Stepwise analysis of thyroid diagnostic modalities with genomic imprinting detection.

BACKGROUND: The current preoperative malignancy risk evaluation for thyroid nodules involves stepwise diagnostic modalities including ultrasonography, thyroid function serology and fine-needle aspiration (FNA) cytopathology, respectively. We aimed to substantiate the stepwise contributions of each diagnostic step and additionally investigate the diagnostic significance of quantitative chromogenic imprinted gene in-situ hybridization (QCIGISH)-an adjunctive molecular test based on epigenetic imprinting alterations. METHODS: A total of 114 cytopathologically-diagnosed and histopathologically-confirmed thyroid nodules with complete ultrasonographic and serological examination records were evaluated using QCIGISH in the study. Logistic regression models for thyroid malignancy prediction were developed with the stepwise addition of each diagnostic modality and the contribution of each step evaluated in terms of discrimination performance and goodness-of-fit. RESULTS: From the baseline model using ultrasonography [area under the receiver operating characteristics curve (AUROC): 0.79; 95% confidence interval (CI): 0.71-0.86], significant improvements in thyroid malignancy discrimination were observed with the stepwise addition of thyroid function serology (AUROC: 0.82; 95% CI: 0.74-0.90; P=0.23) and FNA cytopathology (AUROC: 0.88; 95% CI: 0.81-0.94; P=0.02), respectively. The inclusion of QCIGISH as an adjunctive molecular test further advanced the preceding model's diagnostic performance (AUROC: 0.95; 95% CI: 0.91-1.00, P=0.007). CONCLUSIONS: Our study demonstrated the significant stepwise diagnostic contributions of standard clinical assessments in the malignancy risk stratification of thyroid nodules. However, the addition of molecular imprinting detection further enabled a more accurate and definitive preoperative evaluation especially for morphologically indeterminate thyroid nodules and cases with potentially discordant results among standard modalities.

The F-box protein RhSAF destabilizes the gibberellic acid receptor RhGID1 to mediate ethylene-induced petal senescence in rose.

Roses are among the most popular ornamental plants cultivated worldwide for their great economic, symbolic, and cultural importance. Nevertheless, rapid petal senescence markedly reduces rose (Rosa hybrida) flower quality and value. Petal senescence is a developmental process tightly regulated by various phytohormones. Ethylene accelerates petal senescence, while gibberellic acid (GA) delays this process. However, the molecular mechanisms underlying the crosstalk between these phytohormones in the regulation of petal senescence remain largely unclear. Here, we identified SENESCENCE-ASSOCIATED F-BOX (RhSAF), an ethylene-induced F-box protein gene encoding a recognition subunit of the SCF-type E3 ligase. We demonstrated that RhSAF promotes degradation of the GA receptor GIBBERELLIN INSENSITIVE DWARF1 (RhGID1) to accelerate petal senescence. Silencing RhSAF expression delays petal senescence, while suppressing RhGID1 expression accelerates petal senescence. RhSAF physically interacts with RhGID1s and targets them for ubiquitin/26S proteasome-mediated degradation. Accordingly, ethylene-induced RhGID1C degradation and RhDELLA3 accumulation are compromised in RhSAF-RNAi lines. Our results demonstrate that ethylene antagonizes GA activity through RhGID1 degradation mediated by the E3 ligase RhSAF. These findings enhance our understanding of the phytohormone crosstalk regulating petal senescence and provide insights for improving flower longevity.

Prohibitin 2: A key regulator of cell function.

The PHB2 gene is located on chromosome 12p13 and encodes prohibitin 2, a highly conserved protein of 37 kDa. PHB2 is a dimer with antiparallel coils, possessing a unique negatively charged region crucial for its mitochondrial molecular chaperone functions. Thus, PHB2 plays a significant role in cell life activities such as mitosis, mitochondrial autophagy, signal transduction, and cell death. This review discusses how PHB2 inhibits transcription factors or nuclear receptors to maintain normal cell functions; how PHB2 in the cytoplasm or membrane ensures normal cell mitosis and regulates cell differentiation; how PHB2 affects mitochondrial structure, function, and cell apoptosis through mitochondrial intimal integrity and mitochondrial autophagy; how PHB2 affects mitochondrial stress and inhibits cell apoptosis by regulating cytochrome c migration and other pathways; how PHB2 affects cell growth, proliferation, and metastasis through a mitochondrial independent mechanism; and how PHB2 could be applied in disease treatment. We provide a theoretical basis and an innovative perspective for a comprehensive understanding of the role and mechanism of PHB2 in cell function regulation.

The relationship between bullous pemphigoid and renal disease and related treatments: a review of the current literature.

INTRODUCTION: Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disorder in older adults. There is increasing evidence that BP has connections with renal diseases, such as glomerulopathy and neoplasm; it is also linked to the receipt of renal replacement therapy. AREAS COVERED: In this review, we summarize the current evidence that BP is a comorbidity of common renal diseases. Furthermore, our exploration of the characteristics and possible mechanisms underlying these connections provides insights that may facilitate the prevention, diagnosis, and management of BP. EXPERT OPINION: There is mounting proof that BP is not just a skin immunological disorder but rather a systemic immune-mediated illness. Quantities of case reports focused on BP as a renal disease comorbidity and the coexistence of them is not accidental. However, the underlying mechanisms are still needed to be investigated. Clinicians should be alert to the comorbidities in order to facilitate effective treatment and improve patient prognosis.

Clinical evidence of the efficacy and safety of a new multi-peptide anti-aging topical eye serum.

BACKGROUND: Skin aging is a complex multifactorial progressive process. With age, intrinsic and extrinsic factors cause the loss of skin elasticity, with the formation of wrinkles, resulting in skin sagging through various pathways. A combination of multiple bioactive peptides could be used as a treatment for skin wrinkles and sagging. OBJECTIVES: This study aimed to evaluate the cosmetic efficacy of a multi-peptide eye serum as a daily skin-care product for improving the periocular skin of women within the ages of 20-45 years. METHODS: The stratum corneum skin hydration and skin elasticity were assessed using a Corneometer CM825 and Skin Elastometer MPA580, respectively. The PRIMOS CR technique based on digital strip projection technology was used for skin image and wrinkle analysis around the "crow's feet" area. Self-assessment questionnaires were filled on Day 14 and 28 of product use. RESULTS: This study included 32 subjects with an average age of 28.5 years. On Day 28, there was a significant decrease in the number, depth, and volume of wrinkles. Skin hydration, elasticity, and firmness increased continuously during the study period, consistent with typical anti-aging claims. A majority of the participants (75.00%) expressed overall satisfaction with their skin appearance after using the product. Most participants noted a visible skin improvement, with an increase in skin elasticity and smoothness, and confirmed the extensibility, applicability, and temperance of the product. No adverse reactions related to product use were observed. CONCLUSIONS: The multi-peptide eye serum uses a multi-targeted mechanism against skin aging to improve the skin appearance, making it an ideal choice for daily skincare.

Affinity selection of double-click triazole libraries for rapid discovery of allosteric modulators for GLP-1 receptor.

The recently developed double-click reaction sequence [G. Meng et al., Nature 574, 86-89 (2019)] is expected to vastly expand the number and diversity of synthetically accessible 1,2,3-triazole derivatives. However, it remains elusive how to rapidly navigate the extensive chemical space created by double-click chemistry for bioactive compound discovery. In this study, we selected a particularly challenging drug target, the glucagon-like-peptide-1 receptor (GLP-1R), to benchmark our new platform for the design, synthesis, and screening of double-click triazole libraries. First, we achieved a streamlined synthesis of customized triazole libraries on an unprecedented scale (composed of 38,400 new compounds). By interfacing affinity-selection mass spectrometry and functional assays, we identified a series of positive allosteric modulators (PAMs) with unreported scaffolds that can selectively and robustly enhance the signaling activity of the endogenous GLP-1(9-36) peptide. Intriguingly, we further revealed an unexpected binding mode of new PAMs which likely act as a molecular glue between the receptor and the peptide agonist. We anticipate the merger of double-click library synthesis with the hybrid screening platform allows for efficient and economic discovery of drug candidates or chemical probes for various therapeutic targets.

Hydrophobic-action-driven removal of six organophosphorus pesticides from tea infusion by modified carbonized bacterial cellulose.

The abuse of organophosphorus pesticides (OPPs) in tea planting makes it easy to transfer from tea into its infusion, bringing potential health risks to consumers. Thus, it is essential to adopt reliable techniques to remove OPPs from tea infusion. In this study, three treatment methods were used to modify carbonized bacterial cellulose (CBC) to improve its adsorption performance. Among them, CBC treated by hydrazine hydrate (N-CBC) had the best adsorption effect, whose removal rate for dicrotophos is 13 times that of CBC. The in-depth study of adsorption mechanism proved that hydrophobic interaction dominated the adsorption of OPPs onto N-CBC. The pseudo-second-order kinetic model and Langmuir isotherm model were more suitable to describe the process. Additionally, there were no significant changes in tea infusion quality after N-CBC treatment. This work clarifies that N-CBC benefitted from simple preparation method, excellent adsorption performance and unique adsorption mechanism has potential applications in tea infusion.

Leukemia cutis in T-cell acute lymphoblastic leukemia: a 3-year follow-up case report.

BACKGROUND: Leukemia cutis (LC) is the infiltration of neoplastic leukocytes in the skin that can be observed in various types of leukemia including chronic lymphocytic leukemia, acute myeloid leukemia, and, occasionally, acute lymphoblastic leukemia. LC is considered an unfavorable prognostic factor in previous studies, and most patients die within 1 year after diagnosis. Herein, we report an uncommon case in which a patient presented with LC as the initial symptom of T-cell acute lymphoblastic leukemia (T-ALL) and remained in excellent clinical condition during a 3-year follow-up after treatment. CASE DESCRIPTION: A 50-year-old Chinese woman manifested with multiple infiltrated purplish plaques and tumors over the face, trunk, and lower extremities for more than 5 months, accompanied by recurrent fever and arthralgia. The diagnosis of T-ALL with LC was established by skin biopsy and bone marrow examination. After treatment with chemotherapy and allogeneic stem cell transplantation, the patient achieved complete remission and remained in good health for 3 years. To our knowledge, this is the first described case of a favorable evolution after a 3-year follow-up. CONCLUSIONS: Although uncommon, LC can be the first indication of the presence of T-ALL. This case highlights that early recognition of possible LC and access to treatment may benefit future patients with T-ALL and improve the prognosis of this aggressive disorder.

Activation of the kynurenine-aryl hydrocarbon receptor axis impairs the chondrogenic and chondroprotective effects of human umbilical cord-derived mesenchymal stromal cells in osteoarthritis rats.

It has been proven that intra-articular injection of mesenchymal stromal cells (MSCs) can alleviate cartilage damage in osteoarthritis (OA) by differentiating into chondrocytes and protecting inherent cartilage. However, the mechanism by which the OA articular microenvironment affects MSCs' therapeutic efficiency is yet to be fully elucidated. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in various cellular processes, such as osteogenesis and immune regulation. Tryptophan (Trp) metabolites, most of which are endogenous ligand for AHR, are abnormally increased in synovial fluid (SF) of OA and rheumatoid arthritis (RA) patients. In this study, the effects of kynurenine (KYN), one of the most important metabolites of Trp, were evaluated on the chondrogenic and chondroprotective effects of human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs). hUC-MSCs were cultured in conditioned medium containing different proportions of OA/RA SF, or stimulated with KYN directly, and then, AHR activation, proliferation, and chondrogenesis of hUC-MSCs were measured. Moreover, the chondroprotective efficiency of short hairpin-AHR-UC-MSC (shAHR-UC-MSC) was determined in a rat surgical OA model (right hind joint). OA SF could activate AHR signaling in hUC-MSCs in a concentration-dependent manner and inhibit the chondrogenic differentiation and proliferation ability of hUC-MSCs. Similar results were observed in hUC-MSCs stimulated with KYN in vitro. Notably, shAHR-UC-MSC exhibited superior therapeutic efficiency in OA rat upon intra-articular injection. Taken together, this study indicates that OA articular microenvironment is not conducive to the therapeutic effect of hUC-MSCs, which is related to the activation of the AHR pathway by tryptophan metabolites, and thus impairs the chondrogenic and chondroprotective effects of hUC-MSCs. AHR might be a promising modification target for further improving the therapeutic efficacy of hUC-MSCs on treatment of cartilage-related diseases such as OA.

High Diagnostic Accuracy of Epigenetic Imprinting Biomarkers in Thyroid Nodules.

PURPOSE: To explore the novel diagnostic value of epigenetic imprinting biomarkers in thyroid nodules. PATIENTS AND METHODS: A total of 550 patients with fine-needle aspiration (FNA)-evaluated and histopathologically confirmed thyroid nodules were consecutively recruited from eight medical centers. Quantitative chromogenic imprinted gene in situ hybridization (QCIGISH) was used to assess the allelic expression of imprinted genes SNRPN and HM13, on the basis of which a diagnostic grading model for thyroid nodules was developed. The model was retrospectively trained on 124 postsurgical thyroid samples, optimized on 32 presurgical FNA samples, and prospectively validated on 394 presurgical FNA samples. Blinded central review-based cytopathologic and histopathologic diagnoses were used as the reference standard. RESULTS: For thyroid malignancy, the QCIGISH test achieved an overall diagnostic sensitivity of 100% (277/277), a specificity of 91.5% (107/117; 95% CI, 86.4 to 96.5), a positive predictive value (PPV) of 96.5% (95% CI, 94.4 to 98.6), and a negative predictive value (NPV) of 100% in the prospective validation, with a diagnostic accuracy of 97.5% (384/394; 95% CI, 95.9 to 99.0). QCIGISH demonstrated a PPV of 97.8% (95% CI, 94.7 to 100) and NPV of 100%, with a diagnostic accuracy of 98.2% (111/113; 95% CI, 95.8 to 100), for indeterminate Bethesda III-V thyroid nodules. QCIGISH demonstrated a PPV of 96.6% (95% CI, 91.9 to 100) and a NPV of 100%, with a diagnostic accuracy of 97.5% (79/81; 95% CI, 94.2 to 100), for Bethesda III-IV. For Bethesda VI, QCIGISH showed a 100% (184/184) accuracy. CONCLUSION: This imprinting biomarker-based test can effectively distinguish malignant from benign thyroid nodules. The high PPV and NPV make the test both an excellent rule-in and rule-out diagnostic tool. With such a diagnostic performance and its technical simplicity, this novel thyroid molecular test is clinically widely applicable.

Hyperglycemia remission after Roux-en-Y gastric bypass: Implicated to altered monocyte inflammatory response in type 2 diabetes rats.

Hyperglycemia remission by metabolic surgery is implicated in the resolution of low-grade inflammation in type 2 diabetes mellitus (T2DM). However, whether this beneficial effect of metabolic surgery is related to improving monocyte inflammatory response remains undefined. This investigation is addressed to evaluate this relationship. For this purpose, T2DM rats were subjected to Roux-en-Y gastric bypass (RYGB) and/or monocyte depletion or splenic sympathetic denervation. Fasting blood glucose (FBG), plasma tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß) were measured, and monocyte inflammatory response was assessed in vitro. The data showed that RYGB significantly reduced lipopolysaccharide (LPS)-induced release of TNF-α and IL-1ß from peripheral monocytes while alleviating hyperglycemia and reducing plasma TNF-α and IL-1ß levels. Hyperglycemia resulting from monocyte depletion by injection of clodronate liposomes resolved one week earlier than vehicle control after RYGB. Splenic denervation abrogated the glucose-lowering effect and decreased LPS-stimulated TNF-α and IL-1ß release from monocytes following RYGB. Overall, our results reveal that a marked reduction of monocyte inflammatory response after RYGB contributes to hyperglycemia remission in T2DM rats. The beneficial effect of RYGB is mediated through vagal-spleen axis anti-inflammatory activity.

Daptomycin-Biomineralized Silver Nanoparticles for Enhanced Photothermal Therapy with Anti-Tumor Effect.

Silver nanoparticles as photothermal agents have the problems of low stability and low photothermal conversion efficiency. Amphiphilic daptomycin can improve the stability of silver nanoparticles, thereby improving their photothermal conversion efficiency. Herein, daptomycin-biomineralized silver nanoparticles (Dap-AgNPs) were prepared by reducing silver nitrate with sodium borohydride in the presence of daptomycin as a stabilizer and biomineralizer. The Dap-AgNPs had good solution stability and peroxidase-like activity. Furthermore, the photothermal conversion efficiency of the Dap-AgNPs was as high as 36.8%. The Dap-AgNPs displayed good photothermal stability under irradiation. More importantly, the Dap-AgNPs showed good cell compatibility with HeLa cells and HT-29 cells without irradiation by 808-nanometer near-infrared light at a concentration of 0.5 mM, and the cell viability was greater than 85.0%. However, the Dap-AgNPs displayed significant anti-tumor ability with irradiation by 808-nanometer near-infrared light, which was due to the increasing temperature of the culture medium caused by the Dap-AgNPs. In conclusion, Dap-AgNPs have potential applications as photothermal agents in the treatment of tumors.

Lentinan stabilized bimetallic PdPt3 dendritic nanoparticles with enhanced oxidase-like property for L-cysteine detection.

The development of nanozymes with enhanced catalytic activity has been drawing great interest. Lentinan with special structure may be used to prepare bimetallic nanomaterials to enhance their catalytic activity. Herein, lentinan stabilized PdPt3 dendritic nanoparticles (PdPt3-LNT NDs) were prepared through reduction of Na2PdCl4 and K2PtCl4 with a molar ratio of 1:3 using lentinan as a biological template. PdPt3-LNT NDs had dendritic shape with size of 10.76 ± 1.82 nm. PdPt3-LNT NDs had the hydrodynamic size about 25.7 nm and the zeta potential between -1.4 mV and - 4.9 mV at different pH. Furthermore, PdPt3-LNT NDs catalyzed 3,3',5,5'-tetramethylbenzidine (TMB) to produce oxidized TMB, suggesting their oxidase-like property. The catalytic activity of PdPt3-LNT NDs was the highest when pH was 4 and the temperature was 40 °C. The catalytic mechanism was the generation of reactive oxygen species- from O2 catalyzed by PdPt3-LNT NDs. More importantly, L-cysteine detection method was set up based on the oxidase-like property of PdPt3-LNT NDs. This method had wide linear range for 0-200 µM and low detection limit for 3.099 µM. Taken together, PdPt3-LNT NDs have good potential applications in bio-related detection in the future.

Structural basis of tethered agonism of the adhesion GPCRs ADGRD1 and ADGRF1.

Adhesion G protein-coupled receptors (aGPCRs) are essential for a variety of physiological processes such as immune responses, organ development, cellular communication, proliferation and homeostasis1-7. An intrinsic manner of activation that involves a tethered agonist in the N-terminal region of the receptor has been proposed for the aGPCRs8,9, but its molecular mechanism remains elusive. Here we report the G protein-bound structures of ADGRD1 and ADGRF1, which exhibit many unique features with regard to the tethered agonism. The stalk region that proceeds the first transmembrane helix acts as the tethered agonist by forming extensive interactions with the transmembrane domain; these interactions are mostly conserved in ADGRD1 and ADGRF1, suggesting that a common stalk-transmembrane domain interaction pattern is shared by members of the aGPCR family. A similar stalk binding mode is observed in the structure of autoproteolysis-deficient ADGRF1, supporting a cleavage-independent manner of receptor activation. The stalk-induced activation is facilitated by a cascade of inter-helix interaction cores that are conserved in positions but show sequence variability in these two aGPCRs. Furthermore, the intracellular region of ADGRF1 contains a specific lipid-binding site, which proves to be functionally important and may serve as the recognition site for the previously discovered endogenous ADGRF1 ligand synaptamide. These findings highlight the diversity and complexity of the signal transduction mechanisms of the aGPCRs.

Paeoniflorin-6'-o-benzene sulfonate ameliorates the progression of adjuvant-induced arthritis by inhibiting the interaction between Ahr and GRK2 of fibroblast-like synoviocytes.

Aryl hydrocarbon receptor (Ahr) is thought to be a crucial factor that regulates immune responses, which may be involved in the pathogenesis of autoimmune inflammation including rheumatoid arthritis (RA). The results of our group in recent years have shown that Paeoniflorin-6'-O-benzene sulfonate (code: CP-25), a novel ester derivative of paeoniflorin, has a good effect on improving RA animal models. However, whether the anti-arthritis effect of CP-25 is related to Ahr remains unclear. Here, we showed that CP-25 treatment ameliorated adjuvant-induced arthritis (AA), a rat model of RA, by inhibiting Ahr-related activities in fibroblasts like synoviocytes (FLS). AA rats were treated with CP-25 or paroxetine from days 17 to 33 after immunization. We showed that CP-25 alleviated arthritis symptoms and the pathological changes. Treatment with CP-25 decreased the expression of Ahr in the synovium of AA rats. CP-25 inhibited the expression of Ahr and the G protein-coupled receptor kinase 2 (GRK2) as well as the co-expression of GRK2 with Ahr in FLS of AA rats. Furthermore, CP-25 down-regulated the production of Kyn in FLS of AA rats. These results suggested that CP-25 may inhibit the expression and activation of Ahr. Besides, treatment with CP-25 reduced the proliferation and migration of MH7A caused by Ahr activation. In addition, we also demonstrated that CP-25 down-regulated the total and nuclear expression of Ahr and the expression of GRK2 in Kyn-treated MH7A. Moreover, the co-expression and co-localization of Ahr and GRK2in Kyn-treated MH7A were also repressed by CP-25. The data presented here demonstrated that CP-25 suppressed FLS dysfunction in rats with AA, which were associated with reduced Ahr activation and the interaction between Ahr and GRK2.

Quickly and efficiently remove multiple pesticides in tea infusions by low-cost carbonized bacterial cellulose.

Soaking tea leaves make tea consumers exposure to pesticide residues more easily. However, there are few studies on the removal of pesticides in tea infusions. Therefore, a low-cost carbonized bacterial cellulose material was prepared by direct calcination method, and used to remove multiple pesticides in tea infusions quickly and efficiently. CBC-350 has the best removal efficiency for 9 pesticides and then screened the best adsorption conditions. The adsorption isotherm experiment was carried out and indicated that the adsorption process was in consist with the Freundlich model. The thermodynamic parameters are also calculated. Moreover, the adsorption mechanism was discussed, which suggests that π-π interaction and hydrophobic action are the driving force during the adsorption process. Exhilaratingly, the CBC-350 also has excellent adsorption capacity compared to other adsorbents and can be reused at least five times.

sTNFRII-Fc modification protects human UC-MSCs against apoptosis/autophagy induced by TNF-α and enhances their efficacy in alleviating inflammatory arthritis.

BACKGROUND: Tumor necrosis factor (TNF)-α inhibitors represented by Etanercept (a fusion protein containing soluble TNF receptor II (sTNFRII) and the Fc segment of human IgG1) play a pivotal role in Rheumatoid arthritis (RA) treatment. However, long-term use increases the risk of infection and tumors for their systemic inhibition of TNF-α, which disrupts the regular physiological function of this molecular. Mesenchymal stem cells (MSCs)-based delivery system provides new options for RA treatment with their "homing" and immune-regulation capacities, whereas inflammatory environment (especially TNF-α) is not conducive to MSCs' therapeutic effects by inducing apoptosis/autophagy. Here, we constructed a strain of sTNFRII-Fc-expressing MSCs (sTNFRII-MSC), aiming to offset the deficiency of those two interventions. METHODS: Constructed sTNFRII-Fc lentiviral vector was used to infect human umbilical cord-derived MSCs, and sTNFRII-MSC stable cell line was generated by monoclonal cultivation. In vitro and vivo characteristics of sTNFRII-MSC were assessed by coculture assay and an acute inflammatory model in NOD/SCID mice. The sTNFRII-MSC were transplanted into CIA model, pathological and immunological indicators were detected to evaluate the therapeutic effects of sTNFRII-MSC. The distribution of sTNFRII-MSC was determined by immunofluorescence assay. Apoptosis and autophagy were analyzed by flow cytometry, western blot and immunofluorescence. RESULTS: sTNFRII-Fc secreted by sTNFRII-MSC present biological activity both in vitro and vivo. sTNFRII-MSC transplantation effectively alleviates mice collagen-induced arthritis (CIA) via migrating to affected area, protecting articular cartilage destruction, modulating immune balance and sTNFRII-MSC showed prolonged internal retention via resisting apoptosis/autophagy induced by TNF-α. CONCLUSION: sTNFRII-Fc modification protects MSCs against apoptosis/autophagy induced by TNF-α, in addition to releasing sTNFRII-Fc neutralizing TNF-α to block relevant immune-inflammation cascade, and thus exert better therapeutic effects in alleviating inflammatory arthritis.

Mutant Kras co-opts a proto-oncogenic enhancer network in inflammation-induced metaplastic progenitor cells to initiate pancreatic cancer.

Kras-activating mutations display the highest incidence in pancreatic ductal adenocarcinoma. Pancreatic inflammation accelerates mutant Kras-driven tumorigenesis in mice, suggesting high selectivity in the cells that oncogenic Kras transforms, although the mechanisms dictating this specificity are poorly understood. Here we show that pancreatic inflammation is coupled to the emergence of a transient progenitor cell population that is readily transformed in the presence of mutant KrasG12D. These progenitors harbor a proto-oncogenic transcriptional program driven by a transient enhancer network. KrasG12D mutations lock this enhancer network in place, providing a sustained Kras-dependent oncogenic program that drives tumors throughout progression. Enhancer co-option occurs through functional interactions between the Kras-activated transcription factors Junb and Fosl1 and pancreatic lineage transcription factors, potentially accounting for inter-tissue specificity of oncogene transformation. The pancreatic ductal adenocarcinoma cell of origin thus provides an oncogenic transcriptional program that fuels tumor progression beyond initiation, accounting for the intra-tissue selectivity of Kras transformation.

Improved photocatalyst: Elimination of triazine herbicides by novel phosphorus and boron co-doping graphite carbon nitride.

A non-metallic and low-cost novel phosphorus and boron co-doping graphite carbon nitride (PB-g-C3N4) photocatalyst was prepared by a facile thermal copolymerization of urea with B2O3 and (NH4)2·HPO4. The novel PB-g-C3N4 exhibited excellent optical and electrical properties and the photocatalytic elimination efficiency for atrazine (AT, can make feminization of male frogs in the wild, and even induce reproductive cancers in humans.) has been greatly improved compared with the pristine g-C3N4. The results of characterization techniques indicate that the introduced B and P atoms most probably to substitute for sp2-hybridized C atoms in triazine rings. O2- and h+ are the dominant active species to induce the elimination of AT demonstrated by the radical-trapping experiments. And a possible elimination pathway is proposed according to the detected main intermediates. In addition, PB-g-C3N4 was applied to the simultaneous photocatalytic elimination of 9 triazine herbicides, and the effects of different initial concentrations, pH, fulvic acid (FA) and ion species on their elimination effects were studied. And it was proved that the photocatalytic performance of PB-g-C3N4 did not significant decrease after 4 times of reuse.

Tolerogenic Dendritic Cells Generated by BAFF Silencing Ameliorate Collagen-Induced Arthritis by Modulating the Th17/Regulatory T Cell Balance.

Tolerogenic dendritic cells (tolDCs) have received much attention because of their capacity to restore immune homeostasis. RNA interference techniques have been used in several studies to generate tolDCs by inactivating certain molecules that regulate DC maturation and immunologic function. BAFF is a key B cell survival factor that is not only essential for B cell function but also T cell costimulation, and DCs are the major source of BAFF. In this study, we determined whether BAFF gene silencing in mature DCs could lead to a tolerogenic phenotype as well as the potential therapeutic effect of BAFF-silenced DCs on collagen-induced arthritis (CIA) in mice. Meanwhile, CRISPR/Cas9-mediated BAFF-/- DC2.4 cells were generated to verify the role of BAFF in DC maturation and functionality. BAFF-silenced DCs and BAFF-/- DC2.4 cells exhibited an immature phenotype and functional state. Further, the transplantation of BAFF-silenced DCs significantly alleviated CIA severity in mice, which correlated with a reduction in Th17 populations and increased regulatory T cells. In vitro, BAFF-silenced DCs promoted Foxp3 mRNA and IL-10 expression but inhibited ROR-γt mRNA and IL-17A expression in CD4+ T cells. Together, BAFF-silenced DCs can alleviate CIA, partly by inducing Foxp3+ regulatory T cells and suppressing Th17 subsets. Collectively, BAFF plays an important role in interactions between DCs and T cells, which might be a promising genetic target to generate tolDCs for autoimmune arthritis treatment.