Anny Usheva

Brown University · Department of Surgery

Although metabolic syndrome (MetS) is linked to an elevated risk of cardiovascular disease (CVD), the cardiac-specific risk mechanism is unknown. Obesity, hypertension, and diabetes (all MetS components) are the most common form of CVD and represent risk factors for worse COVID-19 outcomes compared to their non MetS peers. Here, we use obese Yorksh...

Background Diabetic (DM) inactivation of small conductance calcium-activated potassium (SK) channels contributes to coronary endothelial dysfunction. However, the mechanisms responsible for this down-regulation of endothelial SK channels are poorly understood. Thus, we hypothesized that the altered metabolic signaling in diabetes regulates endothel...

Although metabolic syndrome (MS) is a significant risk of cardiovascular disease (CVD), the cardiac response (MR) to MS remains unclear due to traditional MS models' narrow scope around a limited number of cell-cycle regulation biomarkers and drawbacks of limited human tissue samples. To date, we developed the most comprehensive platform studying M...

Although the high-fat-diet-induced metabolic syndrome (MetS) is a precursor of human cardiac pathology, the myocardial metabolic state in MetS is far from clear. The discrepancies in metabolite handling between human and small animal models and the difficulties inherent in obtaining human tissue complicate the identification of the myocardium-speci...

Although the high-fat-diet-induced metabolic syndrome (MetS) is a precursor of human cardiac pathology, the myocardial metabolic state in MetS is far from clear. The discrepancies in metabolite handling between human and small animal models and the difficulties inherent in obtaining human tissue complicate the identification of the myocardium-speci...

Introduction: Obesity and metabolic syndrome (MetS) are rapidly expanding worldwide. One of the most concerning implications of this trend is the association between MetS and the increased risk of cardiovascular disease (CVD) . There is a little data on cross-talk between metabolomics alterations and myocardial functionality. Hypothesis: Because of...

Our data point out to a transcriptionally controlled fuel gauge in the metabolic syndrome (MetS) heart that enzymatically turns down glucose and fatty acids oxidation and activates nutritional ketolysis. This study represents a significant step towards characterizing the metabolic state of the heart in MetS and provides potential avenues for therap...

A major reason medicine seek assisted regenerative cell therapy is for regeneration of lost tissue functions. Adult and stem cells reprogramming holds much promise for a variety of diseases. A general disadvantage of the presently available methods however, is the low reprogramming efficiency, which restricts their routine therapeutic application....

Objectives: The modification of serine and threonine residues of nuclear and cytoplasmic proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) has emerged as a highly dynamic post-translational modification that plays a critical role in regulating numerous biological processes. Our focus was to establish the difference of O-linked glycosylation in...

Background: Emerging data suggest a link between calpain activation and the enhanced inflammatory response of the cardiovascular system. We hypothesize that calpain activation associates with altered inflammatory protein expression in correlation with the proinflammatory profile of the myocardium. Our pig hypercholesterolemic model with chronic my...

Hyperoxia is still broadly used in clinical practice in order to assure organ oxygenation in critically ill patients, albeit known toxic effects. In this present study, we hypothesize that lysophosphatidic acid (LPA) mediates NKT cell activation in a mouse model of hyperoxic lung injury. In vitro, pulmonary NKT cells were exposed to hyperoxia for 7...

Schizophrenia (SZ) genome-wide association studies (GWASs) have identified common risk variants in >100 susceptibility loci; however, the contribution of rare variants at these loci remains largely unexplored. One of the strongly associated loci spans MIR137 (miR137) and MIR2682 (miR2682), two microRNA genes important for neuronal function. We sequ...

CD39 (ENTPD1) is expressed by subsets of pathogenic human CD4(+) T cells, such as Th17 cells. These Th17 cells are considered important in intestinal inflammation, such as seen in Crohn's disease (CD). Recently, CD161 (NKR-P1A) was shown to be a phenotypic marker of human Th17 cells. In this study, we report that coexpression of CD161 and CD39 not...

Experimental and bioinformatic studies of transcription initiation by RNA polymerase II (RNAP2) have revealed a mechanism of RNAP2 transcription initiation less uniform across gene promoters than initially thought. However, the general transcription factor TFIIB is presumed to be universally required for RNAP2 transcription initiation. Based on bio...

Extracellular adenosine, a key regulator of physiology and immune cell function that is found at elevated levels in neonatal blood, is generated by phosphohydrolysis of adenine nucleotides released from cells and catabolized by deamination to inosine. Generation of adenosine monophosphate (AMP) in blood is driven by cell-associated enzymes, whereas...

Despite recent advances in medical procedures, cardiovascular disease remains a clinical challenge and the leading cause of mortality in the western world. The condition causes progressive smooth muscle cell (SMC) dedifferentiation, proliferation, and migration that contribute to vascular restenosis. The incidence of disease of the internal mammary...

We report that terahertz (THz) irradiation of mouse mesenchymal stem cells (mMSCs) with a single-frequency (SF) 2.52 THz laser or pulsed broadband (centered at 10 THz) source results in irradiation specific heterogenic changes in gene expression. The THz effect depends on irradiation parameters such as the duration and type of THz source, and on th...

Physicochemical properties of DNA, such as shape, affect protein-DNA recognition. However, the properties of DNA that are most relevant for predicting the binding sites of particular transcription factors (TFs) or classes of TFs have yet to be fully understood. Here, using a model that accurately captures the melting behavior and breathing dynamics...

EPBD model algorithms and implementations. This supporting text provides a listing of the parameter values of the EPBD model, information about the algorithms used in our calculations, and links to source codes of available software implementations of these algorithms. (PDF)

Previously characterized in vitro Fis binding sites. Information for all previously in vitro characterized Fis bindings site used in our analysis. Nucleotides located in bubble formation regions are highlighted in blue, while points-of-contact with DNA are highlighted in yellow. (XLSX)

Summary of previous studies identifying Fis binding sites in the E. coli genome. (XLSX)

Examined Fis binding sites' locations in the E. coli genome. (XLSX)

Parameters of the EPBD model. (PDF)

Unlabelled: Liver cancer is associated with chronic inflammation, which is linked to immune dysregulation, disordered metabolism, and aberrant cell proliferation. Nucleoside triphosphate diphosphohydrolase-1; (CD39/ENTPD1) is an ectonucleotidase that regulates extracellular nucleotide/nucleoside concentrations by scavenging nucleotides to ultimate...

In the living cell, the double-stranded DNA molecule experiences thermal motions that induce spontaneous openings and re-closings of the double helix known as “DNA breathing,” or “DNA transient bubbles” (Englander et al., 1980). The propensity for breathing is interconnected with DNA local stability and flexibility (Vafabakhsh & Ha, 2012), which pl...

In a previous study, we detected a 6p25-p24 region linked to schizophrenia in families with high composite cognitive deficit (CD) scores, a quantitative trait integrating multiple cognitive measures. Association mapping of a 10 Mb interval identified a 260 kb region with a cluster of single-nucleotide polymorphisms (SNPs) significantly associated w...

Aims: In this study, we identify components of the complement system present in human follicular fluid that affect oocyte development and maturation. Material and Methods: Using bottom-up liquid chromatography/mass spectrometry/mass spectrometry, we identified complement factors as consistently present in human follicular fluid from 15 different su...

The genome-wide mapping of the major gene expression regulators, the transcription factors (TFs) and their DNA binding sites, is of great importance for describing cellular behavior and phenotypic diversity. Presently, the methods for prediction of genomic TF binding produce a large number of false positives, most likely due to insufficient descrip...

Retinol-binding protein 4 (RBP4), the sole retinol transporter in blood, is secreted from adipocytes and liver. Serum RBP4 levels correlate highly with insulin resistance, other metabolic syndrome factors, and cardiovascular disease. Elevated serum RBP4 causes insulin resistance, but the molecular mechanisms are unknown. Here we show that RBP4 indu...

The biological effects of bilirubin, still poorly understood, are concentration-dependent ranging from cell protection to toxicity. Here we present data that at high nontoxic physiological concentrations, bilirubin inhibits growth of proliferating human coronary artery smooth muscle cells by three events. It impairs the activation of Raf/ERK/MAPK p...

In recent years, terahertz radiation sources are increasingly being exploited in military and civil applications. However, only a few studies have so far been conducted to examine the biological effects associated with terahertz radiation. In this study, we evaluated the cellular response of mesenchymal mouse stem cells exposed to THz radiation. We...

Trinucleotide repeats sequences (TRS) represent a common type of genomic DNA motif whose expansion is associated with a large number of human diseases. The driving molecular mechanisms of the TRS ongoing dynamic expansion across generations and within tissues and its influence on genomic DNA functions are not well understood. Here we report results...

Human follicular fluid (hFF), as an extra oocyte microenvironment, is essential to the biological processes of oocyte development. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified 426 proteins as consistently present in hFF from different participants. According to our gene chip data, the granulosa cells in the follicl...

To identify aldosterone and precursors in ovarian follicles and to relate levels of mineralocorticoids to previously described renin-angiotensin system follicular fluid content. Experimental. Academic laboratory and affiliated large private practice. Women undergoing oocyte retrieval for in vitro fertilization (IVF). The concentrations of mineraloc...

We report that extended exposure to broad-spectrum terahertz radiation results in specific changes in cellular functions that are closely related to DNA-directed gene transcription. Our gene chip survey of gene expression shows that whereas 89% of the protein coding genes in mouse stem cells do not respond to the applied terahertz radiation, certai...

Examples of DNA duplex instability profiles. This file contains figures showing the DNA duplex instability profiles for two promoter sequences, with bubble size ranging from k = 1 to k = 9 for each sequence. The genes used for these examples are CFTR and TJP2.

DNA instability profiles have been used recently for predicting the transcriptional start site and the location of core promoters, and to gain insight into promoter action. It was also shown that the use of these profiles can significantly improve the performance of motif finding programs. In this work we introduce a new method for computing DNA in...

Accelerated atherosclerosis is the leading cause of morbidity and mortality in diabetic patients. Hyperglycemia is a recognized independent risk factor for heightened atherogenesis in diabetes mellitus (DM). However, our understanding of the mechanisms underlying glucose damage to the vasculature remains incomplete. High glucose and hyperglycemia r...

To investigate the distribution of vascular endothelial growth factor (VEGF) isoforms and soluble form of VEGF receptor 1 (sFlt-1) in the follicular fluid (FF) of in vitro fertilization (IVF) patients in relationship to age, body mass index (BMI), diagnosis of polycystic ovary syndrome (PCOS), and their correlation with IVF outcomes. Prospective st...

We consider the influence of a terahertz field on the breathing dynamics of double-stranded DNA. We model the spontaneous formation of spatially localized openings of a damped and driven DNA chain, and find that linear instabilities lead to dynamic dimerization, while true local strand separations require a threshold amplitude mechanism. Based on o...

Questions about the changes of biological systems in response to hostile environmental factors are important but not easy to answer. Often, the traditional description with differential equations is difficult due to the overwhelming complexity of the living systems. Another way to describe complex systems is by simulating them with phenomenological...

We assess the role of DNA breathing dynamics as a determinant of promoter strength and transcription start site (TSS) location. We compare DNA Langevin dynamic profiles of representative gene promoters, calculated with the extended non-linear PBD model of DNA with experimental data on transcription factor binding and transcriptional activity. Our r...

Bile acids, end products of the pathway for cholesterol elimination, are required for dietary lipid and fat-soluble vitamin absorption and maintain the balance between cholesterol synthesis in the liver and cholesterol excretion. They are composed of a steroid structure and are primarily made in the liver by the oxidation of cholesterol. Cholestero...

Apoptosis signal-regulating kinase 1 (ASK1) is a key regulatory kinase in the proapoptotic response to various stresses. ASK1 phosphorylation of Daxx, an ASK1 activator protein, increases Daxx accumulation in cells and further enhances ASK1 activity through a positive feedback mechanism. Here, we show that ASK1-dependent phosphorylation of Daxx ind...

Daxx is a regulatory protein for apoptosis signal-regulating kinase 1 (ASK1) which activates c-Jun NH2-terminal kinase (JNK) and p38 pathways in response to stressors such as tumor necrosis factor-alpha (TNFalpha). Here, we show that TNFalpha treatment induces the accumulation of Daxx protein through ASK1 activation by preventing its proteasome-dep...

Xenograft outcomes are dictated by xenoantigen expression, for example, Gal alpha1, 3Gal (Gal), but might also depend on differing vascular responses. We investigated whether differential vascular gene expression in kidney and cardiac xenografts correlate with development of thrombotic microangiopathy (TM) and consumptive coagulation (CC). Immunosu...

No simple model exists that accurately describes the melting behavior and breathing dynamics of double-stranded DNA as a function of nucleotide sequence. This is especially true for homogenous and periodic DNA sequences, which exhibit large deviations in melting temperature from predictions made by additive thermodynamic contributions. Currently, n...

Establishing the general and promoter-specific mechanistic features of gene transcription initiation requires improved understanding of the sequence-dependent structural/dynamic features of promoter DNA. Experimental data suggest that a spontaneous dsDNA strand separation at the transcriptional start site is likely to be a requirement for transcrip...

To investigate the relationship between interleukin-8 (IL-8) in the human ovarian follicle and follicular size, patient age, and fertility factors in IVF cycles. Prospective study. University hospital research laboratory and infertility clinic. Women undergoing IVF with oocyte retrieval. Follicular fluid (FF) aspiration, oocyte isolation, FF storag...

Vascular smooth muscle cell (VSMC) migration and proliferation are critical steps in the pathogenesis of atherosclerosis, post-angioplasty restenosis, neointimal hyperplasia, and chronic allograft rejection. Extracellular nucleotides are known to influence both migration and proliferation of VSMC. Although it is well established that vascular endot...

To investigate involvement of specific apolipoproteins in the process of human oocyte maturation and age-related infertility as molecular constituents of follicular fluid. Laboratory-based observational study. Basic science laboratory at a large academic institution. Follicular fluid obtained from healthy women aged 18 to 45 years undergoing in vit...

We discuss connections between the nonlinear dynamics of double-stranded DNA, experimental findings, and specific DNA functions. We begin by discussing how thermally induced localized openings (bubbles) of the DNA double strand are important for interpreting dynamic force spectroscopy data. Then we demonstrate a correlation between a sequence-depen...

The geldanamycin derivatives 17-allylamino-17-demethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) are promising chemotherapeutic drugs that inhibit heat shock protein 90 (HSP90) function. Previous studies have shown that 17-AAG/DMAG treatment induces the degradation of mutant BRAF (V600E) and inhibits th...