Structure–activity relationship of ipglycermide binding to phosphoglycerate mutases

Catalysis of human phosphoglycerate mutase is dependent on a 2,3-bisphosphoglycerate cofactor (dPGM), whereas the nonhomologous isozyme in many parasitic species is cofactor independent (iPGM). This mechanistic and phylogenetic diversity offers an opportunity for selective pharmacologic targeting of glycolysis in disease-causing organisms. We previously discovered ipglycermide, a potent inhibitor of iPGM, from a large combinatorial cyclic peptide library. To fully delineate the ipglycermide pharmacophore, herein we construct a detailed structure–activity relationship using 280 substituted ipglycermide analogs. Binding affinities of these analogs to immobilized Caenorhabditis elegans iPGM, measured as fold enrichment relative to the index residue by deep sequencing of an mRNA display library, illuminated the significance of each amino acid to the pharmacophore. Using cocrystal structures and binding kinetics, we show that the high affinity of ipglycermide for iPGM orthologs, from Brugia malayi, Onchocerca volvulus, Dirofilaria immitis, and Escherichia coli, is achieved by a codependence between (1) the off-rate mediated by the macrocycle Cys14 thiolate coordination to an active-site Zn2+ in the iPGM phosphatase domain and (2) shape complementarity surrounding the macrocyclic core at the phosphotransferase–phosphatase domain interface. Our results show that the high-affinity binding of ipglycermide to iPGMs freezes these structurally dynamic enzymes into an inactive, stable complex

Role of vitamin D supplementation in the management of musculoskeletal diseases: update from an European Society of Clinical and Economical Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group.

Vitamin D is a key component for optimal growth and for calcium-phosphate homeostasis. Skin photosynthesis is the main source of vitamin D. Limited sun exposure and insufficient dietary vitamin D supply justify vitamin D supplementation in certain age groups. In older adults, recommended doses for vitamin D supplementation vary between 200 and 2000 IU/day, to achieve a goal of circulating 25-hydroxyvitamin D (calcifediol) of at least 50 nmol/L. The target level depends on the population being supplemented, the assessed system, and the outcome. Several recent large randomized trials with oral vitamin D regimens varying between 2000 and 100,000 IU/month and mostly conducted in vitamin D-replete and healthy individuals have failed to detect any efficacy of these approaches for the prevention of fracture and falls. Considering the well-recognized major musculoskeletal disorders associated with severe vitamin D deficiency and taking into account a possible biphasic effects of vitamin D on fracture and fall risks, an European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group convened, carefully reviewed, and analyzed the meta-analyses of randomized controlled trials on the effects of vitamin D on fracture risk, falls or osteoarthritis, and came to the conclusion that 1000 IU daily should be recommended in patients at increased risk of vitamin D deficiency. The group also addressed the identification of patients possibly benefitting from a vitamin D loading dose to achieve early 25-hydroxyvitamin D therapeutic level or from calcifediol administration

Thermoregulatory traits combine with range shifts to alter the future of montane ant assemblages

Predicting and understanding the biological response to future climate change is a pressing challenge for humanity. In the 21st century, many species will move into higher latitudes and higher elevations as the climate warms. In addition, the relative abundances of species within local assemblages are likely to change. Both effects have implications for how ecosystems function. Few biodiversity forecasts, however, take account of both shifting ranges and changing abundances. We provide a novel analysis predicting the potential changes to assemblage‐level relative abundances in the 21st century. We use an established relationship linking ant abundance and their colour and size traits to temperature and UV‐B to predict future abundance changes. We also predict future temperature driven range shifts and use these to alter the available species pool for our trait‐mediated abundance predictions. We do this across three continents under a low greenhouse gas emissions scenario (RCP2.6) and a business‐as‐usual scenario (RCP8.5). Under RCP2.6, predicted changes to ant assemblages by 2100 are moderate. On average, species richness will increase by 26%, while species composition and relative abundance structure will be 26% and 30% different, respectively, compared with modern assemblages. Under RCP8.5, however, highland assemblages face almost a tripling of species richness and compositional and relative abundance changes of 66% and 77%. Critically, we predict that future assemblages could be reorganized in terms of which species are common and which are rare: future highland assemblages will not simply comprise upslope shifts of modern lowland assemblages. These forecasts reveal the potential for radical change to montane ant assemblages by the end of the 21st century if temperature increases continue. Our results highlight the importance of incorporating trait–environment relationships into future biodiversity predictions. Looking forward, the major challenge is to understand how ecosystem processes will respond to compositional and relative abundance changes.Australian Research Council, Grant/Award Number: DP120100781; University of Pretoria; Leverhulme Trust; NERC; DST‐NRF CIB.http://wileyonlinelibrary.com/journal/gcb2020-06-01hj2019Zoology and Entomolog

Validation of TROPOMI Surface UV Radiation Product

The TROPOspheric Monitoring Instrument (TROPOMI) onboard the Sentinel-5 Precursor (S5P) satellite was launched on 13 October 2017 to provide the atmospheric composition for atmosphere and climate research. The S5P is a sun-synchronous polar-orbiting satellite providing global daily coverage. The TROPOMI swath is 2600 km wide, and the ground resolution for most data products is 7.2x3.5 km2 (5.6x3.5 km2 since 6 August 2019) at nadir. The Finnish Meteorological Institute (FMI) is responsible for the development and processing of the TROPOMI Surface Ultraviolet (UV) Radiation Product which includes 36 UV parameters in total. Ground-based data from 25 sites located in arctic, subarctic, temperate, equatorial and antarctic areas were used for validation of TROPOMI overpass irradiance at 305, 310, 324 and 380 nm, overpass erythemally weighted dose rate / UV index and erythemally weighted daily dose for the period from 1 January 2018 to 31 August 2019. The validation results showed that for most sites 60–80% of TROPOMI data was within ±20% from ground-based data for snow free surface conditions. The median relative differences to ground-based measurements of TROPOMI snow free surface daily doses were within ±10% and ±5% at two thirds and at half of the sites, respectively. At several sites more than 90% of clear sky TROPOMI data were within ±20% from ground-based measurements. Generally median relative differences between TROPOMI data and ground-based measurements were a little biased towards negative values, but at high latitudes where nonhomogeneous topography and albedo/snow conditions occurred, the negative bias was exceptionally high, from -30% to -65%. Positive biases of 10–15% were also found for mountainous sites due to challenging topography. The TROPOMI Surface UV Radiation Product includes quality flags to detect increased uncertainties in the data due to heterogeneous surface albedo and rough terrain which can be used to filter the data retrieved under challenging conditions

Clinical practice guidelines for BRCA1 and BRCA2 genetic testing

BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed. The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis. An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer. These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices

Closing gaps to our origins : EUVO: the ultraviolet-visible window into the Universe

This article reproduces the contents of the White Paper entitled by the same name submitted to the call issued by the European Space Agency soliciting ideas from the scientific community for the science themes that should be covered during the Voyage 2050 planning cycle. This contribution focus in the investigation of the emergence of life and the role that astronomy has to play in it. Three fundamental areas of activity are identified: [1] measuring the chemical enrichment of the Universe, [2] investigating planet formation and searching for exoplanets with signatures of life and, [3] determining the abundance of amino acids and the chemical routes to amino acid and protein growth in astronomical bodies. This proposal deals with the first two. The building blocks of life in the Universe began as primordial gas processed in stars and mixed at galactic scales. The mechanisms responsible for this development are not well-understood and have changed over the intervening 13 billion years. To follow the evolution of matter over cosmic time, it is necessary to study the strongest (resonance) transitions of the most abundant species in the Universe. Most of them are in the ultraviolet (UV; 950 Å - 3000 Å ) spectral range that is unobservable from the ground; the “missing” metals problem cannot be addressed without this access. Habitable planets grow in protostellar discs under ultraviolet irradiation, a by-product of the accretion process that drives the physical and chemical evolution of discs and young planetary systems. The electronic transitions of the most abundant molecules are pumped by this UV field that is the main oxidizing agent in the disc chemistry and provides unique diagnostics of the planet-forming environment that cannot be accessed from the ground. Knowledge of the variability of the UV radiation field is required for the astrochemical modelling of protoplanetary discs, to understand the formation of planetary atmospheres and the photochemistry of the precursors of life. Earth’s atmosphere is in constant interaction with the interplanetary medium and the solar UV radiation field. The exosphere of the Earth extends up to 35 planetary radii providing an amazing wealth of information on our planet’s winds and the atmospheric compounds. To access to it in other planetary systems, observation of the UV resonance transitions is required. The investigation for the emergence of life calls for the development of large astronomical facilities, including instrumentation in optical and UV wavelengths. In this contribution, the need to develop a large observatory in the optical and in the UV is revealed, in order to complete the scientific goals to investigate the origin of life, inaccessible through other frequencies in the electromagnetic spectrum

Design status of ASPIICS, an externally occulted coronagraph for PROBA-3

The "sonic region" of the Sun corona remains extremely difficult to observe with spatial resolution and sensitivity sufficient to understand the fine scale phenomena that govern the quiescent solar corona, as well as phenomena that lead to coronal mass ejections (CMEs), which influence space weather. Improvement on this front requires eclipse-like conditions over long observation times. The space-borne coronagraphs flown so far provided a continuous coverage of the external parts of the corona but their over-occulting system did not permit to analyse the part of the white-light corona where the main coronal mass is concentrated. The proposed PROBA-3 Coronagraph System, also known as ASPIICS (Association of Spacecraft for Polarimetric and Imaging Investigation of the Corona of the Sun), with its novel design, will be the first space coronagraph to cover the range of radial distances between ~1.08 and 3 solar radii where the magnetic field plays a crucial role in the coronal dynamics, thus providing continuous observational conditions very close to those during a total solar eclipse. PROBA-3 is first a mission devoted to the in-orbit demonstration of precise formation flying techniques and technologies for future European missions, which will fly ASPIICS as primary payload. The instrument is distributed over two satellites flying in formation (approx. 150m apart) to form a giant coronagraph capable of producing a nearly perfect eclipse allowing observing the sun corona closer to the rim than ever before. The coronagraph instrument is developed by a large European consortium including about 20 partners from 7 countries under the auspices of the European Space Agency. This paper is reviewing the recent improvements and design updates of the ASPIICS instrument as it is stepping into the detailed design phase

Ultraviolet Index measurements in Antananarivo, Indian Ocean

Within the framework of various programmes funded by Europe, Reunion Council or CNES (French Space Agency), the University of Réunion Island has developed a specialized network for the measurement of UV radiation and cloud cover in the south-western part of the Indian Ocean, known as the UV-Indien network. The western Indian Ocean is mainly located in the tropical region of the southern hemisphere. This part of the world is therefore potentially impacted by the changes in radiation described above. However, this geographical area suffers from a very large measurement deficit, both for ozone and UV radiation on the ground. The data-sets presented here are original and, as mentioned, concern an extremely poorly measured region of the globe, which highlights their importance. They include the UV index at 9 stations, the cloud fraction measured at 4 stations. These measurements are ideally suited for assessing the effect of UV radiation on the health of people or ecosystems in this region. This network currently has 9 stations in 5 countries of the Region (France, Madagascar, Seychelles, Comoros and Mauritius), with 8 scientific, institutional or meteorological partners. All stations are now equipped with a Kipp & Zonen UVS-E-T broadband radiometer. Reunion Island is also equipped with a Bentham UV spectroradiometer. The raw UV measurements obtained by the radiometers are reprocessed considering the calibrations and TOC measured simultaneously. The broadband radiometers will be calibrated every 2 years at the Moufia super site (University of Reunion Island, St Denis) using the Bentham UV spectrometer, itself calibrated every 3 months Cloud cover measurements are carried out using the wide-angle total sky imager, SkyCamVision (SCV), , manufactured by Reuniwatts (http://www.reuniwatt.com/). Cloud fractions (CF) are calculated following a cloud segmentation algorithm