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Background: In the last decade, a large amount of microarray gene expression data has been accumulated in public repositories. Integrating and analyzing high-throughput gene expression data have become key activities for exploring gene functions, gene networks and biological pathways. Effectively utilizing these invaluable microarray data remains challenging due to a lack of powerful tools to integrate large-scale gene-expression information across diverse experiments and to search and visualize a large number of gene-expression data points. Results: Gene Expression Browser is a microarray data integration, management and processing system with webbased search and visualization functions. An innovative method has been developed to define a treatment over a control for every microarray experiment to standardize and make microarray data from different experiments homogeneous. In the browser, data are pre-processed offline and the resulting data points are visualized online with a 2-layer dynamic web display. Users can view all treatments over control that affect the expression of a selected gene via Gene View, and view all genes that change in a selected treatment over control via treatment over control View. Users can also check the changes of expression profiles of a set of either the treatments over control or genes via Slide View. In addition, the relationships between genes and treatments over control are computed according to gene expression ratio and are shown as co-responsive genes and co-regulation treatments over control. Conclusion: Gene Expression Browser is composed of a set of software tools, including a data extraction tool, a microarray data-management system, a data-annotation tool, a microarray data-processing pipeline, and a data search & visualization tool. The browser is deployed as a free public web service (http://www.ExpressionBrowser. com) that integrates 301 ATH1 gene microarray experiments from public data repositories (viz. the Gene Expression Omnibus repository at the National Center for Biotechnology Information and Nottingham Arabidopsis Stock Center). The set of Gene Expression Browser software tools can be easily applied to the large-scale expression data generated by other platforms and in other species. [ABSTRACT FROM AUTHOR]

The anthracycline antibiotic doxorubicin (DOX) has been used successfully for treating various types of cancers. However, the therapeutic efficacy of DOX was greatly restricted by its cumulative dose-related cardiotoxicity and common side effects such as bone marrow and immune suppression. Quercetin had better cardioprotective and hepatoprotective activities. The present study was to observe whether quercetin could improve therapeutic index of DOX and explore its mechanisms. Effects of quercetin on doxorubicin (DOX)-induced cytotoxicity were investigated in 4T1 cells and murine spleen cells by methylthiazoletetrazolium assay, flow cytometry and single cell gel electrophoresis. Influences of quercetin on therapeutic efficacy and systemic toxicity of DOX were evaluated in BALB/c mice with 4T1 breast cancer. Hypoxia-inducible factor-1 alpha (HIF-1α) in tumor and normal cells was examined to explore mechanisms of quercetin by Western blot and enzyme-linked immunosorbent assay. In vitro, quercetin at dose less than 100 μM had only slight effects on cell viability and DOX-induced cytotoxicity in 4T1 cells under normoxia, but it could reverse 4T1 cell resistance to DOX under hypoxia and protect spleen cells against DOX-induced cytotoxicity. In vivo, quercetin suppressed tumor growth and prolonged survival in BALB/c mice bearing 4T1 breast cancer. Importantly, quercetin enhanced therapeutic efficacy of DOX and simultaneously reduced DOX-induced toxic side effects. Further study showed that quercetin suppressed intratumoral HIF-1α in a hypoxia-dependent way but increased its accumulation in normal cells. HIF-1α siRNA abolished effects of quercetin on both tumor and normal cells. These results suggested that quercetin could improve therapeutic index of DOX by its opposing effects on HIF-1α in tumor and normal cells, and was a promising candidate as anticancer agents. [ABSTRACT FROM AUTHOR]

Background and objective Glut1 is the main carrier which intervenes the glucose uptake of cell, and the expression of Glut1 was positively correlated to the uptake of FDG. The aim of this study is to select the CT characteristics and clinicopathological parameters which can reflect the levels of glucose metabolism of human non-small lung cancer (NSLC). Methods Thirty-three cases of the NSLC (squamous carcinoma 11 cases and adenocarcinoma 22 cases) have undergone the scanning of FDG PET/CT before operation. The tumor pathological classification, degree of differentiation and lymph node metastasis were collected. The CT characteristics which included the diameter, deep lobulation, thin and short spiculation, spinous protuberance, cavity sign, vessel convergence sign and pleural retraction sign were described. Tracer uptake of suspected lesions was assessed by visual assessment and quantitatively by the maximum standardized uptake values (SUVmax). The expression of Glut1 which were examined by means of SP immunohistochemical technique was also analyzed. Results The positive rate of Glut1 was 66.67% (squamous carcinoma was 90.91% and adenocarcinoma was 54.55%). The positive rate of Glut1 and SUVmax of squamous carcinoma were significant higher than adenocarcinoma (Pbilateral=0.037, Punilateral=0.045). Through visual assessment and SUVmax, the uptake and the positive rate of Glut1 which size =2 cm were higher than the size <2 cm (Pbilateral=0.002, Pbilateral=0.001, Punilateral=0.049). The uptake intense of FDG was related to the thin and short spiculation through visual assessment (Pbilateral=0.006). Conclusion The study suggested that the levels of glucose metabolism of squamous carcinoma higher than adenocarcinoma, the diameter upper than 2 cm and the thin and short speculation were higher. [ABSTRACT FROM AUTHOR]

Noroviruses (NoVs) are a leading cause of acute gastroenteritis worldwide. P particles are a potential vaccine candidate against NoV. Simvastatin is a cholesterol-reducing drug that is known to increase NoV infectivity. In this study, we examined simvastatin’s effects on P particle-induced protective efficacy and T-cell immunogenicity using the gnotobiotic pig model of human NoV infection and diarrhea. Pigs were intranasally inoculated with three doses (100 µg/dose) of GII.4/VA387-derived P particles together with monophosphoryl lipid A and chitosan adjuvants. Simvastatin-fed pigs received 8 mg/day orally for 11 days prior to challenge. A subset of pigs was orally challenged with 10 ID50 of a NoV GII.4/2006b variant at post-inoculation day (PID) 28 and monitored for 7 days post-challenge. Intestinal and systemic T cell responses were determined pre- and postchallenge. Simvastatin abolished the P particle’s protection and significantly increased diarrhea severity after NoV infection. Simvastatin decreased proliferation of virus-specific and non-specific CD8 T cells in duodenum and virus-specific CD4 and CD8 T cells in spleen and significantly reduced numbers of intestinal mononuclear cells in vaccinated pigs. Furthermore, simvastatin significantly decreased numbers of duodenal CD4+IFN-γ+, CD8+IFN-γ+ and regulatory T cells and total duodenal activated CD4+ and CD8+ T cells in vaccinated pigs pre-challenge at PID 28. Following challenge, simvastatin prevented the IFN-γ+ T cell response in spleen of vaccinated pigs. These results indicate that simvastatin abolished P particle vaccine-induced partial protection through, at least in part, impairing T cell immunity. The findings have specific implications for the development of preventive and therapeutic strategies against NoV gastroenteritis, especially for the elderly population who takes statin-type drugs.

Background/purpose: This study aimed to evaluate the immunomodulatory effects and signaling mechanisms of Lactobacillus rhamnosus GG (LGG) and its components [surface-layer protein (SLP), DNA, exopolysaccharides, and CpG oligodeoxynucleotides] on lipopolysaccharide (LPS)-stimulated porcine intestinal epithelial cell (IEC) IPEC-J2. Methods: The mRNA expressions of inflammatory cytokines and Toll-like receptors (TLRs) were measured by quantitative real-time polymerase chain reaction. Activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling was detected by western blot and immunofluorescence. Results: Pretreatment of IPEC-J2 cells with LGG, SLP, or exopolysaccharides significantly alleviated LPS-induced inflammatory cytokines and TLR activation at mRNA level. LGG, SLP, and exopolysaccharides also attenuated LPS-induced MAPK and NF-κB signaling activations. CpG oligodeoxynucleotides significantly increased the interleukin 12, tumor necrosis factor α, and TLR9 mRNA levels and enhanced NF-κB signaling activation in LPS-stimulated cells. Conclusion: LGG had immunomodulatory effects on LPS-induced porcine IECs by modulating TLR expressions and inhibiting MAPK and NF-κB signaling to decrease inflammatory cytokine expressions. Components of LGG exerted immunomodulatory effects on porcine IECs, especially immunostimulatory CpG oligodeoxynucleotides.

Abstract Background Oculocutaneous albinism (OCA) is a group of heterogeneous autosomal recessive genetic disorder of melanin synthesis results in hypopigmented hair, skin, and eyes. OCA type 1, OCA type 2, and OCA type 4, which are respectively caused by mutations in TYR, OCA2, and SLC45A2 have high morbidity rates in Asia. Methods TYR, OCA2, and SLC45A2 mutation analysis was carried out on 18 nonconsanguineous OCA patients and four fetuses were included for prenatal diagnose. Three genes of all individuals were amplified by polymerase chain reaction and examined by Sanger sequencing. The pathogenicity of the detected mutations were analyzed by Mutation Taster, PolyPhen 2, and SIFT software, and the conservation of the substituted amino acids were analyzed by MEGA software. Results Eleven TYR mutations, three OCA2 mutations, and two SLC45A2 mutations were identified in 14 OCA type 1 patients, two OCA type 2 patients, and two OCA type 4 patients. c.1021A>G, p.R341G in TYR, c.1096_1104del, p.V366*, and c.1079C>T, p.S360F in OCA2 were novel. One of the four fetuses carried compound heterozygous mutation of TYR and became spontaneous abortion, the other three carried no mutations and appeared normal at birth. Conclusion In this study, specific clinical characteristics of OCA patients were described. Three novel pathogenic mutations were identified which will enrich the mutation spectrum of OCA, and the prenatal genetic screening in fetus at risk of OCA can provide vital information for genetic counseling.

Background: Milroy disease (MD) is rare and autosomal dominant resulting from mutations of the vascular endothelial growth factor receptor-3 (VEGFR-3 or FLT4), which leads to dysgenesis of the lymphatic system.Methods: Here we report a Chinese MD family with 2 affected members of two generations. We identified the mutation of c.3075G>A in one allele of FLT4 in Chinese population firstly. The father and child presented lymphedema under knees both. Unfortunately, the child was premature delivered for a car accident of the mother and then died of asphyxia. Then we gathered the tissue of the lower-limb from the child with permission from the parents and ethic committee. We stained the tissue with lymphatic marker D2-40 and hematoxylin-eosin to explore the histological changes. Afterwards, we compared the results with a normal child who unfortunately died of premature delivery also.Results: It is firstly identified the mutation of FLT4: c.3075G>A in Chinese population, and the mutation Inherited in the lineage. The histological evaluation indicated: (1) The number of lymphatic vessels decreased; (2) The morphology and structure of lymphatic vessels was abnormal. And what is added to our knowledge: (1) Capillary hyperemia and phlebectasia is severe; (2) Vascular malformations; (3) The number of vascular endothelial cells and vascular smooth muscle cells decreased; (4) Large sheets of epidermis desquamated; (5) The numbers of cutaneous appendages reduced in MD.Conclusions: Based on the new findings, we assume that mutation of FLT4 not only affect the lymphogenesis, but also the angiogenesis, and epidermis structure.

Difficulties related to storage and transport of currently available live oral rotavirus vaccines can have detrimental consequences on the efficacy of the vaccines. Thus, there is a great need for thermostable vaccines that can eliminate the necessity for cold chain storage or reconstitution before administration. In this study, we developed a dissolvable oral polymeric film comprised of a live attenuated thermostable tetravalent rhesus-human reassortant rotavirus vaccine (RRV-TV) powder and antacid (CaCO3). Immunogenicity and protective efficacy of the vaccine after buccal delivery was evaluated in the gnotobiotic pig model of human rotavirus (HRV) infection and diarrhea. Two doses of the vaccine were highly immunogenic and conferred strong protection against virus shedding and diarrhea upon challenge with a high dose of a virulent G1 HRV in gnotobiotic pigs. Those pigs vaccinated with the preserved film vaccine had significantly delayed onset of diarrhea; reduced duration and area under the curve of diarrhea; delayed onset of fecal virus shedding; and reduced duration and peak of fecal virus shedding titers compared to pigs in both the placebo and the reconstituted liquid oral RRV-TV vaccine groups. Associated with the strong protection, high titers of serum virus neutralization antibodies against each of the four RRV-TV mono-reassortants and G1 HRV-specific serum IgA and IgG antibodies, as well as intestinal IgA antibodies, were induced by the preserved film vaccine. These results demonstrated the effectiveness of our thermostable buccal film rotavirus vaccine and warrant further investigation into the promise of the novel technology in addressing drawbacks of the current live oral HRV vaccines.

Transitional cell carcinoma (TCC) of the ovary is a rare subtype of epithelial ovarian cancer. The present study reports the case of a 55-year-old patient from The Affiliated Tumor Hospital of Harbin Medical University (Harbin, Heilongjiang, China) who underwent successful surgery for recurrence of a TCC of the ovary with rectum metastases following the initial surgery and chemotherapy. Positron emission tomography/computed tomography (PET-CT) was used in the pre-operative detection of the tumor and the post-operative follow-up of the patient. To date, the patient has experienced 8 years of disease-free survival. The aim of the present study was to convey the good survival rate of the patient following recurrent TCC of the ovary, and the role of PET-CT in detection and follow-up, in order to aid in the future selection of appropriate diagnostic methods and therapies for this disease. [ABSTRACT FROM AUTHOR]

Human noroviruses (HuNoVs) are the leading causative agents of epidemic and sporadic acute gastroenteritis that affect people of all ages worldwide. However, very few dose–response studies have been carried out to determine the median infectious dose of HuNoVs. In this study, we evaluated the median infectious dose (ID50) and diarrhea dose (DD50) of the GII.4/2003 variant of HuNoV (Cin-2) in the gnotobiotic pig model of HuNoV infection and disease. Using various mathematical approaches (Reed–Muench, Dragstedt–Behrens, Spearman–Karber, logistic regression, and exponential and approximate beta-Poisson dose–response models), we estimated the ID50 and DD50 to be between 2400–3400 RNA copies, and 21,000–38,000 RNA copies, respectively. Contemporary dose–response models offer greater flexibility and accuracy in estimating ID50. In contrast to classical methods of endpoint estimation, dose–response modelling allows seamless analyses of data that may include inconsistent dilution factors between doses or numbers of subjects per dose group, or small numbers of subjects. Although this investigation is consistent with state-of-the-art ID50 determinations and offers an advancement in clinical data analysis, it is important to underscore that such analyses remain confounded by pathogen aggregation. Regardless, challenging virus strain ID50 determination is crucial for identifying the true infectiousness of HuNoVs and for the accurate evaluation of protective efficacies in pre-clinical studies of therapeutics, vaccines and other prophylactics using this reliable animal model.

Human rotavirus (HRV) is a leading cause of severe childhood diarrhea, and there is limited vaccine efficacy in the developing world. Neonatal gnotobiotic pigs consuming a prophylactic synbiotic combination of probiotics and rice bran (Pro+RB) did not exhibit HRV diarrhea after challenge. Multiple immune, gut barrier protective, and anti-diarrheal mechanisms contributed to the prophylactic efficacy of Pro+RB when compared to probiotics (Pro) alone. In order to understand the molecular signature associated with diarrheal protection by Pro+RB, a global non-targeted metabolomics approach was applied to investigate the large intestinal contents and serum of neonatal gnotobiotic pigs. The ultra-high performance liquid chromatography-tandem mass spectrometry platform revealed significantly different metabolites (293 in LIC and 84 in serum) in the pigs fed Pro+RB compared to Pro, and many of these metabolites were lipids and amino acid/peptides. Lipid metabolites included 2-oleoylglycerol (increased 293.40-fold in LIC of Pro+RB, p = 3.04E-10), which can modulate gastric emptying, andhyodeoxycholate (decreased 0.054-fold in the LIC of Pro+RB, p = 0.0040) that can increase colonic mucus production to improve intestinal barrier function. Amino acid metabolites included cysteine (decreased 0.40-fold in LIC, p = 0.033, and 0.62-fold in serum, p = 0.014 of Pro+RB), which has been found to reduce inflammation, lower oxidative stress and modulate mucosal immunity, and histamine (decreased 0.18-fold in LIC, p = 0.00030, of Pro+RB and 1.57-fold in serum, p = 0.043), which modulates local and systemic inflammatory responses as well as influences the enteric nervous system. Alterations to entire LIC and serum metabolic pathways further contributed to the anti-diarrheal and anti-viral activities of Pro+RB such as sphingolipid, mono/diacylglycerol, fatty acid, secondary bile acid, and polyamine metabolism. Sphingolipid and long chain fatty acid profiles influenced the ability of HRV to both infect and replicate within cells, suggesting that Pro+RB created a protective lipid profile that interferes with HRV activity. Polyamines act on enterocyte calcium-sensing receptors to modulate intracellular calcium levels, and may directly interfere with rotavirus replication. These results support that multiple host and probiotic metabolic networks, notably those involving lipid and amino acid/peptide metabolism, are important mechanisms through which Pro+RB protected against HRV diarrhea in neonatal gnotobiotic pigs.

Vaccine development and pathogenesis studies for human enterovirus 71 are limited by a lack of suitable animal models. Here, we report the development of a novel neonatal gnotobiotic pig model using the non-pig-adapted neurovirulent human enterovirus 71 strain BJ110, which has a C4 genotype. Porcine small intestinal epithelial cells, peripheral blood mononuclear cells and neural cells were infected in vitro. Oral and combined oral–nasal infection of 5-day-old neonatal gnotobiotic pigs with 5×108 fluorescence forming units (FFU) resulted in shedding up to 18 days post-infection, with viral titers in rectal swab samples peaking at 2.22×108 viral RNA copies/mL. Viral capsid proteins were detected in enterocytes within the small intestines on post-infection days (PIDs) 7 and 14. Additionally, viral RNA was detected in intestinal and extra-intestinal tissues, including the central nervous system, the lung and cardiac muscle. The infected neonatal gnotobiotic pigs developed fever, forelimb weakness, rapid breathing and some hand, foot and mouth disease symptoms. Flow cytometry analysis revealed increased frequencies of both CD4+ and CD8+ IFN-γ-producing T cells in the brain and the blood on PID 14, but reduced frequencies were observed in the lung. Furthermore, high titers of serum virus-neutralizing antibodies were generated in both orally and combined oral–nasally infected pigs on PIDs 7, 14, 21 and 28. Together, these results demonstrate that neonatal gnotobiotic pigs represent a novel animal model for evaluating vaccines for human enterovirus 71 and for understanding the pathogenesis of this virus and the associated immune responses.

Probiotics have been recognized as vaccine adjuvants and therapeutic agents to treat acute gastroenteritis in children. We previously showed that rice bran reduced human rotavirus diarrhea in gnotobiotic pigs. Human noroviruses (HuNoVs) are the major pathogens causing nonbacterial acute gastroenteritis worldwide. In this study, Lactobacillus rhamnosus GG (LGG) and Escherichia coli Nissle 1917 (EcN) were first screened for their ability to bind HuNoV P particles and virions derived from clinical samples containing HuNoV genotype GII.3 and GII.4, then the effects of LGG+EcN and rice bran on HuNoV infection and diarrhea were investigated using the gnotobiotic pig model. While LGG+EcN colonization inhibited HuNoV shedding, probiotic cocktail regimens in which rice bran feeding started 7 days prior to or 1 day after viral inoculation in the LGG+EcN colonized gnotobiotic pigs exhibited high protection against HuNoV diarrhea and shedding, characterized by significantly reduced incidence (89% versus 20%) and shorter mean duration of diarrhea (2.2 versus 0.2 days), as well as shorter mean duration of virus shedding (3.2 versus 1.0 days). In both probiotic cocktail groups, the diarrhea reduction rates were 78% compared with the control group, and diarrhea severity was reduced as demonstrated by the significantly lower cumulative fecal scores. The high protective efficacy of the probiotic cocktail regimens was attributed to stimulation of IFN-γ+ T cell responses, increased production of intestinal IgA and IgG, and maintenance of healthy intestinal morphology (manifested as longer villi compared with the control group). Therefore, probiotic cocktail regimens containing LGG+EcN and rice bran may represent highly efficacious strategies to prevent and treat HuNoV gastroenteritis, and potentially other human enteric pathogens.

This study aims to establish a human gut microbiota (HGM) transplanted gnotobiotic (Gn) pig model of human rotavirus (HRV) infection and diarrhea, and to verify the dose-effects of probiotics on HRV vaccine-induced immune responses. Our previous studies using the Gn pig model found that probiotics dose-dependently regulated both T cell and B cell immune responses induced by rotavirus vaccines. We generated the HGM transplanted neonatal Gn pigs through daily feeding of neonatal human fecal suspension to germ-free pigs for 3 days starting at 12 hours after birth. We found that attenuated HRV (AttHRV) vaccination conferred similar overall protection against rotavirus diarrhea and virus shedding in Gn pigs and HGM transplanted Gn pigs. HGM promoted the development of the neonatal immune system, as evidenced by the significantly enhanced IFN-γ producing T cell responses and reduction of regulatory T cells and their cytokine production in the AttHRV-vaccinated pigs. The higher dose Lactobacillus rhamnosus GG (LGG) feeding (14 doses, up to 109 colony-forming-unit [CFU]/dose) effectively increased the LGG counts in the HGM Gn pig intestinal contents and significantly enhanced HRV-specific IFN-γ producing T cell responses to the AttHRV vaccine. Lower dose LGG (9 doses, up to 106 CFU/dose) was ineffective. Neither doses of LGG significantly improved the protection rate, HRV-specific IgA and IgG antibody titers in serum, or IgA antibody titers in intestinal contents compared to the AttHRV vaccine alone, suggesting that an even higher dose of LGG is needed to overcome the influence of the microbiota to achieve the immunostimulatory effect in the HGM pigs. This study demonstrated that HGM Gn pig is an applicable animal model for studying immune responses to rotavirus vaccines and can be used for studying interventions (i.e., probiotics and prebiotics) that may enhance the immunogenicity and protective efficacy of vaccines through improving the gut microbiota.

Few-mode vertical-cavity surface-emitting lasers that can be controlled to emit certain modes and polarization states simply by changing the biased contacts are proposed and fabricated. By directly etching trenches in the p-doped distributed Bragg reflector, the upper mesa is separated into several submesas above the oxide layer. Individual contacts are then deposited. Each contact is used to control certain transverse modes with different polarization directions emitted from the corresponding submesa. These new devices can be seen as a prototype of compact laser sources in mode division multiplexing communications systems. [ABSTRACT FROM AUTHOR]

Post-transplant complications such as graft-versus-host disease and graft ischemia-reperfusion injury are crucial challenges in transplantation. Hydrogen can act as a potential antioxidant, playing a preventive role against post-transplant complications in animal models of multiple organ transplantation. Herein, the authors review the current literature regarding the effects of hydrogen on graft ischemia-reperfusion injury and graft-versus-host disease. Existing data on the effects of hydrogen on ischemia-reperfusion injury related to organ transplantation are specifically reviewed and coupled with further suggestions for future work. The reviewed studies showed that hydrogen (inhaled or dissolved in saline) improved the outcomes of organ transplantation by decreasing oxidative stress and inflammation at both the transplanted organ and the systemic levels. In conclusion, a substantial body of experimental evidence suggests that hydrogen can significantly alleviate transplantation-related ischemia-reperfusion injury and have a therapeutic effect on graft-versus-host disease, mainly via inhibition of inflammatory cytokine secretion and reduction of oxidative stress through several underlying mechanisms. Further animal experiments and preliminary human clinical trials will lay the foundation for hydrogen use as a drug in the clinic.

The emergence rate and vitality of maize are directly affected by the sowing depth, and the uniformity of this depth is an important performance indicator of a planter, while the effective soil surface height information acquisition is the prerequisite for ensuring the accuracy of sowing depth control. The soil surface height variation acquisition system of a precision corn planter often produces profiling errors when performing active profiling due to interference from ground debris. In this study, a multipoint soil surface height variation information acquisition system was investigated, which consists of a ranging sensor group and a microcontroller unit (MCU) using a data comparison and screening method. The structure and specifications of the ranging sensors were determined according to the soil surface height variation and debris size, and a nonessential profiling control program was developed. Performed tests on the information acquisition system indicated that the measurement accuracy of the system was 3 mm, and when advancing at a speed of 8 km/h, the accuracy of the profiling decision and the system stability were 97.1% and 94.1%, respectively, indicating that the system was capable of nonessential profile control. The designed ranging system could provide a reference for the design of a ground information acquisition system of precision planters with an active profiling mechanism. [ABSTRACT FROM AUTHOR]