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Dysregulation of pathogen-recognition pathways of the innate immune system is associated with multiple autoimmune disorders. Due to the intricacies of the molecular network involved, the identification of pathway- and disease-specific therapeutics has been challenging. Using a phenotypic assay monitoring the degradation of the immune adapter TASL, we identify feeblin, a chemical entity which inhibits the nucleic acid-sensing TLR7/8 pathway activating IRF5 by disrupting the SLC15A4-TASL adapter module. A high-resolution cryo-EM structure of feeblin with SLC15A4 reveals that the inhibitor binds a lysosomal outward-open conformation incompatible with TASL binding on the cytoplasmic side, leading to degradation of TASL. This mechanism of action exploits a conformational switch and converts a target-binding event into proteostatic regulation of the effector protein TASL, interrupting the TLR7/8-IRF5 signaling pathway and preventing downstream proinflammatory responses. Considering that all components involved have been genetically associated with systemic lupus erythematosus and that feeblin blocks responses in disease-relevant human immune cells from patients, the study represents a proof-of-concept for the development of therapeutics against this disease. The authors identify feeblin, an inhibitory compound of the proinflammatory TLR7/8/9-IRF5 pathway with therapeutic potential, which acts by binding SLC15A4 via an allosteric mechanism mediating degradation of its signaling partner TASL. [ABSTRACT FROM AUTHOR]

The global energy consumption of data centers (DCs) has experienced exponential growth over the last decade, that is expected to continue in the near future. Reasonable utilization of DC waste heat, which is dissipated during the computational process, can potentially be an effective solution to mitigate the environmental impact. However, the practical implementation of waste heat utilization in the DC environment is a very challenging task. The possible benefits of waste heat utilization are uncertain and difficult to quantify with the methods that are common in practice. This paper introduces a feasibility study in which dynamic simulation tools were used to predict the energy performance of a university campus resulting from the integration of a proposed DC system with an existing aquifer thermal energy storage (ATES). The presented study utilizes building energy simulation (BES) to evaluate uncertainty of the waste heat potential associated to various thermal management strategies of the proposed DC. Further in the feasibility study, the carbon footprint of the integrated approach is assessed for both the current and future situation based on measured data from the existing university campus and its district ATES system. [ABSTRACT FROM AUTHOR]

The paper discusses a novel delta-sigma (ΔΣ) modulator structure, which compensates for the influence of a higher harmonic distortion to achieve a high resolution of up to 16 bits for the OSR = 100. The proposed approach combines the advantages of single-bit quantizer ΔΣ modulators with those provided by multi-bit ΔΣ devices. In the initial part of the article, we present the novel second-order structure, verify its correct functioning via the MATLAB simulation environment, and examine the requirements for a partial block. The related sections of the paper then analyze the design of a ΔΣ converter comprising the novel modulator structure and utilizing both the switched capacitor technique and the ONSemi I3T25 (350 nm) technology. The advantages and disadvantages of the discussed solution are evaluated, and the structure is compared with common versions of the ΔΣ modulator. The value of SNDR = 86 dB (ENOB = 14 bits) was achieved in the entire bandwidth. [ABSTRACT FROM AUTHOR]