Crystal Structure of Human TWEAK in Complex with the Fab Fragment of a Neutralizing Antibody Reveals Insights into Receptor Binding.

The tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine playing a key role in tissue regeneration and remodeling. Dysregulation of TWEAK signaling is involved in various pathological processes like autoimmune diseases and cancer. The unique interaction with its cognate receptor Fn14 makes both ligand and receptor promising targets for novel therapeutics. To gain insights into this important signaling pathway, we determined the structure of soluble human TWEAK in complex with the Fab fragment of an antibody selected for inhibition of receptor binding. In the crystallized complex TWEAK is bound by three Fab fragments of the neutralizing antibody. Homology modeling shows that Fab binding overlaps with the putative Fn14 binding site of TWEAK. Docking of the Fn14 cysteine rich domain (CRD) to that site generates a highly complementary interface with perfectly opposing charged and hydrophobic residues. Taken together the presented structure provides new insights into the biology of TWEAK and the TWEAK/Fn14 pathway, which will help to optimize the therapeutic strategy for treatment of related cancer types and autoimmune diseases

Design and Implementation of a Thermoelectric Cooling Solution for a CCD-based NUV Spectrograph

The Colorado Ultraviolet Transit Experiment (CUTE) is a 6U CubeSat designed to obtain transit spectra of more than ten close-orbiting exoplanets. To this end, CUTE houses a near-ultraviolet (~250 – 330 nm) spectrograph based around a novel rectangular Cassegrain telescope; the spectrograph sensor is an off-the-shelf Teledyne e2v CCD. To achieve desired spectral signal-to-noise ratio (SNR), dark current is reduced by cooling the CCD to a temperature of −50 °C with a thermoelectric cooler (TEC). The TEC is driven by a constant current buck converter with an H-bridge topology for bidirectional current control. The packaging of the CCD imposes a maximum time rate of change of temperature of 5 K/min. A cascaded software control loop (discussed here) was developed that constrains this time rate of change within allowable bounds while simultaneously driving the CCD temperature to a desired setpoint. Criteria for sizing a TEC to the application and initial laboratory results are discussed, as well as digital filtering methods employed and possible solutions to integral wind-up

The Colorado Ultraviolet Transit Experiment: The First Dedicated Ultraviolet Exoplanet Mission

The past few years of space mission development have seen an increase in the use of small satellites as platforms for dedicated astrophysical research; they offer unique capabilities for time-domain science and complementary advantages over large shared resource facilities like the Hubble Space Telescope, including: (1) low cost and relatively quick development timelines; (2) observing strategies dedicated to niche but important science questions; and (3) ample opportunity for students and early career scientists and engineers to be involved on the front lines of space mission development. The Colorado Ultraviolet Transit Experiment (CUTE) is a NASA-supported 6U CubeSat assembled and tested at the Laboratory for Atmospheric and Space Physics within the University of Colorado Boulder. It is designed to observe the evolving atmospheres on short-period exoplanets with a dedicated science mission unachievable by current and planned future space missions. CUTE operates with a bandpass of ∼2487 – 3376 Å and an average spectral resolution element of 3.9 Å. The mission launched in September of 2021 and is in the process of conducting transit spectroscopy of approximately one dozen short-period exoplanets during its primary mission. This proceeding describes the overall CUTE satellite program, including the mission development integration and testing, anticipated science return, and lessons learned to improve both universities’ and commercial companies’ ability to create and collaborate on successful academically and research-focused small satellite missions. While CubeSats are becoming increasingly accessible and utilized for scientific research and student education, CUTE serves as an example that university small satellite programs have specific needs to successfully and efficiently achieve both scientific and educational elements. These include (1) a minimum threshold of commercial-off-the-shelf product quality, performance, and support; (2) specific and timely guidelines from launch service providers regarding launch readiness and delivery requirements; (3) and sufficient funding to provide multi-disciplinary engineering and program management support across the developmental life-cycle of the mission

Drivers of Change or Cut-Throat Competitors? Challenging Cultures of Innovation of Chinese and Nigerian Migrant Entrepreneurs in West Africa

L'afflux remarquable des entrepreneurs migrants chinois dans différents pays d'Afrique occidentale au cours des dernières années a été heurtée à une résistance de plus en plus farouche par des entrepreneurs locaux établis. Que le premiers ont un avantage concurrentiel sur ce dernier en raison de traits socio-culturels distinctifs, ou si l'efficacité supposée chinoise est juste une caractéristique de toutes les diasporas mercantiles, est ouvert à la question. Cette étude exploratoire des migrants entrepreneuriales chinois et nigérians au Ghana et au Bénin tente de répondre à cette question. Apparemment, les forces culturels des agents du changement migrants ne sont pas limités à des systèmes de valeurs héritées ou religions, comme une éthique protestante ou le confucianisme, mais ils sont adaptés en permanence et ont inventé de nouveau par des réseaux transnationaux de la migration dans un monde globalisé. Il n'y a aucune preuve d'une prétendue supériorité de la culture d’innovation chinois par rapport aux cultures d’innovation africains des migrants entrepreneuriales. Plutôt, il existe une capacité accrue d'innovation d'une diaspora mercantile en général vis à vis des entrepreneurs locaux, indépendamment de l'origine de la culture nationale dans lequel il est intégré. En outre, la rivalité des entrepreneurs migrants chinois et nigérians dans les marchés africains ne conduit pas nécessairement à la concurrence coupe-gorge souvent suspectée sous l'impact de la mondialisation. Souvent, les deux groupes agissent plutôt complémentaires. Cela contribue, sous certaines conditions, même à la réduction de la pauvreté dans le pays d'accueil

Coastal Erosion of Permafrost Soils Along the Yukon Coastal Plain and Fluxes of Organic Carbon to the Canadian Beaufort Sea

Reducing uncertainties about carbon cycling is important in the Arctic where rapid environmental changes contribute to enhanced mobilization of carbon. Here we quantify soil organic carbon (SOC) contents of permafrost soils along the Yukon Coastal Plain and determine the annual fluxes from coastal erosion. Different terrain units were assessed based on surficial geology, morphology, and ground ice conditions. To account for the volume of wedge ice and massive ice in a unit, SOC contents were reduced by 19% and sediment contents by 16%. The SOC content in a 1 m² column of soil varied according to the height of the bluff, ranging from 30 to 662 kg, with a mean value of 183 kg. Forty‐four per cent of the SOC was within the top 1 m of soil and values varied based on surficial materials, ranging from 30 to 53 kg C/m³, with a mean of 41 kg. Eighty per cent of the shoreline was erosive with a mean annual rate of change of −0.7 m/yr. This resulted in a SOC flux per meter of shoreline of 132 kg C/m/yr, and a total flux for the entire 282 km of the Yukon coast of 35.5 × 10^6 kg C/yr (0.036 Tg C/yr). The mean flux of sediment per meter of shoreline was 5.3 × 103 kg/m/yr, with a total flux of 1,832 × 10^6 kg/yr (1.832 Tg/yr). Sedimentation rates indicate that approximately 13% of the eroded carbon was sequestered in nearshore sediments, where the overwhelming majority of organic carbon was of terrestrial origin

Model of the TWEAK – Fn14 receptor interaction.

<p>A) Side view of the TWEAK trimer showing the solvent accessible electrostatic surface potential (red −4 kT to blue +4 kT). The positively charged patch indicating the possible receptor binding site (dashed ellipse) is covered by the antibody selected for inhibiting TWEAK-Fn14 interaction (cartoon model of Hv in green and Lv in blue). B) Same view as in A with the antibody and TWEAK surface set transparence. After superposition of cytokine-receptor structures APRIL-BCMA (blue; PDB ID 1XU2), APRIL-TACI (brown; PDB ID 1XU1), TALL-BCMA (red; PDB ID 1OQD) and TALL-BAFFR (green; PDB ID 1OQE) the CRD of the receptors co-localize and mark the putative binding site of Fn14 on TWEAK (only the CRD of the receptors is shown as colored cartoon model). C) The NMR model of the Fn14 CRD (blue; PDB ID 2RPJ) is placed at the putative receptor binding site of TWEAK according to the complex structures shown in B. The basic patch is indicated with the dashed ellipse. Only one of the three receptors is shown. D) Stereo view of the modeled TWEAK-Fn14 CRD interface. Upon rigid body and positional refinement of the putative TWEAK-Fn14 CRD complex a dense hydrogen bond network is formed at the interface. The perfect complementarities of charged and hydrophobic patches, as well as the involvement of Fn14 side chains already shown to play an important role in TWEAK binding support this model.</p

Interaction of the antibody with TWEAK.

<p>A) Ribbon representation of one Fab fragment binding to one TWEAK protomer (orange:TWEAK, blue:light chain, green:heavy chain). B) Stereo representation of the epitope recognition with interacting residues as labeled stick model and important hydrogen bond interaction highlighted as dashed lines. The binding is mainly mediated by CDR loop 1 and 2 of the heavy chain interacting with residues of the loops connecting strands D/E and B’/B and residues of strand G. In addition Y93 of CDR3 of the light chain interacts with a main chain N and stacks with the guanidinium group of R130 of TWEAK. C) Interestingly not only canonical CDR loops are involved in TWEAK binding, but an additional hydrogen bond is formed between light chain R68 of a non CDR loop with D75 of a second subunit of the trimeric TWEAK complex (gray).</p