bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chaperone-mediated heterotypic phase separation regulates liquid-to-solid phase transitions into amyloid fibrils
Authors: Rai Sandeep K. , Khanna Roopali , Sarbahi Anusha , Joshi Ashish , Mukhopadhyay Samrat 
Published: June 2024

AbstractBiomolecular condensates formed via the phase separation of proteins and nucleic acids are thought to regulate a myriad of cellular processes with exquisite spatiotemporal precision. However, such highly dynamic, viscoelastic, mesoscopic, intracellular membraneless bodies can undergo aberrant liquid-to-solid transitions into a range of amyloid-like species. The formation of such pathological assemblies necessitates their clearance by the cellular protein quality control machinery comprising molecular chaperones. Nonetheless, the mechanism underlying the chaperone-mediated regulation of protein homeostasis within biomolecular condensates remains elusive. Here, we present a unique case demonstrating that a heat shock protein 40 (Hsp40), Ydj1, promotes the heterotypic phase separation of intrinsically disordered tau via intermolecular electrostatic and hydrophobic interactions. Through a diverse array of tools involving high-resolution fluorescence imaging, single-droplet steady-state and picosecond time-resolved fluorescence anisotropy, and single-molecule FRET (Förster resonance energy transfer), we elucidate the diverse structural conformations of tau present within phase-separated heterotypic condensates that are otherwise predisposed to aggregation. Our vibrational Raman spectroscopy and electron microscopy data show that the presence of Ydj1 in tau-Ydj1 condensates abolishes the formation of amyloid fibrils, unlike tau-only droplets. By sequentially deleting segments, we identify amyloidogenic hexapeptide motifs located in the hydrophobic microtubule-binding region of tau that foster contacts with the peptide-binding regions of Ydj1, promoting the formation of tau-Ydj1 binary condensates. Additionally, we show that the underlying network of interactions governing these condensates can be further tuned by RNA. Our results underscore an intriguing interplay of molecular drivers that govern chaperone-associated phase separation, with broader implications for the chaperoning of a wide range of intrinsically disordered proteins involved in physiology and disease.
Phylogenomics of the North American Desert RadiationLinanthus(Polemoniaceae) Reveals Mixed Trait Lability and No Single Geographic Mode of Speciation
Authors: Anghel Ioana G. , Smith Lydia L. , Lichter-Marck Isaac H. , Zapata Felipe 
Published: June 2024

ABSTRACTPremiseUnderstanding how arid-adapted plants have diversified in harsh environments is a central question in evolutionary biology.Linanthus(Polemoniaceae) occurs in biodiverse dry areas of Western North America and exhibits extensive floral trait variation, multiple color polymorphisms, differences in blooming time, and variation in life history strategies. Here, we reconstruct the evolutionary history of this group.MethodsWe generated restriction-site associated (ddRAD) sequences for 180 individuals and target capture (TC) sequences for 63 individuals, with complete species sampling. Using maximum likelihood and pseudo-coalescent approaches, we inferred phylogenies ofLinanthusand used these phylogenies to model the evolution of phenotypic traits and investigate the geographic speciation history of this genus.Key resultsShallow relationships are consistent and well supported with both ddRAD and TC data. Most species are monophyletic despite rampant local sympatry and range overlap, suggesting strong isolating barriers. The non-monophyly of some species is possibly due to rapid speciation or issues with current species delimitation. Perenniality likely evolved from annuality, a rare shift in angiosperms. Night blooming evolved three times independently. Flower color polymorphism is an evolutionarily labile trait and is likely ancestral. No single geographic mode of speciation characterizes the radiation but most species overlap in range, suggesting they evolved in parapatry.ConclusionsOur results illustrate the complexity of phylogenetic inference for recent radiations, even with multiple sources of genomic data and extensive sampling. This analysis provides a foundation to understand aridity adaptations, such as evolution of flower color polymorphisms, night blooming, and perenniality, as well as speciation mechanisms.
Towards measurements of absolute membrane potential in Bacillus subtilis using fluorescence lifetime
Authors: Roy Debjit , Michalet Xavier , Miller Evan W. , Bharadwaj Kiran , Weiss Shimon 
Published: June 2024

ABSTRACTMembrane potential (MP) changes can provide a simple readout of bacterial functional and metabolic state or stress levels. While several optical methods exist for measuring fast changes in MP in excitable cells, there is a dearth of such methods for absolute and precise measurements of steady-state membrane potentials (MPs) in bacterial cells. Conventional electrode-based methods for the measurement of MP are not suitable for calibrating optical methods in small bacterial cells. While optical measurement based on Nernstian indicators have been successfully used, they do not provide absolute or precise quantification of MP or its changes. We present a novel, calibrated MP recording approach to address this gap. In this study, we used a fluorescence lifetime-based approach to obtain a single-cell resolved distribution of the membrane potential and its changes upon extracellular chemical perturbation in a population of bacterial cells for the first time. Our method is based on (i) a unique VoltageFluor (VF) optical transducer, whose fluorescence lifetime varies as a function of MP via photoinduced electron transfer (PeT) and (ii) a quantitative phasor-FLIM analysis for high-throughput readout. This method allows MP changes to be easily visualized, recorded and quantified. By artificially modulating potassium concentration gradients across the membrane using an ionophore, we have obtained aBacillus subtilis-specific MP versus VF lifetime calibration and estimated the MP for unperturbedB. subtiliscells to be −65 mV (in MSgg), −127 mV (in M9) and that for chemically depolarized cells as −14 mV (in MSgg). We observed a population level MP heterogeneity of ∼6-10 mV indicating a considerable degree of diversity of physiological and metabolic states among individual cells. Our work paves the way for deeper insights into bacterial electrophysiology and bioelectricity research.
Near Real-Time Measures of Interregional Mobility Restrictions on COVID-19 Transmission
Authors: Berríos Jesús , Marín Flores César , Gutierrez Bernardo , Bravo Loreto , Ferres Leo 
Published: June 2024

AbstractThe global SARS-CoV-2 pandemic prompted nations to implement mobility limitations to curb virus spread. In Chile, targeted interregional measures were employed to mitigate the social and economic costs. Here, we employ a novel real-time methodology to assess the impact of such mobility restrictions on epidemic control. Leveraging telecom-derived eXtended Detail Records (XDR) and official COVID-19 epidemiological data, we estimate interregional mobility and disease prevalence. Employing Bayesian adjustments, we compare different mobility restriction scenarios: business-as-usual (BAU), initial measures, and total lockdown. Mobility reductions significantly curtailed cases and risk across regions. Even modest mobility declines under total lockdowns considerably lowered imported cases. The high-risk Santiago Region, a national source of infections to other regions, demonstrated lowered risk due to mobility restrictions. Our approach facilitates rapid regional insights for informed policy responses.Author summaryThe implementation of mobility restrictions is a coarse approach to limiting pathogen transmission during the early stages of an epidemic. Disentangling the effects of the reduced population mixing and the effects of new seeding events can be challenging to perform in real time, making any evaluation of the efficacy of such interventions a post hoc exercise. Here we present an approach that uses aggregated data from individual mobile phone locations within the national network of antennas to statistically correct for changes in human mobility and estimate the changes in COVID-19 transmission across regions in Chile during the first wave of the pandemic. We estimate a risk score that can be implemented nearly in real time to estimate the effects of mobility restrictions on viral transmission and highlight that important urban centres that seed other regions, like the Santiago Region, are at low risk of experiencing increased viral transmission due to new seeding events from other regions.
Genome-wide association studies of lifetime and frequency cannabis use in 131,895 individuals
Authors: Thorpe Hayley H A , Fontanillas Pierre , Meredith John J , Jennings Mariela V , Cupertino Renata B , Pakala Shreya ,   23andMe Research Team, Elson Sarah L , Khokhar Jibran Y , Davis Lea K , Johnson Emma C , Palmer Abraham A , Sanchez-Roige Sandra 
Published: June 2024

SummaryCannabis is one of the most widely used drugs globally. Decriminalization of cannabis is further increasing cannabis consumption. We performed genome-wide association studies (GWASs) of lifetime (N=131,895) and frequency (N=73,374) of cannabis use. Lifetime cannabis use GWAS identified two loci, one nearCADM2(rs11922956,p=2.40E-11) and another nearGRM3(rs12673181,p=6.90E-09). Frequency of use GWAS identified one locus nearCADM2(rs4856591,p=8.10E-09;r2=0.76 with rs11922956). Both traits were heritable and genetically correlated with previous GWASs of lifetime use and cannabis use disorder (CUD), as well as other substance use and cognitive traits. Polygenic scores (PGSs) for lifetime and frequency of cannabis use associated cannabis use phenotypes inAllofUsparticipants. Phenome-wide association study of lifetime cannabis use PGS in a hospital cohort replicated associations with substance use and mood disorders, and uncovered associations with celiac and infectious diseases. This work demonstrates the value of GWASs of CUD transition risk factors.
Ancient biomolecular analysis of 39 mammoth individuals from Kostenki 11-Ia elucidates Upper Palaeolithic human resource use
Authors: Rey-Iglesia Alba , Pryor Alexander J.E. , Wilson Tess , Teeter Mathew A. , Margaryan Ashot , Khaskhanov Ruslan , Le Meillour Louise , de Jager Deon , Troché Gaudry , Welker Frido , Szpak Paul , Dudin Alexander E. , Lorenzen Eline D. 
Published: June 2024

AbstractCircular structures made from woolly mammoth bones are found across Ukraine and west Russia, yet the origin of the bones remains uncertain. We present ten new mammoth radiocarbon dates from the largest circular structure at Kostenki 11-Ia, identifying two mammoth mandibles ∼200-1,200 years older than the other dated materials from the site, suggesting skeletal material from long-dead individuals was scavenged and used in the site construction. Biomolecular sexing of 30 individuals showed a predominance of females, suggesting the Kostenki mammoths are primarily from herds. We identify six mitochondrial lineages across 16 samples, showing they are not all from the same matriline. Integrating biomolecular sexing with stableδ13C andδ15N isotope analysis, we find no isotopically-differentiated resource use by females and males, providing the first analysis of foraging differences between sexes in any Late Pleistocene megafauna. Our study highlights the significance of integrating ancient biomolecular approaches in archaeological inference.TeaserIntegrating14C dating, ancient DNA, palaeoproteomics, and stable isotopes improves our understanding of Kostenki 11-Ia
Novel insights into the economic relevant phenotypes ofBombyx moristrains from Romanian breeding centres
Authors: Baci Gabriela-Maria , Ionascu Adrian , Ratiu Attila Cristian , Dezmirean Daniel Severus 
Published: June 2024

AbstractThe silkworm,Bombyx mori, has an inestimable economic and pharmaceutical value, but it is also a very effective model organism for biological and biotechnological sciences. Herein, we characterize several phenotypic parameters particular for Băneasa 1 (B1) and Galben de Băneasa (GB) Romanian silkworm breeds, as well as of Auriu Chinez (ACH) and JH3 breeds originating from China and, respectively, Japan. Our analysis revealed concrete differences and similarities between the phenotypic properties of the four breeds, allowing their grouping consecutive to PCA and KODAMA analyses. Our study is the first to characterize the four breeds regarding their biological competencies and offers a glimpse at various ventures aiming at the employment and amelioration of these silkworm breeds.
Synthesis and pharmacological characterization of UVI3502, a novel cannabinoid receptor 1 (CB1) antagonist/inverse agonist
Authors: de Tena Iker Bengoetxea , Pereira-Castelo Gorka , Martínez-Gardeazabal Jonatan , Moreno-Rodríguez Marta , Manuel Iván , Martínez Claudio , Vaz Belén , González-Ricarte Javier , Álvarez Rosana , Torres-Mozas Angel , Peccati Francesca , Jiménez-Osés Gonzalo , De Lera Ángel Rodríguez , Rodríguez-Puertas Rafael 
Published: June 2024

AbstractThe endocannabinoid (eCB) system regulates several brain functions and is implicated in neurological disorders. The pharmacological blockade of cannabinoid receptors has a therapeutic potential for various cognitive deficits, but also produces severe psychiatric side effects. Hence, new cannabinoid compounds that potentiate therapeutic effects, while minimizing toxicity, are required. In this study, we synthesized and characterized a novel antagonist/inverse agonist of CB1receptors. UVI3502 showed affinity for two [3H]CP55,940 binding sites (IC50Hi0.47 ± 1.94 nM and IC50Lo1470 ± 1.80 nM). Subsequent binding assays performed in CB1and CB2overexpressing membranes determined that the low affinity binding site corresponded to CB1, but the high-affinity binding site of UVI3502 did not correspond to CB2and the possibility of it corresponding to GPR55 was analyzed. The affinity of UVI3502 for CB1receptors was further confirmed with neuroanatomical specificity by autoradiography in key brain areas, in which functional [35S]GTPɣS assays demonstrated that UVI3502 behaved as an antagonist/inverse agonist of CB1receptors, blocking the stimulation evoked by potent cannabinoid receptor agonist CP55,940 and decreasing basal [35S]GTPɣS binding. Thein silicocharacterization of the binding to CB1receptor through molecular docking and molecular dynamics suggests that this activity is explained by the planar and rigid structure of UVI3502, which is optimal for interactions with the inactive state of the receptor. These results indicate that UVI3502 is a novel antagonist/inverse agonist of CB1receptors, making it a compelling candidate for pharmacologically blocking cannabinoid receptors in the central nervous system.Significance StatementUVI3502 is a novel antagonist/inverse agonist of CB1receptors, with almost no affinity for CB2receptors and an additional high-affinity binding site for a third, cannabinoid-like receptor, potentially GPR55. In relevant brain areas for learning and memory processes with a high expression of CB1, UVI3502 blocks the stimulation evoked by the cannabinoid receptor agonist CP55,940, rendering it as an interesting compound for the pharmacological blockade of cannabinoid receptors in the central nervous system.
Giant pore formation in vesicles under msPEF-induced electroporation: role of charging time and waveform
Authors: Behera Nalinikanta , Thaokar Rochish M. 
Published: June 2024

AbstractGiant unilamellar vesicle is the closest possible prototypical model for investigating membrane electrodeformation and electroporation in biological cells. In this paper, the effect of membrane charging time on vesicle electroporation, an unresolved issue, is exclusively investigated under milli-second pulsed-electric-field (msPEF) of different waveforms, using numerical simulations. The existing analytical models uncover several fundamental features of cell or vesicle electroporation, but remain far from being realistic as electrode-formation effects were neglected. Our numerical approach, which implements the effect of electric stretching on membrane tension and precise calculation of pore energy, successfully predicts the formation of giant pores ofO(µm) size as observed in past experiments. The poration zone is found to extend up to certain angles from the poles, termed critical angles. Increase in charging time delays pore formation, decreases the pore density as well as trim downs the poration zone. Counterintuitively, this effect promotes significant pore growth. Thus, more pores evolve into giant pores resulting in higher fractional pore area. Moreover, there exists a cut-off charging time above which pore formation is completely inhibited. This phenomenon is particularly pronounced with bipolar pulses. Comparisons with the past experimental results reveal that electrodeformation-poration-induced membrane surface area variation and that induced by electroporation evolves in a similar fashion. Therefore, although the agreements are qualitative, the present electroporation model can be used as the simplest tool to predict the transient electrodeformation of a porated vesicle in the laboratory experiments.
Proteasome inhibition induces DNA methylation alteration by attenuating the synthesis of DNA methyltransferase 1 and 3B in colorectal cancer
Authors: Zhou Wenwen , Sheng Yuling , Hu Dingxue , An Yunyun , Yang Mengqi , Wang Wanqiu , Basnet Shiva , Yan Jingyu , Zhang Shuxia , Liu Qi , Li Yunze , Tan Yi , Gao Jing , Sun Kun , Du Changzheng 
Published: June 2024

AbstractProteasome is an essential organelle in guarding cellular protein homeostasis. Here, we report that inhibition of proteasome leads to alterations in DNA methylation patterns in colorectal cancer (CRC) by surpressing the synthesis of DNA methyltransferases (DNMTs). We found that treating CRC cells with proteasome inhibitors results in attenuated translation of DNMT1 and DNMT3B, mediated by the inactivation of AKT and mammalian target of rapamycin (mTOR), which is dependent on the accumulation of p300, an acetyltransferase that inhibits AKT through acetylation modification. Furthermore, we demonstrated that downregulation of DNMT1 and DNMT3B confers protection against proteasome inhibitor treatment, potentially through reprogramming the transcriptome of CRC cells, highlighting the significant role of DNMTs in response to disruptions in protein homeostasis. Interestingly, the proteasome inhibitor-induced downregulation of DNMT1 and DNMT3B appears to be CRC specific, notwithstanding the underlying mechanism remains unclear. Altogether, our findings reveal an epigenetic effect of proteasome on DNA methylation in CRC through its regulation of DNA methyltransferase synthesis.
Structural basis for membrane remodelling by the AP5:SPG11-SPG15 complex
Authors: Mai Xinyi , Wang Yang , Wang Xi , Liu Ming , Teng Fei , Liu Zheng , Su Ming-Yuan , Stjepanovic Goran 
Published: June 2024

SummaryThe human spastizin (spastic paraplegia 15, SPG15) and spatacsin (spastic paraplegia 11, SPG11) complex is involved in cargo sorting from late endosomes to the Golgi, and mutations in these two proteins are linked with hereditary autosomal recessive spastic paraplegia (HSP). SPG11-SPG15 can cooperate with evolutionarily ancient fifth adaptor protein complex (AP5). We employed cryo-electron microscopy andin silicopredictions to investigate the structural assemblies of SPG11-SPG15 and AP5:SPG11-SPG15 complex. The W-shaped SPG11-SPG15 intertwined in a head-to-head fashion, and the N-terminal region of SPG11 is required for AP5 complex interaction and assembly. The AP5 complex is in a super open conformation. We employedin vitrolipid binding assays and cellular localization analysis to investigate AP5:SPG11-SPG15 membrane binding properties. Here we solve a major problem in understanding AP5:SPG11-SPG15 function in autophagic lysosome reformation (ALR), using a fully reconstituted system. We reveal that the AP5:SPG11-SPG15 complex binds PI3P molecules, can sense membrane curvature and drive membrane remodellingin vitro. These studies provide key insights into the structure and function of the spastic paraplegia AP5:SPG11-SPG15 complex, which is essential for the initiation of autolysosome tubulation.
Gene Regulatory Programs that Specify Age-Related Differences during Thymocyte Development
Authors: Sankaran Divya Ganapathi , Zhu Hongya , Maymi Viviana I. , Forlastro Isabel M. , Jiang Ya , Laniewski Nathan , Scheible Kristin M. , Rudd Brian D. , Grimson Andrew W. 
Published: June 2024

SUMMARYT cell development is fundamental to immune system establishment, yet how this development changes with age remains poorly understood. Here, we construct a transcriptional and epigenetic atlas of T cell developmental programs in neonatal and adult mice, revealing the ontogeny of divergent gene regulatory programs and their link to age-related differences in phenotype and function. Specifically, we identify a gene module that diverges with age from the earliest stages of genesis and includes programs that govern effector response and cell cycle regulation. Moreover, we reveal that neonates possess more accessible chromatin during early thymocyte development, likely establishing poised gene expression programs that manifest later in thymocyte development. Finally, we leverage this atlas, employing a CRISPR-based perturbation approach coupled with single-cell RNA sequencing as a readout to uncover a conserved transcriptional regulator,Zbtb20,that contributes to age-dependent differences in T cell development. Altogether, our study defines transcriptional and epigenetic programs that regulate age-specific differences in T cell development.