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author:("Kumar, shives")
1.  Epicardial Adipose Tissue Volume as a Marker of Coronary Artery Disease Severity in Patients with Diabetes Independent of Coronary Artery Calcium: Findings from the CTRAD study 
The association between epicardial adipose tissue (EAT) volume and coronary artery disease (CAD) severity was evaluated, independent of traditional risk factors and coronary artery calcium (CAC) scores, in patients with diabetes type 2 (DM-2) using cardiac computed tomography angiography (CTA).
A multivariate analysis was utilized to assess for an independent association after calculating EAT volume, CAD severity, and calcium scores in 92 patients with DM-II from the CTRAD study. We graded CAD severity as none (normal coronaries), mild-moderate (<70% stenosis), and severe (70% or greater stenosis).
A total of 39 (42.3 %) asymptomatic patients with diabetes did not have CAD; 30.4% had mild/moderate CAD; and 27.1% had severe CAD. Mean EAT volume was highest in patients with severe CAD (143.14 cm3) as compared to mild/moderate CAD (112.7 cm3), and no CAD (107.5 cm3) (p= 0.003). After adjustment of clinical risk factors, notably, CAC score, multivariate regression analysis showed EAT volume was an independent predictor of CAD severity in this sample (odds ratio 11.2, 95% confidence interval 1.7 –73.8, p =0.01).
Increasing EAT volume in asymptomatic patients with DM-II is associated with presence of severe CAD, independent of BMI and CAC, as well as traditional risk factors.
PMCID: PMC4261017  PMID: 25262111
EAT; Pericardial fat; Coronary Artery Disease; Multi-detector Computed Tomography; Computed Tomography Angiography; Diabetes; Metabolic Syndrome
2.  Comparison of Epicardial Adipose Tissue Volume and Coronary Artery Disease Severity in Asymptomatic Adults with versus without Diabetes Mellitus 
The American journal of cardiology  2014;114(5):686-691.
Epicardial adipose tissue (EAT) has been shown to have important effects on the development of coronary artery disease (CAD) via local paracrine influences on the vascular bed. We compared a cohort of asymptomatic patients with Type II Diabetes (DM) without known CAD to an age and gender matched group of asymptomatic patients without DM from the CTRAD study in which patients underwent a cardiac computed tomography angiogram (CTA), for early detection of CAD. Mean EAT volumes of 118.6 ± 43.0 and 70.0 ± 44.0 cm3 were found in the DM and non-DM groups respectively. When stratified by presence and severity of CAD, it was found that in the DM (p=0.003) and non-DM groups (p<0.001) there was a statistically significant increase in EAT volume as the patients were found to have increasingly severe CAD. After adjusting for age, race, gender, DM, hypertension, insulin use, BMI, and coronary artery calcium (CAC) score, the presence of >120 cm3 of EAT was found to be highly correlated with the presence of significant CAD (Adjusted Odds Ratio 4.47, 95% CI (1.35–14.82)). We found that not only is EAT volume an independent predictor of CAD, but that an increasing volume of EAT predicted increasing severity of CAD even after adjustment for CAC score.
PMCID: PMC4216806  PMID: 25037677
Coronary Artery Disease; Epicardial Adipose Tissue; Diabetes
3.  Asymmetric hetero-domain interface stabilizes a response regulator-DNA complex 
Nature communications  2014;5:3282.
Two-component signal transduction systems consisting of pairs of histidine kinases and response regulators (RRs) mediate adaptive responses to environmental cues via phosphorylation-triggered inactive to active transition of RRs. Most activated RRs regulate transcription by binding tightly to promoter DNA. The molecular basis for formation of stable RR-DNA complexes that precede the assembly of RNA polymerases is unclear. Here, we present structures of DNA complexed to KdpE, a member of the OmpR/PhoB family. The distinctively asymmetric complex in an active-like conformation reveals a unique intramolecular interface between the receiver domain (RD) and the DNA-binding domain (DBD) of only one of the two RRs in the complex. Structure-function studies show that this RD-DBD interface is necessary to form stable complexes that support gene expression. The conservation of sequence and structure suggest that these findings extend to a large group of RRs that act as transcriptional factors.
PMCID: PMC4399498  PMID: 24526190
4.  Flexibility of EF-hand motifs: structural and thermodynamic studies of Calcium Binding Protein-1 from Entamoeba histolytica with Pb2+, Ba2+, and Sr2+ 
BMC Biophysics  2012;5:15.
EF-hand proteins can be activated by the binding of various heavy metals other than calcium, and such complexes can disturb the calcium-signaling pathway and cause toxicity and disease causing state. So far, no comprehensive study has been done to understand different heavy metals binding to calcium signaling proteins.
In this work, the flexibility of the EF-hand motifs are examined by crystallographic and thermodynamic studies of binding of Pb2+, Ba2+ and Sr2+ to Calcium Binding Protein-1 from Entamoeba histolytica (EhCaBP1). The structures of the EhCaBP1- heavy metal complexes are found to be overall similar, nevertheless specific differences in metal coordination, and small differences in the coordination distances between the metal and the ligands in the metal binding loop. The largest such distances occur for the Ba2+- EhCaBP1 complex, where two bariums are bound with partial occupancy at the EF2 motif. Thermodynamic studies confirm that EhCaBP1 has five binding sites for Ba2+ compared to four binding sites for the other metals. These structures and thermodynamic studies reveal that the EF-hand motifs can accommodate several heavy atoms with similar binding affinities. The binding of Ca2+ to the 1st, 2nd and 4th sites and the binding of Ba2+ to the 1st, 2nd, 4th and 5th sites are both enthalpically and entropically driven, whereas the binding of Sr2+ to the 1st, 2nd and 4th sites are simply enthalpy driven, interestingly in agreement with ITC data, Sr2+ do not coordinate with water in this structure. For all the metals, binding to the 3rd site is only entropy driven.
Energetically, Ca2+ is preferred in three sites, while in one site Ba2+ has better binding energy. The Sr2+-coordination in the EF hand motifs is similar to that of the native Ca2+ bound structure, except for the lack of water coordination. Sr2+ coordination seems to be a pre-formed in nature since all seven coordinating atoms are from the protein itself, which also correlates with entropy contributions in Sr2+ binding. These findings improve our understanding of metal association with calcium binding proteins and of metal induced conformational changes.
PMCID: PMC3483242  PMID: 22906057
Calcium sensor; Calcium binding protein; Coordination geometry; EF-hand motifs; Anthropogenic toxicant; Domain swapped manner; Anomalous signal
5.  N- and C-Terminal Domains of the Calcium Binding Protein EhCaBP1 of the Parasite Entamoeba histolytica Display Distinct Functions 
PLoS ONE  2009;4(4):e5269.
Entamoeba histolytica, a protozoan parasite, is the causative agent of amoebiasis, and calcium signaling is thought to be involved in amoebic pathogenesis. EhCaBP1, a Ca2+ binding protein of E. histolytica, is essential for parasite growth. High resolution crystal structure of EhCaBP1 suggested an unusual arrangement of the EF-hand domains in the N-terminal part of the structure, while C-terminal part of the protein was not traced. The structure revealed a trimer with amino terminal domains of the three molecules interacting in a head-to-tail manner forming an assembled domain at the interface with EF1 and EF2 motifs of different molecules coming close to each other. In order to understand the specific roles of the two domains of EhCaBP1, the molecule was divided into two halves, and each half was separately expressed. The domains were characterized with respect to their structure, as well as specific functional features, such as ability to activate kinase and bind actin. The domains were also expressed in E. histolytica cells along with green fluorescent protein. The results suggest that the N-terminal domain retains some of the properties, such as localization in phagocytic cups and activation of kinase. Crystal structure of EhCaBP1 with Phenylalanine revealed that the assembled domains, which are similar to Calmodulin N-terminal domain, bind to Phenylalanine revealing the binding mode to the target proteins. The C-terminal domain did not show any of the activities tested. However, over-expression in amebic cells led to a dominant negative phenotype. The results suggest that the two domains of EhCaBP1 are functionally and structurally different from each other. Both the domains are required for structural stability and full range of functional diversity.
PMCID: PMC2668073  PMID: 19384409

Results 1-5 (5)