[Research advances on the role and mechanism of microRNA in hypertrophic scar].

Hypertrophic scar (HS) affects the function and beauty of patients, and brings a heavy psychological burden to patients. However, the specific pathogenesis mechanism of HS in molecular biology level is not yet clear, and this disease is still one of the clinical diseases difficult to prevent and cure. MicroRNA (miR) is a family of single-stranded endogenous noncoding RNAs that can regulate gene expression. The abnormal transcription of miR in hypertrophic scar fibroblasts can affect the transduction and expression of downstream signal pathway or protein, and the exploration of miR and its downstream signal pathway and protein helps deeply understand the occurrence and development mechanism of scar hyperplasia. This article summarized and analyzed how miR and multiple signal pathways involve in the formation and development of HS in recent years, and further outlined the interaction between miR and target genes in HS.

[Analysis of respiratory syncytial virus infection in hospitalized children with acute lower respiratory tract infection in China from 2017 to 2020].

Objective: To understand the detection rate, epidemic pattern of respiratory syncytial virus (RSV) in hospitalized children with acute lower respiratory tract infection (ALRTI) in China. Methods: From June 2017 to March 2020, a prospective multi-center study on the viral aetiology among hospitalized children with ALRTI was conducted in six pediatrics hospital of North China, Northeast, Northwest, South China, Southeast, and Southwest China. A total of 2 839 hospitalized children with ALRTI were enrolled, and the respiratory specimens were collected from these cases. A multiplex real-time RT-PCR assay were employed to screen the respiratory viruses, and the molecular epidemiological and clinical characteristics of children infected with RSV were analyzed. Results: The positve rate of RSV was 18.6% (528/2 839), and the positive rate of RSV in different regions ranged from 5.5% to 44.3%. The positive rate of RSV in male was higher than that in female (20.2% vs 16.3%), and there was a significant statistically difference between two groups (χ2=6.74, P=0.009). The positive rate of RSV among children under 5 years old was higher than that among children older than 5 years old (22.3% vs 4.5%), and there was a significant statistically difference between two groups (χ2=97.98,P<0.001). The positive rate of RSV among the <6 months age group was higher than that of other age groups (all P<0.05). During January 2018 and December 2019, RSV was detected in almost all through the year, and showed peaks in winter and spring. RSV-positive cases accounted for 17.0% (46/270) among children with severe pneumonia, including 36 cases infected with RSV alone. Conclusion: RSV is an important viral pathogen in children under 5 years old with ALRTI in China. The virus can be detected almost all through the year and reached the peak in winter and spring. RSV could lead to severe pneumonia in children and caused huge threaten to children's health.

[Indirubin relieves inflammatory injury of chondrocytes in a mouse model of osteoarthritis].

OBJECTIVE: To investigate the effect of indirubin for relieving joint inflammation and injury in a rat model of osteoarthritis. METHODS: Articular cartilage chondrocytes were isolated from adult rat knee joint and cultured in the presence of interleukin-1ß (IL-1ß) and 0.1, 0.5, 1.0, or 2.0 µmol/L indirubin. The cells were transfected with NPAS2 siRNA or a non-specific siRNA, and the cell proliferation and apoptosis were evaluated using tetramethylthiazole blue staining and flow cytometry. The protein expression levels of Bax, Bcl-2, ACAN, COL2A1, MMP-13 and NPAS2 were detected with Western blotting, and the levels of NO, PGE2 and TNF-α in the culture supernatant were determined with ELISA. The mRNA expression levels of NPAS2, ACAN, COL2A1 and MMP-13 were detected using fluorescence quantitative PCR. In a C57BL/6 mouse model of osteoarthritis, the effect of indirubin on BAX, Bcl-2, ACAN and MMP-13 protein expressions in the bone and joint tissues were evaluated with Western blotting. RESULTS: Treatment with 0.1 µmol/L indirubin produced no significant changes in chondrocyte proliferation, apoptosis, caspase-3 activity, or BAX and Bcl-2 protein expressions. At higher doses (0.5, 1.0 and 2.0 µmol/L), indirubin significantly promoted cell proliferation, increased Bcl-2 protein expression, and lowered cell apoptosis rate, caspase-3 activity and Bax protein expression (P < 0.05). Indirubin treatment at 0.5 µmol/L up-regulated the protein and mRNA expressions of NPAS2, ACAN and COL2A1, and down-regulated the expressions of MMP-13, NO, PGE2 and TNF-α (P < 0.05). Interference of NPAS2 expression significantly attenuated the protective effect of 0.5 µmol/L indirubin against IL-1ß-induced chondrocyte injury. The mouse model of osteoarthritis showed obviously increased protein levels of BAX and MMP-13 (P < 0.01) and decreased levels of Bcl-2 (P < 0.05) and ACAN (P < 0.01) in the knee joint, and indirubin treatment of the mouse models significantly inhibited the increase of BAX and MMP-13 protein expressions (P < 0.01) and up-regulated the protein expressions of Bcl-2 and ACAN (P < 0.05). CONCLUSION: Indirubin has a protective effect on osteoarthritis tissue and alleviates inflammation and damage of osteoarthritis chondrocytes possibly through NPAS2.

PD1/PDL1 expression is associated with increased TIM3 expression and tumor-infiltrating T lymphocytes in fibroblastic tumors

PurposeThe combined therapy of inhibiting T cell immunoglobulin domain and mucin domain 3 (TIM3) and programmed cell death 1/programmed death-ligand 1 (PD1/PDL1) has shown encouraging therapeutic effects in some solid tumors. However, the expression of PD1/PDL1 and TIM3 in fibroblastic tumors is ill defined, which has limited the application of these immune checkpoint inhibitors in such tumors.MethodsImmunostaining of 68 tissue microarray cores of fibroblastic tumors, including intermediate dermatofibrosarcoma protuberans and malignant myxofibrosarcoma and adult-type fibrosarcoma, was used to determine the expression of PD1, PDL1 and TIM3, as well as their relationship with the accumulation of tumor-infiltrating T lymphocytes (TILs).ResultsBoth PD1 and PDL1 expression was only observed in a small proportion of fibroblastic tumors, whereas TIM3 was expressed in almost all tumors. However, only the positive expression of PDL1 was related to tumors with high grade and staging. A considerable number of TILs, including CD4- and CD8A-positive T cells and a small group of FoxP3-positive T cells, was also observed in most tumors. The density of TIM3 was positively correlated with that of TILs. Furthermore, higher densities of TIM3, CD4, CD8A and FoxP3 were observed in PD1 and PDL1 double-positive fibroblastic tumors.ConclusionsThis study indicates that TILs with high expression of TIM3 may contribute to immunosuppression in the tumor microenvironment of fibroblastic tumors. Patients with fibroblastic tumors with high expression of PD1/PDL1 and TIM3 may therefore benefit from combination therapy with PD1/PDL1 and TIM3 inhibitors.

PD1/PDL1 expression is associated with increased TIM3 expression and tumor-infiltrating T lymphocytes in fibroblastic tumors.

PURPOSE: The combined therapy of inhibiting T cell immunoglobulin domain and mucin domain 3 (TIM3) and programmed cell death 1/programmed death-ligand 1 (PD1/PDL1) has shown encouraging therapeutic effects in some solid tumors. However, the expression of PD1/PDL1 and TIM3 in fibroblastic tumors is ill defined, which has limited the application of these immune checkpoint inhibitors in such tumors. METHODS: Immunostaining of 68 tissue microarray cores of fibroblastic tumors, including intermediate dermatofibrosarcoma protuberans and malignant myxofibrosarcoma and adult-type fibrosarcoma, was used to determine the expression of PD1, PDL1 and TIM3, as well as their relationship with the accumulation of tumor-infiltrating T lymphocytes (TILs). RESULTS: Both PD1 and PDL1 expression was only observed in a small proportion of fibroblastic tumors, whereas TIM3 was expressed in almost all tumors. However, only the positive expression of PDL1 was related to tumors with high grade and staging. A considerable number of TILs, including CD4- and CD8A-positive T cells and a small group of FoxP3-positive T cells, was also observed in most tumors. The density of TIM3 was positively correlated with that of TILs. Furthermore, higher densities of TIM3, CD4, CD8A and FoxP3 were observed in PD1 and PDL1 double-positive fibroblastic tumors. CONCLUSIONS: This study indicates that TILs with high expression of TIM3 may contribute to immunosuppression in the tumor microenvironment of fibroblastic tumors. Patients with fibroblastic tumors with high expression of PD1/PDL1 and TIM3 may therefore benefit from combination therapy with PD1/PDL1 and TIM3 inhibitors.

[Effect of endoscopic vidian neurectomy in patients with coexisting allergic rhinitis and bronchial asthma].

Objective: To evaluate the clinical significance of endoscopic vidian neurectomy (EVN) on outcomes in patients with coexisting refractory allergic rhinitis (AR) and bronchial asthma, and to analyze its influence factor. Methods: Clinical data of 109 patients with moderate to severe persistent intractable AR and bronchial asthma who were allocated to the bilateral EVN group (surgery group, 70 cases) or conservative medication group (drug group, 39 cases) from 1 May 2008 to 30 April 2013 in Department of Otorhinolaryngology Head and Neck Surgery, Third Xiangya Hospital, Central South University were retrospectively analyzed, including 47 cases of male and 62 cases of female aged (32.7±6.8) years.Ninety-five patients were followed up for at least 3 years. The Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), Visual Analog Scale (VAS), Asthma Quality of Life Questionnaire (AQLQ), Total Asthma Symptom Score (TASS), forced expiratory volume in 1 second of predicted (FEV1) and medication scores were evaluated at 6 months, 1 year and 3 years after undergoing the initial treatments in the two groups. Multiple factor analysis was used to determine the factors influencing the improvement after EVN. Results: Postoperative scores of RQLQ were significantly lower than preoperative scores during follow-up in surgery group (the preoperative score and postoperative score at 6 months, 1 year, 3 years after operation was 2.39±0.61 (x±s), 0.81±0.43, 0.89±0.32, 1.06±0.24, respectively, all P<0.001). Postoperative scores of VAS were significantly lower than preoperative scores during follow-up in surgery group (the preoperative score and postoperative score at 6 months, 1 year,3 years after operation was 7.13±1.04, 2.52±1.47, 2.70±1.42, 2.85±1.64, respectively, all P<0.05). Scores of RQLQ and VAS in surgery group were significantly lower than those of drug group. Postoperative scores of AQLQ were significantly higher than preoperative scores during follow-up in surgery group (the preoperative score and postoperative score at 6 months, 1 year, 3 years after operation was 3.78±0.81, 4.99±0.45, 4.75±0.71, 4.62±0.64, respectively, all P<0.05), and were significantly higher than those of drug group. The TASS and FEV1 were not significantly changed in surgery group. The postoperative medication scores for AR were gradually reduced after surgery (the preoperative score and postoperative score at 6 months, 1 year, 3 years after operation was 0.99±0.21, 0.37±0.12, 0.39±0.26, 0.45±0.11, respectively, all P<0.05), and the postoperative medication scores for Asthma were gradually reduced after surgery too (the preoperative score and postoperative score at 6 months, 1 year, 3 years after operation was 1.27±0.31, 0.82±0.29, 0.85±0.23, 0.96±0.19, respectively, all P<0.05), and all the postoperative medication scores were significantly lower than those of drug group. At the end of the follow-up, the improvement rates for AR and asthma were 90.6% (58/64) and 45.3% (29/64), respectively. Asthma outcomes were significantly improved by controlling rhinitis symptoms in patients whose asthma attacks were induced by "rhinitis onset" or "climate change" . Conclusion: For patients with AR and bronchial asthma, EVN can significantly control AR symptoms, and improve asthma outcomes in patients whose asthma attacks are induced by rhinitis onset and/or climate change.

[Spatial-temporal characteristics of other infectious diarrhea in Jiangsu province, 2010-2017].

Objective: To analyze the spatial-temporal characteristics of other infectious diarrhea (OID) in Jiangsu province from 2010 to 2017, and to provide evidence for setting up prevention and control programs of the disease. Methods: Data was from the Chinese Center for Disease Control and Prevention and the Statistics Bureau of Jiangsu province. Descriptive methods were used to illustrate the epidemiological characteristics of OID from 2010 to 2017. Global autocorrelation statistics method (Moran's I) was used to detect the spatial autocorrelation of OID, annually. Kulldorff M spatiotemporal scan statistics was used to analyze the spatial-temporal clustering of OID. ArcGIS 10.0 software, SaTScan 9.4 software and Excel 2017 software were also applied. Results: A total of 126 341 OID cases were found in Jiangsu province from 2010 to 2017 with an average annual incidence as 19.96/100 000. Children under five accounted for 55.08% (69 590/126 341) of the total cases. Obvious seasonal backshift with the increasing trends of the OID was noticed. There appeared four areas with high incidence of OID in the whole province, including Wuxi, Suzhou, Yancheng and Xuzhou. OID showed positive spatial autocorrelation at the county level with higher Moran's I from 0.19 to 0.33 (P<0.01). There appeared four positive clusters, all occurred in the high incidence period of OID, including the cluster area from the intersection areas of Changzhou and Wuxi (RR=7.61, LLR=2 605.80, P<0.01), respectively. Conclusion: With the increasing trends and the seasonal backshift of OID cases, pathogen surveillance programs set for those scattered children under five, in clustered regions and epidemic seasons should be strengthened.

MBD2 regulates differentiation and function of Th17 cells in neutrophils- dominant asthma via HIF-1α.

BACKGROUND: T helper 17 (Th17) cells have proven to be crucial in the pathogenesis of neutrophils-dominant asthma. Hypoxia inducible factor-1α (HIF-1α) is involved in allergic responses in asthma. Our previous studies indicated that Methtyl-CpG binding domain protein 2 (MBD2) expression was increased in asthma patients. The aim of the present study is to understand how MBD2 interacts with HIF-1α to regulate Th17 cell differentiation and IL-17 expression in neutrophils-dominant asthma. METHODS: A neutrophils-dominant asthma mouse model was established using female C57BL/6 mice to investigate Th17 cell differentiation and MBD2 and HIF-1α expression regulation using flow cytometry, western blot or qRT-PCR. MBD2 and HIF-1α genes were silenced or overexpressed through lentiviral transduction to explore the roles of MBD2 in Th17 cell differentiation and IL-17 release in neutrophils-dominant asthma. RESULTS: A neutrophilic inflammatory asthma phenotype model was established successfully. This was characterized by airway hyperresponsiveness (AHR), increased BALF neutrophil granulocytes, activated Th17 cell differentiation, and high IL-17 levels. MBD2 and HIF-1α expression were significantly increased in the lung and spleen cells of mice with neutrophils-dominant asthma. Through overexpression or silencing of MBD2 and HIF-1α genes, we have concluded that MBD2 and HIF-1α regulate Th17 cell differentiation and IL-17 secretion. Moreover, MBD2 was also found to regulate HIF-1α expression. CONCLUSIONS: Our findings have uncovered new roles for MBD2 and HIF-1α, and provide novel insights into the epigenetic regulation of neutrophils-dominant asthma.

Role of von Willebrand factor and ADAMTS-13 in early brain injury after experimental subarachnoid hemorrhage.

Essentials von Willebrand Factor (VWF) and ADAMTS13 may affect early injury after subarachnoid hemorrhage (SAH). Early brain injury was assessed in VWF-/- , ADAMTS13-/- and recombinant (r) ADAMTS13 treated mice. VWF-/- and rADAMTS13 treated mice had less brain injury than ADAMTS13-/- and wild-type mice. Early administration of rADAMTS13 may improve outcome after SAH by reducing early brain injury. SUMMARY: Background Early brain injury is an important determinant of poor functional outcome and case fatality after aneurysmal subarachnoid hemorrhage (SAH), and is associated with early platelet aggregation. No treatment exists for early brain injury after SAH. We investigated whether von Willebrand factor (VWF) is involved in the pathogenesis of early brain injury, and whether ultra-early treatment with recombinant ADAMTS-13 (rADAMTS-13) reduces early brain injury after experimental SAH. Methods Experimental SAH in mice was induced by prechiasmatic injection of non-anticoagulated blood from a littermate. The following experimental SAH groups were investigated: C57BL/6J control (n = 21), VWF-/- (n = 25), ADAMTS-13-/- (n = 23), and C57BL/6J treated with rADAMTS-13 (n = 26). Mice were killed at 2 h after SAH. Primary outcome measures were microglial activation (IBA-1 surface area) and neuronal injury (number of cleaved caspase-3-positive neurons). Results As compared with controls, microglial activation was decreased in VWF-/- mice (mean difference of - 20.0%, 95% confidence interval [CI] - 4.0% to - 38.6%), increased in ADAMTS-13-/- mice (mean difference of + 34.0%, 95% CI 16.2-51.7%), and decreased in rADAMTS-13-treated mice (mean difference of - 22.1%, 95% CI - 3.4% to - 39.1%). As compared with controls (185 neurons, interquartile range [IQR] 133-353), neuronal injury in the cerebral cortex was decreased in VWF-/- mice (63 neurons, IQR 25-78), not changed in ADAMTS-13-/- mice (53 neurons, IQR 26-221), and reduced in rADAMTS-13-treated mice (45 neurons, IQR 9-115). Conclusions Our findings suggest that VWF is involved in the pathogenesis of early brain injury, and support the further study of rADAMTS-13 as a treatment option for early brain injury after SAH.

Regulatory role of CDX2 and NOX4 expression associated with recurrent nasopharyngeal carcinoma.

OBJECTIVE: Nasopharyngeal carcinoma (NPC) is a malignancy caused by Epstein-Barr virus (EBV). NPC is radiosensitive and has a high frequency of treatment failure due to metastasis, which results in recurrent nasopharyngeal carcinoma (rNPC). PATIENTS AND METHODS: In the present study, nasopharyngeal carcinoma biopsies were obtained from NPC and rNPC patients, as well as healthy controls, and reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, and immunoblotting analyses were performed. RESULTS: The RTPCR data showed expression of CDX2 and NOX4 in rNPC biopsy samples but not in control or NPC samples. Immunohistochemical and immunoblotting analyses confirmed the expression of CDX2 and NOX4 in rNPC samples, but not in NPC biopsy samples. CONCLUSIONS: The finding concludes that an association of CDX2 and NOX4 expression with rNPC was noted; thus, these proteins may have value as prognostic indicators and may facilitate the development of novel therapeutics for rNPC patients.

[Genetic characterization of norovirus isolated in an outbreak of gastroenteritis in Jiangsu province].

Objective: To analyze the genetic characterization of norovirus isolated in an outbreak of gastroenteritis in Jiangsu province. Methods: Extracted viral RNA from the swab samples of cases of acute gastroenteritis outbreak in Jiangsu province on December 16-27, 2016 was reversely transcribed to cDNA, and partial RNA-dependent RNA polymerase sequence and complete capsid sequence (VP1) were amplified by RT-PCR. Amplification products were sequenced for the analysis of genetic characteristics. Results: Based on sequence alignment, the variant shared a high level of identity with the strain GⅡ.g isolated in Spain and Finland (98.7%) in the RNA-dependent RNA polymerase region, and with the strain GⅡ.1 isolated in American (99.4%) in the VP1. The recombination was determined by using software Simplot, and the breakpoint of recombination was located in the ORF1/2 overlap region at position 5 106 of VP1. The result of amino acids alignment in capsid region showed that there were no mutations in the amino acids of the predicted epitopes and receptor binding site Ⅰ-Ⅲ, but a unique amino acid change was detected at position 132 (N-S). Conclusion: The norovirus isolated in the outbreak of gastroenteritis in Jiangsu province was a rare recombinant norovirus variant GⅡ.g-GⅡ.1.

DHX15 promotes prostate cancer progression by stimulating Siah2-mediated ubiquitination of androgen receptor.

Androgen receptor (AR) activation is critical for prostate cancer (PCa) development and progression, including castration resistance. The nuclear export signal of AR (NESAR) has an important role in AR intracellular trafficking and proteasome-dependent degradation. Here, we identified the RNA helicase DHX15 as a novel AR co-activator using a yeast mutagenesis screen and revealed that DHX15 regulates AR activity by modulating E3 ligase Siah2-mediated AR ubiquitination independent of its ATPase activity. DHX15 and Siah2 form a complex with AR, through NESAR. DHX15 stabilized Siah2 and enhanced its E3 ubiquitin-ligase activity, resulting in AR activation. Importantly, DHX15 was upregulated in PCa specimens and its expression was correlated with Gleason scores and prostate-specific antigen recurrence. Furthermore, DHX15 immunostaining correlated with Siah2. Finally, DHX15 knockdown inhibited the growth of C4-2 prostate tumor xenografts in mice. Collectively, our data argue that DHX15 enhances AR transcriptional activity and contributes to PCa progression through Siah2.

EAF2 regulates DNA repair through Ku70/Ku80 in the prostate.

Androgens are known to protect prostate cancer cells from DNA damage. Recent studies showed regulation of DNA repair genes by androgen receptor signaling in prostate cancers. ELL-associated factor 2 (EAF2) is an androgen-regulated tumor suppressor and its intracellular localization can be modulated by ultraviolet light, suggesting a potential role for EAF2 in androgen regulation of DNA repair in prostate cancer cells. Here we show that knockdown of EAF2 or its homolog EAF1 sensitized prostate cancer cells to DNA damage and the sensitization did not require p53. EAF2 knockout mouse prostate was also sensitized to γ-irradiation. Furthermore, EAF2 knockdown blocked androgen repression of LNCaP or C4-2 cells from doxorubicin induction of γH2ax, a DNA damage marker. In human prostate cancer specimens, EAF2 expression was inversely correlated with the level of γH2ax. Further analysis showed that EAF2 and EAF1 are required for the recruitment and retention of Ku70/Ku80 to DNA damage sites and play a functional role in nonhomologous end-joining DNA repair. These findings provide evidence for EAF2 as a key factor mediating androgen protection of DNA damage via Ku70/Ku80 in prostate cancer cells.

Cryopreservation of Schisandra chinensis (Turcz.) Baill callus and subsequent plant regeneration.

Cryopreservation has been proven significance as a technique for promising the long-term conservation of plant germplasms. This study aimed to establish a cryopreservation protocol for calli of Schisandra chinensis (Turcz.) Baill, and to explore the effects of different process parameters on callus viability. Effects of desiccation duration, cryoprotectants and cryopreservation methods, thawing temperature, and post-culture conditions on the viability of cryopreserved calli were assessed. Among different cryoprotectants and freezing procedures, the highest survival was recorded when the water content of callus after 30 min desiccation was 57.3%, were loaded into a cryoprotectant containing 10% ethylene glycol, 8% glucose, and 10% DMSO, and frozen slowly (-1°C/min). Rapid thawing at 40°C for 2 min demonstrated the best recovery of cryopreserved S. chinensis calli. Post-culturing in darkness for one week before transfer to light conditions (under 16 h photoperiod at 36 µmol·m-2·s-1) was beneficial to callus regeneration. Plants regenerated through somatic embryogenesis from cryopreserved calli remained ploidy stable after cryopreservation. The callus cryopreservation procedure established in this study is a promising tool for the conservation of S. chinensis resources.

Accelerated wound healing in a diabetic rat model using decellularized dermal matrix and human umbilical cord perivascular cells.

There is an unmet clinical need for novel wound healing strategies to treat full thickness skin defects, especially in diabetic patients. We hypothesized that a scaffold could perform dual roles of a biomechanical support and a favorable biochemical environment for stem cells. Human umbilical cord perivascular cells (HUCPVCs) have been recently reported as a type of mesenchymal stem cell that can accelerate early wound healing in skin defects. However, there are only a limited number of studies that have incorporated these cells into natural scaffolds for dermal tissue engineering. The aim of the present study was to promote angiogenesis and accelerate wound healing by using HUCPVCs and decellularized dermal matrix (DDM) in a rat model of diabetic wounds. The DDM scaffolds were prepared from harvested human skin samples and histological, ultrastructural, molecular and mechanical assessments were carried out. In comparison with the control (without any treatment) and DDM alone group, full thickness excisional wounds treated with HUCPVCs-loaded DDM scaffolds demonstrated an accelerated wound closure rate, faster re-epithelization, more granulation tissue formation and decreased collagen deposition. Furthermore, immunofluorescence analysis showed that the VEGFR-2 expression and vascular density in the HUCPVCs-loaded DDM scaffold treated group were also significantly higher than the other groups at 7days post implantation. Since the rates of angiogenesis, re-epithelization and formation of granulation tissue are directly correlated with full thickness wound healing in patients, the proposed HUCPVCs-loaded DDM scaffolds may fulfil a role neglected by current treatment strategies. This pre-clinical proof-of-concept study warrants further clinical evaluation. STATEMENT OF SIGNIFICANCE: The aim of the present study was to design a novel tissue-engineered system to promote angiogenesis, re-epithelization and granulation of skin tissue using human umbilical cord perivascular stem cells and decellularized dermal matrix natural scaffolds in rat diabetic wound models. The authors of this research article have been working on stem cells and tissue engineering scaffolds for years. According to our knowledge, there is a lack of an efficient system for the treatment of skin defects using tissue engineering strategy. Since the rates of angiogenesis, re-epithelization and granulation tissue are directly correlated with full thickness wound healing, the proposed HUCPVCs-loaded DDM scaffolds perfectly fills the niche neglected by current treatment strategies. This pre-clinical study demonstrates the proof-of-concept that necessitates clinical evaluations.

Plasma soluble Tim-3 emerges as an inhibitor in sepsis: sepsis contrary to membrane Tim-3 on monocytes.

Immune dysfunction is the main characteristic of sepsis. T cell Ig and mucin domain protein 3 (Tim-3) on the monocytes has been reported to promote immune homeostasis during sepsis, but the influences of plasm soluble Tim-3 (sTim-3) on the immune system during sepsis remain unknown. Here, 100 patients with different severities of sepsis (40 sepsis, 42 severe sepsis, and 18 septic shock) were enrolled in this study. The Tim-3 and human leukocyte antigen-DR (HLA-DR) on the circulating monocytes were detected using flow cytometry. Plasma sTim-3 was detected by enzyme-linked immunosorbent assay. Inflammatory factors and two kinds of A disintegrin and metalloprotease (ADAM) - ADAM10 and ADAM17 were assessed. The Tim-3 and HLA-DR on the monocytes decreased with increasing sepsis severity. The sTim-3 was reduced in the sepsis and severe sepsis patients but was elevated in the septic shock patients who exhibited significant immunosuppression as predicted by HLA-DR. sTim-3 levels were negatively correlated with IL-12 and TNF-α. ADAM10 and ADAM17, sheddases of Tim-3, exhibited trends toward elevations in the septic shock group. In conclusion, sTim-3 was involved in the development of sepsis. The homeostasis-promoting role of the Tim-3 on the monocytes was disrupted, while the inhibitory role of sTim-3 emerged during sepsis-induced immunosuppression.

Emergence of a new GII.17 norovirus variant in patients with acute gastroenteritis in Jiangsu, China, September 2014 to March 2015.

From September 2014 to March 2015, 23 outbreaks of norovirus (NoV) acute gastroenteritis occurred in Jiangsu, China. Partial sequencing of the NoV capsid gene suggested that 16 of the 23 outbreaks were related to a new GII.17 variant. This variant was first detected in sporadic specimens in October 2014, and became predominant in February 2015. Analysis of the RNA-dependent RNA polymerase (RdRp), and complete capsid including the protruding domain P2 sequences confirmed this GII.17 variant as distinct from previously identified GII variants.

Cardiac over-expression of microRNA-1 induces impairment of cognition in mice.

Large cohort studies have revealed a close relationship between cognitive impairment and cardiovascular diseases, although the mechanism underlying this relationship remains incompletely understood. In this study, using a transgenic (Tg) mouse model of cardiac-specific over-expression of microRNA-1-2 (miR-1-2), we observed that microRNA-1 (miR-1) levels were increased not only in the heart but also in the hippocampus and blood, whereas its levels did not change in the skeletal muscle of Tg mice compared with age-matched wild-type (WT) mice. Six-month-old Tg mice showed cognitive impairment compared with age-matched WT mice, as assessed using the Morris Water Maze test. The brain-derived neurotrophic factor (BDNF) level and cyclic AMP-responsive element-binding protein (CREB) phosphorylation were also significantly reduced in the hippocampi of the Tg mice, as evaluated by Western blot. Further examination showed that BDNF protein expression was down- or up-regulated by miR-1 over-expression or inhibition, respectively, and was unchanged by binding site mutations or miRNA-masks for the 3'UTR of Bdnf, indicating that this gene is a potential target of miR-1. Knockdown of miR-1 by hippocampal stereotaxic injection of an anti-miR-1 oligonucleotide fragment carried by a lentivirus vector (lenti-pre-AMO-miR-1) led to up-regulation of BDNF expression and prevented the reduction in cognitive performance in the Tg mice without affecting cardiac function. Our findings demonstrate that cardiac over-expression of miR-1 also induces behavioral abnormalities that may be associated, at least in part, with the down-regulation of BDNF expression in the hippocampus. This study definitely contributes to the understanding of the relationship between cardiovascular disease and cognitive impairment.

Antimalarial activity of 4-amidinoquinoline and 10-amidinobenzonaphthyridine derivatives.

Chloroquine (CQ) has been used as first line malaria therapeutic drug for decades. Emergence of CQ drug-resistant Plasmodium falciparum malaria throughout endemic areas of the world has limited its clinical value. Mefloquine (MQ) has been used as an effective malaria prophylactic drug due to its being long-acting and having a high potency against blood stage P. falciparum (Pf). However, serious CNS toxicity of MQ has compromised its clinical value as a prophylaxis drug. Therefore, new and inexpensive antimalarial drugs with no cross-resistance to CQ or CNS toxicity are urgently needed to combat this deadly human disease. In this study, a series of new 4-amidinoquinoline (4-AMQ) and 10-amidinobenzonaphthyridine (10-AMB) derivatives were designed, prepared, and assessed to search for new therapeutic agents to replace CQ and MQ. The new derivatives displayed high activity in vitro and in vivo, with no cross-resistance to CQ, and none were toxic in mice up to 160 mpk × 3. The best compound shows IC50 < 1 ng/mL against D6, W2 and C235 Pf clones, low inhibitory activity in hERG K(+) channel blockage testing, negativity in the Ames test, and 5/5 cure @ <15 mpk × 3 in mice infected with Plasmodium berghei. In addition to these desirable pharmacological profiles, compound 13b, one of the most active compounds, is metabolically stable in both human and mouse liver microsomal preparations and has a plasma t(1/2) of 50 h in mice, which made it a good MQ replacement candidate.