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Dipankar Nandi

Publications and source records attributed to Dipankar Nandi.

At least 19 recordsLinked to original sources
PubMed2006

Characterization and role of Peptidase N from Salmonella enterica serovar Typhimurium.

ATP-independent peptidases are important during the distal steps of cytosolic protein degradation. The contribution of a member of this group, Peptidase N (PepN) was studied in Salmonella enterica serovar Typhimurium (Salmonella typhimurium). The DeltapepN strain displays greatly reduced cleavage of 9 out of a total of 13 exopeptidase substrates, demonstrating a significant contribution of PepN to cytosolic aminopeptidase activity. The cleavage profile of purified S. typhimurium PepN is Arg>Ala>Thr, demonstrating broad specificity. Comparative biochemical studies with purified PepN from Escherichia coli and S. typhimurium revealed the latter to be distinct: S. typhimurium PepN cleaves Thr-AMC more efficiently and is less sensitive to inhibition by N-ethylmaleimide. Studies with DeltapepN and PepN overexpression demonstrated its importance for growth during nutritional downshift in combination with high temperature stress. In summary, S. typhimurium PepN contributes significantly to cytosolic aminopeptidase activity and its role is manifested under selected stress conditions.

Aminopeptidases↗
PubMed2006

A dominant bursting electromyograph pattern in dystonic conditions predicts an early response to pallidal stimulation.

Although chronic pallidal deep brain stimulation (DBS) is effective in the treatment of medically intractable dystonia, there is no way of predicting the variations in clinical outcome, partly due to our limited understanding of the pathophysiological mechanisms underlying this condition. We recorded electromyographic (EMG) activity from the most severely affected muscle groups in seven dystonia patients before and after pallidal DBS. Patient EMG recordings could be classified into two groups: one consisting of patients who at rest demonstrated a dominant low frequency component of activity on power spectral analysis (ranging from 2 to 5 Hz), and one group in which this dominant pattern was absent. Early postoperative improvements (within 2-3 days) were observed in the former group, whereas the latter group benefited more gradually (over several months). Analysis of EMG activity may provide a sensitive means of identifying dystonic patients who are likely to be most responsive to functional neurosurgical intervention.

Action Potentials↗
PubMed2006

Pedunculopontine nucleus electric stimulation alleviates akinesia independently of dopaminergic mechanisms.

The symptom of Parkinson's disease that is most disabling and difficult to treat is akinesia. We have previously shown that low-frequency stimulation of the pedunculopontine nucleus can alleviate such akinesia in a macaque rendered Parkinsonian using 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine. Here, we have extended that study to show that adding stimulation of the pedunculopontine nucleus to levodopa treatment in this Parkinsonian monkey increased its motor activity significantly more than levodopa alone. This additivity suggests that pedunculopontine nucleus stimulation may improve movement by acting at a site downstream from where levodopa therapy affects the basal ganglia.

Animals↗
PubMed2006

Modulation of cell cycle progression by CTLA4-CD80/CD86 interactions on CD4+ T cells depends on strength of the CD3 signal: critical role for IL-2.

Cytotoxic T-lymphocyte antigen 4 (CTLA4) is a well-studied T cell costimulatory receptor that is known to inhibit T cell activation. In this study, the relationship between strength of the first signal and costimulatory interactions on primary mouse CD4(+) T cells was investigated. CTLA4-CD80/CD86 interactions differentially modulate T cell cycling based on the mode of CD3 signal: Activation with plate-bound (pb) anti-CD3 generates a strong signal compared with a weak signal with soluble (sol) anti-CD3, resulting in approximately sevenfold higher amounts of interleukin (IL)-2 and an increase in cell cycling. Activation of T cells with sol anti-CD3 (weak signal) together with CTLA4-CD80/CD86 blockade lowers IL-2 production and cell cycling, demonstrating an enhancing role for these interactions. Conversely, blockade of CTLA4-CD80/CD86 interactions on T cells activated with pb anti-CD3 (strong signal) increases proliferation, which is consistent with CTLA4 as a negative regulator. Also, coculture of T cells with Chinese hamster ovary cells expressing CD80 or CD86 demonstrates that the strength of the primary signal plays an important role. It is important that modulation of IL-2 amounts leads to distinct alterations in the functional effects of CTLA4-CD80/CD86 interactions. On increasing IL-2 amounts, activation of T cells stimulated with sol anti-CD3 (weak signal) and CTLA4-CD80/CD86 blockade is greater compared with control. Concurrently, neutralization of IL-2 greatly reduces activation of T cells stimulated with pb anti-CD3 (strong signal) and CTLA4-CD80/CD86 blockade compared with control. These results underscore the importance of strength of first signal, CTLA4-CD80/CD86 interactions, and IL-2 amounts in modulating primary CD4(+) T cell responses.

Animals↗
PubMed2006

The ubiquitin-proteasome system.

The 2004 Nobel Prize in chemistry for the discovery of protein ubiquitination has led to the recognition of cellular proteolysis as a central area of research in biology. Eukaryotic proteins targeted for degradation by this pathway are first 'tagged' by multimers of a protein known as ubiquitin and are later proteolyzed by a giant enzyme known as the proteasome. This article recounts the key observations that led to the discovery of ubiquitin-proteasome system (UPS). In addition, different aspects of proteasome biology are highlighted. Finally, some key roles of the UPS in different areas of biology and the use of inhibitors of this pathway as possible drug targets are discussed.

Animals↗
PubMed2005

CTLA4-CD80/CD86 interactions on primary mouse CD4+ T cells integrate signal-strength information to modulate activation with Concanavalin A.

The mechanisms by which concanavalin A (Con A), a lectin, activates T cells are poorly studied. A low dose of Con A is stimulatory for T cells, whereas a high dose of Con A results in suppression of proliferation and enhanced T cell death. The expression and functional roles of costimulatory receptors, CD28 and cytotoxic T-lymphocyte antigen 4 (CTLA4), and their ligands, CD80 and CD86, on primary mouse CD4(+) T cells after activation with different doses of Con A were studied. CTLA4-CD80/CD86 interactions in this T:T cell activation model demonstrate distinct outcomes depending on the dose of Con A. CTLA4-CD80/CD86 interactions inhibit CD4(+) T cell cycling and survival after activation with a suppressive dose of Con A by increasing oxidative stress and decreasing levels of BclX(L). The enhanced CD4(+) T cell death with a suppressive dose of Con A is dependent on excess H(2)O(2) and nitric oxide but is independent of Fas and caspase activity. It is surprising that the increased proliferation of CD4(+) T cells with a suppressive dose of Con A on blocking CTLA4-CD80/CD86 interactions is largely interleukin (IL)-2-independent but is cyclosporine A-sensitive. On activation with a stimulatory dose of Con A, CTLA4-CD80/CD86 interactions enhance T cell activation and survival by reducing the production of reactive oxygen species, increasing IL-2 and BclX(L) levels. Here IL-10 but not transforming growth factor-beta plays a functional role. In summary, CTLA4-CD80/CD86 interactions on T cells integrate signal strength, based on the dose of Con A, to enhance or inhibit primary mouse CD4(+) T cell cycling and survival.

Animals↗
PubMed2005

Deep brain stimulation for generalised dystonia and spasmodic torticollis.

Dystonia appears distinct from the other tremulous disorders in that improvement following deep brain stimulation frequently appears in a delayed and progressive manner. The rate of this improvement and the point at which no further progress can be expected are presently unknown. The establishment of these parameters is important in the provision of accurate and relevant prognostic information to these patients, their carers, and their treating physicians. We studied 12 consecutive patients with generalised dystonia (n=6) and spasmodic torticollis (n=6) who underwent bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) and were followed up for a minimum of 2 years postoperatively. Standard rating scales were used to quantify their neurological improvement. Both groups experienced a statistically significant improvement in their rating scores at both one and two years following surgery. At 2 years follow-up, the spasmodic torticollis group exhibited a 59% improvement in their total Toronto Western Spasmodic Torticoilis Rating Scale (TWSTRS) rating score and the generalised dystonia group attained a 46% improvement in their overall Burke, Fahn and Marsden Dystonia Rating Scale (BFMDRS) evaluation. Ninety-five percent of the final improvement was attained by 6.4 months in the generalised dystonia group and by 6.6 months in those with spasmodic torticollis. There was no significant improvement after one year postoperatively. These findings add further support to GPi DBS as an effective treatment for generalised dystonia and spasmodic torticollis, and furnish important information as to the expected rate of improvement and the point at which no further gains can be reasonably anticipated.

Adolescent↗
PubMed2005

Effect of GPi DBS on functional imaging of the brain in dystonia.

Five patients with idiopathic dystonic conditions, treated successfully with deep brain stimulation (DBS) of the globus pallidus internus (GPi), were studied using single-photon emission tomography (SPET) in order to evaluate brain perfusion in the presence and absence of DBS. Comparison was made between the "on" and "off" DBS scans on an individual basis and also as part of a group analysis. Whilst the individual data suggested great regional variation in cerebral perfusion between individuals, the results of the group analysis revealed several topographically similar areas of the brain where relative hyperperfusion in the absence of DBS was common to all patients. Based on these results we postulate on possible mechanisms for this phenomenon.

Adult↗
PubMed2005

Somatotopic organization of the human periventricular gray matter.

The periventricular gray (PVG) matter is an established anatomical target for chronic deep brain stimulation (DBS) in the treatment of certain intractable pain syndromes. Data relating to the representation of pain and other somatosensory modalities within the PVG in humans are negligible. We examined the character and location of somatosensory responses elicited by electrical stimulation along the length of the PVG in a patient who underwent unilateral DBS for intractable nociceptive head pain. Consistent responses were obtained and indicated the presence of a somatotopic representation in this region. The contralateral lower limb was represented cranially, followed by the upper limb and trunk, with the face area located caudally, near the level of the superior colliculi. Bilateral representation was only observed in the forehead and scalp.

Adult↗
PubMed2005

Thalamotomy versus thalamic stimulation for multiple sclerosis tremor.

Disabling intractable tremor occurs frequently in patients with multiple sclerosis (MS). There is currently no effective medical treatment available, and the results of surgical intervention have been variable. Thalamotomy has been the mainstay of neurosurgical therapy for intractable MS tremor, however the popularisation of deep brain stimulation (DBS) has led to the adoption of chronic thalamic stimulation in an attempt to ameliorate this condition. With the goal of examining the relative efficacy and adverse effects of these two surgical strategies, we studied twenty carefully selected patients with intractable MS tremor. Thalamotomy was performed in 10 patients, with chronic DBS administered to the remaining 10. Both thalamotomy and thalamic stimulation produced improvements in postural and intention tremor. The mean improvement in postural tremor at 16.2 months following surgery was 78%, compared with a 64% improvement after thalamic stimulation (14.6 month follow-up) (P > 0.05). Intention tremor improved by 72% in the group undergoing thalamotomy, a significantly larger gain than the 36% tremor reduction following DBS (P < 0.05). Early postoperative complications were common in both groups. Permanent complications related to surgery occurred in four patients overall. Following thalamotomy, long-term adverse effects were observed in three patients (30%), and comprised hemiparesis and seizures. Only one patient in the thalamic stimulation group experienced a permanent deficit (monoparesis). We conclude that thalamotomy is a more efficacious surgical treatment for intractable MS tremor, however the higher incidence of persistent neurological deficits in patients receiving lesional surgery may support the use of DBS as the preferred surgical strategy.

Adult↗
PubMed2004

Pedunculopontine nucleus stimulation improves akinesia in a Parkinsonian monkey.

We have studied the effects of stimulating the pedunculopontine nuclei through a fully implanted macroelectrode with a s.c. implantable pulse generator whose parameters can be programmed telemetrically, in a macaque before and after inducing Parkinsonian akinesia with MPTP. Our results show that in the normal monkey high frequency stimulation of the pedunculopontine nuclei reduces motor activity while low frequency stimulation increases it significantly over baseline. After making the monkey Parkinsonian with MPTP, unilateral low frequency stimulation of the pedunculopontine nuclei led to significant increases in activity. These results suggest that pedunculopontine nuclei stimulation could be clinically effective in treating advanced Parkinson's disease and other akinetic disorders.

Animals↗
PubMed2004

The MHC-encoded class I molecule, H-2Kk, demonstrates distinct requirements of assembly factors for cell surface expression: roles of TAP, Tapasin and beta2-microglobulin.

Major histocompatibility complex encoded class I (MHC-I) molecules display peptides derived from endogenous proteins for perusal by CD8+ T lymphocytes. H6, a mouse hepatoma cell line, expresses low levels of surface H-2Dd but not H-2Kk. Surface H-2Dd molecules are unstable and their levels, but not H-2Kk, are induced at 22 degrees C. Immunoprecipitation experiments revealed that H-2Kk, H-2Dd and beta2-microglobulin (beta2m) are expressed intracellularly; however no conformed MHC-I are present. Transcriptional profiling of factors required for MHC-I assembly demonstrated greatly reduced levels of the Transporter associated with antigen processing (Tap)2 subunit. The role of key assembly molecules in the MHC-I pathway was investigated by ectopic expression studies. Overexpression of beta2m enhanced surface H-2Dd, but not H-2Kk, levels whereas overexpression of TAP2 rescued surface H-2Kk, but not H-2Dd, levels. Interestingly, Tapasin plays a dual role: first, in quality control by reducing the induced surface expression of TAP2-mediated H-2Kk and beta2m-mediated H-2Dd levels. Secondly, Tapasin overexpression increases Tap2 transcripts and cooperates with TAPl or human beta2m to enhance surface H-2Kk expression; this synergy is TAP-dependent as demonstrated by infected cell protein 47 (ICP47) inhibition studies. Unlike the well studied H-2 MHC-I alleles, H-2Kb, H-2Db, H-2Kd and H-2Dd, a functional TAP is "essential" for H-2Kk cell surface expression.

ATP-Binding Cassette Transporters↗
PubMed2004

Comparative genomics and functional roles of the ATP-dependent proteases Lon and Clp during cytosolic protein degradation.

The general pathway involving adenosine triphosphate (ATP)-dependent proteases and ATP-independent peptidases during cytosolic protein degradation is conserved, with differences in the enzymes utilized, in organisms from different kingdoms. Lon and caseinolytic protease (Clp) are key enzymes responsible for the ATP-dependent degradation of cytosolic proteins in Escherichia coli. Orthologs of E. coli Lon and Clp were searched for, followed by multiple sequence alignment of active site residues, in genomes from seventeen organisms, including representatives from eubacteria, archaea, and eukaryotes. Lon orthologs, unlike ClpP and ClpQ, are present in most organisms studied. The roles of these proteases as essential enzymes and in the virulence of some organisms are discussed.

Adenosine Triphosphate↗