bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metallo-protease Peptidase M84 fromBacillus altitudinisinduces ROS dependent apoptosis in ovarian cancer cells by targeting PAR-1
Authors: Nag Niraj , Ray Tanusree , Tapader Rima , Gope Animesh , Das Rajdeep , Mahapatra Elizabeth , Saha Saibal , Pal Ananda , Prasad Parash , Chatterjee Shruti , Roy Sib Sankar , Pal Amit 
Published: September 2023

AbstractIn pursuit of isolating novel anticancer proteases from environmental microbial isolates, we have purified and identified an extracellular metallo-protease fromBacillus altitudinisnamed Peptidase M84. This protease selectively triggered apoptosis in human ovarian adenocarcinoma cells (PA-1, SKOV3) and mouse ovarian carcinoma cells (ID8), in addition to exhibiting no significant effect on normal human epithelial ovarian cell (IOSE) and mouse peritoneal macrophage (PEMФ) cell viabilities. Protease activated receptor-1 (PAR-1); a GPCR which is reported to be overexpressed in ovarian cancer cells was identified as a novel target of Peptidase M84. We observed that Peptidase M84 induced PAR-1 overexpression along with activating its downstream signalling effectors NFκB and MAPK to promote excessive reactive oxygen species (ROS) generation in ovarian cancer cells. This disrupted mitochondrial membrane potential, allowed cytosolic release of mitochondrial cytochrome c, increased the Bax (pro-apoptotic) to Bcl-2 (anti-apoptotic) ratio and promoted DNA damage to evoke apoptotic death of the ovarian cancer cells. Peptidase M84 also reduced nuclear ki-67 expression in these malignant cells to render an anti-proliferative role. Inin vivoset-up, weekly intraperitoneal administration of Peptidase M84 (12 µg/kg body-weight) in the ID8 mice model significantly diminished ascitic fluid accumulation through induction of oxidative stress, increasing murine survival rates by 60%. Collectively, ourin vitroandin vivofindings suggested that Peptidase M84 triggered PAR-1 mediated oxidative stress to act as an apoptosis inducer in ovarian cancer cells. This established Peptidase M84 as a promising drug candidate for receptor mediated targeted-therapy of ovarian cancer.Graphical Abstract
MammalMethylClock R package: software for DNA Methylation-Based Epigenetic Clocks in Mammals
Authors: Zoller Joseph A. , Horvath Steve 
Published: September 2023

ABSTRACTEpigenetic clocks are prediction methods that relate cytosine methylation levels at specific genomic sites to chronological age, accounting for nuances such as genome mapping information and possibly life history traits such as age at sexual maturity. Defined as multivariate regression models, these DNA methylation-based biomarkers have gained prominence in species conservation efforts and preclinical studies. Once built, these models predict an individual’s age from their tissue sample’s methylation profile, with great potential for aging research, disease risk prediction, gauging intervention impacts. Through the collaborative efforts of our Mammalian Methylation Consortium, we’ve described epigenetic clocks for numerous mammalian species. Our R package includes the utility for implementing these pre-existing mammalian clocks. Overall, we present software tools and a dedicated R package calledMammalMethylClock, designed for the construction and assessment of epigenetic clocks.
A Manifold-Based Framework for Studying the Dynamics of the Vaginal Microbiome
Authors: Tsamir-Rimon Mor , Borenstein Elhanan 
Published: September 2023

AbstractThe vaginal bacterial community plays a crucial role in preventing infections. The composition of this community can be classified into five main groups, termed community state types (CSTs). Four of these CSTs, which are primarily consisted of Lactobacillus species, are considered healthy, while the fifth, which is composed of non-Lactobacillus populations, is considered less protective. This latter CST is often considered to represent a state termed Bacterial vaginosis (BV) – a common disease condition associated with unpleasant symptoms and increased susceptibility to sexually transmitted diseases. However, the exact mechanisms underlying BV development are not yet fully understood, including specifically, the dynamics of the vaginal microbiome in BV, and the possible routes it may take from a healthy to a BV state. This study aims to identify the progression from healthy Lactobacillus-dominant populations to symptomatic BV by analyzing 8,026 vaginal samples and using a manifold-detection framework. This approach is inspired by single-cell analysis and aims to identify low-dimensional trajectories in the high-dimensional composition space. This framework further order samples along these trajectories and assign a score (pseudo-time) to each sample based on its proximity to the BV state. Our results reveal distinct routes of progression between healthy and BV state for each CST, with pseudo-time scores correlating with community diversity and quantifying the health state of each sample. BV indicators, including Nugent score, positive Amsel’s test, and several Amsel’s criteria, can also be successfully predicted based on pseudo-time scores. Additionally, Gardnerella vaginalis can be identified as a key taxon in BV development using this approach, with increased abundance in samples with high pseudo-time, indicating an unhealthier state across all BV-development routes on the manifold. Taken together, these findings demonstrate how manifold detection can be used to successfully characterizes the progression from healthy Lactobacillus-dominant populations to BV and to accurately quantify the health condition of new samples along the route of BV development.
GOT1 primes the cellular response to hypoxia by supporting glycolysis and HIF1α stabilisation
Authors: Grimm Fiona , Asuaje Agustín , Jain Aakriti , dos Santos Mariana Silva , Kleinjung Jens , Nunes Patrícia M. , Gehrig Stefanie , Fets Louise , MacRae James I. , Anastasiou Dimitrios 
Published: September 2023

SUMMARYAdaptation to chronic hypoxia occurs through changes in protein expression, which are controlled by hypoxia inducible factor 1a (HIF1α) and are necessary for cancer cell survival. However, the mechanisms that enable cancer cells to adapt in early hypoxia, prior to full activation of HIF1α, remain poorly understood. Here we show that aspartate transaminase 1 (GOT1), which supports NAD+production by malate dehydrogenase 1 (MDH1), is required, in addition to reserve lactate dehydrogenase (LDH) capacity, for the HIF1α-independent increase in glycolysis we observe early upon exposure of cells to hypoxia. Additionally, GOT1 maintains low α-ketoglutarate levels, thereby limiting prolyl hydroxylase activity to promote HIF1α stabilisation in early hypoxia and robust HIF1α target gene expression in later hypoxia. Our findings reveal that, in normoxia, GOT1 maintains cells in a primed state and ready to support increased glycolysis and HIF1α stabilisation upon oxygen limitation, until other adaptive processes that require more time, are fully established.
Causal Genetic Loci for a Motivated Behavior Spectrum Harbor Psychiatric Risk Genes
Authors: Xu Jiale , Casanave Romelo , Chitre Apurva S. , Wang Qiyang , Nguyen Khai-Minh , Blake Chiara , Wagle Mahendra , Cheng Riyan , Polesskaya Oksana , Palmer Abraham A. , Guo Su 
Published: September 2023

SummaryBehavioral diversity is critical for population fitness. Individual differences in risk-taking are observed across species, but underlying genetic mechanisms and conservation are largely unknown. We examined dark avoidance in larval zebrafish, a motivated behavior reflecting an approach-avoidance conflict. Brain-wide calcium imaging revealed significant neural activity differences between approach-inclined versus avoidance-inclined individuals. We used a population of ∼6,000 to perform the first genome-wide association study (GWAS) in zebrafish, which identified 34 genomic regions harboring many genes that are involved in synaptic transmission and human psychiatric diseases. We used CRISPR to study several causal genes: serotonin receptor-1b (htr1b), nitric oxide synthase-1 (nos1), and stress-induced phosphoprotein-1 (stip1). We further identified 52 conserved elements containing 66 GWAS significant variants. One encoded an exonic regulatory element that influenced tissue-specificnos1expression. Together, these findings reveal new genetic loci and establish a powerful, scalable animal system to probe mechanisms underlying motivation, a critical dimension of psychiatric diseases.
Systems genetics analysis of human body fat distribution genes identifies Wnt signaling and mitochondrial activity in adipocytes
Authors: Reed Jordan N , Huang Jiansheng , Li Yong , Ma Lijiang , Banka Dhanush , Wabitsch Martin , Wang Tianfang , Ding Wen , Björkegren Johan L.M. , Civelek Mete 
Published: September 2023

AbstractBACKGROUNDExcess fat in the abdomen is a sexually dimorphic risk factor for cardio-metabolic disease. The relative storage between abdominal and lower-body subcutaneous adipose tissue depots is approximated by the waist-to-hip ratio adjusted for body mass index (WHRadjBMI). Genome-wide association studies (GWAS) identified 346 loci near 495 genes associated with WHRadjBMI. Most of these genes have unknown roles in fat distribution, but many are expressed and putatively act in adipose tissue. We aimed to identify novel sex- and depot-specific drivers of WHRadjBMI using a systems genetics approach.METHODSWe used two independent cohorts of adipose tissue gene expression with 362 - 444 males and 147 - 219 females, primarily of European ancestry. We constructed sex- and depot- specific Bayesian networks to model the gene-gene interactions from 8,492 adipose tissue genes. Key driver analysis identified genes that, in silico and putatively in vitro, regulate many others, including the 495 WHRadjBMI GWAS genes. Key driver gene function was determined by perturbing their expression in human subcutaneous pre-adipocytes using lenti-virus or siRNA.RESULTS51 - 119 key drivers in each network were replicated in both cohorts. We used single-cell expression data to select replicated key drivers expressed in adipocyte precursors and mature adipocytes, prioritized genes which have not been previously studied in adipose tissue, and used public human and mouse data to nominate 53 novel key driver genes (10 - 21 from each network) that may regulate fat distribution by altering adipocyte function. In other cell types, 23 of these genes are found in crucial adipocyte pathways: Wnt signaling or mitochondrial function. We selected seven genes whose expression is highly correlated with WHRadjBMI to further study their effects on adipogenesis/Wnt signaling (ANAPC2, PSME3, RSPO1, TYRO3) or mitochondrial function (C1QTNF3, MIGA1, PSME3, UBR1).Adipogenesis was inhibited in cells overexpressing ANAPC2 and RSPO1 compared to controls. RSPO1 results are consistent with a positive correlation between gene expression in the subcutaneous depot and WHRadjBMI, therefore lower relative storage in the subcutaneous depot. RSPO1 inhibited adipogenesis by increasing β-catenin activation and Wnt-related transcription, thus repressing PPARG and CEBPA. PSME3 overexpression led to more adipogenesis than controls. In differentiated adipocytes, MIGA1 and UBR1 downregulation led to mitochondrial dysfunction, with lower oxygen consumption than controls; MIGA1 knockdown also lowered UCP1 expression.SUMMARYANAPC2, MIGA1, PSME3, RSPO1,andUBR1affect adipocyte function and may drive body fat distribution.
Loss of Ezh2 in the medial ganglionic eminence alters interneuron fate, cell morphology and gene expression profiles
Authors: Rhodes Christopher T. , Asokumar Dhanya , Sohn Mira , Naskar Shovan , Elisha Lielle , Stevenson Parker , Lee Dongjin R. , Zhang Yajun , Rocha Pedro P. , Dale Ryan K. , Lee Soohyun , Petros Timothy J. 
Published: September 2023

SUMMARYEnhancer of zeste homolog 2 (Ezh2) is responsible for trimethylation of histone 3 at lysine 27 (H3K27me3), resulting in gene repression. Here, we explore the role of Ezh2 in forebrain GABAergic interneuron development. Loss ofEzh2increases somatostatin-expressing (SST+) and decreases parvalbumin-expressing (PV+) interneurons in multiple brain regions. We also observe fewer MGE-derived interneurons in the first postnatal week, indicating reduced interneuron production. Intrinsic electrophysiological properties in SST+ and PV+ interneurons are normal, but PV+ interneurons display increased axonal complexity inEzh2mutant mice. Single cell multiome analysis revealed differential gene expression patterns in the embryonic MGE that are predictive of these cell fate changes. Lastly, CUT&Tag analysis revealed differential H3K27me3 levels at specific genomic loci, with some genes displaying a relative increase in H3K27me3 indicating they may be resistant to epigenetic modifications. Thus, loss of Ezh2 in the MGE alters interneuron fate, morphology, and gene expression and regulation.
Molecular Basis of Human Trace Amine-Associated Receptor 1 Activation
Authors: Zilberg Gregory , Parpounas Alexandra K. , Warren Audrey L. , Yang Shifan , Wacker Daniel 
Published: September 2023

AbstractThe human trace amine-associated receptor 1 (hTAAR1, hTA1) is a key regulator of monoaminergic neurotransmission and the actions of psychostimulants. Despite preclinical research demonstrating its tractability as a drug target, its molecular mechanisms of activation remain unclear. Moreover, poorly understood pharmacological differences between rodent and human TA1 complicate the translation of findings from preclinical disease models into novel pharmacotherapies. To elucidate hTA1’s mechanisms on the molecular scale and investigate the underpinnings of its divergent pharmacology from rodent orthologs, we herein report the structure of the human TA1 receptor in complex with a Gαs heterotrimer. Our structure reveals shared structural elements with other TAARs, as well as with its closest monoaminergic ortholog, the serotonin receptor 5-HT4R. We further find that a single mutation dramatically shifts the selectivity of hTA1 towards that of its rodent orthologs, and report on the effects of substituting residues to those found in serotonin and dopamine receptors. Strikingly, we also discover that the atypical antipsychotic medication and pan-monoaminergic antagonist asenapine potently and efficaciously activates hTA1. Together our studies provide detailed insight into hTA1 structure and function, contrast its molecular pharmacology with that of related receptors, and uncover off-target activities of monoaminergic drugs at hTA1.
The genome and population genomics of allopolyploidCoffea arabicareveal the diversification history of modern coffee cultivars
Authors: Salojärvi Jarkko , Rambani Aditi , Yu Zhe , Guyot Romain , Strickler Susan , Lepelley Maud , Wang Cui , Rajaraman Sitaram , Rastas Pasi , Zheng Chunfang , Muñoz Daniella Santos , Meidanis João , Paschoal Alexandre Rossi , Bawin Yves , Krabbenhoft Trevor , Wang Zhen Qin , Fleck Steven , Aussel Rudy , Bellanger Laurence , Charpagne Aline , Fournier Coralie , Kassam Mohamed , Lefebvre Gregory , Métairon Sylviane , Moine Déborah , Rigoreau Michel , Stolte Jens , Hamon Perla , Couturon Emmanuel , Tranchant-Dubreuil Christine , Mukherjee Minakshi , Lan Tianying , Engelhardt Jan , Stadler Peter , De Lemos Samara Mireza Correia , Suzuki Suzana Ivamoto , Sumirat Ucu , Man Wai Ching , Dauchot Nicolas , Orozco-Arias Simon , Garavito Andrea , Kiwuka Catherine , Musoli Pascal , Nalukenge Anne , Guichoux Erwan , Reinout Havinga , Smit Martin , Carretero-Paulet Lorenzo , Filho Oliveiro Guerreiro , Braghini Masako Toma , Padilha Lilian , Sera Gustavo Hiroshi , Ruttink Tom , Henry Robert , Marraccini Pierre , Van de Peer Yves , Andrade Alan , Domingues Douglas , Giuliano Giovanni , Mueller Lukas , Pereira Luiz Filipe , Plaisance Stephane , Poncet Valerie , Rombauts Stephane , Sankoff David , Albert Victor A. , Crouzillat Dominique , de Kochko Alexandre , Descombes Patrick 
Published: September 2023

AbstractCoffea arabica, an allotetraploid hybrid ofC. eugenioidesandC. canephora, is the source of approximately 60% of coffee products worldwide, and its cultivated accessions have undergone several population bottlenecks. We present chromosome-level assemblies of a di-haploidC. arabicaaccession and modern representatives of its diploid progenitors,C. eugenioidesandC. canephora. The three species exhibit largely conserved genome structures between diploid parents and descendant subgenomes, with no obvious global subgenome dominance. We find evidence for a founding polyploidy event 350,000-610,000 years ago, followed by several pre-domestication bottlenecks, resulting in narrow genetic variation. A split between wild accessions and cultivar progenitors occurred ∼30.5 kya, followed by a period of migration between the two populations. Analysis of modern varieties, including lines historically introgressed withC. canephora, highlights their breeding histories and loci that may contribute to pathogen resistance, laying the groundwork for future genomics-based breeding ofC. arabica.
Episymbiotic bacterium induces intracellular lipid droplet production in its host bacteria
Authors: Dong Pu-Ting , Tian Jing , Kobayashi-Kirschvink Koseki J. , Cen Lujia , McLean Jeffrey S. , Bor Batbileg , Shi Wenyuan , He Xuesong 
Published: September 2023

AbstractSaccharibacteria(formerly TM7)Nanosynbacter lyticustype strain TM7x exhibits a remarkably compact genome and an extraordinarily small cell size. This obligate epibiotic parasite forms a symbiotic relationship with its bacterial host,Schaalia odontolytica, strain XH001 (formerlyActinomyces odontolyticusstrain XH001). Due to its limited genome size, TM7x possesses restrained metabolic capacities, predominantly living on the surface of its bacterial host to sustain this symbiotic lifestyle. To comprehend this intriguing, yet understudied interspecies interaction, a thorough understanding of the physical interaction between TM7x and XH001 is imperative. In this study, we employed super-resolution fluorescence imaging to investigate the physical association between TM7x and XH001. We found that the binding with TM7x led to a substantial alteration in the membrane fluidity of the host bacterium XH001. Unexpectedly, we revealed the formation of intracellular lipid droplets in XH001 when forming episymbiosis with TM7x, a feature not commonly observed in oral bacteria cells. The TM7x-induced LD accumulation in XH001 was further confirmed by label-free non-invasive Raman spectroscopy, which also unveiled additional phenotypical features when XH001 cells are physically associated with TM7x. Further exploration through culturing host bacterium XH001 alone under various stress conditions showed that LD accumulation was a general response to stress. Intriguingly, a survival assay demonstrated that the presence of LDs likely plays a protective role in XH001, enhancing its overall survival under adverse conditions. In conclusion, our study sheds new light on the intricate interaction betweenSaccharibacteriaand its host bacterium, highlighting the potential benefit conferred by TM7x to its host, and further emphasizing the context-dependent nature of symbiotic relationships.
In the social amoebaD. discoideum, shortened stalks limit obligate cheater success even when exploitable partners are available
Authors: Medina James , Larsen Tyler , Queller David , Strassmann Joan 
Published: September 2023

AbstractCooperation is widespread across life, but its existence can be threatened by exploitation. The rise of obligate social cheaters that are incapable of contributing to a necessary cooperative function can lead to the loss of that function and to the extinction of populations. In the social amoebaDictyostelium discoideum, obligate social cheaters cannot form dead stalk cells and in chimeras instead form living spore cells. This gives them a competitive advantage within chimeras. However, obligate cheaters of this kind are not found in nature, probably because they are often enough in clonal populations that they need to retain the ability to produce stalks. In this study we discovered an additional cost to obligate cheaters. Even when there are wild-type cells to parasitize, the chimeric fruiting bodies that result have shorter stalks and these are disadvantaged in spore dispersal. The inability of obligate cheaters to form fruiting bodies when they are on their own combined with the lower functionality of fruiting bodies when they are not represent limits on obligate social cheating as a strategy.
Deletion of FAT1 in hybrid EMT cells stimulates the migration of neighboring non-mutant cells through secretion of extracellular vesicles
Authors: Geay Juliana , Seetharaman Shailaja , Vianay Benoît , Gélin Matthieu , Fresnoy Olivia , Blanchoin Laurent , Théry Manuel 
Published: September 2023

AbstractCells in hybrid state of the epithelial-to-mesenchymal transition (EMT) have been shown to be responsible for tumor cell metastasis. However, the precise mechanisms underlying the morphological changes and acquisition of invasive phenotypes in hybrid EMT cells are still unknown. Here, we introduced the deletion of a proto-cadherin and well described oncogene, FAT1, in skin carcinoma cells to generate a hybrid state of EMT. Surprisingly, the FAT1 knock-out (KO) cells were less motile than the parental non-mutated cell line they were derived from. However, we observed that FAT1 KO cells secrete specific factors in the form of extra-cellular vesicles into their microenvironment, which promote the migration of surrounding non-mutant cells. When stimulated with these extracellular vesicles, groups of non-mutated parental cells collectively migrated faster and formed finger-like instabilities at the migrating front. Furthermore, we found that the actomyosin contractility of FAT1 KO cells in hybrid EMT states was much lower than the parental cells. It appeared that the factors secreted by FAT1 KO cells relaxed the traction forces in recipient cells. This force release likely fostered the scattering and migration of non-mutated cells surrounding FAT1 mutant cells. Thus, we characterized a non-autonomous promotion of cell invasiveness in the cancer cells surrounding FAT1-deficient cells.Figure:Schematic showing how FAT1 deletion stimulates the migration of neighboring non mutant cells. FAT1 KO cells secrete extracellular vesicles that carry factors that promote migration of non-mutant control cells, possibly through relaxation of traction forces in the recipient cells.