Viral infection and spread are inhibited by the polyubiquitination and downregulation of TRPV2 channel by the interferon-stimulated gene TRIM21.

Interferon (IFN) contributes to the host's antiviral response by inducing IFN-stimulated genes (ISGs). However, their functional targets and the mechanism of action remain elusive. Here, we report that one such ISG, TRIM21, interacts with and degrades the TRPV2 channel in myeloid cells, reducing its expression and providing host protection against viral infections. Moreover, viral infection upregulates TRIM21 in paracrine and autocrine manners, downregulating TRPV2 in neighboring cells to prevent viral spread to uninfected cells. Consistently, the Trim21-/- mice are more susceptible to HSV-1 and VSV infection than the Trim21+/+ littermates, in which viral susceptibility is rescued by inhibition or deletion of TRPV2. Mechanistically, TRIM21 catalyzes the K48-linked ubiquitination of TRPV2 at Lys295. TRPV2K295R is resistant to viral-infection-induced TRIM21-dependent ubiquitination and degradation, promoting viral infection more profoundly than wild-type TRPV2 when reconstituted into Lyz2-Cre;Trpv2fl/fl myeloid cells. These findings characterize targeting the TRIM21-TRPV2 axis as a conducive strategy to control viral spread to bystander cells.

Insights into the Mechanism of Selective Removal of Heavy Metal Ions by the Pulsed/Direct Current Electrochemical Method.

Heavy metal pollution treatment in industrial wastewater is crucial for protecting biological and environmental safety. However, the highly efficient and selective removal of heavy metal ions from multiple cations in wastewater is a significant challenge. This work proposed a pulse electrochemical method with a low-/high-voltage periodic appearance to selectively recover heavy metal ions from complex wastewater. It exhibited a higher recovery efficiency for heavy metal ions (100% for Pb2+ and Cd2+, >98% for Mn2+) than other alkali and alkaline earth metal ions (Na+, Ca2+, and Mg2+ were kept below 3.6, 1.3, and 2.6%, respectively) in the multicomponent solution. The energy consumption was only 34-77% of that of the direct current electrodeposition method. The results of characterization and experiment unveil the mechanism that the low-/high-voltage periodic appearance can significantly suppress the water-splitting reaction and break the mass-transfer limitation between heavy metal ions and electrodes. In addition, the plant study demonstrates the feasibility of treated wastewater for agricultural use, further proving the high sustainability of the method. Therefore, it provides new insights into the selective recovery of heavy metals from industrial wastewater.

Knocking out FAM20C in pre-osteoblasts leads to up-regulation of osteoclast differentiation to affect long bone development.

Family with sequence similarity 20 member C (FAM20C) is a Golgi casein kinase that phosphorylates extracellularly-secreted regulatory proteins involved in bone development and mineralization, but its specific role in bone development is still largely unknown. In this study, to examine the specific mechanisms that FAM20C influences bone development, we cross-bred Osx-Cre with FAM20Cflox/flox mice to establish a Osx-Cre; FAM20Cflox/flox knockout (oKO) mouse model; FAM20C was KO in pre-osteoblasts. oKO development was examined at 1-10 weeks, in which compared to control FAM20Cflox/flox, they had lower body weights and bone tissue mineralization. Furthermore, oKO had lower bone volume fractions, thickness, and trabecular numbers, along with higher degrees of trabecular separation. These mice also had decreased femoral metaphyseal cartilage proliferation layer, along with thickened hypertrophic layer and increased apoptotic cell counts. Transcriptomic analysis found that differentially-expressed genes in oKO were concentrated in the osteoclast differentiation pathway, in line with increased osteoclast presence. Additionally, up-regulation of osteoclast-related, and down-regulation of osteogenesis-related genes, were identified, in which the most up-regulated genes were signal regulatory protein ß-1 family (Sirpb1a-c) and mitogen-activated protein kinase 13. Overall, FAM20C KO in pre-osteoblasts leads to abnormal long bone development, likely due to subsequent up-regulation of osteoclast differentiation-associated genes.

UDP-glucose dehydrogenase supports autophagy-deficient PDAC growth via increasing hyaluronic acid biosynthesis.

Autophagy is an essential degradation and recycling process that maintains cellular homeostasis during stress or nutrient deprivation. However, certain types of tumors such as pancreatic cancers can circumvent autophagy inhibition to sustain growth. The mechanism that autophagy-deficient pancreatic ductal adenocarcinoma (PDAC) uses to grow under nutrient deprivation is poorly understood. Our data show that nutrient deprivation in PDAC results in UDP-glucose dehydrogenase (UGDH) degradation, which is dependent on autophagic cargo receptor sequestosome 1 (p62). Moreover, we demonstrate that accumulated UGDH is indispensable for autophagy-deficient PDAC cells proliferation by promoting hyaluronic acid (HA) synthesis upon energy deprivation. Using an orthotopic mouse model of PDAC, we find that inhibition of HA synthesis by targeting UGDH in PDAC reduces tumor weight. Thus, the combined inhibition of HA and autophagy might be an attractive strategy for PDAC treatment.

Selective Capacitive Removal of Pb2+ from Wastewater over Biochar Electrodes by Zinc Regulation.

Biochar materials have shown great potential for broad catalytic application. However, using these materials in the capacitive deionization technology (CDI) system for heavy metal removal still faces a significant challenge due to their low specific capacity and removal capability. Here, a comprehensive regulation on the interfacial/bulk electrochemistry of biochar by Zn doping is reported, which suggests a high renewable capacity (20 mg g-1 ) and outstanding selective capacitive removal ability (SCR) of Pb2+ from leachate. The SCR efficiency of Pb2+ is as high as 99% compared to K+ (8%), Na+ (13%), and Cd2+ (37%). This work proves that the doped Zn on the biochar can combine with OH- generated by water splitting to form M─OH bonds, which is beneficial for improving the specific capacity. Significantly, the relationship between double-layer capacitance and pseudo-capacitance can also be optimized by regulating the content of Zn, leading to different removal abilities of heavy metals. Therefore, this work offers insights into charge-storage kinetics, which provide valuable guidelines for designing and optimizing the biochar electrode for broader environmental applications.

Porcine epidemic diarrhea virus strain CH/HLJ/18 isolated in China: characterization and phylogenetic analysis.

BACKGROUND: Porcine epidemic diarrhea (PED) is an infectious disease of the digestive tract caused by the porcine epidemic diarrhea virus (PEDV), characterized by vomiting, severe diarrhea, and high mortality rates in piglets. In recent years, the distribution of this disease in China has remarkably increased, and its pathogenicity has also increased. PEDV has been identified as the main cause of viral diarrhea in piglets. This study aimed to understand the genetic evolution and diversity of PEDV to provide a theoretical basis for the development of new vaccines and the prevention and treatment of PED. METHODS: A PEDV strain was isolated from the small intestine of a diarrheal piglet using Vero cells. The virus was identified using reverse transcription-polymerase chain reaction (RT-PCR), indirect immunofluorescence assay (IFA), and transmission electron microscopy. The whole genome sequence was sequenced, phylogenetic analysis was conducted using MEGA (version 7.0), and recombination analysis was performed using RDP4 and SimPlot. The S protein amino acid sequence was aligned using Cluster X (version 2.0), and the S protein was modeled using SWISS-MODEL to compare differences in structure and antigenicity. Finally, the piglets were inoculated with PEDV to evaluate its pathogenicity in newborn piglets. RESULT: PEDV strain CH/HLJ/18 was isolated. CH/HLJ/18 shared 89.4-99.2% homology with 52 reference strains of PEDV belonging to the GII-a subgroup. It was a recombinant strain of PEDV BJ-2011-1 and PEDV CH_hubei_2016 with a breakpoint located in ORF1b. Unique amino acid deletions and mutations were observed in the CH/HLJ/18 S protein. The piglets then developed severe watery diarrhea and died within 7 d of inoculation with CH/HLJ/18, suggesting that CH/HLJ/18 was highly pathogenic to newborn piglets. CONCLUSION: A highly pathogenic recombinant PEDV GII-a strain, CH/HLJ/18, was identified in China, with unique deletion and mutation of amino acids in the S protein that may lead to changes in protein structure and antigenicity. These results will be crucial for understanding the prevalence and variation of PEDV and for preventing and controlling PED.

Fam20c regulates the calpain proteolysis system through phosphorylating Calpasatatin to maintain cell homeostasis.

BACKGROUND: The family with sequence similarity 20-member C (FAM20C) kinase, a Golgi casein kinase, which is responsible for phosphorylating the majority of the extracellular phosphoproteins within S-x-E/pS motifs, and is fundamentally associated with multiple biological processes to maintain cell proliferation, biomineralization, migration, adhesion, and phosphate homeostasis. In dissecting how FAM20C regulates downstream molecules and potential mechanisms, however, there are multiple target molecules of FAM20C, particularly many phenomena remain elusive, such as changes in cell-autonomous behaviors, incompatibility in genotypes and phenotypes, and others. METHODS: Here, assay for transposase-accessible chromatin using sequencing (ATAC-seq), RNA sequencing (RNA-seq), proteomics, and phosphoproteomics were performed in Fam20c-dificient osteoblasts and to facilitate an integrated analysis and determine the impact of chromatin accessibility, genomic expression, protein alterations, signaling pathway, and post translational modifcations. RESULTS: By combining ATAC-seq and RNA-seq, we identified TCF4 and Wnt signaling pathway as the key regulators in Fam20c-dificient cells. Further, we showed Calpastatin/Calpain proteolysis system as a novel target axis for FAM20C to regulate cell migration and F-actin cytoskeleton by integrated analysis of proteomics and phosphoproteomics. Furthermore, Calpastatin/Calpain proteolysis system could negatively regulate the Wnt signaling pathway. CONCLUSION: These observations implied that Fam20c knockout osteoblasts would cause cell homeostatic imbalance, involving changes in multiple signaling pathways in the conduction system.

The deubiquitinase OTUD4 inhibits the expression of antimicrobial peptides in Paneth cells to support intestinal inflammation and bacterial infection.

Dysfunction of the intestinal epithelial barrier causes microbial invasion that would lead to inflammation in the gut. Antimicrobial peptides (AMPs) are essential components of the intestinal epithelial barrier, while the regulatory mechanisms of AMPs expression are not fully characterized. Here, we report that the ovarian tumor family deubiquitinase 4 (OTUD4) in Paneth cells restricts the expression of AMPs and thereby promotes experimental colitis and bacterial infection. OTUD4 is upregulated in the inflamed mucosa of ulcerative colitis patients and in the colon of mice treated with dextran sulfate sodium salt (DSS). Knockout of OTUD4 promotes the expression of AMPs in intestinal organoids after stimulation with lipopolysaccharide (LPS) or peptidoglycan (PGN) and in the intestinal epithelial cells (IECs) of mice after DSS treatment or Salmonella typhimurium (S.t.) infection. Consistently, Vil-Cre;Otud4fl/fl mice and Def-Cre;Otud4fl/fl mice exhibit hyper-resistance to DSS-induced colitis and S.t. infection compared to Otud4fl/fl mice. Mechanistically, knockout of OTUD4 results in hyper K63-linked ubiquitination of MyD88 and increases the activation of NF-κB and MAPKs to promote the expression of AMPs. These findings collectively highlight an indispensable role of OTUD4 in Paneth cells to modulate AMPs production and indicate OTUD4 as a potential target for gastrointestinal inflammation and bacterial infection.

Radiation characteristics analysis for spallation products of lead-bismuth target and tungsten-iron-nickel target.

The radiation characteristics of spallation products are important references for evaluating the materials used as spallation targets. Therefore, it is necessary to study the radiation characteristics of spallation products. In this study, the spallation products of tungsten-iron-nickel target and lead-bismuth target were calculated and analyzed based on the radionuclide distributions and decay photon shielding of the spallation products. The radionuclide distributions of the spallation products were calculated using FLUKA, and the shielding of decay photons was calculated with OpenMC. In addition, the variance reduction function with an importance card was added to the OpenMC code to allow its use for calculating deep penetration problems.

Autophagy loss impedes cancer-associated fibroblast activation via downregulating proline biosynthesis.

Cancer-associated fibroblasts (CAFs) are considered one of the most critical stromal cells that interact with pancreatic ductal adenocarcinoma (PDAC) and promote tumor growth, metastasis, and treatment resistance. Previous studies illustrated macroautophagy/autophagy contributes to CAF activation during tumor progression. Here in our study, we found that autophagy deficiency in CAFs impedes CAF activation by inhibiting proline biosynthesis and collagen production. Furthermore, we uncovered that autophagy promotes proline biosynthesis through mitophagy-mediated regulation of NADK2 (NAD kinase 2, mitochondrial), an enzyme responsible for production of mitochondrial NADP(H). Using an orthotopic mouse model of PDAC, we found that inhibiting mitophagy by targeting PRKN (parkin RBR E3 ubiquitin protein ligase) in the stroma reduced tumor weight. Thus, inhibition of CAFs mitophagy might be an attractive strategy for stroma-focused anti-cancer intervention. Abbreviations: ACTA2/α-SMA: actin alpha 2, smooth muscle, aorta; ACTB/ß-actin: actin, beta; ALDH18A1/P5CS: aldehyde dehydrogenase 18 family, member A1; ATG3: autophagy related 3; ATG5: autophagy related 5; BNIP3L: BCL2/adenovirus E1B interacting protein 3-like; CAFs:cancer-associated fibroblasts; COL1A1: collagen, type I, alpha 1; DES: desmin; ECM: extracellular matrix; FABP4: fatty acid binding protein 4, adipocyte; FAP/FAPα: fibroblast activation protein; IHC: immunohistochemical staining; LAMP1: lysosomal-associated membrane protein 1; NADK2: NAD kinase 2, mitochondrial; PC1: pro-collagen 1; PDAC: pancreatic ductal adenocarcinoma; PDGFR: platelet derived growth factor receptor; PDPN: podoplanin; PRKN: parkin RBR E3 ubiquitin protein ligase; PSCs: pancreatic stellate cells; VIM: vimentin; WT: wild-type.

Functionalized Prussian Blue Nanozyme as Dual-Responsive Drug Therapeutic Nanoplatform Against Maxillofacial Infection via Macrophage Polarization.

Purpose: Maxillofacial infection is a common disease in stomatology and is difficult to treat owing to its high potential to spread to vital anatomical structures. Excessive levels of reactive oxygen species (ROS) in infected tissues lead to cellular damage and impede tissue regeneration. However, uncontrollable strategies to remove ROS have limited therapeutic efficacy. Nanoparticle systems for scavenging ROS and remodeling the inflammatory microenvironment offer much promise in the treatment of maxillofacial inflammation. Methods: Here, a novel microenvironment-stimuli-responsive drug delivery nanoplatform (HMPB@Cur@PDA) based on a polydopamine (PDA)-functionalized hollow mesoporous Prussian blue (HMPB) nanozyme was developed for the delivery of curcumin (Cur) in the treatment of maxillofacial infection. Low pH and excess ROS in the inflammatory microenvironment cause degradation of the outer PDA layer of the nanocomplex, exposing the HMPB nanozyme and loaded Cur, which synergistically act as a ROS scavenger and anti-inflammatory agent, respectively, and induce macrophage polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype. Results: Experiments in vitro provided strong evidence for the application of novel nanocomplexes in scavenging multiple ROS and inhibiting lipopolysaccharide-induced inflammation. In addition, in vivo results obtained using a mouse maxillofacial infection model demonstrated that HMPB@Cur@PDA had excellent biocompatibility, significantly attenuated the inflammatory response in periodontal tissue, and improved the repair of damaged tissue. Conclusion: Our results indicate that HMPB@Cur@PDA nanocomposites have great potential for ROS regulation as well as having anti-inflammatory effects, providing new insights for the development of dual-response maxillofacial infection treatments.

The Transient Receptor Potential Vanilloid 2 (TRPV2) Channel Facilitates Virus Infection Through the Ca2+ -LRMDA Axis in Myeloid Cells.

The transient receptor potential vanilloid 2 (TRPV2) channel is a nonselective cation channel that has been implicated in multiple sensory processes in the nervous system. Here, it is shown that TRPV2 in myeloid cells facilitates virus penetration by promoting the tension and mobility of cell membrane through the Ca2+ -LRMDA axis. Knockout of TRPV2 in myeloid cells or inhibition of TRPV2 channel activity suppresses viral infection and protects mice from herpes simplex virus 1 (HSV-1) and vesicular stomatitis virus (VSV) infection. Reconstitution of TRPV2 but not the Ca2+ -impermeable mutant TRPV2E572Q into LyZ2-Cre;Trpv2fl/fl bone marrow-derived dendritic cells (BMDCs) restores viral infection. Mechanistically, knockout of TRPV2 in myeloid cells inhibits the tension and mobility of cell membrane and the penetration of viruses, which is restored by reconstitution of TRPV2 but not TRPV2E572Q . In addition, knockout of TRPV2 leads to downregulation of Lrmda in BMDCs and BMDMs, and knockdown of Lrmda significantly downregulates the mobility and tension of cell membrane and inhibits viral infections in Trpv2fl/fl but not LyZ2-Cre;Trpv2fl/fl BMDCs. Consistently, complement of LRMDA into LyZ2-Cre;Trpv2fl/fl BMDCs partially restores the tension and mobility of cell membrane and promotes viral penetration and infection. These findings characterize a previously unknown function of myeloid TRPV2 in facilitating viral infection though the Ca2+ -LRMDA axis.

Human dendritic cell targeting peptide can be targeted to porcine dendritic cells to improve antigen capture efficiency to stimulate stronger immune response.

Dendritic cells (DCs) play a key role in the natural recognition of pathogens and subsequent activation of adaptive immune responses due to their potent antigen-presenting ability. Dendritic cell-targeting peptide (DCpep) is strongly targeted to DCs, which often express antigens, to enhance the efficacy of vaccines. Our previous study showed that recombinant Lactobacillus expressing human DCpep could significantly induce stronger immune responses than recombinant Lactobacillus without DCpep, but the mechanism remains unclear. In this study, the mechanism by which DCpep enhances the immune response against recombinant Lactobacillus was explored. Fluorescence-labeled human DCpep was synthesized to evaluate the binding ability of human DCpep to porcine monocyte-derived dendritic cells (Mo-DCs) and DCs of the small intestine. The effects of Mo-DC function induced by recombinant Lactobacillus expressing human DCpep fused with the porcine epidemic diarrhea virus (PEDV) core neutralizing epitope (COE) antigen were also investigated. The results showed that human DCpep bind to porcine DCs, but not to porcine small intestinal epithelial cells. Human DCpep can also improve the capture efficiency of recombinant Lactobacillus by Mo-DCs, promote the maturation of dendritic cells, secrete more cytokines, and enhance the ability of porcine DCs to activate T-cell proliferation. Taken together, these results promote advanced understanding of the mechanism by which DCpep enhances immune responses. We found that some DCpeps are conserved between humans and pigs, which provides a theoretical basis for the development of a DC-targeted vaccine.

Role of ferroptosis-related genes in periodontitis based on integrated bioinformatics analysis.

BACKGROUND: Cell survival or death is one of the key scientific issues of inflammatory response. To regulate cell death during the occurrence and development of periodontitis, various forms of programmed cell death, such as pyroptosis, ferroptosis, necroptosis, and apoptosis, have been proposed. It has been found that ferroptosis characterized by iron-dependent lipid peroxidation is involved in cancer, degenerative brain diseases and inflammatory diseases. Furthermore, NCOA4 is considered one of ferroptosis-related genes (FRGs) contributing to butyrate-induced cell death in the periodontitis. This research aims to analyze the expression of FRGs in periodontitis tissues and to explore the relationship between ferroptosis and periodontitis. METHOD: Genes associated with periodontitis were retrieved from two Gene Expression Omnibus datasets. Then, we normalized microarray data and removed the batch effect using the R software. We used R to convert the mRNA expression data and collected the expression of FRGs. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), transcription factor (TF) and protein-protein interaction (PPI) network analyses were used. In addition, we constructed a receiver operating characteristic curve and obtained relative mRNA expression verified by quantitative reverse-transcription polymerase chain reaction (PCR). RESULTS: Eight and 10 FRGs related to periodontitis were upregulated and downregulated, respectively. GO analysis showed that FRGs were enriched in the regulation of glutathione biosynthetic, glutamate homeostasis, and endoplasmic reticulum-nucleus signaling pathway. The top TFs included CEBPB, JUND, ATF2. Based on the PPI network analysis, FRGs were mainly linked to the negative regulation of IRE1-mediated unfolded protein response, regulation of type IIa hypersensitivity, and regulation of apoptotic cell clearance. The expression levels of NCOA4, SLC1A5 and HSPB1 using PCR were significantly different between normal gingival samples and periodontitis samples. Furthermore, the diagnostic value of FRGs for periodontitis were "Good". CONCLUSIONS: We found significant associations between FRGs and periodontitis. The present study not only provides a new possible pathomechanism for the occurrence of periodontitis but also offers a new direction for the diagnosis and treatment of periodontitis.

A novel electrocatalytic system with high reactive chlorine species utilization capacity to degrade tetracycline in marine aquaculture wastewater.

The problems of high salinity and coexistence of antibiotics in mariculture wastewater pose a great challenge to the traditional wastewater treatment technology. Herein, an electrocatalytic system based on cathodes to sustain reactive chlorine species (RCS) in a high chlorine environment was proposed. The results show that the content of RCS is affected by cathodes. The electrocatalytic system with FeNi/NF as cathode has the largest RCS retention capacity when compared with other cathode systems (carbon felt, nickel foam, copper foam, stainless steel, and nickel-iron foam). This is related to FeNi/NF's higher hydrogen production activity, which inhibits the reduction reaction of RCS. Furthermore, the degradation of tetracycline by the proposed FeNi/NF system maintained long-term effective performance across 20 cycles. Thus, the application of high chlorine resistance electrocatalysis system provides a possibility for practical electrocatalysis treatment of mariculture wastewater.

RNF115 Inhibits the Post-ER Trafficking of TLRs and TLRs-Mediated Immune Responses by Catalyzing K11-Linked Ubiquitination of RAB1A and RAB13.

The subcellular localization and intracellular trafficking of Toll-like receptors (TLRs) critically regulate TLRs-mediated antimicrobial immunity and autoimmunity. Here, it is demonstrated that the E3 ubiquitin ligase RNF115 inhibits the post-endoplasmic reticulum (ER) trafficking of TLRs and TLRs-mediated immune responses by catalyzing ubiquitination of the small GTPases RAB1A and RAB13. It is shown that the 14-3-3 chaperones bind to AKT1-phosphorylated RNF115 and facilitate RNF115 localizing on the ER and the Golgi apparatus. RNF115 interacts with RAB1A and RAB13 and catalyzes K11-linked ubiquitination on the Lys49 and Lys61 residues of RAB1A and on the Lys46 and Lys58 residues of RAB13, respectively. Such a modification impairs the recruitment of guanosine diphosphate (GDP) dissociation inhibitor 1 (GDI1) to RAB1A and RAB13, a prerequisite for the reactivation of RAB proteins. Consistently, knockdown of RAB1A and RAB13 in Rnf115+/+ and Rnf115-/- cells markedly inhibits the post-ER and the post-Golgi trafficking of TLRs, respectively. In addition, reconstitution of RAB1AK49/61R or RAB13K46/58R into Rnf115+/+ cells but not Rnf115-/- cells promotes the trafficking of TLRs from the ER to the Golgi apparatus and from the Golgi apparatus to the cell surface, respectively. These findings uncover a common and step-wise regulatory mechanism for the post-ER trafficking of TLRs.

Mesenchymal-to-epithelial transition of osteoblasts induced by Fam20c knockout.

BACKGROUND: Fam20c is intimately related to tissue development and diseases. At present, it has been reported that Fam20c regulates the mineralization of osteoblasts, but there are few reports on other effects. OBJECTIVE: To study the effect of Fam20c on osteoblasts by knocking out the Fam20c gene. METHODS: Fam20c knockout osteoblasts were constructed by transfecting mouse osteoblasts with lentivirus. The proliferation, migration and mineralization of Fam20c knockout cells were detected by CCK-8, scratch test and alizarin red staining assays. The subcellular structure was observed by transmission electron microscopy. RT-PCR was used to detect the differential expression of mesenchymal-to-epithelial transition (MET)-related marker genes and core transcription factors. The differential expression of MET-related proteins was detected by immunofluorescence or Western blot. Transcriptome analysis of Fam20c knockout osteoblasts was performed, and real-time PCR was used to verify transcriptome analysis related to MET. RESULTS: The proliferation ability of osteoblasts was not significantly changed after Fam20c deletion, but the migration ability and mineralization ability were significantly weakened. There were tight junctions between Fam20c knockout cells. The expression of mesenchymal cell marker genes and core transcription factors was significantly decreased, and the expression of epithelial cell marker genes was significantly increased. The expression of mesenchymal cell marker proteins was significantly decreased, and the expression of epithelial cell marker proteins was significantly increased. Multiple signalling molecules and pathways involved in MET have changed. CONCLUSIONS: Knockdown of Fam20c resulted in MET. Fam20c affects the transcription of key factors in osteoblast MET.

IL-36γ and IL-36Ra Reciprocally Regulate NSCLC Progression by Modulating GSH Homeostasis and Oxidative Stress-Induced Cell Death.

The balance between antioxidants and reactive oxygen species (ROS) critically regulates tumor initiation and progression. However, whether and how the tumor-favoring redox status is controlled by cytokine networks remain poorly defined. Here, it is shown that IL-36γ and IL-36Ra reciprocally regulate the progression of non-small cell lung cancer (NSCLC) by modulating glutathione metabolism and ROS resolution. Knockout, inhibition, or neutralization of IL-36γ significantly inhibits NSCLC progression and prolongs survival of the KrasLSL-G12D/+ Tp53fl/fl and KrasLSL-G12D/+ Lkb1fl/fl mice after tumor induction, whereas knockout of IL-36Ra exacerbates tumorigenesis in these NSCLC mouse models and accelerates death of mice. Mechanistically, IL-36γ directly upregulates an array of genes involved in glutathione homeostasis to reduce ROS and prevent oxidative stress-induced cell death, which is mitigated by IL-36Ra or IL-36γ neutralizing antibody. Consistently, IL-36γ staining is positively and negatively correlated with glutathione biosynthesis and ROS in human NSCLC tumor biopsies, respectively. These findings highlight essential roles of cytokine networks in redox for tumorigenesis and provide potential therapeutic strategy for NSCLC.

Hybrid dual-gain tunable integrated InP-Si3N4 external cavity laser.

We present a hybrid dual-gain integrated external cavity laser with full C-band wavelength tunability. Two parallel reflective semiconductor optical amplifier gain channels are combined by a Y-branch in the Si3N4 photonic circuit to increase the optical gain. A Vernier ring filter is integrated in the Si3N4 photonic circuit to select a single longitudinal mode and meanwhile reduce the laser linewidth. The side-mode suppression ratio is ∼67 dB with a pump current of 75 mA. The linewidth of the unpackaged laser is 6.6 kHz under on-chip output power of 23.5 mW. The dual-gain operation of the laser gives higher output power and narrower linewidth compared to the single gain operation. It is promising for applications in optical communications and light detection and ranging systems.

Silicon reconfigurable mode-selective modulation for on-chip mode-multiplexed photonic systems.

Recently, optical mode-division multiplexing has drawn a lot of attention due to its ability to increase the optical communication capacity in one physical channel with a single wavelength carrier. In this Letter, we demonstrate reconfigurable mode-selective modulation which is potentially useful for on-chip mode-multiplexed photonic systems. The device consists of two mode exchangers and one TE1 mode modulator. The mode exchanger is based on a Mach-Zehnder interferometer that performs mode exchange between TE0 and TE1 modes. The TE1 mode modulator consists of a pair of 1×3/3×1 multimode interferometers acting as a mode (de)multiplexer. It only selectively modulates the TE1 mode while bypassing the TE0 mode. 32 Gb/s on-off keying (OOK) modulation is successfully demonstrated for both input TE0 and TE1 modes. This device can be used as a building block for on-chip multimode interconnect networks.