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Protein–protein interactions (PPIs) are increasingly important targets for drug discovery. Efficient fragment-based drug discovery approaches to tackle PPIs are often stymied by difficulties in the production of stable, unliganded target proteins. Here, we report an approach that exploits protein engineering to “humanise” thermophilic archeal surrogate proteins as targets for small-molecule inhibitor discovery and to exemplify this approach in the development of inhibitors against the PPI between the recombinase RAD51 and tumour suppressor BRCA2. As human RAD51 has proved impossible to produce in a form that is compatible with the requirements of fragment-based drug discovery, we have developed a surrogate protein system using RadA from Pyrococcus furiosus. Using a monomerised RadA as our starting point, we have adopted two parallel and mutually instructive approaches to mimic the human enzyme: firstly by mutating RadA to increase sequence identity with RAD51 in the BRC repeat binding sites, and secondly by generating a chimeric archaeal human protein. Both approaches generate proteins that interact with a fourth BRC repeat with affinity and stoichiometry comparable to human RAD51. Stepwise humanisation has also allowed us to elucidate the determinants of RAD51 binding to BRC repeats and the contributions of key interacting residues to this interaction. These surrogate proteins have enabled the development of biochemical and biophysical assays in our ongoing fragment-based small-molecule inhibitor programme and they have allowed us to determine hundreds of liganded structures in support of our structure-guided design process, demonstrating the feasibility and advantages of using archeal surrogates to overcome difficulties in handling human proteins., Graphical Abstract Image 1, Highlights • Archeal RadA, humanised to resemble RAD51, binds the fourth BRC repeat with high affinity. • Chimeric archeal/human RAD51 shows increased thermal stability. • Robust crystallographic system enables fragment-based drug discovery against RAD51. • Dedicated surrogate proteins were needed for different assays.

Continuous multiyear records of sediment-trap-gained microorganism fluxes are scarce. Such studies are important to identify and to understand the main forcings behind seasonal and multiannual evolution of microorganism flux dynamics. Here, we assess the long-term flux variations and population dynamics of diatoms, coccolithophores, calcareous and organic dinoflagellate cysts, foraminifera and pteropods in the eastern boundary upwelling ecosystem of the Canary Current. A multiannual, continuous sediment trap experiment was conducted at the mooring site CBeu (Cap Blanc eutrophic; ∼20∘ N, 18∘ W; trap depth is ca. 1300 m) off Mauritania (northwest Africa), between June 2003 and March 2008. Throughout the study, the reasonably consistent good match of fluxes of microorganisms and bulk mass reflects the seasonal occurrence of the main upwelling season and relaxation and the contribution of microorganisms to mass flux off Mauritania. A clear successional pattern of microorganisms, i.e., primary producers followed by secondary producers, is not observed. High fluxes of diatoms, coccolithophores, organic dinoflagellate cysts, and planktonic foraminifera occur simultaneously. Peaks of calcareous dinoflagellate cysts and pteropods mostly occurred during intervals of upwelling relaxation. A striking feature of the temporal variability of population occurrences is the persistent pattern of seasonal groups contributions. Species of planktonic foraminifera, diatoms, and organic dinoflagellate cysts typical of coastal upwelling, as well as cooler-water planktonic foraminifera and the coccolithophore Gephyrocapsa oceanica, are abundant at times of intense upwelling (late winter through early summer). Planktonic foraminifera and calcareous dinoflagellate cysts are dominant in warm pelagic surface waters, and all pteropod taxa are more abundant in fall and winter when the water column stratifies. Similarly, coccolithophores of the upper and lower photic zones, together with Emiliania huxleyi, and organic dinoflagellate cysts dominate the assemblage during phases of upwelling relaxation and deeper layer mixing. A significant shift in the “regular” seasonal pattern of taxa relative contribution is observed between 2004 and 2006. Benthic diatoms strongly increased after fall 2005 and dominated the diatom assemblage during the main upwelling season. Additional evidence for a change in population dynamics is the short dominance of the coccolithophore Umbilicosphaera annulus, the occurrence of the pteropod Limacina bulimoides and the strong increase in the flux of calcareous dinoflagellate cysts, abundant in warm tropical oligotrophic waters south of the study area after fall 2005. Altogether, this suggests that pulses of southern waters were transported to the sampling site via the northward Mauritania Current. Our multiannual trap experiment provides a unique opportunity to characterize temporal patterns of variability that can be extrapolated to other eastern boundary upwelling ecosystems (EBUEs), which are experiencing or might experience similar future changes in their plankton community.

Cruise M160 is part of concerted MOSES/REEBUS Eddy Study featuring three major research expeditions (M156, M160, MSM104). It aims to develop both a qualitative and quantitative understanding of the role of physical-chemical-biological coupling in eddies for the biological pump. The study is part of the MOSES “Ocean Eddies” event chain, which follows three major hypotheses to be addressed by the MOSES/REEBUS field campaigns: (1) Mesoscale and sub-mesoscale eddies play an important role in transferring energy along the energy cascade from the large-scale circulation to dissipation at the molecular level. (2) Mesoscale and sub-mesoscale eddies are important drivers in determining onset, magnitude and characteristics of biological productivity in the ocean and contribute significantly to global primary production and particle export and transfer to the deep ocean. (3) Mesoscale and sub-mesoscale eddies are important for shaping extreme biogeochemical environments (e.g., pH, oxygen) in the oceans, thus acting as a source/sink function for greenhouse gases. In contrast to the other two legs, MOSES Eddy Study II during M160 did not include any benthic work but focused entirely on the pelagic dynamics within eddies. It accomplished a multi-disciplinary, multi-parameter and multi-platform study of two discrete cyclonic eddies in an unprecedented complexity. The pre-cruise search for discrete eddies suitable for detailed study during M160 had already started a few months prior to the cruise. Remote sensing data products (sea surface height, sea surface temperature, ocean color/chlorophyll a) were used in combination with eddy detection algorithms and numerical modelling to identify and track eddies in the entire eddy field off West Africa. In addition, 2 gliders and 1 waveglider had been set out from Mindelo/Cabo Verde for pre-cruise mapping of the potential working area north of the Cabo Verdean archipelago. At the start of M160, a few suitable eddies – mostly of cyclonic type – had been identified, some of which were outside the safe operation range of the motorglider plane. As technical problems delayed the flight operations, the first eddy (center at 14.5°N/25°W) for detailed study was chosen to the southwest of the island of Fogo. It was decided to carry out a first hydrographic survey there followed by the deployment of a suite of instruments (gliders, waveglider, floats, drifter short-term mooring). Such instrumented, we left this first eddy and transited – via a strong anticyclonic feature southwest of the island of Santiago – to the region northeast of the island of Sal, i.e. in the working range of the glider plane. During the transit, a full suite of underway measurements as well as CTD/RO section along 22°W (16°-18.5°N) were carried in search for sub-surface expressions of anticyclonic eddy features. In the northeast, we had identified the second strong cyclonic eddy (center at 18°N/22.5°W) which was chosen for detailed study starting with a complete hydrographic survey (ADCP, CTD/RO, other routine station work). After completion of the mesoscale work program, we identified a strong frontal region at the southwestern rim of the cyclonic eddy, which was chosen for the first sub-mesoscale study with aerial observation component. There, the first dye release experiment was carried out which consisted of the dye release itself followed by an intense multi-platforms study of the vertical and horizontal spreading of the initial dye streak. This work was METEOR-Berichte, Cruise M160, Mindelo – Mindelo, 23.11.2019 4 – 20.12.2019 supported and partly guided by aerial observation of the research motorglider Stemme, which was still somewhat compromised by technical issues and meteorological conditions (high cloud cover, Saharan dust event). Nevertheless, this first dye release experiment was successful and showed rapid movement of the dynamic meandering front. After completion of work on this second eddy and execution of a focused sampling program at the Cape Verde Ocean Observation, RV METEOR returned to the first eddy for continuation of the work started there in the beginning of the cruise. This was accompanied by a relocation of the airbase of Stemme from the international airport of Sal to the domestic airport of Fogo. The further execution of the eddy study at this first eddy, which again included a complete hydrographic survey followed by a mesoscale eddy study with dye release, was therefore possible with aerial observations providing important guidance for work on RV METEOR. Overall, M160 accomplished an extremely intense and complex work program with 212 instrument deployments during station work, 137 h of observation with towed instruments and a wide range of underway measurements throughout the cruise. Up to about 30 individually tracked platforms (Seadrones, glider, wavegliders, drifters, floats) were in the water at the same time providing unprecedented and orchestrated observation capabilities in an eddy. All planned work components were achieved and all working groups acquired the expected numbers of instrument deployments and sampling opportunities.

NAOMI was developed by a consortium composed of IPAG and ESO. Its Provisional Acceptance Chile review was held in April 2019. The NAOMI systems that have been installed on the Auxiliary Telescopes make the Very Large Telescope Interferometer (VLTI) and its instruments much less dependent on the atmospheric and dome seeing conditions. NAOMI increases the interferometer’s operability and improves the performance of its instruments and, very early on, was identified as being critical to the VLTI. In this article, we review the project, describe its principles and architecture, and offer a preview of the improvements it brings to VLTI instruments., Published in The Messenger vol. 177, pp. 19-23, September 2019.

Graphical abstract, Highlights • Protein–protein interactions can be modulated by more than orthosteric disruption. • Modulator categories: ‘orthosteric versus allosteric’ and ‘disrupting versus stabilising’. • Interfacial binders exert secondary effects. • Non-competitive modulation is a way around low affinity molecules. • Non-competitive modulators require tailored screening strategies., Protein–protein interactions (PPI) have become increasingly popular drug targets, with a number of promising compounds currently in clinical trials. Recent research shows, that PPIs can be modulated in more ways than direct inhibition, where novel non-competitive modes of action promise a solution for the difficult nature of PPI drug discovery. Here, we review recently discovered PPI modulators in light of their mode of action and categorise them as disrupting versus stabilising, orthosteric versus allosteric and by their ability to affect the proteins’ dynamics. We also give recent examples of compounds successful in the clinic, analyse their physicochemical properties and discuss how to overcome the hurdles in discovering alternative modes of modulation.

La mosca suramericana de la fruta Anastrepha fraterculus (Wiedemann) (Diptera: Tephritidae) es una plaga cuarentenaria de la feijoa. Frutas infestadas artificialmente se sometieron al tratamiento "t 107-a" (1,1° C durante 15 dias) exigido por USDA- APHIS para su exportacion y se compararon con frutos almacenados a temperatura ambiente. Cada fruto se infesto con cuatro larvas de tercer instar, en dos tratamientos con-50 repeticiones. Se evaluo diariamente la longitud, el volumen corporal, el comportamiento. la mortalidad y cambios de coloraciòn de las larvas, en una muestra de tres frutos, El primer comportamiento observable de las larvas bajo tratamiento cuarentenario fue el intento de abandonar el fruto. No se observo ninguna variaciòn en la longitud o el volumen corporal de las larvas bajo frio. En el control a temperatura ambiente, las larvas aumentaron de volumen hasta la muda a pupa. El tratamiento en frio modifico el desarrollo larval y la muda larva-pupa. El 100% de las larvas murio ocho dias despues de estar sometidas al tratamiento de frio. La mayoria de las larvas murieron en un estado intermedio de la muda y presentaron una coloracion oscura o "muda parcial". Bajo el tratamiento cuarentenario el daño a la pulpa no supero el 24%, mientras en el testigo alcanzo el 74%. Este es el primer tratamiento cuarentenario probado para esta plaga en feijoas en Colombia y mostro control total. El cumplimiento de los requisitos cuarentenarios de USDA-APHIS abren el mercado internacional para exportadores colombianos de feijoa. The South American fruit fly Anastrepha fraterculus (Wiedemann) (Diptera: Tephritidae) is a quarantine pest of pineapple guava. Artificially infested fruits were subjected to cold treatment "t 107a" (1.1° C for 15 d), required by USDA-APHIS for exportation and were compared to control fruits maintained at room temperature. Four third-instar larvae were infested per individual fruit in two treatments with 50 replicates. Body length, volume, behavior, mortality and color changes of the larvae were recorded daily in a sample of three fruits. The first behavioral change observed in larvae under cold quarantine treatment was an attempt to abandon the fruits. No variation in body length or volume was observed under the cold quarantine treatment. In the untreated control, larvae increased body volume up to the final molt to pupa. The cold quarantine treatment affected larval development and the larva-pupa molt. All larvae died on the eighth day of cold treatment. Most larvae died while molting to pupa and exhibited a dark coloration or "partial molt". Under the cold quarantine treatment, damage to fruits did not exceed 24% where as in the untreated control it reached 74%. This is the first cold quarantine treatment tested for this pest of pineapple guavas in Colombia and it provided total control. Compliance with the quarantine requirements of USDA-APHIS opens the international market for Colombian exporters of pineapple guava.

Sin resumen

Gerhard August Fischer

Myostatin, a key regulator of muscle mass in vertebrates, is biosynthesised as a latent precursor in muscle and is activated by sequential proteolysis of the pro-domain. To investigate the molecular mechanism by which pro-myostatin remains latent, we have determined the structure of unprocessed pro-myostatin and analysed the properties of the protein in its different forms. Crystal structures and SAXS analyses show that pro-myostatin adopts an open, V-shaped structure with a domain-swapped arrangement. The pro-mature complex, after cleavage of the furin site, has significantly reduced activity compared with the mature growth factor and persists as a stable complex that is resistant to the natural antagonist follistatin. The latency appears to be conferred by a number of distinct features that collectively stabilise the interaction of the pro-domains with the mature growth factor, enabling a regulated stepwise activation process, distinct from the prototypical pro-TGF-β1. These results provide a basis for understanding the effect of missense mutations in pro-myostatin and pave the way for the design of novel myostatin inhibitors.

Bone morphogenetic proteins (BMPs) are secreted growth factors that promote differentiation processes in embryogenesis and tissue development. Regulation of BMP signalling involves binding to a variety of extracellular proteins, among which are many von Willebrand factor C (vWC) domain-containing proteins. While the crystal structure of the complex of crossveinless-2 (CV-2) vWC1 and BMP-2 previously revealed one mode of the vWC:BMP binding mechanism, other vWC domains may bind to BMP differently. Here, using X-ray crystallography, we present for the first time structures of the vWC domains of two proteins thought to interact with BMP-2—collagen IIA and matricellular protein CCN3. We found that these two vWC domains share a similar N-terminal fold that differs greatly from that in CV-2 vWC, which comprises its BMP-2-binding site. We analysed the ability of these vWC domains to directly bind to BMP-2 and detected an interaction only between the collagen IIa vWC and BMP-2. Guided by the collagen IIa vWC domain crystal structure and conservation of surface residues among orthologous domains, we mapped the BMP-binding epitope on the subdomain 1 of the vWC domain. This binding site is different from that previously observed in the complex between CV-2 vWC and BMP-2, revealing an alternative mode of interaction between vWC domains and BMPs., This work was supported by Cambridge Overseas Trust and China Scholarship Council through a postgraduate scholarship to E-R. X.

This paper reports on a transdisciplinary undergraduate university course designed to bring together fine art/visual communication design and computer science students for the creation and implementation of collaborative visual/audial projects that draw upon the specialised knowledge of both these disciplines. While an overview of syllabus and teaching methodologies is undertaken in the introduction, the focus of the paper concentrates upon an in-depth discussion and analysis of 3 specific projects that were developed by 3 distinct teams of students comprised of one artist/designer and one engineer.

Our society operates in such a way as to put whiteness at the center of everything, including individual consciousness--so much so that we seldom question the centrality of white- ness, and most people, on hearing 'race', hear 'black'. That is, whiteness is treated as the norm, against which all differences are measured. 1 Race shapes white women's lives. In the same way that both men's and women's lives are shaped by their gender, and that both heterosexual and lesbian women's experiences in the world are marked by their sexuality, white people and people of color live racially structured lives. In other words, any system of differentiation shapes those on whom it bestows privi- lege as well as those it oppresses. White people are 'raced' just as men are 'gendered'. 2

Boolean analysis is a partial order generalization of scalogram analysis. It enables one to build a family of implication schemes that bears a 1-1-relationship with a data set. Unlike scalogram analysis, this method does not impose any constraints on the data structure. As a result, implication schemes may become extremely complex and may contain errors. Therefore, methods are needed for the selection of subsets of data to be modeled (dichotomization methods). In this chapter, a dichotomization method is introduced which uses the relative frequency of data patterns with the same number of correct responses as a given criterion. It is argued that the present approach yields implication schemes which comply better with the underlying data structure, especially when the subjects show similar abilities in solving the items.