Therapeutic implication of MicroRNA-320a antagonist in attenuating blood clots formed during venous thrombosis.

Venous thrombosis (VT) is a complex multi-factorial disease and a major health concern worldwide. Its clinical implications include deep vein thrombosis (DVT) and pulmonary embolism (PE). VT pathogenesis involves intricate interplay of various coagulants and anti-coagulants. Growing evidences from epidemiological studies have shown that many non-coding microRNAs play significant regulatory role in VT pathogenesis by modulating expressions of large number of gene involved in blood coagulation. Present study aimed to investigate the effect of human micro RNA (hsa-miR)-320a antagonist on thrombus formation in VT. Surgery was performed on Sprague-Dawley (SD) rats, wherein the inferior vena cava (IVC) was ligated to introduce DVT. Animals were divided into four groups (n = 5 in each group); Sham controls (Sham), IVC ligated-DVT (DVT), IVC ligated-DVT + transfection reagent (DVT-NC) and IVC ligated-DVT + miR320a antagonist (DVT-miR-320a antagonist). IVC was dissected after 6 h and 24 h of surgery to estimate thrombus weight and coagulatory parameters such as levels of D-dimer, clotting time and bleeding time. Also, ELISA based biochemical assays were formed to assess toxicity of miRNA antagonist in animals. Our experimental analysis demonstrated that there was a marked reduction in size of thrombus in hsa-miR-320a antagonist treated animals, both at 6 h and 24 h. There was a marked reduction in D-dimer levels in hsa-miR-320a antagonist treated animals. Also, blood clotting time was delayed and bleeding time was increased significantly in hsa-miR-320a antagonist treated rats compared to the non-treated and Sham rats. There was no sign of toxicity in treated group compared to control animals. Hsa-miR-320a antagonist could be promising therapeutic target for management of VT.

"Mitochondrial pathogenic mutations and metabolic alterations associated with COVID-19 disease severity".

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) caused global pandemic and drastically affected the humankind. Mitochondrial mutations have been found to be associated with several respiratory diseases. Missense mutation and pathogenic mitochondrial variants might unveil the potential involvement of the mitochondrial genome in coronavirus disease 2019 (COVID-19) pathogenesis. The present study aims to elucidate the role of mitochondrial DNA (mtDNA) mutations, mitochondrial haplogroup, and energy metabolism in disease severity. The study was performed on 58 subjects comprising COVID-19-positive (n = 42) and negative (n = 16) individuals. COVID-19-positive subjects were further categorized into severe deceased (SD), severe recovered (SR), moderate (Mo), and mild (Mi) patients, while COVID-19-negative subjects were healthy control (HC) for the study. High throughput next-generation sequencing was done to investigate mtDNA mutations and haplogroups. The computational approach was applied to study the effect of mtDNA mutations on protein secondary structure. Real time polymerase chain reaction was used for mtDNA copy number determination and mitochondrial function parameters were also analyzed. We found 15 mtDNA mutations in MT-ND5, MT-ND4, MT-ND2, and MT-COI genes uniquely associated with COVID-19 severity affecting the secondary structure of proteins in COVID-19-positive subjects. Haplogroup analysis suggests that mtDNA haplogroups M3d1a and W3a1b might be potentially associated with COVID-19 pathophysiology. The mitochondrial function parameters were significantly altered in severe patients (SD and SR; p < 0.05). No significant relationship was found between mtDNA mutations and oxidative stress markers (p > 0.05). The study highlights the importance of mitochondrial reprogramming in COVID-19 patients and may provide a feasible approach toward finding a path for therapeutic interventions to COVID-19 disease.

Implications of COVID-19 on Thrombotic Profile of Severely Affected Patients.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is a novel viral disease that spread as a global pandemic in 2020 by infecting millions of people across the world. Its clinical prognosis is dependent on various coagulatory parameters since thrombotic events are frequently associated with infection severity. METHODS: A total of 383 COVID-19 patients enrolled in Rajiv Gandhi Super Specialty Hospital, Delhi, India, were included in the present retrospective study. Patients were divided into three categories, severe (n = 141), moderate (n = 138), and mild (n = 104) based on infection severity. Various thrombotic parameters and anticoagulant levels were measured in 70 patients and further analyzed. RESULTS: Coagulopathy is seen in COVID-19 patients (n = 70) with a significant increase in fibrinogen, D-dimer levels, and prothrombin time in patients with severe and moderate disease compared to patients with a mild infection. Approximately, 70% of patients with severe and moderate disease demonstrated fibrinogen levels higher than the standard reference range. 60.41% of patients with severe disease showed significantly higher D-dimer levels. Thrombotic parameters were notably elevated in the nonsurvivors group compared to COVID-19 survivors. Nearly, 91% of patients with severe infection had anticoagulant protein S levels below the reference range. CONCLUSION: COVID-19 infection severely impacts the blood coagulation cascade, which might lead to the manifestation of severe symptoms and increased mortality in patients.

Potential association of COVID-19 and ABO blood group: An Indian study.

Coronavirus disease 2019 (COVID-19) transmits from person to person mainly through respiratory droplets and coughing. Infection severity ranges from asymptomatic and mild infection to those with moderate and severe symptoms which may lead to multiple organ failure and mortality. Infection severity largely depends on individual's immune response, age and co-morbidities. Present study categorized COVID-19 infected patients based on their infection severity and linked COVID-19 severity with age, gender and ABO blood group types. Clinical details of 383 COVID-19 patients were collected from Rajiv Gandhi Super Specialty hospital (RGSSH), India; divided into three groups; mild, moderate and severe patients, based on their symptoms. Present analysis revealed that age plays major role in infection severity, as the symptoms are more severe in patients above 45 years. Infection rate was higher in males compared to females. Most patients with A(+ve) and B(+ve) blood group were severely affected compared to those of blood group type O(+ve) and AB(+ve). O(+ve) blood group was least represented in severe patients. Present findings could be helpful in generating awareness amongst the population regarding susceptibility towards the COVID-19 infection. This supportive information would help clinicians and health workers to propose new strategies and tactical solution against COVID-19 infection.

Influence of integrins on thrombus formation: a road leading to the unravelling of DVT.

Integrins are a group of transmembrane glycoprotein receptors that are responsible for platelet activation through bidirectional signalling. These receptors have left their footprints in various cellular events and have intrigued many groups of scientists that have led to some significant discoveries. A lot of the recent understanding of haemostasis has been possible due to the integrins filling the gaps in between several cellular mechanism. Apart from this, other important functions carried out by integrins are growth and maturation of cardiomyocytes, mechano-transduction, and interaction with actin cytoskeleton. The signalling cascade for integrin activation involves certain intracellular interacting proteins, which initiates the step-by-step activation procedure through 'inside-out' signalling. The signalling cascade gets activated through 'outside-in' signalling with the involvement of agonists such as ADP, Fibronectin, Vitronectin, and so on. This is a crucial step for the downstream processes of platelet spreading, followed by aggregation, clot progression and finally thrombus formation. Researchers throughout the world have shown direct relation of integrins with CVD and cardiac remodelling. The present review aims to summarize the information available so far on the involvement of integrins in thrombosis and its relationship to DVT. This information could be a bedrock of hidden answers to several questions on pathogenesis of deep vein thrombosis.

Targeted gene expression study using TaqMan low density array to gain insights into venous thrombo-embolism (VTE) pathogenesis at high altitude.

Venous thrombo-embolism (VTE) is multi-factorial disease involving several genetic and acquired risk factors responsible for its onset. It may occur spontaneously upon climbing at High Altitude (HA). Several studies demonstrated that hypoxic conditions prevailing at HA pose an independent risk factor for VTE; however, molecular mechanism remains unknown. Present study aims to identify genes associated with HA-induced VTE pathophysiology using real time TaqMan Low-Density Array (TLDA) of known candidate genes. Gene expression of total 93 genes were studied and analyzed in patients of VTE from HA (HA-VTE) and from sea level (SL-VTE) in comparison to respective controls. Both HA-VTE and SL-VTE patients showed up-regulation of 37 genes involved in blood coagulation cascade, clot formation, platelet formation, endothelial response, angiogenesis, cell adhesion and calcium channel activity. Seven genes including ACE, EREG, C8A, DLG2, USF1, F2 and PCDHA7 were up-regulated in both HA-controls and VTE patients (both HA-VTE and SL-VTE) indicating their role during VTE event and also upon HA exposure. Ten genes; CDH18, FGA, EDNBR, GATA2, MAPK9, BCAR1, FRK, F11, PCDHA1 and ST8SIA4 were uniquely up-regulated in HA-VTE. The differentially expressed genes from the present study could be determining factors for HA-VTE susceptibility and provide insights into VTE occurrence at HA.

von Willebrand factor antagonizes nitric oxide synthase to promote insulin resistance during hypoxia.

Hypoxic respiratory diseases or hypoxia exposures are frequently accompanied by glucose intolerance and impaired nitric oxide (NO) availability. However, the molecular mechanism responsible for impaired NO production and insulin resistance (IR) during hypoxia remains obscure. In this study, we investigated the possible mechanism of impaired NO production and IR during hypoxia in a mouse model. Mice were exposed to hypoxia for different periods of time (0-24 h), and parameters of IR and endothelial dysfunctions were analyzed. Exposure to hypoxia resulted in a time-dependent increase in IR as well as multimeric forms of von Willebrand factor (vWF) and subsequently a decrease in eNOS activity. Preincubation with plasma of hypoxia-exposed animals (different time points) or human vWF inhibited insulin-induced NO production in a dose-dependent manner; larger doses of insulin reversed the effect. In contrast, preincubation of vWF-immunodepleted plasma failed to inhibit insulin-induced NO production, whereas vWF immunoneutralization abolished the effect of hypoxia-induced IR and D-[U-(14)C]glucose uptake. Furthermore, the interactions between vWF and eNOS were studied by far-Western blotting, co-immunoprecipitation, and surface plasma resonance spectroscopy. Kinetic analyses showed that the dissociation constant (KD), inhibitory constant (Ki), and half-maximal inhibitory concentration (IC50) were 1.79 × 10(-8) M, 250 pM, and 18.31 pM, respectively, suggesting that vWF binds to eNOS with a high affinity and greater efficacy for activator (insulin) inhibition. These results indicated that vWF, an antagonist of eNOS, inhibits insulin-induced NO production and causes IR.

Children's perspective on the dentist's attire.

BACKGROUND: Despite many advances in paediatric dentistry, the greatest challenge for any paediatric dentist is to remove the anxiety related to a dental visit and get the child patient to accept the treatment readily. The manner in which the dentist presents himself plays an important role in cementing a friendly relation with the child. AIM: To assess school children's perceptions and preferences towards dentist's attire so as to understand their psych and promote a successful relationship with the patient. DESIGN: A questionnaire designed to evaluate children's attitudes and preferences towards dentists was distributed in public schools and was completed by 619 children (322 males, 297 females) aged between 6-14 years. RESULTS: The study found that majority of children preferred dental professionals to wear traditional formal attire with a white coat and name badge. They preferred the use of plain masks and white gloves but disliked protective eyewear or headcaps. Most children liked dentists with closed shoes and no jewellery but preferred the use of a wrist watch. CONCLUSIONS: The results obtained from this study can help dentists decide what is appropriate to wear when dealing with children so as to minimise their anxiety and improve delivery of health care.

Gene expression profiling in Venous thromboembolism: Insights from publicly available datasets.

BACKGROUND: Venous thromboembolism (VTE) is the third most common cardiovascular disease and is a major cause of mobility and mortality worldwide. VTE is a complex multifactorial disease and genetic mechanisms underlying its pathogenesis is yet to be completely elucidated. The aim of the present study was to identify hub genes and pathways involved in development and progression of blood clot during VTE using gene expression data from public repositories. METHODOLOGY: Differential gene expression (DEG) data from two datasets, GSE48000 and GSE19151 were analysed using GEO2R tool. Gene expression data of VTE patients were compared to that of healthy controls using various bioinformatics tools. RESULTS: When the differentially expressed genes of the two datasets were compared, it was found that 19 genes were up-regulated while 134 genes were down-regulated. Gene ontology (GO) and pathway analysis revealed that pathways such as complement and coagulation cascade and B-cell receptor signalling along with DNA methylation, DNA alkylation and inflammatory genes were significantly up-regulated in VTE patients. On the other hand, differentially down-regulated genes included mitochondrial translation elongation, termination and biosysthesis along with heme biosynthesis, erythrocyte differentiation and homeostasis. The top 5 up-regulated hub genes obtained by protein-protein interaction (PPI) network analysis included MYC, FOS, SGK1, CR2 and CXCR4, whereas the top 5 down-regulated hub genes included MRPL13, MRPL3, MRPL11, RPS29 and RPL9. The up-regulated hub genes are functionally involved in maintain vascular integrity and complementation cascade while the down-regulated hub genes were mostly mitochondrial ribosomal proteins. CONCLUSION: Present study highlights significantly enriched pathways and genes associated with VTE development and prognosis. The data hereby obtained could be used for designing newer diagnostic and therapeutic tools for VTE management.

Evaluation of altered miRNA expression pattern to predict COVID-19 severity.

Outbreak of COVID-19 pandemic in December 2019 affected millions of people globally. After substantial research, several biomarkers for COVID-19 have been validated however no specific and reliable biomarker for the prognosis of patients with COVID-19 infection exists. Present study was designed to identify specific biomarkers to predict COVID-19 severity and tool for formulating treatment. A small cohort of subjects (n = 43) were enrolled and categorized in four study groups; Dead (n = 16), Severe (n = 10) and Moderate (n = 7) patients and healthy controls (n = 10). Small RNA sequencing was done on Illumina platform after isolation of microRNA from peripheral blood. Differential expression (DE) of miRNA (patients groups compared to control) revealed 118 down-regulated and 103 up-regulated known miRNAs with fold change (FC) expression ≥2 folds and p ≤ 0.05. DE miRNAs were then subjected to functional enrichment and network analysis. Bioinformatic analysis resulted in 31 miRNAs (24 Down-regulated; 7 up-regulated) significantly associated with COVID-19 having AUC>0.8 obtained from ROC curve. Seventeen out of 31 DE miRNAs have been linked to COVID-19 in previous studies. Three miRNAs, hsa-miR-147b-5p and hsa-miR-107 (down-regulated) and hsa-miR-1299 (up-regulated) showed significant unique DE in Dead patients. Another set of 4 miRNAs, hsa-miR-224-5p (down-regulated) and hsa-miR-4659b-3p, hsa-miR-495-3p and hsa-miR-335-3p were differentially up-regulated uniquely in Severe patients. Members of three miRNA families, hsa-miR-20, hsa-miR-32 and hsa-miR-548 were significantly down-regulated in all patients group in comparison to healthy controls. Thus a distinct miRNA expression profile was observed in Dead, Severe and Moderate COVID-19 patients. Present study suggests a panel of miRNAs which identified in COVID-19 patients and could be utilized as potential diagnostic biomarkers for predicting COVID-19 severity.

A key role of toll-like receptor 3 in tissue factor activation through extracellular signal regulated kinase 1/2 pathway in a murine hypoxia model.

Hypoxemia in the circulation can lead to venous thrombosis (VT) through tissue factor (TF) activation, but the mechanism of TF activation in hypoxia remains obscure. Ligands released from damaged tissues or cells due to hypoxia are identified by various pattern-recognition receptors (PRR), including Toll-like receptor3 (TLR3). In the present study, we investigated the mechanism of TF activation during acute hypoxia in a rat model. The expression of TLR3 and TF was analyzed by immunoblotting and RT-PCR. The TF activity was evaluated by two-stage chromogenic assay and fibrin deposition was detected by immunohistochemistry. The expression of TLR3, TF, and TF activity was increased significantly 6 h post acute hypoxia and then decreased gradually. The contribution of TLR3 in TF activation was investigated by poly I:C and TLR3 neutralizing antibody. We also found increased ERK phosphorylation both in acute hypoxia and poly I:C treatment. We further showed that the pre-treatment of TLR3 neutralizing antibody or ERK inhibitor (PD98059) 2 h prior to acute hypoxia or poly I:C treatment completely abrogated ERK phosphorylation and TF activation. The pre-treatment of TLR3 neutralizing antibody also inhibited fibrin deposition in lung vasculature. These data indicate that acute hypoxia induced TF activation is mediated through TLR3-ERK1/2 pathway.

Gene variants in pro-coagulant and anti-coagulant genes could be prognostic genetic markers of COVID-19 susceptibility.

Background: Present study aimed to identify DNA polymorphisms (variants) which can modulate the risk of COVID-19 infection progression to severe condition. TaqMan based SNP genotyping assay was performed for 11 single nucleotide polymorphisms (SNPs) in pro-coagulant and anti-coagulant genes. Methodology: A total of 33 COVID-19 patients, including dead, severe and moderately infected individuals were compared to 35 healthy controls. Both alleles in the SNP were labelled with two different fluorescent dyes (FAM and VIC) during assay formulation. DNA of study subjects were mixed with SNP assay and TaqMan master mix on 96 well PCR plate according to manufacturer's protocol and RT-PCR was performed. Allelic discrimination assay gave clear results for presence of specific allele in each sample. Three SNPs were located in the pro-coagulant genes, another three involved in blood clot dissolution while rest five were in the genes encoding natural anti-coagulants. COVID-19 infected patients were further sub-divided into three groups, deceased (n = 16), severe (n = 10) and moderately infected (n = 7). Results: SNP genotyping showed significant differences between COVID-19 patients and controls in two SNPs, rs6133 in Selectin-P (SELP) and rs5361 in Selectin-E (SELE) gene. Also, rs2020921 and rs8176592, in clot dissolution genes, tissue Plasminogen activator (tPA) and tissue factor pathway inhibitor (TFPI) respectively showed significant genotypic and allelic difference in patients of COVID-19 compared to healthy controls. Further three SNPs rs2227589, rs757583846, and rs121918476 in natural anti-coagulant genes anti-thrombin III (ATIII), protein C (PROC), and protein S (PROS) respectively showed statistically significant difference between the study groups. Conclusion: Our findings indicate that gene variants, those involved in coagulation and anti-coagulation may play a major role in determining individual susceptibility to COVID-19.

Identification of haptoglobin and apolipoprotein A-I as biomarkers for high altitude pulmonary edema.

We have investigated the plasma proteome using 2D gel electrophoresis and matrix-assisted laser desorption/ionization tandem time of flight from patients with high altitude pulmonary edema (HAPE). A complete proteomic analysis was performed on 20 patients with HAPE and ten healthy sea level controls. In total, we have identified 25 protein spots in human plasma and found that 14 of them showed altered changes in HAPE patients, which mainly were acute phase proteins (APPs), compliment components, and apolipoproteins among others. Among the APPs, haptoglobin α2 chain, haptoglobin ß chain, transthyretin, and plasma retinol binding precursor showed overexpression in HAPE patients as compared to controls. To validate the result of proteomic analysis, two proteins were selected for enzyme-linked immunosorbent assay and Western blotting analysis. Our data conclusively shows that two proteins, haptoglobin and apolipoprotein A-I are upregulated in plasma of HAPE patients. These proteins may provide a fast and effective control of inflammatory damage until the subsequent mechanisms can begin to operate. Taken together, our findings further support the hypothesis that inflammatory response system is linked to the pathophysiology of HAPE.

Assessment of nitric oxide (NO) potential to mitigate COVID-19 severity.

Novel coronavirus disease by SARS-CoV-2 virus (also known as COVID-19) has emerged as major health concern worldwide. While, there is no specific drugs for treating this infection till date, SARS-CoV-2 had spread to most countries around the globe. Nitric oxide (NO) gas serves as an important signaling molecule having vasodilatory effects as well as anti-microbial properties. Previous studies from the 2004 SARS-CoV infection demonstrated that NO may also help to reduce respiratory tract infection by inactivating viruses and inhibiting their replication cycle and is an effective supportive measure for treating infection in patients with pulmonary complications. NO gas inhalation is being suggested as potential therapy for managing severe acute respiratory distress syndrome in COVID-19 patients. In view of COVID-19 pandemic, several clinical trials are underway to examine the effects of NO inhalation on infected patients. Previously published reports on beneficial effects of endogenous NO and NO inhalation therapy were thoroughly searched to assess the potential of NO therapy for treating COVID-19 patients. Present report summarized the therapeutic importance of NO to reverse pulmonary hypertension, restore normal endothelial activity and produce anti-thrombotic effects. In addition to this, NO also reduces viral infection by inhibiting its replication and entry into the host cell. In absence of vaccine and effective treatment strategies, we suggest that NO inhalation therapy and NO releasing foods/compounds could be considered as an alternative measure to combat COVID-19 infection.

COVID-19 infection and thrombosis.

BACKGROUND: Recent reports on outbreak of SARS-CoV-2 coronavirus (COVID-19) have shown its association with abnormal blood clots. The viral infection initiates inflammatory responses leading to endothelial damage and coagulation cascade dysfnction. Spread of COVID-19 has been associated with disseminated intravascular coagulation (DIC) and subsequent coagulopathy. Initially coagulopathy in COVID-19 patients result in significant elevation of D-dimer, fibrin/fibrinogen degradation products (FDP), and abnormalities in coagulatory parameters, which resulting in formation of thrombus and eventually death. METHODOLOGY: Present report intends to summarize the information of the research reports available so far on the complications of formation of unusal blood clots (thrombosis) during COVID-19 infection and its therapeutic strategies. Extensive web search was done for various reports associating COVID-19 infection with increased coagulopathy and abnormal coagulatory parameters such as PT, PTT, and platelet counts; along with increased D-dimer and fibrinogen levels. RESULTS AND CONCLUSION: Findings of these research reports were summarized to recommend cautions for clinicians while treating COVID-19 patient. Screening of coagulatory parameters upon admission and during entire course of treatment is recommended, especially those who are at increased risk of thrombosis. Also, anticoagulant treatment can be used as thromboprophylaxis measure. Dose and duration of anticoagulation treatment requirement may vary and thus regular monitoring is needed.

SARS-CoV-2 infection: physiological and environmental gift factors at high altitude.

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has emerged as a global pandemic. This viral disease primarily causes lung pneumonia and has a wide range of clinical manifestations. The severity of infection ranges from those who are asymptomatic or with mild symptoms which do not require hospital admission, to those who require ventilator support and eventually die, depending on immunity, age and other comorbidities existing with the patients. The present report is an attempt to study the effect of physiological and environmental factors existing at high altitudes (HA) with spread of SARS-CoV-2 infection. Analysis of existing data revealed that HA natives do possess certain physiological advantages such as (1) improved hypoxic ventilatory response, (2) higher concentration of oxygen carrying molecules, haemoglobin, (3) increased production of Vitamin D, due to intense solar radiation, (4) lower rates of comorbidities such as lung infections, obesity etc. and (5) most importantly reduced production of angiotensin converting enzyme 2, a carrier molecule for SARS-CoV-2 virus entry into the host cell; all of which can collectively account for improved tolerance to SARS-CoV-2 infection in HA natives. In addition, environmental factors at HA such as (6) dry and chilly winds, (7) low air density and (8) intense UV radiations may further inhibit viral growth and spread into the atmosphere. We thus conclude that, high altitude natives may posses physiological and environmental advantage over low landers in terms of reduced severity of SARS-CoV-2 infection and its limited spread. Graphic abstract: Gift factors associated with COVID-19 spread at high altitude.

MicroRNAs in venous thrombo-embolism.

BACKGROUND: Venous Thrombo-embolism (VTE) is the major preventable cause of death and disability worldwide. It has the third highest incidence rate of hospital death after coronary artery disease (CAD) and stroke. With the establishment of Virchow's triad stating the major factors responsible for VTE including stasis, hypercoagulability and endothelial dysfunction, the last decade reported number of studies regarding its diagnosis and prophylaxis. Till date the most commonly used clinical marker for its diagnosis is the D-dimer test, detecting endogenous fibrinolysis. This test often gives false positive results and has low specificity. Other markers of coagulation are being used in combination with D-dimer; however, a reliable and sensitive biomarker is still needed for early and accurate diagnosis of VTE. Non-coding regulatory RNAs such as MicroRNAs (miRNAs) are small molecules that play a significant role in RNA silencing and post-transcriptional gene expression regulation. They can specifically bind to their target genes forming silencing complex, thereby inducing degradation and altered gene expression. A wide range of miRNAs have extensively been studied in a variety of cardiovascular diseases such as CAD, stroke, myocardial infarction (MI), atherosclerosis, obstructive sleep apnoea (OSA) and other complex diseases such as cancer. It has been demonstrated that circulating miRNAs have enormous potential to function as clinical diagnostic biomarkers for many diseases. This review comprehends recent studies establishing the inevitable role of miRNAs in pathogenesis of complex diseases with special emphasis on venous thrombosis. The differential expression pattern of these miRNAs shows a strong positive correlation with the manifestation of the pathological symptoms of diseases. Systematic consolidation of different miRNAs linked to VTE in various studies could be helpful in finding accurate diagnostic markers for thrombosis and may also find its place in VTE therapeutics. However, more extensive research and confirmatory experiments are needed to establish the role of these miRNAs as biomarkers.

micro-RNAs dependent regulation of DNMT and HIF1α gene expression in thrombotic disorders.

MicroRNAs (miRNAs) are involved in a wide variety of cellular processes and post-transcriptionally regulate several mechanism and diseases. However, contribution of miRNAs functioning during hypoxia and DNA methylation together is less understood. The current study was aimed to find a shared miRNAs signature upstream to hypoxia (via HIF gene family members) and methylation (via DNMT gene family members). This was followed by the global validation of the hypoxia related miRNA signature using miRNA microarray meta-analysis of the hypoxia induced human samples. We further concluded the study by looking into thrombosis related terms and pathways enriched during protein-protein interaction (PPI) network analysis of these two sets of gene family. Network prioritization of these shared miRNAs reveals miR-129, miR-19band miR-23b as top regulatory miRNAs. A comprehensive meta-analysis of microarray datasets of hypoxia samples revealed 29 differentially expressed miRNAs. GSEA of the interacting genes in the DNMT-HIF PPI network indicated thrombosis associated pathways including "Hemostasis", "TPO signaling pathway" and "angiogenesis". Interestingly, the study has generated a novel database of candidate miRNA signatures shared between hypoxia and methylation, and their relation to thrombotic pathways, which might aid in the development of potential therapeutic biomarkers.

Perspective: DNA Copy Number Variations in Cardiovascular Diseases.

Human genome contains many variations, often called mutations, which are difficult to detect and have remained a challenge for years. A substantial part of the genome encompasses repeats and when such repeats are in the coding region they may lead to change in the gene expression profile followed by pathological conditions. Structural variants are alterations which change one or more sequence feature in the chromosome such as change in the copy number, rearrangements, and translocations of a sequence and can be balanced or unbalanced. Copy number variants (CNVs) may increase or decrease the copies of a given region and have a pivotal role in the onset of many diseases including cardiovascular disorders. Cardiovascular disorders have a magnitude of well-established risk factors and etiology, but their correlation with CNVs is still being studied. In this article, we have discussed history of CNVs and a summary on the diseases associated with CNVs. To detect such variations, we shed light on the number of techniques introduced so far and their limitations. The lack of studies on cardiovascular diseases to determine the frequency of such variants needs clinical studies with larger cohorts. This review is a compilation of articles suggesting the importance of CNVs in multitude of cardiovascular anomalies. Finally, future perspectives for better understanding of CNVs and cardiovascular disorders have also been discussed.