Triggering the Cambrian Explosion: carbon cycle reorganisation and the rise of Metazoans

Numerous detailed geochemical studies of Ediacaran (~635 – 541 Ma) marine successions provide snapshots into the palaeoenvironmental redox conditions which accompanied examples of the earliest metazoans in the fossil record. Spatial heterogeneity with respect to palaeomarine redox is evident from reconstructions of geographically-widespread Ediacaran environments. This project provides new data of local-scale redox within a paleogeographic and sequence stratigraphic framework in order to explore the mechanisms which controlled water column redox variations and the potential impact on early macro-benthic ecosystems. Lower than present atmospheric and oceanic oxygen concentrations enabled some shallow marine settings to remain poised at iron reduction until well into the Cambrian and likely influenced regional-scale ecosystem structure and stability. Many basins had a shallow and highly dynamic chemocline above anoxic (ferruginous or euxinic) or low oxygen (manganous) waters. Regional differences in palaeoredox were likely controlled primarily by local detrital nutrient provision and organic matter remineralisation and the redox state of the global deep ocean was most likely similarly heterogeneous (but this remains uncertain). It is suggested that cratonic positioning and migration throughout the Ediacaran Period, in combination with gradually increasing dissolved oxygen loading, may have provided a long-term control on redox evolution through regulating circulation mechanisms in the Mirovian Ocean. Some unrestricted lower slope environments from mid-high latitudes benefited from sustained oxygenation via downwelling, whilst cratonic isolation or transit towards more equatorial positions stifled pervasive ventilation either through ineffective surface ocean mixing, Ekman-induced upwelling, elevated surface ocean productivity, or a combination of these processes. Co-preservation of largely-enigmatic fossil forms within sedimentary rocks of the late Ediacaran Nama Group of southern Namibia have allowed the four-dimensional reconstruction of local redox dynamics and associated biotic establishment. This has been made possible through collation of previously published fossil occurrence and geochemical information alongside new palaeoredox and palaeoproductivity estimates based on iron speciation, major element and carbonate-bound iodine data. This is further supplemented by the first detailed assessment of the paragenetic sequence and diagenetic relationships of carbonates which precipitated within the earliest metazoan reef framework. Skeletal invertebrate taxa in the Zaris Sub-Basin of the lower Nama Group (~550-547 Ma), grew above wave base where micritic carbonate sediment often shows evidence for early dolomitisation. Mid-ramp Cloudina reefs composed of open, highly porous structures formed multiple, successive assemblages. Thin layers of dolomitised sediment and dolomite cement terminate each assemblage. Reef cements show a paragenetic sequence from synsedimentary, early marine cement through to final burial, each of which were precipitated under dynamic redox conditions. These cements likely record a general shallow to deeper water transect, from oxic shallow waters to low oxygen manganous waters and finally to oxic, shallow burial conditions. Transient incursions of upwelled, anoxic, ferruginous and dolomitising waters may have occurred during short-term, transgressive cycles, although the timing for this is poorly constrained. Such incursions may have terminated Ediacaran benthic communities that grew close to the chemocline. Viewed in its entirety, the palaeoredox record of the Nama Group reveals evidence for a pronounced shift in the depth of the ferruginous redoxcline from shallow to deeper levels in the water column through time, which was accompanied by a reduced frequency of anoxic incursions onto the shallow shelf. This transition approximately coincided with the first appearance and subsequent diversification of novel sediment bioturbators in the Lower Urusis Formation (~547-542 Ma). It is proposed that the observed coevolution of palaeoredox and ichnofossil diversity may directly relate to the impact of bioturbation on phosphorus retention. In this way, the diversification of burrowing forms effectively oxygenated the sediment column, prevented efficient P recycling to the water column and limited the detrimental impact of productivity-induced anoxia in the local environment. However, this hypothesis remains to be tested and would benefit from a focused study of palaeoproductivity employing targeted analyses of total organic carbon and sedimentary phosphorus speciation. It is further proposed that the persistent spatial separation of anoxic deep waters from habitable ecospace, implied by the fossil distribution of phylogenetically-enigmatic soft-bodied forms, qualitatively supports the inference that at least intermittently oxic conditions (at or above EH typical of ferrous iron oxidation) were a metabolic requirement of these organisms. Finally, four new sections of the late Ediacaran, deposited approximately time-equivalent to aforementioned sediments of the Nama Group, are described and preliminary geochemical data reported. These include two shallow marine carbonate-dominated sections of the southeast Siberian Craton which correspond to the Yudoma Formation and two sections of the Dengying and lower Zhujiaqing (and correlative) Formations deposited on the Yangtze Block, South China. Integrated proxy methods are able to distinguish palaeoredox heterogeneity between and within early animal ecosystems and test the influence of anoxia on ecosystem structure. The first and last appearances of Treptichnus pedum and Cloudina respectively, which globally bracket the boundary between the Ediacaran and Cambrian Periods, show no identifiable range overlap in any sections analysed in this study. This suggests that the first appearance of the organism responsible for characteristic T. pedum may have lived approximately contemporaneous in oxic habitable refuges of all regions in this study, regardless of the dominance of reducing conditions that persisted in coeval deeper environments in many areas

Integrated records of environmental change and evolution challenge the Cambrian Explosion.

The 'Cambrian Explosion' describes the rapid increase in animal diversity and abundance, as manifest in the fossil record, between ~540 and 520 million years ago (Ma). This event, however, is nested within a far more ancient record of macrofossils extending at least into the late Ediacaran at ~571 Ma. The evolutionary events documented during the Ediacaran-Cambrian interval coincide with geochemical evidence for the modernisation of Earth's biogeochemical cycles. Holistic integration of fossil and geochemical records leads us to challenge the notion that the Ediacaran and Cambrian worlds were markedly distinct, and places biotic and environmental change within a longer-term narrative. We propose that the evolution of metazoans may have been facilitated by a series of dynamic and global changes in redox conditions and nutrient supply, which, potentially together with biotic feedbacks, enabled turnover events that sustained multiple phases of radiation. We argue that early metazoan diversification should be recast as a series of successive, transitional radiations that extended from the late Ediacaran and continued through the early Palaeozoic. We conclude that while the Cambrian Explosion represents a radiation of crown-group bilaterians, it was simply one phase amongst several metazoan radiations, some older and some younger

Lead optimization of a pyrazole sulfonamide series of trypanosoma brucei N -myristoyltransferase inhibitors:Identification and evaluation of CNS penetrant compounds as potential treatments for stage 2 human african trypanosomiasis

[Image: see text] Trypanosoma bruceiN-myristoyltransferase (TbNMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis (HAT). From previous studies, we identified pyrazole sulfonamide, DDD85646 (1), a potent inhibitor of TbNMT. Although this compound represents an excellent lead, poor central nervous system (CNS) exposure restricts its use to the hemolymphatic form (stage 1) of the disease. With a clear clinical need for new drug treatments for HAT that address both the hemolymphatic and CNS stages of the disease, a chemistry campaign was initiated to address the shortfalls of this series. This paper describes modifications to the pyrazole sulfonamides which markedly improved blood–brain barrier permeability, achieved by reducing polar surface area and capping the sulfonamide. Moreover, replacing the core aromatic with a flexible linker significantly improved selectivity. This led to the discovery of DDD100097 (40) which demonstrated partial efficacy in a stage 2 (CNS) mouse model of HAT

Targeted agents and immunotherapies: optimizing outcomes in melanoma

Treatment options for patients with metastatic melanoma, and especially BRAF-mutant melanoma, have changed dramatically in the past 5 years, with the FDA approval of eight new therapeutic agents. During this period, the treatment paradigm for BRAF-mutant disease has evolved rapidly: the standard-of-care BRAF-targeted approach has shifted from single-agent BRAF inhibition to combination therapy with a BRAF and a MEK inhibitor. Concurrently, immunotherapy has transitioned from cytokine-based treatment to antibody-mediated blockade of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and, now, the programmed cell-death protein 1 (PD-1) immune checkpoints. These changes in the treatment landscape have dramatically improved patient outcomes, with the median overall survival of patients with advanced-stage melanoma increasing from approximately 9 months before 2011 to at least 2 years - and probably longer for those with BRAF-V600-mutant disease. Herein, we review the clinical trial data that established the standard-of-care treatment approaches for advanced-stage melanoma. Mechanisms of resistance and biomarkers of response to BRAF-targeted treatments and immunotherapies are discussed, and the contrasting clinical benefits and limitations of these therapies are explored. We summarize the state of the field and outline a rational approach to frontline-treatment selection for each individual patient with BRAF-mutant melanoma

Advanced surgical skills for exposure in trauma (ASSET): the first 25 courses

The Advanced Surgical Skills for Exposure in Trauma (ASSET) course was developed to address limited experience of residents and practicing surgeons (PS) in rapid exposure of major blood vessels for trauma. This one day, case based, scenario driven, fresh cadaver dissection course emphasizes rapid surgical exposure of the vasculature of the neck, chest, abdomen, pelvis and extremities with additional focus on fasciotomies and pelvic packing. Contained herein are the results of the first 25 courses. Data collected from 25 ASSET courses conducted between September 2010 and February 2012 included self-reported comfort level (5 point Likert scale) with each of 25 specific skills before and upon completion of the course, and evaluation of the course content. Statistical analysis was accomplished using the Student t-test with α set at P < 0.05. Ninety-one surgical trainees and 123 PS were taught at 11 ASSET sites. Self-assessed comfort levels for all 25 queried skills and exposures improved significantly over baseline with P values ranging from 1.6 × 10−7 to 3.9 × 10−41. Participants gained new knowledge (4.83 on 5 point scale); learned new techniques (4.83), felt better prepared to expose traumatically injured vessels (4.88), and would recommend the course to a colleague (4.92). The ASSET course was well received and significantly improved self-reported confidence in the exposures needed to care for trauma in both surgical trainees and PS. Ongoing experience with this course will enable more comprehensive psychometric analysis and further validation of this curriculum

Plasma Levels of Parent Compound and Metabolites after Doses of Either d-Fenfluramine or d-3,4-Methylenedioxymethamphetamine (MDMA) that Produce Long-Term Serotonergic Alterations

Plasma levels of parent compounds and metabolites were determined in adult rhesus monkeys after doses of either 5 mg/kg d-fenfluramine (FEN) or 10 mg/kg d-3, 4-methylenedioxymethamphetamine (MDMA) i.m. twice daily for four consecutive days. These treatment regimens have been previously shown to produce long-term serotonin (5-HT) depletions. Peak plasma levels of 2.0±0.4 μM FEN were reached within 40 min after the first dose of FEN, and then declined rapidly, while peak plasma levels (0.4±0.1 μM) of the metabolite norfenfluramine (NFEN) were not reached until 6 h after dosing. After the seventh (next to last) dose of FEN, peak plasma levels of FEN were 35% greater than after the first dose while peak NFEN-levels were 500% greater. The t 1/2 for FEN was 2.6±0.3 h after the first dose and 3.2±0.2 h after the seventh. The estimated t 1/2 for NFEN was more than 37.6±20.5 h. Peak plasma levels of 9.5±2.5 μM MDMA were reached within 20 min after the first dose of MDMA, and then declined rapidly, while peak plasma levels (0.9±0.2 μM) of the metabolite 3,4-methylenedioxyamphetamine (MDA) were not reached until 3–6 h after dosing. After the seventh (next to last) dose of MDMA, peak plasma levels of MDMA were 30% greater than the first dose while peak MDA levels were elevated over 200%. The t 1/2 for MDMA was 2.8±0.4 h after the first and 3.9±1.1 h after the seventh dose. The estimated t 1/2 for MDA was about 8.3±1.0 h. Variability in plasma levels of MDMA and MDA between subjects was much greater than that for FEN and NFEN. This variability in MDMA and MDA exposure levels may have lead to variability in the subsequent disruption of some behaviors seen in these same subjects. There were 80% reductions in the plasma membrane-associated 5-HT transporters 6 months after either the FEN or MDMA dosing regimen indicating that both treatments produced long-term serotonergic effects