Compact and low-insertion-loss polarization beam-splitting multimode filter using pixelated waveguides.

A polarization beam-splitting multimode filter using pixelated waveguides has been presented and experimentally demonstrated in this paper. Finite difference time domain method and direct binary search optimization algorithm are employed to optimize pixelated waveguides to realize compact size, broad bandwidth, large extinction ratio, low insertion loss, and good polarization extinction ratio. Measurement results show that, in a wavelength range from 1520 to 1560 nm, for the fabricated device working at transverse-electric polarization, the measured insertion loss is less than 1.23 dB and extinction ratio is larger than 15.14 dB, while for transverse-magnetic polarization, the corresponding insertion loss lower than 0.74 dB and extinction ratio greater than 15.50 dB are realized. The measured polarization extinction ratio larger than 15.02 dB is achieved. The device's length is only 15.4 µm.

Recombinant human IL-37 attenuates acute cardiac allograft rejection in mice.

BACKGROUND: Allograft rejection remains a major obstacle to long-term graft survival. Although previous studies have demonstrated that IL-37 exhibited significant immunomodulatory effects in various diseases, research on its role in solid organ transplantation has not been fully elucidated. In this study, the therapeutic effect of recombinant human IL-37 (rhIL-37) was evaluated in a mouse cardiac allotransplantation model. METHODS: The C57BL/6 recipients mouse receiving BALB/c donor hearts were treated with rhIL-37. Graft pathological and immunohistology changes, immune cell populations, and cytokine profiles were analyzed on postoperative day (POD) 7. The proliferative capacities of Th1, Th17, and Treg subpopulations were assessed in vitro. Furthermore, the role of the p-mTOR pathway in rhIL-37-induced CD4+ cell inhibition was also elucidated. RESULTS: Compared to untreated groups, treatment of rhIL-37 achieved long-term cardiac allograft survival and effectively alleviated allograft rejection indicated by markedly reduced infiltration of CD4+ and CD11c+ cells and ameliorated graft pathological changes. rhIL-37 displayed significantly less splenic populations of Th1 and Th17 cells, as well as matured dendritic cells. The percentages of Tregs in splenocytes were significantly increased in the therapy group. Furthermore, rhIL-37 markedly decreased the levels of TNF-α and IFN-γ, but increased the level of IL-10 in the recipients. In addition, rhIL-37 inhibited the expression of p-mTOR in CD4+ cells of splenocytes. In vitro, similar to the in vivo experiments, rhIL-37 caused a decrease in the proportion of Th1 and Th17, as well as an increase in the proportion of Treg and a reduction in p-mTOR expression in CD4+ cells. CONCLUSIONS: We demonstrated that rhIL-37 effectively suppress acute rejection and induce long-term allograft acceptance. The results highlight that IL-37 could be novel and promising candidate for prevention of allograft rejection.

Upregulation of TCPTP in Macrophages Is Involved in IL-35 Mediated Attenuation of Experimental Colitis.

Ulcerative colitis (UC) is a chronic intestinal inflammatory disease with complex etiology. Interleukin-35 (IL-35), as a cytokine with immunomodulatory function, has been shown to have therapeutic effects on UC, but its mechanism is not yet clear. Therefore, we constructed Pichia pastoris stably expressing IL-35 which enables the cytokines to reach the diseased mucosa, and explored whether upregulation of T-cell protein tyrosine phosphatase (TCPTP) in macrophages is involved in the mechanisms of IL-35-mediated attenuation of UC. After the successful construction of engineered bacteria expressing IL-35, a colitis model was successfully induced by giving BALB/c mice a solution containing 3% dextran sulfate sodium (DSS). Mice were treated with Pichia/IL-35, empty plasmid-transformed Pichia (Pichia/0), or PBS by gavage, respectively. The expression of TCPTP in macrophages (RAW264.7, BMDMs) and intestinal tissues after IL-35 treatment was detected. After administration of Pichia/IL-35, the mice showed significant improvement in weight loss, bloody stools, and shortened colon. Colon pathology also showed that the inflammatory condition of mice in the Pichia/IL-35 treatment group was alleviated. Notably, Pichia/IL-35 treatment not only increases local M2 macrophages but also decreases the expression of inflammatory cytokine IL-6 in the colon. With Pichia/IL-35 treatment, the proportion of M1 macrophages, Th17, and Th1 cells in mouse MLNs were markedly decreased, while Tregs were significantly increased. In vitro experiments, IL-35 significantly promoted the expression of TCPTP in macrophages stimulated with LPS. Similarly, the mice in the Pichia/IL-35 group also expressed more TCPTP than that of the untreated group and the Pichia/0 group.

Low-loss and broadband polarization-insensitive high-order mode pass filter based on photonic crystal and tapered coupler.

In this Letter, a polarization-insensitive high-order mode pass filter is presented, designed, and experimentally demonstrated. When TE0, TM0, TE1, and TM1 modes are injected into the input port, TM0 and TE0 modes are filtered, and TE1 and TM1 modes exit from the output port. To attain compactness, broad bandwidth, low insertion loss, excellent extinction ratio, and polarization-insensitive property, the finite difference time domain method and direct-binary-search or particle swarm optimization algorithm are employed for the optimization of structural parameters of the photonic crystal region and the coupling region in the tapered coupler. Measurement results reveal that, for the fabricated filter working at TE polarization, the extinction ratio and insertion loss are 20.42 and 0.32 dB at 1550 nm. In the case of TM polarization, the corresponding extinction ratio and insertion loss are 21.43 and 0.30 dB. Within a bandwidth from 1520 to 1590 nm, insertion loss smaller than 0.86 dB and extinction ratio larger than 16.80 dB are obtained for the fabricated filter working at TE polarization, while in the case of TM polarization, insertion loss lower than 0.79 dB and extinction ratio greater than 17.50 dB are realized.

Chryseobacterium luquanense sp. nov., a casein-hydrolysing bacterium from the Jiaozi Mountain in Yunnan, PR China.

Strain KC 927T was isolated during an investigation of the soil bacteria diversity on Jiaozi Mountain, central Yunnan, Southwest China. The strain was Gram-stain-negative, rod-shaped, non-motile, oxidase-negative, catalase-positive and aerobic. Results of 16S rRNA gene alignment and phylogenetic analysis indicated that strain KC 927T was a member of the genus Chryseobacterium and closely related to Chryseobacterium caseinilyticum GCR10T (98.4%), Chryseobacterium piscicola DSM 21068T (98.3 %) and 'Chryseobacterium formosus' CCTCC AB 2015118T (97.9 %). With a genome size of 4 348 708 bp, strain KC 927T had 33.5 mol% DNA G+C content and contained 4012 protein-coding genes and 77 RNA genes. The average nucleotide identity and digital DNA-DNA hybridization values between strain KC 927T and C. caseinilyticum GCR10T, C. piscicola DSM 21068T and 'C. formosus' CCTCC AB 2015118T were 80.1, 79.6 and 90.7 %, and 25.5, 23.6 and 42.0 %, respectively. The main polar lipid of strain KC 927T was phosphatidylethanolamine and the respiratory quinone was MK-6. The major fatty acids (≥10 %) were iso-C15 : 0, iso-C17 : 1 ω9c and iso-C17 : 0 3-OH. Evidence from phenotypic, phylogenetic and chemotaxonomic analyses support that strain KC 927T represents a new species of the genus Chryseobacterium, for which the name Chryseobacterium luquanense sp. nov. is proposed. The type strain is KC 927T (=CGMCC 1.18760T=JCM 35707T).

The genome of medicinal leech (Whitmania pigra) and comparative genomic study for exploration of bioactive ingredients.

BACKGROUND: Leeches are classic annelids that have a huge diversity and are closely related to people, especially medicinal leeches. Medicinal leeches have been widely utilized in medicine based on the pharmacological activities of their bioactive ingredients. Comparative genomic study of these leeches enables us to understand the difference among medicinal leeches and other leeches and facilitates the discovery of bioactive ingredients. RESULTS: In this study, we reported the genome of Whitmania pigra and compared it with Hirudo medicinalis and Helobdella robusta. The assembled genome size of W. pigra is 177 Mbp, close to the estimated genome size. Approximately about 23% of the genome was repetitive. A total of 26,743 protein-coding genes were subsequently predicted. W. pigra have 12346 (46%) and 10295 (38%) orthologous genes with H. medicinalis and H. robusta, respectively. About 20 and 24% genes in W. pigra showed syntenic arrangement with H. medicinalis and H. robusta, respectively, revealed by gene synteny analysis. Furthermore, W. pigra, H. medicinalis and H. robusta expanded different gene families enriched in different biological processes. By inspecting genome distribution and gene structure of hirudin, we identified a new hirudin gene g17108 (hirudin_2) with different cysteine patterns. Finally, we systematically explored and compared the active substances in the genomes of three leech species. The results showed that W. pigra and H. medicinalis exceed H. robusta in both kinds and gene number of active molecules. CONCLUSIONS: This study reported the genome of W. pigra and compared it with other two leeches, which provides an important genome resource and new insight into the exploration and development of bioactive molecules of medicinal leeches.

Insights into gut microbiota communities of Poecilobdella manillensis, a prevalent Asian medicinal leech.

AIMS: Medicinal leeches (Annelida: Hirudinea) are fresh water ectoparasitic species which have been applied as traditional therapy. However, gut microbiota could bring high risks of opportunistic infections after leeching and arouses great interests. Here, gut bacterial and fungal communities of an Asian prevalent leech Poecilobdella manillensis were characterized and analysed through culture-independent sequencing. METHODS AND RESULTS: With high coverage in 18 samples (>0.999), a more complicated community was apparent after comparing with previous leech studies. A total of 779/939 OTUs of bacteria and fungi were detected from leech guts. The bacterial community was dominated by the phylum Bacteroidetes and Synergistetes. Genera Mucinivorans and Fretibacterium accounted mostly at the genus level, and genus Aeromonas showed an extremely low abundance (2.02%) on average. The fungal community was dominated by the phylum Ascomycota and Basidiomycota. At the genus level, the dominant OTUs included Mortierella, Geminibasidium and Fusarium. The analysis of core taxa included those above dominant genera and some low-abundance genera (>1%). The functional annotation of the bacterial community showed a close correlation with metabolism (34.8 ± 0.6%). Some fungal species were predicted as opportunistic human pathogens including Fusarium and Chaetomiaceae. CONCLUSIONS: The present study provides fundamental rationales for further studies of such issues as bacteria-fungi-host interactions, host fitness, potential pathogens, and infecting risks after leeching. It shall facilitate in-depth explorations on the safe utilization of leech therapy. SIGNIFICANCE AND IMPACT OF STUDY: Present paper is the first-ever exploration on microbiota of a prevalent Asian medicinal leech based on culture-independent technical. And it is also the first report of gut fungi community of medicinal leech. The diversity and composition of bacteria in P. manillensis was far different from that of the European leech. The main components and core OTUs indicate a particular gut environment of medicinal leech. Unknown bacterial and fungal species were also recovered from leech gut.

Why do followers feel inauthentic and withdraw? The joint effect of leader Machiavellianism and perceived collectivistic work climate.

OBJECTIVE: Although past research has shown the negative consequences of state inauthenticity (i.e., the experience of inauthenticity), what triggers state inauthenticity remains to be better understood. We focus on leader Machiavellianism (Mach), defined as the extent to which leaders engage in unethical and manipulative behaviors to attain their goals, as a predictor of follower state inauthenticity. Drawing on the social misfit argument, we examined a model in which leader Mach, jointly with a perceived collectivistic work climate, determines follower state inauthenticity and subsequent work withdrawal. METHOD: We used a vignette-based lab study (303 participants from the United States) and a daily diary field study (476 daily responses from 69 participants recruited from China). RESULTS: Across two studies, we found that follower state inauthenticity mediated the relationship between leader Mach and follower work withdrawal. The positive relationship between leader Mach and follower state inauthenticity was strengthened by a perceived collectivistic work climate. CONCLUSIONS: The present research underlines the importance of the social environment in influencing follower state inauthenticity at work and shifts research attention from the consequences of state inauthenticity to its predictors.

IL-37 overexpression enhances the therapeutic effect of endometrial regenerative cells in concanavalin A-induced hepatitis.

BACKGROUND AIMS: Mesenchymal stromal cells and immunosuppressive factor IL-37 can both suppress concanavalin A (Con A)-induced hepatitis in mice. Endometrial regenerative cells (ERCs), novel types of mesenchymal-like stromal cells, possess powerful immunomodulatory effects and are effective in treating various diseases. The aim of this study was to explore the effects of ERCs in suppressing Con A-induced hepatitis and determine whether IL-37 overexpression could enhance the therapeutic effect of ERCs in this process. METHODS: ERCs were extracted from the menstrual blood of healthy female volunteer donors. The IL-37 gene was transferred into ERCs, and the expression of IL-37 in cells was detected by western blot and enzyme-linked immunosorbent assay. Hepatitis was induced by Con A in C57BL/6 mice that were randomly divided into groups treated with phosphate-buffered saline, ERCs, IL-37 or ERCs transfected with the IL-37 gene (IL-37-ERCs). Cell tracking, liver function, histopathological and immunohistological changes, immune cell proportions and levels of cytokines were measured 24 h after Con A administration. RESULTS: Compared with ERC or IL-37 treatment, IL-37-ERCs further reduced levels of liver enzymes (alanine aminotransferase and aspartate aminotransferase) and improved histopathological changes in the liver. In addition, IL-37-ERC treatment further reduced the proportions of M1 macrophages and CD4+ T cells and increased the proportion of regulatory T cells. Moreover, IL-37-ERC treatment resulted in lower levels of IL-12 and interferon gamma, and higher level of transforming growth factor beta. CONCLUSIONS: The results of this study suggest that ERCs can effectively alleviate Con A-induced hepatitis. Furthermore, IL-37 overexpression can significantly enhance the therapeutic efficacy of ERCs by augmenting the immunomodulatory and anti-inflammatory properties of ERCs. This study may provide a promising strategy for treatment of T-cell-dependent hepatitis.

A stress model of psychological contract violation among ethnic minority employees.

OBJECTIVES: Integrating the transactional theory of stress and coping and research on discrimination perception/attribution, we propose a stress model of psychological contract (PC) violation among ethnic minority employees. We argue that ethnic minority employees tend to appraise PC violation as a threat and attribute it to personal ethnic discrimination (as well as low organizational trustworthiness), which in turn leads ethnic minority employees to engage in fear-driven silence as a form of emotion-based withdrawal coping. METHOD: We conducted two survey studies (Studies 1 and 2), an experimental study (Study 3), and a supplementary meta-analysis of the three studies. RESULTS: We found support for our model. Ethnic minority employees' perception of personal ethnic discrimination, rather than their perception of low organizational trustworthiness, translated PC violation to fear-driven silence. Our result patterns remained the same when we controlled for neuroticism and social desirability. CONCLUSIONS: By delineating ethnic minorities' appraisal/attribution of and coping with PC violation, the current research advances the literatures on both PC and ethnic discrimination. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Icaritin attenuates ischemia-reperfusion injury by anti-inflammation, anti-oxidative stress, and anti-autophagy in mouse liver.

BACKGROUND: Hepatic ischemia-reperfusion (IR) injury is a major complication of liver transplantation and gravely affects patient prognosis. Icaritin (ICT), the primary plasma metabolite of icariin (ICA), plays a critical role in anti-inflammatory and immunomodulatory processes. However, the role of ICT in hepatic IR injury remains largely undefined. In this study, we aimed to elucidate the role of ICT in hepatic IR injury. METHODS: We established hepatic IR injury models in animals, as well as an oxygen-glucose deprivation/reperfusion (OGD/R) cell model. Liver injury in vivo was assessed by measuring serum alanine aminotransferase (ALT) levels, necrotic areas by liver histology and local hepatic inflammatory responses. For in vitro analyses, we implemented flow-cytometric and western blot analyses, transmission electron microscopy, and an mRFP-GFP-LC3 adenovirus reporter assay to assess the effects of ICT on OGD/R injury in AML12 and THLE-2 cell lines. Signaling pathways were explored in vitro and in vivo to identify possible mechanisms underlying ICT action in hepatic IR injury. RESULTS: Compared to the mouse model group, ICT preconditioning considerably protected the liver against IR stress, and diminished the levels of necrosis/apoptosis and inflammation-related cytokines. In additional studies, ICT treatment dramatically boosted the expression ratios of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR proteins in hepatic cells following OGD/R damage. We also applied LY294002 (a PI3K inhibitor) and RAPA (rapamycin, an mTOR inhibitor), which blocked the protective effects of ICT in hepatocytes subjected to OGD/R. CONCLUSION: This study indicates that ICT attenuates ischemia-reperfusion injury by exerting anti-inflammation, anti-oxidative stress, and anti-autophagy effects, as demonstrated in mouse livers. We thus posit that ICT could have therapeutic potential for the treatment of hepatic IR injury.

Low SAA4 gene expression is associated with advanced HCC stage and a poor prognosis.

At present, although there are tumor markers for hepatocellular carcinoma (HCC), markers with better predictive efficiency are needed. SAA4 gene expression in liver tumor and paracancerous tissues was analyzed using The Cancer Genome Atlas database. The differentially expressed genes (DEGs) were analyzed and visualized by heatmap and volcano plot. Survival analysis was performed based on SAA4 expression. SAA4 expression was compared in patients grouped based on clinicopathological features, and gene set enrichment analysis (GSEA) was conducted. Immunohistochemical staining was used to verify the SAA4 protein staining intensity from The Human Protein Atlas database and our center's samples. The diagnostic value of SAA4 for HCC was evaluated by receiver operating characteristic curves. SAA4 was expressed at low levels in HCC tissues, and low SAA4 expression was associated with a poor prognosis in HCC. In addition, SAA4 expression decreased with HCC progression. There were 188 upregulated DEGs and 1551 downregulated DEGs between the high and low SAA4 expression groups. Complement and coagulation cascades, fatty acid metabolism, and ECM receptor interaction were significantly enriched in the GSEA. SAA4 had good predictive efficacy for HCC and even early HCC and was superior to AFP. In general, low SAA4 expression was associated with advanced HCC stage and a poor prognosis. In addition, SAA4 may be helpful for the diagnosis of early HCC and may become a novel tumor marker with good predictive power for HCC.

Humor research in management: Humor as Social Information (HASI).

Humor research is flourishing in Management. Diverse theories have been adopted and diverse factors have been used in research. Nonetheless, these disconnected efforts pose challenges to the development of a coherent body of knowledge on humor in organizational life. I propose the Humor-as-Social-Information (HASI) framework regarding the social effects of humor, and use it to guide my review on recent humor research in Management. Humor evokes affective and inferential processes leading to perceivers' cognitions and behaviors, and these processes are moderated by two sets of factors, including (1) information-processing motivation/ability and (2) humor inappropriateness. The proposed HASI framework highlights how humor exerts social influence within organizations, and paves new avenues for future research that will help further develop "humor science."

Integrative Multi-Omics Analysis of Identified Ferroptosis-Marker RPL8 as a Candidate Oncogene Correlates with Poor Prognosis and Immune Infiltration in Liver Cancer.

BACKGROUND: Liver Hepatocellular Carcinoma (LIHC) is characterized by high malignancy, poor prognosis, and high recurrence rate worldwide. The role of ferroptosis in tumorigenesis and progression has been confirmed in previous studies. However, the multi-omics analysis in liver cancer of ferroptosis-markers RPL8 remains to be elucidated. METHODS: In this analysis, the RPL8 mRNA expression was analyzed via the GEPIA, TIMER and UALCAN databases. In addition, we verified the mRNA expression of RPL8 by qRT-PCR experiment. The Kaplan-Meier plotter, UALCAN, TCGAportal and HPA databases were applied to evaluate RPL8 on prognosis and clinicopathological parameters. Moreover, we used TIMER and Kaplan-Meier plotter to analyze the correlation of RPL8 to immune cell infiltration and immune cell type markers to prognosis. In addition, networks and function enrichment between RPL8 coexpression genes were analyzed by GeneMANIA, cBioportal and Metascape databases. What's more, we used FerrDb and GEPIA databases to analyze the correlation of 23 Ferroptosis-related genes with RPL8. RESULTS: The mRNA expression of RPL8 was over-expressed in multiple cancers. In addition, transcription and translation levels of RPL8 in LIHC were significantly higher than normal tissues. Furthermore, higher expression of RPL8 was closely related to shorter OS in LIHC patients. The analysis of Kaplan-Meier plotter proved that RPL8 expression was related to stage, Sorafenib treatment, alcohol consumption and hepatitis virus. Moreover, the results showed that the methylation expression level of RPL8 was significantly associated with age, gender, grade, stage and TP53 mutation of LIHC. RPL8 and its co-expression genes were primarily involved in liver regeneration and immune system process. Immune infiltration analysis showed the RPL8 expression had positively correlated with immune cells and immune subtypes in LIHC. Furthermore, qRT-PCR experiment validated the expression difference of RPL8 in liver cancer. CONCLUSION: Our findings elucidated that ferroptosis-markers RPL8 may play an important role in prognosis, and significantly correlate with ferroptosis-related genes, it also revealed the potential of RPL8 as a novel therapeutic target for LIHC treatment and prognosis assessment.

CD73 mediates the therapeutic effects of endometrial regenerative cells in concanavalin A-induced hepatitis by regulating CD4+ T cells.

BACKGROUND: As a kind of mesenchymal-like stromal cells, endometrial regenerative cells (ERCs) have been demonstrated effective in the treatment of Concanavalin A (Con A)-induced hepatitis. However, the therapeutic mechanism of ERCs is not fully understood. Ecto-5`-nucleotidase (CD73), an enzyme that could convert immune-stimulative adenosine monophosphate (AMP) to immune-suppressive adenosine (ADO), was identified highly expressed on ERCs. The present study was conducted to investigate whether the expression of CD73 on ERCs is critical for its therapeutic effects in Con A-induced hepatitis. METHODS: ERCs knocking out CD73 were generated with lentivirus-mediated CRISPR-Cas9 technology and identified by flow cytometry, western blot and AMPase activity assay. CD73-mediated immunomodulatory effects of ERCs were investigated by CD4+ T cell co-culture assay in vitro. Besides, Con A-induced hepatitis mice were randomly assigned to the phosphate-buffered saline treated (untreated), ERC-treated, negative lentiviral control ERC (NC-ERC)-treated, and CD73-knockout-ERC (CD73-KO-ERC)-treated groups, and used to assess the CD73-mediated therapeutic efficiency of ERCs. Hepatic histopathological analysis, serum transaminase concentrations, and the proportion of CD4+ T cell subsets in the liver and spleen were performed to assess the progression degree of hepatitis. RESULTS: Expression of CD73 on ERCs could effectively metabolize AMP to ADO, thereby inhibiting the activation and function of conventional CD4+ T cells was identified in vitro. In addition, ERCs could markedly reduce levels of serum and liver transaminase and attenuate liver damage, while the deletion of CD73 on ERCs dampens these effects. Furthermore, ERC-based treatment achieved less infiltration of CD4+ T and Th1 cells in the liver and reduced the population of systemic Th1 and Th17 cells and the levels of pro-inflammatory cytokines such as IFN-γ and TNF-α, while promoting the generation of Tregs in the liver and spleen, while deletion of CD73 on ERCs significantly impaired their immunomodulatory effects locally and systemically. CONCLUSION: Taken together, it is concluded that CD73 is critical for the therapeutic efficiency of ERCs in the treatment of Con A-induced hepatitis.

Two novel transporters NtNRAMP6a and NtNRAMP6b are involved in cadmium transport in tobacco (Nicotiana tabacum L.).

Plant natural resistance-associated macrophage protein (NRAMP) plays important roles in metal transport and tolerance. Tobacco is a typical cadmium (Cd) accumulator, while research on NRAMP in tobacco has been limited. In the current study, two novel NRAMP genes (NtNRAMP6a and NtNRAMP6b) were identified from the allotetraploid plant Nicotiana tabacum L. Real time‒PCR and GUS (ß-glucuronidase) staining results showed that the two genes were expressed in roots, stems, leaves and flowers and induced by Cd stress. Subcellular localization revealed that they were located in the plasma membrane. Heterologously expressed NtNRAMP6a and NtNRAMP6b significantly increased the Cd sensitivity of the Δycf1 mutant, indicating that NtNRAMP6a and NtNRAMP6b had Cd transport functions in yeast. The difference in the manganese (Mn) transport activity of the two genes was demonstrated by point mutation, which was caused by the difference in the 18th amino acid. NRAMP6-N18K is a new key active site for manganese transport. After 50 µM Cd treatment for 7 days, the contents of Cd and Mn of the ntnramp6a/6b mutants was significantly lower than those of wild type in shoots, while the contents in roots were higher. Additionally, the mutant lines showed higher chorphyll contentration and lighter leaf damage. Knockout of NtNRAMP6a and NtNRAMP6b reduced Cd and Mn accumulation in tobacco shoots by influence root-to-shoot translocation. This provides new idea for cultivating tobacco varieties with low cadmium accumulation and high cadmium tolerance.

Metronomic capecitabine with rapamycin exerts an immunosuppressive effect by inducing ferroptosis of CD4+ T cells after liver transplantation in rat.

Liver transplantation is one of the most effective treatments for hepatocellular carcinoma (HCC). The balance between inhibiting immune rejection and preventing tumor recurrence after liver transplantation is the key to determining the long-term prognosis of patients with HCC after liver transplantation. In our previous study, we found that capecitabine (CAP), an effective drug for the treatment of HCC, could exert an immunosuppressive effect after liver transplantation by inducing T cell ferroptosis. Recent studies have shown that ferroptosis is highly associated with autophagy. In this study, we confirmed that the autophagy inducer rapamycin (RAPA) combined with metronomic capecitabine (mCAP) inhibits glutathione peroxidase 4 (GPX4) and promotes ferroptosis in CD4+ T cells to exert immunosuppressive effects after rat liver transplantation. Compared with RAPA or mCAP alone, the combination of RAPA and mCAP could adequately reduce liver injury in rats with acute rejection after transplantation. The CD4+ T cell counts in peripheral blood, spleen, and transplanted liver of recipient rats significantly decreased, and the oxidative stress level and ferrous ion concentration of CD4+ T cells significantly increased in the combination group. In vitro, the combination of drugs significantly promoted autophagy, decreased GPX4 protein expression, and induced ferroptosis in CD4+ T cells. In conclusion, the autophagy inducer RAPA improved the mCAP-induced ferroptosis in CD4+ T cells. Our results support the concept of ferroptosis as an autophagy-dependent cell death and suggest that the combination of ferroptosis inducers and autophagy inducers is a new research direction for improving immunosuppressive regimens after liver transplantation.

Metronomic capecitabine inhibits liver transplant rejection in rats by triggering recipients' T cell ferroptosis.

BACKGROUND: Capecitabine (CAP) is a classic antimetabolic drug and has shown potential antirejection effects after liver transplantation (LT) in clinical studies. Our previous study showed that metronomic CAP can cause the programmed death of T cells by inducing oxidative stress in healthy mice. Ferroptosis, a newly defined non-apoptotic cell death that occurs in response to iron overload and lethal levels of lipid peroxidation, is an important mechanism by which CAP induces cell death. Therefore, ferroptosis may also play an important role in CAP-induced T cell death and play an immunosuppressive role in acute rejection after trans-plantation. AIM: To investigate the functions and underlying mechanisms of antirejection effects of metronomic CAP. METHODS: A rat LT model of acute rejection was established, and the effect of metronomic CAP on splenic hematopoietic function and acute graft rejection was evaluated 7 d after LT. In vitro, primary CD3+ T cells were sorted from rat spleens and human peripheral blood, and co-cultured with or without 5-fluorouracil (5-FU) (active agent of CAP). The levels of ferroptosis-related proteins, ferrous ion concentration, and oxidative stress-related indicators were observed. The changes in mito-chondrial structure were observed using electron microscopy. RESULTS: With no significant myelotoxicity, metronomic CAP alleviated graft injury (Banff score 9 vs 7.333, P < 0.001), prolonged the survival time of the recipient rats (11.5 d vs 16 d, P < 0.01), and reduced the infiltration rate of CD3+ T cells in peripheral blood (6.859 vs 3.735, P < 0.001), liver graft (7.459 vs 3.432, P < 0.001), and spleen (26.92 vs 12.9, P < 0.001), thereby inhibiting acute rejection after LT. In vitro, 5-FU, an end product of CAP metabolism, induced the degradation of the ferritin heavy chain by upregulating nuclear receptor coactivator 4, which caused the accumulation of ferrous ions. It also inhibited nuclear erythroid 2 p45-related factor 2, heme oxygenase-1, and glutathione peroxidase 4, eventually leading to oxidative damage and ferroptosis of T cells. CONCLUSION: Metronomic CAP can suppress acute allograft rejection in rats by triggering CD3+ T cell ferroptosis, which makes it an effective immunosuppressive agent after LT.