Tunable nonreciprocal metasurfaces based on a nonlinear quasi-bound state in the continuum.

Nonreciprocal devices are essential and crucial in optics for source protection and signal separation. A hybrid grating system consisting of a silicon grating, a graphene layer, and a silicon waveguide layer is employed to create a high-Q quasi-BIC (bound state in the continuum). Then, the high-Q properties of the quasi-BIC are harnessed to enhance the third-order nonlinear effect of silicon, thereby improving the nonreciprocal characteristics of the device. The nonreciprocal transmittance ratio of the device can be tunable by adjusting the graphene Fermi energy level, achieving tunability ranging from 0.0865 to 30.57 dB. It also enables the best performance of the device over a wider range of frequency bands. This study provides a new, to the best of our knowledge, method for designing tunable nonreciprocal devices with a wide range of potential applications.

Enterococcus-derived tyramine hijacks α2A-adrenergic receptor in intestinal stem cells to exacerbate colitis.

Inflammatory bowel disease (IBD) is characterized by dysbiosis of the gut microbiota and dysfunction of intestinal stem cells (ISCs). However, the direct interactions between IBD microbial factors and ISCs are undescribed. Here, we identify α2A-adrenergic receptor (ADRA2A) as a highly expressed GPCR in ISCs. Through PRESTO-Tango screening, we demonstrate that tyramine, primarily produced by Enterococcus via tyrosine decarboxylase (tyrDC), serves as a microbial ligand for ADRA2A. Using an engineered tyrDC-deficient Enterococcus faecalis strain and intestinal epithelial cell-specific Adra2a knockout mice, we show that Enterococcus-derived tyramine suppresses ISC proliferation, thereby impairing epithelial regeneration and exacerbating DSS-induced colitis through ADRA2A. Importantly, blocking the axis with an ADRA2A antagonist, yohimbine, disrupts tyramine-mediated suppression on ISCs and alleviates colitis. Our findings highlight a microbial ligand-GPCR pair in ISCs, revealing a causal link between microbial regulation of ISCs and colitis exacerbation and yielding a targeted therapeutic approach to restore ISC function in colitis.

Novel adaptive activated sludge process leverages flow fluctuations for simultaneous nitrification and denitrification in rural sewage treatment.

The fluctuating characteristics of rural sewage flow pose a significant challenge for wastewater treatment plants, leading to poor effluent quality. This study establishes a novel adaptive activated sludge (AAS) process specifically designed to address this challenge. By dynamically adjusting to fluctuating water flow in situ, the AAS maintains system stability and promotes efficient pollutant removal. The core strategy of AAS leverages the inherent dissolved oxygen (DO) variations caused by flow fluctuations to establish an alternating anoxic-aerobic environment within the system. This alternating operation mode fosters the growth of aerobic denitrifiers, enabling the simultaneous nitrification and denitrification (SND) process. Over a 284-day operational period, the AAS achieved consistently high removal efficiencies, reaching 94 % for COD and 62.8 % for TN. Metagenomics sequencing revealed HN-AD bacteria as the dominant population, with the characteristic nap gene exhibiting a high relative abundance of 0.008 %, 0.010 %, 0.014 %, and 0.015 % in the anaerobic, anoxic, dynamic, and oxic zones, respectively. Overall, the AAS process demonstrates efficient pollutant removal and low-carbon treatment of rural sewage by transforming the disadvantage of flow fluctuation into an advantage for robust DO regulation. Thus, AAS offers a promising model for SND in rural sewage treatment.

AEP promotes aberrant RNA splicing through DDX3X cleavage in solid tumors.

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 HIF1A-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.

Nitrogen removal efficiency and mechanisms of an improved anaerobic-anoxic-oxic system for decentralized sewage treatment.

The unstable operation and poor effluent quality often associated with decentralized sewage treatment systems due to fluctuating water flows have garnered significant attention. In this study, a novel integrated process combining anoxic denitrification and simultaneous nitrification and denitrification was developed to address these challenges. The improved anaerobic-anoxic-aerobic system achieved average effluent concentrations of 20.83 mg/L and 4.63 mg/L for chemical oxygen demand and NH4+-N, with average removal rates of 91 % and 68 %, respectively. Moreover, the aerobic zone demonstrated an impressive efficiency of 40.8 % for simultaneous nitrification and denitrification. The key bacteria groups driving the system's performance were heterotrophic and aerobic nitrifying bacteria, which dominated the microbial populations. Overall, the system optimizes the traditional anaerobic-anoxic-aerobic process, providing an effective solution for fluctuating wastewater flows. It establishes a successful coexistence model for multiple microbial populations, highlighting its applicability for superior nitrogen removal performance, and reference for optimizing rural sewage treatment. TAKE HOME MESSAGE SENTENCE: The improved anaerobic-anoxic-aerobic system for fluctuating wastewater treatment has superior nitrogen removal performance depending on multiple microbial populations.

A novel carbon emission evaluation model for anaerobic-anoxic-oxic urban sewage treatment.

The proposal of the dual carbon goal and the blue economy in China has sparked a keen interest in carbon emissions reduction from sewage treatment. Carbon accounting in urban sewage plants serves as the foundation for carbon emission reduction in sewage treatment. This paper re-evaluated carbon accounting in the operational processes for urban sewage treatment plants to develop a novel carbon emission evaluation model for anaerobic-anoxic-oxic treatment plants. The results show that the carbon emissions generated by non-carbon dioxide gases far exceed the carbon emissions from carbon dioxide alone. Moreover, the recycling of sewage leads to carbon emissions reduction that offsets the carbon emissions generated during the operation of the sewage plant. Also, the carbon emissions generated by sewage treatment plants are lower than those generated by untreated sewage. The findings and insights provided in this paper provide valuable references for carbon accounting and the implementation of low-carbon practices in urban sewage treatment plants.

The effect of stabilized culture of Lactobacillus rhamnosus GCC-3 on gut and liver health, and anti-viral immunity of zebrafish.

Probiotics are promising antibiotics alternatives to improve growth and disease resistance of cultured fish. Our study aimed to investigate the effect of dietary stabilized culture of Lactobacillus rhamnosus GCC-3 on growth performance, gut and liver health and anti-viral ability of zebrafish (Danio rerio). Zebrafish (0.161 ± 0.001 g) were fed control and the experimental diet containing 1% GCC-3 culture (1 × 107 CFU/g diet) for four weeks. Growth performance and gut and liver health parameters were monitored after four weeks feeding. The gut microbiota was analyzed by 16S rRNA gene sequencing. In another experiment, zebrafish (0.212 ± 0.001 g) were fed with basal or GCC-3 diets and challenged by spring viremia of carp virus (SVCV) at the end of feeding. The antiviral immune response was evaluated at 2nd and 4th days post SVCV infection and survival rate was calculated 14 days after challenge. The results showed that adding 1% GCC-3 significantly improved growth performance of zebrafish (P < 0.05). The intestinal expression of hypoxia-inducible factor Hif-1α, tight junction protein ZO-1α and ZO-1ß was significantly up-regulated in 1% GCC-3 group compared with control (P < 0.05). Besides, 1% GCC-3 decreased the content of MDA and increased total antioxidant capacity in the intestine, and the relative expression of SOD, GST and Gpxa was improved. The abundance of Proteobacteria was reduced while Firmicutes was enriched in the intestinal microbiota of 1% GCC-3 group compared with control (P < 0.05). Zebrafish fed 1% GCC-3 showed higher survival rate after SVCV challenge. Accordingly, the expression of antiviral genes in the spleen was increased at 2nd and 4th days post infection. In conclusion, our results indicate that dietary 1% GCC-3 supplementation can improve gut and liver health as well as antiviral immunity of zebrafish.

Evaluation of toxicity and biocompatibility of a novel Mg-Nd-Gd-Sr alloy in the osteoblastic cell.

BACKGROUND: We investigated the toxicity and biocompatibility of a novel Mg-3Nd-1Gd-0.3Sr-0.2Zn-0.4Zr (abbreviated to Mg-Nd-Gd-Sr) alloy in the osteoblastic cell line MC3T3-E1 as osteoblasts play an important role in bone repair and remodeling. METHODS: We used cytotoxicity tests and apoptosis to investigate the effects of the Mg-Nd-Gd-Sr alloy on osteoblastic cells. Cell bioactivity, cell adhesion, cell proliferation, mineralization, ALP activity, and expression of BMP-2 and OPG by osteoblastic cells were also used to investigate the biocompatibility of Mg-Nd-Gd-Sr alloy. RESULTS: The results showed that the Mg-Nd-Gd-Sr alloy had no obvious cytotoxicity, and did not induce apoptosis to MC3T3-E1 cells. Compared with the control group, the number of adherent cells within 12 h was increased significantly in each experimental group (P < 0.05); the OD value of MC3T3-E1 cells was increased significantly in each experimental group on days 1 and 3 of culture (P < 0.05); the number of mineralized nodules formed in each experimental group was significantly increased (P < 0.05), and ALP activity was significantly increased in each experimental group (P < 0.05). RT-PCR results showed that the mRNA expression of BMP-2 and OPG was significantly higher in each experimental group compared with the control group (P < 0.05). Western blotting showed that the Mg-Nd-Gd-Sr alloy extract significantly increased the protein expression of BMP-2 and OPG compared with the control group (P < 0.05). CONCLUSIONS: Our data indicated that the novel Mg-Nd-Gd-Sr-Zn-Zr alloy had no obvious cytotoxic effects, and did not cause apoptosis to MC3T3-E1 cells; meanwhile it promoted cell adhesion, cell proliferation, mineralization, and ALP activity of osteoblasts. During this process, there was an increase in the expressions of BMP-2 and OPG mRNAs and proteins.

Effect of symmetry breaking on multi-plasmon-induced transparency based on single-layer graphene metamaterials with strips and rings.

A single-layer graphene metamaterial consisting of a horizontal graphene strip, four vertical graphene strips, and two graphene rings is proposed to realize tunable multi-plasma-induced transparency (MPIT) by the coupled mode theory and the finite-difference time-domain method. A switch with three modulation modes is realized by dynamically adjusting the Fermi level of graphene. Moreover, the effect of symmetry breaking on MPIT is investigated by controlling the geometric parameters of graphene metamaterials. Triple-PIT, dual-PIT, single-PIT can be transformed into each other. The proposed structure and results provide guidance for applications such as designing photoelectric switches and modulators.

Acceptable risk assessment and management of environmental pollution emergency events base on distance model.

Existing environmental management regulations and assessment methods can help understand and relieve pollution problems greatly affecting the natural world. However, what is lacking is awareness and targeted recommendations for environmental pollution emergency events (EPEEs). Here we analyzed a total of 2164 EPEEs in China from 2000 to 2021 in terms of annual variations, spatial distributions, phases of regional development, and pollution sources. The findings showed that regional economies can have significant impacts on the occurrence of EPEEs. Regarding the four causes of pollution, the contribution from industrial sources was above 80 %, especially water pollution events, for which it accounted for 84 %. The probability of pollution events specifically relates to regional GDP and it was highest in those provinces with the highest GDP rankings, albeit there were marked differences in the industrial structure. In order to better manage EPEEs, an Environment-Emergency Distance Model (EEDM) is proposed. This model uses the Multidimensional psychological distance to quantitatively evaluate the acceptable public risk level after the occurrence of EPEEs. This method provides a basis for pollution prevention and remediation by visualizing the risk acceptable for the public and provides guidance for sustainable environmental development.

THz broadband and dual-channel perfect absorbers based on patterned graphene and vanadium dioxide metamaterials.

This paper proposes a novel and perfect absorber based on patterned graphene and vanadium dioxide hybrid metamaterial, which can not only achieve wide-band perfect absorption and dual-channel absorption in the terahertz band, but also realize their conversion by adjusting the temperature to control the metallic or insulating phase of VO2. Firstly, the absorption spectrum of the proposed structure is analyzed without graphene, where the absorption can reach as high as 100% at one frequency point (f = 5.956 THz) when VO2 is in the metal phase. What merits attention is that the addition of graphene above the structure enhances the almost 100% absorption from one frequency point (f = 5.956 THz) to a wide frequency band, in which the broadband width records 1.683 THz. Secondly, when VO2 is the insulating phase, the absorption of the metamaterial structure with graphene outperforms better, and two high absorption peaks are formed, logging 100% and 90.7% at f3 = 5.545 THz and f4 = 7.684 THz, respectively. Lastly, the adjustment of the Fermi level of graphene from 0.8 eV to 1.1 eV incurs an obvious blueshift of the absorption spectra, where an asynchronous optical switch can be achieved at fK1 = 5.782 THz and fK2 = 6.898 THz. Besides, the absorber exhibits polarization sensitivity at f3 = 5.545 THz, and polarization insensitivity at f4 = 7.684 THz with the shift in the polarization angle of incident light from 0° to 90°. Accordingly, this paper gives insights into the new method that increases the high absorption width, as well as the great potential in the multifunctional modulator.

Partially replacing dietary fish meal by Saccharomyces cerevisiae culture improve growth performance, immunity, disease resistance, composition and function of intestinal microbiota in channel catfish (Ictalurus punctatus).

The aim of the present study was to investigate the partial replacement of fish meal by Saccharomyces cerevisiae culture on growth performance, immunity, composition and function of intestinal microbiota and disease resistance in channel catfish (Ictalurus punctatus). Two equal nitrogen and energy diets were prepared including a basal diet (containing 10% fish meal, Control) and an experimental diet (replacing 20% of the fish meal of the basal diet with yeast culture, RFM). Channel catfish were fed with the diets for 12 weeks. The results showed that weight gain and condition factor were significantly increased, and FCR was significantly decreased in RFM group (P < 0.05). The gene expression of intestinal HIF1α was significantly increased in RFM group (P < 0.05), while the expressions of NF-κB in the intestine and liver were significantly decreased (P < 0.05). The relative abundance of Firmicutes tended to increase, and the Turicibacter had an upward trend (0.05 < P < 0.2). In addition, the survival rate of channel catfish was significantly increased in RFM group after challenged with Aeromonas veronii Hm091 and Aeromonas hydrophila NJ-1 (P < 0.05). Compared with intestinal microbiota of channel catfish of control group, intestinal microbiota of channel catfish of RFM group significantly increased the expression of HIF1α, and decreased the expression of IL-1ß and TNF-α (P < 0.05) in germ-free zebrafish. Intestinal microbiota induced by RFM diet also significantly increased disease resistance to Aeromonas veronii Hm091 and Aeromonas hydrophila NJ-1. In conclusion, replacement of fish meal by the yeast culture improved the growth, immunity and disease resistance of channel catfish, and intestinal microbiota of channel catfish induced by the yeast culture played a critical role in these effects.

Effect of dietary supplementation of Cetobacterium somerae XMX-1 fermentation product on gut and liver health and resistance against bacterial infection of the genetically improved farmed tilapia (GIFT, Oreochromis niloticus).

The purpose of this study was to evaluate the effects of Cetobacterium somerae XMX-1 fermentation product on gut and liver health and resistance against bacterial infection in genetically improved farmed tilapia (GIFT, Oreochromis niloticus). Fingerling GIFTs (n = 120; initial weight 1.33 ± 0.00 g) were randomly assigned to twelve 90-L tanks (four tanks per diet, 10 fish per tank) with three groups: control group (basal high fat diet), 1% XMX-1 group and 2% XMX-1 group (basal diet supplemented with 10 and 20 g XMX-1/kg feed respectively). After 49 days feeding trial, the growth performance and gut and liver health parameters of tilapia were evaluated. Also the gut microbiota and virome were detected by sequencing. 2% XMX-1 fermentation product had no effect on growth performance. For gut health, the expression of hypoxia-inducible factor-lα (Hif-1α) tend to increase in 1% XMX-1 group (P = 0.053). The expression of intestinal interleukin-6 (IL-6) and tumor growth factor ß (TGF-ß) was significantly down-regulated in 1% and 2% XMX-1 groups (P < 0.05), and the intestinal expression of interleukin-1ß (IL-1ß) had a trend to decrease (P = 0.08) in 1% XMX-1 group versus control. 1% and 2% XMX-1 groups also increased the intestinal expression of tight junction genes Claudin (P = 0.06 and 0.07, respectively). For liver health, XMX-1 fermentation product significantly decreased liver TAG (P < 0.05). Furthermore, the hepatic expression of lipid synthesis gene fatty acid synthase (FAS) was significantly decreased and the expression of lipid catabolism related-gene uncoupling protein 2 (UCP2) was significantly increased in 1% XMX-1 and 2% XMX-1 groups (P < 0.01). And the hepatic expression of IL-1ß and IL-6 significantly decreased in 1% XMX-1 and 2% XMX-1 groups (P < 0.05). XMX-1 fermentation product increased the abundance of Fusobacteria in the gut microbiota and 2% XMX-1 group led to alteration in the virome composition at family level. Lastly, the time of tilapia death post Aeromoans challenge was delayed in 1% XMX-1 and 2% XMX-1 groups compared with control. To sum up, our results show that the dietary supplementation of XMX-1 fermentation product can improve the gut and liver health as well as the resistance against pathogenic bacteria of tilapia.

Stabilized fermentation product of Cetobacterium somerae improves gut and liver health and antiviral immunity of zebrafish.

Probiotics are widely used in aquafeeds and exhibited beneficial effects on fish by improving host health and resisting pathogens. However, probiotics applied to aquaculture are mainly from terrestrial sources instead of the host animal. The purpose of the work was to evaluate the effects of stabilized fermentation product of commensal Cetobacterium somerae XMX-1 on gut, liver health and antiviral immunity of zebrafish. A total of 240 zebrafish were assigned to the control (fed a basal diet) and XMX-1 group (fed a basal diet with 10 g XMX-1/kg diet). After four weeks feeding, growth performance, feed utilization, hepatic steatosis score, TAG, lipid metabolism related genes and serum ALT were evaluated. Furthermore, serum LPS, the expression of Hif-1α, intestinal inflammation score, antioxidant capability and gut microbiota were tested. The survival rate and the expression of antiviral genes were analyzed after challenge by spring viremia of carp virus (SVCV). Results showed that dietary XMX-1 did not affect growth of zebrafish. However, dietary XMX-1 significantly decreased the level of serum LPS, intestinal inflammation score and intestinal MDA, as well as increased T-AOC and the expression of Hif-1α in zebrafish intestine (p < 0.05). Furthermore, XMX-1 supplementation decreased the relative abundance of Proteobacteria and increased Firmicutes and Actinobacteria. Additionally, XMX-1 supplementation significantly decreased hepatic steatosis score, hepatic TAG, serum ALT and increased the expression of lipolysis genes versus control (p < 0.05). Zebrafish fed XMX-1 diet exhibited higher survival rate after SVCV challenge. Consistently, dietary XMX-1 fermentation product increased the expression of IFNφ2 and IFNφ3 after 2 days of SVCV challenge and the expression of IFNφ1, IFNφ2 and MxC after 4 days of SVCV challenge in the spleen in zebrafish versus control (p < 0.05). In conclusion, our results indicate that dietary XMX-1 can improve liver and gut health, while enhancing antiviral immunity of zebrafish.

Dietary Nucleotides Alleviate Hepatic Lipid Deposition via Exogenous AMP-Mediated AMPK Activation in Zebrafish.

BACKGROUND: Dietary nucleotides (NTs) have been reported to affect hepatic function and composition. However, the effects on hepatic lipid deposition are less studied. OBJECTIVES: We aimed to identify the regulatory role of dietary NTs in hepatic lipid deposition of zebrafish and elucidate the underlying mechanisms. METHODS: Zebrafish (60 ± 1.69 mg; 1 mo old) were fed control diet (16.2% energy as fat) or diet supplemented with 0.1% NTs or 0.02% AMP in feeding experiments 1 and 2. Experiment 3 was conducted with zebrafish larvae. In experiment 4, 1-mo-old zebrafish were fed a high-fat diet (HFD, 38.2% energy as fat) or an HFD supplemented with 0.1% NTs or 0.02% AMP. Hepatic lipid deposition was evaluated by triglyceride (TG) content and staining. Phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) was assayed by immunoblotting. Zebrafish liver (ZFL) cells were treated with exogenous adenosine. Small interfering RNA was used to knock down AMPK or nucleoside transporter SLC28a1 in ZFL cells. Vivo-morpholino was used to knock down AMPK in zebrafish larvae. RESULTS: Dietary 0.1% NTs or 0.02% AMP reduced hepatic TGs by 62% and 32%, respectively, compared with control (P < 0.05). Dietary AMP enhanced hepatic AMPK and ACC phosphorylation. Consistently, exogenous adenosine enhanced AMPK and ACC phosphorylation by 111% and 53%, respectively, in ZFL cells (P < 0.01) and reduced TG content by 56% (P < 0.05). Knockdown of AMPK and SLC28a1 abolished the effect of adenosine on lipid deposition in ZFL cells, and AMPK morpholino blocked the hepatic lipid-lowering effect of dietary AMP in vivo. Finally, dietary NTs and AMP activated AMPK and attenuated hepatic lipid deposition (28% and 30%, P < 0.05) in fish fed an HFD. CONCLUSIONS: Dietary NTs and AMP reduce hepatic lipid deposition in zebrafish, which involves exogenous AMP-mediated AMPK activation. Our results suggest that dietary NTs can contribute to alleviation of hepatic steatosis.

Necroptosis Underlies Neutrophilic Inflammation Associated with the Chronic Rhinosinusitis with Nasal Polyps (CRSwNP).

BACKGROUND: Necroptosis is an inflammatory cell death associated with a variety of chronic diseases. Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease accompanied by eosinophil and neutrophil infiltration. The role of necroptosis in the pathogenesis of CRSwNP remains elusive. METHODS: Cell death, including apoptosis, pyroptosis and necroptosis in control sinonasal mucosa and CRSwNP, were analyzed by immunoblotting, immunohistochemistry (IHC) and immunofluorescence (IF) staining for cleaved caspase 3, cleaved gasdermin D and p-MLKL, respectively. Correlations between necroptosis, inflammatory cytokines and neutrophil infiltration were assessed and a possible role of necroptosis in CRSwNP was evaluated. Primary nasal polyp cells (DNPCs) were stimulated with damage-associated molecular patterns (DAMPs) including ATP or IL-1α and their expression of inflammatory cytokines was analyzed using RT-PCR. The expression of TNF-α and IFNs in nasal polyps was measured by ELISA; human monocyte THP-1 cells were treated with TNF-α or IFN-γ and cell death was measured by LDH release. RESULTS: Necroptosis, rather than apoptosis or pyroptosis, was overtly activated in both eosinophilic and non-eosinophilic CRSwNP as evidenced by the presence of prominent phosphorylation of MLKL compared to controls. The abundance of DAMPs (IL-1α, HMGB1), inflammatory cytokines (IL-6) and chemokines (IL-8, CXCL-1) were all increased especially in non-eosinophilic CRSwNP. The extent of necroptosis was positively correlated with the abundance of DAMPs and cytokines, and neutrophil infiltration in CRSwNP. In DNPCs, ATP and IL-1α induced the expression of IL-8 and CXCL-1. Macrophage was found to be the predominant cell type positive for p-MLKL in CRSwNP. Concomitant treatment with TNF-α and IFN-γ, which were abundantly present in CRSwNP, triggered marked necroptosis in THP-1 cells. CONCLUSION: Necroptosis induced by TNF-α and IFN-γ may facilitate the production and release of a myriad of proinflammatory cytokines and entailed neutrophil infiltration to exacerbate inflammation in CRSwNP.

Regulation of Anion Channel LRRC8 Volume-Regulated Anion Channels in Transport of 2'3'-Cyclic GMP-AMP and Cisplatin under Steady State and Inflammation.

The recently identified anion channel LRRC8 volume-regulated anion channels (VRACs) are heteromeric hexamers constituted with the obligate LRRC8A subunit paired with at least one of the accessory LRRC8B to LRRC8E subunits. In addition to transport chloride, taurine, and glutamate, LRRC8 VRACs also transport the anticancer agent cisplatin and STING agonists 2'3'-cyclic GMP-AMP (cGAMP) and cyclic dinucleotides; hence, they are implicated in a variety of physiological and pathological processes, such as cell swelling, stroke, cancer, and viral infection. Although the subunit composition largely determines VRAC substrate specificity, the opening of various VRAC pores under physiological and pathological settings remains enigmatic. In this study, we demonstrated that VRACs comprising LRRC8A and LRRC8E (LRRC8A/E-containing VRACs), specialized in cGAMP transport, can be opened by a protein component present in serum under resting condition. Serum depletion ablated the tonic activity of LRRC8A/E-containing VRACs, decreasing cGAMP transport in various human and murine cells. Also, heating or proteinase K treatment abolished the ability of serum to activate VRAC. Genetic analyses revealed a crucial role for cGAMP synthase (cGAS) in serum/TNF-promoted VRAC activation. Notably, the presence of cGAS on the plasma membrane, rather than its DNA-binding or enzymatic activity, enabled VRAC activation. Moreover, phospholipid PIP2 seemed to be instrumental in the membrane localization of cGAS and its association with VRACs. Corroborating a role for LRRC8A/D-containing VRACs in cisplatin transport, serum and TNF markedly potentiated cisplatin uptake and killing of cancer cells derived from human or mouse. Together, these observations provide new insights into the complex regulation of VRAC activation and suggest a novel approach to enhance the efficacy of cGAMP and cisplatin in treating infection and cancer.

Research progress on the regulation of nutrition and immunity by microRNAs in fish.

MicroRNAs (miRNAs) are a class of highly conserved, endogenous non-coding single-stranded small RNA molecules with a length of 18-25 nucleotides. MiRNAs can negatively regulate the target gene through complementary pairing with the mRNA. It has been more than 20 years since the discovery of miRNA molecules, and many achievements have been made in fish research. This paper reviews the research progress in the regulation of fish nutrition and immunity by miRNAs in recent years. MiRNAs regulate the synthesis of long-chain polyunsaturated fatty acids, and are involved in the metabolism of glucose, lipids, as well as cholesterol in fish. Moreover, miRNAs play various roles in antibacterial and antiviral immunity of fish. They can promote the immune response of fish, but may also participate in the immune escape mechanism of bacteria or viruses. One important aspect of miRNAs regulation on fish immunity is mediated by targeting pattern recognition receptors and downstream signaling factors. Together, current results indicate that miRNAs are widely involved in the complex regulatory network of fish. Further studies on fish miRNAs may deepen our understanding of the regulatory network of fish nutrition and immunity, and have the potential to promote the development of microRNA-based products and detection reagents that can be applied in aquaculture industry.

TSC1 Suppresses Macrophage Necroptosis for the Control of Infection by Fungal Pathogen Candida albicans.

Candida albicans is the most common, opportunistic human fungal pathogen whose complex interplay with the host innate immune system remains incompletely understood. In this study, we revealed that infection macrophages with C. albicans triggers prominent cell death, which is largely attributed to the RIPK3/MLKL-mediated necroptosis. Our results further demonstrated that the TSC1-mTOR pathway plays a pivotal role in the control of macrophage necroptosis upon engaging the Dectin-1/2 and TLR-2/4 pathways through fungal components ß-glucan/α-mannan or Sel1, respectively. Notably, the rapamycin-sensitive mTORC1 pathway, rather than the rapamycin-insensitive mTORC2 pathway, was responsible for elevated activation of RIPK1, RIPK3, and MLKL in TSC1-deficient macrophages. Following systemic infection with C. albicans, mice with macrophage/neutrophil-specific deletion of Tsc1 (Tsc1 M/N-/-) showed heightened fungal burden in multiple organs, such as the kidney, liver, and spleen, severe morbidity, and mortality. Notably, Tsc1 M/N-/- kidneys exhibited prominent cell death and concomitant loss of tissue-resident macrophages, which likely contributing to a dampened phagocytosis of fungal pathogens. Together, our data demonstrate a crucial role for the TSC1-mTOR pathway in the regulation of macrophage necroptosis and suggest that both Dectin- and TLRs-induced necroptosis may undermine the immune defense effector functions of these innate receptors during C. albicans infection.

Interactions between commensal bacteria and viral infection: insights for viral disease control in farmed animals.

Viral diseases cause serious economic loss in farmed animals industry. However, the efficacy of remedies for viral infection in farmed animals is limited, and treatment strategies are generally lacking for aquatic animals. Interactions of commensal microbiota and viral infection have been studied in recent years, demonstrating a third player in the interaction between hosts and viruses. Here, we discuss recent developments in the research of interactions between commensal bacteria and viral infection, including both promotion and inhibition effect of commensal bacteria on viral pathogenesis, as well as the impact of viral infection on commensal microbiota. The antiviral effect of commensal bacteria is mostly achieved through priming or regulation of the host immune responses, involving differential microbial components and host signaling pathways, and gives rise to various antiviral probiotics. Moreover, we summarize studies related to the interaction between commensal bacteria and viral infection in farmed animals, including pigs, chickens, fish and invertebrate species. Further studies in this area will deepen our understanding of antiviral immunity of farmed animals in the context of commensal microbiota, and promote the development of novel strategies for treatment of viral diseases in farmed animals.