Transcriptomics- and Genomics-Guided Drug Repurposing for the Treatment of Vesicular Hand Eczema.

Vesicular hand eczema (VHE), a clinical subtype of hand eczema (HE), showed limited responsiveness to alitretinoin, the only approved systemic treatment for severe chronic HE. This emphasizes the need for alternative treatment approaches. Therefore, our study aimed to identify drug repurposing opportunities for VHE using transcriptomics and genomics data. We constructed a gene network by combining 52 differentially expressed genes (DEGs) from a VHE transcriptomics study with 3 quantitative trait locus (QTL) genes associated with HE. Through network analysis, clustering, and functional enrichment analyses, we investigated the underlying biological mechanisms of this network. Next, we leveraged drug-gene interactions and retrieved pharmaco-transcriptomics data from the DrugBank database to identify drug repurposing opportunities for (V)HE. We developed a drug ranking system, primarily based on efficacy, safety, and practical and pricing factors, to select the most promising drug repurposing candidates. Our results revealed that the (V)HE network comprised 78 genes that yielded several biological pathways underlying the disease. The drug-gene interaction search together with pharmaco-transcriptomics lookups revealed 123 unique drug repurposing opportunities. Based on our drug ranking system, our study identified the most promising drug repurposing opportunities (e.g., vitamin D analogues, retinoids, and immunomodulating drugs) that might be effective in treating (V)HE.

Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits.

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

Antifungal activity of Fe3O4@SiO2/Schiff-base/Cu(II) magnetic nanoparticles against pathogenic Candida species.

The antifungal efficacy and cytotoxicity of a novel nano-antifungal agent, the Fe3O4@SiO2/Schiff-base complex of Cu(II) magnetic nanoparticles (MNPs), have been assessed for targeting drug-resistant Candida species. Due to the rising issue of fungal infections, especially candidiasis, and resistance to traditional antifungals, there is an urgent need for new therapeutic strategies. Utilizing Schiff-base ligands known for their broad-spectrum antimicrobial activity, the Fe3O4@SiO2/Schiff-base/Cu(II) MNPs have been synthesized. The Fe3O4@SiO2/Schiff-base/Cu(II) MNPs was characterized by Fourier Transform-Infrared Spectroscopy (FT-IR), X-ray Diffraction (XRD), Transmission Electron Microscopy (TEM), Scanning Electron Microscopy (SEM), Dynamic Light Scattering (DLS), Energy-dispersive X-ray (EDX), Vibrating Sample Magnetometer (VSM), and Thermogravimetric analysis (TGA), demonstrating successful synthesis. The antifungal potential was evaluated against six Candida species (C. dubliniensis, C. krusei, C. tropicalis, C. parapsilosis, C. glabrata, and C. albicans) using the broth microdilution method. The results indicated strong antifungal activity in the range of 8-64 µg/mL with the lowest MIC (8 µg/mL) observed against C. parapsilosis. The result showed the MIC of 32 µg/mL against C. albicans as the most common infection source. The antifungal mechanism is likely due to the disruption of the fungal cell wall and membrane, along with increased reactive oxygen species (ROS) generation leading to cell death. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay for cytotoxicity on mouse L929 fibroblastic cells suggested low toxicity and even enhanced cell proliferation at certain concentrations. This study demonstrates the promise of Fe3O4@SiO2/Schiff-base/Cu(II) MNPs as a potent antifungal agent with potential applications in the treatment of life-threatening fungal infections, healthcare-associated infections, and beyond.

A genome-wide association meta-analysis implicates Hedgehog and Notch signaling in Dupuytren's disease.

Dupuytren's disease (DD) is a highly heritable fibrotic disorder of the hand with incompletely understood etiology. A number of genetic loci, including Wnt signaling members, have been previously identified. Our overall aim was to identify novel genetic loci, to prioritize genes within the loci for functional studies, and to assess genetic correlation with associated disorders. We performed a meta-analysis of six DD genome-wide association studies from three European countries and extensive bioinformatic follow-up analyses. Leveraging 11,320 cases and 47,023 controls, we identified 85 genome-wide significant single nucleotide polymorphisms in 56 loci, of which 11 were novel, explaining 13.3-38.1% of disease variance. Gene prioritization implicated the Hedgehog and Notch signaling pathways. We also identified a significant genetic correlation with frozen shoulder. The pathways identified highlight the potential for new therapeutic targets and provide a basis for additional mechanistic studies for a common disorder that can severely impact hand function.

The Need for Smart Materials in an Expanding Smart World: MXene-Based Wearable Electronics and Their Advantageous Applications.

As a result of the transformation of inflexible electronic structures into flexible and stretchy devices, wearable electronics now provide great advantages in a variety of fields, including mobile healthcare sensing and monitoring, human-machine interfaces, portable energy storage and harvesting, and more. Because of their enriched surface functionalities, large surface area, and high electrical conductivity, transition metal nitrides and carbides (also known as MXenes) have recently come to be extensively considered as a group of functioning two-dimensional nanomaterials as well as exceptional fundamental elements for forming flexible electronics devices. This Review discusses the most recent advancements that have been made in the field of MXene-enabled flexible electronics for wearable electronics. The emphasis is placed on extensively established nonstructural features in order to highlight some MXene-enabled electrical devices that were constructed on a nanometric scale. These attributes include devices configured in three dimensions: printed materials, bioinspired structures, and textile and planar substrates. In addition, sample applications in electromagnetic interference (EMI) shielding, energy, healthcare, and humanoid control of machinery illustrate the exceptional development of these nanodevices. The increasing potential of MXene nanoparticles as a new area in next-generation wearable electronic technologies is projected in this Review. The design challenges associated with these electronic devices are also discussed, and possible solutions are presented.

Nanofibrous polycaprolactone/gelatin scaffold containing gold nanoparticles: Physicochemical and biological characterization for wound healing.

In this study, gold nanoparticles were loaded into poly (ε-caprolactone) (PCL)/gelatin nanofibrous matrices to fabricate a potential wound dressing. The mats were produced by electrospinning of PCL/gelatin solution supplemented with synthesized gold nanoparticles (200, 400 and 800 ppm). Prepared scaffolds were investigated regarding their chemical properties, morphology, mechanical properties, surface wettability, water-uptake capacity, water vapor permeability, porosity, blood compatibility, microbial penetration test and cellular response. In addition to in vivo study, a full-thickness excisional wound in a rat model was used to evaluate the healing effect of prepared scaffolds. Results showed appropriate mechanical properties and porosity of prepared scaffolds. With L929 cells, the PCL/gelatin scaffold containing 400 ppm gold nanoparticles demonstrated the greatest cell growth. In vivo results validated the favorable wound-healing benefits of the scaffold incorporating gold nanoparticles, which triggered wound healing compared to sterile gauze. Our results showed the capability of nanofibrous matrices containing gold nanoparticles for successful wound treatment.

Exploring new subgroups for irritable bowel syndrome using a machine learning algorithm.

Irritable bowel syndrome (IBS) is a complicated gut-brain axis disorder that has typically been classified into subgroups based on the major abnormal stool consistency and frequency. The presence of components other than lower gastrointestinal (GI) symptoms, such as psychological burden, has also been observed in IBS manifestations. The purpose of this research is to redefine IBS subgroups based on upper GI symptoms and psychological factors in addition to lower GI symptoms using an unsupervised machine learning algorithm. The clustering of 988 individuals who met the Rome III criteria for diagnosis of IBS was performed using a mixed-type data clustering algorithm. Nine sub-groups emerged from the proposed clustering: (I) High diarrhea, pain, and psychological burden, (II) High upper GI, moderate lower GI, and psychological burden, (III) High psychological burden and moderate overall GI, (IV) High constipation, moderate upper GI, and high psychological burden, (V) moderate constipation and low psychological burden, (VI) High diarrhea and moderate psychological burden, (VII) moderate diarrhea and low psychological burden, (VIII) Low overall GI, and psychological burden, (IX) Moderate lower GI, and low psychological burden. The proposed procedure led to the discovery of new homogeneous clusters in addition to certain well-known Rome sub-types for IBS.

Re-investigation of functional gastrointestinal disorders utilizing a machine learning approach.

BACKGROUND: Functional gastrointestinal disorders (FGIDs), as a group of syndromes with no identified structural or pathophysiological biomarkers, are currently classified by Rome criteria based on gastrointestinal symptoms (GI). However, the high overlap among FGIDs in patients makes treatment and identifying underlying mechanisms challenging. Furthermore, disregarding psychological factors in the current classification, despite their approved relationship with GI symptoms, underlines the necessity of more investigation into grouping FGID patients. We aimed to provide more homogenous and well-separated clusters based on both GI and psychological characteristics for patients with FGIDs using an unsupervised machine learning algorithm. METHODS: Based on a cross-sectional study, 3765 (79%) patients with at least one FGID were included in the current study. In the first step, the clustering utilizing a machine learning algorithm was merely executed based on GI symptoms. In the second step, considering the previous step's results and focusing on the clusters with a diverse combination of GI symptoms, the clustering was re-conducted based on both GI symptoms and psychological factors. RESULTS: The first phase clustering of all participants based on GI symptoms resulted in the formation of pure and non-pure clusters. Pure clusters exactly illustrated the properties of most pure Rome syndromes. Re-clustering the members of the non-pure clusters based on GI and psychological factors (i.e., the second clustering step) resulted in eight new clusters, indicating the dominance of multiple factors but well-discriminated from other clusters. The results of the second step especially highlight the impact of psychological factors in grouping FGIDs. CONCLUSIONS: In the current study, the existence of Rome disorders, which were previously defined by expert opinion-based consensus, was approved, and, eight new clusters with multiple dominant symptoms based on GI and psychological factors were also introduced. The more homogeneous clusters of patients could lead to the design of more precise clinical experiments and further targeted patient care.

Moving beyond nanotechnology to uncover a glimmer of hope in diabetes medicine: Effective nanoparticle-based therapeutic strategies for the management and treatment of diabetic foot ulcers.

Hyperglycemia, a distinguishing feature of diabetes mellitus that might cause a diabetic foot ulcer (DFU), is an endocrine disorder that affects an extremely high percentage of people. Having a comprehensive understanding of the molecular mechanisms underlying the pathophysiology of diabetic wound healing can help researchers and developers design effective therapeutic strategies to treat the wound healing process in diabetes patients. Using nanoscaffolds and nanotherapeutics with dimensions ranging from 1 to 100 nm represents a state-of-the-art and viable therapeutic strategy for accelerating the wound healing process in diabetic patients, particularly those with DFU. Nanoparticles can interact with biological constituents and infiltrate wound sites owing to their reduced diameter and enhanced surface area. Furthermore, it is noteworthy that they promote the processes of vascularization, cellular proliferation, cell signaling, cell-to-cell interactions, and the formation of biomolecules that are essential for effective wound healing. Nanomaterials possess the ability to effectively transport and deliver various pharmacological agents, such as nucleic acids, growth factors, antioxidants, and antibiotics, to specific tissues, where they can be continuously released and affect the wound healing process in DFU. The present article elucidates the ongoing endeavors in the field of nanoparticle-mediated therapies for the management of DFU.

Breast cancer brain metastasis: from etiology to state-of-the-art modeling.

Currently, breast carcinoma is the most common form of malignancy and the main cause of cancer mortality in women worldwide. The metastasis of cancer cells from the primary tumor site to other organs in the body, notably the lungs, bones, brain, and liver, is what causes breast cancer to ultimately be fatal. Brain metastases occur in as many as 30% of patients with advanced breast cancer, and the 1-year survival rate of these patients is around 20%. Many researchers have focused on brain metastasis, but due to its complexities, many aspects of this process are still relatively unclear. To develop and test novel therapies for this fatal condition, pre-clinical models are required that can mimic the biological processes involved in breast cancer brain metastasis (BCBM). The application of many breakthroughs in the area of tissue engineering has resulted in the development of scaffold or matrix-based culture methods that more accurately imitate the original extracellular matrix (ECM) of metastatic tumors. Furthermore, specific cell lines are now being used to create three-dimensional (3D) cultures that can be used to model metastasis. These 3D cultures satisfy the requirement for in vitro methodologies that allow for a more accurate investigation of the molecular pathways as well as a more in-depth examination of the effects of the medication being tested. In this review, we talk about the latest advances in modeling BCBM using cell lines, animals, and tissue engineering methods.

An intriguing approach toward antibacterial activity of green synthesized Rutin-templated mesoporous silica nanoparticles decorated with nanosilver.

In recent years, mesoporous silica nanoparticles (MSNs) have been applied in various biomedicine fields like bioimaging, drug delivery, and antibacterial alternatives. MSNs could be manufactured through green synthetic methods as environmentally friendly and sustainable synthesis approaches, to improve physiochemical characteristics for biomedical applications. In the present research, we used Rutin (Ru) extract, a biocompatible flavonoid, as the reducing agent and nonsurfactant template for the green synthesis of Ag-decorated MSNs. Transmission electron microscopy (TEM), zeta-potential, x-ray powder diffraction (XRD), fourier transform infrared (FTIR) spectroscopy analysis, scanning electron microscopy (SEM), brunauer-emmett-teller (BET) analysis, and energy-dispersive system (EDS) spectroscopy were used to evaluate the Ag-decorated MSNs physical characteristics. The antimicrobial properties were evaluated against Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), and also different types of candida. The cytotoxicity test was performed by using the MTT assay. Based on the findings, the significant antimicrobial efficacy of Ru-Ag-decorated MSNs against both gram positive and gram negative bacteria and different types of fungi was detected as well as acceptable safety and low cytotoxicity even at lower concentrations. Our results have given a straightforward and cost-effective method for fabricating biodegradable Ag-decorated MSNs. The applications of these MSNs in the domains of biomedicine appear to be promising.

Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus.

Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.

Neuro-nanotechnology: diagnostic and therapeutic nano-based strategies in applied neuroscience.

Artificial, de-novo manufactured materials (with controlled nano-sized characteristics) have been progressively used by neuroscientists during the last several decades. The introduction of novel implantable bioelectronics interfaces that are better suited to their biological targets is one example of an innovation that has emerged as a result of advanced nanostructures and implantable bioelectronics interfaces, which has increased the potential of prostheses and neural interfaces. The unique physical-chemical properties of nanoparticles have also facilitated the development of novel imaging instruments for advanced laboratory systems, as well as intelligently manufactured scaffolds and microelectrodes and other technologies designed to increase our understanding of neural tissue processes. The incorporation of nanotechnology into physiology and cell biology enables the tailoring of molecular interactions. This involves unique interactions with neurons and glial cells in neuroscience. Technology solutions intended to effectively interact with neuronal cells, improved molecular-based diagnostic techniques, biomaterials and hybridized compounds utilized for neural regeneration, neuroprotection, and targeted delivery of medicines as well as small chemicals across the blood-brain barrier are all purposes of the present article.

A better roadmap for designing novel bioactive glasses: effective approaches for the development of innovative revolutionary bioglasses for future biomedical applications.

The introduction of bioactive glasses (BGs) precipitated a paradigm shift in the medical industry and opened the path for the development of contemporary regenerative medicine driven by biomaterials. This composition can bond to live bone and can induce osteogenesis by the release of physiologically active ions. 45S5 BG products have been transplanted effectively into millions of patients around the world, primarily to repair bone and dental defects. Over the years, many other BG compositions have been introduced as innovative biomaterials for repairing soft tissue and delivering drugs. When research first started, many of the accomplishments that have been made today were unimaginable. It appears that the true capacity of BGs has not yet been realized. Because of this, research involving BGs is extremely fascinating. However, to be successful, it requires interdisciplinary cooperation between physicians, glass chemists, and bioengineers. The present paper gives a picture of the existing clinical uses of BGs and illustrates key difficulties deserving to be faced in the future. The challenges range from the potential for BGs to be used in a wide variety of applications. We have high hopes that this paper will be of use to both novice researchers, who are just beginning their journey into the world of BGs, as well as seasoned scientists, in that it will promote conversation regarding potential additional investigation and lead to the discovery of innovative medical applications for BGs.

A Bright Horizon of Intelligent Targeted-cancer Therapy: Nanoparticles Against Breast Cancer Stem Cells.

Breast cancer stem cells (BCSCs) are heterogeneous tumor-initiating cell subgroups of breast cancers that possess some stem cell markers and are sustained after chemotherapy. Due to BCSCs being sufficient for tumor relapse, and given that the biological behaviors of BCSCs are so complex, it is critical to figure out exactly how they work, learn more about their cell biology, and discover biomarkers and strategies for explicitly targeting and destructing cancer stem cells. In order to accomplish innovative treatment for breast cancer, it is also essential to target BCSCs. Despite the vast quantities of BCSC target chemicals, their therapeutic implementation is limited due to off-target behavior and bioavailability issues. Targeted drug delivery systems based on nanoparticles have advantages for transporting anti-BCSC materials, especially to targeted locations. Hence, breast cancer therapy using a nanoparticle-based BCSCs targeting system is a promising strategy. Such targeted drug delivery systems can resolve the biodistribution obstacles of nanosystems. Throughout this paper, we highlight various strategies for targeting BCSCs utilizing nano-based systems. In conclusion, issues about the inadequate stability of nanoparticles and the possibility of loaded drug leakage during delivery systems have yet to be answered. More fundamental and applied research, and proper methods such as coating or surface modification are required.

Effective treatment of intractable diseases using nanoparticles to interfere with vascular supply and angiogenic process.

Angiogenesis is a vital biological process involving blood vessels forming from pre-existing vascular systems. This process contributes to various physiological activities, including embryonic development, hair growth, ovulation, menstruation, and the repair and regeneration of damaged tissue. On the other hand, it is essential in treating a wide range of pathological diseases, such as cardiovascular and ischemic diseases, rheumatoid arthritis, malignancies, ophthalmic and retinal diseases, and other chronic conditions. These diseases and disorders are frequently treated by regulating angiogenesis by utilizing a variety of pro-angiogenic or anti-angiogenic agents or molecules by stimulating or suppressing this complicated process, respectively. Nevertheless, many traditional angiogenic therapy techniques suffer from a lack of ability to achieve the intended therapeutic impact because of various constraints. These disadvantages include limited bioavailability, drug resistance, fast elimination, increased price, nonspecificity, and adverse effects. As a result, it is an excellent time for developing various pro- and anti-angiogenic substances that might circumvent the abovementioned restrictions, followed by their efficient use in treating disorders associated with angiogenesis. In recent years, significant progress has been made in different fields of medicine and biology, including therapeutic angiogenesis. Around the world, a multitude of research groups investigated several inorganic or organic nanoparticles (NPs) that had the potential to effectively modify the angiogenesis processes by either enhancing or suppressing the process. Many studies into the processes behind NP-mediated angiogenesis are well described. In this article, we also cover the application of NPs to encourage tissue vascularization as well as their angiogenic and anti-angiogenic effects in the treatment of several disorders, including bone regeneration, peripheral vascular disease, diabetic retinopathy, ischemic stroke, rheumatoid arthritis, post-ischemic cardiovascular injury, age-related macular degeneration, diabetic retinopathy, gene delivery-based angiogenic therapy, protein delivery-based angiogenic therapy, stem cell angiogenic therapy, and diabetic retinopathy, cancer that may benefit from the behavior of the nanostructures in the vascular system throughout the body. In addition, the accompanying difficulties and potential future applications of NPs in treating angiogenesis-related diseases and antiangiogenic therapies are discussed.

Nanotechnology Advances in the Detection and Treatment of Cancer: An Overview.

Over the last few years, progress has been made across the nanomedicine landscape, in particular, the invention of contemporary nanostructures for cancer diagnosis and overcoming complexities in the clinical treatment of cancerous tissues. Thanks to their small diameter and large surface-to-volume proportions, nanomaterials have special physicochemical properties that empower them to bind, absorb and transport high-efficiency substances, such as small molecular drugs, DNA, proteins, RNAs, and probes. They also have excellent durability, high carrier potential, the ability to integrate both hydrophobic and hydrophilic compounds, and compatibility with various transport routes, making them especially appealing over a wide range of oncology fields. This is also due to their configurable scale, structure, and surface properties. This review paper discusses how nanostructures can function as therapeutic vectors to enhance the therapeutic value of molecules; how nanomaterials can be used as medicinal products in gene therapy, photodynamics, and thermal treatment; and finally, the application of nanomaterials in the form of molecular imaging agents to diagnose and map tumor growth.

The brilliance of nanoscience over cancer therapy: Novel promising nanotechnology-based methods for eradicating glioblastoma.

Given the limited sensitivity of screening methods and the lack of effective therapeutic interventions for malignant brain tumors such as glioblastoma multiforme (also known as GBM), diagnostic and therapeutic procedures for these tumors are rarely performed on a routine basis. Nanostructures with great selectivity, including silica-based nanovehicles, metallic nanostructures, lipid nanoparticles, quantum dots, and polymeric nanoparticles, have been demonstrated to have excellent potential for passing the BBB efficiently. Based on tumor-derived cells, surface modification, encapsulation of contrast agent, bio composition, and functionalities by appropriate coating materials can all be used to take advantage of the photodynamic, magnetic, and optical capabilities of nanostructures. As a result, nanotechnology has revolutionized the detection, screening, as well as treatment of malignancies and brain tumors. In recent years, nanostructures with biomimetic activities have been designed for uptake by tumors in deep cancer regions, with the goal of monitoring and treating the disease. Also, nanostructures are exceptional nano-vehicles for delivering therapeutic agents to their targeted areas due to their special physicochemical properties, which include nanosized dimensions, larger surface area, specific geometrical characteristics, and the capabilities to encompass various substances within their inner parts or on their exterior surface. This paper describes the current developments of several nanostructures such as dendrimers, liposomes, carbon dots, carbon nanotubes, micelles, and metallic nanoparticles for efficient detection of GBM as well as drug delivery in GBM treatment. The importance of metallic nanoparticle-based radiosensitization, as well as immunotherapy, as good ways to fight metastasis and GBM growth, will also be discussed.

Multidisciplinary approach to functional somatic syndromes: study protocol for a population-based prospective cohort study.

INTRODUCTION: Isfahan functional disorders (ISFUN) cohort study aims to describe the interplay of genetic and environmental factors in shaping the characteristics of functional somatic syndromes (FSS). This study is primarily intended to investigate the epidemiology, risk factors, course and prognosis of FSSs in a sample of adult Iranian population. The other aim is to develop a new delimitation of FSSs based on an integrated multidisciplinary approach comprising of phenotypic and multiomics data. METHODS AND ANALYSIS: ISFUN is a population-based prospective cohort study designed to follow a population of randomly selected seemingly healthy adults (18-65 years) through annual visits during a 4-year observation period. Structured questionnaires are used for data collection and clinical assessment of the participants. Questionnaire-based diagnosis of FSSs are validated in a medical interview. Human DNA genotyping, microbial amplicon sequencing and urine analysis is under progress for genomics, microbiota and metabolomics profiling, respectively. Enrolment began in September 2017, and study completion is expected in 2022. A total number of 1943 participants were initially recruited. ETHICS AND DISSEMINATION: Ethical approval for data collection was granted by the National Research Ethics Committee of the Iranian Ministry of Health and Medical Education and the Research Ethics Committee of Isfahan University of Medical Sciences (IR.MUI.REC.1395.1.149). Following the description of the study procedure, we obtained written informed consent from all study participants. Study findings will be disseminated through peer-reviewed publications and presentations at scientific meetings.

Large-Scale Multi-Omics Studies Provide New Insights into Blood Pressure Regulation.

Recent genome-wide association studies uncovered part of blood pressure's heritability. However, there is still a vast gap between genetics and biology that needs to be bridged. Here, we followed up blood pressure genome-wide summary statistics of over 750,000 individuals, leveraging comprehensive epigenomic and transcriptomic data from blood with a follow-up in cardiovascular tissues to prioritise likely causal genes and underlying blood pressure mechanisms. We first prioritised genes based on coding consequences, multilayer molecular associations, blood pressure-associated expression levels, and coregulation evidence. Next, we followed up the prioritised genes in multilayer studies of genomics, epigenomics, and transcriptomics, functional enrichment, and their potential suitability as drug targets. Our analyses yielded 1880 likely causal genes for blood pressure, tens of which are targets of the available licensed drugs. We identified 34 novel genes for blood pressure, supported by more than one source of biological evidence. Twenty-eight (82%) of these new genes were successfully replicated by transcriptome-wide association analyses in a large independent cohort (n = ~220,000). We also found a substantial mediating role for epigenetic regulation of the prioritised genes. Our results provide new insights into genetic regulation of blood pressure in terms of likely causal genes and involved biological pathways offering opportunities for future translation into clinical practice.