Induction of Siglec-G by RNA viruses inhibits the innate immune response by promoting RIG-I degradation.

RIG-I is a critical RNA virus sensor that serves to initiate antiviral innate immunity. However, posttranslational regulation of RIG-I signaling remains to be fully understood. We report here that RNA viruses, but not DNA viruses or bacteria, specifically upregulate lectin family member Siglecg expression in macrophages by RIG-I- or NF-κB-dependent mechanisms. Siglec-G-induced recruitment of SHP2 and the E3 ubiquitin ligase c-Cbl to RIG-I leads to RIG-I degradation via K48-linked ubiquitination at Lys813 by c-Cbl. By increasing type I interferon production, targeted inactivation of Siglecg protects mice against lethal RNA virus infection. Taken together, our data reveal a negative feedback loop of RIG-I signaling and identify a Siglec-G-mediated immune evasion pathway exploited by RNA viruses with implication in antiviral applications. These findings also provide insights into the functions and crosstalk of Siglec-G, a known adaptive response regulator, in innate immunity.

Gestational Hypoxia and Developmental Plasticity.

Hypoxia is one of the most common and severe challenges to the maintenance of homeostasis. Oxygen sensing is a property of all tissues, and the response to hypoxia is multidimensional involving complicated intracellular networks concerned with the transduction of hypoxia-induced responses. Of all the stresses to which the fetus and newborn infant are subjected, perhaps the most important and clinically relevant is that of hypoxia. Hypoxia during gestation impacts both the mother and fetal development through interactions with an individual's genetic traits acquired over multiple generations by natural selection and changes in gene expression patterns by altering the epigenetic code. Changes in the epigenome determine "genomic plasticity," i.e., the ability of genes to be differentially expressed according to environmental cues. The genomic plasticity defined by epigenomic mechanisms including DNA methylation, histone modifications, and noncoding RNAs during development is the mechanistic substrate for phenotypic programming that determines physiological response and risk for healthy or deleterious outcomes. This review explores the impact of gestational hypoxia on maternal health and fetal development, and epigenetic mechanisms of developmental plasticity with emphasis on the uteroplacental circulation, heart development, cerebral circulation, pulmonary development, and the hypothalamic-pituitary-adrenal axis and adipose tissue. The complex molecular and epigenetic interactions that may impact an individual's physiology and developmental programming of health and disease later in life are discussed.

Analysis of chloroplast genome characteristics and codon usage bias in 14 species of Annonaceae.

For the study of species evolution, chloroplast gene expression, and transformation, the chloroplast genome is an invaluable resource. Codon usage bias (CUB) analysis is a tool that is utilized to improve gene expression and investigate evolutionary connections in genetic transformation. In this study, we analysed chloroplast genome differences, codon usage patterns and the sources of variation on CUB in 14 Annonaceae species using bioinformatics tools. The study showed that there was a significant variation in both gene sizes and numbers between the 14 species, but conservation was still maintained. It's worth noting that there were noticeable differences in the IR/SC sector boundary and the types of SSRs among the 14 species. The mono-nucleotide repeat type was the most common, with A/T repeats being more prevalent than G/C repeats. Among the different types of repeats, forward and palindromic repeats were the most abundant, followed by reverse repeats, and complement repeats were relatively rare. Codon composition analysis revealed that all 14 species had a frequency of GC lower than 50%. Additionally, it was observed that the proteins in-coding sequences of chloroplast genes tend to end with A/T at the third codon position. Among these species, 21 codons exhibited bias (RSCU > 1), and there were 8 high-frequency (HF) codons and 5 optimal codons that were identical across the species. According to the ENC-plot and Neutrality plot analysis, natural selection had less impact on the CUB of A. muricate and A. reticulata. Based on the PR2-plot, it was evident that base G had a higher frequency than C, and T had a higher frequency A. The correspondence analysis (COA) revealed that codon usage patterns different in Annonaceae.

TTK inhibition activates STING signal and promotes anti-PD1 immunotherapy in breast cancer.

Despite progress in the application of checkpoint immunotherapy against various tumors, attempts to utilize immune checkpoint blockade (ICB) agents in triple negative breast cancer (TNBC) have yielded limited clinical benefits. The low overall response rate of checkpoint immunotherapy in TNBC may be attributed to the immunosuppressive tumor microenvironment (TME). In this study, we investigated the role of mitogen-associated kinase TTK in reprogramming immune microenvironment in TNBC. Notably, TTK inhibition by BAY-1217389 induced DNA damage and the formation of micronuclei containing dsDNA in the cytosol, resulting in elicition of STING signal pathway and promoted antitumor immunity via the infiltration and activation of CD8+ T cells. Moreover, TTK inhibition also upregulated the expression of PD-L1, demonstrating a synergistic effect with anti-PD1 therapy in 4T1 tumor-bearing mice. Taken together, TTK inhibition facilitated anti-tumor immunity mediated by T cells and enhanced sensitivity to PD-1 blockade, providing a rationale for the combining TTK inhibitors with immune checkpoint blockade in clinical trials.

Advanced Hollow Cubic FeCo-N-C Cathode Electrocatalyst for Ultrahigh-Power Aluminum-Air Battery.

The exploration of electrocatalysts toward oxygen reduction reaction (ORR) is pivotal in the development of diverse batteries and fuel cells that rely on ORR. Here, a FeCo-N-C electrocatalyst (FeCo-HNC) featuring with atomically dispersed dual metal sites (Fe-Co) and hollow cubic structure is reported, which exhibits high activity for electrocatalysis of ORR in alkaline electrolyte, as evidenced by a half-wave potential of 0.907 V, outperforming that of the commercial Pt/C catalyst. The practicality of such FeCo-HNC catalyst is demonstrated by integrating it as the cathode catalyst into an alkaline aluminum-air battery (AAB) paring with an aluminum plate serving as the anode. This AAB demonstrates an unprecedented power density of 804 mW cm-2 in ambient air and an impressive 1200 mW cm-2 in an oxygen-rich environment. These results not only establish a new benchmark but also set a groundbreaking record for the highest power density among all AABs reported to date. Moreover, they stand shoulder to shoulder with state-of-the-art H2-O2 fuel cells. This AAB exhibits robust stability with continuous operation for an impressive 200 h. This groundbreaking achievement underscores the immense potential and forward strides that the present work brings to the field.

Ion channel Piezo1 activation aggravates the endothelial dysfunction under a high glucose environment.

BACKGROUND: Vasculopathy is the most common complication of diabetes. Endothelial cells located in the innermost layer of blood vessels are constantly affected by blood flow or vascular components; thus, their mechanosensitivity plays an important role in mediating vascular regulation. Endothelial damage, one of the main causes of hyperglycemic vascular complications, has been extensively studied. However, the role of mechanosensitive signaling in hyperglycemic endothelial damage remains unclear. METHODS: Vascular endothelial-specific Piezo1 knockout mice were generated to investigate the effects of Piezo1 on Streptozotocin-induced hyperglycemia and vascular endothelial injury. In vitro activation or knockdown of Piezo1 was performed to evaluate the effects on the proliferation, migration, and tubular function of human umbilical vein endothelial cells in high glucose. Reactive oxygen species production, mitochondrial membrane potential alternations, and oxidative stress-related products were used to assess the extent of oxidative stress damage caused by Piezo1 activation. RESULTS: Our study found that in VECreERT2;Piezo1flox/flox mice with Piezo1 conditional knockout in vascular endothelial cells, Piezo1 deficiency alleviated streptozotocin-induced hyperglycemia with reduced apoptosis and abscission of thoracic aortic endothelial cells, and decreased the inflammatory response of aortic tissue caused by high glucose. Moreover, the knockout of Piezo1 showed a thinner thoracic aortic wall, reduced tunica media damage, and increased endothelial nitric oxide synthase expression in transgenic mice, indicating the relief of endothelial damage caused by hyperglycemia. We also showed that Piezo1 activation aggravated oxidative stress injury and resulted in severe dysfunction through the Ca2+-induced CaMKII-Nrf2 axis in human umbilical vein endothelial cells. In Piezo1 conditional knockout mice, Piezo1 deficiency partially restored superoxide dismutase activity and reduced malondialdehyde content in the thoracic aorta. Mechanistically, Piezo1 deficiency decreased CaMKII phosphorylation and restored the expression of Nrf2 and its downstream molecules HO-1 and NQO1. CONCLUSION: In summary, our study revealed that Piezo1 is involved in high glucose-induced oxidative stress injury and aggravated endothelial dysfunction, which have great significance for alleviating endothelial damage caused by hyperglycemia.

Adenosine kinase inhibits ß-cell proliferation by upregulating DNA methyltransferase 3A expression.

AIM: To investigate the effects of adenosine kinase (ADK), a key enzyme in determining intracellular adenosine levels, on ß cells, and their underlying mechanism. METHODS: Genetic animal models and transgenic immortalized cells were applied to study the effect of ADK on islet beta-cell proliferation and function. The beta-cell mass and response to glucose were measured in vivo using mice with beta-cell-specific ADK overexpression, and in vitro using ADK-overexpressed immortalized beta-cell. RESULTS: The expression of ADK in human islets at high abundance, especially in ß cells, was decreased during the process of ß-cell proliferation. Additionally, a transgenic mouse model (ADKtg/tg /Mip-Cre) was generated wherein the mouse Insulin1 gene promoter specifically overexpressed ADK in pancreatic ß cells. The ADKtg/tg /Mip-Cre model exhibited impaired glucose tolerance, decreased fasting plasma insulin, loss of ß-cell mass, and inhibited ß-cell proliferation. Proteomic analysis revealed that ADK overexpression inhibited the expression of several proteins that promote cell proliferation and insulin secretion. Upregulating ADK in the ß-cell line inhibited the expression of ß-cell related regulatory molecules, including FoxO1, Appl1, Pxn, Pdx-1, Creb and Slc16a3. Subsequent in vitro experiments indicated that the inhibition of ß-cell proliferation and the decreased expression of Pdx-1, Creb and Slc16a3 were rescued by DNA methyltransferase 3A (DNMT3A) knockdown in ß cells. CONCLUSION: In this study, we found that the overexpression of ADK decreased the expression of several genes that regulate ß cells, resulting in the inhibition of ß-cell proliferation and dysfunction by upregulating the expression of DNMT3A.

Synthesis and Biological Activities of Scleropentaside D.

We report the first total synthesis of scleropentaside D, a unique C-glycosidic ellagitannin, from the ketal derivative of scleropentaside A employing site-selective O4-protection of C-acyl glycoside and copper-catalyzed oxidative coupling reaction of galloyl groups as the key steps. Our study confirms the proposed structure of this natural product, scleropentaside D, and demonstrates its effectiveness as an inhibitor of α-glycosidase.

OTUD1 promotes hypertensive kidney fibrosis and injury by deubiquitinating CDK9 in renal epithelial cells.

Hypertensive renal disease (HRD) contributes to the progression of kidney dysfunction and ultimately leads to end-stage renal disease. Understanding the mechanisms underlying HRD is critical for the development of therapeutic strategies. Deubiquitinating enzymes (DUBs) have been recently highlighted in renal pathophysiology. In this study, we investigated the role of a DUB, OTU Domain-Containing Protein 1 (OTUD1), in HRD models. HRD was induced in wild-type or Otud1 knockout mice by chronic infusion of angiotensin II (Ang II, 1 µg/kg per min) through a micro-osmotic pump for 4 weeks. We found that OTUD1 expression levels were significantly elevated in the kidney tissues of Ang II-treated mice. Otud1 knockout significantly ameliorated Ang II-induced HRD, whereas OTUD1 overexpression exacerbated Ang II-induced kidney damage and fibrosis. Similar results were observed in TCMK-1 cells but not in SV40 MES-13 cells following Ang II (1 µM) treatment. In Ang II-challenged TCMK-1 cells, we demonstrated that OTUD1 bound to CDK9 and induced CDK9 deubiquitination: OTUD1 catalyzed K63 deubiquitination on CDK9 with its Cys320 playing a critical role, promoting CDK9 phosphorylation and activation to induce inflammatory responses and fibrosis in kidney epithelial cells. Administration of a CDK9 inhibitor NVP-2 significantly ameliorated Ang II-induced HRD in mice. This study demonstrates that OTUD1 mediates HRD by targeting CDK9 in kidney epithelial cells, suggesting OTUD1 is a potential target in treating this disease.

A thematic content analysis of the structure and effects of good doctor abilities in China.

BACKGROUND: The efforts to explore and build the structure of good doctor abilities are important because they help improve the quality of education for medical students and better standardize the working performance of doctors. However, at present, no worldwide standards for such a structure have been established. In this study, we endeavoured to map the structure of good doctor abilities and identify their effects. METHODS: With a focus on China, a thematic content analysis was adopted in this study to analyse the personal profiles of 50 widely recognized good doctors. NVivo11 software was used. RESULTS: The Structure and Effects of Good Doctor Abilities in China model was proposed, and interpretations were made based on AMO theory. Good doctor abilities fall within six categories: rigorous clinical thinking, skilled in diagnosis and therapy, clinical empathy, continuous learning and innovation, enhancing and sharing experiences, and communication and coordination. These abilities have positive impacts on doctors' work performances and social benefits by encouraging good behaviours, ultimately promoting the sustainable development of the hospitals where they serve. CONCLUSIONS: In this study, we established a model of the structure and effects of good-doctor abilities in China and interpreted its mechanism, innovation and theory diversification in "good-doctor" research. Moreover, this study has practical significance because it provides systematic and well-targeted criteria for improving the professionalism of doctors, promoting more good doctor behaviours, providing guidance for regulating doctors' conduct and providing a reference for medical education and working performance reviews worldwide.

Preservation of the celiac branch of the vagus nerve reduces the incidence of postoperative diarrhea in gastric cancer: a cohort study.

BACKGROUND: To investigate the short-term and long-term outcomes of preserving the celiac branch of the vagus nerve during laparoscopic distal gastrectomy. METHODS: A total of 149 patients with prospective diagnosis of gastric cancer who underwent laparoscopic-assisted distal gastrectomy (LADG) combined with Billroth-II anastomosis and D2 lymph node dissection between 2017 and 2018 were retrospectively analyzed. The patients were divided into the preserved LADG group (P-LADG, n = 56) and the resected LADG group (R-LADG, n = 93) according to whether the vagus nerve celiac branch was preserved. We selected 56 patients (P-LADG, n = 56) with preservation of the celiac branch of the vagus nerve and 56 patients (R-LADG, n = 56) with removal of the celiac branch of the vagus nerve by propensity-matched score method. Postoperative nutritional status, weight change, short-term and long-term postoperative complications, and gallstone formation were evaluated in both groups at 5 years of postoperative follow-up. The status of residual gastritis and bile reflux was assessed endoscopically at 12 months postoperatively. RESULTS: The incidence of diarrhea at 5 years postoperatively was lower in the P-LADG group than in the R-LADG group (p < 0.05). In the multivariate logistic analysis, the removal of vagus nerve celiac branch was an independent risk factor for the occurrence of postoperative diarrhea (odds ratio = 3.389, 95% confidential interval = 1.143-10.049, p = 0.028). In the multivariate logistic analysis, the removal of vagus nerve celiac branch was an independent risk factor for the occurrence of postoperative diarrhea (odds ratio = 4.371, 95% confidential interval = 1.418-13.479, p = 0.010). CONCLUSIONS: Preservation of the celiac branch of the vagus nerve in LADG reduced the incidence of postoperative diarrhea postoperatively in gastric cancer. TRIAL REGISTRATION: This study was registered with the Ethics Committee of the First Affiliated Hospital of Dalian Medical University in 2014 under the registration number: LCKY2014-04(X).

Toxic effects of combined exposure to homoyessotoxin and nitrite on the survival, antioxidative responses, and apoptosis of the abalone Haliotis discus hannai.

Homoyessotoxin (homo-YTX) and nitrite (NO2-N), released during harmful dinoflagellate cell lysis adversely affect abalones. However, their toxicity mechanisms in shellfish remain unclear. This study investigated the economic abalone species Haliotis discus hannai exposed to varying concentrations of homo-YTX (0, 2, 5, and 10 µg L-1) and NO2-N (0, 3, and 6 mg L-1) on the basis of their 12 h LC50 values (5.05 µg L-1 and 4.25 mg L-1, respectively) and the environmentally relevant dissolved concentrations during severe dinoflagellate blooms, including mixtures. The test abalones were exposed to homo-YTX and NO2-N for 12 h. The mortality rate (D), reactive oxygen species (ROS) levels, antioxidant defense capabilities, and expression levels of antioxidant-related, Hsp-related, and apoptosis-related genes in abalone gills were assessed. Results showed that the combined exposure to homo-YTX and NO2-N increased the D and ROS levels and upregulated B-cell lymphoma-2 (BCL2)-associated X (BAX) and caspase3 (CASP3) expression levels while reducing glutathione peroxidase (GPx) activity and GPx, CuZnSOD, and BCL2 expression levels. High concentrations of homo-YTX (10 µg L-1) and NO2-N (6 mg L-1) solutions and the combinations of these toxicants inhibited the activities of superoxide dismutase (SOD) and catalase (CAT) and downregulated the expression levels of MnSOD, CAT, Hsp70, and Hsp90. The ROS levels were negatively correlated with the activities of SOD, CAT, and GPx and the expression levels of MnSOD, CuZnSOD, CAT, GPx, Hsp70, Hsp90, and BCL2. These results suggest that homo-YTX, in conjunction with NO2-N, induces oxidative stress, disrupts antioxidant defense systems, and triggers caspase-dependent apoptosis in the gills of abalone. ROS-mediated antioxidative and heat-shock responses and apoptosis emerge as potential toxicity mechanisms affecting the survival of H. discus hannai due to homo-YTX and NO2-N exposure.

Single-cell RNA sequencing reveals diverse B cell phenotypes in patients with anti-NMDAR encephalitis.

BACKGROUNDS: Anti-N-methyl-D-aspartate receptor encephalitis (NMDAR-E) is a severe autoimmune disorder characterized by prominent psychiatric symptoms. Although the role of NMDAR antibodies in the disease has been extensively studied, the phenotype of B cell subsets is still not fully understood. METHODS: We utilized single-cell RNA sequencing, single-cell B cell receptor sequencing (scBCR-seq), bulk BCR sequencing, flow cytometry, and enzyme-linked immunosorbent assay to analyze samples from both NMDAR-E patients and control individuals. RESULTS: The cerebrospinal fluid (CSF) of NMDAR-E patients showed significantly increased B cell counts, predominantly memory B (Bm) cells. CSF Bm cells in NMDAR-E patients exhibited upregulated expression of differential expression genes (DEGs) associated with immune regulatory function (TNFRSF13B and ITGB1), whereas peripheral B cells upregulated DEGs related to antigen presentation. Additionally, NMDAR-E patients displayed higher levels of IgD- CD27- double negative (DN) cells and DN3 cells in peripheral blood (PB). In vitro, DN1 cell subsets from NMDAR-E patients differentiated into DN2 and DN3 cells, while CD27+ and/or IgD+ B cells (non-DN) differentiated into antibody-secreting cells (ASCs) and DN cells. NR1-IgG antibodies were found in B cell culture supernatants from patients. Differential expression of B cell IGHV genes in CSF and PB of NMDAR-E patients suggests potential antigen class switching. CONCLUSION: B cell subpopulations in the CSF and PB of NMDAR-E patients exhibit distinct compositions and transcriptomic features. In vitro, non-DN cells from NMDAR-E can differentiate into DN cells and ASCs, potentially producing NR1-IgG antibodies. Further research is necessary to investigate the potential contribution of DN cell subpopulations to NR1-IgG antibody production.

Comparative analysis of codon usage patterns in the chloroplast genomes of nine forage legumes.

Leguminosae is one of the three largest families of angiosperms after Compositae and Orchidaceae. It is widely distributed and grows in a variety of environments, including plains, mountains, deserts, forests, grasslands, and even waters where almost all legumes can be found. It is one of the most important sources of starch, protein and oil in the food of mankind and also an important source of high-quality forage material for animals, which has important economic significance. In our study, the codon usage patterns and variation sources of the chloroplast genome of nine important forage legumes were systematically analyzed. Meanwhile, we also constructed a phylogenetic tree based on the whole chloroplast genomes and protein coding sequences of these nine forage legumes. Our results showed that the chloroplast genomes of nine forage legumes end with A/T bases, and seven identical high-frequency (HF) codons were detected among the nine forage legumes. ENC-GC3s mapping, PR2 analysis, and neutral analysis showed that the codon bias of nine forage legumes was influenced by many factors, among which natural selection was the main influencing factor. The codon usage frequency showed that the Nicotiana tabacum and Saccharomyces cerevisiae can be considered as receptors for the exogenous expression of chloroplast genes of these nine forage legumes. The phylogenetic relationships of the chloroplast genomes and protein coding genes were highly similar, and the nine forage legumes were divided into three major clades. Among the clades Melilotus officinalis was more closely related to Medicago sativa, and Galega officinalis was more closely related to Galega orientalis. This study provides a scientific basis for the molecular markers research, species identification and phylogenetic studies of forage legumes. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01421-0.

TET2 confers a mechanistic link of microRNA-210 and mtROS in hypoxia-suppressed spontaneous transient outward currents in uterine arteries of pregnant sheep.

Hypoxia during pregnancy impairs uterine vascular adaptation via microRNA-210 (miR-210)-mediated mitochondrial dysfunction and mitochondrial reactive oxygen species (mtROS) generation. TET methylcytosine dioxygenase 2 (TET2) participates in regulating inflammation and oxidative stress and its deficiency contributes to the pathogenesis of multiple cardiovascular diseases. Thus, we hypothesize a role of TET2 in hypoxia/miR-210-mediated mtROS suppressing spontaneous transient outward currents (STOCs) in uterine arteries. We found that gestational hypoxia downregulated TET2 in uterine arteries of pregnant sheep and TET2 was a target of miR-210. Knockdown of TET2 with small interfering RNAs suppressed mitochondrial respiration, increased mtROS, inhibited STOCs and elevated myogenic tone. By contrast, overexpression of TET2 negated hypoxia- and miR-210-induced mtROS. The effects of TET2 knockdown in uterine arteries on mtROS, STOCs and myogenic contractions were blocked by the mitochondria-targeted antioxidant MitoQ. In addition, the recovery effects of inhibiting endogenous miR-210 with miR-210-LNA on hypoxia-induced suppression of STOCs and augmentation of myogenic tone were reversed by TET2 knockdown in uterine arteries. Together, our study reveals a novel mechanistic link between the miR-210-TET2-mtROS pathway and inhibition of STOCs and provides new insights into the understanding of uterine vascular maladaptation in pregnancy complications associated with gestational hypoxia. KEY POINTS: Gestational hypoxia downregulates TET methylcytosine dioxygenase 2 (TET2) in uterine arteries of pregnant sheep. TET2 is a downstream target of microRNA-210 (miR-210) and miR-210 mediates hypoxia-induced TET2 downregulation. Knockdown of TET2 in uterine arteries recapitulates the effect of hypoxia and miR-210 and impairs mitochondrial bioenergetics and increases mitochondrial reactive oxygen species (mtROS) . Overexpression of TET2 negates the effect of hypoxia and miR-210 on increasing mtROS. TET2 knockdown reiterates the effect of hypoxia and miR-210 and suppresses spontaneous transient outward currents (STOCs) and elevates myogenic tone, and these effects are blocked by MitoQ. Knockdown of TET2 reverses the miR-210-LNA-induced reversal of the effects of hypoxia on STOCs and myogenic tone in uterine arteries.

Screening of Tnfaip1-Interacting Proteins in Zebrafish Embryonic cDNA Libraries Using a Yeast Two-Hybrid System.

TNFAIP1 regulates cellular biological functions, including DNA replication, DNA repair, and cell cycle, by binding to target proteins. Identification of Tnfaip1-interacting proteins contributes to the understanding of the molecular regulatory mechanisms of their biological functions. In this study, 48 hpf, 72 hpf, and 96 hpf wild-type zebrafish embryo mRNAs were used to construct yeast cDNA library. The library titer was 1.12 × 107 CFU/mL, the recombination rate was 100%, and the average length of the inserted fragments was greater than 1000 bp. A total of 43 potential interacting proteins of Tnfaip1 were identified using zebrafish Tnfaip1 as a bait protein. Utilizing GO functional annotation and KEGG signaling pathway analysis, we found that these interacting proteins are mainly involved in translation, protein catabolic process, ribosome assembly, cytoskeleton formation, amino acid metabolism, and PPAR signaling pathway. Further yeast spotting analyses identified four interacting proteins of Tnfaip1, namely, Ubxn7, Tubb4b, Rpl10, and Ybx1. The Tnfaip1-interacting proteins, screened from zebrafish embryo cDNA in this study, increased our understanding of the network of Tnfaip1-interacting proteins during the earliest embryo development and provided a molecular foundation for the future exploration of tnfaip1's biological functions.

Low-dose decitabine modulates T-cell homeostasis and restores immune tolerance in immune thrombocytopenia.

Our previous clinical study showed that low-dose decitabine exhibited sustained responses in nearly half of patients with refractory immune thrombocytopenia (ITP). The long-term efficacy of decitabine in ITP is not likely due to its simple role in increasing platelet production. Whether decitabine has the potential to restore immune tolerance in ITP is unknown. In this study, we analyzed the effect of decitabine on T-cell subpopulations in ITP in vitro and in vivo. We found that low-dose decitabine promoted the generation and differentiation of regulatory T (Treg) cells and augmented their immunosuppressive function. Splenocytes from CD61 knockout mice immunized with CD61+ platelets were transferred into severe combined immunodeficient mouse recipients to induce a murine model of ITP. Low-dose decitabine alleviated thrombocytopenia and restored the balance between Treg and helper T (Th) cells in active ITP mice. Treg deletion and depletion offset the effect of decitabine in restoring CD4+ T-cell subpopulations in ITP mice. For patients who received low-dose decitabine, the quantity and function of Treg cells were substantially improved, whereas Th1 and Th17 cells were suppressed compared with the pretreatment levels. Next-generation RNA-sequencing and cytokine analysis showed that low-dose decitabine rebalanced T-cell homeostasis, decreased proinflammatory cytokines, and downregulated phosphorylated STAT3 in patients with ITP. STAT3 inhibition analysis suggested that low-dose decitabine might restore Treg cells by inhibiting STAT3 activation. In conclusion, our data indicate that the immunomodulatory effect of decitabine provides one possible mechanistic explanation for the sustained response achieved by low-dose decitabine in ITP.

The consequence and mechanism of dietary flavonoids on androgen profiles and disorders amelioration.

Androgen is a kind of steroid hormone that plays a vital role in reproductive system and homeostasis of the body. Disrupted androgen balance serves as the causal contributor to a series of physiological disorders and even diseases. Flavonoids, as an extremely frequent family of natural polyphenols, exist widely in plants and foods and have received great attention when considering their inevitable consumption and estrogen-like effects. Mounting evidence illustrates that flavonoids have a propensity to interfere with androgen synthesis and metabolism, and also have a designated improvement effect on androgen disorders. Therefore, flavonoids were divided into six subclasses based on the structural feature in this paper, and the literature about their effects on androgens published in the past ten years was summarized. It could be concluded that flavonoids have the potential to regulate androgen levels and biological effects, mainly by interfering with the hypothalamic-pituitary-gonadal axis, androgen synthesis and metabolism, androgen binding with its receptors and membrane receptors, and antioxidant effects. The faced challenges about androgen regulation by flavonoids masterly include target mechanism exploration, individual heterogeneity, food matrixes interaction, and lack of clinical study. This review also provides a scientific basis for nutritional intervention using flavonoids to improve androgen disorder symptoms.

Cationic Half-Sandwich Tetrahydrofluorenyl Rare-Earth Metal Complexes as Stable Single-Site Catalysts for (Co)Polymerization of Styrene and Butadiene.

As indenyl-derivates, the tetrahydrofluorenyl ligands had an expanded "wingspan" with considerable steric hindrance. In this text, the rare-earth metal complexes bearing tetrahydrofluorenyl ligands have been synthesized and fully characterized by NMR (1H and 13C) and X-ray diffraction analyses. Upon the activation by [Ph3C][B(C6F5)4], all the scandium complexes exhibited excellent catalytic activity for highly syndioselective polymerization of styrene with a narrow molecular weight distribution (Mw/Mn < 2.0), suggesting the beneficial influence of tetrahydrofluorenyl ligands in stabilizing the single-site active species during the polymerization. Moreover, the scandium-based catalytic systems also promoted the 1,4-regular polymerization of butadiene and its copolymerization with styrene, affording diblock copolymers featuring a highly syndiotactic polystyrene block and a 1,4-specific PBD block. The kinetics investigation revealed the huge gap in TMS-Sc-catalyzed polymerization reactivity ratios (rBD/rSt > 300) between butadiene and styrene, and this further proved the block structure of styrene-butadiene copolymers. The morphology and mechanical property of the selected diblock copolymer were, respectively, investigated by atomic force microscopy and stress-strain experiments.

New P,Nsp3 ligands for palladium-catalyzed asymmetric allylic substitutions.

New P,Nsp3 bidentate ligands containing two chiral carbon centers were developed and applied to palladium-catalyzed asymmetric allylic substitution reactions. Good generalities with various nucleophiles, including carbon, nitrogen and oxygen containing nucleophiles, were achieved with up to 96% ee and 98% yield. This reaction provides an efficient method for the asymmetric formation of C-C, C-N and C-O bonds.