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The central concern of this paper is to examine intersectionalities between the ideals of cosmopolitanism, patriotism, ethnocentrism and nationalism in general, and their changing facets and interfaces in India. It argues that being a multiethnic and plural society, the civilisational ethos of India is conventionally founded on cosmopolitanism. The practice of patriotism and its accommodative principle of unity in diversity have provided the building blocks to this cosmopolitanism. During India’s independence struggle these ideals encountered the forces of modernism, ethnocentrism, communalism and ethno-nationalism. In contemporary India the forces of economic neoliberalism, developmental imbalances and persisting social and economic inequalities, post modernism, hyper modernism, populism, and cultural politics have become part of social reality. Notwithstanding the prevalence of the ideals of cosmopolitanism and civilisational interactive processes, these encounters have brought cumulative fluidity in the social, economic and political orientations in contemporary society, and have created further space for the influence of ethnocentrism and cultural politics as a means to remain rooted in society.

Abstract Coronavirus spike glycoproteins presented on the virion surface mediate receptor binding, and membrane fusion during virus entry and constitute the primary target for vaccine and drug development. How the structure dynamics of the full-length spikes incorporated in viral lipid envelope correlates with the virus infectivity remains poorly understood. Here we present structures and distributions of native spike conformations on vitrified human coronavirus NL63 (HCoV-NL63) virions without chemical fixation by cryogenic electron tomography (cryoET) and subtomogram averaging, along with site-specific glycan composition and occupancy determined by mass spectrometry. The higher oligomannose glycan shield on HCoV-NL63 spikes than on SARS-CoV-2 spikes correlates with stronger immune evasion of HCoV-NL63. Incorporation of cryoET-derived native spike conformations into all-atom molecular dynamic simulations elucidate the conformational landscape of the glycosylated, full-length spike that reveals a role of hinge glycans in modulating spike bending. We show that glycosylation at N1242 at the upper portion of the stalk is responsible for the extensive orientational freedom of the spike crown. Subsequent infectivity assays implicated involvement of N1242-glyan in virus entry. Our results suggest a potential therapeutic target site for HCoV-NL63.

Abstract Mutations in the TP53 tumor suppressor gene occur in >80% of the triple-negative or basal-like breast cancer. To test whether neomorphic functions of specific TP53 missense mutations contribute to phenotypic heterogeneity, we characterized phenotypes of non-transformed MCF10A-derived cell lines expressing the ten most common missense mutant p53 proteins and observed a wide spectrum of phenotypic changes in cell survival, resistance to apoptosis and anoikis, cell migration, invasion and 3D mammosphere architecture. The p53 mutants R248W, R273C, R248Q, and Y220C are the most aggressive while G245S and Y234C are the least, which correlates with survival rates of basal-like breast cancer patients. Interestingly, a crucial amino acid difference at one position—R273C vs. R273H—has drastic changes on cellular phenotype. RNA-Seq and ChIP-Seq analyses show distinct DNA binding properties of different p53 mutants, yielding heterogeneous transcriptomics profiles, and MD simulation provided structural basis of differential DNA binding of different p53 mutants. Integrative statistical and machine-learning-based pathway analysis on gene expression profiles with phenotype vectors across the mutant cell lines identifies quantitative association of multiple pathways including the Hippo/YAP/TAZ pathway with phenotypic aggressiveness. Further, comparative analyses of large transcriptomics datasets on breast cancer cell lines and tumors suggest that dysregulation of the Hippo/YAP/TAZ pathway plays a key role in driving the cellular phenotypes towards basal-like in the presence of more aggressive p53 mutants. Overall, our study describes distinct gain-of-function impacts on protein functions, transcriptional profiles, and cellular behaviors of different p53 missense mutants, which contribute to clinical phenotypic heterogeneity of triple-negative breast tumors.

Influenza A viruses (IAVs) exploit host glycans in airway mucosa for entry and infection. Detection of changes in IAV glycan-binding phenotype can provide early indication of transmissibility and infection potential. While zoonotic viruses are monitored for mutations, the influence of host glycan presentation on viral specificity remains obscured. Here, we describe an array platform which uses synthetic mimetics of mucin glycoproteins to model how receptor presentation and density in the mucinous glycocalyx may impact IAV recognition. H1N1 and H3N2 binding in arrays of α2,3- and α2,6-sialyllactose receptors confirmed their known sialic acid-binding specificities and revealed their different sensitivities to receptor presentation. Further, the transition of H1N1 from avian to mammalian cell culture improved the ability of the virus to recognize mucin-like displays of α2,6-sialic acid receptors. Support vector machine (SVM) learning efficiently characterized this shift in binding preference and may prove useful to study viral evolution to a new host.

Cryo-electron microscopy (EM) requires molecular modeling to refine structural details from data. Ensemble models arrive at low free-energy molecular structures, but are computationally expensive and limited to resolving only small proteins that cannot be resolved by cryo-EM. Here, we introduce CryoFold - a pipeline of molecular dynamics simulations that determines ensembles of protein structures directly from sequence by integrating density data of varying sparsity at 3-5 Å resolution with coarse-grained topological knowledge of the protein folds. We present six examples showing its broad applicability for folding proteins between 72 to 2000 residues, including large membrane and multi-domain systems, and results from two EMDB competitions. Driven by data from a single state, CryoFold discovers ensembles of common low-energy models together with rare low-probability structures that capture the equilibrium distribution of proteins constrained by the density maps. Many of these conformations, unseen by traditional methods, are experimentally validated and functionally relevant. We arrive at a set of best practices for data-guided protein folding that are controlled using a Python GUI.

This paper describes outcomes of the 2019 Cryo-EM Model Challenge. The goals were to (1) assess the quality of models that can be produced from cryogenic electron microscopy (cryo-EM) maps using current modeling software, (2) evaluate reproducibility of modeling results from different software developers and users and (3) compare performance of current metrics used for model evaluation, particularly Fit-to-Map metrics, with focus on near-atomic resolution. Our findings demonstrate the relatively high accuracy and reproducibility of cryo-EM models derived by 13 participating teams from four benchmark maps, including three forming a resolution series (1.8 to 3.1 Å). The results permit specific recommendations to be made about validating near-atomic cryo-EM structures both in the context of individual experiments and structure data archives such as the Protein Data Bank. We recommend the adoption of multiple scoring parameters to provide full and objective annotation and assessment of the model, reflective of the observed cryo-EM map density.

Transients in GPS time series can occur due to post-seismic deformation, seasonal hydrological loads, sea-level changes, flood and drought conditions, excessive groundwater withdrawal and recharge, etc. We report two new cases where the application of external loading, namely, earthquake loading and surface loading due to impoundment of hydroelectric reservoir, probably altered the local hydrological conditions to cause anomalous transients in the surface displacement. In the first case, moderate shaking due to the 2015 Gorkha earthquake at Patna (Bihar, India) caused transients in ground deformation in the following 50–60 days of the earthquake which are recorded by a continuous GPS site at Patna. In the second case, impoundment of the Tehri reservoir and its seasonal variations in the Garhwal Himalaya probably altered the local hydrological conditions which is causing anomalous biannual cyclic deformation at a site KUNR, near the reservoir.

Transporters of the Nramp (Natural resistance-associated macrophage protein) family import divalent transition metal ions into cells of most organisms. By supporting metal homeostasis, Nramps prevent diseases and disorders related to metal insufficiency or overload. Previous studies revealed that Nramps take on a LeuT fold and identified the metal-binding site. We present high-resolution structures of Deinococcus radiodurans (Dra)Nramp in three stable conformations of the transport cycle revealing that global conformational changes are supported by distinct coordination geometries of its physiological substrate, Mn2+, across conformations, and by conserved networks of polar residues lining the inner and outer gates. In addition, a high-resolution Cd2+-bound structure highlights differences in how Cd2+ and Mn2+ are coordinated by DraNramp. Complementary metal binding studies using isothermal titration calorimetry with a series of mutated DraNramp proteins indicate that the thermodynamic landscape for binding and transporting physiological metals like Mn2+ is different and more robust to perturbation than for transporting the toxic Cd2+ metal. Overall, the affinity measurements and high-resolution structural information on metal substrate binding provide a foundation for understanding the substrate selectivity of essential metal ion transporters like Nramps.

Cryo-electron microscopy (cryo-EM) has produced a number of structural models of the SARS-CoV-2 spike, already prompting biomedical outcomes. However, these reported models and their associated electrostatic potential maps represent an unknown admixture of conformations stemming from the underlying energy landscape of the spike protein. As with any protein, some of the spike's conformational motions are expected to be biophysically relevant, but cannot be interpreted only by static models. Using experimental cryo-EM images, we present the energy landscape of the glycosylated spike protein, and identify the diversity of low-energy conformations in the vicinity of its open (so called 1RBD-up) state. The resulting atomic refinement reveal global and local molecular rearrangements that cannot be inferred from an average 1RBD-up cryo-EM model. Here we report varied degrees of “openness” in global conformations of the 1RBD-up state, not revealed in the single-model interpretations of the density maps, together with conformations that overlap with the reported models. We discover how the glycan shield contributes to the stability of these low-energy conformations. Five out of six binding sites we analyzed, including those for engaging ACE2, therapeutic mini-proteins, linoleic acid, two different kinds of antibodies, switch conformations between their known apo- and holo-conformations, even when the global spike conformation is 1RBD-up. This apo-to-holo switching is reminiscent of a conformational preequilibrium. We found only one binding site, namely that of AB-C135 remains in apo state within all the sampled free energy-minimizing models, suggesting an induced fit mechanism for the docking of this antibody to the spike.

Collective identities of people have remained largely transitional despite largely remaining rooted in certain inherited essentialities. The essential dynamics of identity often get negotiated with various forces and processes like those of the economic transformation, technological reorientation, collective mobilisation, modernisation, colonisation, globalisation, penetration of information and communication technologies (ICTs), mass and social media among others. The contemporary society is marked by the fast transformation of its economic order from agriculture and industry to knowledge/information-driven post-industrial society, fast transference of information, images, ideas, services, goods and people across spaces and the borderless expansion of ICTs. These have paved the way for the emergence of a new social order which has been widely described as the knowledge society. Within this emerging economic, social and technological order, new varieties of social interaction and solidarities are constructed from within the pre-existing varieties causing a good deal of fluidity of collective identities on the one hand and their consolidation on the other. Thus, with fast social transformation and increasing interconnectivity and mobility of people across the globe on the one hand and consolidation of new forms of social collectivities on the other, the contours of contraction and configuration of identities have undergone phenomenal change. Against such a backdrop, this article is an attempt to develop an understanding of the nuances of identity: its essence, construction, transformation and configuration within the broad processes of social transition. This article is arranged in five sections. The Dynamics of Identity section deals with the dynamics of identity. In the Social Movements. Modernity, Colonisation, Globalisation and Identity: Changing Facets of Fluidity and Solidarity section, the processes of construction and reconfiguration of identity in the context of social movements, modernity, colonisation and globalisation are discussed. The key dimensions of the emergence of knowledge society are explained in the Emerging Knowledge Society and its Key Dynamics section. In the Solidarity and Fluidity in Identity: The Emerging Facets section, the emerging facets of solidarity and fluidity of identity are elucidated. Finally, the Conclusion section makes the concluding arguments.

There is a great interest in retrieving functional pathways from cryo-EM single-particle data. Here, the authors present an approach that combines cryo-EM with advanced data-analytical methods and molecular dynamics simulations to reveal the functional pathways traversed on experimentally derived energy landscapes using the ryanodine receptor type 1 as an example.

Diabetes mellitus (DM) is a multifactorial disease of significant public health concern globally. This study aimed to assess the in-vitro effect of hydro-methanol (3:2) Bauhinia acuminata stem bark extract on diabetes and diabetes-linked oxidative stress to develop an herbal-based product against diabetic complications. Qualitative analysis, TLC, and LC-MS were performed to determine the phytomolecule(s) in the extract. Diabetes was induced in rats by a single intramuscular injection of streptozotocin. The liver, kidney, small intestine, heart, and skeletal muscle were dissected from the control and diabetic groups on the 29th day of streptozotocin injection and placed immediately into the in-vitro media and dosed with the extract except for the control and untreated diabetic groups. Carbohydrate metabolic enzymes, anti-oxidative markers, and general toxicity sensors were evaluated. Dosing of extract at 10, 20, and 40 mg/10 mL of invitro media reduced the activity of glucose-6-phosphatase significantly (p<0.05), but hexokinase activity in liver, skeletal, and cardiac muscle were unchanged compared with the untreated diabetic group. Inhibition in enteric alpha-glucosidase activity was noted. The activities of antioxidant enzymes and thiobarbituric acid reactive substances level were recovered significantly (p<0.05) in the hepatic and renal tissues after extract treatment compared to the untreated diabetic group. Glutamate oxaloacetate transaminase and glutamate pyruvate transaminase activities were reduced in the tissues of treated groups compared to the untreated diabetic group. This study showed that at 1mg/ml, the extract exhibited significant effects on the metabolic function of diabetic rat tissues with an increase in endogenous antioxidant levels. [ABSTRACT FROM AUTHOR]