Diseases Research Articles

NcRNA Editing: Functional Characterization and Computational Resources.

Non-coding RNAs (ncRNAs) play crucial roles in gene expression regulation, translation, and disease development, including cancer. They are classified by size in short and long non-coding RNAs. This chapter focuses on the functional implications of adenosine-to-inosine (A-to-I) RNA editing in both short (e.g., miRNAs) and long ncRNAs. RNA editing dynamically alters the sequence and structure of primary transcripts, impacting ncRNA biogenesis and function. Notable findings include the role of miRNA editing in promoting glioblastoma invasiveness, characterizing RNA editing hotspots across cancers, and its implications in thyroid cancer and ischemia. This chapter also highlights bioinformatics resources and next-generation sequencing (NGS) technologies that enable comprehensive ncRNAome studies and genome-wide RNA editing detection. Dysregulation of RNA editing machinery has been linked to various human diseases, emphasizing the potential of RNA editing as a biomarker and therapeutic target. This overview integrates current knowledge and computational tools for studying ncRNA editing, providing insights into its biological significance and clinical applications.

Shared mechanisms of enhanced plasmid maintenance and antibiotic tolerance mediated by the VapBC toxin:antitoxin system.

Our work addresses two processes, the maintenance of plasmids and antibiotic tolerance; both contribute to the development of antimicrobial resistance in bacteria that cause human disease. Here, we found a single nucleotide change in the vapBC toxin:antitoxin system that stabilizes the large virulence plasmid of Shigella sonnei. The mutation is in the vapB antitoxin gene and makes the antitoxin more likely to be degraded, releasing the VapC toxin to efficiently kill cells without the plasmid (and thus unable to produce more antitoxin as an antidote). We found that vapBC mutations in E. coli that lead to antibiotic tolerance (a precursor to resistance) also operate by the same mechanism (i.e., generating VapB that is prone to cleavage); free VapC during tolerance will arrest bacterial growth and prevent susceptibility to antibiotics. This work shows the mechanistic links between plasmid maintenance and tolerance, and has applications in biotech and in the design and evaluation of vaccines against shigellosis.

Molecular basis for plasma membrane recruitment of PI4KA by EFR3.

The lipid kinase phosphatidylinositol 4 kinase III α (PI4KIIIα/PI4KA) is a master regulator of the lipid composition and asymmetry of the plasma membrane. PI4KA exists primarily in a heterotrimeric complex with its regulatory proteins TTC7 and FAM126. Fundamental to PI4KA activity is its targeted recruitment to the plasma membrane by the lipidated proteins EFR3A and EFR3B. Here, we report a cryogenic electron microscopy structure of the C terminus of EFR3A bound to the PI4KA-TTC7B-FAM126A complex, with extensive validation using both hydrogen deuterium exchange mass spectrometry, and mutational analysis. The EFR3A C terminus undergoes a disorder-order transition upon binding to the PI4KA complex, with an unexpected direct interaction with both TTC7B and FAM126A. Complex disrupting mutations in TTC7B, FAM126A, and EFR3 decrease PI4KA recruitment to the plasma membrane. Multiple posttranslational modifications and disease linked mutations map to this site, providing insight into how PI4KA membrane recruitment can be regulated and disrupted in human disease.

The emerging role of long non-coding RNA SOX2-OT in cancers and non-malignant diseases.

SOX2 overlapping transcript (SOX2-OT) is a long non-coding RNA located at chromosome 3q26.33 in humans. Convincing data confirm that SOX2-OT is evolutionarily conserved and plays a significant role in various malignant and non-malignant diseases. In most cancers, the upregulation of SOX2-OT acts as an oncogenic factor, strongly correlating with tumor risk, adverse clinicopathological features, and poor prognosis. Mechanistically, SOX2-OT is regulated by seven transcription factors and influences cellular behavior by modulating SOX2 expression, competitively binding 20 types of miRNAs, stabilizing protein expression, or promoting protein ubiquitination. It also participates in epigenetic modifications and activates multiple signaling pathways to regulate cancer cell proliferation, apoptosis, migration, invasion, autophagy, immune evasion, and resistance to chemotherapy/targeted therapies. Additionally, SOX2-OT triggers apoptosis, oxidative stress, and inflammatory responses, contributing to neurodevelopmental disorders, cardiovascular diseases, and diabetes-related conditions. Genetic polymorphisms of SOX2-OT have also been linked to breast cancer, gastric cancer, recurrent miscarriage, sepsis, and eating disorders in patients with bipolar disorder. This review provides an overview of recent research progress on SOX2-OT in human diseases, highlights its substantial potential as a prognostic and diagnostic biomarker, and explores its future clinical applications.

Mono-allelic epigenetic regulation of polycistronic transcription initiation by RNA polymerase II in Trypanosoma brucei.

Unique for a eukaryote, protein-coding genes in trypanosomes are arranged in polycistronic transcription units (PTUs). This genome arrangement has led to a model where Pol II transcription of PTUs is unregulated and changes in gene expression are entirely post-transcriptional. Trypanosoma brucei brucei is unable to infect humans because of its susceptibility to an innate immune complex, trypanosome lytic factor (TLF) in the circulation of humans. The initial step in TLF-mediated lysis of T.b.brucei requires high affinity haptoglobin/hemoglobin receptor (HpHbR) binding. Here, we demonstrate that by in vitro selection with TLF, resistance is obtained in a stepwise process correlating with loss of HpHbR expression at an allelic level. RNA-seq, Pol II ChIP, and run-on analysis indicate HpHbR silencing is at the transcriptional level, where loss of Pol II binding at the promoter region specifically shuts down transcription of the HpHbR-containing gene cluster and the adjacent opposing gene cluster. Reversible transcriptional silencing of the divergent PTUs correlates with DNA base J modification of the shared promoter region. Base J function in establishing transcriptional silencing, rather than maintenance, is suggested by the maintenance of PTU silencing following the inhibition of J-biosynthesis and subsequent loss of the modified DNA base. Therefore, we show that epigenetic mechanisms exist to regulate gene expression via Pol II transcription initiation of gene clusters in a mono-allelic fashion. These findings suggest epigenetic chromatin-based regulation of gene expression is deeply conserved among eukaryotes, including early divergent eukaryotes that rely on polycistronic transcription.IMPORTANCEThe single-cell parasite Trypanosoma brucei causes lethal diseases in both humans and livestock. T. brucei undergoes multiple developmental changes to adapt in different environments during its digenetic life cycle. With protein-coding genes organized as polycistronic transcription and apparent absence of promoter-mediated regulation of transcription initiation, it is believed that developmental gene regulation in trypanosomes is essentially post-transcriptional. In this study, we found reversible Pol II transcriptional silencing of two adjacent polycistronic gene arrays that correlate with the novel DNA base J modification of the shared promoter region. Our findings support epigenetic regulation of Pol II transcription initiation as a viable mechanism of gene expression control in T. brucei. This has implications for our understanding how trypanosomes utilize polycistronic genome organization to regulate gene expression during its life cycle.

Nanotherapeutics in Kidney Disease: Innovations, Challenges, and Future Directions.

The treatment and management of kidney disease present a significant global challenge, affecting over 800 million individuals and necessitating innovative therapeutic strategies that transcend symptomatic relief. The application of nanotechnology to renal therapies, while still in its early stages, holds transformative potential for improving treatment outcomes. Recent advancements in nanoparticle-based drug delivery leverage the unique physicochemical properties of nanoparticles for targeted and controlled therapeutic delivery to the kidneys. Current research is focused on understanding the functional and phenotypic changes in kidney cells during both acute and chronic conditions, allowing for the identification of optimal target cells. Additionally, the development of tailored nanomedicines enhances their retention and binding to key renal membranes and cell populations, ultimately improving localization, tolerability, and efficacy. However, significant barriers remain, including inconsistent nanoparticle synthesis and the complexity of kidney-specific targeting. To overcome these challenges, the field requires advanced synthesis techniques, refined targeting strategies, and the establishment of animal models that accurately reflect human kidney disease. These efforts are critical for the clinical application of nanotherapeutics, which promise novel solutions for kidney disease management. This review evaluates a substantial body of in vivo research, highlighting the prospects, challenges, and opportunities presented by nanotechnology-mediated therapies and their potential to transform kidney disease treatment.

HPV vaccination and anal HPV infection in gay, bisexual, and other men who have sex with men.

Gay, bisexual, and other men who have sex with men (gbMSM) have a higher risk of human papillomavirus (HPV) infection and related diseases and would benefit from preventive measures such as HPV vaccination. We assessed the association between HPV vaccination and anal HPV infection in HIV-negative gbMSM and gbMSM living with HIV from the Lubricant Investigation in Men to Inhibit Transmission of HPV Infection study. Participants attended 7 visits over 12months where they provided a nurse-collected anal sample and self-completed a questionnaire on risk factors and HPV vaccination. Samples were tested for HPV using polymerase chain reaction assays. We assessed the association with HPV vaccination and anal HPV prevalence and incidence using logistic and Cox regression, respectively. Analyses at the individual- (unit of analysis=participant) and HPV-level (unit of analysis=HPV type) considered vaccine-targeted types (any of HPVs 6/11/16/18) as the outcome. To assess construct validity, we repeated analyses considering incidence of non-vaccine-targeted (within- and cross-species) HPV types at the HPV-level. Estimates were adjusted for a propensity score to predict cumulative HPV positivity based on selected study and participant characteristics. Of 258 enrolled participants (18.2-71.7years; 69 being HIV-positive), 23.3% were vaccinated at baseline. At the individual-level, there was no association between vaccination and HPVs 6/11/16/18 prevalence (n=250, aOR=1.12, 95% CI=0.56-2.22) or incidence (n=152, aHR=0.34, 95% CI=2.19×10-18-1.38). At the HPV-level, while there was no association with HPVs 6/11/16/18 prevalence (n=1000, aOR=0.99, 95% CI=0.57-1.71), vaccination was associated with a reduction in HPVs 6/11/16/18 incidence (n=754, aHR=0.22, 95% CI=6.01×10-18-0.79). Vaccination was not associated with incidence of within-species (n=2299, aHR=0.76, CI=0.42-1.24) or cross-species (n=3774, aHR=1.28, CI=0.89-1.85) HPV types. Results were similar by HIV status. Our findings support that HPV vaccination protects against incident anal infection of vaccine-targeted HPV types, thus, gbMSM should be encouraged to get vaccinated against HPV.

Characterisation of GPR17-expressing oligodendrocyte precursors in human ischaemic lesions and correlation with reactive glial responses.

White matter damage and subsequent demyelination significantly contribute to long-term functional impairment after ischaemic stroke. Identifying novel pharmacological targets to restore myelin integrity by promoting the maturation of oligodendrocyte precursor cells (OPCs) into new myelinating oligodendrocytes may open new perspectives for ischaemic stroke treatment. In this respect, previous studies highlighted the role of the G protein-coupled membrane receptor 17 (GPR17) as a key regulator of OPC differentiation in experimental models of brain injury, including ischaemic stroke. To determine the translational value of GPR17 as a possible target in the context of human disease, we exploited immunohistochemistry to characterise the distribution of GPR17-expressing cells in brain tissue samples from ischaemic stroke cases and correlated it with the reactive state of neighbouring glial cells. The results showed that GPR17 specifically decorates a subpopulation of differentiation-committed OPCs, labelled by the peculiar marker breast carcinoma-amplified sequence 1 (BCAS1), that accumulates in the peri-infarct region in the later stages after the ischaemic event. Interestingly, the response of GPR17-expressing cells appears to be paralleled by the switch of reactive microglia/macrophages from a phagocytic to a dystrophic phenotype and by astrocytic scar formation. A negative correlation was found between GPR17-expressing OPCs and reactive microglia/macrophages and astrocytes surrounding chronic ischaemic lesions in female subjects, while the same relationship was less pronounced in males. These results were reinforced by bioinformatic analysis of a publicly available transcriptomic dataset, which implicated a possible role of inflammation and defective neuron-to-OPC communication in remyelination failure after ischaemic damage. Hence, these data strengthen the relevance of GPR17-based remyelinating therapies for the treatment of ischaemic stroke. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Transcription as a double-edged sword in genome maintenance.

Genome maintenance is essential for the integrity of the genetic blueprint, of which only a small fraction is transcribed in higher eukaryotes. DNA lesions occurring in the transcribed genome trigger transcription pausing and transcription-coupled DNA repair. There are two major transcription-coupled DNA repair pathways. The transcription-coupled nucleotide excision repair (TC-NER) pathway has been well studied for decades, while the transcription-coupled homologous recombination repair (TC-HR) pathway has recently gained attention. Importantly, recent studies have uncovered crucial roles of RNA transcripts in TC-HR, opening exciting directions for future research. Transcription also plays pivotal roles in regulating the stability of highly specialized genomic structures such as telomeres, centromeres, and fragile sites. Despite their positive function in genome maintenance, transcription and RNA transcripts can also be the sources of genomic instability, especially when colliding with DNA replication and forming unscheduled pathological RNA:DNA hybrids (R-loops), respectively. Pathological R-loops can result from transcriptional stress, which may be induced by transcription dysregulation. Future investigation into the interplay between transcription and DNA repair will reveal novel molecular bases for genome maintenance and transcriptional stress-associated genomic instability, providing therapeutic targets for human disease intervention.

Cell type transcriptional identities are maintained in cultured ex vivo human brain tissue.

It is becoming more broadly accepted that human-based models are needed to better understand the complexities of the human nervous system and its diseases. The recently developed human brain organotypic culture model is one highly promising model that requires the involvement of neurosurgeons and neurosurgical patients. Studies have investigated the electrophysiological properties of neurons in such ex vivo human tissues, but the maintenance of other cell types within explanted brain remains largely unknown. Here, using single-nucleus RNA sequencing, we systematically evaluate the transcriptional identities of the various cell types found in six patient samples after fourteen days in culture (83,501 nuclei from day 0 samples and 45,738 nuclei from day 14 samples). We used two pediatric temporal lobectomy samples, an adult frontal cortex sample, two IDH wild-type glioblastoma samples, and one medulloblastoma sample. We found remarkably high correlations of day 14 transcriptional identities to day 0 tissue, especially in tumor cells (r = 0.90 to 0.93), though microglia (r = 0.86), oligodendrocytes (r = 0.80), pericytes (r = 0.77), endothelial cells (r = 0.78), and fibroblasts (r = 0.76) showed strong preservation of their transcriptional profiles as well. Astrocytes and excitatory neurons showed more moderate preservation (r = 0.66 and 0.47, respectively). Because the main difficulty with organotypic brain cultures is the acquisition of human tissue, which is readily available to neurosurgeons, this model is easily accessible to neurosurgeon-scientists and neurosurgeons affiliated with research laboratories. Broad uptake of this more representative model should prompt advances in our understanding of many uniquely human diseases, lead to more reliable clinical trial performance, and ultimately yield better therapies for our patients.

Assessment of Replicability and Efforts to Refine an Operant Conditioning Procedure for Larval Zebrafish.

The zebrafish model is rapidly advancing numerous areas of basic and translational research, including toxicology, drug discovery, molecular genetics, genomic research, developmental biology, and the study of human diseases (reviewed in [...].

Docetaxel response in BRCA1,p53-deficient mammary tumor cells is affected by Huntingtin and BAP1

Taxanes are frequently used anticancer drugs known to kill tumor cells by inducing mitotic aberrations and segregation defects. A defining feature of specific cancers, notably triple-negative breast cancer (TNBC) and particularly those deficient in BRCA1, is chromosomal instability (CIN). Here, we focused on understanding the mechanisms of docetaxel-induced cytotoxicity, especially in the context of BRCA1-deficient TNBC. Using functional genetic screens in CIN+ cells, we identified genes that mediate docetaxel response and found an interaction between Huntingtin (HTT) and BRCA1-associated protein-1 (BAP1). We employed Brca1-/-;p53-/- mammary tumor cells, derived from genetically engineered mouse tumors that closely mimic the human disease, to investigate the role of these genes in CIN+ BRCA1-deficient cells. Specifically, we observed that loss of HTT sensitizes CIN+ BRCA1-deficient mammary tumor cells to docetaxel by shortening mitotic spindle poles and increasing spindle multipolarity. In contrast, BAP1 depletion protected cells against these spindle aberrations by restoring spindle length and enhancing mitotic clustering of the extra centrosomes. In conclusion, our findings shed light on the roles of HTT and BAP1 in controlling mitotic spindle multipolarity and centrosome clustering, specifically in the absence of BRCA1. This affects the response to microtubule-targeting agents and suggests that further studies of the interaction of these genes with the mitotic spindle may provide useful insights into how to target CIN+ cells, particularly in the challenging therapeutic landscape of BRCA1-deficient TNBC.

Genetic and neuro-epigenetic effects of divergent artificial selection for feather pecking behaviour in chickens

Feather pecking (FP) is a repetitive behaviour in chickens, influenced by genetic, epigenetic, and environmental factors, similar to behaviours seen in human developmental disorders (e.g., hyperactivity, autism). This study examines genetic and neuro-epigenetic factors in the thalamus of chickens from lines selected for seven generations for high or low FP behaviour (HFP or LFP). We integrate data on Differentially Methylated Regions (DMRs), Single Nucleotide Polymorphisms (SNPs), and Copy Number Variations (CNVs) in this controlled artificial selection process. Significant differences in behaviour, immunology, and neurology have been reported in these lines. We identified 710 SNPs in these lines that indicate new potentially important genes for FP such as TMPRSS6 (implicated in autism), and SST and ARNT2 (somatostatin function). CNV were the omic level most affected during selection. The largest CNVs found were in RIC3 (gain in HFP) and SH3RF2 (gain in LFP) genes, linked to nicotinic acetylcholine receptor regulation and human oncogenesis, respectively. Our study also suggests that promoters and introns are hotspots for CpG depletion. The overlapping of the omic levels investigated here with data from a public FP Quantitative Trait Loci (QTL) database revealed novel candidate genes for understanding repetitive behaviours, such as RTKN2, associated with Alzheimer’s disease in humans. This study suggests CNVs as a crucial initial step for genomic diversification, potentially more impactful than SNPs.

Melioidosis in goats at a single Australian farm was caused by multiple diverse lineages of Burkholderia pseudomallei present in soil.

Burkholderia pseudomallei, causative agent of melioidosis, is a One Health concern as it is acquired directly from soil and water and causes disease in humans and agricultural and wild animals. We examined B. pseudomallei in soil and goats at a single farm in the Northern Territory of Australia where >30 goats acquired melioidosis over nine years. We cultured 45 B. pseudomallei isolates from 35 goats and sampled soil in and around goat enclosures to isolate and detect B. pseudomallei and evaluate characteristics associated with its occurrence; 33 soil isolates were obtained from 1993-1994 and 116 in 2006. Ninety-two goat and soil isolates were sequenced; mice were challenged with six soil isolates to evaluate virulence. Sampling depth and total N/organic C correlated with B. pseudomallei presence. Twelve sequence types (STs) were identified. Most goat infections (74%) were ST617, some with high similarity to 2006 soil isolates, suggesting ST617 was successful at persisting in soil and infecting goats. ST260 and ST266 isolates were highly virulent in mice but other isolates produced low/intermediate virulence; three of these were ST326 isolates, the most common soil ST in 2006. Thus, virulent and non-virulent lineages can co-occur locally. Three genes associated with virulence were present in ST260 and ST266, absent in most ST326 isolates, and present or variably present in ST617. Agricultural animals can influence B. pseudomallei abundance and diversity in local environments. This effect may persist, as B. pseudomallei was detected more often from soil collected inside and adjacent to goat enclosures years after most goats were removed. Following goat removal, the low virulence ST326, which was not isolated from soil when goats were present, became the predominant ST in soil by 2006. Although multiple diverse lineages of B. pseudomallei may exist in a given location, some may infect mammals more efficiently than others.

Unveiling the Potential of Natural Resources-Derived Therapeutics for Improved Malaria Management: Computational to Experimental Studies.

Malaria kills millions of people annually, and it is one of the major causes of preventable mortality in the world. Of the different plasmodium species that induce malaria, Plasmodium falciparum and Plasmodium vivax account for the most severe form of malarial disease in humans. This review focuses on understanding preventive measures, mutation-based disease evolution, malaria-related biomarkers, and potential plant bioactive components for the treatment and management of malaria. The burden of malaria drug resistance has made it necessary for scientists to focus on alternative therapeutics, with particular interests in those involving plant-based bioactive components that could mediate biochemical pathways, consisting of metabolic interactions essential for parasitic inhibition. To avoid artefacts or false positives, these bioactive components from plant sources are further filtered using the "pan-assay-interfering compounds" (PAINS) tool. This review discussed the history of malaria treatment, current treatment options, malaria preventive measures, and challenges associated with current treatment strategies. Additionally, this work discusses the barriers while developing drugs from phytochemicals and the steps needed to accelerate the development of new antimalarial from the lead compounds.

Legionella pneumophila, a Rosetta stone to understanding bacterial pathogenesis.

Legionella pneumophila is an environmentally acquired pathogen that causes respiratory disease in humans. While the discovery of L. pneumophila is relatively recent compared to other bacterial pathogens, over the past 50 years, L. pneumophila has emerged as a powerhouse for studying host-pathogen interactions. In its natural habitat of fresh water, L. pneumophila interacts with a diverse array of protozoan hosts and readily evolve to expand their host range. This has led to the accumulation of the most extensive arsenal of secreted virulence factors described for a bacterial pathogen and their ability to infect humans. Within amoebae and human alveolar macrophages, the bacteria replicate within specialized membrane-bound compartments, establishing L. pneumophila as a model for studying intracellular vacuolar pathogens. In contrast, the virulence factors required for intracellular replication are specifically tailored to individual host cells types, allowing the pathogen to adapt to variation between disparate niches. The broad host range of this pathogen, combined with the extensive diversity and genome plasticity across the Legionella genus, has thus established this bacterium as an archetype to interrogate pathogen evolution, functional genomics, and ecology. In this review, we highlight the features of Legionella that establish them as a versatile model organism, new paradigms in bacteriology and bacterial pathogenesis resulting from the study of Legionella, as well as current and future questions that will undoubtedly expand our understanding of the complex and intricate biology of the microbial world.

Uji Daya Hambat Ekstrak Daun Jambu (Psidium guajava) Terhadap Pertumbuhan Jamur Candida albicans Secara In Vitro

Fungi are one of the microorganisms that cause disease in humans. A disease caused by fungi in humans is called mycosis. Types of mycosis are divided into two, namely superficial mycosis and systemic mycosis. Superficial mycosis is an infection by fungi that spread on the surface of the body only, while systemic mycosis is an infection by fungi that attack the entire body. One type of pathogenic fungus is Candida albicans which causes canker sores, vaginal discharge, skin irritation to cancer. This study aims to determine the effect of guava leaf extract (Psidium guajava) on the growth of Candida albicans fungi. This type of research is purely experimental. Guava leaf extract (P.guajava) was obtained by maceration technique using 96% ethanol solvent. Inhibitory power testing of extracts using the Kibry-Bauer method with blank discs. Candida albicans was obtained from the Microbiology Laboratory of FMIPA USU. The results of the study obtained the diameter of the inhibitory zone of guava leaf extract against the growth of Candida albicans fungus 14.6 mm at a concentration of 100% guava leaf extract which is classified as a strong inhibitory zone criterion

The role of ARID1A in malignant neoplasms of the female reproductive system: a modern view on diagnostic and therapeutic opportunities

Сhromatin remodeling tumor suppressor protein ARID1A (AT-rich interaction domain 1A) is coded by the ARID1A gene as one of the most frequently mutated genes in human oncological diseases. Inactivating mutations in the ARID1A gene have a pronounced effect on cell survival, chemoresistance, transcription and cell cycle regulation. To date, a large number of studies have focused on assessing the effect of mutations leading to loss of ARID1A function on tumor emergence, progression and therapy resistance. The high frequency of ARID1A mutations in malignant tumors of the female reproductive system opens up unique opportunities for targeted preventive and therapeutic intervention. Clear cell ovarian carcinoma and uterine body cancer bearing ARID1A mutations do not respond well to standard chemotherapy proposing no current effective targeted therapy, which underlines a need for further research in the field. ARID1A can be used as a biomarker of precancerous diseases, as well as as a tool for predicting а response to radiation therapy, immunotherapy and targeted therapies. Currently, clinical trials assessing several low molecular weight and epigenetic inhibitors are being conducted in tumors of the female reproductive system with ARID1A deficiency.

Revealing an unprecedented diversity of episymbiotic Saccharibacteria in a high-quality genome collection

The episymbiotic Candidatus Saccharibacteria is the most studied lineage of candidate phyla radiation. Living an epiparasitic lifestyle, Saccharibacteria might be associated with human mucosal diseases by modulating the structure of the oral microbiome through interactions with host bacteria. However, the knowledge of Saccharibacterial genomic diversity and the potential underlying their adaptation to a wide range of habitats remains limited. Here, we construct a high-quality genome collection of Saccharibacteria from multiple sources, providing 2041 high-quality genomes and previously unidentified taxa. The comparative genomic analysis shows the widespread metabolic defects of Saccharibacteria. Specific metabolic modules are commonly found in Saccharibacteria of different habitats, suggesting Saccharibacteria might have undergone habitat adaptation during the transition from different environments. We additionally show that Saccharibacteria account for ~1% of the Chinese oral microbiome. A preliminary analysis of rheumatoid arthritis individuals and healthy controls implies that Saccharibacteria might be associated with human systemic disease.

Single-cell RNA sequencing reveals the contribution of smooth muscle cells and endothelial cells to fibrosis in human atrial tissue with atrial fibrillation

AimsAtrial fibrillation (AF) has high mortality and morbidity rates. However, the intracellular molecular complexity of the atrial tissue of patients with AF has not been adequately assessed.Methods and resultsWe investigated the cellular heterogeneity of human atrial tissue and changes in differentially expressed genes between cells using single-cell RNA sequencing, fluorescence in situ hybridization, intercellular communication, and cell trajectory analysis. Using genome-wide association studies (GWAS) and proteomics, we discovered cell types enriched for AF susceptibility genes. We discovered eight different cell types, which were further subdivided into 23 subpopulations. In AF, the communication strength between smooth muscle cells (SMCs) and fibroblast (FB) 3 cells increased and the relevant signaling pathways were quite similar. Subpopulations of endothelial cells (ECs) are mainly involved in fibrosis through TXNDC5 and POSTN. AF susceptibility genes revealed by GWAS were especially enriched in neuronal and epicardial cells, FB3, and lymphoid (Lys) cells, whereas proteomic sequencing differential proteins were concentrated in FB3 cells and SMCs.ConclusionsThis study provides a cellular landscape based on the atrial tissue of patients with AF and highlights intercellular changes and differentially expressed genes that occur during the disease process. A thorough description of the cellular populations involved in AF will facilitate the identification of new cell-based interventional targets with direct functional significance for the treatment of human disease.