Genetic evidence of bidirectional mendelian randomization study on the causality between gut microbiome and respiratory diseases contributes to gut-lung axis.

Observational studies and clinical trials have suggested the relationship between the gut microbiome and respiratory diseases, but the causality between them remains unclear. Firstly, we selected eight respiratory diseases Genome-wide association study (GWAS) datasets mainly from the FinnGen collaboration as outcomes. The exposure was based on GWAS statistics about the gut microbiome, sourced from the MiBioGen consortium, including gut microbial taxa. The causal link between the gut microbiome and respiratory illnesses was then estimated using a Two-sample Mendelian randomization (MR) analysis, including the inverse-variance weighted (IVW), weighted median, MR-Egger, simple mode, and weighted mode. To ensure reliability, F-statistics and sensitivity tests were conducted. Furthermore, we performed a reverse MR analysis of the pre-Mendelian positive findings to possible reverse causality. For the 196 gut microbe taxa, the IVW analysis suggested 88 potential associations with eight clinically prevalent respiratory diseases. Among them, 30 causal associations were found in more than one MR method. Multiple statistical corrections have confirmed three causal associations: genus Holdemanella was a risk factor for chronic obstructive pulmonary disease (COPD) (P = 1.3 × 10-4, OR = 1.18), family FamilyXIII was a protective factor for COPD (P = 1.3 × 10-3, OR = 0.75), and genus Oxalobacter was a risk factor for asthma (P = 2.1 × 10-4, OR = 1.09). Our MR analysis results indicate that there would be a causal relationship between the gut microbiome and respiratory diseases, contributing to the gut-lung axis. This finding offers new insights into the gut microbiome's roles in respiratory diseases' clinical prevention, pathogenesis, and improvement of clinical symptoms. Further randomized controlled trials are necessary to clarify the protective effect of probiotics and fecal microbial transplantation on respiratory health.

Exploring the relationship between sarcopenia and 11 respiratory diseases: a comprehensive mendelian randomization analysis.

BACKGROUND: Sarcopenia (SP) is an aging-related loss of muscle mass and function, affecting the respiratory system. However, the causality of the association between sarcopenia on lung diseases remains elusive. METHODS: The bidirectional univariate Mendelian randomization (UVMR), multivariate MR (MVMR) analysis, and mediation MR were utilized to systematically investigate the genetic causal relationship of SP and 11 respiratory diseases. Independent genomic variants related to sarcopenia or respiratory diseases were identified as instrumental variables (IVs), and the summary level data of genome-wide associated studies (GWAS) were obtained from the UK biobank and FinnGen. MVMR analysis was conducted to explore the mediation effects of body mass index (BMI), Alcohol Use Disorders Identification Test (AUDIT), smoking, education attainment (EA), physical activity, and Type 2 Diabetes Mellitus (T2DM). RESULTS: Forward UVMR analysis based on the primary method revealed that pneumoconiosis was associated with a higher risk of appendicular lean mass (ALM) (OR = 1.01, p = 0.03), and BMI (10.65%), smoking (10.65%), and physical activity (17.70%) had a mediating role in the effect of pneumoconiosis on ALM. In reverse MR analysis, we found that genetically predicted ALM was significantly associated with an increased risk of pulmonary embolism (PE) (OR = 1.24, p = 7.21E-05). Chronic obstructive pulmonary disease (COPD) (OR = 0.98, p = 0.002) and sarcoidosis (OR = 1.01, p = 0.004) were identified to increase the loss of left-hand grip strength (HGS). Conversely, the increase in left- HGS presented a protective effect on chronic bronchitis (CB) (OR = 0.35, p = 0.03), (OR = 0.80, p = 0.02), and asthma (OR = 0.78, p = 0.04). Similarly, the loss of the right-HGS elevated the risk of low respiratory tract infection (LRTI) (OR = 0.97, p = 0.02) and bronchiectasis (OR = 1.01, p = 0.03), which is also an independent protective factor for LRTI and asthma. In the aspects of low HGS, the risk of LRTI was increased after MVMR analysis, and the risk of sarcoidosis and pneumoconiosis was elevated in the reverse analysis. Lastly, asthma was found to be related to the loss of the usual walking pace, and the reverse MR analysis suggested a causal relationship between the usual walking pace and LRTI (OR = 0.32, p = 2.79 × 10-5), asthma (OR = 0.24, p = 2.09 × 10-6), COPD (OR = 0.22, p = 6.64 × 10-4), and PE(OR = 0.35, p = 0.03). CONCLUSIONS: This data-driven MR analysis revealed SP was bidirectional causally associated with lung diseases, providing genetic evidence for further mechanistic and clinical studies to understand the crosstalk between SP and lung diseases.

TOLLIP and MUC5B modulate the effect of ambient NO2 on respiratory symptoms in infancy.

BACKGROUND: Current knowledge suggests that the gene region containing MUC5B and TOLLIP plays a role in airway defence and airway inflammation, and hence respiratory disease. It is also known that exposure to air pollution increases susceptibility to respiratory disease. We aimed to study whether the effect of air pollutants on the immune response and respiratory symptoms in infants may be modified by polymorphisms in MUC5B and TOLLIP genes. METHODS: 359 healthy term infants from the prospective Basel-Bern Infant Lung Development (BILD) birth cohort were included in the study. The main outcome was the score of weekly assessed respiratory symptoms in the first year of life. Using the candidate gene approach, we selected 10 single nucleotide polymorphisms (SNPs) from the MUC5B and TOLLIP regions. Nitrogen dioxide (NO2) and particulate matter ≤10 µm in aerodynamic diameter (PM10) exposure was estimated on a weekly basis. We used generalised additive mixed models adjusted for known covariates. To validate our results in vitro, cells from a lung epithelial cell line were downregulated in TOLLIP expression and exposed to diesel particulate matter (DPM) and polyinosinic-polycytidylic acid. RESULTS: Significant interaction was observed between modelled air pollution (weekly NO2 exposure) and 5 SNPs within MUC5B and TOLLIP genes regarding respiratory symptoms as outcome: E.g., infants carrying minor alleles of rs5744034, rs3793965 and rs3750920 (all TOLLIP) had an increased risk of respiratory symptoms with increasing NO2 exposure. In vitro experiments showed that cells downregulated for TOLLIP react differently to environmental pollutant exposure with DPM and viral stimulation. CONCLUSION: Our findings suggest that the effect of air pollution on respiratory symptoms in infancy may be influenced by the genotype of specific SNPs from the MUC5B and TOLLIP regions. For validation of the findings, we provided in vitro evidence for the interaction of TOLLIP with air pollution.

Shared genetic aetiology of respiratory diseases: a genome-wide multitraits association analysis.

OBJECTIVE: This study aims to explore the common genetic basis between respiratory diseases and to identify shared molecular and biological mechanisms. METHODS: This genome-wide pleiotropic association study uses multiple statistical methods to systematically analyse the shared genetic basis between five respiratory diseases (asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, lung cancer and snoring) using the largest publicly available genome wide association studies summary statistics. The missions of this study are to evaluate global and local genetic correlations, to identify pleiotropic loci, to elucidate biological pathways at the multiomics level and to explore causal relationships between respiratory diseases. Data were collected from 27 November 2022 to 30 March 2023 and analysed from 14 April 2023 to 13 July 2023. MAIN OUTCOMES AND MEASURES: The primary outcomes are shared genetic loci, pleiotropic genes, biological pathways and estimates of genetic correlations and causal effects. RESULTS: Significant genetic correlations were found for 10 paired traits in 5 respiratory diseases. Cross-Phenotype Association identified 12 400 significant potential pleiotropic single-nucleotide polymorphism at 156 independent pleiotropic loci. In addition, multitrait colocalisation analysis identified 15 colocalised loci and a subset of colocalised traits. Gene-based analyses identified 432 potential pleiotropic genes and were further validated at the transcriptome and protein levels. Both pathway enrichment and single-cell enrichment analyses supported the role of the immune system in respiratory diseases. Additionally, five pairs of respiratory diseases have a causal relationship. CONCLUSIONS AND RELEVANCE: This study reveals the common genetic basis and pleiotropic genes among respiratory diseases. It provides strong evidence for further therapeutic strategies and risk prediction for the phenomenon of respiratory disease comorbidity.

The impact of PM2.5 on lung function and chronic respiratory diseases: insights from genetic evidence.

BACKGROUND: PM2.5 has been associated with various adverse health effects, particularly affecting lung function and chronic respiratory diseases. However, the genetic causality relationship between PM2.5 exposure and lung function as well as chronic respiratory diseases remains poorly understood. METHOD: We conducted a two-sample Mendelian randomization analysis to investigate the causal impact of PM2.5 on lung function and chronic respiratory diseases. Instrumental variables were carefully selected, with significance thresholds (P < 5 × 10- 8), and linkage disequilibrium with an r2 value below 0.001. Additionally, SNPs with an F-statistic exceeding 10 were included to mitigate potential bias stemming from weak instrumental variables. The primary analytical approach employed the Inverse Variance Weighted method, supplemented by the Weighted Median, MR-Egger, Simple Model, and Weighted Model. Furthermore, pleiotropy and heterogeneity were evaluated through the MR-Egger intercept test and Cochrane's Q test, with a sensitivity analysis conducted using the leave-one-out method. RESULTS: Eight SNPs significantly associated with PM2.5 exposure were identified as Instrumental variables. Mendelian randomization analysis revealed a significant causal association between PM2.5 exposure and lung function (FEV), with an OR of 0.7284 (95% CI: 0.5799-0.9150). Similarly, PM2.5 exposure demonstrated a substantial causal effect on asthma, with an OR of 1.5280 (95% CI: 1.0470-2.2299). However, no causal association was observed between PM2.5 exposure and chronic obstructive pulmonary disease, with an OR of 1.5176 (95% CI: 0.8294-2.7768). CONCLUSION: These findings emphasize the necessity for continued research efforts in environmental health to develop effective strategies for the prevention and management of chronic respiratory diseases.

CRISPR/Cas9 gene editing: a novel strategy for fighting drug resistance in respiratory disorders.

Respiratory disorders are among the conditions that affect the respiratory system. The healthcare sector faces challenges due to the emergence of drug resistance to prescribed medications for these illnesses. However, there is a technology called CRISPR/Cas9, which uses RNA to guide DNA targeting. This technology has revolutionized our ability to manipulate and visualize the genome, leading to advancements in research and treatment development. It can effectively reverse epigenetic alterations that contribute to drug resistance. Some studies focused on health have shown that targeting genes using CRISPR/Cas9 can be challenging when it comes to reducing drug resistance in patients with respiratory disorders. Nevertheless, it is important to acknowledge the limitations of this technology, such as off-target effects, immune system reactions to Cas9, and challenges associated with delivery methods. Despite these limitations, this review aims to provide knowledge about CRISPR/Cas9 genome editing tools and explore how they can help overcome resistance in patients with respiratory disorders. Additionally, this study discusses concerns related to applications of CRISPR and provides an overview of successful clinical trial studies.

Genetic perturbation of IL-6 receptor signaling pathway and risk of multiple respiratory diseases.

Dysregulation of inflammation can lead to multiple chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and asthma. Interleukin-6 (IL6) is crucial in regulating the inflammatory cascade, but the causal link between IL6 signaling downregulation and respiratory diseases risk is unclear. This study uses Mendelian randomization to examine the effects of IL6R blockade on respiratory diseases. Analyzing data from 522,681 Europeans, 26 genetic variants were obtained to mimic IL6R inhibition. Our findings show that IL6R blockade significantly reduces the risk of COPD (OR = 0.71, 95% CI = 0.60-9.84) and asthma (OR = 0.82, 95% CI = 0.74-0.90), with protective trends for bronchitis, pulmonary embolism, and lung cancer. Results were consistent across methods, with no significant heterogeneity or pleiotropy. These insights suggest IL6R downregulation as a potential therapeutic target for respiratory diseases, meriting further clinical investigation.

MicroRNA-26a in respiratory diseases: mechanisms and therapeutic potential.

MicroRNAs (miRNAs) are short, non-coding single-stranded RNA molecules approximately 22 nucleotides in length, intricately involved in post-transcriptional gene expression regulation. Over recent years, researchers have focused keenly on miRNAs, delving into their mechanisms in various diseases such as cancers. Among these, miR-26a emerges as a pivotal player in respiratory ailments such as pneumonia, idiopathic pulmonary fibrosis, lung cancer, asthma, and chronic obstructive pulmonary disease. Studies have underscored the significance of miR-26a in the pathogenesis and progression of respiratory diseases, positioning it as a promising therapeutic target. Nevertheless, several challenges persist in devising medical strategies for clinical trials involving miR-26a. In this review, we summarize the regulatory role and significance of miR-26a in respiratory diseases, and we analyze and elucidate the challenges related to miR-26a druggability, encompassing issues such as the efficiency of miR-26a, delivery, RNA modification, off-target effects, and the envisioned therapeutic potential of miR-26a in clinical settings.

Review: Opportunities and challenges for the genetic selection of dairy calf disease traits.

Interest in dairy cow health continues to grow as we better understand health's relationship with production potential and animal welfare. Over the past decade, efforts have been made to incorporate health traits into national genetic evaluations. However, they have focused on the mature cow, with calf health largely being neglected. Diarrhoea and respiratory disease comprise the main illnesses with regard to calf health. Conventional methods to control calf disease involve early separation of calves from the dam and housing calves individually. However, public concern regarding these methods, and growing evidence that these methods may negatively impact calf development, mean the dairy industry may move away from these practices. Genetic selection may be a promising tool to address these major disease issues. In this review, we examined current literature for enhancing calf health through genetics and discussed alternative approaches to improve calf health via the use of epidemiological modelling approaches, and the potential of indirectly selecting for improved calf health through improving colostrum quality. Heritability estimates on the observed scale for diarrhoea ranged from 0.03 to 0.20, while for respiratory disease, estimates ranged from 0.02 to 0.24. The breadth in these ranges is due, at least in part, to differences in disease prevalence, population structure, data editing and models, as well as data collection practices, which should be all considered when comparing literature values. Incorporation of epidemiological theory into quantitative genetics provides an opportunity to better determine the level of genetic variation in disease traits, as it accounts for disease transmission among contemporaries. Colostrum intake is a major determinant of whether a calf develops either respiratory disease or diarrhoea. Colostrum traits have the advantage of being measured and reported on a continuous scale, which removes the issues classically associated with binary disease traits. Overall, genetic selection for improved calf health is feasible. However, to ensure the maximum response, first steps by any industry members should focus efforts on standardising recording practices and encouragement of uploading information to genetic evaluation centres through herd management software, as high-quality phenotypes are the backbone of any successful breeding programme.

Farm animal exposure, respiratory illnesses, and nasal cell gene expression.

BACKGROUND: Farm exposures in early life reduce the risks for childhood allergic diseases and asthma. There is less information about how farm exposures relate to respiratory illnesses and mucosal immune development. OBJECTIVE: We hypothesized that children raised in farm environments have a lower incidence of respiratory illnesses over the first 2 years of life than nonfarm children. We also analyzed whether farm exposures or respiratory illnesses were related to patterns of nasal cell gene expression. METHODS: The Wisconsin Infant Study Cohort included farm (n = 156) and nonfarm (n = 155) families with children followed to age 2 years. Parents reported prenatal farm and other environmental exposures. Illness frequency and severity were assessed using illness diaries and periodic surveys. Nasopharyngeal cell gene expression in a subset of 64 children at age 2 years was compared to farm exposure and respiratory illness history. RESULTS: Farm versus nonfarm children had nominally lower rates of respiratory illnesses (rate ratio 0.82 [95% CI, 0.69, 0.97]) with a stepwise reduction in illness rates in children exposed to 0, 1, or ≥2 animal species, but these trends were nonsignificant in a multivariable model. Farm exposures and preceding respiratory illnesses were positively related to nasal cell gene signatures for mononuclear cells and innate and antimicrobial responses. CONCLUSIONS: Maternal and infant exposure to farms and farm animals was associated with nonsignificant trends for reduced respiratory illnesses. Nasal cell gene expression in a subset of children suggests that farm exposures and respiratory illnesses in early life are associated with distinct patterns of mucosal immune expression.

Genetic insights into lung function inform better management of respiratory diseases.

Shrine et al.1 conducted the largest multi-ancestry genome-wide meta-analysis of lung function and identified 1,020 signals associated with lung function. These provide novel insights into the genetic underpins of lung function and may inform better clinical management of respiratory disorders.

Exploring the potential benefits of pharmacogenomics in chronic respiratory diseases.

Tweetable abstract Opportunities for pharmacogenetics implementation in chronic respiratory diseases through the employment of genotype-guided prescriptions in treating nonrespiratory comorbidities.

Hematological and gene co-expression network analyses of high-risk beef cattle defines immunological mechanisms and biological complexes involved in bovine respiratory disease and weight gain.

Bovine respiratory disease (BRD), the leading disease complex in beef cattle production systems, remains highly elusive regarding diagnostics and disease prediction. Previous research has employed cellular and molecular techniques to describe hematological and gene expression variation that coincides with BRD development. Here, we utilized weighted gene co-expression network analysis (WGCNA) to leverage total gene expression patterns from cattle at arrival and generate hematological and clinical trait associations to describe mechanisms that may predict BRD development. Gene expression counts of previously published RNA-Seq data from 23 cattle (2017; n = 11 Healthy, n = 12 BRD) were used to construct gene co-expression modules and correlation patterns with complete blood count (CBC) and clinical datasets. Modules were further evaluated for cross-populational preservation of expression with RNA-Seq data from 24 cattle in an independent population (2019; n = 12 Healthy, n = 12 BRD). Genes within well-preserved modules were subject to functional enrichment analysis for significant Gene Ontology terms and pathways. Genes which possessed high module membership and association with BRD development, regardless of module preservation ("hub genes"), were utilized for protein-protein physical interaction network and clustering analyses. Five well-preserved modules of co-expressed genes were identified. One module ("steelblue"), involved in alpha-beta T-cell complexes and Th2-type immunity, possessed significant correlation with increased erythrocytes, platelets, and BRD development. One module ("purple"), involved in mitochondrial metabolism and rRNA maturation, possessed significant correlation with increased eosinophils, fecal egg count per gram, and weight gain over time. Fifty-two interacting hub genes, stratified into 11 clusters, may possess transient function involved in BRD development not previously described in literature. This study identifies co-expressed genes and coordinated mechanisms associated with BRD, which necessitates further investigation in BRD-prediction research.

Consequences of exposure to pollutants on respiratory health: From genetic correlations to causal relationships.

Modern society grew rapidly over the last few decades and this led to an alarming increase in air pollutants and a worsening of the human health, especially in relation to the respiratory system. Indeed, chronic respiratory diseases were the third main cause of death in 2017, with over 3 million of deaths. Furthermore, the pollution has considerable consequences both for burden medical expenses and environmental. However, the mechanisms linking pollutants to the onset of these diseases remain unclear. Thus, in this study we addressed this problem through the United Kingdom BioBank database, analyzing 170 genome-wide association studies (103 related to respiratory diseases and 67 related to pollutants). We analyzed the genetic correlations and causal relationships of these traits, leveraging the summary statistics and bioinformatics packages such as Linkage Disequilibrium Score Regression and Latent Causal Variable. We obtained 158 significant genetic correlations and subsequently we analyzed them through the Latent Causal Variable analysis, obtaining 20 significant causal relationships. The most significant were between "Workplace full of chemicals or other fumes: Sometimes" and "Condition that has ever been diagnosed by a doctor: Asthma" and between "Workplace very dusty: Sometimes" and "Condition that has ever been diagnosed by a doctor: Emphysema or chronic bronchitis". Finally, we identified single nucleotide polymorphisms independently associated with sveral pollutants to analyze the genes and pathways that could be involved in the onset of the aforementioned respiratory system disorders and that could be useful clinical target. This study highlighted how crucial are the air condition of the working environments and the type of transport used in the onset of respiratory-related morbidity. Based on that, we also suggested some interventions, in order to improve quality life and develop new and eco-friendly society and life style, such as improving indoor air circulation, the use of public transport and urban reforestation.

The roles of long noncoding RNA-mediated macrophage polarization in respiratory diseases.

Macrophages play an essential role in maintaining the normal function of the innate and adaptive immune responses during host defence. Macrophages acquire diverse functional phenotypes in response to various microenvironmental stimuli, and are mainly classified into classically activated macrophages (M1) and alternatively activated macrophages (M2). Macrophage polarization participates in the inflammatory, fibrotic, and oncogenic processes of diverse respiratory diseases by changing phenotype and function. In recent decades, with the advent of broad-range profiling methods such as microarrays and next-generation sequencing, the discovery of RNA transcripts that do not encode proteins termed "noncoding RNAs (ncRNAs)" has become more easily accessible. As one major member of the regulatory ncRNA family, long noncoding RNAs (lncRNAs, transcripts >200 nucleotides) participate in multiple pathophysiological processes, including cell proliferation, differentiation, and apoptosis, and vary with different stimulants and cell types. Emerging evidence suggests that lncRNAs account for the regulation of macrophage polarization and subsequent effects on respiratory diseases. In this review, we summarize the current published literature from the PubMed database concerning lncRNAs relevant to macrophage polarization and the underlying molecular mechanisms during the occurrence and development of respiratory diseases. These differentially expressed lncRNAs are expected to be biomarkers and targets for the therapeutic regulation of macrophage polarization during disease development.

Prevalence of monogenic disease in paediatric patients with a predominant respiratory phenotype.

OBJECTIVE: This study aimed to investigate the prevalence and clinical characteristics of monogenic disease in paediatric patients with a predominant respiratory phenotype. METHODS: Exome sequencing was performed in a cohort of 971 children with a predominant respiratory phenotype and suspected genetic aetiology. A total of 140 positive cases were divided into subgroups based on recruitment age and the primary biological system(s) involved. RESULTS: There were 140 (14.4%) patients with a positive molecular diagnosis, and their primary clinical manifestations were respiratory distress (12.9%, 18 of 140), respiratory failure (12.9%, 18 of 140) and recurrent/persistent lower respiratory infections (66.4%, 93 of 140). Primary immunodeficiency (49.3%), multisystem malformations/syndromes (17.9%), and genetic lung disease (16.4%) were the three most common genetic causes in the cohort, and they varied among the age subgroups. A total of 72 (51.4%) patients had changes in medical management strategies after genetic diagnosis, and the rate in those with genetic lung disease (82.6%, 19 of 23) was far higher than that in patients with genetic disease with lung involvement (45.3%, 53 of 117) (p=0.001). CONCLUSION: Our findings demonstrate that exome sequencing is a valuable diagnostic tool for monogenic diseases in children with a predominant respiratory phenotype, and the genetic spectrum varies with age. Taken together, genetic diagnoses provide invaluable clinical and prognostic information that may also facilitate the development of precision medicine for paediatric patients.

Genome-wide association studies for production, respiratory disease, and immune-related traits in Landrace pigs.

Identification of a quantitative trait locus (QTL) related to a chronic respiratory disease such as Mycoplasmal pneumonia of swine (MPS) and immune-related traits is important for the genetic improvement of disease resistance in pigs. The objective of this study was to detect a novel QTL for a total of 22 production, respiratory disease, and immune-related traits in Landrace pigs. A total of 874 Landrace purebred pigs, which were selected based on MPS resistance, were genotyped using the Illumina PorcineSNP60 BeadChip. We performed single nucleotide polymorphism (SNP)-based and haplotype-based genome-wide association studies (GWAS) to detect a novel QTL and to evaluate the possibility of a pleiotropic QTL for these traits. SNP-based GWAS detected a total of six significant regions in backfat thickness, ratio of granular leucocytes to lymphatic cells, plasma concentration of cortisol at different ages, and complement alternative pathway activity in serum. The significant region detected by haplotype-based GWAS was overlapped across the region detected by SNP-based GWAS. Most of these detected QTL regions were novel regions with some candidate genes located in them. With regard to a pleiotropic QTL among traits, only three of these detected QTL regions overlapped among traits, and many detected regions independently affected the traits.

Genes, environment, and developmental timing: New insights from translational approaches to understand early origins of respiratory diseases.

Over the past decade, "omics" approaches have advanced our understanding of the molecular programming of the airways in humans. Several studies have identified potential molecular mechanisms that contribute to early life epigenetic reprogramming, including DNA methylation, histone modifications, microRNAs, and the homeostasis of the respiratory mucosa (epithelial function and microbiota). Current evidence supports the notion that early infancy is characterized by heightened susceptibility to airway genetic reprogramming in response to the first exposures in life, some of which can have life-long consequences. Here, we summarize and analyze the latest insights from studies that support a novel epigenetic paradigm centered on human maturational and developmental programs including three cardinal elements: genes, environment, and developmental timing. The combination of these factors is likely responsible for the functional trajectory of the respiratory system at the molecular, functional, and clinical levels.

TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation.

The transient receptor potential melastatin subtype 8 (TRPM8) is a cold sensor in humans, activated by low temperatures (>10, <28 °C), but also a polymodal ion channel, stimulated by voltage, pressure, cooling compounds (menthol, icilin), and hyperosmolarity. An increased number of experimental results indicate the implication of TRPM8 channels in cold thermal transduction and pain detection, transmission, and maintenance in different tissues and organs. These channels also have a repercussion on different kinds of life-threatening tumors and other pathologies, which include urinary and respiratory tract dysfunctions, dry eye disease, and obesity. This compendium firstly covers newly described papers on the expression of TRPM8 channels and their correlation with pathological states. An overview on the structural knowledge, after cryo-electron microscopy success in solving different TRPM8 structures, as well as some insights obtained from mutagenesis studies, will follow. Most recently described families of TRPM8 modulators are also covered, along with a section of molecules that have reached clinical trials. To finalize, authors provide an outline of the potential prospects in the TRPM8 field.

A human respiratory tract-associated bacterium with an extremely small genome.

Recent advances in culture-independent microbiological analyses have greatly expanded our understanding of the diversity of unculturable microbes. However, human pathogenic bacteria differing significantly from known taxa have rarely been discovered. Here, we present the complete genome sequence of an uncultured bacterium detected in human respiratory tract named IOLA, which was determined by developing a protocol to selectively amplify extremely AT-rich genomes. The IOLA genome is 303,838 bp in size with a 20.7% GC content, making it the smallest and most AT-rich genome among known human-associated bacterial genomes to our best knowledge and comparable to those of insect endosymbionts. While IOLA belongs to order Rickettsiales (mostly intracellular parasites), the gene content suggests an epicellular parasitic lifestyle. Surveillance of clinical samples provides evidence that IOLA can be predominantly detected in patients with respiratory bacterial infections and can persist for at least 15 months in the respiratory tract, suggesting that IOLA is a human respiratory tract-associated bacterium.