The state and violence: perspectives from ancient India

The instant we recognise violence as an important and intimate part of human experience, the way we look at history, the questions we ask, the answers we seek, all change dramatically. In my recent book on the subject, I examined political violence in ancient India between c. 600 BCE and 600 CE, with special reference to the state’s punitive role, war, and interactions with the forest. I pointed out that all traditions, including the religions of nonviolence, Jainism and Buddhism, accepted th..

Corporate Ownership, Dividend Policy, and Capital Structure Under Asymmetric Information.

This study investigates the role of insider ownership in the dividend policy and the leverage decision of the firm. An asymmetric information model is developed with the proportion of equity owned by insiders, dividend payout, and debt as signals of firm value. Analysis of the model yields testable hypotheses that insider ownership is negatively related to the payout and debt ratio of a firm. Cross-sectional regression analysis of leverage and payout ratio of the insider ownership is performed to test for the hypotheses. The hypothesis that firms with large insider holdings have lower leverage than firms with small insider holdings is a joint test of the signalling and risk aversion explanations. An examination of the systematic and nonsystematic risk across closely and widely held firms is used to differentiate between the alternative explanations. The empirical evidence is consistent with the hypotheses that closely held firms have lower leverage and payout ratios compared to widely held firms. Two insider ownership variables: (1) percentage of insider ownership and (2) number of insiders are used to measure ownership control. The percentage of insider ownership is negatively related to the payout and leverage while the number of insiders has a positive relationship. The relationships are stable over time. The results also indicate that industry factors are significant in explaining variations in payout and leverage ratios across firms. A significant positive relationship is observed between insider ownership and the non-systematic risk of a firm. This finding tends to reject the risk aversion explanation, as firms with large non-systematic risk have higher insider shareholdings than firms with small non-systematic risk, after controlling for size. The relationship between insider ownership and systematic risk is negative, which is consistent with lower leverage for such firms. Finally, the study finds conflicting evidence for dividends and leverage being substitute signals of firm value. In some industries analyzed, payout and leverage ratios are positively related while in other industries the relationship is negative

High-Throughput Screening of Entamoeba Identifies Compounds Which Target Both Life Cycle Stages and Which Are Effective Against Metronidazole Resistant Parasites

Neglected tropical diseases, especially those caused by parasites, are significantly underserved by current drug development efforts, mostly due to the high costs and low economic returns. One method for lowering the costs of drug discovery and development for these diseases is to repurpose drugs developed for other indications. Here, we present the results of a screen of five repurposed drug libraries to identify potential new lead compounds to treat amebiasis, a disease that affects tens of millions of people and causes ~100,000 deaths annually. E. histolytica, the causative agent of amebiasis, has two major life cycle stages, the trophozoite and the cyst. The current primary treatment for amebiasis, nitroimidazole compounds, do not eliminate parasites from the colonic lumen, necessitating a multi-drug treatment regimen. We aimed to address this problem by screening against both life stages, with the aim of identifying a single drug that targets both. We successfully identified eleven compounds with activity against both cysts and trophozoites, as well as multiple compounds that killed trophozoites with improved efficacy over existing drugs. Two lead compounds (anisomycin and prodigiosin) were further characterized for activity against metronidazole (MNZ) resistant parasites and mature cysts. Anisomycin and prodigiosin were both able to kill MNZ resistant parasites while prodigiosin and its analog obatoclax were active against mature cysts. This work confirms the feasibility of identifying drugs that target both Entamoeba trophozoites and cysts, and is an important step toward developing improved treatment regimens for Entamoeba infection

Odor representations in the mammalian olfactory bulb

A first key step in studying a sensory modality is to define how the brain represents the features of the sensory stimulus. This has proven to be a challenge in olfaction, where even the stimulus features have been a matter of considerable debate. In this review, we focus on olfactory representations in the first stage of the olfactory pathway, the olfactory bulb (OB). We examine the diverging viewpoints on spatially organized versus distributed representations. We then consider how odor sampling through respiration is a key part of the odorant code. Finally, we ask how the bulb handles the challenging task of representing mixtures. We suggest that current evidence points toward a representation that is spatially organized at the inputs but later distributed, with the spatial organization not being used for much computation. Nevertheless, this is a simple representation that effectively represents multiple individual odorants, as well as odor mixtures

Energy Efficiency in Cloud Data Centers Using Load Balancing

ABSTRACT Cloud computing is an expanding area in research and industry today, which involves virtualization, distributed computing, internet, and software and web services. This paper presents an approach for scheduling algorithms that can maintain the load balancing. In this research work we have developed power optimization algorithm which over comes the limitations of the previous algorithms[Round Robin, Equally Spread Current Execution Algorithm, Throttled Load Balancing which are used for the over load management of the data leading to positive consequences in terms of overall power consumption of the data centre thus helping in green computing. As due to undue overload of traffic and then overhead due to mitigation and migration of the virtual machines to balance out the operations there is always an impact on the power consumption, if there is more overload, there is bound to be more power consumption, and if balancing works well, there is bound to be an optimized trade-off for energy consumption. Results have shown that overall impact of power consumption is reduced by using the proposed algorithm

Growth of the protozoan parasite Entamoeba histolytica in 5-azacytidine has limited effects on parasite gene expression

BACKGROUND: In higher eukaryotes DNA methylation regulates important biological functions including silencing of gene expression and protection from adverse effects of retrotransposons. In the protozoan parasite Entamoeba histolytica, a DNA methyltransferase has been identified and treatment with 5-azacytidine (5-AzaC), a potent inhibitor of DNA methyltransferase, has been reported to attenuate parasite virulence. However, the overall extent of DNA methylation and its subsequent effects on global gene expression in this parasite are currently unknown. RESULTS: In order to identify the genome-wide effects of DNA methylation in E. histolytica, we used a short oligonucleotide microarray representing 9,435 genes (~95% of all annotated amebic genes) and compared the expression profile of E. histolytica HM-1:IMSS parasites with those treated with 23 μM 5-AzaC for up to one week. Overall, 2.1% of genes tested were transcriptionally modulated under these conditions. 68 genes were upregulated and 131 genes down regulated (2-fold change; p-value < 0.05). Sodium-bisulfite treatment and sequencing of genes indicated that there were at least two subsets of genes with genomic DNA methylation in E. histolytica: (i) genes that were endogenously silenced by genomic DNA methylation and for which 5-AzaC treatment induced transcriptional de-repression, and (ii) genes that have genomic DNA methylation, but which were not endogenously silenced by the methylation. We identified among the genes down regulated by 5-AzaC treatment a cysteine proteinase (2.m00545) and lysozyme (52.m00148) both of which have known roles in amebic pathogenesis. Decreased expression of these genes in the 5-AzaC treated E. histolytica may account in part for the parasites reduced cytolytic abilities. CONCLUSION: This work represents the first genome-wide analysis of DNA-methylation in Entamoeba histolytica and indicates that DNA methylation has relatively limited effects on gene expression in this parasite

Time of Day and Performance on Cognitive Tests in Patients with Mild Dementia

Background Cognitive screening for elderly patients with mild dementia is typically conducted in the morning under the impression that testing at this time will optimize performance and cooperation of patients. This study was conducted to determine if the time of day in which several cognitive screening tests would be normally given could significantly affect test performance in patients with mild dementia and normal control subjects. Methods Fifty nursing home residents with mild to moderate dementia and twenty normal control subjects were given three commonly used cognitive tests in two separate sessions (morning and afternoon) with a two week interval between sessions. Half of subjects were tested first in the morning and second in the afternoon, the other half first in the afternoon and second in the morning. Evaluation tools included the Mini Mental Status Exam (MMSE), the Mini-Cog Test, and Semantic Verbal Fluency (for animal names) at each session. Test scores were compared within each subject between the morning and afternoon sessions. Results Across all subjects, better scores were observed for afternoon performance in the MMSE score (p\u3c0.005) and Mini-Cog (p\u3c0.011) for subjects who tested first in the morning and second in the afternoon. No differences were observed in the reverse condition. The morning/afternoon differences and trends across all subjects were strongest for the mild dementia group (MMSE, p\u3c0.003; Mini-Cog, p\u3c0.075). However, the analysis also indicated that test experience contributed to some of the observed differences, such that no clear effect of time of day on performance could be substantiated. Conclusion Under the conditions of this study, we could not conclude that performance on cognitive tests was significantly affected by the time of day of administration. A more comprehensive study will be necessary to better define the potential factors identified

Should ACE2 be given a chance in COVID-19 therapeutics: a semi-systematic review of strategies enhancing ACE2

The severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) has resulted in almost 28 million cases of COVID-19 (Corona virus disease-2019) and more than 900000 deaths worldwide since December 2019. In the absence of effective antiviral therapy and vaccine, treatment of COVID-19 is largely symptomatic. By making use of its spike (S) protein, the virus binds to its primary human cell receptor, angiotensin converting enzyme 2 (ACE2) which is present in the pulmonary epithelial cells as well as other organs. SARS-CoV-2 may cause a downregulation of ACE2. ACE2 plays a protective role in the pulmonary system through its Mas-receptor and alamandine-MrgD-TGR7 pathways. Loss of this protective effect could be a major component of COVID-19 pathogenesis. An attractive strategy in SARS-CoV-2 therapeutics would be to augment ACE2 either directly by supplementation or indirectly through drugs which increase its levels or stimulate its downstream players. In this semi-systematic review, we have analysed the pathophysiological interplay between ACE and ACE2 in the cardiopulmonary system, the modulation of these two proteins by SARS-CoV-2, and potential therapeutic avenues targeting ACE-Ang II and ACE2-Ang (1-7) axes, that can be utilized against COVID-19 disease progression

The genome and transcriptome of the enteric parasite Entamoeba invadens, a model for encystation

BACKGROUND: Several eukaryotic parasites form cysts that transmit infection. The process is found in diverse organisms such as Toxoplasma, Giardia, and nematodes. In Entamoeba histolytica this process cannot be induced in vitro, making it difficult to study. In Entamoeba invadens, stage conversion can be induced, but its utility as a model system to study developmental biology has been limited by a lack of genomic resources. We carried out genome and transcriptome sequencing of E. invadens to identify molecular processes involved in stage conversion. RESULTS: We report the sequencing and assembly of the E. invadens genome and use whole transcriptome sequencing to characterize changes in gene expression during encystation and excystation. The E. invadens genome is larger than that of E. histolytica, apparently largely due to expansion of intergenic regions; overall gene number and the machinery for gene regulation are conserved between the species. Over half the genes are regulated during the switch between morphological forms and a key signaling molecule, phospholipase D, appears to regulate encystation. We provide evidence for the occurrence of meiosis during encystation, suggesting that stage conversion may play a key role in recombination between strains. CONCLUSIONS: Our analysis demonstrates that a number of core processes are common to encystation between distantly related parasites, including meiosis, lipid signaling and RNA modification. These data provide a foundation for understanding the developmental cascade in the important human pathogen E. histolytica and highlight conserved processes more widely relevant in enteric pathogens

Identification of putative transcriptional regulatory networks in Entamoeba histolytica using Bayesian inference

Few transcriptional regulatory networks have been described in non-model organisms. In Entamoeba histolytica seminal aspects of pathogenesis are transcriptionally controlled, however, little is known about transcriptional regulatory networks that effect gene expression in this parasite. We used expression data from two microarray experiments, cis-regulatory motif elucidation, and a naïve Bayesian classifier to identify genome-wide transcriptional regulatory patterns in E. histolytica. Our algorithm identified promoter motifs that accurately predicted the gene expression level of 68% of genes under trophozoite conditions. We identified a promoter motif (A/TAAACCCT) associated with high gene expression, which is highly enriched in promoters of ribosomal protein genes and tRNA synthetases. Additionally, we identified three promoter motifs (GAATGATG, AACTATTTAAACATC/TC and TGAACTTATAAACATC) associated with low gene expression. The promoters of a large gene family were highly enriched for these motifs, and in these genes the presence of ⩾2 motifs predicted low baseline gene expression and transcriptional activation by heat shock. We demonstrate that amebic nuclear protein(s) bind specifically to four of the motifs identified herein. Our analysis suggests that transcriptional regulatory networks can be identified using limited expression data. Thus, this approach is applicable to the multitude of systems for which microarray and genome sequence data are emerging