bluuebunny/crossref_metadata_2025 huggingface dataset:
Prebiotic Gas Flow Environment Enables Isothermal Nucleic Acid Replication
Authors: Schwintek Philipp , Eren Emre , Mast Christof , Braun Dieter
Published: June 2024

Nucleic acid replication is a central process at the origin of life. On early Earth, replication is challenged by the dilution of molecular building blocks and the difficulty of separating daughter from parent strands, a necessity for exponential replication. While thermal gradient systems have been shown to address these problems, elevated temperatures lead to degradation. Also, compared to constant temperature environments, such systems are rare. The isothermal system studied here models an abundant geological environment of the prebiotic Earth, in which water is continuously evaporated at the point of contact with the gas flows, inducing up-concentration and circular flow patterns at the gas-water interface through momentum transfer. We show experimentally that this setting drives a 30-fold accumulation of nucleic acids and their periodic separation by a 3-fold reduction in salt and product concentration. Fluid dynamic simulations agree with observations from tracking fluorescent beads. In this isothermal system, we were able to drive exponential DNA replication with Taq polymerase. The results provide a model for a ubiquitous non-equilibrium system to host early Darwinian molecular evolution at constant temperature.
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

The 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 summary

The 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

Cannabis 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

Circular 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.

Teaser

Integrating14C 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

The 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

The 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 Statement

UVI3502 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

Giant 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

Proteasome 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

The 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

T 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.
Large-Scale Genome-Wide Optimization and Prediction of the Cre Recombinase System for Precise Genome Manipulation in Mice
Authors: Erhardt Valerie , Hartig Elli , Lorenzo Kristian , Megathlin Hannah R. , Tarchini Basile , Hosur Vishnu
Published: June 2024

The Cre-Lox recombination system is a powerful tool in mouse genetics, offering spatial-temporal control over gene expression and facilitating the large-scale generation of conditional knockout mice. Its versatility also extends to other research models, such as rats, pigs, and zebrafish. However, the Cre-Lox technology presents a set of challenges that includes high costs, a time-intensive process, and the occurrence of unpredictable recombination events, which can lead to unexpected phenotypic outcomes. To better understand factors affecting recombination, we embarked on a systematic and genome-wide analysis of Cre-mediated recombination in mice. To ensure uniformity and reproducibility, we generated 11 novel strains with conditional alleles at theROSA26locus, utilizing a single inbred mouse strain background, C57BL/6J. We examined several factors influencing Cre-recombination, including the inter-loxPdistance, mutantloxPsites, the zygosity of the conditional alleles, chromosomal location, and the age of the breeders. We discovered that the selection of the Cre-driver strain profoundly impacts recombination efficiency. We also found that successful and complete recombination is best achieved whenloxPsites are spaced between 1 to 4 kb apart, with mutantloxPsites facilitating recombination at distances of 1 to 3 kb. Furthermore, we demonstrate that complete recombination does not occur at an inter-loxPdistance of ≥ 15 kb with wildtypeloxPsites, nor at a distance of ≥ 7 kb with mutantlox71/66sites. Interestingly, the age of the Cre-driver mouse at the time of breeding emerged as a critical factor in recombination efficiency, with best results observed between 8 and 20 weeks old. Moreover, crossing heterozygous floxed alleles with the Cre-driver strain resulted in more efficient recombination than using homozygous floxed alleles. Lastly, maintaining an inter-loxPdistance of 4 kb or less ensures efficient recombination of the conditional allele, regardless of the chromosomal location. While CRISPR/Cas has revolutionized genome editing in mice, Cre-Lox technology remains a cornerstone for the generation of sophisticated alleles and for precise control of gene expression in mice. The knowledge gained here will enable investigators to select a Cre-Lox approach that is most efficient for their desired outcome in the generation of both germline and non-germline mouse models of human disease, thereby reducing time and cost of Cre-Lox technology-mediated genome modification.
Heterogenous organization in condensates of multiple transcription factors in embryonic stem cells
Authors: Mizutani Azuki , Tan Cheng , Sugita Yuji , Takada Shoji
Published: June 2024

Biomolecular condensates formed via liquid-liquid phase separation are ubiquitous in cells, especially in the nucleus. While condensates containing one or two kinds of biomolecules have been relatively well characterized, those with more heterogenous biomolecular components and interactions between biomolecules inside are largely unknown. This study used residue-resolution molecular dynamics simulations to investigate heterogeneous protein assemblies that include four master transcription factors in mammalian embryonic stem cells: Oct4, Sox2, Klf4, and Nanog. Simulations of the mixture systems showed highly heterogeneous and dynamic behaviors; the condensates mainly contained Sox2, Klf4, and Nanog, while Oct4 was dissolved into the dilute phase. Condensates consisted of loosely interacting clusters in which Klf4 was the most abundant in the cores. We suggest that Klf4 serves as a scaffold of the condensate where Sox2 and Nanog are bound to stabilize the condensate, whereas Oct4 is moderately recruited to the condensate, serving as a client mainly via its interaction with Sox2.

Biological significance

In eukaryotes, transcription is known to be regulated by many regulatory factors such as transcription factors, co-activators, and RNA polymerases, but precise molecular mechanisms of regulation remain obscured. A recently proposed model suggests that transcription-related proteins condense via liquid-liquid phase separation (LLPS) using their intrinsically disordered regions, which serves to control transcription. Master transcription factors in mammalian embryonic stem cells have been a model system. It was revealed that several master transcription factors exhibit LLPS by themselves, but dynamics and molecular structure of these proteins in their mixture have not been well addressed. In this study, we study molecular structures of condensates in a mixture of four master transcription factors, Oct4, Sox2, Klf4, and Nanog, via molecular dynamics simulation. We found that the three transcription factors Sox2, Klf4, and Nanog form mixed condensates, while Oct4 was largely dissolved. Klf4 mainly served as a scaffold of the condensate. The three proteins formed micelle-like structures as was recently found in the Nanog condensate. The condensates weakly recruited Oct4. Formation of heterogeneous condensates may provide fertile local environments in cells.
Network Analysis Reveals Protein Modules Associated with Childhood Respiratory Diseases
Authors: Prince Nicole , Begum Sofina , Mendez Kevin M , Ramirez Lourdes G , Chen Yulu , Chen Qingwen , Chu Su H , Kachroo Priyadarshini , Levy Ofer , Diray-Arce Joann , Palma Paolo , Litonjua Augusto A , Weiss Scott T , Kelly Rachel S , Lasky-Su Jessica A
Published: June 2024

Background

The first year of life is a period of rapid immune development that can impact health trajectories and the risk of developing respiratory-related diseases, such as asthma, recurrent infections, and eczema. However, the biology underlying subsequent disease development remains unknown.

Methods

Using weighted gene correlation network analysis (WGCNA), we derived modules of highly correlated immune-related proteins in plasma samples from children at age 1 year (N=294) from the Vitamin D Antenatal Asthma Reduction Trial (VDAART). We applied regression analyses to assess relationships between protein modules and development of childhood respiratory diseases up to age 6 years. We then characterized genomic, environmental, and metabolomic factors associated with modules.

Results

WGCNA identified four protein modules at age 1 year associated with incidence of childhood asthma and/or recurrent wheeze (Padjrange: 0.02-0.03), respiratory infections (Padjrange: 6.3×10-9-2.9×10-6), and eczema (Padj=0.01) by age 6 years; three modules were associated with at least one environmental exposure (Padjrange: 2.8×10-10-0.03) and disrupted metabolomic pathway(s) (Padjrange: 2.8×10-6-0.04). No genome-wide SNPs were identified as significant genetic risk factors for any protein module. Relationships between protein modules with clinical, environmental, and ‘omic factors were temporally sensitive and could not be recapitulated in protein profiles at age 6 years.

Conclusion

These findings suggested protein profiles as early as age 1 year predicted development of respiratory-related diseases through age 6 and were associated with changes in pathways related to amino acid and energy metabolism. These may inform new strategies to identify vulnerable individuals based on immune protein profiling.
Music-related Bodily Sensation Map in Individuals with Depressive Tendencies
Authors: Tanaka Masaki , Daikoku Tatsuya
Published: June 2024

Music has the power to influence people’s emotions. Therefore, music is also used as an intervention to reduce the stress in mental disorders such as depression and anxiety. Recent research has suggested that the body plays a key role in the connection between music and emotion with a correlation between the head sensations and negative emotions while listening to music. Additionally, strong sensations in the head have been suggested as a bodily perception associated with depression. In this study, we investigated the bodily sensations experienced by people with depressive tendencies when listening to music and their association with specific emotional states, using body mapping and musical chord progression. Our results revealed that individuals with depressive tendencies experience strong head sensations, with unpleasantness and low aesthetics, particularly for chord progression with a high level of surprise and uncertainty. This study sheds light on the intricate relationship between music, bodily sensations, and emotional states, providing valuable insights for research on the body and for developing musical therapeutic interventions targeting depression and related conditions.
Dogs density drives the reproductive effort of American Oystercatchers (Haematopus palliatus) in disturbed habitats of the Maule Region, central Chile
Authors: Díaz Jesús , Medrano Fernando , Imbernón Daniel , Villalobos Franco , Silva Juan , Sandvig Erik M. , Montecino Sharon
Published: June 2024

The American Oystercatcher (Haematopus palliatus) is a shorebird specialized in coastal environments across the Americas. Thus, anthropic extensive use of the shoreline including the introduction of dogs and vehicles to beaches could directly impact fitness, and ultimately the persistence of the species’ populations. In this study, we aimed to assess the impact of pedestrians, vehicles and dogs on the nest density, productivity and hatching success of the American Oystercatcher in the Maule Region, central Chile. To this end, we sampled sandy beaches, quantifying the number of nests, eggs, chicks, but also pedestrians, vehicles and dogs during the breeding seasons of 2023 and 2024. We assessed for the influence of these threats on parameters of reproductive output by using Generalized Linear Mixed Models. We found that the number of dogs is the only variable that negatively impacts the number of nests, eggs and chicks of the American Oystercatcher in the sampled areas. Reducing the impact of dogs is a ubiquitous challenge in coastal environments of central Chile, however current regulations do not allow management relying on removal of dogs from important areas for biodiversity.
Sulfur oxidation through rDsr in a novel Sox-free marine Roseobacter lineage
Authors: Lin Xingqin , Feng Xiaoyuan , Wang Xiaojun , Long Hongan , Crowe Sean A. , Luo Haiwei
Published: June 2024

Sulfur oxidation is an essential biogeochemical process in coastal sediments. Of the two typical sulfur-oxidizing metabolic pathways, the reverse dissimilatory sulfite reductase pathway (rDsr) is recognized for its superior energy conservation efficiency compared to the Sox multi-enzyme system and thus might be important in intertidal habitats where electron acceptors are periodically limited. Here, we isolated 10 intertidal sediment strains that compose a novelRuegerialineage in the globally abundant marine Roseobacter group. They possess a complete rDsr pathway but lack the entire Sox system, whereas all known sulfur-oxidizing Roseobacters rely on Sox. In fact, rDsr-carrying but Sox-free bacteria are rare among all sequenced bacterial genomes (only 20 out of 35798), and how sulfur oxidation is driven exclusively by rDsr has not been investigated. Physiological assays, sulfur intermediate measurements, and transcriptomic analyses reveal that rDsr activation in thisRuegerialineage occurs exclusively under microaerobic conditions and is coupled with thiosulfate oxidation in tandem with denitrification. Metagenomic analysis shows that rDsr sequences are enriched in marine habitats characterized by oxygen depletion, consistent with our physiological data. Further, theRhodobacteralesorder whereRuegeriabelongs accounts for approximately 5% of the rDsr-bearing bacterial community in intertidal sediments globally, underscoring its significant role in sulfur oxidation in this important marine environment.
Weighted variance component test for the integrative multi-omics analysis of microbiome data
Authors: Zhang Angela , Ling Wodan , Little Amarise , Williams-Nguyen Jessica S. , Moon Jee-Young , Burk Robert D. , Knight Rob , Wang Dong D. , Qi Qibin , Kaplan Robert C. , Zhao Ni , Wu Michael C.
Published: June 2024

Metabolic dysregulation and alterations have been linked to various diseases and conditions. Innovations in high-throughput technology now allow rapid profiling of the metabolome and metagenome — often the gene content of bacterial populations -– for characterizing metabolism. Due to the small sample sizes and high dimensionality of the data, pathway analysis (wherein the effect of multiple genes or metabolites on an outcome is cumulatively assessed) of metabolomic data is commonly conducted and also represents a standard for metagenomic analysis. However, how to integrate both data types remains unclear. Recognizing that a metabolic pathway can be complementarily characterized by both metagenomics and metabolomics, we propose a weighted variance components framework to test if the joint effect of genes and metabolites in a biological pathway is associated with outcomes. The approach allows analytic p-value calculation, correlation between data types, and optimal weighting. Power simulations show that our approach often outperforms other strategies while maintaining type I error. The approach is illustrated on real data.
Integrative Network Analysis Reveals Novel Moderators of Aβ-Tau Interaction in Alzheimer’s Disease
Authors: Kitani Akihiro , Matsui Yusuke
Published: June 2024

Background

Although interactions between amyloid-beta and tau proteins have been implicated in Alzheimer’s disease (AD), the precise mechanisms by which these interactions contribute to disease progression are not yet fully understood. Moreover, despite the growing application of deep learning in various biomedical fields, its application in integrating networks to analyze disease mechanisms in AD research remains limited. In this study, we employed BIONIC, a deep learning-based network integration method, to integrate proteomics and protein–protein interaction data, with an aim to uncover factors that moderate the effects of the Aβ-tau interaction on mild cognitive impairment (MCI) and early-stage AD.

Methods

Proteomic data from the ROSMAP cohort were integrated with protein–protein interaction (PPI) data using a Deep Learning-based model. Linear regression analysis was applied to histopathological and gene expression data, and mutual information was used to detect moderating factors. Statistical significance was determined using the Benjamini-Hochberg correction (p < 0.05).

Results

Our results suggested that astrocytes and GPNMB+ microglia moderate the Aβ-tau interaction. Based on linear regression with histopathological and gene expression data, GFAP and IBA1 levels andGPNMBgene expression positively contributed to the interaction of tau with Aβ in non-dementia cases, replicating the results of the network analysis.

Conclusions

These findings indicate that GPNMB+ microglia moderate the Aβ-tau interaction in early AD and therefore are a novel therapeutic target. To facilitate further research, we have made the integrated network available as a visualization tool for the scientific community (URL:https://igcore.cloud/GerOmics/AlzPPMap).
A phage nucleus-associated protein from the jumbophage Churi inhibits bacterial growth through protein translation interference
Authors: Wannasrichan Wichanan , Krobthong Sucheewin , Morgan Chase J , Armbruster Emily G , Gerovac Milan , Yingchutrakul Yodying , Wongtrakoongate Patompon , Vogel Jörg , Aonbangkhen Chanat , Nonejuie Poochit , Pogliano Joe , Chaikeeratisak Vorrapon
Published: June 2024

Antibacterial proteins inhibitingPseudomonas aeruginosahave been identified in various phages and explored as antibiotic alternatives. Here, we isolated a phiKZ-like phage, Churi, which encodes 364 open reading frames. We examined 15 early-expressed phage proteins for their ability to inhibit bacterial growth, and found that gp335, closely related to phiKZ-gp14, exhibits antibacterial activity. Similar to phiKZ-gp14, recently shown to form a complex with theP. aeruginosaribosome, we predict experimentally that gp335 interacts with ribosomal proteins, suggesting its involvement in protein translation. GFP-tagged gp335 clusters around the phage nucleus as early as 15 minutes post-infection and remains associated with it throughout the infection, suggesting its role in protein expression in the cell cytoplasm. CRISPR-Cas13-mediated deletion of gp355 reveals that the mutant phage has a prolonged latent period. Altogether, we demonstrate that gp335 is an antibacterial protein of nucleus-forming phages that associates with the ribosomes at the phage nucleus.
Cyclophilin A Facilitates HIV-1 DNA Integration
Authors: Padron Adrian , Dwivedi Richa , Chakraborty Rajasree , Prakash Prem , Kim Kyusik , Shi Jiong , Ahn Jinwoo , Pandhare Jui , Luban Jeremy , Aiken Christopher , Balasubramaniam Muthukumar , Dash Chandravanu
Published: June 2024

Cyclophilin A (CypA) promotes HIV-1 infection by facilitating reverse transcription, nuclear entry and by countering the antiviral activity of TRIM5α. These multifunctional roles of CypA are driven by its binding to the viral capsid. Interestingly, recent studies suggest that the HIV-1 capsid lattice enters the nucleus of an infected cell and uncoats just before integration. Therefore, we tested whether CypA-capsid interaction regulates post-nuclear entry steps of infection, particularly integration. First, we challenged CypA-expressing (CypA+/+) and CypA-depleted (CypA-/-) cells with HIV-1 particles and quantified the resulting levels of provirus. Surprisingly, CypA-depletion significantly reduced integration, an effect that was independent of CypA’s effect on reverse transcription, nuclear entry, and the presence or absence of TRIM5α. Additionally, cyclosporin A, an inhibitor that disrupts CypA-capsid binding, inhibited HIV-1 integration in CypA+/+cells but not in CypA-/-cells. Accordingly, HIV-1 capsid mutants (G89V and P90A) deficient in CypA binding were also blocked at integration in CypA+/+cells but not in CypA-/-cells. Then, to understand the mechanism, we assessed the integration activity of HIV-1 preintegration complexes (PICs) extracted from infected cells. The PICs from CypA-/-cells had lower activityin vitrocompared to those from CypA+/+cells. PICs from cells depleted for CypA and TRIM5α also had lower activity, suggesting that CypA’s effect on PIC activity is independent of TRIM5α. Finally, addition of CypA protein significantly stimulated the integration activity of PICs extracted from both CypA+/+and CypA-/-cells. Collectively, these results suggest that CypA promotes HIV-1 integration, a previously unknown role of this host factor.

Importance

HIV-1 capsid interaction with host cellular factors is essential for establishing a productive infection. However, the molecular details of such virus-host interactions are not fully understood. Cyclophilin A (CypA) is the first host protein identified to specifically bind to the HIV-1 capsid. Now it is established that CypA promotes reverse transcription and nuclear entry steps of HIV-1 infection. In this report, we show that CypA promotes HIV-1 integration by binding to the viral capsid. Specifically, our results demonstrate that CypA promotes HIV-1 integration by stimulating the activity of the viral preintegration complex and identifies a novel role of CypA during HIV-1 infection. This new knowledge is important because recent reports suggest that an operationally intact HIV-1 capsid enters the nucleus of an infected cell.
Transferrin receptor-based circulating tumor cell enrichment provides a snapshot of the molecular landscape of solid tumors and correlates with clinical outcomes
Authors: Galletti Giuseppe , Halima Ahmed , Gjyrezi Ada , Zhang Jiaren , Zimmerman Bob , Worroll Daniel , Kallergi Galatea , Barreja Rohan , Ocean Allyson , Saxena Ashish , McGraw Timothy E. , Nanus David M. , Elemento Olivier , Altorki Nasser K. , Tagawa Scott T. , Giannakakou Paraskevi
Published: June 2024

Circulating tumor cells (CTCs) captured from the bloodstream of patients with solid tumors have the potential to accelerate precision oncology by providing insight into tumor biology, disease progression and response to treatment. However, their potential is hampered by the lack of standardized CTC enrichment platforms across tumor types. EpCAM-based CTC enrichment, the most commonly used platform, is limited by EpCAM downregulation during metastasis and the low EpCAM expression in certain tumor types, including the highly prevalent and lethal NSCLC. In this study we demonstrate that Transferrin Receptor (TfR) is a selective, efficient biomarker for CTC identification and capture in patients with prostate, pancreatic and NSCLC. TfR identifies significantly higher CTC counts than EpCAM, and TfR+-CTC enumeration correlates with disease progression in metastatic prostate and pancreatic cancers, and overall survival and osimetrinib-resistance in non-small cell lung cancer (NSCLC). Profiling of TfR+-CTCs provides a snapshot of the molecular landscape of each respective tumor type and identifies potential mechanisms underlying treatment response to EGFR TKi and immune checkpoint inhibitors in NSCLC.

One sentence summary

Transferrin Receptor identifies circulating tumor cells in solid tumors
Efficacy of Mechanical Thrombectomy in Medium Vessel Occlusions of the MCA in the Extended Time Window
Authors: Berger Marcel Cedric , Simgen Andreas , Dietrich Philipp , Naziri Weis
Published: June 2024

Background

Mechanical thrombectomy (MT) has significantly improved outcomes in acute ischemic stroke (AIS) due to large vessel occlusions (LVOs) up to 24 hours post-onset. The effectiveness of MT for medium vessel occlusions (MeVOs) in the M2 or M3 segments of the middle cerebral artery beyond 6 hours is less investigated.

Methods

This retrospective study analyzed 80 patients who underwent MT for primary, isolated M2 or M3 segment occlusions between January 2020 and August 2023. Patients were categorized by time from stroke onset to groin puncture into two groups: ≤6 hours (n=61) and >6 hours (n=19). Outcomes assessed included clinical severity (NIH Stroke Scale [NIHSS]), functional outcomes (modified Rankin Scale [mRS]), symptomatic intracranial hemorrhages (sICH), and reperfusion success (modified Thrombolysis in Cerebral Infarction [mTICI] scale).

Results

Mean onset-to-puncture time was 192±57 minutes for the ≤6 hours group and 611±327 minutes for the >6 hours group. Baseline NIHSS scores were 9.5 (IQR 9) and 7 (IQR 8), respectively (p=0.418). While the NIHSS improvement was greater in the ≤6 hours group (median: −5 vs. −2; p=0.028), both groups showed significant improvement from baseline NIHSS scores (p<0.001 and p=0.014). Rates of sICH were low in both groups (1.5% vs. 0.5%; p=0.421). Recanalization rates were lower in the >6 hours group (84.2% vs. 96.7%; p=0.084), with more attempts (2.37 vs. 1.66; p=0.024).

Conclusion

MT for M2 and M3 segment occlusions in the MCA shows benefits beyond 6 hours from stroke onset, with earlier treatment yielding greater improvement. Extending MT’s treatment window could be valuable for MeVOs in the MCA.
Protein-coding mutation inAdcy3increases adiposity and alters emotional behaviors sex-dependently in rats
Authors: Fitzpatrick Mackenzie , Szalanczy Alexandria , Beeson Angela , Vora Anusha , Scott Christina , Grzybowski Michael , Klotz Jason , Der Nataley , Chen Rong , Geurts Aron M. , Woods Leah C. Solberg
Published: June 2024

1

Objective

Adenylate cyclase 3 (Adcy3)has been linked to both obesity and major depressive disorder (MDD). Our lab identified a protein-coding variant in the 2ndtransmembrane (TM) helix ofAdcy3in rats, and similar obesity variants have been identified in humans. The current study investigates the role of a TM variant in adiposity and behavior.

Methods

We used CRISPR-SpCas9 to mutate the TM domain ofAdcy3in WKY rats (Adcy3mut/mut). We also created a heterozygous knockout rat in the same strain (Adcy3+/-). Wild-type (WT), Adcy3+/-, and Adcy3mut/mutrats were fed a high-fat diet for 12 weeks. We measured body weight, fat mass, glucose tolerance, food intake, metabolism, emotion-like behaviors, and memory.

Results

Adcy3+/-and Adcy3mut/mutrats weighed more than WT rats due to increased fat mass. There were key sex differences: adiposity was driven by increased food intake in males but by decreased energy expenditure in females. Adcy3mut/mutmales displayed increased passive coping and decreased memory while Adcy3mut/mutfemales displayed increased anxiety-like behavior.

Conclusions

These studies show that the ADCY3 TM domain plays a role in protein function, thatAdcy3may contribute to the relationship between obesity and MDD, and that sex influences the relationships betweenAdcy3, metabolism, and behavior.

Study Importance Questions

What is already known about this subject?

Adcy3has been linked to both obesity and depression in humans, with protein-coding variants in the transmembrane domain leading to increased obesity. Yet the underlying mechanisms are unknown, and it is unknown if the sameAdcy3variants can cause both obesity and depression.

RodentAdcy3knockout models show increased adiposity and altered emotional behaviors, but no rodent models have assessed the role of protein-coding variants inAdcy3.Very few studies have assessed sex differences.

What are the new findings in your manuscript?

This is the first study to assess the role of a protein-coding variant in the transmembrane domain ofAdcy3, showing increases in both obesity and emotion-like behaviors in a rat model.

We observed striking sex differences, where male and female rats had different factors driving their adiposity and different patterns of altered behavior.

How might your results change the direction of research or the focus of clinical practice?

Understanding the role ofAdcy3in obesity and MDD may lead to improved treatments for both diseases.

Improving our understanding of the sex differences caused by the sameAdcy3mutation emphasizes the importance of studying both sexes and paves the way for personalized medicine approaches.
SETD1A-dependent EME1 transcription drives PARPi sensitivity in HR deficient tumour cells
Authors: Sweatman Ellie , Bayley Rachel , Selemane Richad , Higgs Martin R.
Published: June 2024

Background

Cells deficient in DNA repair factors breast cancer susceptibility 1/2 (BRCA1/2) or ataxia-telangiectasia mutated (ATM) are sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Building on our previous findings, we asked how the lysine methyltransferase SETD1A contributed to PARP inhibitor-mediated cell death and determined the mechanisms responsible.

Methods

We used cervical, breast, lung and ovarian cancer cells bearing mutations inBRCA1orATMand depleted SETD1A using siRNA or CRISPR/Cas9. We assessed the effects of the PARPi Olaparib on cell viability, homologous recombination, and DNA repair. We assessed underlying transcriptional perturbations using RNAseq. We also used data from The Cancer Genomics Atlas (TCGA) to investigate overall patient survival.

Results

Loss of SETD1A from both BRCA1-deficient and ATM-deficient cancer cells was associated with resistance to Olaparib, explained by an partial restoration of homologous recombination. Mechanistically, SETD1A-dependent transcription of the crossover junction endonuclease EME1 correlated with sensitivity to Olaparib in these cells. Accordingly, when SETD1A or EME1 was lost, BRCA1 or ATM-mutated cells became resistant to Olaparib, and homologous recombination was partially restored.

Conclusions

Loss of SETD1A or EME1 may explain why patients develop resistance to PARP inhibitors in the clinic.
Unraveling Lineage Roadmaps and Cell Fate Determinants to Postnatal Neural Stem Cells and Ependymal cells in the Developing Ventricular Zone
Authors: Zheng Jianqun , Chen Yawen , Hu Yukun , Lin Jie , Zhu Yujian , Xu Manlin , Song Weihong , Chen Xi
Published: June 2024

The ventricular zone (VZ) is made up of adult neural stem cells (NSCs) and multi-ciliated ependymal cells (EPCs). Both NSCs and EPCs are derived from radial glial cells (RGCs). To date, the transcriptomic dynamics and the molecular mechanisms guiding the cell fate commitment during the differentiation remain poorly understood. In this study, we analysed the developing VZ at the single-cell resolution and identified three distinct cellular states of RGCs: bipotent glial progenitor cells (bGPCs), neonatal NSC-neuroblasts (nNSC-NBs) and neonatal EPCs (nEPCs). The differentiation from bGPCs to nNSC-NBs and nEPCs forms a continuous bifurcating trajectory. Further molecular analysis along the NSC branch unveiled a novel intermediate state of cells expressing oligodendrocyte precursor cell (OPC) and neuroblast (NB) marker genes. Several transcription factors (TFs) were proved to be essential for the EPC-lineage differentiation, with TFEB emerging as a key regulator dictating the bGPC fate. The activation of TFEB promoted differentiation towards NSC-NBs while restrained the trajectory towards EPCs. Our findings offer detailed insights into further understanding VZ development and lay the groundwork for investigating potential therapeutic strategies against VZ-related disorders, such as hydrocephalus and neurodegenerative diseases (NDDs).
Phasing or purging: tackling the genome assembly of a highly heterozygous animal species in the era of high-accuracy long reads
Authors: Guiglielmoni Nadège , Schiffer Philipp H
Published: June 2024

The revolution of high-accuracy long reads offers unprecedented quality and contiguity in genome assembly. Pacific Biosciences (PacBio) and Oxford Nanopore Technologies have made significant strides in improving their sequencing technologies, yielding reads with error rates below 1% and lengths ranging from kilobases to megabases. These advancements have prompted the development of assembly tools tailored to leverage the enhanced accuracy of long reads. However, the challenge of collapsing haplotypes into high-quality haploid assemblies persists, especially for highly heterozygous genomes. This raises questions about the feasibility and desirability of phased assemblies versus collapsed haploid assemblies. To address these challenges, we benchmarked five assembly tools on ultra-low input PacBio HiFi and Nanopore R10.4 reads from the parthenogenetic nematode species Plectus sambesii. We propose a comprehensive methodology for assessing phased assemblies, repurposing existing evaluation programs to collect haplotype-relevant statistics. Our evaluation criteria include assembly size, contiguity, and completeness, with a focus on assessing the accuracy of phased assemblies by examining duplicated BUSCO orthologs and k-mer spectra. Additionally, we present strategies for generating collapsed assemblies by purging haplotigs. This study provides valuable insights and guidelines for generating high-quality phased and collapsed de novo genome assemblies from highly accurate long reads, particularly beneficial for non-model species genome assembly projects.