Linking Redox Processes and Black Shale Resource Potential

Black shales, such as the Mississippian (~330 Ma) Bowland Shale Formation, are targets for unconventional hydrocarbon exploration in the UK and in equivalents across Europe. Despite this interest, global decarbonisation, by definition, will either require; (1) complete replacement of natural gas with renewables and nuclear power generation, or; (2) moderate to limited natural gas use globally or locally, for example as a ‘bridge fuel’, as a source for hydrogen via steam reformation, or coupled to carbon capture and storage (CCS) technology. Any of these scenarios will increase the demand for transition metals such as V, Co and Ni, key elements used for energy storage and as catalysts in steam reformation. Black shales in general can host ore-grade enrichments in these metals, although the exact resource potential of UK Mississippian black shales remains unresolved. We integrate comprehensive sedimentological and geochemical data from three sections through the Bowland Shale in the Craven Basin (Lancashire, UK) to explore the links between controls on hydrocarbon and metal prospectivity. The Bowland Shale at these sites is a highly heterogeneous and complex ~120 m thick succession comprising carbonate-rich, siliceous and siliciclastic, argillaceous mudstones. These sedimentary facies developed in response to a combination of high-frequency (~111 kyr) sea level changes, fault activity at the basin margins and linkage with the nearby prograding Pendle delta system. Palaeoredox proxies such as Fe-speciation, redox-sensitive trace elements and S isotope analysis from extracted pyrite (δ34Spy) demonstrate intervals associated with metal enrichment were deposited under anoxic and at least intermittently euxinic (sulphidic) bottom water conditions. Trace element enrichment ‘V scores’ (sum of V+Mo+Se+Ni+Zn in ppm) indicate the greatest enrichments in these key transition metals and non-metals are associated with deposition under strongly sulphidic conditions during marine transgressions. V scores in these intervals are often >400 ppm and sometimes >1000 ppm. These bulk enrichments are comparable to stratiform low-grade ores such as the Upper Mudstone Member of the Devonian Popovich Formation (Nevada, USA). Hosts for these metals likely include solid sulphides such as pyrite, organic matter and possibly phosphates or carbonates. Critically, a process of switching between ferruginous and euxinic conditions in anoxic porewaters, termed ‘redox oscillation’, is recognised by a distinctive redox-sensitive trace element enrichment pattern, particularly competition between V and Ni metalation. Redox oscillation operated during periods of reduced sea level, where an increased supply of reactive Fe to the basin promoted development of intermittently ferruginous conditions in bottom waters and early diagenetic porewaters. Therefore the distribution of many redox-sensitive elements through the Bowland Shale is predictable. If these elements can be efficiently extracted from the mineral or organic hosts, UK Mississippian black shales may represent a significant resource. This work also improves understanding of the potential for co-extraction of metals during hydraulic fracturing, or during remediation of waste water. Future work will seek to understand which minerals or organic compounds host these redox-sensitive trace elements

The development and implementation of a regional network of physiotherapists for exercise therapy in patients with peripheral arterial disease, a preliminary report

BACKGROUND: Exercise therapy (ET) is the main conservative and proven effective treatment of patients with intermittent claudication. Currently, the most frequent exercise prescription is a single 'go home and walk' advise, without supervision or follow-up. There is no evidence to support the efficacy of this advise and compliance is known to be low. Therefore, a systematic approach was used to guarantee quality and standardisation of treatment, optimal guideline adherence and improved of inter-professional communication between vascular surgeons and physiotherapists. In this preliminary report we would like to outline the steps taken for the development and implementation of the Network Exercise Therapy Parkstad METHODS: In October 2003 all 59 regional physiotherapy practices were invited to attend a symposium regarding ET in a physiotherapeutic setting. Attending physiotherapists interested in providing ET and willing to follow a certified course on ET, were asked to register. Three tastkgroups were formed to accomplish the set targets: Exercise therapy education, Exercise therapy implementation and continuity, and Inter-professional communication in the Parkstad region. RESULTS: In total 27 physiotherapists, from 22 different practices followed the educational program and are now trained and accredited to provide ET according to the guideline of the Royal Dutch Society for Physiotherapy. A web-based database wasdesigned to contain information on disease specific items provided by the vascular surgery department, and aspects with respect to ET registered by the physiotherapist. The information is regularly updated and available online. Access tothe database is restricted to vascular surgeons and physiotherapists in the network. The secondary purpose of the database is to register essential benchmark data for future analysis of ET in a physiotherapeutic setting in the Netherlands and to enable physiotherapists continuous feedback on patient performance. A triage system was developed to detect patients with a compromised cardiac history. This group receives ET at the in-hospital department of revalidation with the possibility of immediate consultation of a cardiologist in case of cardiac complications or even CPR. CONCLUSION: The Network Exercise Therapy Parkstad of supervised ET is the first initiative in the Netherlands to provide ET close to the patient's home environment. With the implementation of supervised ET in an outpatient physiotherapeutic setting for all eligible patients with symptomatic PAD, the access to care has been improved. A web-based communication system provides physiotherapists and vascular surgeons with all the necessary and continues updated patient information. Future research, currently in progress, will investigate the therapeutic benefits and cost-effectiveness of exercise therapy in a physiotherapeutic setting

SMA CARNI-VAL TRIAL PART II: A Prospective, Single-Armed Trial of L-Carnitine and Valproic Acid in Ambulatory Children with Spinal Muscular Atrophy

Multiple lines of evidence have suggested that valproic acid (VPA) might benefit patients with spinal muscular atrophy (SMA). The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and l-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2–8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children.This study involved 33 genetically proven type 3 SMA subjects ages 3–17 years. Subjects underwent two baseline assessments over 4–6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend), timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP), handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores.Twenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful.This study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356

No abstract available