IRF8 Regulates Transcription of Naips for NLRC4 Inflammasome Activation.

Inflammasome activation is critical for host defenses against various microbial infections. Activation of the NLRC4 inflammasome requires detection of flagellin or type III secretion system (T3SS) components by NLR family apoptosis inhibitory proteins (NAIPs); yet how this pathway is regulated is unknown. Here, we found that interferon regulatory factor 8 (IRF8) is required for optimal activation of the NLRC4 inflammasome in bone-marrow-derived macrophages infected with Salmonella Typhimurium, Burkholderia thailandensis, or Pseudomonas aeruginosa but is dispensable for activation of the canonical and non-canonical NLRP3, AIM2, and Pyrin inflammasomes. IRF8 governs the transcription of Naips to allow detection of flagellin or T3SS proteins to mediate NLRC4 inflammasome activation. Furthermore, we found that IRF8 confers protection against bacterial infection in vivo, owing to its role in inflammasome-dependent cytokine production and pyroptosis. Altogether, our findings suggest that IRF8 is a critical regulator of NAIPs and NLRC4 inflammasome activation for defense against bacterial infection.

IRGB10 Liberates Bacterial Ligands for Sensing by the AIM2 and Caspase-11-NLRP3 Inflammasomes.

The inflammasome is an intracellular signaling complex, which on recognition of pathogens and physiological aberration, drives activation of caspase-1, pyroptosis, and the release of the pro-inflammatory cytokines IL-1ß and IL-18. Bacterial ligands must secure entry into the cytoplasm to activate inflammasomes; however, the mechanisms by which concealed ligands are liberated in the cytoplasm have remained unclear. Here, we showed that the interferon-inducible protein IRGB10 is essential for activation of the DNA-sensing AIM2 inflammasome by Francisella novicida and contributed to the activation of the LPS-sensing caspase-11 and NLRP3 inflammasome by Gram-negative bacteria. IRGB10 directly targeted cytoplasmic bacteria through a mechanism requiring guanylate-binding proteins. Localization of IRGB10 to the bacterial cell membrane compromised bacterial structural integrity and mediated cytosolic release of ligands for recognition by inflammasome sensors. Overall, our results reveal IRGB10 as part of a conserved signaling hub at the interface between cell-autonomous immunity and innate immune sensing pathways.

Critical Role for the DNA Sensor AIM2 in Stem Cell Proliferation and Cancer.

Colorectal cancer is a leading cause of cancer-related deaths. Mutations in the innate immune sensor AIM2 are frequently identified in patients with colorectal cancer, but how AIM2 modulates colonic tumorigenesis is unknown. Here, we found that Aim2-deficient mice were hypersusceptible to colonic tumor development. Production of inflammasome-associated cytokines and other inflammatory mediators was largely intact in Aim2-deficient mice; however, intestinal stem cells were prone to uncontrolled proliferation. Aberrant Wnt signaling expanded a population of tumor-initiating stem cells in the absence of AIM2. Susceptibility of Aim2-deficient mice to colorectal tumorigenesis was enhanced by a dysbiotic gut microbiota, which was reduced by reciprocal exchange of gut microbiota with healthy wild-type mice. These findings uncover a synergy between a specific host genetic factor and gut microbiota in determining the susceptibility to colorectal cancer. Therapeutic modulation of AIM2 expression and microbiota has the potential to prevent colorectal cancer.

FISI: frequency domain integration sequential imaging at 1.26×1013 frames per second and 108 lines per millimeter.

High spatial resolution on the image plane (intrinsic spatial resolution) has always been a problem for ultrafast imaging. Single-shot ultrafast imaging methods can achieve high spatial resolution on the object plane through amplification systems but with low intrinsic spatial resolutions. We present frequency domain integration sequential imaging (FISI), which encodes a transient dynamic by an inversed 4f (IFF) system and decodes it using optical spatial frequencies recognition (OFR), which overcomes the limitation of the spatial frequencies recognition algorithm. In an experiment on the process of an air plasma channel, FISI achieved shadow imaging of the channel with a framing rate of 1.26×1013 fps and an intrinsic spatial resolution of 108 lp/mm (the spatial resolution on the image plane). Owing to its excellent framing time and high intrinsic spatial resolution, FISI can probe both repeatable and unrepeatable ultrafast phenomena, such as laser-induced damage, plasma physics, and shockwave interactions in living cells with high quality.

NLRC3 is an inhibitory sensor of PI3K-mTOR pathways in cancer.

NLRs (nucleotide-binding domain and leucine-rich repeats) belong to a large family of cytoplasmic sensors that regulate an extraordinarily diverse range of biological functions. One of these functions is to contribute to immunity against infectious diseases, but dysregulation of their functional activity leads to the development of inflammatory and autoimmune diseases. Cytoplasmic innate immune sensors, including NLRs, are central regulators of intestinal homeostasis. NLRC3 (also known as CLR16.2 or NOD3) is a poorly characterized member of the NLR family and was identified in a genomic screen for genes encoding proteins bearing leucine-rich repeats (LRRs) and nucleotide-binding domains. Expression of NLRC3 is drastically reduced in the tumour tissue of patients with colorectal cancer compared to healthy tissues, highlighting an undefined potential function for this sensor in the development of cancer. Here we show that mice lacking NLRC3 are hyper-susceptible to colitis and colorectal tumorigenesis. The effect of NLRC3 is most dominant in enterocytes, in which it suppresses activation of the mTOR signalling pathways and inhibits cellular proliferation and stem-cell-derived organoid formation. NLRC3 associates with PI3Ks and blocks activation of the PI3K-dependent kinase AKT following binding of growth factor receptors or Toll-like receptor 4. These findings reveal a key role for NLRC3 as an inhibitor of the mTOR pathways, mediating protection against colorectal cancer.

All-optical high spatial-temporal resolution photography with raster principle at 2 trillion frames per second.

A novel single-shot ultrafast all-optical photography with raster principle (OPR) that can capture real-time imaging of ultrafast phenomena is proposed and demonstrated. It consists of a sequentially timed module (STM), spectral-shaping module (SSM), and raster framing camera (RFC). STM and SSM are used for linearly encoding frequency-time mapping and system calibration, respectively. The function of the RFC is sampling the target by microlens arrays and framing on the basis of frequency-time-spatial positions conversion. We demonstrated the recording of transient scenes with the spatial resolution of ∼90lp/mm, the frame number of 12 and the frame rate of 2 trillion frames per second (Tfps) in single-shot. Thanks to its high spatial-temporal resolution, high frame rate (maximum up to 10 Tfps or more) and sufficient frame number, our OPR can observe the dynamic processes with complex spatial structure at the atomic time scale (10 fs∼1ps), which is promising for application in plasma physics, shock waves in laser-induced damage, and dynamics of condensed matter materials.

Localized modes and dark solitons sustained by nonlinear defects.

Dark solitons and localized defect modes against periodic backgrounds are considered in arrays of waveguides with defocusing Kerr nonlinearity, constituting a nonlinear lattice. Bright defect modes are supported by a local increase in nonlinearity, while dark defect modes are supported by a local decrease in nonlinearity. Dark solitons exist for both types of defects, although in the case of weak nonlinearity, they feature side bright humps, making the total energy propagating through the system larger than the energy transferred by the constant background. All considered defect modes are found stable. Dark solitons are characterized by relatively narrow windows of stability. Interactions of unstable dark solitons with bright and dark modes are described.

Gasdermin D Promotes AIM2 Inflammasome Activation and Is Required for Host Protection against Francisella novicida.

The DNA sensor absent in melanoma 2 (AIM2) forms an inflammasome complex with ASC and caspase-1 in response to Francisella tularensis subspecies novicida infection, leading to maturation of IL-1ß and IL-18 and pyroptosis. AIM2 is critical for host protection against F. novicida infection in vivo; however, the role of pyroptosis downstream of the AIM2 inflammasome is unknown. Recent studies have identified gasdermin D (GSDMD) as the molecule executing pyroptosis by forming pores on the plasma membrane following activation by inflammatory caspase-1 and -11. In this study, we report that GSDMD-deficient mice were susceptible to F. novicida infection compared with wild type mice. Interestingly, we observed that GSDMD is required for optimal caspase-1 activation and pyroptotic cell death in F. novicida-infected bone marrow-derived macrophages. Furthermore, caspase-1 activation was compromised in bone marrow-derived macrophages lacking GSDMD stimulated with other AIM2 inflammasome triggers, including poly(dA:dT) transfection and mouse CMV infection. Overall, our study highlights a function, to our knowledge previously unknown, for GSDMD in promoting caspase-1 activation by AIM2 inflammasome.

Cutting Edge: Distinct Regulatory Mechanisms Control Proinflammatory Cytokines IL-18 and IL-1ß.

Interleukin-18 and IL-1ß, which are cytokines of the IL-1 family, are synthesized as precursor proteins and activated by the inflammasome via proteolytic processing. IL-1ß is only induced in response to inflammatory stimuli, but IL-18 is constitutively expressed. However, how IL-18 and IL-1ß expression is regulated by different inflammatory signals remains poorly studied. In this study, we found that IL-18 and IL-1ß are differentially regulated. Despite being constitutively expressed, IL-18 expression was increased and sustained after stimulation of TLRs. In contrast, IL-1ß was induced but not sustained after chronic treatment. Furthermore, type I IFN signaling was essential for induction of IL-18 and macrophages lacking type I IFN signaling were impaired in their ability to promote IL-18 induction. Thus, our findings reveal a fundamental difference in IL-18 and IL-1ß regulation and uncover novel mechanisms that are relevant to the inflammatory settings where these proinflammatory cytokines play a critical role.

[Long-term prognosis of vesicoureteral reflux: a follow-up observation of 138 children].

OBJECTIVE: To study the long-term prognosis of vesicoureteral reflux in children. METHODS: A retrospective analysis was performed for the clinical data of 138 children (218 ureters with reflux) who were diagnosed with vesicoureteral reflux for the first time from November 2005 to March 2017 and received medical treatment and regular follow-up. According to the initial grade of reflux, the ureters with reflux were divided into a low-grade group (141 ureters, grade I-III) and a high-grade group (77 ureters, grade IV-V), and the two groups were compared in terms of clinical data and follow-up results. RESULTS: Among the 138 children, there were 82 boys and 56 girls. Their age ranged from 31 days to 10 years at the time of confirmed diagnosis, with a median age of 8 months. The follow-up time ranged from 8 months to 7 years, with a median follow-up time of 1.4 years. At the time of confirmed diagnosis, the high-grade group had significantly higher levels of urinary N-acetyl-ß-D-glucosaminidase, urinary microalbumin and urinary immunoglobulin G than the low-grade group (P<0.05). Among the 218 ureters with reflux, 132 (60.6%) achieved a reduction in the grade of reflux (among which 74 achieved complete disappearance of reflux), 43 had no change in the grade of reflux, and 43 had an increase in the grade of reflux. Compared with the high-grade group, the low-grade group had a significantly higher complete remission rate (41.1% vs 19.5%, P=0.001) and a significantly shorter time to complete remission of reflux (P=0.002). CONCLUSIONS: Most children with vesicoureteral reflux can achieve a reduction in the grade of reflux or even complete disappearance of reflux during follow-up, and the children with low-grade reflux have better prognosis than those with high-grade reflux.

Cutting edge: STING mediates protection against colorectal tumorigenesis by governing the magnitude of intestinal inflammation.

Stimulator of IFN genes (STING) is a cytoplasmic innate immune sensor for cyclic dinucleotides that also serves a dual role as an adaptor molecule for a number of intracellular DNA receptors. Although STING has important functions in the host defense against pathogens and autoimmune diseases, its physiological role in cancer is unknown. In this study, we show that STING-deficient mice are highly susceptible to colitis-associated colorectal cancer. Colons of STING-deficient mice exhibit significant intestinal damage and overt proliferation during early stages of tumorigenesis. Moreover, STING-deficient mice fail to restrict activation of the NF-κB- and STAT3-signaling pathways, which leads to increased levels of the proinflammatory cytokines IL-6 and KC. Therefore, our results identified an unexpected and important role for STING in mediating protection against colorectal tumorigenesis.

Clinicopathological features of kidney injury in patients receiving immune checkpoint inhibitors (ICPi) combined with anti-vascular endothelial growth factor (anti-VEGF) therapy.

BACKGROUND: Immune checkpoint inhibitor (ICPi) combined with anti-vascular endothelial growth factor (VEGF) therapy has increasingly become a promising strategy in various malignancies. However, the combination might be associated with increased risk of nephrotoxicity. METHODS: We retrospectively recruited patients who suffered kidney injury and received renal biopsy after anti-VEGF/ICPi mono- or combination therapy and divided them into three groups: anti-VEGF monotherapy, ICPi monotherapy and combination therapy. Clinical and histopathological features of three groups were analysed. All patients were followed-up for 3 months after biopsy, with or without glucocorticoid treatment, and renal outcome were compared. RESULTS: A total of 46 patients were enrolled. Eighteen patients received anti-VEGF monotherapy, 12 received ICPi monotherapy and 16 received combined treatment of anti-VEGF and ICPi. Proteinuria level of anti-VEGF group, ICPi group and combination group were 4.07±3.17 g/day, 0.60±0.61 g/day and 2.05±2.50 g/day, respectively (p=0.002). The peak serum creatinine level of combination group (1.75±0.77 mg/dL) was also in between ICPi group (2.79±0.90 mg/dL) and anti-VEGF group (1.34±0.60 mg/dL) (p<0.001). Multiple histopathological patterns involving glomerulus, tubulointerstitium and vessel existed in the majority of cases in combination group (68.8%). Renal complete and partial recovery rate of combination therapy were also in between monotherapy (57.1% vs 40.0% in anti-VEGF group, 100.0% in ICPi group, respectively). CONCLUSIONS: Kidney injury in patients treated with combination therapy of ICPi and anti-VEGF shows hybrid pathological patterns and intermediate clinical features compared with monotherapy. Cohorts with larger sample and better design, as well as basic research, are needed to elucidate the mechanism of 'protection' effect of combination anti-cancer therapy to renal function.

Small RNAs: An expanding world with therapeutic promises.

Small non-coding RNAs (sncRNAs), such as microRNAs (miRNAs), small interfering RNAs (siRNAs), PIWI-interacting RNAs (piRNAs), and transfer RNA (tRNA)-derived small RNAs (tsRNAs), play essential roles in regulating various cellular and developmental processes. Over the past three decades, researchers have identified novel sncRNA species from various organisms. These molecules demonstrate dynamic expression and diverse functions, and they are subject to intricate regulation through RNA modifications in both healthy and diseased states. Notably, certain sncRNAs in gametes, particularly sperm, respond to environmental stimuli and facilitate epigenetic inheritance. Collectively, the in-depth understanding of sncRNA functions and mechanisms has accelerated the development of small RNA-based therapeutics. In this review, we present the recent advances in the field, including new sncRNA species and the regulatory influences of RNA modifications. We also discuss the current limitations and challenges associated with using small RNAs as either biomarkers or therapeutic drugs.

Strain-induced recognition of molecular and chirality in cholesteric liquid crystal droplets for distance and curvature sensing.

Chirality is universal in nature and in biological systems, and the chirality of cholesteric liquid crystals (Ch-LC) is both controllable and quantifiable. Herein, a strategy for precise chirality recognition in a nematic LC host within soft microscale confined droplets is reported. This approach facilitates applications in distance and curvature sensing as well as on-site characterization of the overall uniformity and bending movements of a flexible device. Due to interfacial parallel anchoring, monodisperse Ch-LC spherical microdroplets show radial spherical structure (RSS) rings with a central radical point-defect hedgehog core. Strain-induced droplet deformation destabilizes the RSS configuration and induces the recognition of chirality, creating "core-shell" structures with distinguishable sizes and colors. In practice, an optical sensor is achieved due to the rich palette of optically active structures that can be utilized for gap distance measuring and the monitoring of curvature bending. The properties reported here and the constructed device have great potential for applications in soft robotics, wearable sensors, and advanced optoelectronic devices.

Epithelial dysfunction is prevented by IL-22 treatment in a Citrobacter rodentium-induced colitis model that shares similarities with inflammatory bowel disease.

Inflammatory bowel disease (IBD) is characterized by a dysregulated intestinal epithelial barrier leading to breach of barrier immunity. Here we identified similar protein expression changes between IBD and Citrobacter rodentium-infected FVB mice with respect to dysregulation of solute transporters as well as components critical for intestinal barrier integrity. We attribute the disease associated changes in the model to the emergence of undifferentiated intermediate intestinal epithelial cells. Prophylactic treatment with IL-22.Fc in C. rodentium-infected FVB mice reduced disease severity and rescued the mice from lethality. Multi-omics and solute analyses revealed that IL-22.Fc treatment prevented disease-associated changes including disruption of the solute transporter machinery and restored proper physiological functions of the intestine, respectively. Taken together, we established the disease relevance of the C. rodentium-induced colitis model to IBD, demonstrated the protective role of IL-22 in amelioration of epithelial dysfunction and elucidated the molecular mechanisms with IL-22's effect on intestinal epithelial cells.

Small Noncoding RNAs in Reproduction and Infertility.

Infertility has been reported as one of the most common reproductive impairments, affecting nearly one in six couples worldwide. A large proportion of infertility cases are diagnosed as idiopathic, signifying a deficit in information surrounding the pathology of infertility and necessity of medical intervention such as assisted reproductive therapy. Small noncoding RNAs (sncRNAs) are well-established regulators of mammalian reproduction. Advanced technologies have revealed the dynamic expression and diverse functions of sncRNAs during mammalian germ cell development. Mounting evidence indicates sncRNAs in sperm, especially microRNAs (miRNAs) and transfer RNA (tRNA)-derived small RNAs (tsRNAs), are sensitive to environmental changes and mediate the inheritance of paternally acquired metabolic and mental traits. Here, we review the critical roles of sncRNAs in mammalian germ cell development. Furthermore, we highlight the functions of sperm-borne sncRNAs in epigenetic inheritance. We also discuss evidence supporting sncRNAs as promising biomarkers for fertility and embryo quality in addition to the present limitations of using sncRNAs for infertility diagnosis and treatment.

Soft-hard hybrid covalent-network polymer sponges with super resilience, recoverable energy dissipation and fatigue resistance under large deformation.

Energy absorption or dissipation ability has been widely developed in tough hydrogels and 3D nano-structured sponges for a variety of applications. However, fully recoverable energy dissipation and fatigue resistance under large deformation is still challenging yet highly desirable. Polymer network with homogeneous chemical crosslinking structures is an efficient way to construct hydrogels with high resilience and fatigue resistance. Unfortunately, such polymer network usually has poor energy dissipation capability. In this paper, we propose a new approach to build the ability of fully recoverable energy dissipation into covalent-crosslink polymer network by integrating soft and hard chains in a uniform crosslinking network and present the one-pot synthesis method for constructing corresponding polymer sponges by low-temperature phase-separation photopolymerization. The application of such polymer sponges as a tissue engineering scaffold, fabricated by using cyclic acetal units and PEG based monomers in particular is demonstrated. For the first time, we show the feasibility of building a synthetic scaffold with the characteristics of high porosity, super compressibility and resilience, fast recovery, completely recoverable energy dissipation, high fatigue resistance, biodegradability and biocompatibility. Such a scaffold is promising in tissue engineering especially in load-bearing applications.

A new species of Diplolepis Geoffroy (Hymenoptera: Cynipidae: Diplolepidini) from northeastern China.

A new species, Diplolepis valtonyci Zhu, Wang Pujade-Villar sp. nova, is described from Rosa rugosa Thunb. (1784) and R. davurica Pall. (1788) from China using an integrative approach based on molecular and morphological data. Diagnosis, distribution, and biology of the new species are given and illustrated. The phylogenetic relationship between D. valtonyci sp. nova and other Diplolepis species are assessed based on COI and Cytb genes. A key to the Chinese species of Diplolepis is provided.

Specification and epigenomic resetting of the pig germline exhibit conservation with the human lineage.

Investigations of the human germline and programming are challenging because of limited access to embryonic material. However, the pig as a model may provide insights into transcriptional network and epigenetic reprogramming applicable to both species. Here we show that, during the pre- and early migratory stages, pig primordial germ cells (PGCs) initiate large-scale epigenomic reprogramming, including DNA demethylation involving TET-mediated hydroxylation and, potentially, base excision repair (BER). There is also macroH2A1 depletion and increased H3K27me3 as well as X chromosome reactivation (XCR) in females. Concomitantly, there is dampening of glycolytic metabolism genes and re-expression of some pluripotency genes like those in preimplantation embryos. We identified evolutionarily young transposable elements and gene coding regions resistant to DNA demethylation in acutely hypomethylated gonadal PGCs, with potential for transgenerational epigenetic inheritance. Detailed insights into the pig germline will likely contribute significantly to advances in human germline biology, including in vitro gametogenesis.

Janus Nanoparticles with Tunable Amphiphilicity for Stabilizing Pickering-Emulsion Droplets via Assembly Behavior at Oil-Water Interfaces.

Janus particles (JNPs) with controlled anisotropies are regarded as promising materials for sophisticated building blocks and assembly. Herein a straightforward method was proposed for the synthesis of uniformly distributed JNPs with controllable anisotropies, showing two compartmental bulbs with different surface wettability. The synthetic strategy is based on the phase separation-induced styrene liquid protrusion on seed poly(styrene-co-acrylic acid) (CPSAA) nanoparticles via controlled swelling, with the formed polystyrene (PS) and CPSAA compartments corresponding to the amount of monomers. The size (lateral length) ratio of formed PS and CPSAA bulbs, DPS/DCPSAA, defined as "Janusity", has been precisely tuned in the range of 0-0.91 by controlling the mass ratio of two monomers. Obtained JNPs with tunable amphiphilicity are utilized as colloid surfactants to prepare Pickering-emulsions of both water-in-oil (W/O) and oil-in-water (O/W) with proper Janusity. The stability of achieved W/O and O/W Pickering-emulsions is dependent on the adhesion energy of a JNP at the water-oil interfaces. Prepared JNPs have also being utilized to prepare and stabilize monodisperse droplets in microfluidic devices, demonstrating their high potential for fundamental research and practical applications.