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The nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 3 (NLRP3) inflammasome is essential in inflammation and inflammatory disorders. Phosphorylation at various sites on NLRP3 differentially regulates inflammasome activation. The Ser725 phosphorylation site on NLRP3 is depicted in multiple inflammasome activation scenarios, but the importance and regulation of this site has not been clarified. The present study revealed that the phosphorylation of Ser725 was an essential step for the priming of the NLRP3 inflammasome in macrophages. We also showed that Ser725 was directly phosphorylated by misshapen (Msn)/NIK-related kinase 1 (MINK1), depending on the direct interaction between MINK1 and the NLRP3 LRR domain. MINK1 deficiency reduced NLRP3 activation and suppressed inflammatory responses in mouse models of acute sepsis and peritonitis. Reactive oxygen species (ROS) upregulated the kinase activity of MINK1 and subsequently promoted inflammasome priming via NLRP3 Ser725 phosphorylation. Eliminating ROS suppressed NLRP3 activation and reduced sepsis and peritonitis symptoms in a MINK1-dependent manner. Altogether, our study reveals a direct regulation of the NLRP3 inflammasome by Msn family kinase MINK1 and suggests that modulation of MINK1 activity is a potential intervention strategy for inflammasome-related diseases.

Timetabling problems have been widely studied, of which Educational Timetabling Problem (ETP) is the biggest section. Generally, ETP can be divided into three modules, namely, course timetabling, school timetabling, and examination timetabling. For solving ETP, many techniques have been developed including conventional algorithms and computational intelligence approaches. Several surveys have been conducted focusing on those methods. Some surveys target on particular categories; some tend to cover all types of approaches. However, there are lack of reviews specifically focusing on computational intelligence in ETP. Therefore, this paper aims at providing a reference of selecting a method for the applications of ETP by reviewing popular computational intelligent algorithms, such as meta-heuristics, hyper-heuristics, hybrid methods, fuzzy logic, and multi-agent systems. The application would be categorised and described into the three types of ETP respectively.

The structural characterization of the NS3-like helicase of a segmented virus from the Flaviviridae is reported., Alongshan virus (ALSV) is an emerging human pathogen that was identified in China and rapidly spread to the European continent in 2019, raising concerns about public health. ALSV belongs to the distinct Jingmenvirus group within the Flaviviridae family with segmented RNA genomes. While segments 2 and 4 of the ALSV genome encode the VP1–VP3 proteins of unknown origin, segments 1 and 3 encode the NS2b–NS3 and NS5 proteins, which are related to Flavivirus nonstructural proteins, suggesting an evolutionary link between segmented and unsegmented viruses within the Flaviviridae family. Here, the enzymatic activity of the ALSV NS3-like helicase (NS3-Hel) was characterized and its crystal structure was determined to 2.9 Å resolution. ALSV NS3-Hel exhibits an ATPase activity that is comparable to those measured for Flavivirus NS3 helicases. The structure of ALSV NS3-Hel exhibits an overall fold similar to those of Flavivirus NS3 helicases. Despite the limited amino-acid sequence identity between ALSV NS3-Hel and Flavivirus NS3 helicases, structural features at the ATPase active site and the RNA-binding groove remain conserved in ALSV NS3-Hel. These findings provide a structural framework for drug design and suggest the possibility of developing a broad-spectrum antiviral drug against both Flavivirus and Jingmenvirus.

Although educational timetabling problems have been studied for decades, one instance of this, the school timetabling problem (STP), has not developed as quickly as examination timetabling and course timetabling problems due to its diversity and complexity. In addition, most STP research has only focused on the educators’ availabilities when studying the educator aspect, and the educators’ preferences and expertise have not been taken into consideration. To fill in this gap, this paper proposes a conceptual model for the school timetabling problem considering educators’ availabilities, preferences and expertise as a whole. Based on a common real-world school timetabling scenario, the artificial bee colony (ABC) algorithm is adapted to this study, as research shows its applicability in solving examination and course timetabling problems. A virtual search space for dealing with the large search space is introduced to the proposed model. The proposed approach is simulated with a large, randomly generated dataset. The experimental results demonstrate that the proposed approach is able to solve the STP and handle a large dataset in an ordinary computing hardware environment, which significantly reduces computational costs. Compared to the traditional constraint programming method, the proposed approach is more effective and can provide more satisfactory solutions by considering educators’ availabilities, preferences, and expertise levels.

The tumor microenvironment (TME) is a unique niche governed by constant crosstalk within and across all intratumoral cellular compartments. In particular, intratumoral high potassium (K

Mycobacterium tuberculosis (Mtb) caused an estimated 10 million cases of tuberculosis and 1.2 million deaths in 2019 globally. The increasing emergence of multidrug-resistant and extensively drug-resistant Mtb is becoming a public health threat worldwide and makes the identification of anti-Mtb drug targets urgent. Elongation factor G (EF-G) is involved in tRNA translocation on ribosomes during protein translation. Therefore, EF-G is a major focus of structural analysis and a valuable drug target of antibiotics. However, the crystal structure of Mtb EF-G1 is not yet available, and this has limited the design of inhibitors. Here, we report the crystal structure of Mtb EF-G1 in complex with GDP. The unique crystal form of the Mtb EF-G1-GDP complex provides an excellent platform for fragment-based screening using a crystallographic approach. Our findings provide a structure-based explanation for GDP recognition, and facilitate the identification of EF-G1 inhibitors with potential interest in the context of drug discovery.

Accurate parasitic parameter extraction of high-frequency transformers is one of the key techniques to efficiently design a Switched-mode power supply(SMPS). An approach to accurately and efficiently extract the parasitic parameters of high-frequency transformers is proposed. The high-frequency transformer is first decomposed into first-order RL and second-order RLC circuits according to inherent step response characteristics. Through the measured discharging pulse and damped oscillation responses of the high-frequency transformer excited by a square wave, we can extract the equivalent circuit parameters through fitting the responses with Particle swarm optimization(PSO). The equivalent circuits of the high-frequency transformer with the desired parameters are obtained for the SMPS design. We validate the effectiveness and accuracy of the proposed method with simulations and measurements.

Kaposi's sarcoma (KS), a highly invasive and angiogenic tumor of endothelial spindle-shaped cells, is the most common AIDS-associated cancer caused by KS-associated herpesvirus (KSHV) infection. KSHV-encoded viral FLICE-inhibitory protein (vFLIP) is a viral oncogenic protein, but its role in the dissemination and angiogenesis of KSHV-induced cancers remains unknown. Here, we report that vFLIP facilitates cell migration, invasion, and angiogenesis by downregulating the SAP18-HDAC1 complex. vFLIP degrades SAP18 through a ubiquitin-proteasome pathway by recruiting E3 ubiquitin ligase TRIM56. Further, vFLIP represses HDAC1, a protein partner of SAP18, by inhibiting Nanog occupancy on the HDAC1 promoter. Notably, vFLIP impairs the interaction between the SAP18/HDAC1 complex and p65 subunit, leading to enhancement of p65 acetylation and NF-κB activation. Our data suggest a novel mechanism of vFLIP activation of the NF-κB by decreasing the SAP18/HDAC1 complex to promote the acetylation of p65 subunit, which contributes to vFLIP-induced activation of the NF-κB pathway, cell invasion, and angiogenesis. These findings advance our understanding of the mechanism of KSHV-induced pathogenesis, and providing a rationale for therapeutic targeting of the vFLIP/SAP18/HDAC1 complex as a novel strategy of AIDS-KS.

Dysregulated B-cell activation plays pivotal roles in systemic lupus erythematosus (SLE), which makes B-cell depletion a potential strategy for SLE treatment. The clinical success of anti-CD19 CAR-T cells in treating B-cell malignancies has attracted the attention of researchers. In this study, we aimed to investigate the feasibility of applying anti-CD19 CAR-T cell therapy to SLE treatment in a mouse disease model. We constructed murine anti-CD19 CARs with either CD28 or 4-1BB as the intracellular costimulatory motif and evaluated the therapeutic function of the corresponding CAR-T cells by infusing them into MRL-lpr mice. Furthermore, anti-CD19 CAR-T cells were transferred to MRL-lpr mice before the onset of disease to determine their role in SLE prevention. According to our observations, compared with antibody treatment, the adoptive transfer of our anti-CD19 CAR-T cells showed a more sustained B-cell-depletion effect in MRL-lpr mice. The transfer of syngeneic anti-CD19 CAR-T cells not only prevented disease pathogenesis before the onset of disease symptoms but also displayed therapeutic benefits at a later stage after disease progression. We also tried to optimize the treatment strategy and found that compared with CAR-T cells with the CD28 costimulatory motif, CAR-T cells with the 4-1BB costimulatory motif showed better therapeutic efficiency without cell enrichment. Taken together, these results show that anti-CD19 CAR-T cell therapy was effective in the prevention and treatment of a murine model of SLE, indicating its potential for clinical use in patients.

Mycobacterium tuberculosis (Mtb) encodes an exceptionally large number of toxin-antitoxin (TA) systems, supporting the hypothesis that TA systems are involved in pathogenesis. We characterized the putative Mtb Rv1044-Rv1045 TA locus structurally and functionally, demonstrating that it constitutes a bona fide TA system but adopts a previously unobserved antitoxicity mechanism involving phosphorylation of the toxin. While Rv1045 encodes the guanylyltransferase TglT functioning as a toxin, Rv1044 encodes the novel atypical serine protein kinase TakA, which specifically phosphorylates the cognate toxin at residue S78, thereby neutralizing its toxicity. In contrast to previous predictions, we found that Rv1044-Rv1045 does not belong to the type IV TA family because TglT and TakA interact with each other as substrate and kinase, suggesting an unusual type of TA system. Protein homology analysis suggests that other COG5340-DUF1814 protein pairs, two highly associated but uncharacterized protein families widespread in prokaryotes, might share this unusual antitoxicity mechanism., Xia Yu et al. report the characterization of a toxin-antitoxin system with an unusual mechanism in Mycobacterium tuberculosis. They find that the antitoxin locus Rv1044 encodes an atypical serine protein kinase that phosphorylates the toxin to neutralize toxicity.

Variable numerous types of equipment/subsystems may exist in complex systems, which makes it difficult to analyze and identify electromagnetic emission sources. A theory named “basic emission waveform theory” is presented in this paper to solve this problem. This innovation theory characterizes emission with four basic waveforms, including square wave, sine wave, damped oscillation, and spike wave. Then, the effectiveness of the theory is discussed in both theoretical and engineering ways. In particular, the basic waveforms reflect the physical characteristics of the equipment. Furthermore, the basic waveforms generally do not vary with the locations or loading conditions. Therefore, the identification and analysis of an emission source can be realized by analyzing the basic waveforms from the emission of a complex system. Finally, the applications of damped oscillation and square wave in emission source identification field are used as validations of the proposed theory. Moreover, an example of emission source identification for an electric vehicle is also presented. The examples show that the proposed theory can be used to simply and accurately identify and analyze the emission sources of complex systems.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). Most tumor cells in these malignancies are latently infected by KSHV. Thus, viral latency is critical for the development of tumor and induction of tumor-associated angiogenesis. KSHV encodes more than two dozens of miRNAs but their roles in KSHV-induced angiogenesis remains unknown. We have recently shown that miR-K12-3 (miR-K3) promoted cell migration and invasion by targeting GRK2/CXCR2/AKT signaling (PLoS Pathog, 2015;11(9):e1005171). Here, we further demonstrated a role of miR-K3 and its induced signal pathway in KSHV latency and KSHV-induced angiogenesis. We found that overexpression of miR-K3 not only promoted viral latency by inhibiting viral lytic replication, but also induced angiogenesis. Further, knockdown of GRK2 inhibited KSHV replication and enhanced KSHV-induced angiogenesis by enhancing the CXCR2/AKT signals. As a result, blockage of CXCR2 or AKT increased KSHV replication and decreased angiogenesis induced by PEL cells in vivo. Finally, deletion of miR-K3 from viral genome reduced KSHV-induced angiogenesis and increased KSHV replication. These findings indicate that the miR-K3/GRK2/CXCR2/AKT axis plays an essential role in KSHV-induced angiogenesis and promotes KSHV latency, and thus may be a potential therapeutic target of KSHV-associated malignancies.

Misshapen (Msn)/NIK-related kinase 1 (MINK1) is a serine/threonine kinase belongs to the germinal center kinase (GCK) family. Previous studies indicated the correlation of MINK1 with tumor cell senescence and Th17 differentiation. Its dual role in modulating both tumor growth and T cell function indicated MINK1 a possible intervention target in tumor immunotherapy. We have utilized the MINK1 deficient mice to explore the possible role of MINK1 in the anti-tumor immune response. By using the subcutaneous tumor-xenograft model, we have found that MINK1 deficiency in mice resulted in slower tumor growth. We have also accumulated evidence in adoptive transfer and CD8+ T cells depletion experiments to show that the genetic ablation of MINK1 suppressed tumor growth primarily via CD8+ T cells without affecting other immune cells. Along with which, MINK1 deficient CD8+ T cells are superior in both tumor infiltration and the expression of effector markers such as TNF-α, IFN-γ, and Granzyme-B when compared to WT CD8+ T cells. Lower expression of exhaustion markers such as PD-1, TIM-3, and TIGIT were also observed in MINK1 KO CD8+ T cells. We are currently exploring the possible mechanisms of how MINK1 regulated CD8+ T cell function, and examine the possibility to target MINK1 in experimental tumor immunotherapy.

A novel method on detecting and analyzing electromagnetic emission components is proposed by this paper. Beginning with the electromagnetic spectrum data, the paper analyzes the damped oscillation component, the harmonic component, and the sinusoidal component gradually. The method to extract these components can be designed to a software tool. With the tool, the hidden electromagnetic emission components can be extracted automatically. The comparison between the quantitative parameters and the actual parameters of equipments can be used to diagnose and locate the causes of over standard. It is important for analyzing and designing electromagnetic compatibility of systems or equipments.

Corynebacterium glutamicum can degrade phenol by a meta-cleavage pathway, which depends on ncgl2588 (phe) of the phe operon encoding phenol hydroxylase. An additional gene, ncgl2587 (pheR), is located upstream of phe. The pheR encodes an AraC/XylR-type regulator protein with 377 amino acid residues and is transcribed in the same direction as phe. Disruption of pheR by homologous recombination resulted in the accumulation of phenol in C. glutamicum. PheR demonstrates a low type of constitutive expression where phenol induces phe expression. PheR shares 75% sequence identity with AraC-type regulator of Corynebacterium lubricantis and 37 conserved residues, characteristic of AraC family, were located. A constructed pK18mobsacB-Pphe:lacZ transcriptional fusion plasmid was transformed into the wild-type, ΔpheR, and ΔpheR+ strains, and the results indicated that PheR activates the expression of phe encoding phenol hydroxylase. Electrophoretic mobility shift assay (EMSA) demonstrated a direct interaction of PheR with the phe promoter region and binding site of PheR on the Pphe was located 109-bp upstream of phe, as indicated by foot printing analysis. Our research provides deep insight into PheR expression and its regulatory function on Phe in C. glutamicum.

Iron sequestration by host proteins contributes to the defence against bacterial pathogens, which need iron for their metabolism and virulence. A Pseudomonas aeruginosa mutant lacking all three known iron acquisition systems retains the ability to grow in media containing iron chelators, suggesting the presence of additional pathways involved in iron uptake. Here we screen P. aeruginosa mutants defective in growth in iron-depleted media and find that gene PA2374, proximal to the type VI secretion system H3 (H3-T6SS), functions synergistically with known iron acquisition systems. PA2374 (which we have renamed TseF) appears to be secreted by H3-T6SS and is incorporated into outer membrane vesicles (OMVs) by directly interacting with the iron-binding Pseudomonas quinolone signal (PQS), a cell–cell signalling compound. TseF facilitates the delivery of OMV-associated iron to bacterial cells by engaging the Fe(III)-pyochelin receptor FptA and the porin OprF. Our results reveal links between type VI secretion, cell–cell signalling and classic siderophore receptors for iron acquisition in P. aeruginosa., Pathogens require iron for their metabolism and virulence. Here the authors identify an iron acquisition system in Pseudomonas aeruginosa involving a protein secreted by a type VI secretion system, the PQS signalling compound and siderophore receptors.

This study establishes an analytical method for the determination of eighteen preservatives in water-based adhesives. The method was based on liquid–liquid extraction by methyl tertiary-butyl ether and subsequent determination by gas chromatography–mass spectrometry. Experimental conditions (instrumental parameters, extraction solvent, extraction mode, dispersant volume, and extraction time) were optimized and validated. When the method was applied to water-based adhesives, the limits of detection and recovery were 2.29–17.59 milligrams per kilogram and 85.7 − 93.9 percent, respectively, and the repeatability was below 5 percent for all analytes. None of the analytes were found in five cigarette adhesives.

Electromagnetic emission spectrum is the reflection of inherent properties of EUT. But time-domain parameters are sometimes required to trouble-shooting or modeling. However, since the phase information of the test emission spectrum is missing, it's hard to obtain the time-domain waveform and its parameters using inverse Fourier transform directly. While, for the emission spectrum generated by periodic signals, a new method for time-domain parameters identification based on feature points fitting and Genetic Algorithm(GA) is proposed. Firstly, fundamental frequency of periodic signal is calculated and the feature points of the spectrum is obtained. Secondly, the time-domain parameters identification is summarized as a multi-objective optimization problem and the GA is used to find the optimal values. Finally, the effectiveness is validated by a simulation example. By using feature points fitting method, the problem of the non-convergence problem can be avoided, and the computational complexity is greatly reduced. By using genetic algorithm method to solve multi-objective optimization problem, it can control the identification accuracy.

In this paper, a parasitic extraction method of PIN diode is proposed based on analyzing the ringing signal in Switch Mode Power Supply (SMPS). As the charge-discharge of filter capacitor and parasitic parameters of PIN diode, ringing occurs in filter circuit of a simple SMPS. Relationship between characteristic parameters of ringing in time/frequency domain and parasitic parameters of PIN diode is obtained, by means of analyzing the mechanism of ringing. On the premise of known circuit model of PIN diode, some series inductors, with known value, are used on one side of PIN diode, and characteristic parameters of ringing in time/frequency domain are obtained. Then the value of parasitic inductor/capacitor/resistor can be solved.

Diseases caused by parasitic helminths cause considerable production and economic losses in livestock worldwide. Understanding the epidemiology of these parasites has important implications for controlling them. The main purpose of the present study was to estimate the prevalence of key parasitic helminths in goats along the Han River in Zhanggang, Hubei Province (from January to December 2014). We used faecal flotation and sedimentation techniques as well as PCR-based DNA sequencing to detect and identify helminths. Results showed that the prevalence of helminths was high throughout the year, particularly for gastrointestinal nematodes. These first findings provide useful baseline information for goat helminths in Zhanggang, and a starting point for the implementation of control programs. With an increased expansion of the goat industry in China, the findings also emphasise the need to undertake prevalence surveys in other regions of China where extensive farming practices are used.

This paper proposed a new method to characterize the harmonic components from Electromagnetic Interference (EMT) spectrum, which is based on the Grey System Theory and the Fourier Envelope Theory. The proposed method first characterizes the harmonic components from the EMI test data. Then proper time-domain component model (e.g. square, sinusoidal, or convergent oscillation, etc) is identified based on the frequency and amplitude of the harmonic components in the spectrum. Finally, the identified time-domain components are quantified. As an application of this method, the EMI spectrum data of equipment under test (EUT) is used to identify and quantify its major time-domain components. Comparisons between the time-domain components obtained by the proposed method and measured by oscilloscope are presented, which show the accuracy of the proposed method. Furthermore, from the waveform types of identified time-domain components, the major EMI sources can be located.