A geoscientific framework for the proposed site of South Africa's second nuclear power plant: Thyspunt, Eastern Cape

This study describes the bedrock lithologies and structure of the Ordovician to early Devonian (485-419 Ma) Table Mountain Group (TMG), the Devonian (419-358 Ma) lower Bokkeveld Group, and the Miocene to Holocene (<23 Ma) overburden sediments of the Algoa Group within an area identified by Eskom for the potential construction of South Africa’s second proposed nuclear power plant (NPP), ‘Nuclear-1’. The study area is located along the southern coastal margin of the Eastern Cape Province, South Africa, between Oyster Bay and St. Francis (approximately 88 km west of Port Elizabeth), and encompasses the Thyspunt site where the proposed NPP will be built. The study aims to supplement existing information about the Thyspunt area, related to the geoscientific topic ‘Geological Setting’, as outlined in section 2.5.1.1 of the US Nuclear Regulatory Commission (USNRC) Standard Review Plan NUREG-800, which details the geological information required for review of a proposed NPP. The results obtained from geoscientific studies are used to determine geological factors that may potentially affect site specific design. Factors considered include: bedrock lithology, stratigraphic bedrock contacts, bedrock palaeotopography, thickness of overburden sediments and structural geology. Work by previous authors is combined with new data to create a GIS based 2½D model of the study area’s geology (geomodel) and on which future research or interpretations can be based. Field mapping and petrographic analyses of the TMG, comprising the Peninsula, Cedarberg, Goudini, Skurweberg and Baviaanskloof Formations as well as the lower undifferentiated Bokkeveld Group were undertaken to define the study area’s lithologies and structure. Interpretation of geophysical results and the integration of existing borehole data aided in defining the variability in overburden sediments, the identification of contacts between TMG formations beneath overburden, and the palaeotopography of bedrock. Borehole data indicates a clear N-S trend in the thickness distribution of Algoa Group aeolian and marine related sediments. Four coast-parallel trending thickness zones (zones A – D) are recognized within the study area. At Thyspunt overburden thickness reaches a maximum of 61 m, approximately 1200 m from the coastline, in areas underlain by the argillaceous Goudini and Cedarberg Formations. Overburden thickness is influenced by a combination of dune relief, bedrock lithology, palaeotopography and the area’s sediment supply. Interpolation of bedrock elevation points and detailed cross sections across bedrock reveals four NW-SE trending palaeovalleys at Thyspunt, Tony’s Bay, Cape St. Francis and St. Francis, where bedrock relief (beneath overburden) is formed to be below present day sea-level. Approximately 450 m NW of Thys Bay, a 1050 m2 (area below sea-level) palaeovalley, gently sloping SE to a depth of -15.5 m asl, is cut into strata of the Goudini Formation resulting in thicker overburden fill in that area. Structural analysis of the TMG confirms that NE-SW striking strata form part of the regional SE plunging, north verging Cape St. Francis anticline. Bedding inclination is controlled by the distance away from the fold axis, varying from a 5° SE dip along the broad fold hinge to 65° along its moderately steeper SE limb. Folds within the study area plunge gently southeastward at shallow angles, with axial planes dipping steeply SW or NE. Fold axes orientated perpendicular to the fold axis of the Cape St. Francis anticline indicate a secondary stress orientation oblique to the main palaeostress direction. The previously identified 40 km long, NW-SE trending Cape St. Francis fault occurring offshore within 17.5 km of Thyspunt show no onshore continuation within the bounds of the study area. Late jointing is pervasive within the study area and four joint systems are identified. The dominant joint set J1, trends N-S to NNE - SSW; perpendicular to bedding and has a subvertical dip. Normal right-lateral and left-lateral micro-faults dip subvertically, with a displacement that ranges from a few centimetres to <3 m. Micro-faults trend parallel to joints sets J1 and J4 (ESE-WSW). Inferred faults, identified by the Atomic Energy Co-operation (AEC), are interpreted as zones of closely spaced jointing (shatter zones), and show little to no recognizable displacement. Faults and joints do not extend into the younger cover deposits of the Algoa Group and are therefore older than 23 Ma years

hTERT promoter activity and CpG methylation in HPV-induced carcinogenesis

<p>Abstract</p> <p>Background</p> <p>Activation of telomerase resulting from deregulated hTERT expression is a key event during high-risk human papillomavirus (hrHPV)-induced cervical carcinogenesis. In the present study we examined hTERT promoter activity and its relation to DNA methylation as one of the potential mechanisms underlying deregulated hTERT transcription in hrHPV-transformed cells.</p> <p>Methods</p> <p>Using luciferase reporter assays we analyzed hTERT promoter activity in primary keratinocytes, HPV16- and HPV18-immortalized keratinocyte cell lines and cervical cancer cell lines. In the same cells as well as cervical specimens we determined hTERT methylation by bisulfite sequencing analysis of the region spanning -442 to +566 (relative to the ATG) and quantitative methylation specific PCR (qMSP) analysis of two regions flanking the hTERT core promoter.</p> <p>Results</p> <p>We found that in most telomerase positive cells increased hTERT core promoter activity coincided with increased hTERT mRNA expression. On the other hand basal hTERT promoter activity was also detected in telomerase negative cells with no or strongly reduced hTERT mRNA expression levels. In both telomerase positive and negative cells regulatory sequences flanking both ends of the core promoter markedly repressed exogenous promoter activity.</p> <p>By extensive bisulfite sequencing a strong increase in CpG methylation was detected in hTERT positive cells compared to cells with no or strongly reduced hTERT expression. Subsequent qMSP analysis of a larger set of cervical tissue specimens revealed methylation of both regions analyzed in 100% of cervical carcinomas and 38% of the high-grade precursor lesions, compared to 9% of low grade precursor lesions and 5% of normal controls.</p> <p>Conclusions</p> <p>Methylation of transcriptionally repressive sequences in the hTERT promoter and proximal exonic sequences is correlated to deregulated hTERT transcription in HPV-immortalized cells and cervical cancer cells. The detection of DNA methylation at these repressive regions may provide an attractive biomarker for early detection of cervical cancer.</p

Earth Stewardship Science—Transdisciplinary Contributions to Quantifying Natural and Cultural Heritage of Southernmost Africa

Evaluating anthropogenic changes to natural systems demand greater quantification through innovative transdisciplinary research focused on adaptation and mitigation across a wide range of thematic sciences. Southernmost Africa is a unique field laboratory to conduct such research linked to earth stewardship, with &lsquo;earth&rsquo; as in our Commons. One main focus of the AEON&rsquo;s Earth Stewardship Science Research Institute (ESSRI) is to quantify the region&rsquo;s natural and cultural heritage at various scales across land and its flanking oceans, as well as its time-scales ranging from the early Phanerozoic (some 540 million years) to the evolution of the Anthropocene (changes) following the emergence of the first human-culture on the planet some 200 thousand years ago. Here we illustrate the value of this linked research through a number of examples, including: (i) geological field mapping with the aid of drone, satellite and geophysical methods, and geochemical fingerprinting; (ii) regional ground and surface water interaction studies; (iii) monitoring soil erosion, mine tailing dam stability and farming practices linked to food security and development; (iv) ecosystem services through specific biodiversity changes based on spatial logging of marine (oysters and whales) and terrestrial (termites, frogs and monkeys) animals. We find that the history of this margin is highly episodic and complex by, for example, the successful application of ambient noise and groundwater monitoring to assess human-impacted ecosystems. This is also being explored with local Khoisan representatives and rural communities through Citizen Science. Our goal is to publicly share and disseminate the scientific and cultural data, through initiatives like the Africa Alive Corridor 10: &lsquo;Homo Sapiens&rsquo; that embraces storytelling along the entire southern coast. It is envisioned that this approach will begin to develop the requisite integrated technological and societal practices that can contribute toward the needs of an ever-evolving and changing global &lsquo;village&rsquo;

Methylation status of the E2 binding sites of HPV16 in cervical lesions determined with the Luminex® xMAP™ system

AbstractCervical carcinogenesis is driven by deregulated E6/E7 expression in dividing cells. A potential deregulating mechanism is methylation of E2 binding sites in the viral long control region, thereby prohibiting HPVE2-mediated transcription regulation. Here the frequency of HPV16E2BS methylation in cervical lesions (SCC, n=29; CIN3, n=17) and scrapes (controls, n=17; CIN3, n=21) was investigated. Three E2BSs were amplified using methylation independent PCR followed by specific detection of methylated CpGs using the Luminex® xMAP™ system. The frequency of E2BS1, E2BS3 and E2BS4 methylation was significantly higher in SCC compared to CIN3, i.e. 93% vs. 21% (p<0.01), 90% vs. 47% (p<0.01) and 69% vs. 5% (p<0.01), respectively and ranged from 6 to 15% in controls. In scrapings of women with CIN3 methylation ranged from 24 to 33%.In conclusion, we showed that the MIP–Luminex system is a highly sensitive method for methylation analysis. HPV16 E2BSs methylation appeared highly frequent in SCC, with particularly E2BS3 methylation occurring proportional to severity of cervical disease

Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial

BackgroundBenzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups.MethodsIn this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (&lt;18 years, 18-65 years, and &gt;65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075.FindingsBetween Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged &lt;18 years), 186 adults (18-65 years), and 51 older adults (&gt;65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group.InterpretationChildren, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus.FundingNational Institute of Neurological Disorders and Stroke, National Institutes of Health

Whole-genome sequencing reveals host factors underlying critical COVID-19

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease