote telomere DNA synthesis in collaboration with the BLM helicase in a SUMO-dependent manner. Collectively, our findings suggest that SUMO condensate formation promotes collaboration among DNA repair factors to support ALT telomere maintenance without PML. Given the promising effects of SUMOylation inhibitors in cancer treatment, our findings suggest their potential use in perturbing telomere maintenance in ALT cancer cells.