Risperidone and its Deconstructed Analogs: Functional Effects on the 5HT2AR

G protein-coupled receptors (GPCRs) are seven-transmembrane domain receptors that sense extracellular signal and activate intracellular signaling pathways. The serotonin 5HT2A receptor (or 2AR) is one of the GPCRs coupled to Gq proteins, activating PLC and hydrolyzing PIP2. This hydrolysis causes a diffusion of bound PIP2 away from the channel binding site resulting in G protein-gated inwardly rectifying K+ channel (GIRK) inhibition and a downstream stimulation of Ca2+ release from endoplasmic reticulum stores. Previous experiments have demonstrated that the serotonin 5HTA receptor is a target of serotonergic psychedelic drugs, such as LSD, and partially mediates the action of many atypical antipsychotic drugs. However, the portion responsible for the functional activity and response of these drugs is unknown. The purpose of this study was to functionally characterize four deconstructed analogs of risperidone, an atypical antipsychotic agent, using two assays: by application to 5HT2A receptors in Xenopus oocytes and by calcium epifluorescence imaging in a HEK293 cell line stably expressing 2AR. Our experiments revealed that two analogs, RHV-006 and RHV-008, are partial agonists by themselves and greatly antagonize the effects of serotonin. RHV-006 and RHV-008 contain the piperidine and benzisoxizole ring systems of risperidone. RHV-023 and RHV-026, on the other hand, are more efficacious agonists than RHV-006 and RHV-008 but display a non-antagonistic effect with serotonin. RHV-023 and RHV-026 contain both the piperidine and benzisoxizole ring systems in addition to part of the diazabicyclo ring, thus containing more of risperidone’s structure than RHV-006 and RHV-008

Combined gene expression analysis in HIV Associated Dementia, Alzheimer’s disease and Parkinson’s disease- An in-silico approach

Human immunodeficiency virus (HIV) Type 1 infection predominantly affects the immune system. Nevertheless, scientific studies have proven its association with the Central Nervous system (CNS) causing several neurological complications leading to HIV Associated Dementia (HAD). HAD is characterized by a progressive, disabling decline in essential CNS functions such as cognition, motor control and behavior. These are the general characteristics of the most common Neuro degenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The genetics of AD and PD is widely studied and clinical studies have shown cohesion in the pathology of HAD, AD and PD. Analysing the concurrent expression patterns of large number of genes amongst these related diseases will aid in establishing correlations between the genes and their functions.We have analysed the gene expression datasets of HAD, AD and PD from GEO database to determine the overlapping genes and transcription factors involved. The datasets were normalized using R-Bioconductor, and statistical analysis was performed to identify the significant genes using limma and related packages in R. Although substantial amount of common proteins among HAD and other Neuro degenerative diseases have been previously reported, our findings can help in expanding the pool of target genes and further enhancing the knowledge about the convergent pathways among HAD, AD and PD. These common markers identified will provide insights into parallel pathways of disease mechanisms and further assist in the understanding of progression of HAD pathogenesis

Coupled heat conduction and deformation in a viscoelastic composite cylinder

This study analyzes the thermo-mechanical response of a composite cylinder made up of two layers of linear isotropic viscoelastic materials that belong to the class of non-Thermorheologically Simple Material. The effect of time-varying temperature field due to unsteady heat conduction phenomenon is analyzed on the short term and long term material response in terms of stress, strain and displacement fields. The material properties of the two layers of the composite cylinder at any given location and time are assumed to depend on the temperature at that location at that given instant of time. Sequentially coupled analyses of heat conduction and deformation of viscoelastic composite cylinder is carried out to obtain the overall response. The stress and strain field developed in the composite cylinder is evaluated as the discontinuity in hoop stress and radial strain at the interface of the two layers caused due to mismatch in material properties may lead to delamination if it exceeds critical value. Analytical solution for the stress, strain and displacement fields of the viscoelastic composite cylinder is developed from the corresponding solution of linear elasticity problem by using the Correspondence Principle. The analytical solution for determining the temperature dependent stress, strain and displacement fields is further developed by incorporating the temperature dependence on the material properties and modeling the material as non-TSM. To analyze more complex geometry with general loading and boundary conditions, Finite Element(FE) analysis of the composite cylinder is performed and the results of analytical and FE method are found to be in good agreement. Parametric studies are carried out to understand the effect of change in material parameters namely the Prony coefficients in the transient creep compliance, characteristic of creep time in transient creep compliance and the instantaneous elastic compliance, on the overall response of the composite cylinder. The effect of different temperature dependent functions of the material properties, namely linear temperature variation and quadratic polynomial variation on the overall material response is also analyzed. It is observed that the effect of change in elastic properties significantly increases the jump in hoop stress and radial strain. It is also observed that when the materials are highly dependent on temperature the jump in radial strain and hoop stress increases significantly. The radial displacement also increases by a significant amount in both the cases

Understanding the Effects of Online Paywalls on Information Access

At the start of the public’s use of the internet in 1983, whatever news made it online was expected to be open and free of charge. However, the idea that news should always be accessible online changed as newspapers moved most of their content online and needed online subscriptions to help account for the decline in physical subscriptions. Paywalls were created to enforce this. An online paywall is a barrier to an article or site that can only be surpassed with paid subscriptions. Paywalls allowed traditional news outlets to move their physical subscriptions to digital models, and attract new, online-only subscribers. While this model generates additional revenue to keep news organizations functional, it also restricts information access for many who cannot or do not want to pay for it. This paper explores the existing literature on paywalls, with the intent of finding potential solutions or alternatives to the traditional online paywall system

Aftermath of pulmonary tuberculosis : computed tomography assessment

Purpose: Pulmonary tuberculosis (PTB) has clinically significant sequelae, even after recommended treatment completion. It is important to recognise these sequelae for accurate assessment of severity and treatment planning, if indicated. Material and methods: We retrospectively analysed contrast-enhanced computed tomography (CT) scans of chest of 100 patients with previous history of treated pulmonary tuberculosis, excluding those with active pulmonary disease. CT findings were analysed based on parenchymal, airway, pleural, mediastinal, and vascular sequelae of PTB. Results: Parenchymal sequelae included fibrosis with architectural distortion and volume loss (90%), cavities (21%) (with aspergillomas noted in 19% of these cases), and tuberculomas (54%). Airway involvement was noted as bronchiectasis (77%) and bronchial stenosis (4%) but none with broncholithiasis. Mediastinal sequelae included lymph node calcification (74%), fibrosing mediastinitis (1%), and pericardial tuberculosis (2%). Pleural sequelae included pleural thickening (22%), with 40.9% of these patients showing calcifications, and one patient with chronic chylous pleural effusion. Vascular sequelae included Rasmussen aneurysms (4%), enlarged bronchial arteries (3%), and systemic bronchial collaterals in 1% of our patients. Conclusions: PTB has multiple appalling sequelae, which require due attention and appropriate treatment in symptomatic cases. Radiological evaluation forms an integral part in patient assessment and decision making

NMR Line Shape Analysis of a Multi-state Ligand Binding Mechanism in Chitosanase

Chitosan interaction with chitosanase was examined through analysis of spectral line shapes in the NMR HSQC titration experiments. We established that the substrate, chitosan hexamer, binds to the enzyme through the three-state induced-fit mechanism with fast formation of the encounter complex followed by slow isomerization of the bound-state into the final conformation. Mapping of the chemical shift perturbations in two sequential steps of the mechanism highlighted involvement of the substrate-binding subsites and the hinge region in the binding reaction. Equilibrium parameters of the three-state model agreed with the overall thermodynamic dissociation constant determined by ITC. This study presented the first kinetic evidence of the induced-fit mechanism in the glycoside hydrolases

OCCLUSION IN IMPLANT-AT A GLANCE

Objectives: Occlusion is a critical and very important component for the clinical success and longevity of dental implants. This review article focuses on the various aspects of implant protective occlusion. Our scientific literature regarding implant occlusion, particularly in implant-supported fixed dental prostheses remains controversial.Materials and methods: A search strategy was performed in MEDLINE/PubMed, Scopus and Google Scholar with keywords – ‘implants’ and ‘occlusion’, ‘implants’ and ‘fixed prosthesis, ‘implants’ and ‘fixed dental prostheses’, ‘implants’ and ‘partial edentulism’, ‘implants’ and ‘complications’, ‘implants’ and ‘failures’, ‘implants’ and ‘cantilever’, ‘implants’ and ‘occlusal load’.Results: 135 articles were retrieved. After hand search a total of 290 articles were identified. Ultimately, 30 articles were selected and summarized and discussed as they met the selection criteria.Conclusion: Most of the available clinical data are controversial. Implant-protected occlusion can be accomplished by decreasing the width of the occlusal table and improving the direction of force. By doing these things, we can minimize overload on bone-implant interfaces and implant prostheses, to maintain an implant load within the physiological limits of individualized occlusion, and ultimately provide long-term stability of implants and implant prostheses. Current clinical practices rely heavily on principles extracted from the natural dentition or removable dental prostheses on complete edentulous patients and on expert opinions

FMRP Control of Ribosome Translocation Promotes Chromatin Modifications and Alternative Splicing of Neuronal Genes Linked to Autism [preprint]

Silencing of FMR1 and loss of its gene product FMRP results in Fragile X Syndrome. FMRP binds brain mRNAs and inhibits polypeptide elongation. Using ribosome profiling of the hippocampus, we find that ribosome footprint levels in Fmr1-deficient tissue mostly reflect changes in RNA abundance. Profiling over a time course of ribosome runoff in wildtype tissue reveals a wide range of ribosome translocation rates; on many mRNAs, the ribosomes are stalled. Sucrose gradient ultracentrifugation of hippocampal slices after ribosome runoff reveals that FMRP co-sediments with stalled ribosomes; and its loss results in decline of ribosome stalling on specific mRNAs. One such mRNA encodes SETD2, a lysine methyltransferase that catalyzes H3K36me3. ChIP-Seq demonstrates that loss of FMRP alters the deployment of this epigenetic mark on chromatin. H3K36me3 is associated with alternative pre-RNA processing, which we find occurs in an FMRP-dependent manner on transcripts linked to neural function and autism spectrum disorders

A rare case of hydatid cyst of the interventricular septum

A Hydatid disease or Echinococcosis is a zoonotic disease caused by the larvae (metacestode) of the cestode species of the genus Echinococcus. Humans are the accidental hosts of the diseases; they usually acquire it from canines; which are the definite host. It can present with systemic cyst, while cardiac manifestation of the disease is rare, due to contractile property of the heart’s muscle fiber which provide resistance. In this case report, the patient is diagnosed with hydatid cyst in the inter ventricular septum; it’s diagnosis and its successful treatment with surgery and albendazole. As, inter ventricular septum hydatid cyst occurs in only 0.5-2% cases, it’s a unique case and its successful treatment and diagnosis can help the physicians in the future to treat a similar case as this