Insights into the Fold Organization of TIM Barrel from Interaction Energy Based Structure Networks

There are many well-known examples of proteins with low sequence similarity, adopting the same structural fold. This aspect of sequence-structure relationship has been extensively studied both experimentally and theoretically, however with limited success. Most of the studies consider remote homology or “sequence conservation” as the basis for their understanding. Recently “interaction energy” based network formalism (Protein Energy Networks (PENs)) was developed to understand the determinants of protein structures. In this paper we have used these PENs to investigate the common non-covalent interactions and their collective features which stabilize the TIM barrel fold. We have also developed a method of aligning PENs in order to understand the spatial conservation of interactions in the fold. We have identified key common interactions responsible for the conservation of the TIM fold, despite high sequence dissimilarity. For instance, the central beta barrel of the TIM fold is stabilized by long-range high energy electrostatic interactions and low-energy contiguous vdW interactions in certain families. The other interfaces like the helix-sheet or the helix-helix seem to be devoid of any high energy conserved interactions. Conserved interactions in the loop regions around the catalytic site of the TIM fold have also been identified, pointing out their significance in both structural and functional evolution. Based on these investigations, we have developed a novel network based phylogenetic analysis for remote homologues, which can perform better than sequence based phylogeny. Such an analysis is more meaningful from both structural and functional evolutionary perspective. We believe that the information obtained through the “interaction conservation” viewpoint and the subsequently developed method of structure network alignment, can shed new light in the fields of fold organization and de novo computational protein design

Engaging with sustainability issues in metropolitan Chennai : city report

Chennai is the largest metropolitan city in South India (8.7 million in 2011) and the provincial capital of the large state of Tamil Nadu (population 72 million in 2011). Before that, under British rule, the city was the capital of the Madras Presidency, and was known as Madras until 1996, when the name was officially changed to Chennai. Located on the east coast of India, on the Bay of Bengal, sea trade has been an important aspect of the regional economy since at least the colonial period. Still today, the city combines political functions with economic command functions for both manufacturing and services, reflecting the region's diversified economy. The Chennai metropolitan area has witnessed strong growth over the last 20 years in automobile manufacturing, software services, hardware manufacturing, healthcare and financial services (CDP 2009). However, it should be noted that only 30% of total employment in the city takes place in the formal sector i.e., is covered by contracts and labour laws, the remaining 70% falls in the informal sector. This underscores the importance of small and micro enterprises and self-employment for providing goods, services and livelihoods in the local economy

Comparative analysis of thermophilic and mesophilic proteins using Protein Energy Networks

<p>Abstract</p> <p>Background</p> <p>Thermophilic proteins sustain themselves and function at higher temperatures. Despite their structural and functional similarities with their mesophilic homologues, they show enhanced stability. Various comparative studies at genomic, protein sequence and structure levels, and experimental works highlight the different factors and dominant interacting forces contributing to this increased stability.</p> <p>Methods</p> <p>In this comparative structure based study, we have used interaction energies between amino acids, to generate structure networks called as Protein Energy Networks (PENs). These PENs are used to compute network, sub-graph, and node specific parameters. These parameters are then compared between the thermophile-mesophile homologues.</p> <p>Results</p> <p>The results show an increased number of clusters and low energy cliques in thermophiles as the main contributing factors for their enhanced stability. Further more, we see an increase in the number of hubs in thermophiles. We also observe no community of electrostatic cliques forming in PENs.</p> <p>Conclusion</p> <p>In this study we were able to take an energy based network approach, to identify the factors responsible for enhanced stability of thermophiles, by comparative analysis. We were able to point out that the sub-graph parameters are the prominent contributing factors. The thermophiles have a better-packed hydrophobic core. We have also discussed how thermophiles, although increasing stability through higher connectivity retains conformational flexibility, from a cliques and communities perspective.</p

Downregulation of the central noradrenergic system by Toxoplasma gondii infection

Toxoplasma gondii is associated with physiological effects in the host. Dysregulation of catecholamines in the central nervous system has previously been observed in chronically-infected animals. In the study described here, the noradrenergic system was found to be suppressed with decreased levels of norepinephrine (NE) in brains of infected animals and in infected human and rat neural cells in vitro. The mechanism responsible for the NE suppression was found to be down-regulation of dopamine β-hydroxylase (DBH) gene expression, encoding the enzyme that synthesizes norepinephrine from dopamine with down-regulation observed in vitro and in infected brain tissue, particularly in the dorsal locus coeruleus/pons region. The down-regulation was sex-specific with males expressing reduced DBH mRNA levels whereas females were unchanged. Rather, DBH expression correlated with estrogen receptor in the female rat brains for this estrogen-regulated gene. DBH silencing was not a general response of neurons to infection as human cytomegalovirus (CMV) did not down-regulate DBH expression. The noradrenergic-linked behaviors of sociability and arousal were altered in chronically-infected animals, with a high correlation between DBH expression and infection intensity. A decrease in DBH expression in noradrenergic neurons can elevate dopamine levels which provides a possible explanation for mixed observations of changes in this neurotransmitter with infection. Decreased NE is consistent with the loss of coordination and motor impairments associated with toxoplasmosis. Further, the altered norepinephrine synthesis observed here may, in part, explain behavioural effects of infection and associations with mental illness

A PQM-1-mediated response triggers transcellular chaperone signaling and regulates organismal proteostasis

In metazoans, tissues experiencing proteotoxic stress induce “transcellular chaperone signaling” (TCS) that activates molecular chaperones, such as hsp-90, in distal tissues. How this form of inter-tissue communication is mediated to upregulate systemic chaperone expression and whether it can be utilized to protect against protein misfolding diseases remain open questions. Using C. elegans, we identified key components of a systemic stress signaling pathway that links the innate immune response with proteostasis maintenance. We show that mild perturbation of proteostasis in the neurons or the intestine activates TCS via the GATA zinc-finger transcription factor PQM-1. PQM-1 coordinates neuron-activated TCS via the innate immunity-associated transmembrane protein CLEC-41, whereas intestine-activated TCS depends on the aspartic protease ASP-12. Both TCS pathways can induce hsp-90 in muscle cells and facilitate amelioration of Aβ₃-₄₂-associated toxicity. This may have powerful implications for the treatment of diseases related to proteostasis dysfunction

RUNX1 Reshapes the Epigenetic Landscape at the Onset of Haematopoiesis

Cell fate decisions during haematopoiesis are governed by lineage-specific transcription factors, such as RUNX1, SCL/TAL1, FLI1 and C/EBP family members. To gain insight into how these transcription factors regulate the activation of haematopoietic genes during embryonic development, we measured the genome-wide dynamics of transcription factor assembly on their target genes during the RUNX1-dependent transition from haemogenic endothelium (HE) to haematopoietic progenitors. Using a $Runx1^{−/−}$ embryonic stem cell differentiation model expressing an inducible Runx1 gene, we show that in the absence of RUNX1, haematopoietic genes bind SCL/TAL1, FLI1 and C/EBPβ and that this early priming is required for correct temporal expression of the myeloid master regulator PU.1 and its downstream targets. After induction, RUNX1 binds to numerous de novo sites, initiating a local increase in histone acetylation and rapid global alterations in the binding patterns of SCL/TAL1 and FLI1. The acquisition of haematopoietic fate controlled by Runx1 therefore does not represent the establishment of a new regulatory layer on top of a pre-existing HE program but instead entails global reorganization of lineage-specific transcription factor assemblies

Cancer somatic mutations cluster in a subset of regulatory sites predicted from the ENCODE data

Background: Transcriptional regulation of gene expression is essential for cellular differentiation and function, and defects in the process are associated with cancer. The ENCODE project has mapped potential regulatory sites across the complete genome in many cell types, and these regions have been shown to harbour many of the somatic mutations that occur in cancer cells, suggesting that their effects may drive cancer initiation and development. The ENCODE data suggests a very large number of regulatory sites, and methods are needed to identify those that are most relevant and to connect them to the genes that they control. Methods: Predictive models of gene expression were developed by integrating the ENCODE data for regulation, including transcription factor binding and DNase1 hypersensitivity, with RNA-seq data for gene expression. A penalized regression method was used to identify the most predictive potential regulatory sites for each transcript. Known cancer somatic mutations from the COSMIC database were mapped to potential regulatory sites, and we examined differences in the mapping frequencies associated with sites chosen in regulatory models and other (rejected) sites. The effects of potential confounders, for example replication timing, were considered. Results: Cancer somatic mutations preferentially occupy those regulatory regions chosen in our models as most predictive of gene expression. Conclusion: Our methods have identified a significantly reduced set of regulatory sites that are enriched in cancer somatic mutations and are more predictive of gene expression. This has significance for the mechanistic interpretation of cancer mutations, and the understanding of genetic regulation

Concordance for clonal hematopoiesis is limited in elderly twins.

Although acquisition of leukemia-associated somatic mutations by 1 or more hematopoietic stem cells is inevitable with advancing age, its consequences are highly variable, ranging from clinically silent clonal hematopoiesis (CH) to leukemic progression. To investigate the influence of heritable factors on CH, we performed deep targeted sequencing of blood DNA from 52 monozygotic (MZ) and 27 dizygotic (DZ) twin pairs (aged 70-99 years). Using this highly sensitive approach, we identified CH (variant allele frequency ≥0.5%) in 62% of individuals. We did not observe higher concordance for CH within MZ twin pairs as compared with that within DZ twin pairs, or to that expected by chance. However, we did identify 2 MZ pairs in which both twins harbored identical rare somatic mutations, suggesting a shared cell of origin. Finally, in 3 MZ twin pairs harboring mutations in the same driver genes, serial blood samples taken 4 to 5 years apart showed substantial twin-to-twin variability in clonal trajectories. Our findings propose that the inherited genome does not exert a dominant influence on the behavior of adult CH and provide evidence that CH mutations may be acquired in utero

Correction to: PiggyBac mutagenesis and exome sequencing identify genetic driver landscapes and potential therapeutic targets of EGFR-mutant gliomas

An amendment to this paper has been published and can be accessed via the original article

Relational approaches to poverty in rural India: social, ecological and technical dynamics

Poverty is now widely recognised as multidimensional, with indicators including healthcare, housing and sanitation. Yet, relational approaches that foreground political-cultural processes remain marginalised in policy discourses. Focusing on India, we review a wide range of relational approaches to rural poverty. Beginning with early approaches that focus on structural reproduction of class, caste and to a lesser extent gender inequality, we examine new relational approaches developed in the last two decades. The new approaches examine diverse ways in which poverty is experienced and shapes mobilisations against deprivation. They draw attention to poor people’s own articulations of deprivation and alternate conceptions of well-being. They also show how intersecting inequalities of class, caste and gender shape governance practices and political movements. Despite these important contributions, the new relational approaches pay limited attention to technologies and ecologies in shaping the experience of poverty. Reviewing studies on the Green Revolution and wider agrarian transformations in India, we then sketch the outlines of a hybrid relational approach to poverty that combines socio-technical and -ecological dynamics. We argue that such an approach is crucial to challenge narrow economising discourses on poverty and to bridge the policy silos of poverty alleviation and (environmentally) sustainable development