Structural Dynamics and Allosteric Signaling in Ionotropic Glutamate Receptors

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate excitatory neurotransmission events in the central nervous system. All distinct classes of iGluRs (AMPA, NMDA, Kainate) are composed of an N-terminal domain (NTD) and a ligand-binding domain (LBD) in their extracellular domain, a transmembrane domain (TMD) and an intracellular carboxy-terminal domain (CTD). Ligand binding to the LBD facilitates ion channel activation. The NTDs modulate channel gating allosterically in NMDA receptors (NMDARs). A similar function of the NTD in AMPA receptors (AMPARs) is still a matter of debate. Taking advantage of recently resolved structures of the NTD and the intact AMPAR, the main focus of this dissertation is a comprehensive examination of iGluR NTD structural dynamics, ligand binding and allosteric potential of AMPARs. We use a multiscale, multi-dimensional approach using coarse-grained network models and all-atom simulations for structural analyses and information theoretic approaches for examination of evolutionary correlations. Our major contribution has been the characterization of the global motions favored by iGluR NTD architecture. These intrinsic motions favor ligand binding in NMDAR NTDs and are also shared by other iGluR NTDs. We also identified structural determinants of flexibility in AMPARs and confirmed their role through in silico mutants. The overall similarity in collective dynamics among iGluRs hints at a putative allosteric capacity of non-NMDARs and has propelled the elucidation of interdomain and intersubunit coupling in the intact AMPAR. To this end, we identified “effector” and “sensor” regions in AMPARs using a perturbation-response technique. We identified potentially functional residues that enable information propagation between effector regions and proposed an efficient mechanism of allosteric communication based on a combination of tools including network models, graph theoretical methods and sequence analyses. Finally, we assessed the “druggability” of iGluR NTDs using molecular dynamics simulations in the presence of probe molecules containing fragments shared by drug-like molecules. Based on our study, we offer key insights into the ligand-binding landscape of iGluR NTD monomers and dimers, and we also identify a novel ligand-binding site in AMPAR dimers. These findings open an avenue of searching for molecules able to bind to iGluR NTDs and allosterically modulate receptor activity

Pulmonary Functions and Work-Related Musculoskeletal Disorders of Road Construction Workers of West Bengal, India

Introduction: Road paving construction workers are exposed to bitumen, asphalt, and other aliphatic amines. They are also exposed to high temperatures and dust during the processing of asphalt production and transport of hot asphalt and bitumen to the working site. Bitumen fumes and asphalt produce respiratory irritations and shortness of breath in asphalt workers. Thus, the purpose of this study was to assess the respiratory impairment of asphalt workers on exposure to bitumen fumes and to assess cardiovascular stress on exposure to high temperatures and heavy workload. Methods: This cross-sectional study has been made on 32 asphalt workers and 20 control group workers of Kolkata city of West Bengal and its surrounding. Anthropometric parameters, blood pressure, and heart rate were measured by standard procedure. Respiratory parameters were taken by Digital Spirometer (Spirovit SP1) and respiratory symptoms & musculoskeletal problems were recorded by a standard questionnaire. Results: The study indicated that prolong exposure to bitumen fumes may enhance the risk of lung impairment by reduction of all respiratory parameters (p< 0.05-0.001). Smoking habits and the reluctance to use protective gadgets among asphalt workers increase the risk of respiratory distress.22% of workers reported chest tightness, 20% had Chronic Bronchitis and10% suffered from Bronchial asthma. The maximum percentage of Paver operators showed Chest tightness (83.33%), Chronic Bronchitis (100%) and Bronchial asthma(66.66%). Musculoskeletal Disorder(MSD) among Paver operators was maximum(33.3-50%). Odds ratio values of the prevalence of respiratory disorder and MSD with >10years of exposure to bitumen fumes vary from 2-4.5.    Exposure to high temperature and heavy workload, mainly among asphalt strippers and paver operators might be the reason for higher heart rate. The awkward working posture might be the cause of musculoskeletal disorders among them. Conclusion: The use of appropriate respiratory protection and the introduction of modern equipment and technologies can reduce the emission of bitumen fumes to protect the health of asphalt workers

THERAPEUTIC AND PREVENTIVE ROLE OF NUTRACEUTICALS AND PRODUCTION OF VITAMINS & LOW-CALORIE SUGARS FROM FOOD-GRADE MICROORGANISMS AS NUTRACEUTICALS

Nutraceuticals may influence number of  disease conditions and many molecular pathways, as well as hundreds of proteins and genes. They frequently influence multiple molecular pathways. The adverse effects of some pharmaceutical therapies and the rise in antibiotic resistance have sparked interest in nutraceutical substances as an alternative therapeutic and preventative approach. They also have the advantage of being more widely available and reasonably priced. Numerous studies have definitely shown how beneficial dietary components are for immune system functions. These include enhancing the mechanism for responding to infections, bolstering immunomodulatory activity, and mitigating the impact of autoimmune disorders and hypersensitivity. Additionally, it has been shown that nutraceuticals have lipid-lowering, anti-inflammatory, anti-cancer, and antioxidant properties. In this review article, we will discuss about the role of microorganisms derived nutraceuticals in human health

Studies on Multifunctional Effect of All-Trans Retinoic Acid (ATRA) on Matrix Metalloproteinase-2 (MMP-2) and Its Regulatory Molecules in Human Breast Cancer Cells (MCF-7)

Background. Vitamin A derivative all-trans retinoic acid (ATRA) is considered as a potent chemotherapeutic drug for its capability of regulating cell growth and differentiation. We studied the effect of ATRA on MMP-2 in MCF-7, human breast cancer cells, and the probable signaling pathways which are affected by ATRA on regulating pro-MMP-2 activity and expression. Methods. Gelatin zymography, RT-PCR, ELISA, Western blot, Immunoprecipitation, and Cell adhesion assay are used. Results. Gelatin zymography showed that ATRA caused a dose-dependent inhibition of pro-MMP-2 activity. ATRA treatment downregulates the expression of MT1-MMP, EMMPRIN, FAK, NF-kB, and p-ERK. However, expression of E-cadherin, RAR, and CRABP increased upon ATRA treatment. Binding of cells to extra cellular matrix (ECM) protein fibronectin reduced significantly after ATRA treatment. Conclusions. The experimental findings clearly showed the inhibition of MMP-2 activity upon ATRA treatment. This inhibitory effect of ATRA on MMP-2 activity in human breast cancer cells (MCF-7) may result due to its inhibitory effect on MT1-MMP, EMMPRIN, and upregulation of TIMP-2. This study is focused on the effect of ATRA on MMP, MMP-integrin-E-cadherin interrelationship, and also the effect of the drug on different signaling molecules which may involve in the progression of malignant tumor development

BRUCELLAR UVEITIS IN EASTERN INDIA

Objective: Brucellosis- one of the major zoonotic diseases, still remains an uncontrolled problem, in regions of high endemicity. Ophthalmic brucellosis is not studied and overlooked in most developing countries.  Considering the severe outcome of undiagnosed ophthalmic brucellosis, in this paper we made attempts to find out whether this disease still remains a health problem in a South East Asian developing country, where study of this disease is largely neglected.  Methods This study was carried out over a one year period from January 2015 to December 2015. Blood samples were collected from clinically confirmed cases of uveitis and they were subjected to five serological and one genus specific molecular investigations, for the detection of Brucella infection.Results Out of 20 uveitis cases, 4 (20%) cases confirmed as brucellar uveitis, by serological tests followed by PCR confirmation. After treatment of brucellosis all the four patients were recovered uneventfully.Conclusion: Brucella infection involving the eye is still a significant problem in South East Asian countries; hence in all uveitis cases in this reason brucellosis should be excluded by available laboratory tests.Government of India (Dept. of Biotechnology the major zoonotic diseases, still remains an uncontrolled problem, in regions of high endemicity. Ophthalmic brucellosis is not studied and overlooked in most developing countries.  Considering the severe outcome of undiagnosed ophthalmic brucellosis, in this paper we made attempts to find out whether this disease still remains a health problem in a South East Asian developing country, where study of this disease is largely neglected.   Methods This study was carried out over a one year period from January 2015 to December 2015. Blood samples were collected from clinically confirmed cases of uveitis and they were subjected to five serological and one genus specific molecular investigations, for the detection of Brucella infection.Results Out of 20 uveitis cases, 4 (20%) cases confirmed as brucellar uveitis, by serological tests followed by PCR confirmation. After treatment of brucellosis all the four patients were recovered uneventfully.Conclusion: Brucella infection involving the eye is still a significant problem in South East Asian countries; hence in all uveitis cases in this reason brucellosis should be excluded by available laboratory tests

NEPHROPROTECTIVE ACTIVITY OF THE ETHNOMEDICINAL PLANTS CAESALPINIA BONDUC AND MOMORDICA DIOICA FROM NE INDIA AGAINST CISPLATIN INDUCED CHEMOTHERAPEUTIC TOXICITY

Objective: Cisplatin a potent anticancer drug is used for treatment against different forms of cancer. However a major limitation of cisplatin is its nephrotoxicity and severe side effects. The main objective of the present study was to investigate the nephroprotective activity of the medicinal plants Caesalpinia bonduc and Momordica dioica against cisplatin-induced nephrotoxicity. Methods: In the present study wistar rat models were intraperitoneally injected with cisplatin for eight consecutive days Plant extracts of different compositions were administered for eight days after injection of cisplatin. The polyphenolic content of the crude extracts was investigated using the Folin Ciocalteau method while the flavonoid estimation was carried out using the aluminium chloride method. The antioxidant activities of the extracts were assayed using the DPPH radical scavenging method. Plant extracts were tested for their nephroprotective ability using modified Berthelot method, uricase method, alkaline picrate method.Results: In the present study it was found that the level of creatinine, urea, uric acid and blood urea nitrogen was lowered by the crude hexane extract of Momordica dioica and ethyl acetate extract of Caesalpinia bonduc as compared to the control group. The total phenolic content and the total flavonoid content was found to be highest in the hexane extract of Momordica dioica with 110.51±1.0 μg/GAE and 1.92±0.15 μg/QE. The methanol extract of Caesalpinia bonduc was found to be the highest in inhibition of the DPPH free radicals with nearly 80% inhibition.Conclusion: The present study revealed the nephroprotective ability of the hexane extract of Momordica dioica and ethyl acetate extract Caeselpinia bonduc. The extracts were also found to have higher antioxidant activity and therefore their nephroprotective activity might be due to attenuation of oxidative stress

Cystathionine β-synthase T833C/844INS68 polymorphism: a family-based study on mentally retarded children

BACKGROUND: Cystathionine β-synthase (CBS) mediates conversion of homocysteine to cystathionine and deficiency in enzyme activity may lead to hyperhomocysteinemia/homocystinuria, which are often associated with mental retardation (MR). A large number of polymorphisms have been reported in the CBS gene, some of which impair its activity and among these, a T833C polymorphism in cis with a 68 bp insertion at 844 in the exon 8 is found to be associated with mild hyperhomocysteinemia in different ethnic groups. METHODS: The present study is aimed at investigating the association between T833C/844ins68 polymorphism and MR. One hundred and ninety MR cases were recruited after psychometric evaluation. Hundred and thirty-eight control subjects, two hundred and sixty-seven parents of MR probands and thirty cardiovascular disorder (CVD) patients were included for comparison. Peripheral blood was collected after obtaining informed written consent. The T833C/844ins68 polymorphism was investigated by PCR amplification of genomic DNA and restriction fragment length polymorphism analysis, followed by statistical analysis. RESULTS: The genotypic distribution of the polymorphism was within the Hardy-Weinberg equilibrium. A slightly increased genotypic frequency was observed in the Indian control population as compared to other Asian populations. Both haplotype-based haplotype relative risk analysis and transmission disequilibrium test reveled lack of association of the T833C/844ins68 polymorphism with MR; nevertheless, the relative risk calculated was higher (>1) and in a limited number of informative MR families, preferential transmission of the double mutant from heterozygous mothers to the MR probands was noticed (χ(2 )= 4.00, P < 0.05). CONCLUSION: This is the first molecular genetic study of CBS gene dealing with T833C/844ins68 double mutation in MR subjects. Our preliminary data indicate lack of association between T833C/844ins68 polymorphism with MR. However, higher relative risk and biased transmission of the double mutation from heterozygous mothers to MR probands are indicative of a risk of association between this polymorphism with mental retardation

Quantum gravity effects in scalar, vector and tensor field propagation

Quantum theory of gravity deals with the physics of the gravitational field at Planck length scale (10^(−35) m). Even though it is experimentally hard to reach the Planck length scale, one can look for evidence of quantum gravity that is detectable in astrophysics. In this thesis, we try to find effects of loop quantum gravity corrections on observable phenomena. We show that the quantum fluctuation strain for LIGO data would be 10^(−125) on the Earth. The correction is, however, substantial near the black hole horizon. We discuss the effect of this for scalar field propagation followed by vector and tensor fields. For the scalar field, the correction introduces a new asymmetry; for the vector field, we found a new perturbation solution and for the tensor field, we found the corrected Einstein equations which are yet to solve. These will affect phenomena like Hawking radiation, black hole entropy and gravitational waves

A Review on Practical Challenges of Aerial Quantum Communication

The increasing demand for the realization of global-scale quantum communication services necessitates critical investigation for a practical quantum secure communication network that relies on full-time all-location coverage. In this direction, the non-terrestrial quantum key distribution is expected to play an important role in providing agility, maneuverability, relay link, on-demand network, and last-mile coverage. In this work, we have summarized the research and development that has happened until now in the domain of quantum communication using non-terrestrial platforms with a specific focus on the associated challenges and the relevant models. Further, to extend the analysis beyond the existing know-how, a hybrid model involving the features of Vasylyev et al. model and Liorni et al. model is introduced here. The hybrid model entails us adapting a spherical beam to an elliptic beam approximation and effectively capturing the characteristics of transmittance in densely humid weather conditions and at low altitudes. Further, to understand the potential impact of the weather conditions of a region on atmospheric attenuation, as an example the average monthly visibility of Pune city was analyzed for the years 2021 and 2022. In addition, a simulation of a generic model is performed using a software-defined network paradigm where quantum teleportation is simulated between distant parties using a swarm of drones in NetSquid.Comment: Quantum Key Distribution, Modelling Aerial Quantum Communication, Drone-based Secure Quantum Communication, Acquisition-Pointing and Tracking (APT), Atmospheric Turbulence, Software Defined Networking, Free-space QK

What do experienced water managers think of water resources of our nation and its management infrastructure?

This article represents the second report by an ASCE Task Committee Infrastructure Impacts of Landscape-driven Weather Change under the ASCE Watershed Management Technical Committee and the ASCE Hydroclimate Technical Committee. Herein, the \u27infrastructure impacts are referred to as infrastructure-sensitive changes in weather and climate patterns (extremes and non-extremes) that are modulated, among other factors, by changes in landscape, land use and land cover change. In this first report, the article argued for explicitly considering the well-established feedbacks triggered by infrastructure systems to the land-atmosphere system via landscape change. In this report by the ASCE Task Committee (TC), we present the results of this ASCE TC\u27s survey of a cross section of experienced water managers using a set of carefully crafted questions. These questions covered water resources management, infrastructure resiliency and recommendations for inclusion in education and curriculum. We describe here the specifics of the survey and the results obtained in the form of statistical averages on the \u27perception\u27 of these managers. Finally, we discuss what these \u27perception\u27 averages may indicate to the ASCE TC and community as a whole for stewardship of the civil engineering profession. The survey and the responses gathered are not exhaustive nor do they represent the ASCE-endorsed viewpoint. However, the survey provides a critical first step to developing the framework of a research and education plan for ASCE. Given the Water Resources Reform and Development Act passed in 2014, we must now take into account the perceived concerns of the water management community. © 2015 Hossain et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited