43 research outputs found
Mutant Exon1 Huntingtin Aggregation is Regulated by T3 Phosphorylation-Induced Structural Changes and Crosstalk between T3 Phosphorylation and Acetylation at K6
No full textHerein, we used protein semisynthesis to investigate, for the first time, the effect of lysine acetylation and phosphorylation, as well as the crosstalk between these modifications on the structure and aggregation of mutant huntingtin exon1 (Httex1). Our results demonstrate that phosphorylation at T3 stabilizes the α-helical conformation of the N-terminal 17 amino acids (Nt17) and significantly inhibits the aggregation of mutant Httex1. Acetylation of single lysine residues, K6, K9 or K15, had no effect on Httex1 aggregation. Interestingly, acetylation at K6, but not at K9 or K15, reversed the inhibitory effect of T3 phosphorylation. Together, our results provide novel insight into the role of Nt17 post-translational modifications in regulating the structure and aggregation of Httex1 and suggest that its aggregation and possibly its function(s) are controlled by regulatory mechanisms involving crosstalk between different PTMs
Resisting the resistible:re-writing myths of partition in the works of Ritwik Ghatak
No full textFor all of the individual, collective and national trauma caused by the Indian Partition, perhaps the most significant legacy has been the way the two new nations of India and Pakistan have written the (hi)stories of Partition to serve contemporary political needs. Both countries have a huge amount of investment in their versions of the past, and public dissemination of knowledge of the past amply demonstrates this. This article will examine the way Partition has featured in the work of Bengali cinema-director, author and playwright Ritwik Ghatak and the way Ghatak resists and rewrites in various ways this state-sanctioned version of his country's and his own past. The Bengal Partition provides the context within which all of Ghatak's work is situated. Interestingly, however, Ghatak never depicts the act of partition itself, choosing instead as his subject the streams of refugees who left what was then East Pakistan and is now Bangladesh, and came to Kolkata in West Bengal. Ghatak's most characteristic story, then, is the story of the educated, middle-to-upper-class East Bengali refugee, who has lost everything by having to move west. This story is the story of Ghatak's own family and the family of the thousands of others, including the present writer, and, as such, it is not surprising that it has become the predominant Bengali narrative of Partition. By focusing on Ghatak's oeuvre, then, this article will examine this narrative of partition, thereby showing how Ghatak uses it to resist the most pernicious, and also most permanent myth of the Indian Partition – that it was an act which led to two different, mutually exclusive, heterogeneous but unified nations
A programmable “build–couple” approach to the synthesis of heterofunctionalized polyvalent molecules
No full textTopics in high dimensional statistical estimation and inference
No full textThis thesis deals with three problems. The first two of the problems are related in that they are concerned with estimation of correlation and precision matrix in spectral norm. These two problems are tackled in Chapters 2, 3. The third problem is the construction of chi-squared type test for groups of variables in high dimensional linear regression. In Chapter 2, we study concentration in spectral norm of nonparametric estimates of correlation matrices. We study two nonparametric estimates of correlation matrices in Gaussian copula models and prove that when both the number of variables and sample size are large, the spectral error of the nonparametric estimators is of no greater order than that of the latent sample covariance matrix, at least when compared with some of the sharpest known error bounds for the later. As an application, we establish the minimax optimal rate in the estimation of high-dimensional bandable correlation matrices via tapering off of these nonparametric estimators. An optimal convergence rate for sparse principal component analysis is also established. In Chapter 3, we study the sparse precision matrix estimation procedure in the same Gaussian copula model as in Chapter 2. We employ the scaled Lasso procedure for inversion of nonparametric correlation matrix estimates based on Kendall’s tau. We prove the optimal rate of convergence in estimation of sparse precision matrices under the weaker condition of bound on the spectral norm of the precision matrix. Chapter 4 deals with confidence regions and approximate chi-squared tests for variable groups in high-dimensional linear regression. We develop a scaled group Lasso for efficient chi-squared-based statistical inference of variable groups. We prove that the proposed methods capture the benefit of group sparsity under proper conditions, for statistical inference of the noise level and variable groups, large and small. Oracle inequalities are provided for the scaled group Lasso in prediction and several estimation losses, and for the group Lasso as well in a weighted mixed loss. Some simulation results are also provided in support of the theory.Ph.D.Includes bibliographical referencesby Ritwik Mitr
Ganciclovir derivatives for modulating innate and adaptive immunity and for use in immunotherapy
No full textCompositions and methods for modulating innate and adaptive immunity and for use in immunotherapy are disclosed. In particular, the invention relates to novel ganciclovir derivatives and methods of using them for the treatment of immune-related disorders, including inflammation, autoimmunity, and infections, and neurological disorders, and cancer.LMN
Elucidating the Role of Site-Specific Nitration of α-Synuclein in the Pathogenesis of Parkinson’s Disease via Protein Semisynthesis and Mutagenesis
No full text
Synthesis of N<sub>3</sub>S, N<sub>3</sub>O, N<sub>2</sub>S<sub>2</sub>, N<sub>2</sub>O<sub>2</sub>, N<sub>2</sub>SO and N<sub>2</sub>OS porphyrins with one meso-unsubstituted carbon
No full textA simple straightforward synthesis of N3S, N2S2, N2O2, N2SO and N2OS porphyrins and an improved method for the synthesis of an N3O porphyrin with one meso-unsubstituted carbon atom are reported from readily available precursors. The reactivity of the meso-unsubstituted carbon atom was demonstrated by carrying out bromination followed by Heck coupling reactions
Elucidating the Role of Site-Specific Nitration of alpha-Synuclein in the Pathogenesis of Parkinson's Disease via Protein Semisynthesis and Mutagenesis
No full textParkinsons disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and the presence of intraneuronal inclusions consisting of aggregated and post-translationally modified a-synuclein (a-syn). Despite advances in the chemical synthesis of a-syn and other proteins, the generation of site-specifically nitrated synthetic proteins has not been reported. Consequently, it has not been possible to determine the roles of nitration at specific residues in regulating the physiological and pathogenic properties of a-syn. Here we report, for the first time, the site-specific incorporation of 3-nitrotyrosine at different regions of a-syn using native chemical ligation combined with a novel desulfurization strategy. This strategy enabled us to investigate the role of nitration at single or multiple tyrosine residues in regulating a-syn structure, membrane binding, oligomerization, and fibrils formation. We demonstrate that different site-specifically nitrated a-syn species exhibit distinct structural and aggregation properties and exhibit reduced affinity to negatively charged vesicle membranes. We provide evidence that intermolecular interactions between the N- and C-terminal regions of a-syn play critical roles in mediating nitration-induced a-syn oligomerization. For example, when Y39 is not available for nitration (Y39F and Y39/125F), the extent of cross-linking is limited mostly to dimer formation, whereas mutants in which Y39 along with one or multiple C-terminal tyrosines (Y125F, Y133F, Y136F and Y133/136F) can still undergo nitration readily to form higher-order oligomers. Our semisynthetic strategy for generating site-specifically nitrated proteins opens up new possibilities for investigating the role of nitration in regulating protein structure and function in health and disease.LMN
A New Caged-Glutamine Derivative as a Tool To Control the Assembly of Glutamine-Containing Amyloidogenic Peptides
No full textWe present the design, synthesis, and characterization of a novel photocaged glutamine derivative (modified on the side chain of glutamine), and describe its use in enhancing peptide stability and solubility. Our results demonstrate that this approach can be used to develop molecular switches to control the folding and β-sheet formation of amyloidogenic peptides.LMN
