Time-dependent recruitment of GAF, ISGF3 and IRF1 complexes shapes IFNα and IFNγ-activated transcriptional responses and explains mechanistic and functional overlap.

To understand in detail the transcriptional and functional overlap of IFN-I- and IFN-II-activated responses, we used an integrative RNAseq-ChIPseq approach in Huh7.5 cells and characterized the genome-wide role of pSTAT1, pSTAT2, IRF9 and IRF1 in time-dependent ISG expression. For the first time, our results provide detailed insight in the timely steps of IFNα- and IFNγ-induced transcription, in which pSTAT1- and pSTAT2-containing ISGF3 and GAF-like complexes and IRF1 are recruited to individual or combined ISRE and GAS composite sites in a phosphorylation- and time-dependent manner. Interestingly, composite genes displayed a more heterogeneous expression pattern, as compared to GAS (early) and ISRE genes (late), with the time- and phosphorylation-dependent recruitment of GAF, ISGF3 and IRF1 after IFNα stimulation and GAF and IRF1 after IFNγ. Moreover, functional composite genes shared features of GAS and ISRE genes through transcription factor co-binding to closely located sites, and were able to sustain IFN responsiveness in STAT1-, STAT2-, IRF9-, IRF1- and IRF9/IRF1-mutant Huh7.5 cells compared to Wt cells. Thus, the ISRE + GAS composite site acted as a molecular switch, depending on the timely available components and transcription factor complexes. Consequently, STAT1, STAT2 and IRF9 were identified as functional composite genes that are part of a positive feedback loop controlling long-term IFNα and IFNγ responses. More important, in the absence of any one of the components, the positive feedback regulation of the ISGF3 and GAF components appeared to be preserved. Together, these findings provide further insight in the existence of a novel ISRE + GAS composite-dependent intracellular amplifier circuit prolonging ISG expression and controlling cellular responsiveness to different types of IFNs and subsequent antiviral activity. It also offers an explanation for the existing molecular and functional overlap between IFN-I- and IFN-II-activated ISG expression.

Untangling determinants of gut microbiota and tumor immunologic status through a multi-omics approach in colorectal cancer.

The changes in gut microbiota have been implicated in colorectal cancer (CRC). The interplays between the host and gut microbiota remain largely unclear, and few studies have investigated these interplays using integrative multi-omics data. In this study, large-scale multi-comic datasets, including microbiome, metabolome, bulk transcriptomics and single cell RNA sequencing of CRC patients, were analyzed individually and integrated through advanced bioinformatics methods. We further examined the clinical relevance of these findings in the mice recolonized with microbiota from human. We found that CRC patients had distinct microbiota compositions compared to healthy controls. A machine-learning model was developed with 28 biomarkers for detection of CRC, which had high accuracy and clinical applicability. We identified multiple significant correlations between genera and well-characterized genes, suggesting the potential role of gut microbiota in tumor immunity. Further analysis showed that specific metabolites worked as profound communicators between these genera and tumor immunity. Integrating microbiota and metabolome perspectives, we cataloged gut taxonomic and metabolomic features that represented the key multi-omics signature of CRC. Furthermore, gut microbiota transplanted from CRC patients compromised the response of CRC to immunotherapy. These phenotypes were strongly associated with the alterations in gut microbiota, immune cell infiltration as well as multiple metabolic pathways. The comprehensive interplays across multi-comic data of CRC might explain how gut microbiota influenced tumor immunity. Hence, we proposed that modifying the CRC microbiota using healthy donors might serve as a promising strategy to improve response to immunotherapy.

Hematologic Neoplasms Associated with Down Syndrome: Cellular and Molecular Heterogeneity of the Diseases.

The molecular basis of Down syndrome (DS) predisposition to leukemia is not fully understood but involves various factors such as chromosomal abnormalities, oncogenic mutations, epigenetic alterations, and changes in selection dynamics. Myeloid leukemia associated with DS (ML-DS) is preceded by a preleukemic phase called transient abnormal myelopoiesis driven by GATA1 gene mutations and progresses to ML-DS via additional mutations in cohesin genes, CTCF, RAS, or JAK/STAT pathway genes. DS-related ALL (ALL-DS) differs from non-DS ALL in terms of cytogenetic subgroups and genetic driver events, and the aberrant expression of CRLF2, JAK2 mutations, and RAS pathway-activating mutations are frequent in ALL-DS. Recent advancements in single-cell multi-omics technologies have provided unprecedented insights into the cellular and molecular heterogeneity of DS-associated hematologic neoplasms. Single-cell RNA sequencing and digital spatial profiling enable the identification of rare cell subpopulations, characterization of clonal evolution dynamics, and exploration of the tumor microenvironment's role. These approaches may help identify new druggable targets and tailor therapeutic interventions based on distinct molecular profiles, ultimately improving patient outcomes with the potential to guide personalized medicine approaches and the development of targeted therapies.

ISGF3 and STAT2/IRF9 Control Basal and IFN-Induced Transcription through Genome-Wide Binding of Phosphorylated and Unphosphorylated Complexes to Common ISRE-Containing ISGs.

In addition to the canonical ISGF3 and non-canonical STAT2/IRF9 complexes, evidence is emerging of the role of their unphosphorylated counterparts in IFN-dependent and -independent ISG transcription. To better understand the relation between ISGF3 and U-ISGF3 and STAT2/IRF9 and U-STAT2/IRF9 in IFN-I-stimulated transcriptional responses, we performed RNA-Seq and ChIP-Seq, in combination with phosphorylation inhibition and antiviral experiments. First, we identified a group of ISRE-containing ISGs that were commonly regulated in IFNα-treated WT and STAT1-KO cells. Thus, in 2fTGH and Huh7.5 WT cells, early and long-term IFNα-inducible transcription and antiviral activity relied on the DNA recruitment of the ISGF3 components STAT1, STAT2 and IRF9 in a phosphorylation- and time-dependent manner. Likewise, in ST2-U3C and Huh-STAT1KO cells lacking STAT1, delayed IFN responses correlated with DNA binding of phosphorylated STAT2/IRF9 but not U-STAT2/IRF9. In addition, comparative experiments in U3C (STAT1-KO) cells overexpressing all the ISGF3 components (ST1-ST2-IRF9-U3C) revealed U-ISGF3 (and possibly U-STAT2/IRF9) chromatin interactions to correlate with phosphorylation-independent ISG transcription and antiviral activity. Together, our data point to the dominant role of the canonical ISGF3 and non-canonical STAT2/IRF9, without a shift to U-ISGF3 or U-STAT2/IRF9, in the regulation of early and prolonged ISG expression and viral protection. At the same time, they suggest the threshold-dependent role of U-ISFG3, and potentially U-STAT2/IRF9, in the regulation of constitutive and possibly long-term IFNα-dependent responses.

Unmet needs in pneumonia research: a comprehensive approach by the CAPNETZ study group.

INTRODUCTION: Despite improvements in medical science and public health, mortality of community-acquired pneumonia (CAP) has barely changed throughout the last 15 years. The current SARS-CoV-2 pandemic has once again highlighted the central importance of acute respiratory infections to human health. The "network of excellence on Community Acquired Pneumonia" (CAPNETZ) hosts the most comprehensive CAP database worldwide including more than 12,000 patients. CAPNETZ connects physicians, microbiologists, virologists, epidemiologists, and computer scientists throughout Europe. Our aim was to summarize the current situation in CAP research and identify the most pressing unmet needs in CAP research. METHODS: To identify areas of future CAP research, CAPNETZ followed a multiple-step procedure. First, research members of CAPNETZ were individually asked to identify unmet needs. Second, the top 100 experts in the field of CAP research were asked for their insights about the unmet needs in CAP (Delphi approach). Third, internal and external experts discussed unmet needs in CAP at a scientific retreat. RESULTS: Eleven topics for future CAP research were identified: detection of causative pathogens, next generation sequencing for antimicrobial treatment guidance, imaging diagnostics, biomarkers, risk stratification, antiviral and antibiotic treatment, adjunctive therapy, vaccines and prevention, systemic and local immune response, comorbidities, and long-term cardio-vascular complications. CONCLUSION: Pneumonia is a complex disease where the interplay between pathogens, immune system and comorbidities not only impose an immediate risk of mortality but also affect the patients' risk of developing comorbidities as well as mortality for up to a decade after pneumonia has resolved. Our review of unmet needs in CAP research has shown that there are still major shortcomings in our knowledge of CAP.

Laparoscopic Sleeve Gastrectomy in Patients with Severe Obesity Restores Adaptive Responses Leading to Nonalcoholic Steatohepatitis.

The surgically induced remission of liver disease represents a model to investigate the signalling processes that trigger the development of nonalcoholic steatohepatitis with the aim of identifying novel therapeutic targets. We recruited patients with severe obesity with or without nonalcoholic steatohepatitis and obtained liver and plasma samples before and after laparoscopic sleeve gastrectomy for immunoblotting, immunocytochemical, metabolomic, transcriptomic and epigenetic analyses. Functional studies were performed in HepG2 cells and primary hepatocytes. Surgery was associated with a decrease in the inflammatory response and revealed the role of mitogen-activated protein kinases. Nonalcoholic steatohepatitis was associated with an increased glutaminolysis-induced production of α-ketoglutarate and the hyperactivation of mammalian target of rapamycin complex 1. These changes were crucial for adenosine monophosphate-activated protein kinase/mammalian target of rapamycin-driven pathways that modulated hepatocyte survival by coordinating apoptosis and autophagy and affected methylation-related epigenomic remodelling enzymes. Hepatic transcriptome signatures and differentially methylated genomic regions distinguished patients with and without steatohepatitis. Our results suggest that the increased glutaminolysis-induced α-ketoglutarate production and the mammalian target of rapamycin complex 1 dysregulation play a crucial role in the inefficient adaptive responses leading to steatohepatitis in obesity.

Glutaminolysis-induced mTORC1 activation drives non-alcoholic steatohepatitis progression.

BACKGROUND & AIMS: A holistic insight on the relationship between obesity and metabolic dysfunction-associated fatty liver disease is an unmet clinical need. Omics investigations can be used to investigate the multifaceted role of altered mitochondrial pathways to promote nonalcoholic steatohepatitis, a major risk factor for liver disease-associated death. There are no specific treatments but remission via surgery might offer an opportunity to examine the signaling processes that govern the complex spectrum of chronic liver diseases observed in extreme obesity. We aim to assess the emerging relationship between metabolism, methylation and liver disease. METHODS: We tailed the flow of information, before and after steatohepatitis remission, from biochemical, histological, and multi-omics analyses in liver biopsies from patients with extreme obesity and successful bariatric surgery. Functional studies were performed in HepG2 cells and primary hepatocytes. RESULTS: The reversal of hepatic mitochondrial dysfunction and the control of oxidative stress and inflammatory responses revealed the regulatory role of mitogen-activated protein kinases. The reversible metabolic rearrangements leading to steatohepatitis increased the glutaminolysis-induced production of α-ketoglutarate and the hyperactivation of mammalian target of rapamycin complex 1. These changes were crucial for the adenosine monophosphate-activated protein kinase/mammalian target of rapamycin-driven pathways that modulated hepatocyte survival by coordinating apoptosis and autophagy. The signaling activity of α-ketoglutarate and the associated metabolites also affected methylation-related epigenomic remodeling enzymes. Integrative analysis of hepatic transcriptome signatures and differentially methylated genomic regions distinguished patients with and without steatohepatitis. CONCLUSION: We provide evidence supporting the multifaceted potential of the increased glutaminolysis-induced α-ketoglutarate production and the mammalian target of rapamycin complex 1 dysregulation as a conceivable source of the inefficient adaptive responses leading to steatohepatitis. LAY SUMMARY: Steatohepatitis is a frequent and threatening complication of extreme obesity without specific treatment. Omics technologies can be used to identify therapeutic targets. We highlight increased glutaminolysis-induced α-ketoglutarate production as a potential source of signals promoting and exacerbating steatohepatitis.

Integrative analysis of the nuclear proteome in Pinus radiata reveals thermopriming coupled to epigenetic regulation.

Despite it being an important issue in the context of climate change, for most plant species it is not currently known how abiotic stresses affect nuclear proteomes and mediate memory effects. This study examines how Pinus radiata nuclei respond, adapt, 'remember', and 'learn' from heat stress. Seedlings were heat-stressed at 45 °C for 10 d and then allowed to recover. Nuclear proteins were isolated and quantified by nLC-MS/MS, the dynamics of tissue DNA methylation were examined, and the potential acquired memory was analysed in recovered plants. In an additional experiment, the expression of key gene genes was also quantified. Specific nuclear heat-responsive proteins were identified, and their biological roles were evaluated using a systems biology approach. In addition to heat-shock proteins, several clusters involved in regulation processes were discovered, such as epigenomic-driven gene regulation, some transcription factors, and a variety of RNA-associated functions. Nuclei exhibited differential proteome profiles across the phases of the experiment, with histone H2A and methyl cycle enzymes in particular being accumulated in the recovery step. A thermopriming effect was possibly linked to H2A abundance and over-accumulation of spliceosome elements in recovered P. radiata plants. The results suggest that epigenetic mechanisms play a key role in heat-stress tolerance and priming mechanisms.

Exomic and transcriptomic alterations of hereditary gingival fibromatosis.

OBJECTIVE: Hereditary gingival fibromatosis (HGF) is a rare oral disease characterized by either localized or generalized gradual, benign, non-hemorrhagic enlargement of gingivae. Although several genetic causes of HGF are known, the genetic etiology of HGF as a non-syndromic and idiopathic entity remains uncertain. SUBJECTS AND METHODS: We performed exome and RNA-seq of idiopathic HGF patients and controls, and then devised a computational framework that specifies exomic/transcriptomic alterations interconnected by a regulatory network to unravel genetic etiology of HGF. Moreover, given the lack of animal model or large-scale cohort data of HGF, we developed a strategy to cross-check their clinical relevance through in silico gene-phenotype mapping with biomedical literature mining and semantic analysis of disease phenotype similarities. RESULTS: Exomic variants and differentially expressed genes of HGF were connected by members of TGF-ß/SMAD signaling pathway and craniofacial development processes, accounting for the molecular mechanism of fibroblast overgrowth mimicking HGF. Our cross-check supports that genes derived from the regulatory network analysis have pathogenic roles in fibromatosis-related diseases. CONCLUSIONS: The computational approach of connecting exomic and transcriptomic alterations through regulatory networks is applicable in the clinical interpretation of genetic variants in HGF patients.

MicroRNAs in Marchantia polymorpha.

Contents Summary 409 I. Introduction 409 II. RNA silencing machinery in Marchantia polymorpha 410 III. miRNA prediction by integrating omics approach 410 IV. miRNAs and their targets in Marchantia polymorpha 410 V. Mpo-miR390-mediated MpTAS3 tasiRNA biogenesis and potential tasiARF target MpARF2 414 VI. Artificial miRNA and CRISPR-CAS9 edited MIR gene in Marchantia polymorpha 414 VII. Conclusions 415 Acknowledgements 415 References 415 SUMMARY: The liverwort Marchantia polymorpha occupies an important phylogenetic position for comparative studies of land plant gene regulation. Multiple gene regulatory pathways mediated by small RNAs, including microRNAs (miRNAs), trans-acting short-interfering RNAs, and heterochromatic siRNAs often associated with RNA-dependent DNA methylation, have been characterized in flowering plants. Genes for essential components for all of these small RNA-mediated gene silencing pathways are found in M. polymorpha as well as the moss Phsycomitrella patens, indicating that these pathways existed in the ancestral land plant. However, only seven miRNAs are conserved across land plants, with both ancestral and novel targets identified in M. polymorpha. There is little or no evidence that any of these conserved miRNAs are present in algae. As with other plants investigated, most miRNAs in M. polypmorpha exhibit lineage-specific evolution. Application of artificial miRNA and CRISPR-Cas9 technologies in genetic studies of M. polymorpha provide avenues to further investigate miRNA biology.

Symposium review: Understanding diet-microbe interactions to enhance productivity of dairy cows.

Ruminants are dependent on the microbiota (bacteria, protozoa, archaea, and fungi) that inhabit the reticulo-rumen for digestion of feedstuffs. Nearly 70% of energy and 50% of protein requirements for dairy cows are met by microbial fermentation in the rumen, emphasizing the need to characterize the role of microbes in feed breakdown and nutrient utilization. Over the past 2 decades, next-generation sequencing technologies have allowed for rapid expansion of knowledge concerning microbial populations and alterations in response to forages, concentrates, supplements, and probiotics in the rumen. Advances in gene sequencing and emerging bioinformatic tools have allowed for increased throughput of data to aid in our understanding of the functional relevance of microbial genomes. In particular, metagenomics can identify specific genes involved in metabolic pathways, and metatranscriptomics can describe the transcriptional activity of microbial genes. These powerful approaches help untangle the complex interactions between microbes and dietary nutrients so that we can more fully understand the physiology of feed digestion in the rumen. Application of genomics-based approaches offers promise in unraveling microbial niches and respective gene repertoires to potentiate fiber and nonfiber carbohydrate digestion, microbial protein synthesis, and healthy biohydrogenation. New information on microbial genomics and interactions with dietary components will more clearly define pathways in the rumen to positively influence milk yield and components.

Jivamrit as a Sustainable Approach: A Review of Natural Farming and Future Agriculture.

Green Revolution aims to boost food production and feed millions of Indians, but it also has negative effects on agriculture and society's health. Natural manures like cow dung and cow urine can counteract the adverse effects of inorganic fertilizer on soil along with improving physicochemical qualities, maintaining the soil quality, and increasing crop output. Zero Budget Natural Farming (ZBNF) formulations like Jivamrit promote soil health and microbial activities and are an excellent source of macronutrients, other micronutrients needed for plant growth, plus adds beneficial microbes, nitrogen (N2), phosphorus (P), potassium (K), and natural carbon (C). Further, conventional agricultural methods, like monocropping and heavy tillage, can damage soil bacteria which contributes to sustainable agriculture through nitrogen fixation, siderophore synthesis and nutrient absorption. A sustainable agricultural system is resource-efficient, socially and commercially competitive, ecologically sound, and supportive of society. Jivamrit, a natural organic manure, is gaining interest due to concerns about the sustainability of input-intensive agriculture systems. It promotes crop growth, quality, and yield, enhances soil pH, population, and activity of beneficial microorganisms, and helps with nitrogen fixation, phosphate solubili-zation, and easy decomposition. Long-term use of Jivamrit, may disrupt soil microbial balance, may leading to overpopulation of certain species. The current review on the Jivamrit emphasizes on the biological and chemical characterization and its significance to the agriculture.

Biomarkers for Health Functional Foods in Metabolic Dysfunction-Associated Steatotic Liver Disorder (MASLD) Prevention: An Integrative Analysis of Network Pharmacology, Gut Microbiota, and Multi-Omics.

Metabolic dysfunction-associated steatotic liver disorder (MASLD) is increasingly prevalent globally, highlighting the need for preventive strategies and early interventions. This comprehensive review explores the potential of health functional foods (HFFs) to maintain healthy liver function and prevent MASLD through an integrative analysis of network pharmacology, gut microbiota, and multi-omics approaches. We first examined the biomarkers associated with MASLD, emphasizing the complex interplay of genetic, environmental, and lifestyle factors. We then applied network pharmacology to identify food components with potential beneficial effects on liver health and metabolic function, elucidating their action mechanisms. This review identifies and evaluates strategies for halting or reversing the development of steatotic liver disease in the early stages, as well as biomarkers that can evaluate the success or failure of such strategies. The crucial role of the gut microbiota and its metabolites for MASLD prevention and metabolic homeostasis is discussed. We also cover state-of-the-art omics approaches, including transcriptomics, metabolomics, and integrated multi-omics analyses, in research on preventing MASLD. These advanced technologies provide deeper insights into physiological mechanisms and potential biomarkers for HFF development. The review concludes by proposing an integrated approach for developing HFFs targeting MASLD prevention, considering the Korean regulatory framework. We outline future research directions that bridge the gap between basic science and practical applications in health functional food development. This narrative review provides a foundation for researchers and food industry professionals interested in developing HFFs to support liver health. Emphasis is placed on maintaining metabolic balance and focusing on prevention and early-stage intervention strategies.

Advantages of omics approaches for elucidating metabolic changes in diabetic peripheral neuropathy.

Various animal and cell culture models of diabetes mellitus (DM) have been established and utilized to study diabetic peripheral neuropathy (DPN). The divergence of metabolic abnormalities among these models makes their etiology complicated despite some similarities regarding the pathological and neurological features of DPN. Thus, this study aimed to review the omics approaches toward DPN, especially on the metabolic states in diabetic rats and mice induced by chemicals (streptozotocin and alloxan) as type 1 DM models and by genetic mutations (MKR, db/db and ob/ob) and high-fat diet as type 2 DM models. Omics approaches revealed that the pathways associated with lipid metabolism and inflammation in dorsal root ganglia and sciatic nerves were enriched and controlled in the levels of gene expression among these animal models. Additionally, these pathways were conserved in human DPN, indicating the pivotal pathogeneses of DPN. Omics approaches are beneficial tools to better understand the association of metabolic changes with morphological and functional abnormalities in DPN.

Role of Epigenetics and Metabolomics in Predicting Endothelial Dysfunction in Type 2 Diabetes.

Type 2 diabetes (T2D) is a worldwide health problem and cardiovascular disease (CVD) is a leading cause of morbidity and mortality in T2D patients, making the prevention of CVD onset a major priority. It is therefore crucial to optimize diagnosis and treatment to reduce this burden. Endothelial dysfunction is one of the most important prognostic factors for CVD progression, thus novel approaches to identify the early phase of endothelial dysfunction may lead to specific preventive measures to reduce the occurrence of CVD. Nowadays, multiomics approaches have provided unprecedented opportunities to stratify T2D patients into endotypes, improve therapeutic treatment and outcome and amend the survival prediction. Among omics strategies, epigenetics and metabolomics are gaining increasing interest. Recently, a dynamic correlation between metabolic pathways and gene expression through chromatin remodeling, such as DNA methylation, has emerged, indicating new perspectives on the regulatory networks impacting cellular processes. Thus, a better understanding of epigenetic-metabolite relationships can provide insight into the physiological processes altered early in the endothelium that ultimately head to disease development. Here, recent studies on epigenetics and metabolomics related to CVD prevention potentially useful to identify disease biomarkers, as well as new therapies hopefully targeting the early phase of endothelial dysfunction are highlighted.

Biotechnological and Biocontrol Approaches for Mitigating Postharvest Diseases Caused by Fungal Pathogens and Their Mycotoxins in Fruits: A Review.

Postharvest diseases caused by fungal pathogens are significant contributors to the postharvest losses of fruits. Moreover, some fungal pathogens produce mycotoxins, which further compromise the safety and quality of fruits. In this review, the potential of biotechnological and biocontrol approaches for mitigating postharvest diseases and mycotoxins in fruits is explored. The review begins by discussing the impact of postharvest diseases on fruit quality and postharvest losses. Next, it provides an overview of major postharvest diseases caused by fungal pathogens. Subsequently, it delves into the role of biotechnological approaches in controlling these diseases. The review also explored the application of biocontrol agents, such as antagonistic yeasts, bacteria, and fungi, which can suppress pathogen growth. Furthermore, future trends and challenges in these two approaches are discussed in detail. Overall, this review can provide insights into promising biotechnological and biocontrol strategies for managing postharvest diseases and mycotoxins in fruits.

Advances of herbivore-secreted elicitors and effectors in plant-insect interactions.

Diverse molecular processes regulate the interactions between insect herbivores and their host plants. When plants are exposed to insects, elicitors induce plant defenses, and complex physiological and biochemical processes are triggered, such as the activation of the jasmonic acid (JA) and salicylic acid (SA) pathways, Ca2+ flux, reactive oxygen species (ROS) burst, mitogen-activated protein kinase (MAPK) activation, and other responses. For better adaptation, insects secrete a large number of effectors to interfere with plant defenses on multiple levels. In plants, resistance (R) proteins have evolved to recognize effectors and trigger stronger defense responses. However, only a few effectors recognized by R proteins have been identified until now. Multi-omics approaches for high-throughput elicitor/effector identification and functional characterization have been developed. In this review, we mainly highlight the recent advances in the identification of the elicitors and effectors secreted by insects and their target proteins in plants and discuss their underlying molecular mechanisms, which will provide new inspiration for controlling these insect pests.

The impact of genomic variants on patient response to inhaled bronchodilators: a comprehensive update.

INTRODUCTION: The bronchodilator response (BDR) depends on many factors, including genetic ones. Numerous single nucleotide polymorphisms (SNPs) influencing BDR have been identified. However, despite several studies in this field, genetic variations are not currently being utilized to support the use of bronchodilators. AREAS COVERED: In this narrative review, the possible impact of genetic variants on BDR is discussed. EXPERT OPINION: Pharmacogenetic studies of ß2-agonists have mainly focused on ADRB2 gene. Three SNPs, A46G, C79G, and C491T, have functional significance. However, other uncommon variants may contribute to individual variability in salbutamol response. SNPs haplotypes in ADRB2 may have a role. Many variants in gene coding for muscarinic ACh receptor (mAChR) have been reported, particularly in the M2 and, to a lesser degree, M3 mAChRs, but no consistent evidence for a pharmacological relevance of these SNPs has been reported. Moreover, there is a link between SNPs and ethnic and/or age profiles regarding BDR. Nevertheless, replication of pharmacogenetic results is limited and often, BDR is dissociated from what is expected based on SNP identification. Pharmacogenetic studies on bronchodilators must continue. However, they must integrate data derived from a multi-omics approach with epigenetic factors that may modify BDR.

[Opportunities of multi-omics approach for the search for new diagnostic and therapeutic targets in multiple sclerosis]. / Perspektivy primeneniya mul'tiomiksnogo podkhoda dlya poiska novykh diagnosticheskikh assotsiatsii i terapevticheskikh mishenei pri rasseyannom skleroze.

Multiple sclerosis is an extremely heterogeneous disease and, despite intensive research, no selective biomarkers have been identified for this pathology, and therefore its diagnosis in the early stages is still challenging. One of the most powerful tools for studying the pathogenesis of multiple sclerosis is the multi-omics approach, which makes it possible to characterize cells involved in the disease progression in the most detailed and versatile way. This review will describe the current directions of research in multiple sclerosis using high-throughput technologies. Also, an assessment of the demand for the use of a multi-omics approach was carried out.

Exploring Newer Biosynthetic Gene Clusters in Marine Microbial Prospecting.

Marine microbes genetically evolved to survive varying salinity, temperature, pH, and other stress factors by producing different bioactive metabolites. These microbial secondary metabolites (SMs) are novel, have high potential, and could be used as lead molecule. Genome sequencing of microbes revealed that they have the capability to produce numerous novel bioactive metabolites than observed under standard in vitro culture conditions. Microbial genome has specific regions responsible for SM assembly, termed biosynthetic gene clusters (BGCs), possessing all the necessary genes to encode different enzymes required to generate SM. In order to augment the microbial chemo diversity and to activate these gene clusters, various tools and techniques are developed. Metagenomics with functional gene expression studies aids in classifying novel peptides and enzymes and also in understanding the biosynthetic pathways. Genome shuffling is a high-throughput screening approach to improve the development of SMs by incorporating genomic recombination. Transcriptionally silent or lower level BGCs can be triggered by artificially knocking promoter of target BGC. Additionally, bioinformatic tools like antiSMASH, ClustScan, NAPDOS, and ClusterFinder are effective in identifying BGCs of existing class for annotation in genomes. This review summarizes the significance of BGCs and the different approaches for detecting and elucidating BGCs from marine microbes.