Negative Self-Regulation of TLR9 Signaling by Its N-Terminal Proteolytic Cleavage Product

TLR signaling is essential to innate immunity against microbial invaders and must be tightly controlled. We have previously shown that TLR9 undergoes proteolytic cleavage processing by lysosomal proteases to generate two distinct fragments. The C-terminal cleavage product plays a critical role in activating TLR9 signaling; however, the precise role of the N-terminal fragment, which remains in lysosomes, in the TLR9 response is still unclear. In this article, we report that the N-terminal cleavage product negatively regulates TLR9 signaling. Notably, the N-terminal fragment promotes the aspartic protease-mediated degradation of the C-terminal fragment in endolysosomes. Furthermore, the N-terminal TLR9 fragment physically interacts with the C-terminal product, thereby inhibiting the formation of homodimers of the C-terminal fragment; this suggests that the monomeric C-terminal product is more susceptible to attack by aspartic proteases. Together, these results suggest that the N-terminal TLR9 proteolytic cleavage product is a negative self-regulator that prevents excessive TLR9 signaling activity.Korea (South). Ministry of Education, Science and Technology (MEST) (National Research Foundation of Korea. Grant 2011-0015372)Korea (South). Ministry of Education, Science and Technology (MEST) (National Research Foundation of Korea. Grant 2010-0009203)Korea. Ministry of Health and Welfare. National Research and Development Program for Cancer Contro

DFT‐Guided Discovery of Ethynyl‐Triazolyl‐Phosphinates as Modular Electrophiles for Chemoselective Cysteine Bioconjugation and Profiling

We report the density functional theory (DFT) guided discovery of ethynyl‐triazolyl‐phosphinates (ETPs) as a new class of electrophilic warheads for cysteine selective bioconjugation. By using CuI‐catalysed azide alkyne cycloaddition (CuAAC) in aqueous buffer, we were able to access a variety of functional electrophilic building blocks, including proteins, from diethynyl‐phosphinate. ETP‐reagents were used to obtain fluorescent peptide‐conjugates for receptor labelling on live cells and a stable and a biologically active antibody‐drug‐conjugate. Moreover, we were able to incorporate ETP‐electrophiles into an azide‐containing ubiquitin under native conditions and demonstrate their potential in protein–protein conjugation. Finally, we showcase the excellent cysteine‐selectivity of this new class of electrophile in mass spectrometry based, proteome‐wide cysteine profiling, underscoring the applicability in homogeneous bioconjugation strategies to connect two complex biomolecules.By means of density functional theory calculations, ethynyl‐triazolyl‐phosphinates (ETPs) were discovered as modular and cysteine‐selective electrophiles for bioconjugation. Using CuI‐click chemistry in aqueous buffers, this functional group can be easily introduced into azide‐containing (bio‐)molecules. These reagents can be used for proteome‐wide cysteine profiling and to obtain functional peptide‐ and protein conjugates, as well as protein–protein conjugates . imageDeutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659Leibniz-Gemeinschaft http://dx.doi.org/10.13039/501100001664Studienstiftung des Deutschen Volkes http://dx.doi.org/10.13039/501100004350Alexander von Humboldt-Stiftung http://dx.doi.org/10.13039/100005156Institute for Basic Science in KoreaPeer Reviewe

DFT‐basierte Entdeckung von Ethynyl‐Triazolyl‐Phosphinaten als modulare Elektrophile für die chemoselektive Cystein‐Biokonjugation und Profilierung

Wir berichten über eine Dichtefunktionaltheorie (DFT)-basierte Entdeckung von Ethinyl-Triazolyl-Phosphinaten (ETP) als eine neue Klasse elektrophiler Verbindungen für die selektive Biokonjugation von Cystein. Mit Hilfe der CuI-katalysierten Azid-Alkin-Cycloaddition (CuAAC) in wässrigem Puffer konnten wir eine Vielzahl funktioneller elektrophiler Bausteine, darunter auch Proteine, aus Diethynylphosphinat herstellen. Wir verwendeten diese ETP-Reagenzien, um fluoreszierende Peptid-Konjugate für die Markierung von Rezeptoren auf lebenden Zellen sowie ein stabiles und biologisch aktives Antikörper-Wirkstoff-Konjugat zu erhalten. Darüber hinaus konnten wir ETP-Elektrophile unter nativen Bedingungen in ein Azid-haltiges Ubiquitin einbauen und ihr Potenzial für die Protein-Protein-Konjugation demonstrieren. Schließlich zeigen wir die exzellente Cystein-Selektivität dieser neuen Klasse von Elektrophilen in Massenspektrometrie basierten, proteomweiten Reaktivitätsstudien und unterstreichen damit die generelle Anwendbarkeit in homogenen Biokonjugationsstrategien zur Verknüpfung zweier komplexer Biomoleküle.Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659Leibniz-Gemeinschaft http://dx.doi.org/10.13039/501100001664Studienstiftung des Deutschen Volkes http://dx.doi.org/10.13039/501100004350Alexander von Humboldt-Stiftung http://dx.doi.org/10.13039/100005156Institute for Basic Science in KoreaPeer Reviewe

Increased viral load in patients infected with severe acute respiratory syndrome coronavirus 2 Omicron variant in the Republic of Korea

Objectives Coronavirus disease 2019 (COVID-19) has been declared a global pandemic owing to the rapid spread of the causative agent, severe acute respiratory syndrome coronavirus 2. Its Delta and Omicron variants are more transmissible and pathogenic than other variants. Some debates have emerged on the mechanism of variants of concern. In the COVID-19 wave that began in December 2021, the Omicron variant, first reported in South Africa, became identifiable in most cases globally. The aim of this study was to provide data to inform effective responses to the transmission of the Omicron variant. Methods The Delta variant and the spike protein D614G mutant were compared with the Omicron variant. Viral loads from 5 days after symptom onset were compared using epidemiological data collected at the time of diagnosis. Results The Omicron variant exhibited a higher viral load than other variants, resulting in greater transmissibility within 5 days of symptom onset. Conclusion Future research should focus on vaccine efficacy against the Omicron variant and compare trends in disease severity associated with its high viral load

Self-Supervised Contextual Data Augmentation for Natural Language Processing

In this paper, we propose a novel data augmentation method with respect to the target context of the data via self-supervised learning. Instead of looking for the exact synonyms of masked words, the proposed method finds words that can replace the original words considering the context. For self-supervised learning, we can employ the masked language model (MLM), which masks a specific word within a sentence and obtains the original word. The MLM learns the context of a sentence through asymmetrical inputs and outputs. However, without using the existing MLM, we propose a label-masked language model (LMLM) that can include label information for the mask tokens used in the MLM to effectively use the MLM in data with label information. The augmentation method performs self-supervised learning using LMLM and then implements data augmentation through the trained model. We demonstrate that our proposed method improves the classification accuracy of recurrent neural networks and convolutional neural network-based classifiers through several experiments for text classification benchmark datasets, including the Stanford Sentiment Treebank-5 (SST5), the Stanford Sentiment Treebank-2 (SST2), the subjectivity (Subj), the Multi-Perspective Question Answering (MPQA), the Movie Reviews (MR), and the Text Retrieval Conference (TREC) datasets. In addition, since the proposed method does not use external data, it can eliminate the time spent collecting external data, or pre-training using external data

Specific Analysis of Web Camera and High Resolution Planetary Imaging

Web camera is usually used for video communication between PC, it has small sensing area, cannot using long exposure application, so that is insufficient for astronomical application. But web camera is suitable for bright planet, moon, it doesn't need long exposure time. So many amateur astronomer using web camera for planetary imaging. We used ToUcam manufactured by Phillips for planetary imaging and Registax commercial program for a video file combining. And then, we are measure a property of web camera, such as linearity, gain that is usually using for analysis of CCD performance. Because of using combine technic selected high quality image from video frame, this method can take higher resolution planetary imaging than one shot image by film, digital camera and CCD. We describe a planetary observing method and a video frame combine method

Compressive Sensing Spectroscopy Using a Residual Convolutional Neural Network

Compressive sensing (CS) spectroscopy is well known for developing a compact spectrometer which consists of two parts: compressively measuring an input spectrum and recovering the spectrum using reconstruction techniques. Our goal here is to propose a novel residual convolutional neural network (ResCNN) for reconstructing the spectrum from the compressed measurements. The proposed ResCNN comprises learnable layers and a residual connection between the input and the output of these learnable layers. The ResCNN is trained using both synthetic and measured spectral datasets. The results demonstrate that ResCNN shows better spectral recovery performance in terms of average root mean squared errors (RMSEs) and peak signal to noise ratios (PSNRs) than existing approaches such as the sparse recovery methods and the spectral recovery using CNN. Unlike sparse recovery methods, ResCNN does not require a priori knowledge of a sparsifying basis nor prior information on the spectral features of the dataset. Moreover, ResCNN produces stable reconstructions under noisy conditions. Finally, ResCNN is converged faster than CNN

Relational Knowledge Distillation

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