Mesenchymal stromal cells and their small extracellular vesicles in allergic diseases: From immunomodulation to therapy.

Mesenchymal stromal cells (MSCs) have long been considered a potential tool for treatment of allergic inflammatory diseases, owing to their immunomodulatory characteristics. In recent decades, the medical utility of MSCs has been evaluated both in vitro and in vivo, providing a foundation for therapeutic applications. However, the existing limitations of MSC therapy indicate the necessity for novel therapies. Notably, small extracellular vesicles (sEV) derived from MSCs have emerged rapidly as candidates instead of their parental cells. The acquisition of abundant and scalable MSC-sEV is an obstacle for clinical applications. The potential application of MSC-sEV in allergic diseases has attracted increasing attention from researchers. By carrying biological microRNAs or active proteins, MSC-sEV can modulate the function of various innate and adaptive immune cells. In this review, we summarise the recent advances in the immunomodulatory properties of MSCs in allergic diseases, the cellular sources of MSC-sEV, and the methods for obtaining high-quality human MSC-sEV. In addition, we discuss the immunoregulatory capacity of MSCs and MSC-sEV for the treatment of asthma, atopic dermatitis, and allergic rhinitis, with a special emphasis on their immunoregulatory effects and the underlying mechanisms of immune cell modulation.

CBX4 contributes to HIV-1 latency by forming phase-separated nuclear bodies and SUMOylating EZH2.

The retrovirus HIV-1 integrates into the host genome and establishes a latent viral reservoir that escapes immune surveillance. Molecular mechanisms of HIV-1 latency have been studied extensively to achieve a cure for the acquired immunodeficiency syndrome (AIDS). Latency-reversing agents (LRAs) have been developed to reactivate and eliminate the latent reservoir by the immune system. To develop more promising LRAs, it is essential to evaluate new therapeutic targets. Here, we find that CBX4, a component of the Polycomb Repressive Complex 1 (PRC1), contributes to HIV-1 latency in seven latency models and primary CD4+ T cells. CBX4 forms nuclear bodies with liquid-liquid phase separation (LLPS) properties on the HIV-1 long terminal repeat (LTR) and recruits EZH2, the catalytic subunit of PRC2. CBX4 SUMOylates EZH2 utilizing its SUMO E3 ligase activity, thereby enhancing the H3K27 methyltransferase activity of EZH2. Our results indicate that CBX4 acts as a bridge between the repressor complexes PRC1 and PRC2 that act synergistically to maintain HIV-1 latency. Dissolution of phase-separated CBX4 bodies could be a potential intervention to reactivate latent HIV-1.

Macrophages regulate healing-associated fibroblasts in diabetic wound.

BACKGROUND: Recovery from a foot ulcer is compromised in a diabetic status, due to the impaired tissue microenvironment that consists of altered inflammation, angiogenesis and fibrosis. Phenotypic alterations in both macrophages and fibroblasts have been detected in the diabetic wound. Recently, a fibroblast subpopulation that expresses high matrix metalloproteinase 1 (MMP1), MMP3, MMP11 and Chitinase-3-Like Protein 1 (CHI3L1) was associated with a successful diabetic wound healing. However, it is not known whether these healing-associated fibroblasts are regulated by macrophages. METHODS AND RESULTS: We used bioinformatic tools to analyze selected public databases on normal and diabetic skin from patients, and identified genes significantly altered in diabetes. In a mouse model for diabetic wound healing, we detected not only a loss of the spatiotemporal changes in interleukin 1ß (IL1ß), IL6, IL10 and vascular endothelial growth factor A (VEGF-A) in wound macrophages, but also a compromised expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in healing-associated wound fibroblasts in a diabetic status. Co-culture with diabetic macrophages significantly reduced the expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in fibroblasts from non-diabetic wound. Co-culture with non-diabetic macrophages or diabetic macrophages supplied with IL6 significantly increased the expression of MMP1, MMP3, MMP11, CHI3L1 and VEGF-A in fibroblasts from diabetic wound. Moreover, macrophage-specific expression of IL6 significantly improved wound healing and angiogenesis in diabetic mice. CONCLUSIONS: Macrophages may induce the activation of wound-healing-associated fibroblasts, while the defective macrophages in diabetes may be corrected with IL6 treatment as a promising therapy for diabetic foot disease.

Surface-engineered Mo2B: a promising electrode material for constructing Ohmic contacts with blue phosphorene for electronic device applications.

The Schottky barrier between a metal and a semiconductor plays an important role in determining the transport efficiency of carriers and improving the performance of devices. In this work, we systematically studied the structure and electronic properties of heterostructures of blue phosphorene (BP) in contact with Mo2B based on density functional theory. The semiconductor properties of BP are destroyed owing to strong interaction with bare Mo2B. The effect of modifying Mo2B with O and OH on the contact properties was investigated. A p-type Schottky contact can be obtained in BP/Mo2BO2. The height of the Schottky barrier can be modulated by interlayer distance to realize a transition from a p-type Schottky contact to a p-type Ohmic contact in BP/Mo2BO2. The BP/Mo2B(OH)2 forms robust Ohmic contacts, which are insensitive to interlayer distance and external electric fields due to the Fermi level pinning effect. Our work provides important clues for contact engineering and improvement of device performance based on BP.

Comparison of recombinant human FSH biosimilar QL1012 with Gonal-f® for ovarian stimulation: a phase-three trial.

RESEARCH QUESTION: Are QL1012 and Gonal-f® equivalent in women undergoing ovarian stimulation for assisted reproductive technology (ART)? DESIGN: This multicentre, randomized, assessor-blinded, phase-three trial was conducted at 13 centres in China. Eligible patients were infertile women; age 20-39 years; body mass index 18-30 kg/m2; regular menstrual cycles; and indication for ART. After successful pituitary downregulation, patients were randomly assigned (1:1) to receive QL1012 or Gonal-f®, stratified by age (initial dose of 75-150 IU for women younger than 30 years, 150-225 IU for women aged 30-34 years and 225-300 IU for women aged ≥35 years, subcutaneously, once daily). The primary end point was the number of oocytes retrieved. RESULTS: Between October 2018, and June 2019, 341 patients were included in the per-protocol set. The mean numbers of oocytes retrieved were 14.7 ± 7.0 in the QL1012 group (n = 169) and 13.4 ± 6.1 in the Gonal-f® group (n = 172). Adjusted by analysis of covariance model, the least-squares mean difference was 1.3 oocytes (95% CI -0.1 to 2.7; P = 0.0650), within the pre-defined equivalence margins of ±3.0. Similar results were observed in the full analysis set. Additionally, no statistical differences were found in secondary end points except oestradiol concentration (median 3948.0 pg/ml versus 3545.3 pg/ml; P = 0.0015). Ovarian hyperstimulation syndrome (12.4% versus 13.1 %) and other adverse events were similar between the two groups. CONCLUSIONS: Therapeutic equivalence and similar safety profiles were demonstrated between QL1012 and Gonal-f® in women undergoing ovarian stimulation for ART.

Evolution of channel flow and Darcy's law beyond the critical Reynolds number.

For incompressible channel flow, there is a critical state, characterized by a critical Reynolds number Rec and a critical wavevector mc along the channel direction, beyond which the channel flow becomes unstable in the linear regime. In this work, we investigate the channel flow beyond the critical state and find the existence of a new fluctuating, quasi-stationary flow that comprises the laminar Poiseuille flow superposed with a counter-flow component, accompanied by vortices and anti-vortices. The net flow rate is reduced by ~ 15% from the linear, laminar regime. Our study is facilitated by the analytical solution of the linearized, incompressible, three-dimensional (3D) Navier-Stokes (NS) equation in the channel geometry, with the Navier boundary condition, alternatively denoted as the hydrodynamic modes (HMs). By using the HMs as the complete mathematical basis for expanding the velocity in the NS equation, the Rec is evaluated to 5-digit accuracy when compared to the well-known Orszag result, without invoking the standard Orr-Sommerfeld equation. Beyond Rec, the analytical solution is indispensable in offering physical insight to those features of the counter-flow component that differs from any of the pressure-driven channel flows. In particular, the counter flow is found to comprise multiple HMs, some with opposite flow direction, that can lead to a net boundary reaction force along the counter-flow direction. The latter is analyzed to be necessary for satisfying Newton's law. Experimental verification of the predictions is discussed.

Development and validation of a risk prediction model for frailty in patients with diabetes.

BACKGROUND: Frailty is the third most common complication of diabetes after macrovascular and microvascular complications. The aim of this study was to develop a validated risk prediction model for frailty in patients with diabetes. METHODS: The research used data from the China Health and Retirement Longitudinal Study (CHARLS), a dataset representative of the Chinese population. Twenty-five indicators, including socio-demographic variables, behavioral factors, health status, and mental health parameters, were analyzed in this study. The study cohort was randomly divided into a training set and a validation set at a ratio of 70 to 30%. LASSO regression analysis was used to screen the variables for the best predictors of the model based on a 10-fold cross-validation. The logistic regression model was applied to explore the associated factors of frailty in patients with diabetes. A nomogram was constructed to develop the prediction model. Calibration curves were applied to evaluate the accuracy of the nomogram model. The area under the receiver operating characteristic curve and decision curve analysis were conducted to assess predictive performance. RESULTS: One thousand four hundred thirty-six patients with diabetes from the CHARLS database collected in 2013 (n = 793) and 2015 (n = 643) were included in the final analysis. A total of 145 (10.9%) had frailty symptoms. Multivariate logistic regression analysis showed that marital status, activities of daily living, waist circumference, cognitive function, grip strength, social activity, and depression as predictors of frailty in people with diabetes. These factors were used to construct the nomogram model, which showed good concordance and accuracy. The AUC values of the predictive model and the internal validation set were 0.912 (95%CI 0.887-0.937) and 0.881 (95% CI 0.829-0.934). Hosmer-Lemeshow test values were P = 0.824 and P = 0.608 (both > 0.05). Calibration curves showed significant agreement between the nomogram model and actual observations. ROC and DCA indicated that the nomogram had a good predictive performance. CONCLUSIONS: Comprehensive nomogram constructed in this study was a promising and convenient tool to evaluate the risk of frailty in patients with diabetes, and contributed clinicians to screening the high-risk population.

Bone metabolism characteristics and gender differences in patients with COPD: a cross-sectional study.

BACKGROUND: Gender differences in bone metabolism of people with chronic obstructive pulmonary disease (COPD) remain unclear. We aim to explore the characteristics of bone metabolism and its clinical significance for patients with COPD. METHODS: A total of 564 cases (282 COPD cases and 282 controls) were preselected. Clinical and analytical characteristics of these cases were assessed. After excluding patients with other conditions known to disturb calcium metabolism, 333 patients (152 COPD cases and 181 controls) were identified. The medical records, indexes of bone turnover markers, serum calcium and phosphorus of the 333 patients were collected and their correlation was analyzed. RESULTS: The 152 cases with COPD were 82.61 ± 7.745 years, 78.3% males, and the 181 age- and sex-matched control cases were 79.73 ± 11.742 years, 72.4% males. Levels of total procollagen type I amino-terminal propeptide (tPINP), osteocalcin (OC), serum calcium and phosphate were significantly lower (P < 0.001) while the level of parathormone (PTH) was significantly higher (P = 0.004) in COPD than in controls. The 25-hydroxycholecalciferol (25(OH)D3) was below the lower limit of normal value (LLN) in both groups, which was significantly lower in COPD males than in control males (P = 0.026). In COPD group, PTH level was significantly higher in females (P = 0.006), and serum P was lower in males (P = 0.006). The adjusted linear regression analysis showed that the levels of tPINP, OC and serum Ca were decreasing greatly in COPD group [ß (95%CI) - 8.958 (- 15.255 to - 2.662), P = 0.005; - 4.584 (- 6.627 to - 2.542), P < 0.001; - 0.065 (- 0.100 to - 0.031), P < 0.001]. Besides, smoke exposure, gender (male) were also related to hypocalcemia [ß (95%CI) - 0.025 (- 0.045 to - 0.005), P = 0.017; - 0.041 (- 0.083 to - 0.001), P = 0.047], and 25(OH)D3 was correlated with serum calcium, phosphorus, and PTH [ß (95%CI) 15.392(7.032-23.753), P < 0.001; - 7.287 (- 13.450 to - 1.124), P = 0.021; - 0.103(- 0.145 to - 0.061), P < 0.001], and female was more likely to have secondary hyperparathyroidism [ß (95%CI) 12.141 (4.047-20.235), P = 0.002]. CONCLUSION: COPD patients have remarkably low bone turnover (indicated by OC) and impaired bone formation (low tPINP), and they are also more prone to low calcium. Smoking and male may play roles in the formation of hypocalcemia, and the secondary hyperparathyroidism is more significant in COPD women. There may be gender differences in bone metabolism abnormalities and their mechanisms of COPD. The conclusion above still need further research and demonstration.

Genome-Wide Identification of the CDPK Gene Family and Their Involvement in Taproot Cracking in Radish.

Taproot cracking, a severe and common physiological disorder, markedly reduces radish yield and commercial value. Calcium-dependent protein kinase (CDPK) plays a pivotal role in various plant developmental processes; however, its function in radish taproot cracking remains largely unknown. Here, 37 RsCDPK gene members were identified from the long-read radish genome "QZ-16". Phylogenetic analysis revealed that the CDPK members in radish, tomato, and Arabidopsis were clustered into four groups. Additionally, synteny analysis identified 13 segmental duplication events in the RsCDPK genes. Analysis of paraffin-embedded sections showed that the density and arrangement of fleshy taproot cortex cells are important factors that affect radish cracking. Transcriptome sequencing of the fleshy taproot cortex revealed 5755 differentially expressed genes (DEGs) (3252 upregulated and 2503 downregulated) between non-cracking radish "HongYun" and cracking radish "505". These DEGs were significantly enriched in plant hormone signal transduction, phenylpropanoid biosynthesis, and plant-pathogen interaction KEGG pathways. Furthermore, when comparing the 37 RsCDPK gene family members and RNA-seq DEGs, we identified six RsCDPK genes related to taproot cracking in radish. Soybean hairy root transformation experiments showed that RsCDPK21 significantly and positively regulates root length development. These findings provide valuable insights into the relationship between radish taproot cracking and RsCDPK gene function.

Genetic Diversity Analysis and Core Germplasm Collection Construction of Radish Cultivars Based on Structure Variation Markers.

Radish is an economically important root vegetable worldwide. In this study, the 217 cultivated radish accessions were collected and genotyped. To detect the genotypes of these accessions, a total of 24 structure variation (SV) markers distributed on nine chromosomes were employed to analyze genetic diversity and construct a core germplasm collection of radish. The results of polymorphism information content (PIC) indicated a good polymorphism of these SV markers. Population structure analysis and principal component analysis (PCA) results showed that the 217 radish accessions fell into three main populations (P1, P2, and P3). Genetic diversity analysis showed that these populations were highly associated with geographical distribution. The values of the fixation index (FST) indicated a high genetic diversity between P2 and P3, and a moderate genetic diversity between P1 and P2, and P1 and P3. Furthermore, the 43 core germplasm were exploited for creating cytoplasmic male sterility (CMS) lines and cultivating new radish varieties. The high genetic diversity of 217 radish germplasms will not only provide valuable resources for future genetic mapping and functional genomic research, but also facilitate core germplasm utilization and the molecular breeding of radish.

Association between bidirectional intergenerational support and successful aging in China: Evidence from CHARLS 2018.

Aging has gradually accelerated in China, and achieving successful aging of older adults has become a public health concern. Intergenerational support is crucial for Chinese older adults in later life due to the culture of filial piety. However, the association between successful aging and intergenerational support remains poorly understood in China. This study aimed to examine the association between patterns of intergenerational support and successful aging of older adults in China. The present study is a secondary analysis of data obtained from the follow-up survey of the China Health and Retirement Longitudinal Study 2018. Data were analyzed using descriptive statistics and logistic regressions. Bidirectional intergenerational support was associated with successful aging in the participants. In addition, there was an association between different intergenerational financial, caring, and emotional support patterns and elements of successful aging.

Decreased expression of GRIM-19 induces autophagy through the AMPK/ULK1 signaling pathway during adenomyosis†.

The processes underlying adenomyosis are similar to those of tumor metastasis, and it is defined as progressive invasion by the endometrium and the subsequent creation of ectopic lesions. GRIM-19 regulates cell death via the mitochondrial respiratory chain. Stress following oxygen deprivation can induce tumor cell autophagy, leading to cell invasion and migration. Here, we revealed that GRIM-19 negatively regulates autophagy, and, at least in adenomyosis, decreased expression of GRIM-19 is accompanied by an increased level of autophagy and 5'-adenosine monophosphate-activated protein kinase-Unc-51 like autophagy activating kinase 1 (AMPK-ULK1) activation. Upregulation of GRIM-19 expression in human primary endometrial cells and ISHIKAWA cells inhibits autophagy via the AMPK-ULK1 pathway and helps control cell invasion and migration. In addition, we also identified increased expression of AMPK and ULK1, and higher levels of autophagy in the uterine tissues of GRIM-19+/- mice. Importantly, the function of the GRIM-19-AMPK-ULK1 axis in regulating autophagy in adenomyosis is similar to that of tumor tissues, which may help elucidate the regulation of adenomyosis tumor-like behavior, and is expected to help identify novel targets for the diagnosis and treatment of adenomyosis.

IRF7 suppresses hematopoietic regeneration under stress via CXCR4.

Hematopoietic stem cells (HSCs) maintain quiescence under steady state; however, they are compelled to proliferate and expand to replenish the blood system under stress. The molecular basis underlying stress hematopoiesis remains to be fully understood. In this study, we reported that IRF7 represents an important regulator of stress hematopoiesis. Interferon regulatory factor 7 (IRF7) was dispensable for normal hematopoiesis, whereas its deficiency significantly enhanced hematopoietic stem and progenitor cells (HSPCs) regeneration and improved long-term repopulation of HSCs under stress. Mechanistic studies showed that CXCR4 was identified as a downstream target of IRF7. Overexpression of CXCR4 abrogated the enhanced proliferation and regeneration of IRF7-deficient HSPCs under stress. Similar results were obtained in HSCs from human umbilical cord blood. These observations demonstrated that IRF7 plays an important role in hematopoietic regeneration under stress.

MRI characteristics of breast edema for assessing axillary lymph node burden in early-stage breast cancer: a retrospective bicentric study.

OBJECTIVES: To investigate whether breast edema characteristics at preoperative T2-weighted imaging (T2WI) could help evaluate axillary lymph node (ALN) burden in patients with early-stage breast cancer. METHODS: This retrospective study included women with clinical T1 and T2 stage breast cancer and preoperative MRI examination in two independent cohorts from May 2014 to December 2020. Low (< 3 LNs+) and high (≥ 3 LNs+) pathological ALN (pALN) burden were recorded as endpoint. Breast edema score (BES) was evaluated at T2WI. Univariable and multivariable analyses were performed by the logistic regression model. The added predictive value of BES was examined utilizing the area under the curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI). RESULTS: A total of 1092 patients were included in this study. BES was identified as the independent predictor of pALN burden in primary (n = 677) and validation (n = 415) cohorts. The analysis using MRI-ALN status showed that BES significantly improved the predictive performance of pALN burden (AUC: 0.65 vs 0.71, p < 0.001; IDI = 0.045, p < 0.001; continuous NRI = 0.159, p = 0.050). These results were confirmed in the validation cohort (AUC: 0.64 vs 0.69, p = 0.009; IDI = 0.050, p < 0.001; continuous NRI = 0.213, p = 0.047). Furthermore, BES was positively correlated with biologically invasive clinicopathological factors (p < 0.05). CONCLUSIONS: In individuals with early-stage breast cancer, preoperative MRI characteristics of breast edema could be a promising predictor for pALN burden, which may aid in treatment planning. KEY POINTS: • In this retrospective study of 1092 patients with early-stage breast cancer from two cohorts, the MRI characteristic of breast edema has independent and additive predictive value for assessing axillary lymph node burden. • Breast edema characteristics at T2WI positively correlated with biologically invasive clinicopathological factors, which may be useful for preoperative diagnosis and treatment planning for individual patients with breast cancer.

Effect of dehydroepiandrosterone administration before in vitro fertilization on the live birth rate in poor ovarian responders according to the Bologna criteria: A randomised controlled trial.

OBJECTIVE: To evaluate the effect of dehydroepiandrosterone (DHEA) pre-treatment before in vitro fertilization and embryo transfer (IVF-ET) on the live birth rate in infertile women with poor ovarian response (POR) defined according to the Bologna criteria. DESIGN: A randomized, double-blind, placebo-controlled trial. SETTING: Nine reproductive medical centers in China. POPULATION: A total of 821 participants with POR defined according to the Bologna criteria were enrolled in the study between April 2016 and December 2018. METHODS: Eligible participants were randomly assigned to receive either DHEA (n = 410) or placebo (n = 411) treatments for 4-12 weeks prior to IVF-ET, in a 1:1 ratio. MAIN OUTCOME MEASURES: Live birth rate after the first embryo transfer. RESULTS: Thirty-six (8.8%) of 410 women in the DHEA group and 37 (9.0%) of 411 women in the placebo group had a live birth, with no significant difference observed between groups (relative risk, 0.98, 95% CI, 0.63-1.51; p = 0.911). There were no significant differences in the number of retrieved oocytes, and the rates of clinical pregnancy, pregnancy loss, and cumulative live births between the two groups. CONCLUSIONS: DHEA administration prior to IVF-ET had no beneficial effect on the live birth rate relative to placebo in women with POR defined according to the Bologna criteria. TWEETABLE ABSTRACT: No benefit was found in poor ovarian responders who received DHEA administration prior to IVF.

Expansion of Group 2 Innate Lymphoid Cells in Patients with End-Stage Renal Disease and Their Clinical Significance.

Group 2 innate lymphoid cells (ILC2s) play an important role in the control of tissue inflammation and homeostasis. However, the role of ILC2s in patients with end-stage renal disease (ESRD) has never been illustrated. In this study, we investigated ILC2s in ESRD patients and their clinical significance. Results showed that the frequencies and absolute numbers of ILC2s, not group 1 innate lymphoid cells or innate lymphoid cell precursors, were significantly elevated in the peripheral blood of ESRD patients when compared with those from healthy donor controls. Moreover, ILC2s from ESRD patients displayed enhanced type 2 cytokine production and cell proliferation. Plasma from ESRD patients significantly increased ILC2 levels and enhanced their effector function after in vitro treatment. The expression of phosphorylation of STAT5 in ILC2s, as well as the amounts of IL-2 in plasma, were increased in ESRD patients when compared with those from healthy donors. Clinically, ESRD patients with higher ILC2 frequencies displayed lower incidence of infectious complications during a mean of 21 month follow-up study. The proportions of ILC2s were negatively correlated with the prognostic biomarkers of chronic kidney disease, including serum parathyroid hormone, creatinine, and phosphorus, whereas they were positively correlated with serum calcium. These observations indicate that ILC2s may play a protective role in ESRD.

Transfer of Fresh versus Frozen Embryos in Ovulatory Women.

BACKGROUND: Elective frozen-embryo transfer has been shown to result in a higher live-birth rate than fresh-embryo transfer among anovulatory women with the polycystic ovary syndrome. It is uncertain whether frozen-embryo transfer increases live-birth rates among ovulatory women with infertility. METHODS: In this multicenter, randomized trial, we randomly assigned 2157 women who were undergoing their first in vitro fertilization cycle to undergo either fresh-embryo transfer or embryo cryopreservation followed by frozen-embryo transfer. Up to two cleavage-stage embryos were transferred in each participant. The primary outcome was a live birth after the first embryo transfer. RESULTS: The live-birth rate did not differ significantly between the frozen-embryo group and the fresh-embryo group (48.7% and 50.2%, respectively; relative risk, 0.97; 95% confidence interval [CI], 0.89 to 1.06; P=0.50). There were also no significant between-group differences in the rates of implantation, clinical pregnancy, overall pregnancy loss, and ongoing pregnancy. Frozen-embryo transfer resulted in a significantly lower risk of the ovarian hyperstimulation syndrome than fresh-embryo transfer (0.6% vs. 2.0%; relative risk, 0.32; 95% CI, 0.14 to 0.74; P=0.005). The risks of obstetrical and neonatal complications and other adverse outcomes did not differ significantly between the two groups. CONCLUSIONS: The live-birth rate did not differ significantly between fresh-embryo transfer and frozen-embryo transfer among ovulatory women with infertility, but frozen-embryo transfer resulted in a lower risk of the ovarian hyperstimulation syndrome. (Funded by the National Key Research and Development Program of China and the National Natural Science Foundation of China; Chinese Clinical Trial Registry number, ChiCTR-IOR-14005406 .).

Understanding the Roles of Electrogenerated Co3+ and Co4+ in Selectivity-Tuned 5-Hydroxymethylfurfural Oxidation.

The Co-based electrocatalyst is among the most promising candidates for electrochemical oxidation of 5-hydroxymethylfurfural (HMF). However, the intrinsic active sites and detailed mechanism of this catalyst remains unclear. We combine experimental evidence and a theoretical study to show that electrogenerated Co3+ and Co4+ species act as chemical oxidants but with distinct roles in selective HMF oxidation. It is found that Co3+ is only capable of oxidizing formyl group to produce carboxylate while Co4+ is required for the initial oxidation of hydroxyl group with significantly faster kinetics. As a result, the product distribution shows explicit dependence on the Co oxidation states and selective production of 5-hydroxymethyl-2-furancarboxylic acid (HMFCA) and 2,5-furandicarboxylic acid (FDCA) are achieved by tuning the applied potential. This work offers essential mechanistic insight on Co-catalyzed organic oxidation reactions and might guide the design of more efficient electrocatalysts.

Enhanced alleviation of aGVHD by TGF-ß1-modified mesenchymal stem cells in mice through shifting MΦ into M2 phenotype and promoting the differentiation of Treg cells.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is the only curative method in treating haematologic malignant diseases. Graft-versus-host disease (GVHD) is a common complication post-allo-HSCT, which can be life-threatening. Mesenchymal stem cells (MSCs) as an adult stem cell with immunoregulatory function have demonstrated efficacy in steroid resistant acute GVHD (aGVHD). However, the outcome of aGVHD treated with MSCs in clinical trials varied and its underlying mechanism is still unclear. TGF-ß1 is a potent cytokine, which plays a key role in immunoregulation. In the present study, we firstly transduced the lentivirus vector containing TGF-ß1 gene with mouse bone marrow-derived MSCs. Then, we investigated the immunosuppressive effect of TGF-ß1 gene-modified MSCs on lymphocytes in vitro and its preventive and therapeutical effects on murine aGVHD model in vivo. Murine MSC was successfully isolated and identified. TGF-ß1 was efficiently transduced into mouse MSCs, and high level TGF-ß1 was detected. MSC-TGF-ß1 shared the same morphology and immunotypic features of normal MSC. In vitro, MSC-TGF-ß1 showed enhanced immunosuppressive function on lymphocyte proliferation. In vivo, MSC-TGF-ß1 showed enhanced amelioration on the severity of aGVHD both in prophylactic and therapeutic murine models. Finally, the macrophages (MØs) derived from MSC-TGF-ß1-treated mice showed a remarkably increasing of anti-inflammatory M2-like phenotype. Furthermore, the differentiation of CD4+ CD25+ Foxp3+ Treg cells was significantly increased in MSC-TGF-ß1-treated group. Taken together, we proved that MSC-TGF-ß1 showed enhanced alleviation of aGVHD severity in mice by skewing macrophages into a M2 like phenotype or increasing the proportion of Treg cells, which opens a new frontier in the treatment of aGVHD.

CEMIP regulates the proliferation and migration of vascular smooth muscle cells in atherosclerosis through the WNT-beta-catenin signaling pathway.

In this study we investigated the regulatory role of cell-migration-inducing and hyaluronan-binding protein (CEMIP) in the proliferation and migration of vascular smooth muscle cells (VSMCs). The mRNA and protein levels of CEMIP were upregulated in the plasma samples from patients with atherosclerosis, and in VSMCs stimulated with platelet-derived growth factor-BB (PDGF-BB), compared with plasma from healthy subjects and untreated VSMCs. Silencing CEMIP suppressed PDGF-BB-induced cell migration and proliferation in VSMCs, as determined using a Cell Counting Kit-8 assays, 5-ethynyl-2'-deocyuridine (EDU) assays, flow cytometry, wound healing assays, and Transwell assays. Overexpression of CEMIP promoted the proliferation and migration of VSMCs via activation of the Wnt-ß-catenin signaling pathway and the upregulation of its target genes, including matrix metalloproteinase-2, matrix metalloproteinase-7, cyclin D1, and c-myc, whereas CEMIP deficiency showed the opposite effects. The knockdown of CEMIP in ApoE-/- mice by intravenous injection of lentiviral vector expressing si-CEMIP protected against high-fat-diet-induced atherosclerosis, as shown by the reduced aortic lesion areas, aortic sinus lesion areas, and the concentration of blood lipids compared with mice normally expressing CEMIP. These results demonstrated that CEMIP regulates the proliferation and migration of VSMCs in atherosclerosis by activating the WNT-ß-catenin signaling pathway, which suggests the therapeutic potential of CEMIP for the management of atherosclerosis.