Given the implications for smoking among HIV-positive individuals and high smoking and HIV rates among men who have sex with men (MSM) in China, we examined sociodemographic, smoking-related, psychosocial, and substance use factors in relation to HIV status; receiving some sort of healthcare provider intervention regarding smoking; and having made a quit attempt in the past year in a sample of MSM smokers in Chengdu. We conducted a cross-sectional survey of 381 MSM smokers recruited by a nongovernmental organization in Chengdu in 2012–2013. Of these, 350 disclosed their HIV status and 344 (188 HIV-positive and 156 HIV-negative) provided completed data. Half (50.0%) reported at least one quit attempt in their lifetime; 30.5% reported a quit attempt in the past year. The majority (59.4%) reported that a healthcare provider had intervened in some way (assessed smoking, advised quitting, provided assistance), most commonly by assessing smoking status (50.0%). HIV-positive individuals were more likely to report a healthcare provider intervening on their smoking (p < .001). Those who received provider intervention were more likely to have attempted to quit ever (p = .009) and in the past year (p < .001). Those HIV-positive were more likely to have attempted to quit since diagnosis if a provider had intervened (p = .001). Multivariate regression documented that being HIV-positive (p < .001), greater cigarette consumption (p = .02), less frequent drinking (p = .03), and greater depressive symptoms (p = .003) were significant correlates of healthcare provider intervention. Multivariate regression also found that healthcare provider intervention (p = .003), older age (p = .01), and higher autonomous motivation (p = .007) were significant correlates of attempting to quit in the past year. Given the impact of healthcare provider intervention regarding smoking on quit attempts among MSM, greater training and support is needed to promote consistent intervention on smoking in the clinical setting among HIV-positive and HIV-negative MSM smokers.
HIV; men who have sex with men; smoking; smoking cessation; healthcare provider
In addition to the widely used mesenchymal stem cells (MSCs), endothelial cells appear to be a favorable cell source for hard tissue regeneration. Previously, fluorapatite was shown to stimulate and enhance mineralization of MSCs. This study aims to investigate the growth of endothelial cells on synthesized ordered fluorapatite surfaces and their effect on the mineralization of adipose-derived stem cells (ASCs) through coculture. Endothelial cells were grown on fluorapatite surfaces and characterized by cell counting, flow cytometry, scanning electron microscopy, and enzyme-linked immunosorbent assay (ELISA). Cells were then cocultured with ASCs and stained for alkaline phosphatase and mineral formation. Fibroblast growth factor (FGF) pathway perturbation and basic FGF (bFGF) treatment of the ASCs were also conducted to observe their effects on differentiation and mineralization of these cells. Fluorapatite surfaces showed good biocompatibility in supporting endothelial cells. Without a mineralization supplement, coculture with endothelial cells induced osteogenic differentiation of ASCs, which was further enhanced by the fluorapatite surfaces. This suggested a combined stimulating effect of endothelial cells and fluorapatite surfaces on the enhanced mineralization of ASCs. Greater amounts of bFGF release by endothelial cells alone or cocultures with ASCs stimulated by fluorapatite surfaces, together with FGF pathway perturbation and bFGF treatment results, suggested that the FGF signaling pathway may function in this process.
The purpose of this study was to investigate the functional role of G-protein-coupled inward rectifier potassium (GIRK) channels in the cardiac ventricle.
Methods and results
Immunofluorescence experiments demonstrated that GIRK4 was localized in outer sarcolemmas and t-tubules in GIRK1 knockout (KO) mice, whereas GIRK4 labelling was not detected in GIRK4 KO mice. GIRK4 was localized in intercalated discs in rat ventricle, whereas it was expressed in intercalated discs and outer sarcolemmas in rat atrium. GIRK4 was localized in t-tubules and intercalated discs in human ventricular endocardium and epicardium, but absent in mid-myocardium. Electrophysiological recordings in rat ventricular tissue ex vivo showed that the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) and acetylcholine (ACh) shortened action potential duration (APD), and that the APD shortening was reversed by either the GIRK channel blocker tertiapin-Q, the adenosine A1 receptor antagonist DPCPX or by the muscarinic M2 receptor antagonist AF-DX 116. Tertiapin-Q prolonged APD in the absence of the exogenous receptor activation. Furthermore, CPA and ACh decreased the effective refractory period and the effect was reversed by either tertiapin-Q, DPCPX or AF-DX 116. Receptor activation also hyperpolarized the resting membrane potential, an effect that was reversed by tertiapin-Q. In contrast, tertiapin-Q depolarized the resting membrane potential in the absence of the exogenous receptor activation.
Confocal microscopy shows that among species GIRK4 is differentially localized in the cardiac ventricle, and that it is heterogeneously expressed across human ventricular wall. Electrophysiological recordings reveal that GIRK current may contribute significantly to ventricular repolarization and thereby to cardiac electrical stability.
GIRK channel; Acetylcholine; Adenosine; Action potential; Repolarization
The efficiency of naloxone for the management of secondary brain injury after severe traumatic brain injury (sTBI) remains undefined. The aim of this study is to evaluate the current evidence regarding the clinical efficiency and safety of naloxone as a treatment for sTBI in mainland China.
A systematic search of the China Biology Medicine disc (CBM), China Science and Technology Journal Database (VIP), China National Knowledge Internet (CNKI), and Wan Fang Database was performed to identify randomized controlled trials (RCTs) of naloxone treatment for patients with sTBI in mainland China. The quality of the included trials was assessed, and the RevMan 5.1 software was employed to conduct this meta-analysis. Nineteen RCTs including 2332 patients were included in this study. The odds ratio (OR) showed statistically significant differences between the naloxone group and the control group (placebo) in terms of mortality at 18 months after treatment (OR, 0.51, 95%CI: 0.38–0.67; p<0.00001), prevalence of abnormal heart rates (OR, 0.30, 95%CI: 0.21–0.43; p<0.00001), abnormal breathing rate (OR, 0.25, 95%CI: 0.17–0.36; p<0.00001) at discharge, the level of intracranial pressure at discharge (OR, 2.00, 95%CI: 1.41–2.83; p = 0.0001), verbal or physical dysfunction rate (OR, 0.65, 95%CI: 0.43–0.98; p = 0.04), and severe disability rate (OR, 0.47, 95%CI: 0.30–0.73; p = 0.0001) at 18 months after the treatment. The mean difference (MD) showed statistically significant differences in awakening time at discharge (MD, −4.81, 95%CI: −5.49 to −4.12; p<0.00001), and GCS at 3 days (MD, 1.00, 95%CI: 0.70–1.30; p<0.00001) and 10 days (MD, 1.76, 95%CI: 1.55–1.97; p<0.00001) after treatment comparing naloxone with placebo group.
This study indicated that applying naloxone in the early stage for sTBI patients might effectively reduce mortality, control intracranial pressure (ICP), and significantly improve the prognosis.
Glycated hemoglobin (HbA1c) is a special fragment formed by the binding of glucose to the C chain or D chain of hemoglobin A and as a result of non-enzymatic catalysis of mature hemoglobin and glucose, which is an indicator used to evaluate the blood glucose control in diabetes mellitus (DM) patients. Recent researches indicated that HbA1c could be applied in gestational diabetes mellitus (GDM) and pregnancy combined DM, and increasing of HbA1c was close associated with adverse outcomes of women with pregnancy combined DM and GDM. HbA1c was reported to have a significant importance in monitoring congenital malformation, abortion, perinatal mortality, preeclampsia, postpartum abnormal glucose metabolism, vascular complications and so on, which could be a test item during the second trimester. Sensitivity of HbA1c in diagnoses of DM is lower than oral glucose tolerance test (OGTT), thus OGTT is still the golden standard of GDM. Emphasis should be put on standardization of detection and threshold of HbA1c and establishment of HbA1c normal ranges of different trimesters, when HbA1c is used to diagnose pregnancy combined DM and GDM, and evaluate effects of treatments.
Glycated haemoglobin; pregnancy; diabetes mellitus
Purpose. To determine the relationship between Hashimoto's thyroiditis (HT) and all stages of papillary thyroid carcinoma (PTC) with or without local lymph node metastasis (LNM). Methods. We conducted a retrospective study of thyroidectomies from 2008–2013 in First Affiliated Hospital of Nanjing Medical University. We categorized patients according to the presence of histopathologically proven HT. The prevalence of mPTC (maximum diameter ≤ 10 mm) and crPTC (clinical relevant PTC) and local LNM rates were compared. Results. We evaluated 6,432 consecutive thyroidectomies. In total, 1,328 specimens were confirmed as HT. The prevalence of PTC in this HT cohort was 43.8%, significantly higher than non-HT group. After adjustment of gender and age, the prevalence of PTC was still higher in HT group. HT was a risk factor for PTC in multivariate analysis with odds ratio 2.725 (95% CI, 2.390–3.109) (P < 0.001). However, no correlation was found between HT and LNM of PTC. Conclusion. HT was associated with an increased prevalence of all stages of PTC, independent of tumor size, gender, and age. In contrast, locally advanced disease defined by LNM was unrelated to HT. These data suggest an association of HT with low risk PTC and a potential protective immunologic effect from further disease progression.
Chronic hepatitis B (CHB) can progress to cirrhosis, hepatocellular carcinoma (HCC) and ultimately liver-related death. Although oral antiviral therapy for patients with CHB reduces the risk of such complications, once cirrhosis is established, the benefits of antiviral therapy are not robustly demonstrated. According to traditional Chinese medicine (TCM), some Chinese herbal medicines promote blood circulation and soften hard masses, and therefore they may block and reverse hepatic fibrosis. The aim of this study is to evaluate the effects of TCM tablets of the compound biejia ruangan (RGT) administered for fibrosis, and entecavir (ETV), on the development of HCC in patients with CHB or hepatitis B virus (HBV)-related compensated cirrhosis.
This multicenter, centrally randomized, double-blind, placebo-controlled, parallel-group study is planned to complete within 5 years. For the study, 1,000 with CHB or HBV-related compensated cirrhosis are randomly assigned in a 1:1 ratio to a treatment group (0.5 mg ETV once daily; 2 g RGT three times daily) or a control group (0.5 mg ETV once daily; 2 g RGT dummy agent three times daily). The primary end points are the development of HCC and liver-related death. Secondary end points include disease progression and overall survival.
Although antiviral therapy can achieve sustained suppression of HBV replication, thereby preventing cirrhosis, patients with CHB treated with nucleos(t)ide analogs (NUCs) retain a higher risk for HCC compared with patients with inactive disease. Although previous clinical trials with RGT have confirmed the efficacy of blocking and reversing hepatic fibrosis in patients with CHB or compensated cirrhosis, the long-term risk for HCC or disease progression in these patients treated with combination of RGT and NUCs compared with NUCs alone is unclear. Therefore, it is necessary to investigate the effects of the RGT blockade and reversal of hepatic fibrosis on the development of HCC in patients with CHB or HBV-related compensated cirrhosis in large, prospective, multicenter, double-blind, randomized, controlled trials in China.
ClinicalTrials.gov Identifier: NCT01965418. Date registered: 17 October 2013
Compound biejia ruangan tablet; multicenter randomized controlled trial; chronic hepatitis B; hepatocellular carcinoma; hepatic fibrosis
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although survival rates have improved, patients with certain biological subtypes still have suboptimal outcomes. Current chemotherapeutic regimens are associated with short- and long-term toxicities and novel, less toxic therapeutic strategies are needed. Mer receptor tyrosine kinase is ectopically expressed in ALL patient samples and cell lines. Inhibition of Mer expression reduces pro-survival signaling, increases chemosensitivity, and delays development of leukaemia in vivo suggesting that Mer tyrosine kinase inhibitors are excellent candidates for targeted therapies. Brain and spinal tumors are the second most common malignancies in childhood. Multiple chemotherapy approaches and radiation have been attempted, yet overall survival remains dismal. Mer is also abnormally expressed in atypical teratoid/rhabdoid tumors (ATRT), providing a rationale for targeting Mer as a therapeutic strategy. We have previously described UNC569, the first small molecule Mer inhibitor. This manuscript describes the biochemical and biological effects of UNC569 in ALL and ATRT. UNC569 inhibited Mer activation and downstream signaling through ERK1/2 and AKT, determined by western blot analysis. Treatment with UNC569 reduced proliferation/survival in liquid culture, decreased colony formation in methylcellulose/soft agar, and increased sensitivity to cytotoxic chemotherapies. MYC transgenic zebrafish with T-ALL were treated with UNC569 (4 µM for 2 weeks). Fluorescence was quantified as indicator of the distribution of lymphoblasts, which express Mer and enhanced green fluorescent protein. UNC569 induced >50% reduction in tumor burden compared to vehicle- and mock-treated fish. These data support further development of Mer inhibitors as effective therapies in ALL and ATRT.
UNC569; Mer Inhibitor; Treatment of ALL
Ethanol induces hypoxia and elevates HIF-1α in the liver. CYP2E1 plays a role in the mechanisms by which ethanol generates oxidative stress, fatty liver and liver injury. The current study evaluated whether CYP2E1 contributes to ethanol-induced hypoxia and activation of HIF-1α in vivo and whether HIF-1α protects against or promotes CYP2E1-dependent toxicity in vitro. Wild type (WT), CYP2E1-knockin (KI) and CYP2E1 knockout (KO) mice were fed ethanol chronically; pair fed controls received isocaloric dextrose. Ethanol produced liver injury in the KI mice to a much greater extent than in the WT and KO mice. Protein levels of HIF-1α and downstream targets of HIF-1α activation were elevated in the ethanol-fed KI mice compared to the WT and KO mice. Levels of HIF prolylhydroxlase 2 which promotes HIF-1α degradation were decreased in the ethanol-fed KI mice in association with the increases in HIF-1α. Hypoxia occurred in the ethanol-fed CYP2E1 KI mice as shown by an increased area of staining using the hypoxia-specific marker pimonidazole. Hypoxia was lower in the ethanol-fed WT mice and lowest in the ethanol fed KO mice and all the dextrose-fed mice. In situ double staining showed that pimonidazole and CYP2E1 were co-localized to the same area of injury in the hepatic centrilobule. Increased protein levels of HIF-1α were also found after acute ethanol treatment of KI mice. Treatment of HepG2 E47 cells which express CYP2E1 with ethanol plus arachidonic (AA) acid or ethanol plus buthionine sulfoximine (BSO) which depletes GSH caused loss of cell viability to greater extent than in HepG2 C34 cells which do not express CYP2E1. These treatments elevated protein levels of HIF-1α to a greater extent in E47 cells than C34 cells. 2-Methoxyestradiol, an inhibitor of HIF-1α, blunted the toxic effects of ethanol plus AA and ethanol plus BSO in the E47 cells in association with inhibition of HIF-1α. The HIF-1α inhibitor also blocked the elevated oxidative stress produced by ethanol/AA or ethanol/BSO in the E47 cells. These results suggest that CYP2E1 plays a role in ethanol-induced hypoxia, oxidative stress and activation of HIF-1α and that HIF-1α contributes to CYP2E1-dependent ethanol-induced toxicity. Blocking HIF-1α activation and actions may have therapeutic implications for protection against ethanol/CYP2E1-induced oxidative stress, steatosis and liver injury.
Ethanol; CYP2E1; Hepatotoxicity; Oxidative Stress; HIF-1α
The aim of the present study was to explore the infection route of ventilator-associated pneumonia (VAP) and assess the effectiveness of a combined nursing strategy to prevent VAP in intensive care units. Bacteria from the gastric juice and drainage from the hypolarynx and lower respiratory tracts of patients with VAP were analyzed using genome macrorestriction-pulsed-field gel electrophoresis (GM-PFGE). A total of 124 patients with tracheal intubation were placed in the intervention group and were treated with a combined nursing strategy, comprising mosapride (gastric motility stimulant) administration and semi-reclining positioning. A total of 112 intubated patients were placed in the control group and received routine nursing care. The incidence rate of VAP, days of ventilation and mortality rate of patients were compared between the two groups. The GM-PFGE fingerprinting results of three strains of Pseudomonas aeruginosa from the gastric juice, subglottic secretion drainage and drainage of the lower respiratory tract in patients with VAP were similar across groups. The number of days spent on a ventilator by patients in the intervention group (7.37±5.32 days) was lower compared with that by patients in the control group (12.34±4.98 days) (P<0.05). The incidence rate of VAP was reduced from 40.81 to 21.25% following intervention with the combined nursing strategy (P<0.05); furthermore, the mortality rate of intubated patients in the intervention group was 29.46%, a significant reduction compared with the 41.94% mortality rate observed in the control group (P<0.05). Gastroesophageal reflux (GER) was confirmed as one of the infection routes for VAP. The combined nursing strategy of gastric motility stimulant administration and the adoption of a semi-reclining position was effective in preventing VAP by reducing the occurrence of GER.
ventilator-associated pneumonia; interventions; intensive care unit; genome macrorestriction-pulsed-field gel electrophoresis
CYP2E1, one of the cytochrome P450 mixed-function oxidases located predominantly in liver, plays a key role in metabolism of xenobiotics including ethanol and procarcinogens. Recently, down-expression of CYP2E1 was found in hepatocellular carcinoma (HCC) with the majority to be chronic hepatitis B virus (HBV) carriers. In this study, we tested a hypothesis that HBx may inhibit CYP2E1 gene expression via hepatocyte nuclear factor 4α (HNF4α). By enforced HBx gene expression in cultured HepG2 cells, we determined the effect of HBx on CYP2E1 mRNA and protein expression. With a bioinformatics analysis, we found a consensus HNF-4α binding sequence located on −318 to −294 bp upstream of human CYP2E1 promoter. Using reporter gene assay and site-directed mutagenesis, we have shown that mutation of this site dramatically decreased CYP2E1 promoter activity. By silencing endogenous HNF-4α, we have further validated knockdown of HNF-4α significantly decreased CYP2E1expression. Ectopic overexpression of HBx in HepG2 cells inhibits HNF-4α expression, and HNF-4α levels were inversely correlated with viral proteins both in HBV-infected HepG2215 cells and as well as HBV positive HCC liver tissues. Moreover, the HBx-induced CYP2E1 reduction could be rescued by ectopic supplement of HNF4α protein expression. Furthermore, human hepatoma cells C34, which do not express CYP2E1, shows enhanced cell growth rate compared to E47, which constitutively expresses CYP2E1. In addition, the significantly altered liver proteins in CYP2E1 knockout mice were detected with proteomics analysis. Together, HBx inhibits human CYP2E1 gene expression via downregulating HNF4α which contributes to promotion of human hepatoma cell growth. The elucidation of a HBx-HNF4α-CYP2E1 pathway provides novel insight into the molecular mechanism underlining chronic HBV infection associated hepatocarcinogenesis.
Umbilical cord mesenchymal stem cells (UCMSCs) have a considerable advantage and potential in treating for central nervous system diseases and have become a novel alternative treatment for spinal cord injury. This study aims to compare the neurological function outcome of stem cell transplantation, rehabilitation therapy, and self-healing for sequelae of spinal cord injury.
Thirty-four cases of thoracolumbar spinal cord injury were randomly divided into three groups: the stem cell transplantation group was given CT-guided UCMSC transplantation twice; the rehabilitation group received rehabilitation therapy; and the blank control group did not receive any specific treatment. AIS grading, ASIA scoring, the manual muscle strength and muscle tension scale, and the Barthel index were used to evaluate the clinical outcome. Urodynamic examination was also performed for patients in the UCMSC group and the rehabilitation therapy group.
Seven of the ten patients in the UCMSC group had significant and stable improvement in movement, self-care ability, and muscular tension; five of the forteen patients (36%) in the rehabilitation group also had certain improvement in these aspects. Urodynamic examination demonstrated that patients in the UCMSC group exhibited an increase in maximum urinary flow rate and maximum bladder capacity, as well as a decrease in residue urine volume and maximum detrusor pressure. The rehabilitation group exhibited decreased maximum bladder capacity, but no perceptible change in maximum urinary flow rate, residue urine volume or maximum detrusor pressure.
UCMSC transplantation can effectively improve neurological functional recovery after spinal cord injury, and its efficacy is superior to that of rehabilitation therapy and self-healing.
The present clinical study was registered at chictr.org (registration number: NCT01393977).
Umbilical cord mesenchymal stem cell; Spinal cord injury; Transplantation; Urodynamic examination
We conducted a systematic investigation of the reflectance diffuse optical tomography using continuous wave (CW) measurements and nonlinear reconstruction algorithms. We illustrated and suggested how to fine-tune the nonlinear reconstruction methods in order to optimize target localization with depth-adaptive regularizations, reduce boundary noises in the reconstructed images using a logarithm based objective function, improve reconstruction quantification using transport models, and resolve crosstalk problems between absorption and scattering contrasts with the CW reflectance measurements. The upgraded nonlinear reconstruction algorithms were evaluated with a series of numerical and experimental tests, which show the potentials of the proposed approaches for imaging both absorption and scattering contrasts in the deep targets with enhanced image quality.
(170.5280) Photon migration; (170.3010) Image reconstruction techniques; (100.3190) Inverse problems; (170.6960) Tomography
This study was designed to evaluate the relationship between the minimal margin size and local tumor progression (LTP) following CT-guided radiofrequency ablation (RFA) of colorectal cancer liver metastases (CLM).
An institutional review board-approved, HIP-PA-compliant review identified 73 patients with 94 previously untreated CLM that underwent RFA between March 2003 and May 2010, resulting in an ablation zone completely covering the tumor 4–8 weeks after RFA dynamic CT. Comparing the pre- with the post-RFA CT, the minimal margin size was categorized to 0, 1–5, 6–10, and 11–15 mm. Follow-up included CT every 2–4 months. Kaplan–Meier methodology and Cox regression analysis were used to evaluate the effect of the minimal margin size, tumor location, size, and proximity to a vessel on LTP.
Forty-five of 94 (47.9 %) CLM progressed locally. Median LTP-free survival (LPFS) was 16 months. Two-year LPFS rates for ablated CLM with minimal margin of 0, 1–5 mm, 6–10 mm, 11–15 mm were 26, 46, 74, and 80 % (p < 0.011). Minimal margin (p = 0.002) and tumor size (p = 0.028) were independent risk factors for LTP. The risk for LTP decreased by 46 % for each 5-mm increase in minimal margin size, whereas each additional 5-mm increase in tumor size increased the risk of LTP by 22 %.
An ablation zone with a minimal margin uniformly larger than 5 mm 4–8 weeks postablation CT is associated with the best local tumor control.
Ablation; Radiofrequency ablation; Minimal margin; Local tumor progression; Colon cancer liver metastasis; Image guided; CT guided; Ablation margin evaluation method
Pheophorbide a oxygenase (PaO) is a key enzyme in chlorophyll catabolism that is known to suppress cell death in maize and Arabidopsis. The catalytic activity of PaO in chlorophyll degradation has been clearly demonstrated, but the function of PaO in the regulation of cell death and plant–microbe interactions is largely unknown. In this study, we characterized a PaO homologue in wheat of the lethal leaf-spot 1 gene, TaLls1, that was induced in leaves infected by Puccinia striiformis f.sp. tritici (Pst) and wounding treatment. The TaLls1 protein contains a conserved Rieske [2Fe-2S] motif and a mononuclear iron-binding site typical of PaOs. Silencing of TaLls1 by virus-induced gene silencing in wheat led to leaf cell death without pathogen attacks, possibly due to the accumulation of pheophorbide a (upstream substrate of PaO), indicating a suppressor role of TaLls1, while overexpression of TaLls1 also triggered cell death in both tobacco and wheat leaves, probably owing to the accumulation of the red chlorophyll catabolite (downstream product of PaO). Further deletion mutant analysis showed that the conserved Rieske domain, but not the iron-binding site, was essential for cell death induction. These results thus suggest a threshold for TaLls1 in maintaining cell homeostasis to adapt in various stresses, and shed new light on the role of TaLls1 in cell death regulation. Furthermore, silencing of TaLls1 in wheat did not change the disease symptoms but enhanced tolerance to Pst via an significant increase in H2O2 generation, elevated cell death occurrence, and upregulation of pathogenesis-related genes.
cell death; disease resistance; pheophorbide a oxygenase; Puccinia striiformis f.sp. tritici; wheat.
Abnormal activation of Mer kinase has been implicated in the oncogenesis of many human cancers including acute lymphoblastic and myeloid leukemia, non-small cell lung cancer, and glioblastoma. We have discovered a new family of small molecule Mer inhibitors, pyrazolopyrimidine sulfonamides, that potently inhibit the kinase activity of Mer. Importantly, these compounds do not demonstrate significant hERG activity in the PatchXpress assay. Through structure-activity relationship studies, 35 (UNC1062) was identified as a potent (IC50 = 1.1 nM) and selective Mer inhibitor. When applied to live tumor cells, UNC1062 inhibited Mer phosphorylation and colony formation in soft agar. Given the potential of Mer as a therapeutic target, UNC1062 is a promising candidate for further drug development.
Mer inhibitors; pyrazolopyrimidines; sulfonamides; leukemia; non-small cell lung cancer; glioblastoma
Subcellular localisation of SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) and their ability to form SNARE complexes are critical for determining the specificity of vesicle fusion. NPSN11, a Novel Plant SNARE (NPSN) gene, has been reported to be involved in the delivery of cell wall precursors to the newly formed cell plate during cytokinesis. However, functions of NPSN genes in plant–pathogen interactions are largely unknown. In this study, we cloned and characterized three NPSN genes (TaNPSN11, TaNPSN12, and TaNPSN13) and three plant defence-related SNARE homologues (TaSYP132, TaSNAP34, and TaMEMB12). TaSYP132 showed a highly specific interaction with TaNPSN11 in both yeast two-hybrid and bimolecular fluorescence complementation (BiFC) assays. We hypothesize that this interaction may indicate a partnership in vesicle trafficking. Expressions of the three TaNPSNs and TaSYP132 were differentially induced in wheat leaves when challenged by Puccinia striiformis f. sp. tritici (Pst). In virus-induced gene silencing (VIGS) assays, resistance of wheat (Triticum aestivum) cultivar Xingzi9104 to the Pst avirulent race CYR23 was reduced by knocking down TaNPSN11, TaNPSN13 and TaSYP132, but not TaNPSN12, implying diversified functions of these wheat SNARE homologues in prevention of Pst infection and hyphal elongation. Immuno-localization results showed that TaNPSN11 or its structural homologues were mainly distributed in vesicle structures near cell membrane toward Pst hypha. Taken together, our data suggests a role of TaNPSN11 in vesicle-mediated resistance to stripe rust.
Bimolecular fluorescence complementation; immuno-localization; Puccinia striiformis f. sp. tritici; qRT-PCR; SNARE; vesicle-mediated resistance; virus-induced gene silencing; wheat; yeast two-hybrid.
Glass is a freezing phase of a deeply supercooled liquid. Despite its simple definition, the origin of glass forming ability (GFA) is still ambiguous, even for binary Cu-Zr alloys. Here, we directly study the stability of the supercooled Cu-Zr liquids where we find that Cu64Zr36 at a supercooled temperature shows deeper undercoolability and longer persistence than other neighbouring compositions with an equivalent driving Gibbs free energy. This observation implies that the GFA of the Cu-Zr alloys is significantly affected by crystal-liquid interfacial free energy. In particular, the crystal-liquid interfacial free energy of Cu64Zr36 in our measurement was higher than that of other neighbouring liquids and, coincidently a molecular dynamics simulation reveals a larger glass-glass interfacial energy value at this composition, which reflects more distinct configuration difference between liquid and crystal phase. The present results demonstrate that the higher crystal-liquid interfacial free energy is a prerequisite of good GFA of the Cu-Zr alloys.
The functional deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR), a plasma membrane chloride channel, leads to the development of cystic fibrosis. The deletion of a phenylalanine at residue 508 (F508del) is the most common cause of CFTR misfolding leading to the disease. The F508del misfolding originates in the first nucleotide-binding domain (NBD1), which induces a global conformational change in CFTR through NBD1’s interactions with other domains. Such global misfolding produces a mutant chloride channel that is impaired in exocytic trafficking, peripheral stability, and channel gating. The nature and atomic details of F508del misfolding have been subject to extensive research during the past decade. Current data support a central role for NBD1 in F508del misfolding and rescue. Many cis-acting NBD1 second-site mutations rescue F508del misfolding in the context of full-length CFTR. While some of these mutations appear to specifically counteract the F508del-induced misfolding, others release certain inherent conformational constraints of the human wild-type CFTR. Several small-molecule correctors were recently found to act on key interdomain interfaces of F508del CFTR. Potential rational approaches have been proposed in an attempt to develop highly effective small molecule modulators that improve the cell surface functional expression of F508del CFTR.
ABC transporter; CFTR; cystic fibrosis; drug discovery; F508del; molecular dynamics simulation; nucleotide-binding domain; protein conformation; protein folding; protein stability
Self-organized V-N co-doped TiO2 nanotube arrays (TNAs) with various doping amount were synthesized by anodizing in association with hydrothermal treatment. Impacts of V-N co-doping on the morphologies, phase structures, and photoelectrochemical properties of the TNAs films were thoroughly investigated. The co-doped TiO2 photocatalysts show remarkably enhanced photocatalytic activity for the CO2 photoreduction to methane under ultraviolet illumination. The mechanism of the enhanced photocatalytic activity is discussed in detail.
TiO2; Photocatalytic; CO2; Nanotube; CH4
A new fabrication method is proposed to produce nanostructures on monocrystalline silicon based on the friction-induced selective etching of its Si3N4 mask. With low-pressure chemical vapor deposition (LPCVD) Si3N4 film as etching mask on Si(100) surface, the fabrication can be realized by nanoscratching on the Si3N4 mask and post-etching in hydrofluoric acid (HF) and potassium hydroxide (KOH) solution in sequence. Scanning Auger nanoprobe analysis indicated that the HF solution could selectively etch the scratched Si3N4 mask and then provide the gap for post-etching of silicon substrate in KOH solution. Experimental results suggested that the fabrication depth increased with the increase of the scratching load or KOH etching period. Because of the excellent masking ability of the Si3N4 film, the maximum fabrication depth of nanostructure on silicon can reach several microns. Compared to the traditional friction-induced selective etching technique, the present method can fabricate structures with lesser damage and deeper depths. Since the proposed method has been demonstrated to be a less destructive and flexible way to fabricate a large-area texture structure, it will provide new opportunities for Si-based nanofabrication.
Friction-induced selective etching; Si3N4 mask; Silicon
Copy number variations (CNVs) are abundant in the human genome. They have been associated with complex traits in genome-wide association studies (GWAS) and expected to continue playing an important role in identifying the etiology of disease phenotypes. As a result of current high throughput whole-genome single-nucleotide polymorphism (SNP) arrays, we currently have datasets that simultaneously have integer copy numbers in CNV regions as well as SNP genotypes. At the same time, haplotypes that have been shown to offer advantages over genotypes in identifying disease traits even though available for SNP genotypes are largely not available for CNV/SNP data due to insufficient computational tools. We introduce a new framework for inferring haplotypes in CNV/SNP data using a sequential Monte Carlo sampling scheme ‘Tree-Based Deterministic Sampling CNV’ (TDSCNV). We compare our method with polyHap(v2.0), the only currently available software able to perform inference in CNV/SNP genotypes, on datasets of varying number of markers. We have found that both algorithms show similar accuracy but TDSCNV is an order of magnitude faster while scaling linearly with the number of markers and number of individuals and thus could be the method of choice for haplotype inference in such datasets. Our method is implemented in the TDSCNV package which is available for download at http://www.ee.columbia.edu/~anastas/tdscnv.
Stem cell therapy has recently been introduced to treat patients with type 2 diabetes mellitus (T2DM). However, no data are available on the efficacy and safety of allogeneic Wharton’s Jelly-derived mesenchymal stem cell (WJ-MSC) transplantation in patients with T2DM. Here we performed a non-placebo controlled prospective phase I/II study to determine efficacy and safety of WJ-MSC transplantation in T2DM.
Twenty-two patients with T2DM were enrolled and received WJ-MSC transplantation through one intravenous injection and one intrapancreatic endovascular injection (catheterization). They were followed up for 12 months after transplantation. The primary endpoints were changes in the levels of glycated hemoglobin and C-peptide and the secondary endpoints included insulin dosage, fasting blood glucose (FBG), post-meal blood glucose (PBG), inflammatory markers and T lymphocyte counts.
WJ-MSC transplantation significantly decreased the levels of glucose and glycated hemoglobin, improved C-peptide levels and beta cell function, and reduced markers of systemic inflammation and T lymphocyte counts. No major WJ-MSC transplantation-related adverse events occurred, but data suggest a temporary decrease in levels of C-peptide and beta cell function at one month after treatment, possibly related to intrapancreatic endovascular injection.
Our data demonstrate that treatment with WJ-MSCs can improve metabolic control and beta cell function in patients with T2DM. The therapeutic mechanism may involve improvements in systemic inflammation and/or immunological regulation.
Chinese Clinical Trial Register ChiCTR-ONC-10000985. Registered 23 September 2010
The current study presents a case of a 43-year-old female with giant bilateral calvarial hyperostosis across the superior sagittal sinus, secondary to brain meningioma. The patient presented with a huge mass in the bilateral calvarial region, and diagnoses of huge skull hyperplasia and meningioma were strongly suggested by computed tomography and magnetic resonance imaging examination. In addition, digital subtraction angiography demonstrated that the left middle meningeal artery and branches of the left superficial temporal artery were the major sources of blood supply to the tumor, with the little involvement of the right middle meningeal artery and branches of the right superficial temporal artery. The patient successfully underwent simultaneous embolization of the tumor-supplying vessels, total resection of the giant calvarial hyperostosis and intracranial tumor and skull cranioplasty. Additionally, histological study of the mass revealed a meningioma. The management of such a case presents a surgical challenge, however, the current study provides a good reference for the future treatment of similar diseases.
hyperostosis; parasagittal meningioma; tumor invasion