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Jun Guo - Top 30 Publications

Effects of Zinc Alpha2 Glycoprotein on Lipid Metabolism of Liver in High-Fat Diet-Induced Obese Mice.

Zinc alpha2 glycoprotein (ZAG) is a new type of adipokine involved in adipose tissue mobilization, however, little is known about its lipid metabolism effect in liver. Therefore, we investigated the effects of ZAG in the regulation of hepatic lipid accumulation. Mice were randomly divided into two groups; one was fed a normal diet and another was fed a high-fat diet for eight weeks to establish obesity model. After that, the normal diet group was divided into ND (injection of pcDNA3.1) and NDZ (injection of ZAG recombinant plasmid) and the high-fat diet group was divided into HF (injection of pcDNA3.1) and HFZ (injection of ZAG recombinant plasmid). The mice were weighed once per week and injected with plasmid once every three days for eight times. The results showed that body weight and hepatic TG content were decreased dramatically in HFZ group compared with HF group. The stearoyl-CoAdesaturase1 (SCD1) and Acyl-CoA Synthetase-1 (ACSS1) protein levels in HFZ group were significantly decreased. Furthermore, phosphorylated hormone sensitive lipase (P-HSL) was significantly higher in HFZ group. In HFZ group, hepatic fatty acid translocase (CD36) and fatty acids binding protein-1 (FABP1) protein levels were reduced. In addition, the expression of phosphorylated protein kinase A (PPKA) in HFZ group was higher than the HF group. Meanwhile, NDZ group showed significantly decreased body weight and increased P-HSL level though the hepatic TG content showed no significantly changes compared with the ND group. Therefore, we conclude that ZAG may be beneficial for preventing high-fat-diet-induced hepatic lipid metabolic disorders.

Mutations in BRAF codons 594 and 596 predict good prognosis in melanoma.

B-Raf proto-oncogene serine/threonine kinase (BRAF) V600E is the most common kinase-activating mutation and is associated with poor prognosis in melanoma. However, the clinical significance of kinase-impairing mutations remains unclear. The present study aimed to analyze kinase-impairing mutations in BRAF codons 594 and 596 in non-Caucasian patients with melanoma and to investigate their possible clinical significance. To detect hotspot mutations, exon 15 of the BRAF gene was amplified using polymerase chain reaction in samples from 1,554 patients with melanoma. Among these patients, a total of 912 valid follow-up data were obtained. These patients were divided into three groups according to their BRAF activation status: BRAF wild-type (n=752), BRAF V600E (n=147); and BRAF D594/G596 (n=13). Then the correlation between BRAF activation status, and the clinicopathological features and overall survival (OS) of the patients were analyzed. The prevalence of BRAF mutations in non-Caucasian patients with melanoma was 24.3% (377/1554). Three patients carried two mutations simultaneously. The overall mutation frequencies of kinase-activating mutations, kinase-impairing mutations, and mutations with unknown effects were 93.4 (355/380), 3.4 (13/380), and 3.2% (12/380), respectively. BRAF V600E was identified to be associated with a poor prognosis. Patients with BRAF mutations in codons 594 and 596 had a longer OS time compared with those with a BRAF V600E mutation [median OS, 45 vs. 25 months; HR, 0.45 (95% confidence interval, 0.31-0.97); P=0.043]. To the best of our knowledge, this is the first study to examine a large number of samples from non-Caucasian patients with melanoma and report the characteristics of BRAF mutations according to mutant kinase activity. Melanoma arising from a mutation in BRAF codon 594 or 596 can be differentiated from BRAF V600E-induced melanoma, and mutations in these codons may be good prognostic factors for melanoma. The results of the present study are thus of significance for the development of accurate personalized medicine to treat melanoma.

Chinese Sacbrood Virus Infection in Asian Honey Bees (Apis cerana cerana) and Host Immune Responses to the Virus Infection.

Chinese Sacbrood virus (CSBV) is a positive-stranded RNAvirus that infects both the European honey bee (Apis mellifera) and the Asian honey bee (A. cerana). However, CSBV has much more devastating effects on Asian honey bees than on European honey bees, posing a serious threat to the agricultural and natural ecosystems that rely on A. cerana for pollination service. Using quantitative RT-PCR method, we conducted studies to examine the CSBV infection in Asian honey bee colonies and immune responses of individual bees in response to CSBV infection. Our study showed that CSBV could cause infection in different developmental stages of workers including eggs, larvae, pupae, newly emerged workers, and foraging workers. In addition, evaluating the tissue tropism and transmission of CSBV in infected bees showed that CSBV was detected in the ovaries, spermatheca, and feces of queens as well as semen of drones of the same colonies, suggesting an existence of vertical transmission of CSBV in Asian honey bees. Further, the detection of CSBV in colony food suggests that healthy bees could pick the infection by the virus-contaminated food, and therefore, a possible existence of a food-borne transmission pathway of CSBV in Asian bee colonies. The expression analysis of transcripts (defensin, abaecin, apidaecin, and hymenoptaecin) involving innate antiviral immune pathways showed that CSBV infection could induce significant immune responses in infected bees. However, the immune responses to CSBV infection varied among different development stages with eggs exhibiting the lowest level of immune expression and forager workers exhibiting the highest level of immune gene expression. The results obtained in the study yield important insights into the mechanisms underlying disease pathogenesis of CSBV infections in Asian honey bees and provide valuable information for a rational design of disease control measures.

Seasonality Affects the Diversity and Composition of Bacterioplankton Communities in Dongjiang River, a Drinking Water Source of Hong Kong.

Water quality ranks the most vital criterion for rivers serving as drinking water sources, which periodically changes over seasons. Such fluctuation is believed associated with the state shifts of bacterial community within. To date, seasonality effects on bacterioplankton community patterns in large rivers serving as drinking water sources however, are still poorly understood. Here we investigated the intra-annual bacterial community structure in the Dongjiang River, a drinking water source of Hong Kong, using high-throughput pyrosequencing in concert with geochemical property measurements during dry, and wet seasons. Our results showed that Proteobacteria, Actinobacteria, and Bacteroidetes were the dominant phyla of bacterioplankton communities, which varied in composition, and distribution from dry to wet seasons, and exhibited profound seasonal changes. Actinobacteria, Bacteroidetes, and Cyanobacteria seemed to be more associated with seasonality that the relative abundances of Actinobacteria, and Bacteroidetes were significantly higher in the dry season than those in the wet season (p < 0.01), while the relative abundance of Cyanobacteria was about 10-fold higher in the wet season than in the dry season. Temperature and [Formula: see text]-N concentration represented key contributing factors to the observed seasonal variations. These findings help understand the roles of various bacterioplankton and their interactions with the biogeochemical processes in the river ecosystem.

MiR-138 protects cardiac cells against hypoxia through modulation of glucose metabolism by targeting pyruvate dehydrogenase kinase 1 (PDK1).

Dysfunction of cardiac cells under hypoxia has been identified as an essential event leading to myocytes functional failure. MicroRNAs (miRNAs) are importantly regulatory small-noncoding RNAs that negatively regulate gene expression through the direct binding of 3'UTR region of their target mRNAs (12). Recent studies have demonstrated that miRNAs are aberrantly expressed in the cardiovascular system under pathological conditions (13-17). Pyruvate Dehydrogenase Kinase 1 (PDK1) is a kinase which phosphorylates Pyruvate Dehydrogenase to inactivate it, leading to elevated anaerobic glycolysis and decreased cellular respiration. In this study, we report miR-138 expressions were significantly suppressed under long exposure to hypoxia. In addition, overexpression of miR-138 protects human cardiac cells against hypoxia. We observed miR-138 inhibits glycolysis but promotes mitochondrial respiration through direct targeting PDK1. Moreover, we demonstrate hypoxia induces cardiac cell death through increased glycolysis and decreased mitochondrial respiration. Inhibition of glycolysis by either glycolysis inhibitor or knockdown glycolysis enzymes, Glut1 or PDK1 contributes to cardiac cells survival. Finally, our results reveal restoration of PDK1 in miR-138 overexpressing cardiac cells recovers cell sensitivity to hypoxia. This study leads to the intervention of novel therapeutic strategies against cardiac cells dysfunction during surgery or ischemia.

Host-induced gene silencing of an important pathogenicity factor PsCPK1 in Puccinia striiformis f. sp. tritici enhances resistance of wheat to stripe rust.

Rust fungi are devastating plant pathogens and cause a large economic impact on wheat production worldwide. To overcome this rapidly loss of varieties resistance, we generated stable transgenic wheat plants expressing short interfering RNAs (siRNAs) targeting potentially vital genes of Puccinia striiformis f. sp. tritici (Pst). Protein kinase A (PKA) has been proved to play important roles in regulating the virulence of phytopathogenic fungi. PsCPK1, a PKA catalytic subunit gene from Pst, is highly induced at the early infection stage of Pst. The instantaneous silencing of PsCPK1 by barley stripe mosaic virus (BSMV)-mediated host-induced gene silencing (HIGS) results in a significant reduction in the length of infection hyphae and disease phenotype. These results indicate that PsCPK1 is an important pathogenicity factor by regulating Pst growth and development. Two transgenic lines expressing the RNA interference (RNAi) construct in a normally susceptible wheat cultivar displayed high levels of stable and consistent resistance to Pst throughout the T3 to T4 generations. The presence of the interfering RNAs in transgenic wheat plants was confirmed by northern blotting, and these RNAs were found to efficiently down-regulate PsCPK1 expression in wheat. The present study addresses important aspects for the development of fungal-derived resistance through the expression of silencing constructs in host plants as a powerful strategy to control cereal rust diseases. This article is protected by copyright. All rights reserved.

Urachal mucinous adenocarcinoma with pseudomyxoma peritonei: A case report.

Pseudomyxoma peritonei is an unusual clinical condition, and the appendix and ovaries are reported as the primary sites.

Erratum: The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex.

Tunable chiral metal organic frameworks toward visible light-driven asymmetric catalysis.

A simple and effective strategy is developed to realize visible light-driven heterogeneous asymmetric catalysis. A chiral organic molecule, which only has very weak catalytic activity in asymmetric α-alkylation of aldehydes under visible light, is utilized as the ligand to coordinate with different types of metal ions, including Zn(2+), Zr(4+), and Ti(4+), for construction of crystalline metal organic frameworks (MOFs). Impressively, when used as heterogeneous catalysts, all of the synthesized MOFs exhibit markedly enhanced activity. Furthermore, the asymmetric catalytic performance of these MOFs could be easily altered by selecting different metal ions, owing to the tunable electron transfer property between metal ions and chiral ligands. This work will provide a new approach for fabrication of heterogeneous catalysts and trigger more enthusiasm to conduct the asymmetric catalysis driven by visible light.

Frequent Genetic Aberrations in the CDK4 Pathway in Acral Melanoma indicate the potential for CDK4/6 Inhibitors in Targeted Therapy.

Effective therapies for the majority of metastatic acral melanoma (AM) patients has not been established. Thus, we investigated genetic aberrations of CDK4 pathway in AM and evaluate the efficacy of CDK4/6 inhibitors in targeted therapy of AM.

Ultrasensitive Terahertz Biosensors Based on Fano Resonance of a Graphene/Waveguide Hybrid Structure.

Graphene terahertz (THz) surface plasmons provide hope for developing functional devices in the THz frequency. By coupling graphene surface plasmon polaritons (SPPs) and a planar waveguide (PWG) mode, Fano resonances are demonstrated to realize an ultrasensitive terahertz biosensor. By analyzing the dispersion relation of graphene SPPs and PWG, the tunable Fano resonances in the terahertz frequency are discussed. It is found that the asymmetric lineshape of Fano resonances can be manipulated by changing the Fermi level of graphene, and the influence of the thickness of coupling layer and air layer in sandwich structure on the Fano resonances is also discussed in detail. We then apply the proposed Fano resonance to realize the ultrasensitive terahertz biosensors, it is shown that the highest sensitivities of 3260 RIU-1 are realized. Our result is two orders of a conventional surface plasmon resonance sensor. Furthermore, we find that when sensing medium is in the vicinity of water in THz, the sensitivity increases with increasing refractive index of the sensing medium.

Basidiomycete-specific PsCaMKL1 encoding a CaMK-like protein kinase is required for full virulence of Puccinia striiformis f. sp. tritici.

Calcium/calmodulin-dependent kinases (CaMKs) are Ser/Thr protein kinases (PKs) that respond to changes in cytosolic free Ca(2+) and play diverse roles in eukaryotes. In fungi, CAMKs are generally classified into four families CAMK1, CAMKL, RAD53 and CAMK-Unique. Among these, CAMKL constitutes the largest family. In some fungal plant pathogens, members of the CaMKL family have been shown to be responsible for pathogenesis. However, little is known about their role(s) in rust fungi. In this study, we functionally characterized a novel PK gene, PsCaMKL1, from Puccinia striiformis f. sp. tritici (Pst). PsCaMKL1 belongs to a group of PKs that is evolutionarily specific to basidiomyceteous fungi. PsCaMKL1 shows little intra-species polymorphism between Pst isolates. PsCaMKL1 transcripts are highly elevated at early infection stages, whereas gene expression is downregulated in barely germinated urediospores under KN93 treatment. Overexpression of PsCaMKL1 in fission yeast increased resistance to environmental stresses. Knock down of PsCaMKL1 using host-induced gene silencing (HIGS) reduced the virulence of Pst accompanied by reactive oxygen species (ROS) accumulation and a hypersensitive response. These results suggest that PsCaMKL1 is a novel pathogenicity factor that exerts it virulence function by regulating ROS production in wheat.

Short- and Long-term Therapeutic Efficacies of Intravenous Transplantation of Bone Marrow Stem Cells on Cardiac Function in Rats with Acute Myocardial Infarction: A Meta-analysis of Randomized Controlled Trials.

Objective To investigate the short- and long-term therapeutic efficacies of intravenous trans- plantation of bone marrow stem cells (MSCs) in rats with experimental myocardial infarction by meta- analysis. Methods Randomized controlled trials were systematically searched from PubMed, Science Citation Index (SCI), Chinese journal full-text database (CJFD) up to December 2014. While the experimental groups (MSCs groups) were injected MSCs intravenously, the control groups were injected Delubecco's minimum essential medium (DMEM) or phosphate buffered saline (PBS). Subgroup analysis for each outcome measure was performed for the observing time point after the transplantation of MSCs. Weighted mean differences (WMD) and 95% confidence intervals (CI) were calculated for outcome parameters including ejection fraction (EF) and fractional shortening (FS), which were measured by echocardiogram after intravenous injection and analyzed by RevMan 5.2 and STATA 12.0. Results Data from 9 studies (190 rats) were included in the meta-analysis. As compared to the control groups, the cardiac function of the experimental groups were not improved at day 7 (EF: WMD=0.08, 95%CI -1.32 to 1.16, P>0.01; FS: WMD=-0.12, 95%CI -0.90 to 0.65, P>0.01) until at day 14 after MSCs' transplantation (EF: WMD=10.79, 95%CI 9.16 to 12.42, P<0.01; FS: WMD=11.34, 95%CI 10.44 to 12.23, P<0.01), and it lasted 4 weeks or more after transplantation of MSCs (EF: WMD=13.94, 95%CI 12.24 to 15.64, P<0.01; FS: WMD=9.64, 95%CI 7.98 to 11.31, P<0.01). Conclusion The therapeutic efficacies of MSCs in rats with myocardid infarction become increasing apparent as time advances since 2 weeks after injection.

Hypoxia reduces mature hERG channels through calpain up-regulation.

Human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium current (IKr) potassium channel, which is important for cardiac repolarization. Impairment of hERG function is the primary cause of acquired long QT syndrome, which predisposes individuals to cardiac arrhythmias and sudden death. Patients with hypoxia due to conditions such as cardiac ischemia or obstructive sleep apnea display increased incidence of cardiac arrhythmias and sudden death. We sought to understand the mechanisms that underlie hypoxia-associated cardiac arrhythmias. Using cell biology and electrophysiologic techniques, we found that hypoxic culture of hERG-expressing human embryonic kidney (HEK) cells and neonatal rat cardiomyocytes reduced hERG current/IKr and mature ERG channel expression with a concomitant increase in calpain expression. Calpain was actively released into the extracellular milieu and degraded cell-surface hERG. In contrast to hERG, the ether-a-go-go (EAG) channel was not reduced by hypoxic culture. By making chimeric channels between hERG and EAG, we identified that hypoxia-induced calpain degraded hERG by targeting its extracellular S5-pore linker. The scorpion toxin BeKm-1, which is known to selectively bind to the S5-pore linker of hERG, prevented hypoxia-induced hERG reduction. Our data provide novel information about hypoxia-mediated hERG dysfunction and may have biological and clinical implications in hypoxia-associated diseases.-Lamothe, S. M., Song, W., Guo, J., Li, W., Yang, T., Baranchuk, A., Graham, C. H., Zhang, S. Hypoxia reduces mature hERG channels through calpain up-regulation.

A prospective, randomized, controlled trial comparing two doses of oestrogen therapy after hysteroscopic adhesiolysis to prevent intrauterine adhesion recurrence.

The aim of this prospective, randomized, controlled trial was to evaluate the efficacy of different doses of oestrogen treatment (2 mg and 6 mg daily) after hysteroscopic adhesiolysis in patients with moderate to severe adhesion according to the American Fertility Society (AFS) classification of intrauterine adhesions. A total of 121 patients were included in the final analysis. Fifty-nine patients received 2 mg oestrogen daily (low-dose group), and 62 received 6 mg oestrogen daily (high-dose group) for three cycles after surgery. Second- and third-look outpatient hysteroscopy was performed 4 and 8 weeks after the initial surgery. There was no difference in the menstrual pattern and AFS scores before and after surgery between the two groups, and AFS scores at the second- and third-look hysteroscopy were found to be significantly lower than the scores before surgery in both groups (both P < 0.01). While this study did not address the fundamental question of whether oestrogen adjuvant therapy prevents the recurrence of intrauterine adhesions, the findings do not support the use of high-dose oestrogen therapy after hysteroscopic adhesiolysis.

Structural Alterations in Chronic Capsular versus Pontine Stroke.

Purpose To investigate whether patients with capsular stroke (CS) and patients with pontine stroke (PS) involving the motor pathway have different types of structural damage and reorganization. Materials and Methods With institutional review board approval and after obtaining written informed consent, structural magnetic resonance imaging data were prospectively acquired in 115 patients with CS, 47 patients with PS, and 116 control subjects by using four imagers from three hospitals. Patients with stroke lesions in the left and right hemispheres were analyzed (timing of follow-up imaging: mean, 597 days; range, 180-2070 days). The gray matter volume (GMV) of each voxel was compared among the three groups while controlling for the effects of age, sex, and imager. Multiple comparisons were corrected by using a false discovery rate method for voxel-wise comparisons and by using the Bonferroni method for post hoc comparisons. Results Both patients with CS and patients with PS exhibited a GMV reduction (6.18%-8.23%) in the ipsilesional anterior insular cortex and a GMV increase (5.11%-11.73%) in the supplementary motor area relative to control subjects (P < .0013). Moreover, a GMV reduction was observed in the ipsilesional sensorimotor cortex in all patients with CS (9.73%-10.41%) and in the cerebellum in all patients with PS (10.58%-15.81%). Additionally, a GMV increase was found in the precuneus in patients with PS with left lesions (17.23%) and in the middle frontal gyrus in patients with CS with right lesions (10.95%). Conclusion The different patterns of structural damage and reorganization in patients with CS versus those with PS may provide useful information in designing individualized rehabilitative strategies for these patients. (©) RSNA, 2017 Online supplemental material is available for this article.

TaARPC3, Contributes to Wheat Resistance against the Stripe Rust Fungus.

The actin cytoskeleton participates in numerous cellular processes, including less-characterized processes, such as nuclear organization, chromatin remodeling, transcription, and signal transduction. As a key regulator of actin cytoskeletal dynamics, the actin related protein 2/3 complex (Arp2/3 complex) controls multiple developmental processes in a variety of tissues and cell types. To date, the role of the Arp2/3 complex in plant disease resistance signaling is largely unknown. Herein, we identified and characterized wheat ARPC3, TaARPC3, which encodes the C3 subunit of the Arp2/3 complex. Expression of TaARPC3 in the arc18 mutant of Saccharomyces cerevisiae Δarc18 resulted in complementation of stress-induced phenotypes in S. cerevisiae, as well as restore wild-type cell shape malformations. TaARPC3 was found predominantly to be localized in the nucleus and cytoplasm when expressed transiently in wheat protoplast. TaARPC3 was significantly induced in response to avirulent race of Puccinia striiformis f. sp. tritici (Pst). Knock-down of TaARPC3 by virus-induced gene silencing resulted in a reduction of resistance against Pst through a specific reduction in actin cytoskeletal organization. Interestingly, this reduction was found to coincide with a block in reactive oxygen species (ROS) accumulation, the hypersensitive response (HR), an increase in TaCAT1 mRNA accumulation, and the growth of Pst. Taken together, these findings suggest that TaARPC3 is a key subunit of the Arp2/3 complex which is required for wheat resistance against Pst, a process that is associated with the regulation of the actin cytoskeleton.

Identification of novel resistance mechanisms to NAMPT inhibition via the de novo NAD(+) biosynthesis pathway and NAMPT mutation.

Cancer cells have an unusually high requirement for the central and intermediary metabolite nicotinamide adenine dinucleotide (NAD(+)), and NAD(+) depletion ultimately results in cell death. The rate limiting step within the NAD(+) salvage pathway required for converting nicotinamide to NAD(+) is catalyzed by nicotinamide phosphoribosyltransferase (NAMPT). Targeting NAMPT has been investigated as an anti-cancer strategy, and several highly selective small molecule inhibitors have been found to potently inhibit NAMPT in cancer cells, resulting in NAD(+) depletion and cytotoxicity. To identify mechanisms that could cause resistance to NAMPT inhibitor treatment, we generated a human fibrosarcoma cell line refractory to the highly potent and selective NAMPT small molecule inhibitor, GMX1778. We uncovered novel and unexpected mechanisms of resistance including significantly increased expression of quinolinate phosphoribosyl transferase (QPRT), a key enzyme in the de novo NAD(+) synthesis pathway. Additionally, exome sequencing of the NAMPT gene in the resistant cells identified a single heterozygous point mutation that was not present in the parental cell line. The combination of upregulation of the NAD(+) de novo synthesis pathway through QPRT over-expression and NAMPT mutation confers resistance to GMX1778, but the cells are only partially resistant to next-generation NAMPT inhibitors. The resistance mechanisms uncovered herein provide a potential avenue to continue exploration of next generation NAMPT inhibitors to treat neoplasms in the clinic.

A self-supporting bimetallic [email protected] core-shell nanoparticle electrocatalyst for the synergistic enhancement of methanol oxidation.

The morphology of Pt-Au bimetal nanostructures plays an important role in enhancing the catalytic capability, catalytic stability and utilization efficiency of the platinum. We designed and successfully prepared [email protected] nanoparticles (NPs) through an economical, surfactant-free and efficient method of seed-mediated growth. The [email protected] NPs displayed electrochemical performances superior to those of commercial Pt/C catalysts because their agglomeration was prevented and exhibited better long-term stability with respect to methanol oxidation in acidic media by efficiently removing intermediates. Among the obtained [email protected] NPs, [email protected] NPs exhibited the most significantly enhanced catalytic performance for the methanol oxidation reaction (MOR). Their mass and electrochemically active surface area (ECSA)-normalized current densities are approximately 3.9 and 4.6 times higher than those of commercial Pt/C catalysts, respectively. The oxidation current densities of the [email protected] NPs are approximately 1.8 times higher than those of commercial Pt/C catalysts after 4000 s of continuous measurement because the small Pt NPs grown on the surface of the [email protected] NPs were effectively stabilized by the Au metal support. This approach may be a facile method for the synthesis of self-supported bimetallic nanostructures, which is of great significance for the development of high performance electrocatalysts and sensors.

Ripk3 induces mitochondrial apoptosis via inhibition of FUNDC1 mitophagy in cardiac IR injury.

Ripk3-required necroptosis and mitochondria-mediated apoptosis are the predominant types of cell death that largely account for the development of cardiac ischemia reperfusion injury (IRI). Here, we explored the effect of Ripk3 on mitochondrial apoptosis. Compared with wild-type mice, the infarcted area in Ripk3-deficient (Ripk3(-/-)) mice had a relatively low abundance of apoptotic cells. Moreover, the loss of Ripk3 protected the mitochondria against IRI and inhibited caspase9 apoptotic pathways. These protective effects of Ripk3 deficiency were relied on mitophagy activation. However, inhibition of mitophagy under Ripk3 deficiency enhanced cardiomyocyte and endothelia apoptosis, augmented infarcted area and induced microvascular dysfunction. Furthermore, ischemia activated mitophagy by modifying FUNDC1 dephosphorylation, which substantively engulfed mitochondria debris and cytochrome-c, thus blocking apoptosis signal. However, reperfusion injury elevated the expression of Ripk3 which disrupted FUNDC1 activation and abated mitophagy, increasing the likelihood of apoptosis. In summary, this study confirms the promotive effect of Ripk3 on mitochondria-mediated apoptosis via inhibition of FUNDC1-dependent mitophagy in cardiac IRI. These findings provide new insight into the roles of Ripk3-related necroptosis, mitochondria-mediated apoptosis and FUNDC1-required mitophagy in cardiac IRI.

MAPK Pathway and TERT Promoter Gene Mutation Pattern and Its Prognostic Value in Melanoma Patients: A Retrospective Study of 2,793 Cases.

Purpose: Ethnic differences are conspicuous in melanoma. This study is to obtain a comprehensive view of a genomic landscape and a better understanding of the correlations of gene mutation status with clinicopathologic characteristics and disease prognosis in the Asian population.Experimental Design: A total of 2,793 melanoma patient samples were retrospectively collected and analyzed for mutations in C-KIT, BRAF, NRAS, and PDGFRA coding regions and telomerase reverse transcriptase (TERT) promoter region by Sanger sequencing. Mutations were correlated to clinicopathologic features and overall survival.Results: The incidences of somatic mutations within the BRAF, NRAS, C-KIT, TERT-228, TERT-250, and PDGFRA genes were 23.7%, 10.4%, 8.0%, 5.9%, 5.5%, and 1.4%, respectively. Hotspot mutations accounted for 95.8% and 87.2% of BRAF and NRAS mutations, respectively; meanwhile, C-KIT and PDGFRA mutations showed more heterogeneity. BRAF, C-KIT, and NRAS mutations were mutually exclusive. BRAF, C-KIT, NRAS, and numbers of gene mutations of the MAPK pathway were all independent negative prognostic factors (P = 0.007, other P < 0.001, respectively). In acral melanoma, BRAF, C-KIT, and NRAS mutations were all independent prognostic factors of worse overall survival (all P < 0.001), whereas in mucosal melanoma, only C-KIT was (P = 0.006). Although correlated with BRAF mutations (P = 0.001 and P < 0.001 for C228T and C250T, respectively), TERT promoter gene mutations were not correlated with overall survival (P = 0.406 and 0.256, respectively).Conclusions: The MAPK pathway and TERT promoter gene mutations are differentially represented in the Asian population. Mutations in BRAF, C-KIT, and NRAS have prognostic values that vary by melanoma subtypes. Clinical treatment targeting these critical pathways should be aimed directly at these poor-prognosis subpopulations for maximum potential impact. Clin Cancer Res; 1-8. ©2017 AACR.

Ultrathin Vein-Like Iridium-Tin Nanowires with Abundant Oxidized Tin as High-Performance Ethanol Oxidation Electrocatalysts.

Iridium (Ir) holds great promise for ethanol oxidation reaction (EOR), while its practical applications suffer from the limited shape-controlled synthesis due to its low-energy barrier for nucleation. To overcome this limitation, the preparation of a new class of ultrathin vein-like Ir-tin nanowires (IrSn NWs) with abundant oxidized Sn is reported. By tuning the ratio of Ir to Sn, the optimized Ir67 Sn33 /C exhibits the highest mass density of 95.6 mA mg(-1) Ir for EOR at low potential (0.04 V), which is 4.1-fold and 20-fold higher than that of Ir/C and the commercial Pt/C, respectively. It also exhibits the smallest Tafel slope of 153 mV dec(-1) and superior stability after 2 h chronoamperometric measurement. Electrochemical measurements and X-ray photoelectron spectra results confirm that the abundant oxidized Sn promotes a complete oxidization of ethanol into CO2 at low potential. This work highlights the importance of non-noble metal on enhancing the EOR performance.

Epithelial cell specific Raptor is required for initiation of type 2 mucosal immunity in small intestine.

Intestinal tuft cells are one of 4 secretory cell linages in the small intestine and the source of IL-25, a critical initiator of the type 2 immune response to parasite infection. When Raptor, a critical scaffold protein for mammalian target of rapamycin complex 1 (mTORC1), was acutely deleted in intestinal epithelium via Tamoxifen injection in Tritrichomonas muris (Tm) infected mice, tuft cells, IL-25 in epithelium and IL-13 in the mesenchyme were significantly reduced, but Tm burden was not affected. When Tm infected mice were treated with rapamycin, DCLK1 and IL-25 expression in enterocytes and IL-13 expression in mesenchyme were diminished. After massive small bowel resection, tuft cells and Tm were diminished due to the diet used postoperatively. The elimination of Tm and subsequent re-infection of mice with Tm led to type 2 immune response only in WT, but Tm colonization in both WT and Raptor deficient mice. When intestinal organoids were stimulated with IL-4, tuft cells and IL-25 were induced in both WT and Raptor deficient organoids. In summary, our study reveals that enterocyte specific Raptor is required for initiating a type 2 immune response which appears to function through the regulation of mTORC1 activity.

Inference-Based Similarity Search in Randomized Montgomery Domains for Privacy-Preserving Biometric Identification.

Similarity search is essential to many important applications and often involves searching at scale on high-dimensional data based on their similarity to a query. In biometric applications, recent vulnerability studies have shown that adversarial machine learning can compromise biometric recognition systems by exploiting the biometric similarity information. Existing methods for biometric privacy protection are in general based on pairwise matching of secured biometric templates and have inherent limitations in search efficiency and scalability. In this paper, we propose an inference-based framework for privacy-preserving similarity search in Hamming space. Our approach builds on an obfuscated distance measure that can conceal Hamming distance in a dynamic interval. Such a mechanism enables us to systematically design statistically reliable methods for retrieving most likely candidates without knowing the exact distance values. We further propose to apply Montgomery multiplication for generating search indexes that can withstand adversarial similarity analysis, and show that information leakage in randomized Montgomery domains can be made negligibly small. Our experiments on public biometric datasets demonstrate that the inference-based approach can achieve a search accuracy close to the best performance possible with secure computation methods, but the associated cost is reduced by orders of magnitude compared to cryptographic primitives.

Systemic Immune-Inflammation Index and Circulating T-Cell Immune Index Predict Outcomes in High-Risk Acral Melanoma Patients Treated with High-Dose Interferon.

High-dose interferon alfa-2b (IFN-α-2b) improves the survival of patients with high-risk melanoma. We aimed to identify baseline peripheral blood biomarkers to predict the outcome of acral melanoma patients treated with IFN-α-2b. Pretreatment baseline parameters and clinical data were assessed in 226 patients with acral melanoma. Relapse-free survival (RFS) and overall survival (OS) were assessed using the Kaplan-Meier method, and multivariate Cox regression analyses were applied after adjusting for stage, lactate dehydrogenase (LDH), and ulceration. Univariate analysis showed that neutrophil-to-lymphocyte ratio ≥2.35, platelet-to-lymphocyte ratio ≥129, systemic immune-inflammation index (SII) ≥615 × 10(9)/l, and elevated LDH were significantly associated with poor RFS and OS. The SII is calculated as follows: platelet count × neutrophil count/lymphocyte count. On multivariate analysis, the SII was associated with RFS [hazard ratio (HR)=1.661, 95% confidence interval (CI): 1.066-2.586, P=.025] and OS (HR=2.071, 95% CI: 1.204-3.564, P=.009). Additionally, we developed a novel circulating T-cell immune index (CTII) calculated as follows: cytotoxic T lymphocytes/(CD4(+) regulatory T cells × CD8(+) regulatory T cells). On univariate analysis, the CTII was associated with OS (HR=1.73, 95% CI: 1.01-2.94, P=.044). The SII and CTII might serve as prognostic indicators in acral melanoma patients treated with IFN-α-2b. The indexes are easily obtainable via routine tests in clinical practice.

The transcription factor PstSTE12 is required for virulence of Puccinia striiformis f. sp. tritici.

Puccinia striiformis f. sp. tritici (Pst) is an obligate biotrophic fungus that causes extensive damage in wheat. The pathogen is now known to be a heteroecious fungus with an intricate life cycle containing sexual and asexual stages. Orthologs of the STE12 transcription factor that regulate mating and filamentation in Saccharomyces cerevisiae as well as virulence in other fungi has been extensively described. Because reliable transformation and gene disruption methods are lacking for Pst, knowledge about the function of its STE12 ortholog is limited. In this study, we identified a putative ortholog of STE12 from Pst in haustoria-enriched transcripts and designated it as PstSTE12. The gene encodes a protein of 879 amino acids containing three helices in the homeodomain, conserved phenylalanine and tryptophan sites, and two C2 /H2 -Zn(2+) finger domains. Real-time RT-PCR analyses revealed that expression of PstSTE12 was highly induced during early infection stages and peaked during haustorium formation and the stage pycniospores in the aecial host barberry. Subcellular localization assays indicated that PstSTE12 is localized in the nucleus and functions as a transcriptional activator. Yeast one-hybrid assays revealed that PstSTE12 exhibits transcriptional activity, and that its C-terminus is necessary for the activation of transcription. PstSTE12 complemented the mating defect in α ste12 mutant of S. cerevisiae. In addition, it partially complemented the defects of the Magnaporthe oryzae mst12 mutant in plant infection. Knocking down PstSTE12 via host-induced gene silencing (HIGS) mediated by barley stripe mosaic virus (BSMV) resulted in a substantial reduction in the growth and spread of hyphae in Pst and weakened virulence of Pst on wheat. Our results suggest that PstSTE12 likely acts at an intersection participating in the invasion and the mating processes of Pst, and provide new insights toward comprehending the variation of virulence in cereal rust fungi. This article is protected by copyright. All rights reserved.

Measurement of Stokes-operator squeezing for continuous-variable orbital angular momentum.

We demonstrate experimentally a measurement scheme for the Stokes operators for the continuous-variable squeezed states of orbital angular momentum (OAM). An OAM squeezed state is generated by coupling a dim Hermite-Gauss HG01-mode quadrature-squeezed light beam with a bright HG10-mode coherent light beam on a 98/2 beam splitter. Using an asymmetric Mach-Zehnder interferometer with an extra Dove prism in one arm, we measured the three orbital Stokes operators of the OAM squeezed states with a self-homodyne detection and finally characterized their positions and noise on the orbital Poincaré sphere.

PtPb/PtNi Intermetallic Core/Atomic Layer Shell Octahedra for Efficient Oxygen Reduction Electrocatalysis.

Although explosive studies on pursuing high-performance Pt-based nanomaterials for fuel cell reactions have been carried out, the combined controls of surface composition, exposed facet, and interior structure of the catalyst remains a formidable challenge. We demonstrate herein a facile chemical approach to realize a new class of intermetallic Pt-Pb-Ni octahedra for the first time. Those nanostructures with unique intermetallic core, active surface composition, and the exposed facet enhance oxygen reduction electrocatalysis with the optimized PtPb1.12Ni0.14 octahedra exhibiting superior specific and mass activities (5.16 mA/cm(2) and 1.92 A/mgPt) for oxygen reduction reaction (ORR) that are ∼20 and ∼11 times higher than the commercial Pt/C, respectively. Moreover, the PtPb1.12Ni0.14 octahedra can endure at least 15 000 cycles with negligible activity decay, showing a new class of Pt-based electrocatalysts with enhanced performance for fuel cells and beyond.

Better methodology and research index are needed.

SAR and characterization of non-substrate isoindoline urea inhibitors of nicotinamide phosphoribosyltransferase (NAMPT).

Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed.