VISTA is an acidic pH-selective ligand for PSGL-1.

Co-inhibitory immune receptors can contribute to T cell dysfunction in patients with cancer1,2. Blocking antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) partially reverse this effect and are becoming standard of care in an increasing number of malignancies3. However, many of the other axes by which tumours become inhospitable to T cells are not fully understood. Here we report that V-domain immunoglobulin suppressor of T cell activation (VISTA) engages and suppresses T cells selectively at acidic pH such as that found in tumour microenvironments. Multiple histidine residues along the rim of the VISTA extracellular domain mediate binding to the adhesion and co-inhibitory receptor P-selectin glycoprotein ligand-1 (PSGL-1). Antibodies engineered to selectively bind and block this interaction in acidic environments were sufficient to reverse VISTA-mediated immune suppression in vivo. These findings identify a mechanism by which VISTA may engender resistance to anti-tumour immune responses, as well as an unexpectedly determinative role for pH in immune co-receptor engagement.

Transcriptome-Wide Analysis of Core Transcription Factors Associated with Defense Responses in Autotetraploid versus Diploid Rice under Saline Stress and Recovery.

Saline stress is a major abiotic stress that inhibits plant growth and yields worldwide. The plant transcription factor (TF) family plays an important role in converting abiotic stress signals into gene expression changes. In this study, a transcriptome-based comparative analysis was performed to investigate the global gene expression of all the TFs in diploid and autotetraploid rice during the early stage of NaCl stress and recovery period. The phenotypic data indicated that the tetraploid rice exhibited a superior salt-tolerant ability compared to the diploid rice. A total of 55 TF families were co-expressed in the tetraploid and diploid rice, and the cumulative number of TF-expressed genes was relatively higher in the diploid rice than in the tetraploid rice at all time points. Unlike the diploid rice, the overall gene expression levels of the tetraploid rice were comparable to the control during recovery. The number of differentially expressed TFs (DE-TFs) in the tetraploid rice decreased after recovery, whereas it increased to a large extent in the diploid rice. GO and KEGG pathway enrichment analysis of the DE-TFs discovered the early switching of the ABA-activated signaling pathway and specific circadian rhythm in the tetraploid rice. Combining the PPI network and heatmap analysis, some core DE-TFs were found that may have potential roles to play in tetraploid salt tolerance. This study will pave the way for elucidating the complex network regulatory mechanisms of salt tolerance in tetraploid rice.

Improvement in Osseointegration of Titanium Dental Implants After Exposure to Ultraviolet-C Light for Varied Durations: An Experimental Study in Beagle Dogs.

PURPOSE: Ultraviolet-mediated photofunctionalization is a valid technology for enhancing the osseointegration of titanium implants. However, there is no consensus on the effective exposure time to ultraviolet light. The objective of this study was to evaluate the effect of different exposure times of ultraviolet-C (UVC) light on aged titanium implants and explore the optimal treatment duration of UVC photofunctionalization for osseointegration in an animal model. METHODS: Eight male beagle dogs (n = 48) were divided into a control group (n = 12) and 3 experimental groups (n = 12/12/12) which received 4-week-old implants without UVC treatment (C) or treated with UVC for 1/6 hour, 1/2 hour, and 1 hour (UVC-1/6 hour, UVC-1/2 hour, UVC-1 hour) immediately before placement. All the implants were placed 12 weeks after mandibular premolars extraction. Four dogs were euthanized after 4 and 12 weeks of healing, respectively. The marginal bone level and implant stability quotient were measured at implant placement and after sacrifice. Subsequently, micro-CT and histomorphometric analyses were performed following block harvesting. RESULTS: No significant difference in marginal bone loss between the UVC-untreated and UVC-treated groups was found at 4 or 12 weeks. At 4 weeks, significantly higher BV/TV and bone-implant contact were observed in the UVC groups than in the C group, irrespective of the UVC-photofunctionalization duration (BV/TV: UVC-1/6 hour 0.48 ± 0.11, UVC-1/2 hour 0.50 ± 0.06, and UVC-1 hour 0.47 ± 0.08, C 0.34 ± 0.04; bone-implant contact : UVC-1/6 hour 84.30 ± 5.02%, UVC-1/2 hour 85.82 ± 5.05%, and UVC-1 hour 84.98 ± 3.86%, C 71.69 ± 3.52%. P < .05), whereas, no significant difference was observed among the UVC groups. At 12 weeks, there were no significant differences between the C group and UVC groups. After 4 and 12 weeks of healing, no significant difference in implant stability quotient values was observed between the C group and UVC groups. CONCLUSIONS: UVC photofunctionalization improved the early osseointegration of aged titanium implants. However, the effect was not dependent on the UVC-light duration within the range from 1/6 hour to 1 hour.

A digital workflow for accurately and rapidly creating an immediate provisional restoration with natural emergence profile using extracted tooth.

To describe a digital workflow for creating a provisional restoration by using an extracted tooth rapidly, finally fixing the provisional restoration in the targeted position precisely and preserving the natural emergence profile from the time of provisional restoration to final restoration. CLINICAL CONSIDERATIONS: The use of extracted tooth as an immediate provisional restoration is an effective method for preserving the shape of the emergence profile. However, the existing methods for creating a provisional restoration by using natural tooth are time-consuming and there is no reliable method to precisely attach tooth to temporary abutment. This case demonstrates a new method for using patient's natural tooth as an immediate provisional restoration under a sequence of guides, which significantly reduces the chair-side time and inconvenience for clinicians and patients. Immediate provisional restoration contributes to preserving the soft tissue architecture after post-extraction implant placement, especially when using the patient's tooth as a provisional restoration. Digital technology can help to improve the chair-side clinical efficiency of dentist. CLINICAL SIGNIFICANCE: Maintaining the natural soft tissue architecture is a huge challenge in dental implantology. Use of the extracted tooth as a provisional restoration is likely to achieve an optimal outcome. And digital technology is helpful to the efficiency and accuracy of treatment.

Comparative Analysis of Physiological, Hormonal and Transcriptomic Responses Reveal Mechanisms of Saline-Alkali Tolerance in Autotetraploid Rice (Oryza sativa L.).

Saline-alkali soil has posed challenges to the growth of agricultural crops, while polyploidy often show greater adaptability in diverse and extreme environments including saline-alkali stress, but its defense mechanisms in rice remain elusive. Herein, we explored the mechanisms of enhanced saline-alkali tolerance of autotetraploid rice 93-11T relative to diploid rice 93-11D, based on physiological, hormonal and transcriptomic profilings. Physiologically, the enhanced saline-alkali tolerance in 93-11T was manifested in higher soluble sugar accumulation and stronger superoxide dismutase (SOD) and peroxidase (POD) activities in leaves during 24 h after saline-alkali shock. Furthermore, various hormone levels in leaves of 93-11T altered greatly, such as the negative correlation between salicylic acid (SA) and the other four hormones changed to positive correlation due to polyploidy. Global transcriptome profiling revealed that the upregulated differentially expressed genes (DEGs) in leaves and roots of 93-11T were more abundant than that in 93-11D, and there were more DEGs in roots than in leaves under saline-alkali stress. Genes related to phytohormone signal transduction of auxin (AUX) and SA in roots, lignin biosynthesis in leaves or roots, and wax biosynthesis in leaves were obviously upregulated in 93-11T compared with 93-11D under saline-alkali condition. Collectively, 93-11T subjected to saline-alkali stress possibly possesses higher osmotic regulation ability due to cuticular wax synthesis, stronger negative regulation of reactive oxygen species (ROS) production by increasing the SA levels and maintaining relative lower levels of IAA, and higher antioxidant capacity by increasing activities of SOD and POD, as well as lignin biosynthesis. Our research provides new insights for exploring the mechanisms of saline-alkali tolerance in polyploid rice and discovering new gene targets for rice genetic improvement.

Alkaline Stress Induces Different Physiological, Hormonal and Gene Expression Responses in Diploid and Autotetraploid Rice.

Saline-alkaline stress is a critical abiotic stress that negatively affects plants' growth and development. Considerably higher enhancements in plant tolerance to saline-alkaline stress have often been observed in polyploid plants compared to their diploid relatives, the underlying mechanism of which remains elusive. In this study, we explored the variations in morphological and physiological characteristics, phytohormones, and genome-wide gene expression between an autotetraploid rice and its diploid relative in response to alkaline stress. It was observed that the polyploidization in the autotetraploid rice imparted a higher level of alkaline tolerance than in its diploid relative. An eclectic array of physiological parameters commonly used for abiotic stress, such as proline, soluble sugars, and malondialdehyde, together with the activities of some selected antioxidant enzymes, was analyzed at five time points in the first 24 h following the alkaline stress treatment between the diploid and autotetraploid rice. Phytohormones, such as abscisic acid and indole-3-acetic acid were also comparatively evaluated between the two types of rice with different ploidy levels under alkaline stress. Transcriptomic analysis revealed that gene expression patterns were altered in accordance with the variations in the cellular levels of phytohormones between diploid and autotetraploid plants upon alkaline stress. In particular, the expression of genes related to peroxide and transcription factors was substantially upregulated in autotetraploid plants compared to diploid plants in response to the alkaline stress treatment. In essence, diploid and autotetraploid rice plants exhibited differential gene expression patterns in response to the alkaline stress, which may shed more light on the mechanism underpinning the ameliorated plant tolerance to alkaline stress following genome duplication.

A digital workflow for the fabrication of an immediate implant-supported interim restoration.

Immediate interim restorations in the esthetic region are usually fabricated in situ by using the pick-up technique, which is time-consuming and has a potential for cross-infection. This article describes a rapid and precise workflow for the fabrication of an immediate implant-supported interim restoration. A cast with gingival contours and an extended tube to accommodate the implant analogs is generated preoperatively based on the virtual implant planning and a predesigned restoration. After guided osteotomy and implant insertion, the actual three-dimensional (3D) implant position is transferred precisely from the mouth to the printed cast by using the surgical guide. This technique can achieve the rapid and precise fabrication of the interim restoration with guidance immediately after the surgery, decreasing the risk of cross-infection and reducing clinical steps and time.

Resensitizing daclatasvir-resistant hepatitis C variants by allosteric modulation of NS5A.

It is estimated that more than 170 million people are infected with hepatitis C virus (HCV) worldwide. Clinical trials have demonstrated that, for the first time in human history, the potential exists to eradicate a chronic viral disease using combination therapies that contain only direct-acting antiviral agents. HCV non-structural protein 5A (NS5A) is a multifunctional protein required for several stages of the virus replication cycle. NS5A replication complex inhibitors, exemplified by daclatasvir (DCV; also known as BMS-790052 and Daklinza), belong to the most potent class of direct-acting anti-HCV agents described so far, with in vitro activity in the picomolar (pM) to low nanomolar (nM) range. The potency observed in vitro has translated into clinical efficacy, with HCV RNA declining by ~3-4 log10 in infected patients after administration of single oral doses of DCV. Understanding the exceptional potency of DCV was a key objective of this study. Here we show that although DCV and an NS5A inhibitor analogue (Syn-395) are inactive against certain NS5A resistance variants, combinations of the pair enhance DCV potency by >1,000-fold, restoring activity to the pM range. This synergistic effect was validated in vivo using an HCV-infected chimaeric mouse model. The cooperative interaction of a pair of compounds suggests that NS5A protein molecules communicate with each other: one inhibitor binds to resistant NS5A, causing a conformational change that is transmitted to adjacent NS5As, resensitizing resistant NS5A so that the second inhibitor can act to restore inhibition. This unprecedented synergistic anti-HCV activity also enhances the resistance barrier of DCV, providing additional options for HCV combination therapy and new insight into the role of NS5A in the HCV replication cycle.

Self-management among type 2 diabetes patients via the WeChat application: A systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: The incidence of diabetes has been rising worldwide and is expected to increase to affect 591.9 million people by 2035 in China. Strict control of blood glucose can significantly reduce the risk of diabetic complications, but traditional interventions lack continuity, timeliness and teleonomy. The development of mobile health management has become a hot topic, as a very popular app in China, WeChat platform, has a large number of users every day. Many studies show the health management of patients with diabetes through WeChat can achieve the ideal effect. This study aims to evaluate the application of WeChat based on clinical research data, provide clinical evidence for medical staff and promote the self-management of patients with diabetes. METHODS: The PubMed, EMBASE, Cochrane Library, CNKI and Wanfang database were searched to identify related reports that were published up to 9 March 2020. The quality of included studies was assessed by Cochrane Collaboration risk assessment tool. Measures of interest were mean difference (MD) and 95% confidence interval (CI). Random-effect model was used according to the absence or presence of significant heterogeneity. Heterogeneity among trials was evaluated by I2 test. Publication bias was assessed by funnel plots. RESULTS AND DISCUSSION: Thirty-eight articles involved 2,709 controls and 2,709 patients who used WeChat were identified. Relative to the traditional group, WeChat group had a lower level in fasting plasma glucose (FPG in mmol/L; MD: 1.36, 95% CI 1.10-1.62, P < .00001), so did 2hPG (MD: 1.91, 95% CI 1.48-2.35, P < .00001) and HbA1C (MD: 1.07, 95% CI 0.86-1.27, P < .00001). Self-efficacy scale improved significantly, including diet score (MD: -1.31, 95% CI -1.77 to -0.86, P < .00001), exercise score (MD: -1.92, 95% CI -2.44 to -1.40, P < .00001), medication taking score (MD: -1.45, 95% CI: -1.94 to -0.97, P < .00001), monitoring of blood glucose score (MD: -1.17, 95% CI -1.83--0.51, P = .0005) and foot care score (MD: -1.71, 95% CI -2.08 to -1.34, P < .00001). Patients' understanding of the disease and satisfaction with follow-up increased significantly, whereas the incidence of adverse reactions and complications decreased. WHAT IS NEW AND CONCLUSION: WeChat follow-up appears to be helpful to improve the level of blood glucose and self-management, reduce the incidence of adverse reactions and complications, and improve the satisfaction rate of patients with type 2 diabetes. It should be noted that this meta-analysis has limitations, such as small sample sizes and the low quality of included literature, as well as the lack of research in Western countries. Therefore, more high-quality studies with larger samples are needed in the future to verify our results.

The discovery and optimization of naphthalene-linked P2-P4 Macrocycles as inhibitors of HCV NS3 protease.

Naphthalene-linked P2-P4 macrocycles within a tri-peptide-based acyl sulfonamide chemotype have been synthesized and found to inhibit HCV NS3 proteases representing genotypes 1a and 1b with single digit nanomolar potency. The pharmacokinetic profile of compounds in this series was optimized through structural modifications along the macrocycle tether as well as the P1 subsite. Ultimately a compound with oral bioavailability of 100% in rat, and a long half-life in plasma was obtained. However, compounds in this macrocyclic series exhibited cardiac effects in an isolated rabbit heart model and for this reason further optimization efforts were discontinued.

Discovery and initial optimization of alkoxyanthranilic acid derivatives as inhibitors of HCV NS5B polymerase.

Alkoxyanthranilic acid derivatives have been identified to inhibit HCV NS5B polymerase, binding in an allosteric site located at the convergence of the palm and thumb regions. Information from co-crystal structures guided the structural design strategy. Ultimately, two independent structural modifications led to a similar shift in binding mode that when combined led to a synergistic improvement in potency and the identification of inhibitors with sub-micromolar HCV NS5B binding potency.

Functionalized triazines as potent HCV entry inhibitors.

A series of potent and novel acylsulfonamide-bearing triazines were synthesized and the structure-activity relationships (SARs) as HCV entry inhibitors were evaluated. This acylsulfonamide series was derived from an early lead, 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid wherein the carboxylic acid was replaced with an acylsulfonamide moiety. This structural modification provided a class of compounds which projected an additional vector off the terminus of the acylsulfonamide functionality as a means to drive activity. This effort led to the discovery of potent analogues within this series that demonstrated sub-nanomolar EC50 values in the HCV pseudotype particle (HCVpp) assay.

Discovery of BMS-961955, an allosteric inhibitor of the hepatitis C virus NS5B polymerase.

The synthesis, structure-activity relationship (SAR) data, and further optimization of the metabolic stability and pharmacokinetic (PK) properties for a previously disclosed class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors are described. These efforts led to the discovery of BMS-961955 as a viable contingency backup to beclabuvir which was recently approved in Japan for the treatment of HCV as part of a three drug, single pill combination marketed as XimencyTM.

Mechanism of inhibition for BMS-791325, a novel non-nucleoside inhibitor of hepatitis C virus NS5B polymerase.

HCV infection is an urgent global health problem that has triggered a drive to discover therapies that specifically target the virus. BMS-791325 is a novel direct antiviral agent specifically targeting HCV NS5B, an RNA-dependent RNA polymerase. Robust viral clearance of HCV was observed in infected patients treated with BMS-791325 in combination with other anti-HCV agents in Phase 2 clinical studies. Biochemical and biophysical studies revealed that BMS-791325 is a time-dependent, non-competitive inhibitor of the polymerase. Binding studies with NS5B genetic variants (WT, L30S, and P495L) exposed a two-step, slow binding mechanism, but details of the binding mechanism differed for each of the polymerase variants. For the clinically relevant resistance variant (P495L), the rate of initial complex formation and dissociation is similar to WT, but the kinetics of the second step is significantly faster, showing that this variant impacts the final tight complex. The resulting shortened residence time translates into the observed decrease in inhibitor potency. The L30S variant has a significantly different profile. The rate of initial complex formation and dissociation is 7-10 times faster for the L30S variant compared with WT; however, the forward and reverse rates to form the final complex are not significantly different. The impact of the L30S variant on the inhibition profile and binding kinetics of BMS-791325 provides experimental evidence for the dynamic interaction of fingers and thumb domains in an environment that supports the formation of active replication complexes and the initiation of RNA synthesis.

Preclinical characterization of BMS-791325, an allosteric inhibitor of hepatitis C Virus NS5B polymerase.

BMS-791325 is an allosteric inhibitor that binds to thumb site 1 of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase. BMS-791325 inhibits recombinant NS5B proteins from HCV genotypes 1, 3, 4, and 5 at 50% inhibitory concentrations (IC50) below 28 nM. In cell culture, BMS-791325 inhibited replication of HCV subgenomic replicons representing genotypes 1a and 1b at 50% effective concentrations (EC50s) of 3 nM and 6 nM, respectively, with similar (3 to 18 nM) values for genotypes 3a, 4a, and 5a. Potency against genotype 6a showed more variability (9 to 125 nM), and activity was weaker against genotype 2 (EC50, 87 to 925 nM). Specificity was demonstrated by the absence of activity (EC50s of >4 µM) against a panel of mammalian viruses, and cytotoxic concentrations (50%) were >3,000-fold above the HCV EC50. Resistance substitutions selected by BMS-791325 in genotype 1 replicons mostly mapped to a single site, NS5B amino acid 495 (P495A/S/L/T). Additive or synergistic activity was observed in combination studies using BMS-791325 with alfa interferon plus ribavirin, inhibitors of NS3 protease or NS5A, and other classes of NS5B inhibitor (palm site 2-binding or nucleoside analogs). Plasma and liver exposures in vivo in several animal species indicated that BMS-791325 has a hepatotropic disposition (liver-to-plasma ratios ranging from 1.6- to 60-fold across species). Twenty-four hours postdose, liver exposures across all species tested were ≥ 10-fold above the inhibitor EC50s observed with HCV genotype 1 replicons. These findings support the evaluation of BMS-791325 in combination regimens for the treatment of HCV. Phase 3 studies are ongoing.

Non-Clinical Safety Evaluation of Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells in Cynomolgus Monkeys.

Purpose: In recent years, exosomes have been proved to be used to treat many diseases. However, due to the lack of uniform quality control standards for exosomes, the safety of exosomes is still a problem to be solved, especially now more and more exosomes are used in clinical trials, and its non-clinical safety evaluation is particularly important. However, there is no safety evaluation standard for exosomes at present. Therefore, this study will refer to the evaluation criteria of therapeutic biological products, adopt non-human primates to evaluate the non-clinical safety of human umbilical cord mesenchymal stem cell exosomes from the general pharmacology and immunotoxicity, aiming at establishing a safety evaluation system of exosomes and providing reference for the clinical application of exosomes in the future. Methods: 3.85 × 1012 exosomes derived from human umbilical cord mesenchymal stem cells were injected into cynomolgus monkeys intravenously. The changes of general clinical conditions, hematology, immunoglobulin, Th1/Th2 cytokines, T lymphocytes and B lymphocytes, and immune organs were observed before and within 14 days after injection. Results: The results showed that exosomes did not have obvious pathological effects on the general clinical conditions, blood, coagulation function, organ coefficient, immunoglobulin, Th1/Th2 cytokines, lymphocytes, major organs, and major immune organs (spleen, thymus, bone marrow) of cynomolgus monkeys. However, the number of granulocyte-macrophage colonies in exosomes group was significantly higher than that in control group. Conclusion: To sum up, the general pharmacological results and immunotoxicity results showed that the injection of 3.85 × 1012 exosomes may have no obvious adverse reactions to cynomolgus monkeys. This dose of exosomes is relatively safe for treatment, which provides basis research for non-clinical safety evaluation of exosomes and provides reliable research basis for future clinical application of exosomes.

Accuracy of Intraoperative Measuring Guide and Conventional Surgical Guide in Anterior Implant Surgery: A Retrospective Case-Control Study

PURPOSE: To verify a novel method that improves the accuracy of static computer-aided implant surgery (sCAIS) through intraoperative measurement. MATERIALS AND METHODS: Forty-seven patients were selected for this study, each with a missing tooth or a tooth that required extraction from the anterior area. The patients were divided into the intraoperative measuring guide (MG) and conventional guide (CG) groups. Following the preoperative implant planning, the surgical guides were designed and fabricated. In the MG group, the drill was guided by double-armed zirconia sleeves, and the axial direction of the drill was assessed using the indicator components. The implant was guided using a resin guide tube. In the CG group, the drills were guided using a metal sleeve and handles, and the implants were placed with the guidance of the metal sleeve only. The angular and linear deviations at the entry and apex between the planned and actual implant positions were measured after matching the preoperative and postoperative CBCT data. The independent-samples t test was used to compare the deviation between the MG and CG groups. RESULTS: The 3D deviations for the MG group at the entry and apex were 0.67 ± 0.44 mm and 0.93 ± 0.40 mm, respectively. The angular deviation was 2.27 ± 0.96 degrees. Statistical differences were found in the 3D deviation at the entry point and apical position between the MG and CG groups, yielding relatively smaller deviations in the MG group. CONCLUSION: The use of an intraoperative measuring guide could improve the accuracy of implant placement in sCAIS.

Chimeric CNS-targeting-peptide engineered exosomes for experimental autoimmune encephalomyelitis therapy.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) that causes demyelination, neuronal damage and white matter loss, but there is still no known cure. Exosomes are 30-200 nm-sized double-layered membrane vesicles that can easily cross the blood-brain barrier (BBB). Exosomes from umbilical cord mesenchymal stem cells（UMSCs） have been found to treat experimental autoimmune encephalomyelitis (EAE) through the action of anti-inflammatory and immunomodulatory, but its clinical translation has been hampered by their inefficacious accumulation in CNS. Therefore, we developed a TAxI-exos, also known as a TAxI-peptide-chimeric UMSC-exos, for CNS-specific accumulation and curative effect in EAE. We used the EAE model in vivo as well as active T cell and BV-2 cell models in vitro to explore the efficacy and mechanisms. Exosomes from UMSCs with TAxI or DiR labels were given to EAE mice in one dosage (150 g) prior to the peak at day 15. The mice were sacrificed on day 30 so that spinal cords, spleens, and blood could be taken for analysis of demyelination, inflammation, microglia, T-cell subset proportions, and inflammatory cytokine expression. In vitro, PBMCs and splenocytes isolated from healthy C57BL/6 mice were activated and incubated with 0.15 mg/mL of UMSC-exos or TAxI-exos for immune mechanism investigations. Activated BV-2 cells were used to investigate the targeting and controlling polarization ability and mechanism of UMSC-exos and TAxI-exos. As expected, TAxI-exos exhibited significantly greater therapeutic action in EAE mice than UMSC-exos due to their improved targeting-ability. The medication reduced T-cell subset proportions and inflammation, reduced active-microglia proportions and promoted M1 to M2 microglial cell polarization through TNF pathway, upregulated IL-4, IL-10, TGF-ß, and IDO-1 expression, and downregulated IL-2, IL-6, IL-17A, IFN-γ, and TNF-α. The CNS-targeting properties of TAxI-exos and their capacity to inhibit degenerative processes in EAE mice have considerable potential therapeutic value for MS and other CNS illnesses.

Evaluating the Differential Response of Transcription Factors in Diploid versus Autotetraploid Rice Leaves Subjected to Diverse Saline-Alkali Stresses.

Saline-alkali stress is a significant abiotic stress factor that impacts plant growth, development, and crop yield. Consistent with the notion that genome-wide replication events can enhance plant stress resistance, autotetraploid rice exhibited a higher level of tolerance to saline-alkali stress than its donor counterparts, which is reflected by differential gene expression between autotetraploid and diploid rice in response to salt, alkali, and saline-alkali stress. In this study, we investigated the expression of the transcription factors (TFs) in the leaf tissues of autotetraploid and diploid rice under different types of saline-alkali stress. Transcriptome analysis identified a total of 1040 genes from 55 TF families that were altered in response to these stresses, with a significantly higher number in autotetraploid rice compared to diploid rice. Contrarily, under these stresses, the number of expressed TF genes in autotetraploid rice was greater than that in diploid rice for all three types of stress. In addition to the different numbers, the differentially expressed TF genes were found to be from significantly distinct TF families between autotetraploid and diploid rice genotypes. The GO enrichment analysis unraveled that all the DEGs were distributed with differentially biological functions in rice, in particular those that were enriched in the pathways of phytohormones and salt resistance, signal transduction, and physiological and biochemical metabolism in autotetraploid rice compared to its diploid counterpart. This may provide useful guidance for studying the biological roles of polyploidization in plant resilience in response to saline-alkali stress.