Molecular dynamics simulation of the phosphorylation-induced conformational changes of a tau peptide fragment

Aggregation of the microtubule associated protein tau (MAPT) within neurons of the brain is the leading cause of tauopathies such as Alzheimer's disease. MAPT is a phospho-protein that is selectively phosphorylated by a number of kinases in vivo to perform its biological function. However, it may become pathogenically hyperphosphorylated, causing aggregation into paired helical filaments and neurofibrillary tangles. The phosphorylation induced conformational change on a peptide of MAPT (htau225-250) was investigated by performing molecular dynamics simulations with different phosphorylation patterns of the peptide (pThr231 and/or pSer235) in different simulation conditions to determine the effect of ionic strength and phosphate charge. All phosphorylation patterns were found to disrupt a nascent terminal ß-sheet pattern (226VAVVR230 and 244QTAPVP249), replacing it with a range of structures. The double pThr231/pSer235 phosphorylation pattern at experimental ionic strength resulted in the best agreement with NMR structural characterization, with the observation of a transient α-helix (239AKSRLQT245). PPII helical conformations were only found sporadically throughout the simulations

Molecular modelling of platelet endothelial cell adhesion molecule 1 and its interaction with glycosaminoglycans

The Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1) has many functions including its roles in leukocyte extravasation as part of the inflammatory response, and in the maintenance of vascular integrity through its contribution to endothelial cell-cell adhesion. Various heterophilic ligands of PECAM-1 have been proposed. The possible interaction of PECAM-1 with glycosaminoglycans (GAGs) is the focus of this thesis. The three dimensional structure of the extracellular immunoglobulin (Ig)-domains of PECAM-1 was constructed using homology modelling and threading methods. Potential heparin/heparan sulfate binding sites were predicted on the basis of their amino acid consensus sequences and a comparison with known structures of sulfate binding proteins. Heparin and other GAG fragments have been docked to investigate the structural determinants of their protein binding specificity and selectivity. It is predicted that two regions in PECAM-1 appear to bind heparin oligosaccharides. A high affinity binding region was located in Ig-domains 2 and 3 and a low affinity region was located in Ig-domains 5 and 6.These GAG binding regions are distinct from regions involved in PECAM-1 homophilic interactions. Docking of heparin fragments of different size revealed that fragments as small as a pentasaccharide appear to be able to bind to domains 2 and 3 with high affinity. Binding of longer heparin fragments suggests that key interactions can occur between six sulfates in a hexasaccharide with no further increase in binding affinity for longer fragments. Molecular dynamics simulations were also used to characterise and quantify the interactions of heparin fragments with PECAM-1. These simulations confirmed the existence of regions of high and low affinity for GAG binding and revealed that both electrostatic and van der Waals interactions determine the specificity and binding affinity of GAG fragments to PECAM-1. The simulations also suggested the existence of ‘open’ and ‘closed’ conformations of PECAM-1 around domains 2 and 3

RobustL2S: Speaker-Specific Lip-to-Speech Synthesis exploiting Self-Supervised Representations

Significant progress has been made in speaker dependent Lip-to-Speech synthesis, which aims to generate speech from silent videos of talking faces. Current state-of-the-art approaches primarily employ non-autoregressive sequence-to-sequence architectures to directly predict mel-spectrograms or audio waveforms from lip representations. We hypothesize that the direct mel-prediction hampers training/model efficiency due to the entanglement of speech content with ambient information and speaker characteristics. To this end, we propose RobustL2S, a modularized framework for Lip-to-Speech synthesis. First, a non-autoregressive sequence-to-sequence model maps self-supervised visual features to a representation of disentangled speech content. A vocoder then converts the speech features into raw waveforms. Extensive evaluations confirm the effectiveness of our setup, achieving state-of-the-art performance on the unconstrained Lip2Wav dataset and the constrained GRID and TCD-TIMIT datasets. Speech samples from RobustL2S can be found at https://neha-sherin.github.io/RobustL2S

Mathematical Doodling using the what-if-not approach

There are many ways of generating new problems. This paper proposes one of them, the “what-if-not” approach. The write- up shares how this approach was used to do explorations and create new problems. Not all the generated problems could be solved but the experience was indeed enriching and overwhelming

Study on Security of Online Voting System Using Biometrics and Steganography

Abstract: It is very important to provide security to voting system and mostly which is online one. In this paper we provide security to online voting system with secure user authentication by providing biometric as well as password security to voter accounts. Basic idea behind this is to combine secret key with cover image on the basis of key image. As a result such new image is produced by system called stego image which is quite same as cover image. The key image is a biometric measure, such as a fingerprint image. Extraction of stego image is take place at server side to perform the voter authentication. The system minimizes the risk factor as hacker needs to find not only the template but also secret key and it is not possible. It makes election procedure to be secure against a variety of fraudulent behaviors. To improve speed SHA 256 used for hashing is replaced with MD5

ParrotTTS: Text-to-Speech synthesis by exploiting self-supervised representations

We present ParrotTTS, a modularized text-to-speech synthesis model leveraging disentangled self-supervised speech representations. It can train a multi-speaker variant effectively using transcripts from a single speaker. ParrotTTS adapts to a new language in low resource setup and generalizes to languages not seen while training the self-supervised backbone. Moreover, without training on bilingual or parallel examples, ParrotTTS can transfer voices across languages while preserving the speaker specific characteristics, e.g., synthesizing fluent Hindi speech using a French speaker's voice and accent. We present extensive results in monolingual and multi-lingual scenarios. ParrotTTS outperforms state-of-the-art multi-lingual TTS models using only a fraction of paired data as latter

Role of visual inspection of cervix with acetic acid and high risk human papilloma virus DNA testing in screening for cervical cancer

Background: To evaluate the role of VIA alone and in combination with high risk Human Papilloma virus DNA testing as a screening test for cervical dysplasia and cancer.Methods: 400 symptomatic patients from the gynecology outpatient department were screened using Pap smear and VIA. HPV DNA testing was done for 62 VIA positive and 100 VIA negative women. Colposcopy was done for all women. Those found positive on any or all of the screening tests were subjected to cervical biopsy. The results were analysed for PAP, VIA, HPV and a combined test using VIA and HPV both.Results: VIA had the highest sensitivity (91%) to detect any grade of dysplasia. The sensitivity of the combination test (VIA + HPV) was 80.6% which was lower than that of VIA (91%) and also lower than that of HR HPV DNA detection (86%). The specificity of the combination test (VIA + HPV) was 68.3 % which was significantly higher than that of VIA alone (39%) (p = 0.000) and also higher than that for HPV DNA detection when used alone (56%). Pap smear had the highest specificity (95.12 %) but sensitivity was much lower at 52.7 %.Conclusions: VIA is a highly sensitive screening test. The main disadvantage is its low specificity. However the combination test of VIA + HR HPV testing overcomes this and at the same time maintains a high sensitivity. Thus a test which combines VIA plus HR HPV testing is better screening method than either of the three tests (VIA, HPV, PAP) done alone

An Insight into Application of Land Use Land Cover Analysis towards Sustainable Agriculture within Jhajjar District, Haryana

The increasing population, depletion of natural resources, semi-arid climatic and poor soil health conditions in Jhajjar district of Haryana have drawn major attention towards the changes in Land Use/Land Cover (LULC). The region's increasing population is mainly dependent upon the agrarian economy; thus, sustainable agricultural production is a major thrust area of research. The present study analyses the LULC changes in the area during two decades 2000 – 2020, using remote sensing and Geographic Information System (GIS). Landsat satellite images (Landsat-7 and Landsat-8 satellites) for 2000 and 2020 were analyzed for mixed classification based on unsupervised classification followed by supervised classification. The study area has experienced an increase in agricultural land, surface water bodies and built-up land by 16.89%, 79.73% and 56.41%, respectively. There is a decrease in barren land and fallow land by 48.53% and 36.97%, respectively, as per the five major LULC classes. The LULC analysis indicates an increase in built-up land, which is responsible for controlling agricultural productivity and unsustainable agricultural activities. The study provides a comprehensive understanding of the land use trajectory in a specific region in two decades and associated unsustainable changes in the agrarian economy through pressure on the increase in agricultural production and conversion of land mass into croplands. It also signifies climate-resilient agriculture and the management of sustainable agriculture

Phosphorylation and O-GlcNAcylation of the PHF-1 Epitope of Tau Protein Induce Local Conformational Changes of the C-Terminus and Modulate Tau Self-Assembly Into Fibrillar Aggregates

Phosphorylation of the neuronal microtubule-associated Tau protein plays a critical role in the aggregation process leading to the formation of insoluble intraneuronal fibrils within Alzheimer’s disease (AD) brains. In recent years, other posttranslational modifications (PTMs) have been highlighted in the regulation of Tau (dys)functions. Among these PTMs, the O-β-linked N-acetylglucosaminylation (O-GlcNAcylation) modulates Tau phosphorylation and aggregation. We here focus on the role of the PHF-1 phospho-epitope of Tau C-terminal domain that is hyperphosphorylated in AD (at pS396/pS404) and encompasses S400 as the major O-GlcNAc site of Tau while two additional O-GlcNAc sites were found in the extreme C-terminus at S412 and S413. Using high resolution NMR spectroscopy, we showed that the O-GlcNAc glycosylation reduces phosphorylation of PHF-1 epitope by GSK3β alone or after priming by CDK2/cyclin A. Furthermore, investigations of the impact of PTMs on local conformation performed in small peptides highlight the role of S404 phosphorylation in inducing helical propensity in the region downstream pS404 that is exacerbated by other phosphorylations of PHF-1 epitope at S396 and S400, or O-GlcNAcylation of S400. Finally, the role of phosphorylation and O-GlcNAcylation of PHF-1 epitope was probed in in-vitro fibrillization assays in which O-GlcNAcylation slows down the rate of fibrillar assembly while GSK3β phosphorylation stimulates aggregation counteracting the effect of glycosylation.Peer Reviewe

Primary Posterior Sagittal Anorectoplasty in male neonates with Anorectal Malformations: A tertiary care hospital experience

Background: The conventional surgical management for a male neonate with intermediate Anorectal Malformation (ARM) involves three stages – the creation of a diversion stoma in the neonatal period, a definitive pull-through procedure/ Posterior Sagittal Anorectoplasty (PSARP) followed by stoma closure. With this background, we present our experience with Single-stage primary definitive repair in selected male neonates with ARM. Methods: Medical records of male ARM cases managed from 2016 to 2018 were reviewed. Male neonates who underwent primary PSARP were analysed retrospectively. Results: A total of 35 records were found, out of which 12 male neonates underwent primary PSARP. The      median gestational age and birth weight were 36.7 weeks and 2.75 kg respectively. Fistula with urinary tract was documented in all. The mean operative time was      65 minutes +/- 15 minutes. Two neonates had minor superficial surgical site infection at neo-anus. Anal dilatations were started after 2 weeks. At follow-up period of 3 years, 11 patients were continent; one patient had constipation with pseudo-incontinence which was successfully being managed by bowel management programme. Conclusions: A primary definitive procedure is feasible when performed on carefully selected male neonates with ARM and also avoids the morbidity of stoma and multiple surgeries and follow-up visits to hospitals