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1.  Base excision repair defects invoke hypersensitivity to PARP inhibition 
Molecular cancer research : MCR  2014;12(8):1128-1139.
Poly (ADP-ribose) polymerase-1 (PARP-1) is important for the recognition of both endogenous and exogenous DNA damage, and binds to DNA strand-breaks including intermediates of base excision repair (BER). Once DNA-bound, PARP-1 becomes catalytically activate synthesizing poly-ADP-ribose (PAR) polymers onto itself and other repair factors (PARylation). As a result, BER repair proteins such as XRCC1 and DNA polymerase β (pol β) are more efficiently and rapidly recruited to sites of DNA damage. In the presence of an inhibitor of PARP activity (PARPi), PARP-1 binds to sites of DNA damage, but PARylation is prevented. BER enzyme recruitment is hindered, but binding of PARP-1 to DNA is stabilized, impeding DNA repair and leading to double-strand DNA breaks (DSB). Deficiencies in pol β−/− and Xrcc1−/− cells resulted in hypersensitivity to the PARP inhibitor 4-AN and re-expression of pol β or XRCC1, in these contexts, reversed the 4-AN hypersensitivity phenotype. BER deficiencies also showed evidence of replication defects that lead to DSB-induced apoptosis upon PARPi treatment. Finally, the clinically relevant PARP inhibitors olaparib and veliparib also exhibited hypersensitivity in both pol β−/− and Xrcc1−/− BER-deficient cells. These results reveal heightened sensitivity to PARPi as a function of BER deficiency.
PMCID: PMC4135006  PMID: 24770870
DNA polymerase; XRCC1; PARP-1; methyl methanesulfonate; PARP inhibitor; poly(ADP-ribose)
2.  Alkaline Phosphatase: An Overview 
Alkaline phosphatase (ALP; E.C.3.I.3.1.) is an ubiquitous membrane-bound glycoprotein that catalyzes the hydrolysis of phosphate monoesters at basic pH values. Alkaline phosphatase is divided into four isozymes depending upon the site of tissue expression that are Intestinal ALP, Placental ALP, Germ cell ALP and tissue nonspecific alkaline phosphatase or liver/bone/kidney (L/B/K) ALP. The intestinal and placental ALP loci are located near the end of long arm of chromosome 2 and L/B/K ALP is located near the end of the short arm of chromosome 1. Although ALPs are present in many mammalian tissues and have been studied for the last several years still little is known about them. The bone isoenzyme may be involved in mammalian bone calcification and the intestinal isoenzyme is thought to play a role in the transport of phosphate into epithelial cells of the intestine. In this review, we tried to provide an overview about the various forms, structure and functions of alkaline phosphatase with special focus on liver/bone/kidney alkaline phosphatase.
PMCID: PMC4062654  PMID: 24966474
Enzymes; Isoenzymes; Alkaline phosphatase; L/B/K alkaline phosphatase; Liver alkaline phosphatase; Intestinal alkaline phosphatase; Placental alkaline phosphatase
3.  Consensus and evidence-based Indian initiative on obstructive sleep apnea guidelines 2014 (first edition) 
Obstructive sleep apnea (OSA) and obstructive sleep apnea syndrome (OSAS) are subsets of sleep-disordered breathing. Awareness about OSA and its consequences among the general public as well as the majority of primary care physicians across India is poor. This necessitated the development of the Indian initiative on obstructive sleep apnea (INOSA) guidelines under the auspices of Department of Health Research, Ministry of Health and Family Welfare, Government of India. OSA is the occurrence of an average five or more episodes of obstructive respiratory events per hour of sleep with either sleep-related symptoms or co-morbidities or ≥15 such episodes without any sleep-related symptoms or co-morbidities. OSAS is defined as OSA associated with daytime symptoms, most often excessive sleepiness. Patients undergoing routine health check-up with snoring, daytime sleepiness, obesity, hypertension, motor vehicular accidents, and high-risk cases should undergo a comprehensive sleep evaluation. Medical examiners evaluating drivers, air pilots, railway drivers, and heavy machinery workers should be educated about OSA and should comprehensively evaluate applicants for OSA. Those suspected to have OSA on comprehensive sleep evaluation should be referred for a sleep study. Supervised overnight polysomnography is the “gold standard” for evaluation of OSA. Positive airway pressure (PAP) therapy is the mainstay of treatment of OSA. Oral appliances (OA) are indicated for use in patients with mild to moderate OSA who prefer OA to PAP, or who do not respond to PAP or who fail treatment attempts with PAP or behavioral measures. Surgical treatment is recommended in patients who have failed or are intolerant to PAP therapy.
PMCID: PMC4502224  PMID: 26180408
Bariatric surgery; continuous positive airway pressure; Indian guidelines; obstructive sleep apnea; obstructive sleep apnea syndrome; polysomnography; sleep apnea; sleep study; syndrome Z
4.  Mutational Analysis of Intracellular Loops Identify Cross Talk with Nucleotide Binding Domains of Yeast ABC Transporter Cdr1p 
Scientific Reports  2015;5:11211.
The ABC transporter Cdr1 protein (Cdr1p) of Candida albicans, which plays a major role in antifungal resistance, has two transmembrane domains (TMDs) and two nucleotide binding domains (NBDs) that are interconnected by extracellular (ECLs) and intracellular (ICLs) loops. To examine the communication interface between the NBDs and ICLs of Cdr1p, we subjected all four ICLs to alanine scanning mutagenesis, replacing each of the 85 residues with an alanine. The resulting ICL mutant library was analyzed by biochemical and phenotypic mapping. Only 18% of the mutants from this library displayed enhanced drug susceptibility. Most of the drug-susceptible mutants displayed uncoupling between ATP hydrolysis and drug transport. The two drug-susceptible ICL1 mutants (I574A and S593A) that lay within or close to the predicted coupling helix yielded two chromosomal suppressor mutations that fall near the Q-loop of NBD2 (R935) and in the Walker A motif (G190) of NBD1. Based on a 3D homology model and kinetic analysis of drug transport, our data suggest that large distances between ICL residues and their respective chromosomal suppressor mutations rule out a direct interaction between them. However, they impact the transport cycle by restoring the coupling interface via indirect downstream signaling.
PMCID: PMC4459223  PMID: 26053667
5.  Mammalian Base Excision Repair: Functional Partnership between PARP-1 and APE1 in AP-Site Repair 
PLoS ONE  2015;10(5):e0124269.
The apurinic/apyrimidinic- (AP-) site in genomic DNA arises through spontaneous base loss and base removal by DNA glycosylases and is considered an abundant DNA lesion in mammalian cells. The base excision repair (BER) pathway repairs the AP-site lesion by excising and replacing the site with a normal nucleotide via template directed gap-filling DNA synthesis. The BER pathway is mediated by a specialized group of proteins, some of which can be found in multiprotein complexes in cultured mouse fibroblasts. Using a DNA polymerase (pol) β immunoaffinity-capture technique to isolate such a complex, we identified five tightly associated and abundant BER factors in the complex: PARP-1, XRCC1, DNA ligase III, PNKP, and Tdp1. AP endonuclease 1 (APE1), however, was not present. Nevertheless, the complex was capable of BER activity, since repair was initiated by PARP-1’s AP lyase strand incision activity. Addition of purified APE1 increased the BER activity of the pol β complex. Surprisingly, the pol β complex stimulated the strand incision activity of APE1. Our results suggested that PARP-1 was responsible for this effect, whereas other proteins in the complex had no effect on APE1 strand incision activity. Studies of purified PARP-1 and APE1 revealed that PARP-1 was able to stimulate APE1 strand incision activity. These results illustrate roles of PARP-1 in BER including a functional partnership with APE1.
PMCID: PMC4447435  PMID: 26020771
6.  Diagnosis of idiopathic pulmonary fibrosis: Current issues 
Idiopathic pulmonary fibrosis (IPF) accounts for the majority of lung diseases classified as idiopathic interstitial pneumonia (IIP). It is considered to be lethal because prognosis is very poor and far worse than other types of IIP. An early and accurate diagnosis of IPF is critical. The diagnostic process is complex and requires a multidisciplinary approach involving a pulmonologist, radiologist and pathologist.
PMCID: PMC4428188  PMID: 25984423
Idiopathic pulmonary fibrosis; idiopathic interstitial pneumonia; diagnosis
8.  Over-Expression of Telomere Binding Factors (TRF1 & TRF2) in Renal Cell Carcinoma and Their Inhibition by Using SiRNA Induce Apoptosis, Reduce Cell Proliferation and Migration Invitro 
PLoS ONE  2015;10(3):e0115651.
Telomere binding factors viz. TRF1 and TRF2 are a part of sheltrin complex that are present exclusively at the ends of chromosomes. These factors play an important role in maintaining chromosomal integrity at the ends. However, their status and role are not clear in renal cell carcinoma (RCC). Therefore, the present study was conducted to evaluate TRF1 and TRF2 expressions in RCC tissues. Further, the role of these factors involved in tumorigenesis was elucidated by gene silencing using siRNA in RCC cell line (A498). The present study documented a significant over-expression of TRF1 (P = 0.005) and TRF2 (P = 0.0048) mRNAs by real time PCR in RCC tissues as compared with adjacent normal kidney tissues. Immunohistochemistry studies also revealed higher expression of TRF1 and TRF2 proteins in RCC. Moreover, TRF1 or TRF2 gene silencing using siRNA showed marked reduction in proliferation of RCC cells (P = 0.000). Further, significantly induced cell cycle arrest (P = 0.000) and apoptosis of RCC cells (P = 0.000) was documented upon TRF1 or TRF2 gene silencing. Henceforth, the results deduce that TRF1 or TRF2 inhibitions play an important role in the induction of apoptosis in A498 cells, which may serve as a potential therapeutic target in RCC.
PMCID: PMC4346586  PMID: 25730259
9.  Complementation of aprataxin deficiency by base excision repair enzymes 
Nucleic Acids Research  2015;43(4):2271-2281.
Abortive ligation during base excision repair (BER) leads to blocked repair intermediates containing a 5′-adenylated-deoxyribose phosphate (5′-AMP-dRP) group. Aprataxin (APTX) is able to remove the AMP group allowing repair to proceed. Earlier results had indicated that purified DNA polymerase β (pol β) removes the entire 5′-AMP-dRP group through its lyase activity and flap endonuclease 1 (FEN1) excises the 5′-AMP-dRP group along with one or two nucleotides. Here, using cell extracts from APTX-deficient cell lines, human Ataxia with Oculomotor Apraxia Type 1 (AOA1) and DT40 chicken B cell, we found that pol β and FEN1 enzymatic activities were prominent and strong enough to complement APTX deficiency. In addition, pol β, APTX and FEN1 coordinate with each other in processing of the 5′-adenylated dRP-containing BER intermediate. Finally, other DNA polymerases and a repair factor with dRP lyase activity (pol λ, pol ι, pol θ and Ku70) were found to remove the 5′-adenylated-dRP group from the BER intermediate. However, the activities of these enzymes were weak compared with those of pol β and FEN1.
PMCID: PMC4344515  PMID: 25662216
10.  A prospective study of ocular toxicity in patients receiving ethambutol as a part of directly observed treatment strategy therapy 
Background and Objectives:
India is among the largest countries to implement the revised National Tuberculosis Control Program (RNTCP). This program provides intermittent regimens to the patients, where the doses of isoniazid and ethambutol are more as compared to the daily regimen, which is a cause of concern, particularly with regard to the ocular toxicity of ethambutol. The present study was undertaken to explore the ocular toxicity in the patients registered under the program.
Materials and Methods:
This was a prospective single center cohort study of 64 patients of categories I and II, coming to the RNTCP-Directly Observed Treatment Strategy (DOTS) center at a tertiary care referral hospital. The detailed history, best corrected visual acuity, fundus examination, and color vision test were carried out in all patients at the start of treatment and then at the first and second month of treatment.
Loss in visual acuity from the baseline was noted at the second month follow up in 12 (9.4%) eyes (P = 0.001), visual field defects were seen in eight (6.3%) eyes (P = 0.0412), and optic disc abnormalities were observed in six (4.7%) (P = 0.013) eyes. Color vision abnormalities were noted in 16 (12.6%) eyes (P = 0.003), four eyes showed impairment in red–green color perception, and the others showed impairment in blue–yellow color perception as well. Patients with ocular symptoms were advised to stop ethambutol and they showed improvement in visual acuity after follow up of one to two months. The overall outcome of treatment was not affected by discontinuation of ethambutol in these patients.
Ethambutol when taken according to program could cause ocular toxicity. The early recognition of ocular symptoms is important to prevent unnecessary delay in diagnosis and probable irreversible visual loss.
PMCID: PMC4298911  PMID: 25624590
Ethambutol toxicity; ocular symptoms; revised national tuberculosis control program; visual defects
11.  An Assessment of Growth Media Enrichment on Lipid Metabolome and the Concurrent Phenotypic Properties of Candida albicans 
PLoS ONE  2014;9(11):e113664.
A critical question among the researchers working on fungal lipid biology is whether the use of an enriched growth medium can affect the lipid composition of a cell and, therefore, contribute to the observed phenotypes. One presumption is that enriched medias, such as YPD (yeast extract, peptone and dextrose), are likely to contain lipids, which may homogenize with the yeast lipids and play a role in masking the actual differences in the observed phenotypes or lead to an altered phenotype altogether. To address this issue, we compared the lipids of Candida albicans, our fungus of interest, grown in YPD or in a defined media such as YNB (yeast nitrogen base). Mass spectrometry-based lipid analyses showed differences in the levels of phospholipids, including phosphatidylinositol, phosphatidylglycerol, lyso-phospholipids; sphingolipids, such as mannosyldiinositolphosphorylceramide; and sterols, such as ergostatetraenol. Significant differences were observed in 70 lipid species between the cells grown in the two media, but the two growth conditions did not affect the morphological characteristics of C. albicans. The lipid profiles of the YNB- and YPD-grown C. albicans cells did vary, but these differences did not influence their response to the majority of the tested agents. Rather, the observed differences could be attributed to the slow growth rate of the Candida cells in YNB compared to YPD. Notably, the altered lipid changes between the two media did impact the susceptibility to some drugs. This data provided evidence that changes in media can lead to certain lipid alterations, which may affect specific pathways but, in general, do not affect the majority of the phenotypic properties of C. albicans. It was determined that either YNB or YPD may be suitable for the growth and lipid analysis of C. albicans, depending upon the experimental requirements, but additional precautions are necessary when correlating the phenotypes with the lipids.
PMCID: PMC4244132  PMID: 25423360
12.  Preventing oxidation of cellular XRCC1 affects PARP-mediated DNA damage responses 
DNA repair  2013;12(9):774-785.
Poly(ADP-ribose) polymerase-1 (PARP-1) binds intermediates of base excision repair (BER) and becomes activated for poly(ADP-ribose) (PAR) synthesis. PAR mediates recruitment and functions of the key BER factors XRCC1 and DNA polymerase β (pol β) that in turn regulate PAR. Yet, the molecular mechanism and implications of coordination between XRCC1 and pol β in regulating the level of PAR are poorly understood. A complex of PARP-1, XRCC1 and pol β is found in vivo, and it is known that pol β and XRCC1 interact through a redox-sensitive binding interface in the N-terminal domain of XRCC1. We confirmed here that both oxidized and reduced forms of XRCC1 are present in mouse fibroblasts. To further understand the importance of the C120-C20 oxidized form of XRCC1 and the interaction with pol β, we characterized cell lines representing stable transfectants in Xrcc1−/− mouse fibroblasts of wild-type XRCC1 and two mutants of XRCC1, a novel reduced form with the C12-C20 disulfide bond blocked (C12A) and a reference mutant that is unable to bind pol β (V88R). XRCC1-deficient mouse fibroblasts are extremely hypersensitive to methyl methanesulfonate (MMS), and transfected wild-type and C12A mutant XRCC1 proteins similarly reversed MMS hypersensitivity. However, after MMS exposure the cellular PAR level was found to increase to a much greater extent in cells expressing the C12A mutant than in cells expressing wild-type XRCC1. PARP inhibition resulted in very strong MMS sensitization in cells expressing wild-type XRCC1, but this sensitization was much less in cells expressing the C12A mutant. The results suggest a role for the oxidized form of XRCC1 in the interaction with pol β in 1) controlling the PAR level after MMS exposure and 2) enabling the extreme cytotoxicity of PARP inhibition during the MMS DNA damage response.
PMCID: PMC3924596  PMID: 23871146
13.  Consensus & Evidence-based INOSA Guidelines 2014 (First edition) 
Obstructive sleep apnoea (OSA) and obstructive sleep apnoea syndrome (OSAS) are subsets of sleep-disordered breathing. Awareness about OSA and its consequences amongst the general public as well as the majority of primary care physcians across India is poor. This necessiated the development of the INdian initiative on Obstructive sleep apnoea (INOSA) guidelines under the auspices of Department of Health Research, Ministry of Health & Family Welfare, Government of India. OSA is the occurrence of an average five or more episodes of obstructive respiratory events per hour of sleep with either sleep related symptoms or co-morbidities or ≥ 15 such episodes without any sleep related symptoms or co-morbidities. OSAS is defined as OSA associated with daytime symptoms, most often excessive sleepiness. Patients undergoing routine health check-up with snoring, daytime sleepiness, obesity, hypertension, motor vehicular accidents and high risk cases should undergo a comprehensive sleep evaluation. Medical examiners evaluating drivers, air pilots, railway drivers and heavy machinery workers should be educated about OSA and should comprehensively evaluate applicants for OSA. Those suspected to have OSA on comprehensive sleep evaluation should be referred for a sleep study. Supervised overnight polysomnography (PSG) is the “gold standard” for evaluation of OSA. Positive airway pressure (PAP) therapy is the mainstay of treatment of OSA. Oral appliances are indicated for use in patients with mild to moderate OSA who prefer oral appliances to PAP, or who do not respond to PAP or who fail treatment attempts with PAP or behavioural measures. Surgical treatment is recommended in patients who have failed or are intolerant to PAP therapy.
PMCID: PMC4248396  PMID: 25366217
Bariatric surgery; CPAP; Indian guidelines; OSA; OSAS; polysomnography; sleep apnoea; sleep study; Syndrome Z
14.  Efflux pump proteins in antifungal resistance 
It is now well-known that the enhanced expression of ATP binding cassette (ABC) and major facilitator superfamily (MFS) proteins contribute to the development of tolerance to antifungals in yeasts. For example, the azole resistant clinical isolates of the opportunistic human fungal pathogen Candida albicans show an overexpression of Cdr1p and/or CaMdr1p belonging to ABC and MFS superfamilies, respectively. Hence, azole resistant isolates display reduced accumulation of therapeutic drug due to its rapid extrusion and that facilitates its survival. Considering the importance of major antifungal transporters, the focus of recent research has been to understand the structure and function of these proteins to design inhibitors/modulators to block the pump protein activity so that the drug already in use could again sensitize resistant yeast cells. The review focuses on the structure and function of ABC and MFS transporters of Candida to highlight the recent advancement in the field.
PMCID: PMC4148622  PMID: 25221515
multidrug resistance; ABC transporters; MFS transporters; azoles; efflux pumps; Candida
15.  Molecular Mechanisms of Action of Herbal Antifungal Alkaloid Berberine, in Candida albicans 
PLoS ONE  2014;9(8):e104554.
Candida albicans causes superficial to systemic infections in immuno-compromised individuals. The concomitant use of fungistatic drugs and the lack of cidal drugs frequently result in strains that could withstand commonly used antifungals, and display multidrug resistance (MDR). In search of novel fungicidals, in this study, we have explored a plant alkaloid berberine (BER) for its antifungal potential. For this, we screened an in-house transcription factor (TF) mutant library of C. albicans strains towards their susceptibility to BER. Our screen of TF mutant strains identified a heat shock factor (HSF1), which has a central role in thermal adaptation, to be most responsive to BER treatment. Interestingly, HSF1 mutant was not only highly susceptible to BER but also displayed collateral susceptibility towards drugs targeting cell wall (CW) and ergosterol biosynthesis. Notably, BER treatment alone could affect the CW integrity as was evident from the growth retardation of MAP kinase and calcineurin pathway null mutant strains and transmission electron microscopy. However, unlike BER, HSF1 effect on CW appeared to be independent of MAP kinase and Calcineurin pathway genes. Additionally, unlike hsf1 null strain, BER treatment of Candida cells resulted in dysfunctional mitochondria, which was evident from its slow growth in non-fermentative carbon source and poor labeling with mitochondrial membrane potential sensitive probe. This phenotype was reinforced with an enhanced ROS levels coinciding with the up-regulated oxidative stress genes in BER-treated cells. Together, our study not only describes the molecular mechanism of BER fungicidal activity but also unravels a new role of evolutionary conserved HSF1, in MDR of Candida.
PMCID: PMC4126717  PMID: 25105295
16.  Curcumin Targets Cell Wall Integrity via Calcineurin-Mediated Signaling in Candida albicans 
Curcumin (CUR) shows antifungal activity against a range of pathogenic fungi, including Candida albicans. The reported mechanisms of action of CUR include reactive oxygen species (ROS) generation, defects in the ergosterol biosynthesis pathway, decrease in hyphal development, and modulation of multidrug efflux pumps. Reportedly, each of these pathways is independently linked to the cell wall machinery in C. albicans, but surprisingly, CUR has not been previously implicated in cell wall damage. In the present study, we performed transcriptional profiling to identify the yet-unidentified targets of CUR in C. albicans. We found that, among 348 CUR-affected genes, 51 were upregulated and 297 were downregulated. Interestingly, most of the cell wall integrity pathway genes were downregulated. The possibility of the cell wall playing a critical role in the mechanism of CUR required further validation; therefore, we performed specific experiments to establish if there was any link between the two. The fractional inhibitory concentration index values of 0.24 to 0.37 show that CUR interacts synergistically with cell wall-perturbing (CWP) agents (caspofungin, calcofluor white, Congo red, and SDS). Furthermore, we could observe cell wall damage and membrane permeabilization by CUR alone, as well as synergistically with CWP agents. We also found hypersusceptibility in calcineurin and mitogen-activated protein (MAP) kinase pathway mutants against CUR, which confirmed that CUR also targets cell wall biosynthesis in C. albicans. Together, these data provide strong evidence that CUR disrupts cell wall integrity in C. albicans. This new information on the mechanistic action of CUR could be employed in improving treatment strategies and in combinatorial drug therapy.
PMCID: PMC3910804  PMID: 24145527
17.  Metallothionein gene expression in renal cell carcinoma 
Metallothioneins (MTs) are a group of low-molecular weight, cysteine-rich proteins. In general, MT is known to modulate three fundamental processes: (1) the release of gaseous mediators such as hydroxyl radical or nitric oxide, (2) apoptosis and (3) the binding and exchange of heavy metals such as zinc, cadmium or copper. Previous studies have shown a positive correlation between the expression of MT with invasion, metastasis and poor prognosis in various cancers. Most of the previous studies primarily used immunohistochemistry to analyze localization of MT in renal cell carcinoma (RCC). No information is available on the gene expression of MT2A isoform in different types and grades of RCC.
Materials and Methods:
In the present study, total RNA was isolated from 38 histopathologically confirmed cases of RCC of different types and grades. Corresponding adjacent normal renal parenchyma was taken as control. Real-time polymerase chain reaction (RT PCR) analysis was done for the MT2A gene expression using β-actin as an internal control. All statistical calculations were performed using SPSS software.
The MT2A gene expression was found to be significantly increased (P < 0.01) in clear cell RCC in comparison with the adjacent normal renal parenchyma. The expression of MT2A was two to three-fold higher in sarcomatoid RCC, whereas there was no change in papillary and collecting duct RCC. MT2A gene expression was significantly higher in lower grade (grades I and II, P < 0.05), while no change was observed in high-grade tumor (grade III and IV) in comparison to adjacent normal renal tissue.
The first report of the expression of MT2A in different types and grades of RCC and also these data further support the role of MT2A in tumorigenesis.
PMCID: PMC4120206  PMID: 25097305
Clear cell carcinoma; grade; metallothionein; renal cell carcinoma; Real time polymerase chain reaction
18.  Optimal Reaction Coordinate as a Biomarker for the Dynamics of Recovery from Kidney Transplant 
PLoS Computational Biology  2014;10(6):e1003685.
The evolution of disease or the progress of recovery of a patient is a complex process, which depends on many factors. A quantitative description of this process in real-time by a single, clinically measurable parameter (biomarker) would be helpful for early, informed and targeted treatment. Organ transplantation is an eminent case in which the evolution of the post-operative clinical condition is highly dependent on the individual case. The quality of management and monitoring of patients after kidney transplant often determines the long-term outcome of the graft. Using NMR spectra of blood samples, taken at different time points from just before to a week after surgery, we have shown that a biomarker can be found that quantitatively monitors the evolution of a clinical condition. We demonstrate that this is possible if the dynamics of the process is considered explicitly: the biomarker is defined and determined as an optimal reaction coordinate that provides a quantitatively accurate description of the stochastic recovery dynamics. The method, originally developed for the analysis of protein folding dynamics, is rigorous, robust and general, i.e., it can be applied in principle to analyze any type of biological dynamics. Such predictive biomarkers will promote improvement of long-term graft survival after renal transplantation, and have potentially unlimited applications as diagnostic tools.
Author Summary
The evolution of disease or the progress of recovery of a patient is usually monitored by collecting physical parameters, which may be simply the body temperature for a common cold or properties of tissue samples for e.g., cancer. Most often clinical decisions are taken based on the current value or because of a sizable change of a relevant parameter. As more advanced diagnostic tools become available, and huge numbers of parameters can be collected at short, frequent time intervals, two related questions arise. The first is, which of the parameters provides relevant information on the progress of disease or recovery as opposed to noise? Is there more information that can be obtained from the history of the evolution of such parameters? Here we propose a novel approach that leads, for the specific case of recovery from kidney transplant, to a positive answer.
PMCID: PMC4072519  PMID: 24967678
20.  Suicidal cross-linking of PARP-1 to AP site intermediates in cells undergoing base excision repair 
Nucleic Acids Research  2014;42(10):6337-6351.
Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme in mammalian cells. The enzyme synthesizes polymers of ADP-ribose from the coenzyme NAD+ and plays multifaceted roles in cellular responses to genotoxic stress, including DNA repair. It had been shown that mouse fibroblasts treated with a DNA methylating agent in combination with a PARP inhibitor exhibit higher cytotoxicity than cells treated with methylating agent alone. This lethality of the PARP inhibitor is dependent on apurinic/apyrimidinic (AP) sites in the DNA and the presence of PARP-1. Here, we show that purified PARP-1 is capable of forming a DNA-protein cross-link (DPC) by covalently attaching to the AP site. This DPC formation is specific to the presence of the natural AP site in DNA and is accompanied by a single-strand DNA incision. Cellular studies confirm the formation of PARP-1 DPCs during alkylating agent-induced base excision repair (BER) and formation of DPCs is enhanced by a PARP inhibitor. Using an N-terminal and C-terminal truncated PARP-1 we show that a polypeptide fragment comprising the zinc 3 and BRCT sub-domains is sufficient for DPC formation. The covalent attachment of PARP-1 to AP site-containing DNA appears to be a suicidal event when BER is overwhelmed or disrupted.
PMCID: PMC4041460  PMID: 24771347
21.  Lipidomics and in Vitro Azole Resistance in Candida albicans 
We have shown earlier that fluconazole (FLC) stress induces global changes in the lipidome of Candida albicans in clinically adapted isolates. However, several laboratories have developed adapted in vitro FLC resistant strains of C. albicans to study azole resistance mechanisms. This study aimed to identify the lipid changes associated with FLC resistance in these in vitro adapted isolates. Using comparative lipidomics and principal component and discriminant analyses, we observed gradual changes in several lipid classes and molecular species upon FLC exposure of in vitro resistant C. albicans strains. Although the lipid imprint of FLC in vitro resistant isolates was very distinct from that of clinical isolates of C. albicans, the overall changes in lipid class compositions were similar in both cases. For example, an increased sterol content and depleted sphingolipid levels were the salient features of FLC resistance in both conditions. Taken together, it appears that the overall cellular lipid homeostasis is a critical factor in the observed FLC resistance and in handling FLC stress in both clinical and laboratory situations. The new observations reported herein have implications for more efficacious antifungal drug development as well as understanding host–infectious agent interactions in postgenomics microbiology practice.
PMCID: PMC3567621  PMID: 23374108
22.  Serum zinc levels and its association with vitamin A levels among tuberculosis patients 
One-third of the total human population is infected with the Mycobacterium tuberculosis. This bacterium causes illness in up to 9 million people annually and is responsible for three deaths every minute world-wide.
To determine the association of serum zinc level with vitamin A level in active pulmonary tuberculosis (TB) cases.
Materials and Methods:
It was a cross-sectional study of 208 active pulmonary TB patients aged 18-55 years. Blood samples were obtained from these patients to determine the serum zinc and serum retinol levels.
The mean age of the patients was 30.56 (±11.38) years ranging from 18 years to 55 years. More than half (54.3%) of the patients were males and 63% were married. Body mass index of the patients was 18.40 ± 3.10. The serum zinc and vitamin A levels among the patients were 9.60 (±0.86) μmol/l and 0.77 (±0.22) μmol/l respectively. However, haemoglobin, white blood cell, erythrocyte sedimentation rate, and serum albumin were 10.02 (±1.33) g/dl, 10076.01 (±1822.67) cell/mm3, 14.50 (±2.95) mm/h and 3.40 (±0.32) g/dl respectively. There was a strong correlation between serum zinc and vitamin A levels (r = 0.86, P < 0.01). Vitamin A levels were not significantly different among the different age groups; however, this was significantly (P = 0.001) higher in male (0.82 ± 0.23, 95% confidence interval [CI] =0.77-0.86) patients as compared to females (0.71 ± 0.20, 95% CI = 0.67-0.75).
Zinc deficiency may indirectly influence the metabolism of Vitamin A via reduction of the levels of circulating proteins.
PMCID: PMC3961917  PMID: 24678211
Deficiency; tuberculosis; vitamin A; zinc
23.  Visual disturbances as a presenting feature of pseudohypoparathyroidism 
Visual disturbance as a presenting feature of pseudohypoparathyroidism (PHP) is uncommon. Although papilledema is commonly reported with hypoparathyroidism primary or secondary, but not reported commonly with PHP.
Description of the Case:
A 10-year-old male child presented to our outpatient service with the complaints of blurring of vision, diplopia, and associated headache. There was no history of seizure episode. Patient had rounded face with a short, stocky built. Shortening of the fourth metacarpal and fifth metatarsal was present. Pitted nails and bilateral cataract. Patient also had clinical signs and biochemical parameters of hypocalcemia, along with normal parathyroid hormone (PTH) levels. Consistent with pseudohypopathyroidism.
In cases of chronic papilledema, the assessment of the calcium serum level is a safe and simple method to exclude hypoparathyroidism or PHP.
PMCID: PMC3830310  PMID: 24251164
Pseudohypoparathyroidism; papilledema; AHO Phenotype
24.  Swyer–James–MacLeod syndrome with ipsilateral herniation of hyperinflated hyperlucent lung 
BMJ Case Reports  2011;2011:bcr0520114191.
Swyer–James–MacLeod syndrome is characterised by unilateral hyperlucency on chest radiograph with small or normal-sized lung on the affected side and compensatory hyperinflation of opposite lung. Hyperinflation of the affected lung is a very rarely reported entity. An adult female patient, who presented with exertional breathlessness and diagnosed to have hypoplastic left pulmonary artery with hyperlucent, hyperinflated and herniated left lung is described.
PMCID: PMC3176363  PMID: 22679043
25.  Congenital Muscular Torticollis-Case Report and an Effective Treatment Plan 
Congenital muscular torticollis results from shortening or excessive contraction of the sternocleidomastoid (SCM) muscle. The reported incidence varies between 0.4 and 1.9%. Various theories have been proposed, but its true aetiology remains obscure. The deformity is characterized by a practically painless, contracted cordlike SCM muscle, which pulls the head toward the side affected, narrows and draws the shoulder upward, forcing the chin in the opposite direction. Torticollis of congenital origin is a deformity not commonly met with in the practice of maxillofacial surgery. The rarity, lack of, or inadequacy of the previous treatment, together with the advanced age and marked deformity appear to warrant an investigation and report of the outcome. A case of congenital muscular torticollis is presented who reported at the age of 18 years and has been successfully treated by unipolar SCM release.
PMCID: PMC3428457  PMID: 23997495

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