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ObjectiveTo develop a semi-automatic model integrating radiomics, deep learning, and clinical features for Bone Metastasis (BM) prediction in prostate cancer (PCa) patients using Biparametric MRI (bpMRI) images.MethodsA retrospective study included 414 PCa patients (BM, n=136; NO-BM, n=278) from two institutions (Center 1, n=318; Center 2, n=96) between January 2016 and December 2022. MRI scans were confirmed with BM status via PET-CT or ECT pre-treatment. Tumor areas on bpMRI images were delineated as tumor’s region of interest (ROI) using auto-delineation tumor models, evaluated with Dice similarity coefficient (DSC). Samples were auto-sketched, refined, and used to train the ResNet BM prediction model. Clinical, radiomics, and deep learning data were synthesized into the ResNet-C model, evaluated using receiver operating characteristic (ROC).ResultsThe auto-segmentation model achieved a DSC of 0.607. Clinical BM prediction’s internal validation had an accuracy (ACC) of 0.650 and area under the curve (AUC) of 0.713; external cohort had an ACC of 0.668 and AUC of 0.757. The deep learning model yielded an ACC of 0.875 and AUC of 0.907 for the internal, and ACC of 0.833 and AUC of 0.862 for the external cohort. The Radiomics model registered an ACC of 0.819 and AUC of 0.852 internally, and ACC of 0.885 and AUC of 0.903 externally. ResNet-C demonstrated the highest ACC of 0.902 and AUC of 0.934 for the internal, and ACC of 0.885 and AUC of 0.903 for the external cohort.ConclusionThe ResNet-C model, utilizing bpMRI scanning strategy, accurately assesses bone metastasis (BM) status in newly diagnosed prostate cancer (PCa) patients, facilitating precise treatment planning and improving patient prognoses.

Aberrant alternative splicing (AS) events have been identified in a variety of cancers. Although somatic mutations of splicing factors and dysregulation of RNA-binding proteins (RBPs) have been linked to AS and tumor malignancy, it remains unclear how upstream mechanisms contribute to cancer development via alternative gene splicing. In this issue of the JCI, Wenrui Zhang and colleagues identified the role of asparagine endopeptidase (AEP), an intracellular cysteine endopeptidase, in promoting solid tumor-associated RNA splicing. The authors demonstrated that tumor environmental factors such as oxygen and nutrient deprivation induce the activity of AEP in a HIFIA-dependent manner. The activated AEP, in turn, cleaves an RNA helicase DDX3X to promote its nuclear retention. The authors further showed that this DDX3X nuclear fraction engages with splicing machinery to induce AS events in several cancer cells. These findings suggest that targeting an AEP-dependent aberrant RNA splicing cascade may facilitate therapeutics for solid tumors., Aberrant RNA splicing in cancers Alternative splicing (AS) is a critical cellular process that contributes to the encoding capacity of transcriptomes of eukaryotic cells (1). Recently, high-throughput sequencing and genome-wide [...]

The influence of frequency characteristics of devices is complex. The effects of AlN barrier thickness, gate length, gate-drain spacing and work function on the frequency characteristics of AlN/ β-Ga2O3 high electron mobility transistor (HEMT) were studied by Sentaurus TCAD in this paper. The following conclusions are obtained: as the thickness of the AlN barrier layer increases from 10 nm to 25 nm, the cutoff frequency (fT) and maximum oscillation frequency (fmax ) rise by 18 and 17 GHz respectively. The decrease of gate capacitance is the main reason for the increase of fT . Furthermore, it was found that the thinner barrier layer enhanced the gate's ability to control the channel electrons. When the gate length is scaled down from 0. 9 μm to 0. 1 μm, fT and fmax increase by 84 and 98 GHz, respectively, representing a far more profound influence on frequency characteristics than the barrier layer thickness. However, when the gate length fell below 0. 1 μm, short-channel effects emerged. As the gate-drain spacing increase, fT exhibits a slight decrease. Coupled with the concurrent reduction in source resistance, this led to a synchronized trend in fmax and fT only when the gate-source voltage (VGS ) exceeds - 1. 2 V. The work function, on the other hand, has minimal impacts on fT and fmax, but an increase in the work function positively influenced the device' s pinch-off characteristics. In summary, this paper indicates that by shortening the gate length while concurrently augmenting the thickness of the AlN barrier layer, gate-drain spacing, and work function, one can enhance the frequency characteristics while also improving the pinch-off characteristics of the device, which has certain guiding significance for the design of HEMT devices. [ABSTRACT FROM AUTHOR]

Although maternal antibodies protect newborn babies from infection.sup.1,2, little is known about how protective antibodies are induced without prior pathogen exposure. Here we show that neonatal mice that lack the capacity to produce IgG are protected from infection with the enteric pathogen enterotoxigenic Escherichia coli by maternal natural IgG antibodies against the maternal microbiota when antibodies are delivered either across the placenta or through breast milk. By challenging pups that were fostered by either maternal antibody-sufficient or antibody-deficient dams, we found that IgG derived from breast milk was crucial for protection against mucosal disease induced by enterotoxigenic E. coli. IgG also provides protection against systemic infection by E. coli. Pups used the neonatal Fc receptor to transfer IgG from milk into serum. The maternal commensal microbiota can induce antibodies that recognize antigens expressed by enterotoxigenic E. coli and other Enterobacteriaceae species. Induction of maternal antibodies against a commensal Pantoea species confers protection against enterotoxigenic E. coli in pups. This role of the microbiota in eliciting protective antibodies to a specific neonatal pathogen represents an important host defence mechanism against infection in neonates. Neonatal mice are protected against infection with the enteric pathogen enterotoxigenic Escherichia coli by maternally derived natural antibodies as well as by maternal commensal microbiota that induce antibodies that recognize antigens expressed by Enterobacteriaceae., Author(s): Wen Zheng [sup.1] , Wenjing Zhao [sup.2] [sup.3] , Meng Wu [sup.1] , Xinyang Song [sup.1] , Florence Caro [sup.3] , Ximei Sun [sup.1] , Francesca Gazzaniga [sup.1] , [...]

The metabolic pathways encoded by the human gut microbiome constantly interact with host gene products through numerous bioactive molecules.sup.1. Primary bile acids (BAs) are synthesized within hepatocytes and released into the duodenum to facilitate absorption of lipids or fat-soluble vitamins.sup.2. Some BAs (approximately 5%) escape into the colon, where gut commensal bacteria convert them into various intestinal BAs.sup.2 that are important hormones that regulate host cholesterol metabolism and energy balance via several nuclear receptors and/or G-protein-coupled receptors.sup.3,4. These receptors have pivotal roles in shaping host innate immune responses.sup.1,5. However, the effect of this host-microorganism biliary network on the adaptive immune system remains poorly characterized. Here we report that both dietary and microbial factors influence the composition of the gut BA pool and modulate an important population of colonic FOXP3.sup.+ regulatory T (T.sub.reg) cells expressing the transcription factor ROR[gamma]. Genetic abolition of BA metabolic pathways in individual gut symbionts significantly decreases this T.sub.reg cell population. Restoration of the intestinal BA pool increases colonic ROR[gamma].sup.+ T.sub.reg cell counts and ameliorates host susceptibility to inflammatory colitis via BA nuclear receptors. Thus, a pan-genomic biliary network interaction between hosts and their bacterial symbionts can control host immunological homeostasis via the resulting metabolites. Both dietary and microbial factors influence the composition of the gut bile acid pool, which in turn modulates the frequencies and functionalities of ROR[gamma]-expressing colonic FOXP3.sup.+ regulatory T cells, contributing to protection from inflammatory colitis., Author(s): Xinyang Song [sup.1] , Ximei Sun [sup.1] , Sungwhan F. Oh [sup.1] [sup.2] , Meng Wu [sup.1] , Yanbo Zhang [sup.1] , Wen Zheng [sup.1] , Naama Geva-Zatorsky [sup.1] [...]

With the significant advancements of deep learning (DL) in the field of remote sensing (RS) imagery, a plethora of change detection (CD) methods based on CNNs, attention mechanisms, and transformers (TRs) have emerged. Presently, a substantial amount of research has gradually relinquished control over parameter quantities in pursuit of enhanced outcomes, resulting in the inflation of networks with numerous stacked modules. This letter is dedicated to integrating lightweight approaches into the CD task. We introduce a lightweight hybrid dual-attention CNN and TR (LHDACT) network based on depthwise over-parameterized convolutional (DO-Conv). In comparison to traditional convolution, DO-Conv combines both traditional and depthwise convolutions, achieving commendable performance enhancement with minimal additional cost. Furthermore, we leverage DO-Conv to enhance the multiscale average pooling (MSAP) module, ensuring global context with low computational overhead. To better discern regions of interest within complex images, we enhance the dual attention module (DAM) by sharing weights across spatial and channel dimensions, thereby bolstering feature region identification. At last, we employ a compact TR module to capture feature differences, enabling precise CD. Our approach is evaluated on the LEVIR-CD, WHU-CD, and GZ-CD datasets, yielding F1 scores of 91.23%, 87.51%, and 85.32%, respectively. These results demonstrate high performance on a cost-effective scale. [ABSTRACT FROM AUTHOR]

With the remarkable success of change detection (CD) in remote sensing images in the context of deep learning, many convolutional neural network (CNN) based methods have been proposed. In the current research, to obtain a better context modeling method for remote sensing images and to capture more spatiotemporal characteristics, several attention-based methods and transformer (TR)-based methods have been proposed. Recent research has also continued to innovate on TR-based methods, and many new methods have been proposed. Most of them require a huge number of calculation to achieve good results. Therefore, using the TR-based mehtod while maintaining the overhead low is a problem to be solved. Here, we propose a GNN-based multi-scale transformer siamese network for remote sensing image change detection (GMTS) that maintains a low network overhead while effectively modeling context in the spatiotemporal domain. We also design a novel hybrid backbone to extract features. Compared with the current CNN backbone, our backbone network has a lower overhead and achieves better results. Further, we use high/low frequency (HiLo) attention to extract more detailed local features and the multi-scale pooling pyramid transformer (MPPT) module to focus on more global features respectively. Finally, we leverage the context modeling capabilities of TR in the spatiotemporal domain to optimize the extracted features. We have a relatively low number of parameters compared to that required by current TR-based methods and achieve a good effect improvement, which provides a good balance between efficiency and performance. [ABSTRACT FROM AUTHOR]

Inflammatory cytokines such as interleukin-17 (IL-17) promote inflammatory autoimmune diseases. Although several microRNAs (miRNAs) have been shown to regulate autoimmune pathogenesis by affecting lymphocyte development and function, the role of miRNAs in resident cells present in inflammatory lesions remains unclear. Here we show that miR-23b is downregulated in inflammatory lesions of humans with lupus or rheumatoid arthritis, as well as in the mouse models of lupus, rheumatoid arthritis or multiple sclerosis. IL-17 downregulates miR-23b expression in human fibroblast-like synoviocytes, mouse primary kidney cells and astrocytes and is essential for the downregulation of miR-23b during autoimmune pathogenesis. In turn, miR-23b suppresses IL-17-, tumor necrosis factor α (TNF-α)- or IL-1β-induced NF-κB activation and inflammatory cytokine expression by targeting TGF-β-activated kinase 1/MAP3K7 binding protein 2 (TAB2), TAB3 and inhibitor of nuclear factor k-B kinase subunit α (IKK-α) and, consequently, represses autoimmune inflammation. Thus, IL-17 contributes to autoimmune pathogenesis by suppressing miR-23b expression in radio-resident cells and promoting proinflammatory cytokine expression., Abnormal inflammatory responses promote tissue damage in autoimmune diseases, including rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus (SLE). (1-3) Most of our understanding of the pathogenesis of autoimmune diseases [...]

It has long been unknown how activation of resident macrophages in the brain, or microglia, is regulated during the inflammatory pathogenesis of multiple sclerosis. Work in a mouse model of [...]

Summary: Host−microbiota interaction plays fundamental roles in the homeostasis of mucosal immunity. Dysbiosis of intestinal microbiota has been demonstrated to participate in various immune responses and many multifactorial diseases. Study of intestinal microbiota has moved beyond the consequences of dysbiosis to the causal microbiota associated with diseases. However, studies of pulmonary microbiota and its dysbiosis are still in their infancy. Improvement of culture‐dependent and ‐independent techniques has facilitated our understanding of lung microbiota that not only exists in healthy lung tissue but also exerts great impact on immune responses under both physiological and pathological conditions. In this review, we summarize recent progresses of lung microbiota dysbiosis and its impact on the local immune system that determines the balance of tolerance and inflammation. We discuss the causal roles of pulmonary dysbiosis under disease settings, and propose that the interaction between lung microbiota and host is critical for establishing the immune homeostasis in lung. [ABSTRACT FROM AUTHOR]

The metabolic pathways encoded by the human gut microbiome constantly interact with host gene products through numerous bioactive molecules1. Primary bile acids (BAs) are synthesized within hepatocytes and released into the duodenum to facilitate absorption of lipids or fat-soluble vitamins2. Some BAs (approximately 5%) escape into the colon, where gut commensal bacteria convert them into various intestinal BAs2 that are important hormones that regulate host cholesterol metabolism and energy balance via several nuclear receptors and/or G-protein-coupled receptors3,4. These receptors have pivotal roles in shaping host innate immune responses1,5. However, the effect of this host–microorganism biliary network on the adaptive immune system remains poorly characterized. Here we report that both dietary and microbial factors influence the composition of the gut BA pool and modulate an important population of colonic FOXP3+ regulatory T (Treg) cells expressing the transcription factor RORγ. Genetic abolition of BA metabolic pathways in individual gut symbionts significantly decreases this Treg cell population. Restoration of the intestinal BA pool increases colonic RORγ+ Treg cell counts and ameliorates host susceptibility to inflammatory colitis via BA nuclear receptors. Thus, a pan-genomic biliary network interaction between hosts and their bacterial symbionts can control host immunological homeostasis via the resulting metabolites.Both dietary and microbial factors influence the composition of the gut bile acid pool, which in turn modulates the frequencies and functionalities of RORγ-expressing colonic FOXP3+ regulatory T cells, contributing to protection from inflammatory colitis. [ABSTRACT FROM AUTHOR]

IL-17 is a pro-inflammatory cytokine implicated a variety of autoimmune diseases. We have recently reported that FGF2 cooperates with IL-17 to protect intestinal epithelium during dextran sodium sulfate (DSS)-induced colitis. Here, we report a pathogenic role of the FGF2-IL-17 cooperation in the pathogenesis of autoimmune arthritis. Combined treatment with FGF2 and IL-17 synergistically induced ERK activation as well as the production of cytokines and chemokines in human synovial intimal resident fibroblast-like synoviocytes (FLS). Furthermore, ectopic expression of FGF2 in mouse joints potentiated IL-17-induced inflammatory cytokine and chemokine production in the tissue. In the collagen-induced arthritis (CIA) model, while ectopic expression of FGF2 in vivo exacerbated tissue inflammation and disease symptom in the wild-type controls, the effect was largely blunted in Il17a −/− mice. Taken together, our study suggests that FGF2 cooperates with IL-17 to promote the pathogenesis of autoimmune arthritis by cooperating with IL-17 to induce inflammatory response.

Interleukin 17 receptor E (IL-17RE) is an orphan receptor of the IL-17 receptor family. Here we show that IL-17RE is a receptor specific to IL-17C and has an essential role in host mucosal defense against infection. IL-17C activated downstream signaling through IL-17RE-IL-17RA complex for the induction of genes encoding antibacterial peptides as well as proinflammatory molecules. IL-17C was upregulated in colon epithelial cells during infection with Citrobacter rodentium and acted in synergy with IL-22 to induce the expression of antibacterial peptides in colon epithelial cells. Loss of IL-17C-mediated signaling in IL-17RE-deficient mice led to lower expression of genes encoding antibacterial molecules, greater bacterial burden and early mortality during infection. Together our data identify IL-17RE as a receptor of IL-17C that regulates early innate immunity to intestinal pathogens. [ABSTRACT FROM AUTHOR]

Melatonin, a widely known indoleamine molecule that mediates various animal and plant physiological processes, is formed from N-acetyl serotonin via N-acetylserotonin methyltransferase (ASMT). ASMT is an enzyme that catalyzes melatonin synthesis in plants in the rate-determining step and is homologous to hydroxyindole-O-methyltransferase (HIOMT) melatonin synthase in animals. To date, little is known about the effect of HIOMT on salinity in apple plants. Here, we explored the melatonin physiological function in the salinity condition response by heterologous expressing the homologous human HIOMT gene in apple plants. We discovered that the expression of melatonin-related gene (MdASMT) in apple plants was induced by salinity. Most notably, compared with the wild type, three transgenic lines indicated higher melatonin levels, and the heterologous expression of HIOMT enhanced the expression of melatonin synthesis genes. The transgenic lines showed reduced salt damage symptoms, lower relative electrolyte leakage, and less total chlorophyll loss from leaves under salt stress. Meanwhile, through enhanced activity of antioxidant enzymes, transgenic lines decreased the reactive oxygen species accumulation, downregulated the expression of the abscisic acid synthesis gene (MdNCED3), accordingly reducing the accumulation of abscisic acid under salt stress. Both mechanisms regulated morphological changes in the stomata synergistically, thereby mitigating damage to the plants' photosynthetic ability. In addition, transgenic plants also effectively stabilized their ion balance, raised the expression of salt stress–related genes, as well as alleviated osmotic stress through changes in amino acid metabolism. In summary, heterologous expression of HIOMT improved the adaptation of apple leaves to salt stress, primarily by increasing melatonin concentration, maintaining a high photosynthetic capacity, reducing reactive oxygen species accumulation, and maintaining normal ion homeostasis. [ABSTRACT FROM AUTHOR]

China and India have unique traditional medicine systems with vast territory and rich medical resources. Traditional medicines in China include traditional Chinese medicine, Tibetan medicine, Mongolian medicine, Uyghur medicine, Dai medicine, etc. In the third national survey of Chinese medicine resources, 12694 medicinal materials were identified. Traditional medicines in India include Ayurveda, Unani, Siddha, Homoeopathy, etc. There are 7263 medicinal materials in India. To reveal the characteristics of medicinal materials between China and India respectively, and to compare the similarities and differences in terms of properties, tastes, medicinal parts and therapeutic uses and to promote the exchange of traditional medicine between China and India and the international trade of traditional medicine industry. The information of medicinal materials between China and India was extracted from The Chinese Traditional Medicine Resource Records and Pharmacopoeia of the People's Republic of China , as well as from 71 Indian herbal monographs. The information of each medicinal material, such as types, families, genera, properties, distribution, medicinal parts, efficacy, therapeutic uses, dosage form and dosage, was recorded in Excel for statistical analysis and visual comparison. A total of 12694 medicinal materials in China and 5362 medicinal materials in India were identified. The medicinal materials were mostly distributed in Southwest China and northern India. Plants were the main sources of medicinal materials. The common medicinal parts in China were whole medicinal materials, roots and rhizomes, and India used more renewable fruits, seeds and leaves. They are commonly used in the treatment of digestive system diseases. There were 1048 medicinal materials used by both China and India, which were distributed in 188 families and 685 genera. The Chinese and Indian pharmacopoeias had a total of 80 species of medicinal materials used by both China and India. The characteristics of medicinal materials between China and India were somewhat different, which was conducive to provide a reference basis for traditional medicine in China or India to increase the medicinal parts and indications when using a certain medicinal material, as well as to expand the source of medicine and introduce new resources. However, there were certain similarities and shared medicinal materials, which can tap the potential of bilateral trade of medicinal materials between China and India, so as to promote the medical cultural exchange and economic and trade cooperation between the two countries. [Display omitted] [ABSTRACT FROM AUTHOR]

Generating clean, efficient, and low-carbon electricity from coal is imperative for limiting the global temperature rise to 1.5 °C. This study presents a near-zero-carbon-emission power generation system that utilizes staged coal gasification. The innovation of this system is the division of coal gasification into two stages: intermediate-temperature pyrolysis, followed by high-temperature gasification. This process begins with utilizing waste heat from the exhaust of a gas turbine to drive the partial gasification of coal during pyrolysis. The nongaseous products from this stage are then completely gasified in the gasifier, and chemical recuperation is performed, in which heat from the syngas at the gasifier's outlet preheats the reactants at the inlet and aids in reforming pyrolysis gas. For CO 2 capture, an oxyfuel combustion strategy is used. Our system produced net electricity and exergy efficiencies of 43.01 and 47.57 %, respectively, surpassing both pre-combustion CO 2 capture systems based on staged coal gasification (improvements of 3.04 and 5.37 %, respectively) and coal-water slurry gasification (improvements of 3.55 and 5.8 %, respectively). Moreover, the carbon emissions from our system are approximately 90 g/kWh lower than those from these systems. Thus, this study offers an environmentally sustainable approach to utilizing coal that may facilitate achieving global environmental goals. • Proposes a near-zero carbon emission coal-based power generation system. • Bifurcates coal gasification into intermediate-temp pyrolysis and high-temp gasification. • Employs oxyfuel combustion strategy for CO 2 capture. • Utilizes high-temperature sensible heat in syngas through chemical recuperation. • Achieves energy and exergy efficiencies of 43.01 and 47.57 %, both superior to the baseline systems. [ABSTRACT FROM AUTHOR]

The connection between innate and adaptive immunity is best exemplified by antigen presentation. Although antigen-presenting cells (APCs) are required for antigen receptor-mediated T-cell activation, how T-cells feedback to APCs to sustain an antigen-specific immune response is not completely clear. Here we show that CD8+ T-cell (also called cytotoxic T lymphocytes, CTL) feedback activates the NLRP3 inflammasome in APCs in an antigen-dependent manner to promote IL-1β maturation. Perforin from antigen-specific CTLs is required for NLRP3 inflammasome activation in APCs. Furthermore, such activation of NLRP3 inflammasome contributes to the induction of antigen-specific antitumour immunity and pathogenesis of graft-versus-host diseases. Our study reveals a positive feedback loop between antigen-specific CTLs and APC to amplify adaptive immunity. [ABSTRACT FROM AUTHOR]

Concentrations of the secondary bile acid, deoxycholic acid (DCA), are aberrantly elevated in colorectal cancer (CRC) patients, but the consequences remain poorly understood. Here, we screened a library of gut microbiota-derived metabolites and identified DCA as a negative regulator for CD8+ T cell effector function. Mechanistically, DCA suppressed CD8+ T cell responses by targeting plasma membrane Ca2+ ATPase (PMCA) to inhibit Ca2+-nuclear factor of activated T cells (NFAT)2 signaling. In CRC patients, CD8+ T cell effector function negatively correlated with both DCA concentration and expression of a bacterial DCA biosynthetic gene. Bacteria harboring DCA biosynthetic genes suppressed CD8+ T cells effector function and promoted tumor growth in mice. This effect was abolished by disrupting bile acid metabolism via bile acid chelation, genetic ablation of bacterial DCA biosynthetic pathway, or specific bacteriophage. Our study demonstrated causation between microbial DCA metabolism and anti-tumor CD8+ T cell response in CRC, suggesting potential directions for anti-tumor therapy. [Display omitted] • DCA suppresses anti-tumor CD8+ T cell immune responses • DCA diminishes Ca2+-NFAT2 signaling by potentiating PMCA activity • DCA concentration negatively correlates with CD8+ T cell function in CRC patients • Targeting microbial DCA metabolism prevents CRC development in mice Our understanding of the impact of microbial metabolites on anti-tumor immunity is incomplete. Cong et al. show aberrant elevation of the microbiota-derived secondary bile acid, deoxycholic acid, in colorectal cancer patients. Deoxycholic acid suppresses cytotoxic CD8+ T cell effector functions by impairing intracellular calcium accumulation, subsequently promoting colorectal tumor growth. [ABSTRACT FROM AUTHOR]

N -acyl lipids are important mediators of several biological processes including immune function and stress response. To enhance the detection of N -acyl lipids with untargeted mass spectrometry-based metabolomics, we created a reference spectral library retrieving N -acyl lipid patterns from 2,700 public datasets, identifying 851 N -acyl lipids that were detected 356,542 times. 777 are not documented in lipid structural databases, with 18% of these derived from short-chain fatty acids and found in the digestive tract and other organs. Their levels varied with diet, microbial colonization, and in people living with diabetes. We used the library to link microbial N -acyl lipids, including histamine and polyamine conjugates, to HIV status and cognitive impairment. This resource will enhance the annotation of these compounds in future studies to further the understanding of their roles in health and disease and highlight the value of large-scale untargeted metabolomics data for metabolite discovery., Competing Interests: Declaration of interests: PCD: PCD is an advisor and holds equity in Cybele, BileOmix and Sirenas and a Scientific co-founder, advisor and holds equity to Ometa, Enveda, and Arome with prior approval by UC-San Diego. PCD also consulted for DSM animal health in 2023. MW: MW is a co-founder of Ometa Labs LLC. RK: Rob Knight is a scientific advisory board member, and consultant for BiomeSense, Inc., has equity and receives income. He is a scientific advisory board member and has equity in GenCirq. He is a consultant for DayTwo, and receives income. He has equity in and acts as a consultant for Cybele. He is a co-founder of Biota, Inc., and has equity. He is a cofounder of Micronoma, and has equity and is a scientific advisory board member. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.

Commensal microorganisms in the human gut produce numerous metabolites by using small molecules derived from the host or diet as precursors. Host or dietary lipid molecules are involved in energy metabolism and maintaining the structural integrity of cell membranes. Notably, gut microbes can convert these lipids into bioactive signaling molecules through their biotransformation and synthesis pathways. These microbiota-derived lipid metabolites can affect host physiology by influencing the body's immune and metabolic processes. This review aims to summarize recent advances in the microbial transformation and host immunomodulatory functions of these lipid metabolites, with a special focus on fatty acids and steroids produced by our gut microbiota.

Th2 immune response is critical for allergic asthma pathogenesis. Molecular mechanisms for regulating Th2 immunity are still not well understood. Here we report that the ubiquitin-specific protease USP38 is crucial for Th2-mediated allergic asthma. TCR stimulation up-regulated the USP38 level, and USP38 in turn mediated the protein stabilization of JunB, a transcription factor specific for Th2 development. Consequently, USP38 was specifically required for TCR-induced production of Th2 cytokines and Th2 development both in vitro and in vivo, and USP38-deficient mice were resistant to asthma pathogenesis induced by OVA or HDM. Mechanistically, USP38 directly associated with JunB, deubiquitinated Lys-48-linked poly-ubiquitination of JunB, and consequently blocked TCR-induced JunB turnover. USP38 represents the first identified deubiquitinase specifically for Th2 immunity and the associated asthma., (© 2018 Chen et al.)

The connection between innate and adaptive immunity is best exemplified by antigen presentation. Although antigen-presenting cells (APCs) are required for antigen receptor-mediated T-cell activation, how T-cells feedback to APCs to sustain an antigen-specific immune response is not completely clear. Here we show that CD8 + T-cell (also called cytotoxic T lymphocytes, CTL) feedback activates the NLRP3 inflammasome in APCs in an antigen-dependent manner to promote IL-1β maturation. Perforin from antigen-specific CTLs is required for NLRP3 inflammasome activation in APCs. Furthermore, such activation of NLRP3 inflammasome contributes to the induction of antigen-specific antitumour immunity and pathogenesis of graft-versus-host diseases. Our study reveals a positive feedback loop between antigen-specific CTLs and APC to amplify adaptive immunity.

CD4(+) T helper cells are classical but constantly reinterpreted T-cell subset, playing critical roles in a diverse range of inflammatory responses or diseases. Depending on the cytokines they release and the immune responses they mediate, CD4(+) T cells are classically divided into two major cell populations: Th1 and Th2 cells. However, recent studies challenged this Th1/Th2 paradigm by discovering several T-helper cell subsets with specific differentiation program and functions, including Th17 cells, Treg cells, and Tfh cells. In this chapter, we summarize the current understanding and recent progresses on the Th17 lineage differentiation and its effector impacts on variety of inflammatory responses or disease pathogenesis.

Interleukin 17 (IL-17) plays critical roles in the pathogenesis of various autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE). How the signals triggered by this powerful inflammatory cytokine are controlled to avoid abnormal inflammatory responses is not well understood. In this study, we report that TRAF3 is a receptor proximal negative regulator of IL-17 receptor (IL-17R) signaling. TRAF3 greatly suppressed IL-17-induced NF-κB and mitogen-activated protein kinase activation and subsequent production of inflammatory cytokines and chemokines. Mechanistically, the binding of TRAF3 to IL-17R interfered with the formation of the receptor signaling activation complex IL-17R-Act1-TRAF6, resulting in suppression of downstream signaling. TRAF3 markedly inhibited IL-17-induced expression of inflammatory cytokine and chemokine genes in vivo and consequently delayed the onset and greatly reduced the incidence and severity of EAE. Thus, TRAF3 is a negative regulator of IL-17R proximal signaling.