Smaller,Stronger, More Stable: Peptide Variants of a SARS-CoV-2 Neutralizing Miniprotein

Based on the structure of a de novo designed miniprotein (LCB1) in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, we have generated and characterized truncated peptide variants of LCB1, which present only two of the three LCB1 helices, and which fully retained the virus neutralizing potency against different SARS-CoV-2 variants of concern (VOC). This antiviral activity was even 10-fold stronger for a cyclic variant of the two-helix peptides, as compared to the full-length peptide. Furthermore, the proteolytic stability of the cyclic peptide was substantially improved, rendering it a better potential candidate for SARS-CoV-2 therapy. In a more mechanistic approach, the peptides also served as tools to dissect the role of individual mutations in the RBD for the susceptibility of the resulting virus variants to neutralization by the peptides. As the peptides reported here were generated through chemical synthesis, rather than recombinant protein expression, they are amenable to further chemical modification, including the incorporation of a wide range of non-proteinogenic amino acids, with the aim to further stabilize the peptides against proteolytic degradation, as well as to improve the strength, as well the breadth, of their virus neutralizing capacity.     

Downstream environmental effects of dam operations: Changes in habitat quality for native fish species

Hydropeaking dam operation and water extractions for irrigation have been broadly stated as alterations to natural flow regimes, which have also been noticed in the Biobío Watershed, in Central Chile, since 1996. In the Biobío River, most of native fish species are endemic and very little is known about them. Their ecological and social values have never been estimated, and there is lack of information about their habitat preferences. Furthermore, changes on fish habitat availability due to natural and/or man‐made causes have not been evaluated. In this study, eight native fish species, in a representative reach of the Biobío River, were studied and their preferred habitats were surveyed and characterized. A hydrodynamic model was built and linked to the fish habitat simulation model CASiMiR. Fuzzy rules and fuzzy sets were developed for describing habitat preference of the native fish species. CASiMiR was then used to simulate how physical habitat conditions vary due to flow control (i.e. upstream dams). Results show how overall habitat quality, expressed as weighted usable area (WUA) and hydraulic habitat suitability (HHS), changes and fluctuates due to the dam operation and how the daily hydropeaking is influencing quantity, quality and location of different habitats. The study suggests that the analysed fish are highly susceptible to flow control, as dams are currently operated, and fish habitat improvement suggestions are proposed. Copyright © 2010 John Wiley & Sons, Ltd.     

Mismatch Modeling and Simulation—A Comprehensive Approach

This article describes a comprehensive approach to mismatch simulation and modeling as needed for integrated circuit design. Local device mismatch as well as global process variations and parameter correlations are regarded. A method for mismatch modeling based on spatial frequencies is described, which enables to overcome insufficiencies of the first order models. Measurement results are presented to demonstrate the achieved modeling precision. All models and methods mentioned here are commercially available in the simulation tool GAME (General Analysis of Mismatch Effects) which is used in the semiconductor industry since 1998.     

Tumor Infiltration with CD20+CD73+ B Cells Correlates with Better Outcome in Colorectal Cancer

Immunotherapy has become increasingly important in the treatment of colorectal cancer (CRC). Currently, CD73, also known as ecto-5′-nucleotidase (NT5E), has gained considerable interest as a potential therapeutic target. CD73 is one of the key enzymes catalyzing the conversion of extracellular ATP into adenosine, which in turn exerts potent immune suppressive effects. However, the role of CD73 expression on various cell types within the CRC tumor microenvironment remains unresolved. The expression of CD73 on various cell types has been described recently, but the role of CD73 on B-cells in CRC remains unclear. Therefore, we analyzed CD73 on B-cells, especially on tumor-infiltrating B-cells, in paired tumor and adjacent normal tissue samples from 62 eligible CRC patients. The highest expression of CD73 on tumor-infiltrating B-cells was identified on class-switched memory B-cells, followed by naive B-cells, whereas no CD73 expression was observed on plasmablasts. Clinicopathological correlation analysis revealed that higher CD73⁺ B-cells infiltration in the CRC tumors was associated with better overall survival. Moreover, metastasized patients showed a significantly decreased number of tumor-infiltrating CD73⁺ B-cells. Finally, neoadjuvant therapy correlated with reduced CD73⁺ B-cell numbers and CD73 expression on B-cells in the CRC tumors. As promising new immune therapies are being developed, the role of CD73⁺ B-cells and their subsets in the development of colorectal cancer should be further explored to find new therapeutic options.     

Absolute characterization of high numerical aperture microscope objectives utilizing a dipole scatterer

Measuring the aberrations of optical systems is an essential step in the fabrication of high precision optical components. Such a characterization is usually ba...     

Fatigue assessment of arc welded automotive components using local stress approaches: Application to a track control arm

The applicability of the structural and notch stress approach is examined on the basis of arc welded and dynamically loaded steel structures, taken from the automotive sector. In detail, this is a transverse control arm. Components and specimens with critical regions of failure are tested under cyclic loading with constant and variable amplitudes. With the help of strain gauges, the crack initiation is determined. The specimens are the basis for the application and evaluation of the different approaches for the assessment of fatigue life. The numerical determination of the nominal, structural and notch stresses is performed with finite-element models. Finally the experimental and computational results allow the derivation of structural and notch Woehler S-N curves.     

Characterizing cerebral oxygen metabolism employing oxygen-17 MRI/MRS at high fields

This article provides a comprehensive overview of oxygen (¹⁷O) magnetic resonance spectroscopy and imaging, including the advantages and challenges offered by the different methods developed thus far. The physiological role and relevance of oxygen, and its participation in aerobic metabolism, are addressed to emphasize the importance of the investigations and the efforts related to these developments. Furthermore, a number of methods employed in the determination of the cerebral metabolic rate of oxygen in neural cells will be presented, focusing primarily on methodologies enabling absolute quantification.