Pharmacological evaluation of novel bioisosteres of an adamantanyl benzamide P2X7 receptor antagonist

Adamantanyl benzamide 1 was identified as a potent P2X7R antagonist but failed to progress further due to poor metabolic stability. We describe the synthesis and SAR of a series of bioisosteres of benzamide 1 to explore improvements in the pharmacological properties of this lead. Initial efforts investigated a series of heteroaromatic bioisosteres, which demonstrated improved physicochemical properties but reduced P2X7R antagonism. Installation of bioisosteric fluorine on the adamantane bridgeheads was well tolerated and led to a series of bioisosteres with improved physicochemical properties and metabolic stability. Trifluorinated benzamide 34 demonstrated optimal physicochemical parameters, superior metabolic stability (ten times longer than lead benzamide 1), and an improved physicokinetic profile and proved effective in the presence of several known P2X7R polymorphisms

Nf-κb Inhibition Rescues Cardiac Function By Remodeling Calcium Genes In A Duchenne Muscular Dystrophy Model

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder causing progressive muscle degeneration. Although cardiomyopathy is a leading mortality cause in DMD patients, the mechanisms underlying heart failure are not well understood. Previously, we showed that NF-κB exacerbates DMD skeletal muscle pathology by promoting inflammation and impairing new muscle growth. Here, we show that NF-κB is activated in murine dystrophic (mdx) hearts, and that cardiomyocyte ablation of NF-κB rescues cardiac function. This physiological improvement is associated with a signature of upregulated calcium genes, coinciding with global enrichment of permissive H3K27 acetylation chromatin marks and depletion of the transcriptional repressors CCCTC-binding factor, SIN3 transcription regulator family member A, and histone deacetylase 1. In this respect, in DMD hearts, NF-κB acts differently from its established role as a transcriptional activator, instead promoting global changes in the chromatin landscape to regulate calcium genes and cardiac function

Bioactive Trace Metals and Their Isotopes as Paleoproductivity Proxies: An Assessment Using GEOTRACES-Era Data

Phytoplankton productivity and export sequester climatically significant quantities of atmospheric carbon dioxide as particulate organic carbon through a suite of processes termed the biological pump. Constraining how the biological pump operated in the past is important for understanding past atmospheric carbon dioxide concentrations and Earth\u27s climate history. However, reconstructing the history of the biological pump requires proxies. Due to their intimate association with biological processes, several bioactive trace metals and their isotopes are potential proxies for past phytoplankton productivity, including iron, zinc, copper, cadmium, molybdenum, barium, nickel, chromium, and silver. Here, we review the oceanic distributions, driving processes, and depositional archives for these nine metals and their isotopes based on GEOTRACES-era datasets. We offer an assessment of the overall maturity of each isotope system to serve as a proxy for diagnosing aspects of past ocean productivity and identify priorities for future research. This assessment reveals that cadmium, barium, nickel, and chromium isotopes offer the most promise as tracers of paleoproductivity, whereas iron, zinc, copper, and molybdenum do not. Too little is known about silver to make a confident determination. Intriguingly, the trace metals that are least sensitive to productivity may be used to track other aspects of ocean chemistry, such as nutrient sources, particle scavenging, organic complexation, and ocean redox state. These complementary sensitivities suggest new opportunities for combining perspectives from multiple proxies that will ultimately enable painting a more complete picture of marine paleoproductivity, biogeochemical cycles, and Earth\u27s climate history

Bioactive Trace Metals and Their Isotopes as Paleoproductivity Proxies: An Assessment Using GEOTRACES-Era Data

Phytoplankton productivity and export sequester climatically significant quantities of atmospheric carbon dioxide as particulate organic carbon through a suite of processes termed the biological pump. Constraining how the biological pump operated in the past is important for understanding past atmospheric carbon dioxide concentrations and Earth\u27s climate history. However, reconstructing the history of the biological pump requires proxies. Due to their intimate association with biological processes, several bioactive trace metals and their isotopes are potential proxies for past phytoplankton productivity, including iron, zinc, copper, cadmium, molybdenum, barium, nickel, chromium, and silver. Here, we review the oceanic distributions, driving processes, and depositional archives for these nine metals and their isotopes based on GEOTRACES-era datasets. We offer an assessment of the overall maturity of each isotope system to serve as a proxy for diagnosing aspects of past ocean productivity and identify priorities for future research. This assessment reveals that cadmium, barium, nickel, and chromium isotopes offer the most promise as tracers of paleoproductivity, whereas iron, zinc, copper, and molybdenum do not. Too little is known about silver to make a confident determination. Intriguingly, the trace metals that are least sensitive to productivity may be used to track other aspects of ocean chemistry, such as nutrient sources, particle scavenging, organic complexation, and ocean redox state. These complementary sensitivities suggest new opportunities for combining perspectives from multiple proxies that will ultimately enable painting a more complete picture of marine paleoproductivity, biogeochemical cycles, and Earth\u27s climate history

Canadian 24-hour movement guidelines for adults aged 18-64 years and adults aged 65 years or older: an integration of physical activity, sedentary behaviour, and sleep

The Canadian Society for Exercise Physiology assembled a Consensus Panel representing national organizations, content experts, methodologists, stakeholders, and end-users and followed an established guideline development procedure to create the Canadian 24-Hour Movement Guidelines for Adults aged 18-64 years and Adults aged 65 years or older: An Integration of Physical Activity, Sedentary Behaviour, and Sleep. These guidelines underscore the importance of movement behaviours across the whole 24-h day. The development process followed the strategy outlined in the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. A large body of evidence was used to inform the guidelines including 2 de novo systematic reviews and 4 overviews of reviews examining the relationships among movement behaviours (physical activity, sedentary behaviour, sleep, and all behaviours together) and several health outcomes. Draft guideline recommendations were discussed at a 4-day in-person Consensus Panel meeting. Feedback from stakeholders was obtained by survey (n = 877) and the draft guidelines were revised accordingly. The final guidelines provide evidence-based recommendations for a healthy day (24-h), comprising a combination of sleep, sedentary behaviours, and light-intensity and moderate-to-vigorous-intensity physical activity. Dissemination and implementation efforts with corresponding evaluation plans are in place to help ensure that guideline awareness and use are optimized. Novelty First ever 24-Hour Movement Guidelines for Adults aged 18-64 years and Adults aged 65 years or older with consideration of a balanced approach to physical activity, sedentary behaviour, and sleep Finalizes the suite of 24-Hour Movement Guidelines for Canadians across the lifespa

Seismic structure across the rift valley of the Mid-Atlantic Ridge at 23°20′ (MARK area): Implications for crustal accretion processes at slow spreading ridges

International audienc

CMS distributed computing workflow experience

The vast majority of the CMS Computing capacity, which is organized in a tiered hierarchy, is located away from CERN. The 7 Tier-1 sites archive the LHC proton-proton collision data that is initially processed at CERN. These sites provide access to all recorded and simulated data for the Tier-2 sites, via wide-area network (WAN) transfers. All central data processing workflows are executed at the Tier-1 level, which contain re-reconstruction and skimming workflows of collision data as well as reprocessing of simulated data to adapt to changing detector conditions. This paper describes the operation of the CMS processing infrastructure at the Tier-1 level. The Tier-1 workflows are described in detail. The operational optimization of resource usage is described. In particular, the variation of different workflows during the data taking period of 2010, their efficiencies and latencies as well as their impact on the delivery of physics results is discussed and lessons are drawn from this experience. The simulation of proton-proton collisions for the CMS experiment is primarily carried out at the second tier of the CMS computing infrastructure. Half of the Tier-2 sites of CMS are reserved for central Monte Carlo (MC) production while the other half is available for user analysis. This paper summarizes the large throughput of the MC production operation during the data taking period of 2010 and discusses the latencies and efficiencies of the various types of MC production workflows. We present the operational procedures to optimize the usage of available resources and we the operational model of CMS for including opportunistic resources, such as the larger Tier-3 sites, into the central production operation

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts