Lithostratigraphy, sedimentation and evolution of the Volta Basin in Ghana

We present a revised lithostratigraphy for the Voltaian Supergroup of Ghana, based on a review of existing literature, interpretations of remotely sensed data and reconnaissance field survey of the Volta Basin. These strata thicken eastwards, to a maximum of between 5 and 6 km adjacent to the Pan-African Dahomeyide orogen. They began to accumulate some time after about 1000 Ma, along the margin of an epicontinental sea. Initial sedimentation, comprising the age-equivalent Kwahu and Bombouaka Groups, shows a cyclical mode of deposition controlled by eustatic changes in sea-level that produced a range of nearshore marine, littoral and terrestrial environments. A major erosional interval was followed by deposition of the 3–4 km thick Oti-Pendjari Group. Basal tillites and associated sandy diamictons are correlated with the Marinoan (end-Cryogenian) glaciation, indicating a maximum depositional age of about 635 Ma. The overlying cap carbonates and tuffs were deposited within a shallow epeiric sea bordered by a volcanically active rift system. The main part of the group records the transition from a rifted passive margin to a fully developed foreland basin receiving marine flysch in the form of argillaceous strata interbedded with highly immature wacke-type sandstones and conglomerates. Maximum accommodation space was developed within a foredeep adjacent to the Dahomeyide belt. Towards the end of the orogenic phase, the foredeep succession became partially inverted and then was buried under coarse terrestrial, red-bed molasse of the Obosum Group

Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery

Caseinolytic peptidase P (ClpP), a double-ring peptidase with 14 subunits, collaborates with ATPases associated with diverse activities (AAA+) partners to execute ATP-dependent protein degradation. Although many ClpP enzymes self-assemble into catalytically active homo-tetradecamers able to cleave small peptides, the Mycobacterium tuberculosis enzyme consists of discrete ClpP1 and ClpP2 heptamers that require a AAA+ partner and protein–substrate delivery or a peptide agonist to stabilize assembly of the active tetradecamer. Here, we show that cyclic acyldepsipeptides (ADEPs) and agonist peptides synergistically activate ClpP1P2 by mimicking AAA + partners and substrates, respectively, and determine the structure of the activated complex. Our studies establish the basis of heteromeric ClpP1P2 assembly and function, reveal tight coupling between the conformations of each ring, show that ADEPs bind only to one ring but appear to open the axial pores of both rings, provide a foundation for rational drug development, and suggest strategies for studying the roles of individual ClpP1 and ClpP2 rings in Clp-family proteolysisNational Institutes of Health (U.S.) (NIH Grant GM-101988)Brown UniversityNational Science Foundation (U.S.) (CAREER award)National Institute of General Medical Sciences (U.S.) (Grant P41 GM103403)United States. Dept. of Energy (Contract DE-AC02-06CH11357

Restriction of the Conformational Dynamics of the Cyclic Acyldepsipeptide Antibiotics Improves Their Antibacterial Activity

The cyclic acyldepsipeptide (ADEP) antibiotics are a new class of antibacterial agents that kill bacteria via a mechanism that is distinct from all clinically used drugs. These molecules bind and dysregulate the activity of the ClpP peptidase. The potential of these antibiotics as antibacterial drugs has been enhanced by the elimination of pharmacological liabilities through medicinal chemistry efforts. Here, we demonstrate that the ADEP conformation observed in the ADEP–ClpP crystal structure is fortified by transannular hydrogen bonding and can be further stabilized by judicious replacement of constituent amino acids within the peptidolactone core structure with more conformationally constrained counterparts. Evidence supporting constraint of the molecule into the bioactive conformer was obtained by measurements of deuterium-exchange kinetics of hydrogens that were proposed to be engaged in transannular hydrogen bonds. We show that the rigidified ADEP analogs bind and activate ClpP at lower concentrations in vitro. Remarkably, these compounds have up to 1200-fold enhanced antibacterial activity when compared to those with the peptidolactone core structure common to two ADEP natural products. This study compellingly demonstrates how rational modulation of conformational dynamics may be used to improve the bioactivities of natural products.National Science Foundation (U.S.) (NSF CAREER Award)Brown UniversityNational Institutes of Health (U.S.) (NIH Grant GM-101988

Contact Patterns Among Bighorn Sheep In and Around Glacier National Park

Identifying patterns of direct contacts among individual animals is important to understanding infectious disease transmission. Social behavior can be influenced by both intrinsic and extrinsic variables and can be explored at 3 levels: social network structure, dyad structure, and contact structure. We investigated drivers of contact structure using GPS locations of 87 male and female bighorn sheep (Ovis canadensis) in and around Glacier National Park in Montana, USA. Focusing on contacts between sheep moving separately, we examined relationships between contact locations and movement variables, land cover, distances to various resources, and variables known to influence survival using a resource selection function. Used and available points were defined as simultaneous locations within 25 m (the contact-used) and 13 km (largest step length- available) of another collared bighorn sheep, thus results of this analysis describe the strengths of these variables relative to habitat use. Data were analyzed separately according to dyad type (male-male, female-female, malefemale). Most contacts occurred in March for male-male and female-female dyads and in November, December, and January for male-female dyads. For male-male dyads, contacts occurred more than expected given habitat use in conifer land cover and locations farther from perennial water sources, high NDVI, little canopy cover, and low and high solar radiation index. For female-female dyads, contacts occurred less than expected given habitat use in grass and barren land cover and locations with intermediate terrain ruggedness, high NDVI, and low and high snow water equivalent. For male-female dyads, contacts occurred most during the night, least during the day, and at locations with intermediate elevation and farther from escape terrain. Together, these results suggest that more specific conditions apply to contact locations than general locations and that we can predict locations where contacts are most likely to occur, which may be useful for disease management

A Simple Fragment of Cyclic Acyldepsipeptides Is Necessary and Sufficient for ClpP Activation and Antibacterial Activity

The development of new antibacterial agents, particularly those with unique biological targets, is essential to keep pace with the inevitable emergence of drug resistance in pathogenic bacteria. We identified the minimal structural component of the cyclic acyldepsipeptide (ADEP) antibiotics that exhibits antibacterial activity. We found that N-acyldifluorophenylalanine fragments function via the same mechanism of action as ADEPs, as evidenced by the requirement of ClpP for the fragments' antibacterial activity, the ability of fragments to activate Bacillus subtilis ClpP in vitro, and the capacity of an N-acyldifluorophenylalanine affinity matrix to capture ClpP from B. subtilis cell lysates. N-acyldifluorophenylalanine fragments are much simpler in structure than the full ADEPs and are also highly amenable to structural diversification. Thus, the stage has been set for the development of non-peptide activators of ClpP that can be used as antibacterial agents.National Science Foundation (U.S.)United States. National Institutes of Health (GM-101988

Pooled analysis of the association of PTGS2 rs5275 polymorphism and NSAID use with invasive ovarian carcinoma risk

Inflammation is postulated to play an important role in ovarian carcinogenesis. Prostaglandin endoperoxide synthase 2 (PTGS2) is responsible for the conversion of arachidonic acid to prostaglandins in response to inflammation. We examined the association of the PTGS2 rs5275 polymorphism with the risk of invasive ovarian carcinoma and the joint effect of rs5275 and use of nonsteroidal antiinflammatory drugs (NSAIDs) on risk in a pooled analysis of two population-based studies, the Hawaii Ovarian Cancer Case-Control Study and the New England Case-Control Study, including 1025 women with invasive ovarian carcinoma and 1687 cancer-free controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. In the pooled analysis, the CC genotype was associated with a reduced risk of nonserous ovarian carcinoma (OR=0.66; CI: 0.44-0.98). In addition, the lowest risk was observed among carriers of the CC genotype who were users of nonaspirin NSAIDs (OR=0.43; CI:0.20-0.93) in all women combined. The association of PTGS2 rs5275 with nonserous ovarian carcinoma and possible effect modification by NSAID use needs further validation, preferably in the prospective studies

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

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

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