Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma

Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wild-type diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes

Characterization of ERK Docking Domain Inhibitors that Induce Apoptosis by Targeting Rsk-1 and Caspase-9

<p>Abstract</p> <p>Background</p> <p>The extracellular signal-regulated kinase-1 and 2 (ERK1/2) proteins play an important role in cancer cell proliferation and survival. ERK1/2 proteins also are important for normal cell functions. Thus, anti-cancer therapies that block all ERK1/2 signaling may result in undesirable toxicity to normal cells. As an alternative, we have used computational and biological approaches to identify low-molecular weight compounds that have the potential to interact with unique ERK1/2 docking sites and selectively inhibit interactions with substrates involved in promoting cell proliferation.</p> <p>Methods</p> <p>Colony formation and water soluble tetrazolium salt (WST) assays were used to determine the effects of test compounds on cell proliferation. Changes in phosphorylation and protein expression in response to test compound treatment were examined by immunoblotting and <it>in vitro </it>kinase assays. Apoptosis was determined with immunoblotting and caspase activity assays.</p> <p>Results</p> <p><it>In silico </it>modeling was used to identify compounds that were structurally similar to a previously identified parent compound, called <b>76</b>. From this screen, several compounds, termed <b>76.2</b>, <b>76.3</b>, and <b>76.4 </b>sharing a common thiazolidinedione core with an aminoethyl side group, inhibited proliferation and induced apoptosis of HeLa cells. However, the active compounds were less effective in inhibiting proliferation or inducing apoptosis in non-transformed epithelial cells. Induction of HeLa cell apoptosis appeared to be through intrinsic mechanisms involving caspase-9 activation and decreased phosphorylation of the pro-apoptotic Bad protein. Cell-based and <it>in vitro </it>kinase assays indicated that compounds <b>76.3 </b>and <b>76.4 </b>directly inhibited ERK-mediated phosphorylation of caspase-9 and the p90Rsk-1 kinase, which phosphorylates and inhibits Bad, more effectively than the parent compound <b>76</b>. Further examination of the test compound's mechanism of action showed little effects on related MAP kinases or other cell survival proteins.</p> <p>Conclusion</p> <p>These findings support the identification of a class of ERK-targeted molecules that can induce apoptosis in transformed cells by inhibiting ERK-mediated phosphorylation and inactivation of pro-apoptotic proteins.</p

Comparative Genomic Analysis of Clinical Strains of Campylobacter jejuni from South Africa

BACKGROUND: Campylobacter jejuni is a common cause of acute gastroenteritis and is also associated with the post-infectious neuropathies, Guillain-Barré and Miller Fisher syndromes. In the Cape Town area of South Africa, C. jejuni strains with Penner heat-stable (HS) serotype HS:41 have been observed to be overrepresented among cases of Guillain-Barré syndrome. The present study examined the genetic content of a collection of 32 South African C. jejuni strains with different serotypes, including 13 HS:41 strains, that were recovered from patients with enteritis, Guillain-Barré or Miller Fisher syndromes. The sequence-based typing methods, multilocus sequence typing and DNA microarrays, were employed to potentially identify distinguishing features within the genomes of these C. jejuni strains with various disease outcomes. METHODOLOGY/PRINCIPAL FINDINGS: Comparative genomic analyses demonstrated that the HS:41 South African strains were clearly distinct from the other South African strains. Further DNA microarray analysis demonstrated that the HS:41 strains from South African patients with the Guillain-Barré syndrome or enteritis were highly similar in gene content. Interestingly, the South African HS:41 strains were distinct in gene content when compared to HS:41 strains from other geographical locations due to the presence of genomic islands, referred to as Campylobacter jejuni integrated elements (CJIEs). Only the integrated element CJIE1, a Campylobacter Mu-like prophage, was present in the South African HS:41 strains whereas this element was absent in two closely-related HS:41 strains from Mexico. A more distantly-related HS:41 strain from Canada possessed both integrated elements CJIE1 and CJIE2. CONCLUSION/SIGNIFICANCE: These findings demonstrate that CJIEs may contribute to the differentiation of closely-related C. jejuni strains. In addition, the presence of bacteriophage-related genes in CJIE1 may contribute to the genomic diversity of C. jejuni strains. This comparative genomic analysis of C. jejuni provides fundamental information that potentially could lead to improved methods for analyzing the epidemiology of disease outbreaks

Interaction of Copper-Based Nanoparticles to Soil, Terrestrial, and Aquatic Systems: Critical Review of the State of the Science and Future Perspectives

In the past two decades, increased production and usage of metallic nanoparticles (NPs) has inevitably increased their discharge into the different compartments of the environment, which ultimately paved the way for their uptake and accumulation in various trophic levels of the food chain. Due to these issues, several questions have been raised on the usage of NPs in everyday life and has become a matter of public health concern. Among the metallic NPs, Cu-based NPs have gained popularity due to their cost-effectiveness and multifarious promising uses. Several studies in the past represented the phytotoxicity of Cu-based NPs on plants. However, comprehensive knowledge is still lacking. Additionally, the impact of Cu-based NPs on soil organisms such as agriculturally important microbes, fungi, mycorrhiza, nematode, and earthworms are poorly studied. This review article critically analyses the literature data to achieve a more comprehensive knowledge on the toxicological profile of Cu-based NPs and increase our understanding of the effects of Cu-based NPs on aquatic and terrestrial plants as well as on soil microbial communities. The underlying mechanism of biotransformation of Cu-based NPs and the process of their penetration into plants has also been discussed herein. Overall, this review could provide valuable information to design rules and regulations for the safe disposal of Cu-based NPs into a sustainable environment

A global experiment on motivating social distancing during the COVID-19 pandemic

Significance Communicating in ways that motivate engagement in social distancing remains a critical global public health priority during the COVID-19 pandemic. This study tested motivational qualities of messages about social distancing (those that promoted choice and agency vs. those that were forceful and shaming) in 25,718 people in 89 countries. The autonomy-supportive message decreased feelings of defying social distancing recommendations relative to the controlling message, and the controlling message increased controlled motivation, a less effective form of motivation, relative to no message. Message type did not impact intentions to socially distance, but people’s existing motivations were related to intentions. Findings were generalizable across a geographically diverse sample and may inform public health communication strategies in this and future global health emergencies. Abstract Finding communication strategies that effectively motivate social distancing continues to be a global public health priority during the COVID-19 pandemic. This cross-country, preregistered experiment (n = 25,718 from 89 countries) tested hypotheses concerning generalizable positive and negative outcomes of social distancing messages that promoted personal agency and reflective choices (i.e., an autonomy-supportive message) or were restrictive and shaming (i.e., a controlling message) compared with no message at all. Results partially supported experimental hypotheses in that the controlling message increased controlled motivation (a poorly internalized form of motivation relying on shame, guilt, and fear of social consequences) relative to no message. On the other hand, the autonomy-supportive message lowered feelings of defiance compared with the controlling message, but the controlling message did not differ from receiving no message at all. Unexpectedly, messages did not influence autonomous motivation (a highly internalized form of motivation relying on one’s core values) or behavioral intentions. Results supported hypothesized associations between people’s existing autonomous and controlled motivations and self-reported behavioral intentions to engage in social distancing. Controlled motivation was associated with more defiance and less long-term behavioral intention to engage in social distancing, whereas autonomous motivation was associated with less defiance and more short- and long-term intentions to social distance. Overall, this work highlights the potential harm of using shaming and pressuring language in public health communication, with implications for the current and future global health challenges

A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic.

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world

Adapting scientific workflow structures using multi-objective optimisation strategies

Scientific workflows have become the primary mechanism for conducting scientific analyses on distributed computing infrastructures such as grids and clouds. In the recent past, the focus of the optimisation of scientific workflows was primarily on compute optimisation. However, as e-Science becomes ever more data intensive, data optimisation is becoming a prime concern. Moreover, scientific workflows are scaling in several dimensions. These include the increasing number of computational tasks, increasing number of resource requirements and increasing data footprints. We explore the use of a multi-objective approach to the optimisation of scientific workflows to achieve both compute and data optimisation. The approach is based on a multi-objective evolutionary approach. The question of when to terminate the evolutionary search in order to conserve computations is tackled with a novel termination criterion. The results presented in this paper, demonstrate the feasibility of the termination criterion and demonstrate that significant optimisation can be achieved with a multi-objective approach for the optimisation of state-of-the-art scientific workflows