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MicroRNA (miRNA) and long noncoding RNA (lncRNA) are both regulators of cancer progression. This study sought to discuss the functional mechanism of miR-96-5p/lncRNA TRIM52 antisense RNA 1 (head-to-head; TRIM52-AS1) in cervical cancer (CC) cell resistance to cisplatin (DDP). DDP-resistant CC cell line was established using increasing concentrations of DDP, followed by transfection with miR-96-5p inhibitor, or si-TRIM52-AS1, or insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) overexpression vector. Expression levels of miR-96-5p, TRIM52-AS1, and IGF2BP2 were determined. Changes in IC50 value to DDP, cell proliferation, and apoptosis rate were evaluated by cell-counting kit-8 assay, colony formation, and flow cytometry. The bindings of miR-96-5p to IGF2BP2 and TRIM52-AS1 to IGF2BP2 were verified by dual-luciferase or RNA pull-down assays. These experiments revealed an up-expression of miR-96-5p and IGF2BP2 while an under-expression of TRIM52-AS1 in CC cells. After DDP treatment, miR-96-5p inhibition increased apoptosis and decreased proliferation and DDP resistance. miR-96-5p bound to TRIM52-AS1 and downregulated TRIM52-AS1 expression, and TRIM52-AS1 bound to IGF2BP2 to inhibit IGF2BP2 expression. TRIM52-AS1 inhibition or IGF2BP2 overexpression neutralized the inhibition of silencing miR-96-5p on CC cell resistance to DDP. Overall, miR-96-5p improved CC cell resistance to DDP by inhibiting TRIM52-AS1 and promoting IGF2BP2.

Purpose: To describe the prevalence and analyse the associated factors of possible sarcopenia and sarcopenia among community-dwelling old adults in China, in order to provide effective strategies for early prevention and treatment of sarcopenia.Methods: This cross-sectional study evaluated community-dwelling old adults aged over 60 years. The basic information, morphological indices, body composition, physical activities were collected and assessed. Possible sarcopenia and sarcopenia were diagnosed by the criteria of Asian Working Group for Sarcopenia (AWGS) in 2019. A multivariate logistic regression model with stepwise method was employed to identify factors associated with possible sarcopenia and sarcopenia.Results: In total 729 old adults from Tianjin were included in this study. 81 participants were diagnosed with possible sarcopenia (prevalence of 11.11%). 75 participants were diagnosed with sarcopenia (prevalence of 10.29%). Age (odds ratio (OR):1.047, 95% confidence interval (CI): 1.055-1.090) and lower physical activities (low level OR:4.171, 95% CI:1.790-9.720; medium level OR:2.634, 95% CI:1.352-5.132) were significantly associated with possible sarcopenia. Age (OR:1.187, 95% CI:1.124-1.253), higher body fat percentage (OR:1.225, 95% CI:1.140-1.317), lower BMI (OR:0.424, 95% CI:0.346-0.519), lower mini-mental state examination (MMSE) scores (OR:0.865,95% CI:0.781-0.958) and low physical activities (OR:4.638, 95% CI:1.683-12.782) were significantly associated with sarcopenia.Conclusion: Possible sarcopenia and sarcopenia are prevalent among community-dwelling old adults in China. Ageing and lower physical activities were both associated with possible sarcopenia and sarcopenia. Old adults with sarcopenia more likely have higher body fat percentage, lower BMI and lower cognitive function compared with those without this condition.

Sing-Ong Lee,1 Li-Ping Huang,1 Chih-Shung Wong1– 3 1Department of Anesthesiology, Cathay General Hospital, Taipei, Taiwan; 2Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan; 3School of Medicine, Fu-Jen Catholic University, New Taipei, TaiwanCorrespondence: Chih-Shung Wong Department of AnesthesiologyCathay General Hospital, #280, Renai Road, Section 4, Taipei, TaiwanTel +886-2-27082121 Ext 3510Fax +886-2-87924835Email w82556@gmail.comPurpose: Perioperative pain management plays a critical role in the effort to promote enhanced recovery after surgery (ERAS). Pain is also the most concern for patients after laparoscopic cholecystectomy (LC). Naldebain (extended-release dinalbuphine sebacate, DS) is an oil-based formulation for intramuscular injection that has been designed for extended release and can be used for preoperative analgesia over a 7-day period. This study was aimed to compare the efficacy of DS injection with that of regular postoperative morphine administered when necessary for the management of post-laparoscopic cholecystectomy pain.Patients and Methods: Forty-four patients scheduled for elective laparoscopic cholecystectomy were included in this prospective study. The patients were allocated randomly into two groups, with equal numbers receiving preoperative DS versus post-operative morphine. A total of 21 and 22 patients completed the study within the preoperative DS and post-operative morphine group, respectively.Results: There were no statistically significant differences between two treatment groups with respect to length of surgery, anesthetics used during operation, or the average visual analog scale pain score in the post-operative anesthesia care unit (PACU), and at 4, 24, 48, and 72 hours post-procedure. Morphine was required only during the first postoperative day among those in the DS group. Safety was comparable in both DS and morphine groups.Conclusion: A single preoperative dose of DS provides sufficient analgesia along with a manageable safety profile and no interference with surgical anesthetics when compared to control cases that underwent surgery without preoperative DS treatment. This pilot study suggests that preoperative administration of DS is safe and may decrease the need for postoperative opioid use after laparoscopic cholecystectomy.Registration: ClinicalTrials.gov Identifier: NCT03713216.Keywords: nalbuphine, enhanced recovery after surgery, multimodal analgesia, preventive analgesia

A phytochemical investigation on the stems of Glycosmis puberula var. craibii led to the isolation of a new indole alkaloid (named glycosmiscrol A, 1), together with four known compounds (2–5). The new structure was elucidated by detailed analysis of comprehensive spectroscopic methods. All isolated compounds were evaluated for their antiproliferative activities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1–5 showed significant antiproliferative effects with IC50 values ranging from 0.16 to 8.58 µM.

In plants, submergence from flooding causes hypoxia, which impairs energy production and affects plant growth, productivity, and survival. In Arabidopsis, hypoxia induces nuclear localization of the group VII ethylene-responsive transcription factor RELATED TO AP2.12 (RAP2.12), following its dissociation from the plasma membrane-anchored ACYL-COA BINDING PROTEIN1 (ACBP1) and ACBP2. Here, we show that polyunsaturated linolenoyl-CoA (18:3-CoA) regulates RAP2.12 release from the plasma membrane. Submergence caused a significant increase in 18:3-CoA, but a significant decrease in 18:0-, 18:1-, and 18:2-CoA. Application of 18:3-CoA promoted nuclear accumulation of the green fluorescent protein (GFP) fusions RAP2.12-GFP, HYPOXIA-RESPONSIVE ERF1-GFP, and RAP2.3-GFP, and enhanced transcript levels of hypoxia-responsive genes. Plants with decreased ACBP1 and ACBP2 (acbp1 ACBP2-RNAi, produced by ACBP2 RNA interference in the acbp1 mutant) had reduced tolerance to hypoxia and impaired 18:3-CoA-induced expression of hypoxia-related genes. In knockout mutants and overexpression lines of LONG-CHAIN ACYL-COA SYNTHASE2 (LACS2) and FATTY ACID DESATURASE 3 (FAD3), the acyl-CoA pool size and 18:3-CoA levels were closely related to ERF-VII-mediated signaling and hypoxia tolerance. These findings demonstrate that polyunsaturation of long-chain acyl-CoAs functions as important mechanism in the regulation of plant hypoxia signaling, by modulating ACBP-ERF-VII dynamics.

ObjectiveTo evaluate the necessity of Covid-19 vaccination in children aged < 12 y by comparing the clinical characteristics in unvaccinated children aged < 12 y with vaccinated patients aged ≥ 12y during the Delta surge (B.1.617.2) in Putian, Fujian, China.MethodsA total of 226 patients with SARS-Cov-2 Delta variant (B.1.167.2; confirmed by Realtime PCR positive and sequencing) were enrolled from Sep 10th to Oct 20th, 2021, including 77 unvaccinated children (aged < 12y) and 149 people aged ≥ 12y, mostly vaccinated. The transmission route was explored and the clinical data of two groups were compared; the effect factors for the time of the nucleic acid negativization (NAN) were examined by R statistical analysis.ResultsThe Delta surge in Putian spread from children in schools to factories, mostly through family contact. Compared with those aged ≥ 12y, patients aged < 12y accounted for 34.07% of the total and showed milder fever, less cough and fatigue; they reported higher peripheral blood lymphocyte counts [1.84(1.32,2.71)×10^9/L vs. 1.31(0.94,1.85)×10^9/L; pp< 0.05]. Upon admission, their COVID19 antibodies (IgM and IgG) and IgG in convalescence were lower [0.13(0.00,0.09) vs. 0.12(0.03,0.41), pp pp=0.13).ConclusionChildren aged < 12y may be critical hidden spreaders, which indicates an urgent need of vaccination for this particular population.

Synaptic pruning during adolescence is important for appropriate neurodevelopment and synaptic plasticity. Aberrant synaptic pruning may underlie a variety of brain disorders such as schizophrenia, autism and anxiety. Dopamine D2 receptor (Drd2) is associated with several neuropsychiatric diseases and is the target of some antipsychotic drugs. Here we generate self-reporting Drd2 heterozygous (SR-Drd2+/−) rats to simultaneously visualize Drd2-positive neurons and downregulate Drd2 expression. Time course studies on the developing anterior cingulate cortex (ACC) from control and SR-Drd2+/− rats reveal important roles of Drd2 in regulating synaptic pruning rather than synapse formation. Drd2 also regulates LTD, a form of synaptic plasticity which includes some similar cellular/biochemical processes as synaptic pruning. We further demonstrate that Drd2 regulates synaptic pruning via cell-autonomous mechanisms involving activation of mTOR signaling. Deficits of Drd2-mediated synaptic pruning in the ACC during adolescence lead to hyper-glutamatergic function and anxiety-like behaviors in adulthood. Taken together, our results demonstrate important roles of Drd2 in cortical synaptic pruning., Synaptic pruning is important during development and synaptic plasticity. Here, the authors show that the dopamine D2 receptor (Drd2) in the anterior cingulate cortex regulates synaptic pruning, affecting LTD and behaviour in transgenic rats.

Phosphatidic acid (PA) is an important lipid essential for several aspects of plant development and biotic and abiotic stress responses. We previously suggested that submergence induces PA accumulation in Arabidopsis thaliana; however, the molecular mechanism underlying PA-mediated regulation of submergence-induced hypoxia signaling remains unknown. Here, we showed that in Arabidopsis, loss of the phospholipase D (PLD) proteins PLDα1 and PLDδ leads to hypersensitivity to hypoxia, but increased tolerance to submergence. This enhanced tolerance is likely due to improvement of PA-mediated membrane integrity. PA bound to the mitogen-activated protein kinase 3 (MPK3) and MPK6 in vitro and contributed to hypoxia-induced phosphorylation of MPK3 and MPK6 in vivo. Moreover, mpk3 and mpk6 mutants were more sensitive to hypoxia and submergence stress compared with wild type, and fully suppressed the submergence-tolerant phenotypes of pldα1 and pldδ mutants. MPK3 and MPK6 interacted with and phosphorylated RELATED TO AP2.12, a master transcription factor in the hypoxia signaling pathway, and modulated its activity. In addition, MPK3 and MPK6 formed a regulatory feedback loop with PLDα1 and/or PLDδ to regulate PLD stability and submergence-induced PA production. Thus, our findings demonstrate that PA modulates plant tolerance to submergence via both membrane integrity and MPK3/6-mediated hypoxia signaling in Arabidopsis.

Ya Gao,1,&ast; Weiru Li,1,&ast; Xiaoyin Bu,1,&ast; Ying Xu,1 Shengchun Cai,1 Jinman Zhong,1 Meixue Du,1 Haitao Sun,2 Liping Huang,3 Yongjian He,4 Xiumei Hu,4 Qifa Liu,1 Hua Jin,1 Qian Wang,2,4 Baohong Ping5 1Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 2Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People’s Republic of China; 3Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 4Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 5Department of Hematology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Baohong PingDepartment of Hematology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of ChinaTel +8615625042109Fax +862061642231Email nfyypingbaohong66@163.comQian WangDepartment of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of ChinaTel +8613822251298Fax +862061643018Email wangqian@smu.edu.cnBackground: Acute graft versus host disease (aGVHD) remains a leading cause of transplant-related mortality following allogeneic haematopoietic cell transplantation (allo-HCT). Human amniotic mesenchymal stem cells (hAMSCs) are a novel mesenchymal stem cells (MSCs), which have stronger proliferation and immunomodulatory ability compared with bone marrow mesenchymal stem cells (BM-MSCs). Besides, as the amniotic membrane is often treated as medical waste after delivery, hAMSCs can be obtained conveniently and noninvasively. The aim of this study was to explore the therapeutic efficacy and underlying mechanisms of hAMSCs transplantation for the humanized aGVHD mouse model.Methods: We established a humanized aGVHD mouse model by transplanting human peripheral blood mononuclear cells (PBMCs) into NOD-PrkdcscidIL2rγnull (NPG) mice, human amniotic membrane collected from discarded placenta of healthy pregnant women after delivery and hAMSCs were extracted from amniotic membrane and expanded in vitro. Mice were divided into untreated group (Control), aGVHD group (aGVHD), and hAMSCs treatment group (aGVHD+hAMSCs), the hAMSCs labeled with GFP were administered to aGVHD mice to explore the homing ability of hAMSCs. T effector and regulatory T cells (Tregs) levels and cytokines of each group in target organs were detected by flow cytometry and cytometric bead array (CBA), respectively.Results: We successfully established a humanized aGVHD mouse model using NPG mice. The hAMSCs have the ability to inhibit aGVHD in this mouse model through reduced villous blunting and lymphocyte infiltration of the gut while reducing inflammatory edema, tissue destruction and lymphocyte infiltration into the parenchyma of the liver and lung. hAMSCs suppressed CD3+CD4+ T and CD3+CD8+ T cell expression and increased the proportion of Tregs, and besides, hAMSCs can reduce the levels of IL-17A, INF-γ, and TNF in aGVHD target organs.Conclusion: The NPG murine environment was capable of activating human T cells to produce aGVHD pathology to mimic aGVHD as in humans. The hAMSCs controlled aGVHD by decreasing inflammatory cytokine secretion within target organs by modulating the balance of Tregs and T effector cells in humanized mice.Keywords: acute graft versus host disease, humanized mouse model, NPG mice, amniotic mesenchymal stem cells, immunomodulatory

BACKGROUND Cryptococcal meningitis (CM)-associated immune reconstitution inflammatory syndrome (IRIS) is associated with high mortality, the epidemiology and pathophysiology of which is poorly understood, especially in non-HIV populations. OBJECTIVES We aim to explore the incidence, clinical risk factors, immunological profiles and potential influence of leukotriene A4 hydroxylase (LTA4H) on non-HIV CM IRIS populations. METHODS In this observational cohort study, 101 previously untreated non-HIV CM patients were included. We obtained data for clinical variables, 27 cerebrospinal fluid (CSF) cytokines levels and LTA4H genotype frequencies. Changes of CSF cytokines levels before and at IRIS occurrence were compared. RESULTS Immune reconstitution inflammatory syndrome was identified in 11 immunocompetent males, generating an incidence of 10.9% in non-HIV CM patients. Patients with higher CrAg titres (> 1:160) were more likely to develop IRIS, and titre of 1:1280 is the optimum level to predict IRIS occurrence. Baseline CSF cytokines were significantly higher in IRIS group, which indicated a severe host immune inflammation response. Four LTA4H SNPs (rs17525488, rs6538697, rs17525495 and rs1978331) exhibited significant genetic susceptibility to IRIS in overall non-HIV CM, while five cytokines were found to be associated with rs1978331, and baseline monocyte chemotactic protein 1 (MCP-1) became the only cytokine correlated with both IRIS and LTA4H SNPs. CONCLUSIONS Our study suggested that non-HIV CM patients with high fungal burden and severe immune inflammation response were more likely to developed IRIS. LTA4H polymorphisms may affect the pathogenesis of IRIS by regulating the level of baseline CSF MCP-1.

Background: Acute graft versus host disease (aGVHD) remains a leading cause of transplant-related mortality following allogeneic haematopoietic cell transplantation(allo-HCT). Although previous studies indicated that mesenchymal stem cells (MSCs) may be a salvage therapeutic agent for aGVHD, the mechanism is not yet fully clear. Human amniotic mesenchymal stem cells (hAMSCs) is a novel MSCs, compared with bone marrow mesenchymal stem cells, it has the advantage of being non-invasive, and also has stronger proliferation ability than that of BM-MSCs and equivalent immune regulation ability as BM-MSCs. The aim of this study was to explore the therapeutic efficacy and underlying mechanisms of human amniotic mesenchymal stem cells transplantation for the humanized aGVHD mouse model.Methods: We established a humanized aGVHD mouse model by transplanting human peripheral blood mononuclear cells (PBMCs) into NOD-PrkdcscidIL2rγnull (NPG) mice, hAMSCs collected from discarded placenta of healthy pregnant women after delivery. Mice were divided into control group (untreated), aGVHD group, and hAMSCs treatment group, the hAMSCs labeled with GFP were administered to aGVHD mice to explore the homing ability of hAMSCs. T effector and Treg cell levels and cytokines of each group in target organs were detected by flow cytometry and cytometric bead array (CBA) respectively.Results: We successfully established a humanized aGVHD mouse model using NPG mice. The hAMSCs have the ability to inhibit aGVHD in this mouse model through reduced villous blunting and lymphocyte infiltration into the lamina propria of the gut while reducing vascular endothelialitis and lymphocyte infiltration into the parenchyma of the liver and lung. hAMSCs suppressed xenogenesis CD3+CD4+ T and CD3+CD8+ T cell expression and increased the proportion of Treg cells, and besides, hAMSCs can reduce the levels of IL-17A, INF-γ, TNF, and IL-2 in aGVHD target organs.Conclusions: The NPG murine environment was capable of activating human T cells to produce aGVHD pathology to mimic aGVHD as in humans. The hAMSCs controlled aGVHD by decreasing inflammatory cytokine secretion within target organs by modulating the balance of Treg and T effector cells in humanized mice.

Surface fuel loading is a key factor in controlling wildfires and planning sustainable forest management. Spatially explicit maps of surface fuel loading can highlight the risks of a forest fire. Geospatial information is critical in enabling careful use of deliberate fire setting and also helps to minimize the possibility of heat conduction over forest lands. In contrast to lidar sensing and/or optical sensing based methods, an approach of integrating in-situ fuel inventory data, geospatial interpolation techniques, and multiple linear regression methods provides an alternative approach to surface fuel load estimation and mapping over mountainous forests. Using a stratified random sampling based inventory and cokriging analysis, surface fuel loading data of 120 plots distributed over four kinds of fuel types were collected in order to develop a total surface fuel loading model (lntSFL-BioTopo model) and a fine surface fuel model (lnfSFL-BioTopo model) for generating tSFL and fSFL maps. Results showed that the combination of topographic parameters such as slope, aspect, and their cross products and the fuel types such as pine stand, non-pine conifer stand, broadleaf stand, and conifer–broadleaf mixed stand was able to appropriately describe the changes in surface fuel loads over a forest with diverse terrain morphology. Based on a cross-validation method, the estimation of tSFL and fSFL of the study site had an RMSE of 3.476 tons/ha and 3.384 tons/ha, respectively. In contrast to the average loading of all inventory plots, the estimation for tSFL and fSFL had a relative error of 38% (PRMSE). The reciprocal of estimation bias of both SFL-BioTopo models tended to be an exponential growth function of the amount of surface fuel load, indicating that the estimation accuracy of the proposed method is likely to be improved with further study. In the regression modeling, a natural logarithm transformation of the surface fuel loading prevented the outcome of negative estimates and thus improved the estimation. Based on the results, this paper defined a minimum sampling unit (MSU) as the area for collecting surface fuels for interpolation using a cokriging model. Allocating the MSUs at the boundary and center of a plot improved surface fuel load prediction and mapping.

AIM: To study the effect of an innovative micro-dissection procedure by radiofrequency ablation (MRA) in removing eyelid nevus. METHODS: Fifty-six consecutive outpatients with eyelid nevus were treated with MRA using a monopolar device. The effect of MRA was determined after following-up for 6mo to 5y. RESULTS: Fifty-two cases (52 eyes, 92.9%) were cured once, and 4 cases (4 eyes, 7.1%) received second treatment for small residual. All cases healed well after surgery, with no pigmentation, no scars, no loss of eyelashes, no deformation of eyelid margin. There was no visual impairment after healing. CONCLUSION: MRA of eyelid nevus using the XL-RFA device is highly efficient without significant complications.

Let Z p s be the residue class ring of integers modulo p s , where p is a prime number and s is a positive integer. We study subspaces and Grassmann graphs for Z p s n . A Grassmann graph for Z p s n , denoted by G d ( n , m , p s ) ( G d for short), has all m-subspaces of Z p s n as its vertices, and two distinct vertices are adjacent if their intersection is of dimension > m − d , where m n and 2 ≤ d ≤ m + 1 . We give the clique number and geometric structures of maximum cliques of G d , etc. By these results, we obtain the Erdős–Ko–Rado theorem for Z p s n and some bounds of the independence number of G d . We also show that an optimal Grassmannian code for Z p s n is a largest independent set of G d . A p s -Kneser graph over Z p s , denoted by Z p s K n : m where n ≥ 2 m ≥ 4 , is the complement of G m ( n , m , p s ) . Finally, we prove that Z p s K n : m is a core when n > 2 m ≥ 4 , and give some estimations for the chromatic number and clique number of Z p s K n : m .

A graph G is called a pseudo-core if every endomorphism of G is either an automorphism or a colouring. A graph G is a core if every endomorphism of G is an automorphism. Let F q be the finite field with q elements where q is a power of an odd prime number. The quadratic forms graph, denoted by Quad ( n , q ) where n ≥ 2 , has all quadratic forms on F q n as vertices and two vertices f and g are adjacent whenever rk ( f − g ) = 1 or 2. We prove that every Quad ( n , q ) is a pseudo-core. Further, when n is even, Quad ( n , q ) is a core. When n is odd, Quad ( n , q ) is not a core. On the other hand, we completely determine the independence number of Quad ( n , q ) .

Natural circulation (NC) loops were widely used in many fields, but still limited in the instability of the loop. The instability characteristics of NC are not fully understood, such as oscillation boundary, amplitude and frequency. To understand the oscillation characteristics, experiments of two-phase natural circulation were performed for R134a in a single loop. Two types of the oscillation were observed and identified by the characteristic frequency in their oscillation spectra. The characteristic frequencies and amplitudes of the oscillations were affected by the system pressure, the heating power and the evaporator inlet subcooling. For the type 1 oscillation, with the increase of the heating power, the main characteristic frequency increased, while the oscillation amplitude decreased; with the increase of the system pressure, the oscillation frequency decreased; with the increase of the subcooling, the frequency decreased. For the type 2 oscillation, with the increase of the heating power, the main characteristic frequency increased, the oscillation amplitude increased; with the increase of subcooling, the frequency decreased, and the amplitude increased. An instability map was built based on the dimensionless numbers: the subcooling number N_sub versus the phase change number N_pch. The stable region of the system was wider at low subcooling condition. Two types of the oscillation may occur at the same time, and the stable region disappeared when subcooling number higher than 3. Combining dimensionless analysis and spectrum analysis, we divided the two-phase natural circulation into five regions in the instability map. Through the oscillation spectrum, this study provided a deep perspective for the instability of two-phase natural circulation. Also, the experimental results of this study can lay the foundation for future research.

Background The 2010 Infectious Diseases Society of America (IDSA) guidelines for management of cryptococcal diseases recommend high dose fluconazole (≥ 800 mg/day), either alone or with other antifungal drugs, as alternative anticryptococcal choices. But evidence for its use in the treatment of HIV-uninfected cryptococcal meningitis (CM) remains sparse. Methods A retrospective analysis of HIV-uninfected CM patients who received fluconazole 800 mg/day for salvage therapy from January 2011 to December 2016 at Huashan Hospital, Shanghai, China was performed. Efficacy and safety were assessed, and mortality and prognostic factors evaluated. Results A total of 44 patients were studied including 19 refractory to amphotericin B induction therapy, 8 refractory to fluconazole consolidation therapy (400 mg/d), and 17 intolerant of antifungal drugs. For salvage, 11 patients received triple therapy of high dose fluconazole, amphotericin B and flucytosine, 20 received dual therapy of high dose fluconazole and flucytosine, 13 received monotherapy of high dose fluconazole. Median duration of high dose fluconazole in salvage regimens was 136.5 days (range, 1–667 days). Clinical response rates were 72.1% (31/43) and 83.7% (36/43) when assessed at 2 weeks and the end of salvage therapy, respectively. Adverse events possibly related to high dose fluconazole occurred in 54.5% (24/44) of the patients, and all were mild or moderate. From the initiation of salvage therapy, 1-year all-cause mortality was 13.6% (6 of 44 patients) among the study population with no significant difference in refractory or intolerant patients. Conclusions Adherence to guideline recommendations of high dose fluconazole, alone or in combination with other antifungals, was safe and often effective for salvage therapy of HIV-uninfected CM patients.

Background Cryptococcal meningitis (CM) is a significant source of mortality, the pathogenesis of which has not been fully understood, especially in non-HIV infected populations. We aimed to compare single nucleotide polymorphisms (SNPs) of Toll-like receptor (TLR) in non-HIV CM patients with those of healthy controls, and to assess the links among TLR SNPs, cytokine concentrations in cerebrospinal fluid (CSF), and clinical severity. Methods This observational cohort study was done in 2 stages: a discovery stage and a validation stage. We conducted a case-control genetic association study between 159 non-HIV CM patients and 468 healthy controls. TLR SNPs significantly related to susceptibility were further validated in a second cohort of 583 subjects from a certain district. Cytokine concentrations in CSF were used to evaluate the in situ immune response of CNS after infection. Correlations among TLR SNPs, CSF cytokine concentrations, and clinical severity were validated in a third prospective cohort of 99 previously untreated non-HIV CM patients. Logistic regression model was used to determine the independent predictors for disease severity. Findings In the discovery stage, the genotype distributions of 8 TLR SNPs in non-HIV CM patients exhibited a significant difference in comparison with controls, of which 3 SNPs remained statistically significant in patients without predisposing factors. In the validation stage, 5 of the 8 nominated TLR SNPs were found to influence CSF cytokine expression. Eighteen cytokines were significantly up-regulated in severely ill patients, among which 12 were affected by TLR2 rs3804099. The rs3804099 was also found in relation to disease severity. High IL-10 levels in CSF (OR 2*97, 95% CI 1*49-5*90; p=0*002) was suggested as an independent predictor for severity after adjusted for possible confounders. Interpretation TLR participate in both the occurrence and the pathogenesis of non-HIV CM. The in situ immune responses of CM were under genetic influence of TLR and contributed to disease severity. Our findings inform of an opportunity for early evaluation and treatment of non-HIV CM. TLR might also become a potential target on which to base host-directed immunotherapy. Funding: National Natural Science Foundation of China and National Key Basic Research Program of China (973 Program). Declaration of Interest: We declare no competing interests. Ethical Approval: Ethical approval was obtained from the medical ethics committee of Huashan Hospital, Mengchao Hepatobiliary Hospital, Fujian HIV/AIDS Diagnosis and Treatment Center, and No. 476 Hospital of Fuzhou General Hospital.

Transmission of plant pathogenic viruses mostly relies on insect vectors. Plant virus could enhance its transmission by modulating the vector. Previously, we showed that feeding on virus infected plants can promote the reproduction of the sweet potato whitefly, Bemisia tabaci MED (Q biotype). In this study, using a whitefly-Tomato chlorosis virus (ToCV)-tomato system, we investigated how ToCV modulates B. tabaci MED reproduction to facilitate its spread. Here, we hypothesized that ToCV-infected tomato plants would increase B. tabaci MED fecundity via elevated vitellogenin (Vg) gene expression. As a result, fecundity and the relative expression of B. tabaci MED Vg was measured on ToCV-infected and uninfected tomato plants on days 4, 8, 12, 16, 20 and 24. The role of Vg on B. tabaci MED reproduction was examined in the presence and absence of ToCV using dietary RNAi. ToCV infection significantly increased B. tabaci MED fecundity on days 12, 16 and 20, and elevated Vg expression on days 8, 12 and 16. Both ovarian development and fecundity of B. tabaci MED were suppressed when Vg was silenced with or without ToCV infection. These combined results suggest that ToCV infection increases B. tabaci MED fecundity via elevated Vg expression.

We conducted a systematic literature review to obtain risk population-based fungal disease incidence or prevalence data from China. Data were categorized by risk factors and extrapolated by using most recent demographic figures. A total of 71,316,101 cases (5.0% of the population) were attributed to 12 risk factors and 17 fungal diseases. Excluding recurrent Candida vaginitis (4,057/100,000 women) and onychomycosis (2,600/100,000 persons), aspergillosis (317/100,000 persons) was the most common problem; prevalence exceeded that in most other countries. Cryptococcal meningitis, an opportunistic infection, occurs in immunocompetent persons almost twice as often as AIDS. The pattern of fungal infections also varies geographically; Talaromyces marneffei is distributed mainly in the Pearl River Basin, and the Yangtze River bears the greatest histoplasmosis burden. New host populations, new endemic patterns, and high fungal burdens in China, which caused a huge impact on public health, underscore the urgent need for building diagnostic and therapeutic capacity.

In order to effectively improve the effect of blended learning, the paper describes a blended learning oriented full-dimensional teaching method. The author first analyzed the characteristics and applicability of each teaching activity involved in blended learning from both the teaching process and teaching method dimensions. On this basis, the authors put forward the corresponding methods for designing teaching activities and organizing teaching materials. Then, the paper takes practice in the course of "object-oriented programming" as an example, and analyzes the practical effect of the full-dimensional teaching method. The results show that the proposed blended learning oriented full-dimensional teaching method can meet the students' individual learning needs, enhance students' learning enthusiasm and initiative, as well as realize the overall improvement of students' learning effect.

SPOC (Small Private Online Course) teaching mode is a combination mode of online and offline teaching mode. It is the mainstream teaching mode at home and abroad, and also an effective teaching mode to effectively improve the quality of education. Based on the course of "Object-Oriented Programming" in the Software College of Northeast University, this paper applies the theories of SPOC teaching mode to construct and apply SPOC course. In the construction of this course, the emphasis is on leading the high-quality resources inside and outside the school into the course, so as to integrate the contents of inside and outside the school, and the integration of excellent courses at home and abroad. From the implementation effect, this kind of teaching mode can effectively improve students' participation in the classroom, enhance students' interests in extracurricular learning, effectively promote students' studying independently ability, and also greatly promote the improvement of teaching quality.

The flavonoid-based natural product genistein is a biologically active compound possessing promising anti-oxidant and anti-cancer properties. Poor pharmacokinetics along with low potency limit however the therapeutic application of genistein in cancer therapy. In order to overcome those limitations and to expand its therapeutic window of efficacy, we sought to covalently attach genistein with a heptamethine cyanine dye&mdash, IR 783&mdash, for cancer cell targeting and enhanced delivery to tumors. Herein we report the synthesis, a selective detailed characterization and preliminary in vitro/in vivo biological evaluation of genistein-IR 783 conjugate 4. The conjugate 4 displayed improved potency against human breast cancer MCF-7 cells (10.4 &plusmn, 1.0 &mu, M) as compared with the parent genistein (24.8 &plusmn, 0.5 &mu, M) or IR 783 (25.7 &plusmn, 0.7 &mu, M) and exhibited selective high uptake in MCF-7 as against the normal mammary gland MCF-10A cells in various assays. In the cell viability assay, conjugate 4 exhibited over threefold lower potency against MCF-10A cells (32.1 &plusmn, 1.1 &mu, M) suggesting that the anti-cancer profile of parent genistein is significantly improved upon conjugation with the dye IR783. Furthermore, the genistein-IR783 conjugate 4 was shown to be especially accumulated in MCF-7 cancer cells by fluorescent intensity measurements and inverted fluorescence microscopy in fixed cells as well as in live cells with time via live cell confocal fluorescence imaging. The mechanism-based uptake inhibition of conjugate 4 was observed with OATPs inhibitor BSP and in part with amiloride, as a macropinocytosis inhibitor. For the first time we have shown amiloride inhibited uptake of cyanine dye by about ~40%. Finally, genistein-IR 783 conjugate 4 was shown to be localized in MCF-7 tumor xenografts of mice breast cancer model via in vivo near infrared fluorescence (NIRF) imaging. In conclusion, conjugation of genistein with cyanine dye IR783 indeed improved its pharmacological profile by cancer cell selective uptake and targeting and therefore warrants further investigations as a new anti-cancer therapeutics derived from natural product genistein.

Plants accumulate the lipids phosphatidic acid (PA), diacylglycerol (DAG), and triacylglycerol (TAG) during cold stress, but how plants balance the levels of these lipids to mediate cold responses remains unknown. The enzymes ACYL-COENZYME A:DIACYLGLYCEROL ACYLTRANSFERASE (DGAT) and DIACYLGLYCEROL KINASE (DGK) catalyze the conversion of DAG to TAG and PA, respectively. Here, we show that DGAT1, DGK2, DGK3, and DGK5 contribute to the response to cold in Arabidopsis (Arabidopsis thaliana). With or without cold acclimation, the dgat1 mutants exhibited higher sensitivity upon freezing exposure compared with the wild type. Under cold conditions, the dgat1 mutants showed reduced expression of C-REPEAT/DRE BINDING FACTOR2 and its regulons, which are essential for the acquisition of cold tolerance. Lipid profiling revealed that freezing significantly increased the levels of PA and DAG while decreasing TAG in the rosettes of dgat1 mutant plants. During freezing stress, the accumulation of PA in dgat1 plants stimulated NADPH oxidase activity and enhanced RbohD-dependent hydrogen peroxide production compared with the wild type. Moreover, the cold-inducible transcripts of DGK2, DGK3, and DGK5 were significantly more up-regulated in the dgat1 mutants than in the wild type during cold stress. Consistent with this observation, dgk2, dgk3, and dgk5 knockout mutants showed improved tolerance and attenuated PA production in response to freezing temperatures. Our findings demonstrate that the conversion of DAG to TAG by DGAT1 is critical for plant freezing tolerance, acting by balancing TAG and PA production in Arabidopsis.

We investigate the generalized bilinear forms graph Γ d over a residue class ring Z p s . The graph Γ d is a connected vertex-transitive graph, and we completely determine its independence number, clique number, chromatic number and maximum cliques. We also prove that cores of both Γ d and its complement are maximum cliques. The graph Γ d is useful for error-correcting codes. We show that there is a largest independent set of Γ d which is a linear MRD code over Z p s .

Our previous work showed that polysaccharide isolated from Portulaca oleracea L. (POP) has an insulinotropic effect. The voltage-gated Na+ channel (VGSC) in the excitement phase plays an important role. This work aims to study the effect of POP on the voltage-gated Na+ channel current (INa) and its channel dynamic characteristics in insulin-secreting β-cell line (INS-1) cells of rat. Our results revealed that POP can inhibit the amplitude of INa and improve cell survival in a concentration-dependent manner. POP concentration of 0.5 mg mL−1 reduced the amplitude of INa, suppressed the INa of steady-state activation, shifted the steady-state inactivation curves of INa to negative potentials, prolonged the time course of INa recovery from inactivation, and enhanced the activity-dependent attenuation of INa. Furthermore, 0.5 mg mL−1 POP or low concentration of tetrodotoxin (TTX, a VGSC-specific blocker) partially inhibited INa and also improved insulin synthesis and cell survival. Collectively, these results revealed that POP protects INS-1 cells and enhances the insulin synthesis in INS-1 cells, and the mechanism through the partial inhibition on INa channel is strongly recommended.

Background/Aims: Islet beta cells (β-cells) are unique cells that play a critical role in glucose homeostasis by secreting insulin in response to increased glucose levels. Voltage-gated ion channels in β-cells, such as K + and Ca 2+ channels, contribute to insulin secretion. The response of voltage-gated Na + channels (VGSCs) in β-cells to the changes in glucose levels remains unknown. This work aims to determine the role of extracellular glucose on the regulation of VGSC. Methods: The effect of glucose on VGSC currents ( I Na ) was investigated in insulin-secreting β-cell line (INS-1) cells of rats using whole-cell patch clamp techniques, and the effects of glucose on insulin content and cell viability were determined using Enzyme-Linked Immunosorbent Assay (ELISA) and Methylthiazolyldiphenyl-tetrazolium Bromide (MTT) assay methods respectively. Results: Our results show that extracellular glucose application can inhibit the peak of I Na in a concentration-dependent manner. Glucose concentration of 18 mM reduced the amplitude of I Na , suppressed the I Na of steady-state activation, shifted the steady-state inactivation curves of I Na to negative potentials, and prolonged the time course of I Na recovery from inactivation. Glucose also enhanced the activity-dependent attenuation of I Na and reduced the fraction of activated channels. Furthermore, 18 mM glucose or low concentration of tetrodotoxin (TTX, a VGSC-specific blocker) partially inhibited the activity of VGSC and also improved insulin synthesis. Conclusion: These results revealed that extracellular glucose application enhances the insulin synthesis in INS-1 cells and the mechanism through the partial inhibition on I Na channel is involved. Our results innovatively suggest that VGSC plays a vital role in modulating glucose homeostasis.