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Biomedical subjects

Joydeep Ghosh

Publications and source records attributed to Joydeep Ghosh.

12 recordsLinked to original sources
PubMed2006

Specificity of Streptococcus pyogenes NAD(+) glycohydrolase in cytolysin-mediated translocation.

The mechanism by which the cytolysin-mediated translocation (CMT) pathway of the Gram-positive pathogen Streptococcus pyogenes injects effector proteins into the cytosol of an infected host cell via the pore-forming protein streptolysin O is unknown. Key questions include whether the pathway can discriminate between different substrates for translocation, and whether the effector protein plays an active or passive role in the translocation process. Here we show that CMT can discriminate between a known effector of the pathway, the S. pyogenes NAD(+) glycohydrolase (SPN), and a second secreted protein, the mitogenic factor (MF), routing the former into the host cell cytosol and the latter into the extracellular milieu. Residues within the amino-terminal 190 residues of SPN were essential for discrimination, as deletions within this domain produced proteins that retained full enzymatic activity, but were completely uncoupled from the translocation pathway. The enzymatic domain itself played a pivotal role in the discrimination as deletions within this domain also produced translocation incompetent proteins and the conversion of MF to a translocation-competent form required fusion with both SPN domains in a contiguous orientation. These data establish that CMT is discriminatory, and that SPN is a multidomain protein that plays an active role in its translocation.

Amino Acid Sequence↗
PubMed2006

Sudden cardiac death in athletes - what can be done?

Sudden death in athletes is a rare event but brings with it an impact that goes beyond sport. There are many causes of sudden death during exercise. While the responsibility of preventing or treating them lays with us physicians, preparticipation screening is largely ineffective and impractical. Definitive, large scale prospective research is required in order to design the most cost-effective system for screening of athletes. In the meanwhile rapid access to defibrillators by trained personnel remains the best possible approach to abort sudden death.

Editorial↗
PubMed2005

Role of implantable cardioverter defibrillators in the treatment of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an important cardiovascular disease with sudden cardiac death as the most devastating presentation. Implantable cardioverter defibrillators (ICD) are the optimal therapy for prevention of sudden death from ventricular tachycardia or fibrillation of any cause. While there is no controversy with implanting ICDs in patients who have already survived a cardiac arrest, identifying high-risk patients for primary prevention in this disease remains a challenge. Implanting ICDs in patients with HCM is an important clinical consideration since many individuals could achieve normal or near-normal lifespans with this protection.

Editorial↗
PubMed2005

Risk stratification for sudden cardiac death in patients with non-ischemic dilated cardiomyopathy.

Non ischemic dilated cardiomyopathy (NIDCM) is a disorder of myocardium. It has varying etiologies. Albeit the varying etiologies of this heart muscle disorder, it presents with symptoms of heart failure, and rarely as sudden cardiac death (SCD). Manifestations of this disorder are in many ways similar to its counterpart, ischemic dilated cardiomyopathy (IDCM). A proportion of patients with NIDCM carries a grave prognosis and is prone to sudden cardiac death from sustained ventricular arrhythmias. Identification of this subgroup of patients who carry the risk of sudden cardiac death despite adequate medical management is a challenge. Yet another method is a blanket treatment of patients with this disorder with anti arrhythmic medications or anti tachyarrhythmia devices like implantable cardioverter defibrillators (ICD). However this modality of treatment could be a costly exercise even for affluent economies. In this review we try to analyze the existing data of risk stratification of NIDCM and its clinical implications in practice.

Journal Article↗
PubMed2005

Disulphide trapping of an in vivo energy-dependent conformation of Escherichia coli TonB protein.

In Escherichia coli, the TonB system transduces the protonmotive force (pmf) of the cytoplasmic membrane to support a variety of transport events across the outer membrane. Cytoplasmic membrane proteins ExbB and ExbD appear to harvest pmf and transduce it to TonB. Experimental evidence suggests that TonB shuttles to the outer membrane, apparently to deliver conformationally stored potential energy to outer membrane transporters. In the most recent model, discharged TonB is then recycled to the cytoplasmic membrane to be re-energized by the energy coupling proteins, ExbB/D. It has been suggested that the carboxy-terminal 75 amino acids of active TonB could be represented by the rigid, strand-exchanged, dimeric crystal structure of the corresponding fragment. In contrast, recent genetic studies of alanine substitutions have suggested instead that in vivo the carboxy-terminus of intact TonB is dynamic and flexible. The biochemical studies presented here confirm and extend those results by demonstrating that individual cys substitution at aromatic residues in one monomeric subunit can form spontaneous dimers in vivo with the identical residue in the other monomeric subunit. Two energized TonBs appear to form a single cluster of 8-10 aromatic amino acids, including those found at opposite ends of the crystal structure. The aromatic cluster requires both the amino-terminal energy coupling domain of TonB, and ExbB/D (and cross-talk analogues TolQ/R) for in vivo formation. The large aromatic cluster is detected in cytoplasmic membrane-, but not outer membrane-associated TonB. Consistent with those observations, the aromatic cluster can form in the first half of the energy transduction cycle, before release of conformationally stored potential energy to ligand-loaded outer membrane transporters. The model that emerges is one in which, after input of pmf mediated through ExbB/D and the TonB transmembrane domain, the TonB carboxy-terminus can form a meta-stable high-energy conformation that is not represented by the crystal structure of the carboxy-terminus.

Amino Acid Substitution↗
PubMed2004

Evidence for dynamic clustering of carboxy-terminal aromatic amino acids in TonB-dependent energy transduction.

Escherichia coli uses the proton motive force of the cytoplasmic membrane and TonB protein to energize the active transport of iron-siderophores and vitamin B12 across the outer membrane. TonB shuttles between the cytoplasmic and outer membranes, presumably during the course of energy transduction. Previous results indicated that the carboxy-terminal 65 amino acids of TonB are essential for both its outer membrane association and activity. A highly conserved region (residues 199-216) within this domain, predicted to be an amphipathic alpha-helix, was the initial focus of this study. Scanning mutagenesis indicated that only the aromatic residues F202, W213 and Y215 were individually important for activity. When the crystal structure of a dimeric TonB carboxy-terminus subsequently became available, we observed that two additional aromatic residues outside that region, F180 and F230, were potentially engaged in end-on hydrophobic interactions with the three residues identified previously. Changing these five aromatic residues individually to alanine reduced TonB activity. Surprisingly, however, each substitution exhibited a unique phenotypic profile with respect to ability to support [55Fe]-ferrichrome transport, sensitivity to colicins B, D, Ia and M or sensitivity to bacteriophage phi80. The phenotypic results suggested that the carboxy-terminus of TonB was a flexible and dynamic domain that could interact specifically with different ligands or transporters, perhaps through the aromatic residues. The possibility of interactions among all the aromatic residues was tested using double-mutant cycle analysis. All possible combinations of alanine substitutions were constructed, with the result that TonB containing any double-alanine substitution was inactive in the phenotypic assays, while retaining the ability to associate with the outer membrane. This synergistic, rather than additive, effect of the double mutants suggested that, consistent with the flexibility suggested by analysis of the single substitutions, all the aromatic residues might be capable of interacting with one another. A means of reconciling these results with the crystal structure is presented.

Alanine↗
PubMed2004

Frequency-sensitive competitive learning for scalable balanced clustering on high-dimensional hyperspheres.

Competitive learning mechanisms for clustering, in general, suffer from poor performance for very high-dimensional (>1000) data because of "curse of dimensionality" effects. In applications such as document clustering, it is customary to normalize the high-dimensional input vectors to unit length, and it is sometimes also desirable to obtain balanced clusters, i.e., clusters of comparable sizes. The spherical kmeans (spkmeans) algorithm, which normalizes the cluster centers as well as the inputs, has been successfully used to cluster normalized text documents in 2000+ dimensional space. Unfortunately, like regular kmeans and its soft expectation-maximization-based version, spkmeans tends to generate extremely imbalanced clusters in high-dimensional spaces when the desired number of clusters is large (tens or more). This paper first shows that the spkmeans algorithm can be derived from a certain maximum likelihood formulation using a mixture of von Mises-Fisher distributions as the generative model, and in fact, it can be considered as a batch-mode version of (normalized) competitive learning. The proposed generative model is then adapted in a principled way to yield three frequency-sensitive competitive learning variants that are applicable to static data and produced high-quality and well-balanced clusters for high-dimensional data. Like kmeans, each iteration is linear in the number of data points and in the number of clusters for all the three algorithms. A frequency-sensitive algorithm to cluster streaming data is also proposed. Experimental results on clustering of high-dimensional text data sets are provided to show the effectiveness and applicability of the proposed techniques. Index Terms-Balanced clustering, expectation maximization (EM), frequency-sensitive competitive learning (FSCL), high-dimensional clustering, kmeans, normalized data, scalable clustering, streaming data, text clustering.

Artificial Intelligence↗
PubMed2003

Comparison of two-dimensional echocardiographic tissue harmonic imaging and gated sestamibi single-photon emission computed tomographic left ventricular ejection fraction measurements.

There was good correlation between left ventricular ejection fraction (EF) measurements employing 2-dimensional echocardiography with tissue harmonic imaging and single-photon emission computed tomography using quantitative gated scintigraphy, although in most patients, echocardiographic EF was lower. There was a high degree of agreement between these 2 techniques in assignment of EF to the categories of normal, mildly, moderately, or severely decreased. However, when EF categories did differ, echocardiography always resulted in assignment to a lower category.

Aged↗
PubMed2003

Plasma arc curing of ceramic brackets: an evaluation of shear bond strength and debonding characteristics.

The aim of this in vitro investigation was to evaluate bond strength and debonding characteristics when a xenon plasma arc curing light is used to bond polycrystalline and monocrystalline ceramic brackets. Brackets were bonded to 240 extracted bovine mandibular incisors with a composite adhesive. Curing intervals of 1, 3, and 6 seconds were chosen for curing with the plasma arc light, and the control group was cured at 10 seconds per bracket with a conventional halogen light. Debonding was performed on a universal testing machine and according to the bracket manufacturers' recommendations. Both the polycrystalline and the monocrystalline brackets consistently debonded at the bracket-adhesive interface, regardless of debonding method, curing interval, or curing light. No enamel fractures were observed after debonding. Bracket fractures were rare and did not affect debonding. Bond strength was significantly higher for the monocrystalline brackets (P <.0001): mean shear bond strength ranged between 9.68 +/- 2.17 MPa (plasma arc curing light, 1 sec curing interval) and 10.73 +/- 3.22 MPa (halogen light, 10 sec curing interval) for the polycrystalline brackets and between 19.85 +/- 2.97 MPa (plasma arc curing light, 1 sec curing interval) and 22.94 +/- 3.20 MPa (plasma arc curing light, 3 sec curing interval) for the monocrystalline brackets. Significant differences were also found for the curing methods used (P =.047). A curing interval of 3 seconds with the plasma arc curing light is recommended for both polycrystalline and monocrystalline ceramic brackets.

Analysis of Variance↗
PubMedDate not supplied

Diabetes mellitus and coronary artery disease: therapeutic considerations.

Diabetes mellitus affects about 6% of the U.S. population and represents a significant public health challenge, with numbers of those affected increasing every year. The most common cause of death in these patients is macrovascular disease, with coronary disease being the predominant form. The pathophysiology of coronary disease in patients with diabetes is complex and involves elements of hyperglycemia, dyslipidemia, hyperinsulinemia, as well as a procoagulant vascular milieu. First-generation trials looking at revascularization of multivessel disease in patients with diabetes have had long clinical follow-up periods and seem to consistently favor coronary bypass grafting over percutaneous interventions; however, newer trials that include the use of stents and glycoprotein IIb/IIIa inhibitor therapy as part of the latter strategy have raised some interesting questions, so that the issue remains controversial and by no means settled.

Cardiomyopathy, Dilated↗
PubMedDate not supplied

Isolated and significant left main coronary artery disease: demographics, hemodynamics and angiographic features.

Left main coronary artery disease carries a poor prognosis. The etiology of isolated and significant left main coronary artery (ILMCA) disease is not well understood. Studies so far were limited by small numbers. The authors identified 46 patients with ILMCA disease from their database over 10 years (group I) and compared them with 83 consecutive patients undergoing catheterization (group II). They also compared patients with ostial vs distal ILMCA disease. Group I represented 0.1% of catheterization patients. The demographic profile and atherosclerotic risk factor profile of the 2 groups as well as ostial and distal ILMCA disease were compared. This is the largest study of ILMCA disease. Risk factors for atherosclerosis were commonly seen. Nonatherosclerotic causes of ILMCA disease were not seen. This study suggests coronary atherosclerosis as the predominant cause of ILMCA disease. ILMCA disease is more common in women. Diabetes is more commonly associated with distal ILMCA lesion. There is a trend suggesting that ostial ILMCA lesion is more common in smokers and women.

Aged↗