Application of the Coastal Hazard Wheel methodology for coastal multi-hazard assessment and management in the state of Djibouti

AbstractThis paper presents the application of a new methodology for coastal multi-hazard assessment and management in a changing global climate on the state of Djibouti. The methodology termed the Coastal Hazard Wheel (CHW) is developed for worldwide application and is based on a specially designed coastal classification system that incorporates the main static and dynamic parameters determining the characteristics of a coastal environment. The methodology provides information on the hazards of ecosystem disruption, gradual inundation, salt water intrusion, erosion and flooding and can be used to support management decisions at local, regional and national level, in areas with limited access to geophysical data. The assessment for Djibouti applies a geographic information system (GIS) to develop a range of national hazard maps along with relevant hazard statistics and is showcasing the procedure for applying the CHW methodology for national hazard assessments. The assessment shows that the coastline of Djibouti is characterized by extensive stretches with high or very high hazards of ecosystem disruption, mainly related to coral reefs and mangrove forests, while large sections along the coastlines of especially northern and southern Djibouti have high hazard levels for gradual inundation. The hazard of salt water intrusion is moderate along most of Djibouti’s coastline, although groundwater availability is considered to be very sensitive to human ground water extraction. High or very high erosion hazards are associated with Djibouti’s sedimentary plains, estuaries and river mouths, while very high flooding hazards are associated with the dry river mouths

Structure-activity relationships in a series of antiplasmodial thieno[2,3-b]pyridines.

BACKGROUND: Malaria is one of the most prevalent tropical infectious diseases. Since recently cases of artemisinin resistance were reported, novel anti-malarial drugs are required which differ from artemisinins in structure and biological target. The plasmodial glycogen synthase kinase-3 (PfGSK-3) was suggested as a new anti-malarial drug target. 4-Phenylthieno[2,3-b]pyridines were previously identified as selective PfGSK-3 inhibitors with antiplasmodial activity. The present study aims at identifying a molecular position on this scaffold for the attachment of side chains in order to improve solubility and antiplasmodial activity. Furthermore, the role of axial chirality in the compound class for antiplasmodial activity and PfGSK-3 inhibition was investigated. METHODS:4-Phenylthieno[2,3-b]pyridines with substituents in 4-position of the phenyl ring were docked into the ATP binding site of PfGSK-3. The compounds were synthesized employing a Thorpe reaction as final step. The enantiomers of one congener were separated by chiral HPLC. All derivatives were tested for inhibition of asexual erythrocytic stages of transgenic NF54-luc Plasmodium falciparum. Selected compounds with promising antiplasmodial activity were further evaluated for inhibition of HEK293 cells as well as inhibition of isolated PfGSK-3 and HsGSK-3. The kinetic aqueous solubility was assessed by laser nephelometry. RESULTS:The para position at the 4-phenyl ring of the title compounds was identified as a suitable point for the attachment of side chains. While alkoxy substituents in this position led to decreased antiplasmodial activity, alkylamino groups retained antiparasitic potency. The most promising of these congeners (4h) was investigated in detail. This compound is a selective PfGSK-3 inhibitor (versus the human GSK-3 orthologue), and exhibits improved antiplasmodial activity in vitro as well as better solubility in aqueous media than its unsubstituted parent structure. The derivative 4b was separated into the atropisomers, and it was shown that the (+)-enantiomer acts as eutomer. CONCLUSIONS:The attachment of alkylamino side chains leads to the improvement of antiplasmodial activity and aqueous solubility of selective PfGSK-inhibitors belonging to the class of 4-phenylthieno[2,3-b]pyridines. These molecules show axial chirality, a feature of high impact for biological activity. The findings can be exploited for the development of improved selective PfGSK-3 inhibitors

CRISPR transcriptional repression devices and layered circuits in mammalian cells

A key obstacle to creating sophisticated genetic circuits has been the lack of scalable device libraries. Here we present a modular transcriptional repression architecture based on clustered regularly interspaced palindromic repeats (CRISPR) system and examine approaches for regulated expression of guide RNAs in human cells. Subsequently we demonstrate that CRISPR regulatory devices can be layered to create functional cascaded circuits, which provide a valuable toolbox for engineering purposes.National Institutes of Health (U.S.) (Grant 5R01CA155320-04)National Institutes of Health (U.S.) (Grant P50 GM098792)Korea (South). Ministry of Science, Information and Communication Technolgy. Intelligent Synthetic Biology Center of Global Frontier Project (2013M3A6A8073557

Toward High Performance Computing Education

High Performance Computing (HPC) is the ability to process data and perform complex calculations at extremely high speeds. Current HPC platforms can achieve calculations on the order of quadrillions of calculations per second with quintillions on the horizon. The past three decades witnessed a vast increase in the use of HPC across different scientific, engineering and business communities, for example, sequencing the genome, predicting climate changes, designing modern aerodynamics, or establishing customer preferences. Although HPC has been well incorporated into science curricula such as bioinformatics, the same cannot be said for most computing programs. This working group will explore how HPC can make inroads into computer science education, from the undergraduate to postgraduate levels. The group will address research questions designed to investigate topics such as identifying and handling barriers that inhibit the adoption of HPC in educational environments, how to incorporate HPC into various curricula, and how HPC can be leveraged to enhance applied critical thinking and problem solving skills. Four deliverables include: (1) a catalog of core HPC educational concepts, (2) HPC curricula for contemporary computing needs, such as in artificial intelligence, cyberanalytics, data science and engineering, or internet of things, (3) possible infrastructures for implementing HPC coursework, and (4) HPC-related feedback to the CC2020 project

Understanding 'non-genetic' inheritance : insights from molecular-evolutionary crosstalk

The idea for this paper was initially proposed by I.A.-K. and was further developed by all authors in a workshop generously funded by grant No 789240 from the European Research Council (ERC) to F.J.W. S.E.S. acknowledges support from Wesleyan University and The John Templeton Foundation.Understanding the evolutionary and ecological roles of 'non-genetic' inheritance (NGI) is daunting due to the complexity and diversity of epigenetic mechanisms. We draw on insights from molecular and evolutionary biology perspectives to identify three general features of 'non-genetic' inheritance systems: (i) they are functionally interdependent with, rather than separate from, DNA sequence; (ii) precise mechanisms vary phylogenetically and operationally; and (iii) epigenetic elements are probabilistic, interactive regulatory factors and not deterministic 'epialleles' with defined genomic locations and effects. We discuss each of these features and offer recommendations for future empirical and theoretical research that implements a unifying inherited gene regulation (IGR) approach to studies of 'non-genetic' inheritance.Publisher PDFPeer reviewe

T cell metabolism drives immunity

Lymphocytes must adapt to a wide array of environmental stressors as part of their normal development, during which they undergo a dramatic metabolic remodeling process. Research in this area has yielded surprising findings on the roles of diverse metabolic pathways and metabolites, which have been found to regulate lymphocyte signaling and influence differentiation, function and fate. In this review, we integrate the latest findings in the field to provide an up-to-date resource on lymphocyte metabolism

Post break-up tectonic inversion across the southwestern cape of South Africa: new insights from apatite and zircon fission track thermochronometry

The south-west African margin is regarded as an example of a passive continental margin formed by continental rifting following a phase of lithospheric extension and thinning. Recent attention focused on this margin has included theoretical modelling studies of rift processes, plate kinematic studies of the opening geometry and timing, and empirical studies focused on documenting the crustal structure and offshore sedimentary record. Here, we examine the onshore geomorphic and tectonic response to rifting and breakup, with a specific focus on the SW Cape of South Africa. We present 75 new apatite and 8 new zircon fission track analyses from outcrop samples and onshore borehole profiles along the western margin of South Africa. The data are used to derive robust thermal histories that record two discrete phases of accelerated erosional cooling during the Early Cretaceous (150-130 Ma) and Late Cretaceous (100-80 Ma), respectively. Both periods of enhanced erosion are regional in extent, involved km-scale erosion, and extend well inland of the current escarpment zone, albeit with spatially variable intensity and style. The Late Cretaceous episode is also expressed more locally by tectonic reactivation and inversion of major faults causing km-scale differential displacement and erosion. The new AFT data do not exclude the possibility of modest surface uplift occurring during the Cenozoic, but they restrict the depth of regional Cenozoic erosion on the western margin to less than c. 1 km. The inferred pattern and chronology of erosion onshore is consistent with the key features and sediment accumulation patterns within the offshore Orange and Bredasdorp basins. It is suggested that the Late Cretaceous event was triggered by a combination of regional dynamic uplift augmented along the western margin and in the SW Cape by local tectonic forces arising from dextral displacement of the Falkland Plateau along the Falkland-Agulhas Fracture Zone

The Australasian Resuscitation In Sepsis Evaluation : fluids or vasopressors in emergency department sepsis (ARISE FLUIDS), a multi-centre observational study describing current practice in Australia and New Zealand

Objectives: To describe haemodynamic resuscitation practices in ED patients with suspected sepsis and hypotension. Methods: This was a prospective, multicentre, observational study conducted in 70 hospitals in Australia and New Zealand between September 2018 and January 2019. Consecutive adults presenting to the ED during a 30-day period at each site, with suspected sepsis and hypotension (systolic blood pressure <100 mmHg) despite at least 1000 mL fluid resuscitation, were eligible. Data included baseline demographics, clinical and laboratory variables and intravenous fluid volume administered, vasopressor administration at baseline and 6- and 24-h post-enrolment, time to antimicrobial administration, intensive care admission, organ support and in-hospital mortality. Results: A total of 4477 patients were screened and 591 were included with a mean (standard deviation) age of 62 (19) years, Acute Physiology and Chronic Health Evaluation II score 15.2 (6.6) and a median (interquartile range) systolic blood pressure of 94 mmHg (87–100). Median time to first intravenous antimicrobials was 77 min (42–148). A vasopressor infusion was commenced within 24 h in 177 (30.2%) patients, with noradrenaline the most frequently used (n = 138, 78%). A median of 2000 mL (1500–3000) of intravenous fluids was administered prior to commencing vasopressors. The total volume of fluid administered from pre-enrolment to 24 h was 4200 mL (3000–5661), with a range from 1000 to 12 200 mL. Two hundred and eighteen patients (37.1%) were admitted to an intensive care unit. Overall in-hospital mortality was 6.2% (95% confidence interval 4.4–8.5%). Conclusion: Current resuscitation practice in patients with sepsis and hypotension varies widely and occupies the spectrum between a restricted volume/earlier vasopressor and liberal fluid/later vasopressor strategy

Mammal responses to global changes in human activity vary by trophic group and landscape

Wildlife must adapt to human presence to survive in the Anthropocene, so it is critical to understand species responses to humans in different contexts. We used camera trapping as a lens to view mammal responses to changes in human activity during the COVID-19 pandemic. Across 163 species sampled in 102 projects around the world, changes in the amount and timing of animal activity varied widely. Under higher human activity, mammals were less active in undeveloped areas but unexpectedly more active in developed areas while exhibiting greater nocturnality. Carnivores were most sensitive, showing the strongest decreases in activity and greatest increases in nocturnality. Wildlife managers must consider how habituation and uneven sensitivity across species may cause fundamental differences in human–wildlife interactions along gradients of human influence.Peer reviewe

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development