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Abstract Antimicrobial peptides (AMPs), ancient scavengers of bacteria, are very poorly induced in macrophages infected by Mycobacterium tuberculosis (M. tuberculosis), but the underlying mechanism remains unknown. Here, we report that L-alanine interacts with PRSS1 and unfreezes the inhibitory effect of PRSS1 on the activation of NF-κB pathway to induce the expression of AMPs, but mycobacterial alanine dehydrogenase (Ald) Rv2780 hydrolyzes L-alanine and reduces the level of L-alanine in macrophages, thereby suppressing the expression of AMPs to facilitate survival of mycobacteria. Mechanistically, PRSS1 associates with TAK1 and disruptes the formation of TAK1/TAB1 complex to inhibit TAK1-mediated activation of NF-κB pathway, but interaction of L-alanine with PRSS1, disables PRSS1-mediated impairment on TAK1/TAB1 complex formation, thereby triggering the activation of NF-κB pathway to induce expression of AMPs. Moreover, deletion of antimicrobial peptide gene β-defensin 4 (Defb4) impairs the virulence by Rv2780 during infection in mice. Both L-alanine and the Rv2780 inhibitor, GWP-042, exhibits excellent inhibitory activity against M. tuberculosis infection in vivo. Our findings identify a previously unrecognized mechanism that M. tuberculosis uses its own alanine dehydrogenase to suppress host immunity, and provide insights relevant to the development of effective immunomodulators that target M. tuberculosis.

Abstract Since sequential recommendation can effectively capture the user’s dynamic interaction pattern according to the user’s historical interaction, it plays one of the important roles in the field of recommendation systems. Nowadays, the sequential recommendation models based on deep learning approaches have achieved good results in reality due to their excellent performance in information retrieval and filtering. However, there are still some challenges that still should be overcome of them. A major disadvantage of them is that they are only considering users’ short-time interests while ignoring their long-term preferences. Moreover, they are incapable of considering the influence of time information in the original interaction sequence, which could be helpful to fully extract various patterns via the different temporal embedding forms. Therefore, this paper proposes a novel model named multi-temporal sequential recommendation model based on the fused learning preference named MTSR-FLP in short. In the proposed framework, this paper adopts an MLP-based state generation module to consider the user’s long-term preferences and the short-time interests simultaneously. In particular, the proposed MTSR-FLP model designs a global representation learning approach to obtain the user’s global preference, and a local representation learning approach to capture the users’ local preference via its historical information. Moreover, the proposed model develops a multiple temporal embedding scheme to encode the positions of user–item interactions of a sequence, in which multiple kernels are utilized for the absolute or relative timestamps to establish unique embedding matrices. Finally, compared with other advanced sequence recommendation models on five public real-world datasets, the experimental results show that the proposed MTSR-FLP model has improved the performance of HR@10 from the 6.68% through 31.10% and NDCG@10 from the 8.60% through 42.54%.

To solve the problem of poor quality in ghost imaging via sparsity constraints (GISC) multispectral image reconstruction with correlation operations and compressed sensing algorithms under low sampling rate detection conditions, we propose an end-to-end deep-learning-based method. Based on the U-Net, Res2Net-SE-Conv is employed instead of convolutional blocks to extract local and global image features at a more fine-grained level while adaptively adjusting the channel feature response. The two-dimensional contextual transformer is constructed to fully use contextual correlation information to enhance the effectiveness of feature representations. We employ the two-dimensional contextual transformer in the decoder part, dubbed CoT-Unet, to reconstruct the desired 3D cube. The results show that compared with U-Net, TSA-Net based on spatial-spectral self-attention, the PSNR of reconstructed images by the CoT-Unet is improved by 5 dB and 3 dB, respectively, SSIM is improved by 0.23 and 0.07, and SAM is decreased by 0.06 and 0.58. Compared with conventional algorithms such as DGI and CS, our method significantly improves the quality of reconstructed images. Furthermore, the comparison results at 10%, 20%, and 30% sampling rates show that our approach has the best quality in reconstructing GISC multispectral images at low sampling rates.

Multispectral image reconstruction, which aims to recover a three-dimensional (3D) spatial–spectral signal from a two-dimensional measurement in a spectral camera based on ghost imaging via sparsity constraint (GISC), has been attracting much attention recently. However, faced with abundant 3D spectral data, the reconstruction quality cannot meet the visual requirements. Based on the robust data processing capability of deep learning, a novel network called SSTU-Net3+ is constructed by improving U-Net3+ with a spatial–spectral transformer (SST). To enhance the feature representation of images during reconstruction, mixed pooling modules and new convolution processes are proposed to improve the performance of the encoder and decoder, with U-Net3+ as the backbone. To boost the quality of reconstructed images, with split and concatenate (Concat) operations, we construct SST modules by exploiting both spatial and spectral correlations of multispectral images to refine the spatial and spectral features. Furthermore, we employ the SST in the decoder to reconstruct the desired 3D cube. Given similar network parameters, experiments on GISC spectral imaging data show that, compared to convolutional neural network–based methods, the average peak signal-to-noise ratio of images reconstructed using SSTU-Net3+ is improved by 3%, the structural similarity is enhanced by 3%, and the spectral angle mapping is cut by 12%. Particularly, compared to differential ghost imaging and compressed sensing, the reconstruction quality of SSTU-Net3+ has been significantly improved. SSTU-Net3+ can process a large amount of 3D multispectral image data more efficiently and construct the target image more accurately than the abovementioned methods.

Summary: Enhancing chemosensitivity is one of the largest unmet medical needs in cancer therapy. Cyclic GMP-AMP synthase (cGAS) connects genome instability caused by platinum-based chemotherapeutics to type I interferon (IFN) response. Here, by using a high-throughput small-molecule microarray-based screening of cGAS interacting compounds, we identify brivanib, known as a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor, as a cGAS modulator. Brivanib markedly enhances cGAS-mediated type I IFN response in tumor cells treated with platinum. Mechanistically, brivanib directly targets cGAS and enhances its DNA binding affinity. Importantly, brivanib synergizes with cisplatin in tumor control by boosting CD8+ T cell response in a tumor-intrinsic cGAS-dependent manner, which is further validated by a patient-derived tumor-like cell clusters model. Taken together, our findings identify cGAS as an unprecedented target of brivanib and provide a rationale for the combination of brivanib with platinum-based chemotherapeutics in cancer treatment.

BackgroundDeafness is the most common sensory defect in humans worldwide. Approximately 50% of cases are attributed to genetic factors, and about 70% are non-syndromic hearing loss (NSHL).ObjectivesTo identify clinically relevant gene variants associated with NSHL in a Chinese family using trio-based whole-exome sequencing (WES).Materials and methodsWES was performed on the 18-month-old female proband, and her parents. Gene variants specific to the family were identified by bioinformatics analysis and evaluated for their relevance to NSHL. We verified the novel variant in this family by the next-generation sequencing.In order to elucidate the frameshift mutation of TMPRSS3 in a Chinese family, we used the Mass spectrometry to detect the gene from 1,010 healthy subjects.ResultsWe identified a novel homozygous deletion (c.51delA) in exon 2 of the type II transmembrane serine protease 3 gene TMPRSS3, which resulted in a frameshift mutation just before the protein transmembrane domain (p.Q17fs). The deletion was present in the proband and her father, but not in her mother and the healthy controls. We also found mutations with potential relevance to hearing loss in DCAF17, which encodes a protein of unknown function (c. T555A: p.H185Q), and ZNF276, which encodes zinc finger protein 276 (c.1350–2A > G).Conclusions and significanceWe shown a novel frameshift mutation in TMPRSS3 associated with autosomal recessive NSHL in a Han Chinese family.

Abstract Pathogenic mycobacteria induce the formation of hypoxic granulomas during latent tuberculosis (TB) infection, in which the immune system contains, but fails to eliminate the mycobacteria. Fatty acid metabolism-related genes are relatively overrepresented in the mycobacterial genome and mycobacteria favor host-derived fatty acids as nutrient sources. However, whether and how mycobacteria modulate host fatty acid metabolism to drive granuloma progression remains unknown. Here, we report that mycobacteria under hypoxia markedly secrete the protein Rv0859/MMAR_4677 (Fatty-acid degradation A, FadA), which is also enriched in tuberculous granulomas. FadA acts as an acetyltransferase that converts host acetyl-CoA to acetoacetyl-CoA. The reduced acetyl-CoA level suppresses H3K9Ac-mediated expression of the host proinflammatory cytokine Il6, thus promoting granuloma progression. Moreover, supplementation of acetate increases the level of acetyl-CoA and inhibits the formation of granulomas. Our findings suggest an unexpected mechanism of a hypoxia-induced mycobacterial protein suppressing host immunity via modulation of host fatty acid metabolism and raise the possibility of a novel therapeutic strategy for TB infection.

Drug-facilitated sexual assault (DFSA) is a sexual act in which the victim is unable to give or rescind consent due to alcohol or drug intoxication, which involved the abuse of benzodiazepines around the world. Conventional techniques used for the analysis of benzodiazepines have the limitation of short detection time window due to the rapid metabolism of these drugs in body. This study aimed to investigate the characteristic changes of metabolites in the blood of rats after ingesting diazepam/clonazepam through a gas chromatography-mass spectrometry-based metabolomics method, allowing the indirect reveal of the rats ingested diazepam/clonazepam. First, we found that diazepam and clonazepam in the blood of rats could not be detected by liquid chromatography-tandem mass spectrometry after 48 h of ingestion. Then, orthogonal partial least squares discrimination analysis regression models were, respectively, constructed to determine whether the rats ingested diazepam/clonazepam after 48 h. The results showed that 5 metabolites were found to be associated with diazepam exposure, and 7 metabolites were found to be associated with clonazepam exposure, which may be characterization for the evaluation of digestion of diazepam and clonazepam in rat.

How Mycobacterium tuberculosis (Mtb) escapes autophagy-mediated clearance is poorly understood. Here, Liu et al. show that Mtb-induced MicroRNA-27a targets the ER-associated calcium transporter CACNA2D3, leading to suppression of antimicrobial autophagy and to enhanced intracellular survival of Mtb.

Gas chromatography-mass spectrometry method was developed for the qualitative and quantitative analyses of chlorpyrifos in human blood samples. The chlorpyrifos and parathion (internal standard) in human blood were extracted with a mixed solvent of hexane and acetonitrile. Chlorpyrifos was well separated from the internal standard. The linear range of chlorpyrifos was 0.01–2 μg/ml in blood. The limit of detection and limit of quantification were estimated at 0.002 and 0.01 μg/ml, respectively. The inter- and intra-day precisions, accuracy, and recovery were assessed to verify this method. The results showed that the developed method is rapid, sensitive, and reliable. It is suitable for the determination of chlorpyrifos in forensic toxicological analysis and clinical diagnosis.

Background: Carbon monoxide (CO) poisoning is one of the most important intoxications in the modern world. This study aimed to identify the characteristics of CO poisoning deaths in Sichuan province in the west of China. Methods: Data on fatal non-fire-related carbon monoxide poisoning in Sichuan from 2008 to 2016 were obtained from the Department of Forensic Analytical Toxicology of Sichuan University and were analyzed by the month and year of registration of death, sex, age group, manner of death, source of CO, and location of CO exposure. Comparing with the previous studies carried out in Wuhan and Shanghai to identify the regional differences of CO poisoning in China. Results: A total of 165 non-fire related CO poisoning cases including 237 victims were recorded. Over 90% of the victims died from accidental poisoning. Non-fire related CO poisoning occurred more frequently in winter months and was most prevalent in individuals aged between 18 and 60 yr old. Showering gas accident and coal or charcoal burning was found to be the major source of CO in accident and in suicide cases, respectively. Furthermore, significant regional differences of CO poisoning have been detected in the manner of death and the source of CO. Conclusion: These findings will be valuable in the targeted prevention of non-fire related CO poisoning in China.

Interleukin-37 (IL-37), a novel member of the IL-1 family, plays fundamental immunosuppressive roles by broadly reducing both innate inflammation and acquired immunity, but whether it is involved in the pathogenesis of tuberculosis (TB) has not been clearly elucidated. In this study, single nucleotide polymorphism (SNP) analysis demonstrated an association of the genetic variant rs3811047 of IL-37 with TB susceptibility. In line with previous report, a significant elevated IL-37 abundance in the sera and increased expression of IL-37 protein in the peripheral blood mononuclear cells (PBMC) were observed in TB patients in comparison to healthy controls. Moreover, release of IL-37 were detected in either macrophages infected with Mycobacterium tuberculosis (Mtb) or the lung of BCG-infected mice, concurrent with reduced production of proinflammatory cytokines including IL-6 and TNF-α. Furthermore, in contrast to wild-type mice, BCG-infected IL-37-Tg mice manifested with reduced mycobacterial burden and tissue damage in the lung, accompanied by higher frequency of Th1 cell and less frequencies of regulatory T cells and Th17 cells in the spleen. Taken together, our findings demonstrated that IL-37 conferred resistance to Mtb infection possibly involving suppressing detrimental inflammation and modulating T cell responses. These findings implicated that IL-37 may be employed as a new molecular target for the therapy and diagnosis of TB.

Enterovirus 71 (EV71) is the most virulent pathogen among enteroviruses that cause hand, foot and mouth disease in children but rarely in adults. The mechanisms that determine the age-dependent susceptibility remain largely unclear. Here, we found that the paucity of invariant natural killer T (iNKT) cells together with immaturity of the immune system was related to the susceptibility of neonatal mice to EV71 infection. iNKT cells were crucial antiviral effector cells to protect young mice from EV71 infection before their adaptive immune systems were fully mature. EV71 infection led to activation of iNKT cells depending on signaling through TLR3 but not other TLRs. Surprisingly, iNKT cell activation during EV71 infection required TLR3 signaling in macrophages, but not in dendritic cells (DCs). Mechanistically, interleukin (IL)-12 and endogenous CD1d-restricted antigens were both required for full activation of iNKT cells. Furthermore, CD1d-deficiency led to dramatically increased viral loads in central nervous system and more severe disease in EV71-infected mice. Altogether, our results suggest that iNKT cells may be involved in controlling EV71 infection in children when their adaptive immune systems are not fully developed, and also imply that iNKT cells might be an intervention target for treating EV71-infected patients.

Pleural tuberculosis (TB), together with lymphatic TB, constitutes more than half of all extrapulmonary cases. Pleural effusions (PEs) in TB are representative of lymphocytic PEs which are dominated by T cells. However, the mechanism underlying T lymphocytes homing and accumulation in PEs is still incompletely understood. Here we performed a comparative analysis of cytokine abundance in PEs from TB patients and non-TB patients by protein array analysis and observed that MCP-2/CCL8 is highly expressed in the TB-PEs as compared to peripheral blood. Meanwhile, we observed that CCR5, the primary receptor used by MCP-2/CCL8, is mostly expressed on pleural CD4(+) T lymphocytes. Furthermore, we found that infection with either Mycobacterium bovis Bacillus Calmette-Guérin (BCG) or Mycobacterium tuberculosis H37Rv induced production of MCP-2/CCL8 at both transcriptional and protein level in Raw264.7 and THP-1 macrophage cells, mouse peritoneal macrophages as well as human PBMC monocyte-derived macrophages (MDMs). The induction of MCP-2/CCL8 by mycobacteria is dependent on the activation of TLR2/PI3K/Akt and p38 signaling pathway. We conclude that accumulation of MCP-2/CCL8 in TB-PEs may function as a biomarker for TB diagnosis.