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Abstract Dengue is emerging as the most important mosquito borne viral disease in the world. In mainland China, sporadic and large outbreaks of dengue illness caused by the four serotypes of dengue virus (DENV-1 to DENV-4) have been well documented. Guangdong province is the major affected area in China, and DENV-1 has dominantly circulated in Guangdong for a long time. In this study, a family cluster of DENV-3 infection in Guangzhou was described. Three cases were diagnosed as dengue fever based on clinical manifestation, serological and RT-PCR assays. Two DENV-3 strains were isolated in C6/36 cells and the complete genome sequences were determined. Phylogenetic analysis revealed that the new DENV-3 isolates from the family cluster were grouped within genotype III. Considering the fact that several DENV-3 strains within genotype V were also identified in Guangzhou in 2009, at least two genotypes of DENV-3 co-circulated in Guangzhou. Careful investigation and virological analysis should be warranted in the future.

Abstract Background Human enterovirus 71 (EV71) has emerged as a significant cause of acute encephalitis and deaths in young children. The clinical manifestations caused by EV71 varied from mild hand, foot and mouth disease to severe neurological complications and deaths, but its pathogenesis remains elusive. Antibody dependent enhancement (ADE) infection has been reported in various viruses and has been shown to contribute to disease severity. Results In this study, the presence of sub-neutralizing antibody was demonstrated to enhance EV71 infection in THP-1 cells and increase the mortality of EV71 infection in a suckling mouse model. Further, a secondary infection model was established to characterize the correlation between ADE and disease severity, and primary asymptomatic EV71 infection was shown to increase the mortality of the secondary EV71 infection in suckling mice. Conclusions Together, these in vitro and in vivo experiments strongly supported the hypothesis of ADE infection of EV71. The present findings indicate ADE might contribute to the pathogenesis of severe EV71 infection, and raise practical issues of vaccine development and antibody-based therapy.

Abstract Background Enterovirus 71 (EV71) is an etiologic agent of hand-foot-and-mouth disease (HFMD), and recent HFMD epidemics worldwide have been associated with a severe form of brainstem encephalitis associated with pulmonary edema and high case-fatality rates. EV71 contains a positive-sense single-stranded genome RNA of approximately 7400 bp in length which encodes a polyprotein with a single open reading frame (ORF), which is flanked by untranslated regions at both the 5' and 3' ends. Results A long distance RT-PCR assay was developed to amplify the full length genome cDNA of EV71 by using specific primes carrying a SP6 promoter. Then the in vitro synthesized RNA transcripts from the RT-PCR amplicons were then transfected into RD cells to produce the rescued virus. The rescued virus was further characterized by RT-PCR and indirect fluorescent-antibody (IFA) assay in comparison with the wild type virus. The rescued viruses were infectious on RD cells and neurovirulent when intracerebrally injected into suckling mice. Conclusions Thus, we established a rapid method to produce the infectious full length cDNA of EV71 directly from RNA preparations and specific mutations can be easily engineered into the rescued enterovirus genome by this method.

Abstract A duplex real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay was improved for simultaneous detection of highly pathogenic H5N1 avian influenza virus and pandemic H1N1 (2009) influenza virus, which is suitable for early diagnosis of influenza-like patients and for epidemiological surveillance. The sensitivity of this duplex real-time RT-PCR assay was 0.02 TCID50 (50% tissue culture infective dose) for H5N1 and 0.2 TCID50 for the pandemic H1N1, which was the same as that of each single-target RT-PCR for pandemic H1N1 and even more sensitive for H5N1 with the same primers and probes. No cross reactivity of detecting other subtype influenza viruses or respiratory tract viruses was observed. Two hundred and thirty-six clinical specimens were tested by comparing with single real-time RT-PCR and result from the duplex assay was 100% consistent with the results of single real-time RT-PCR and sequence analysis.

One of the emphases of this paper was the enhancement of drag prediction as well as the decomposition of drag into its physical components. The drag-prediction capability of the improved WBVS code for transonic flow about wing/body combination was verified by two approaches, code to code and code to experiment. The good agreements indicate that the wing body viscous has the capability to assess the aerodynamic performance in the supercritical wing design for civil transport aircraft. Another task of the present study was to redesign a supercritical wing for a new regional jet aircraft by employing the improved code as an analysis tool for wing/body combination, To accomplish this, a geometry-modifying technique was employed to gradually improve the upper-and lower-surface shapes of wing sections.

To the Editor: Hand, foot, and mouth disease (HFMD) is an acute viral infectious disease in infants and young children. However, since 2008, HFMD has emerged as a major public [...]

Excessive activation and proliferation of inflammatory cell and uncontrolled release of cytokines and chemokines, also known as cytokine storm, is considered to be the main cause of sepsis. Accumulating evidence has indicated that autophagy may play an important role in regulating immune response and controlling excessive inflammation. Recent studies have showed that minocycline has immunomodulatory effects on cytokine and chemokine production. It has also been reported that minocycline can induce autophagy, suggesting that autophagy may be involved in the process of minocycline regulating inflammation and immune response. However, the precise mechanism is unclear. In the present study, we used enzyme-linked immunosorbent assays (ELISA) to measure the production of cytokines following minocycline treatment of lipopolysaccharide- (LPS-) stimulated THP-1 cells. Western blotting analysis was performed to confirm autophagy and the mTOR signal pathway. Cell proliferation was measured by WST-1 cell proliferation assay. We demonstrated that LPS induced autophagy in a tumor necrosis factor- (TNF-) α-mediated manner, and simultaneously, LPS induced the release of TNF-α to trigger inflammation and activated mammalian target of rapamycin (mTOR) to potentiate cell proliferation. Minocycline, which induces autophagy by inhibiting mTOR, suppresses cytokine production and cell proliferation and protects THP-1 cells from LPS toxicity. Further study demonstrated that there might be an intimate crosstalk between the inhibitor kappa B kinase (IKK)/nuclear factor-kappa B (NF-κB) signaling pathway and autophagy flux in modification of inflammatory responses. In addition, rapamycin, the mTOR inhibitor, has cooperative effect with minocycline on suppression of TNF-α release and induction of autophagy by repressing mTOR. Our data brought a novel clue to evaluate minocycline using as a potential therapeutic medicine for sepsis. [ABSTRACT FROM AUTHOR]

Lung cancer is a common malignant cancer. Kirsten rat sarcoma oncogene (KRAS) mutations have been considered as a key driver for lung cancers. KRAS p.G12C mutations were most predominant in NSCLC which was comprised about 11–16% of lung adenocarcinomas (p.G12C accounts for 45–50% of mutant KRAS). But it is still not clear how the KRAS mutation triggers lung cancers. To study the molecular mechanisms of KRAS mutation in lung cancer. We analyzed the gene expression profiles of 156 KRAS mutation samples and other negative samples with two stage feature selection approach: (1) minimal Redundancy Maximal Relevance (mRMR) and (2) Incremental Feature Selection (IFS). At last, 41 predictive genes for KRAS mutation were identified and a KRAS mutation predictor was constructed. Its leave one out cross validation MCC was 0.879. Our results were helpful for understanding the roles of KRAS mutation in lung cancer. [ABSTRACT FROM AUTHOR]

Background In this study, we investigated the clinical significance of endobronchial ultrasound elastography for differentiating malignant and benign intrathoracic lymph nodes. Methods A meta-analysis was performed to evaluate the sensitivity and specificity of endobronchial ultrasound elastography in diagnosing intrathoracic lymph nodes. Publications before October 1, 2017, were included for analysis. Sensitivity, specificity, and other variables were pooled using the bivariate mixed-effects regression model. Results Seven studies met the inclusion criteria and were included. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio was 0.93 (95% confidence interval [CI], 0.85 to 0.97), 0.85 (95% CI, 0.78 to 0.90), 6.3 (95% CI, 4.2 to 9.2), 0.08 (95% CI, 0.04 to 0.18), and 74 (95% CI, 33 to 168), respectively. The summary receiver operating characteristic curve was 0.93 (95% CI, 0.91 to 0.95). Conclusions The results revealed endobronchial ultrasound elastography is a new technique with high sensitivity and specificity. It has a fine performance in diagnosing intrathoracic lymph nodes. [ABSTRACT FROM AUTHOR]

Issues are presented concerning the development of a numerical simulation for evaluating the flowfield around the wing-mounted nacelles of transport aircraft. A multiblock point-matched grid-generation approach is used.

Human adenovirus type 55 (HAdV-B55) represents a re-emerging human pathogen, and this adenovirus has been reported to cause outbreaks of acute respiratory diseases among military trainees and in school populations around the world. HAdV-B55 has been revealed to have evolved from homologous recombination between human adenovirus type 14 (HAdV-B14) and type 11 (HAdV-B11), but it presents different clinical manifestations from parental virus HAdV-B11. In the present paper, we report the distinct biological features of HAdV-B55 in comparison with the parental viruses HAdV-B11 and HAdV-B14 in cell cultures. The results showed that HAdV-B55 replicated well in various cells, similar to HAdV-B11 and HAdV-B14, but that its processing had a slower and milder cytopathic effect in the early stages of infection. Viral fitness analysis showed that HAdV-B55 exhibited higher levels of replication in respiratory cells than did either of its parents. Cytotoxicity and apoptosis analyses in A549 cells indicated that HAdV-B55 was less cytotoxic than HAdV-B11 and HAdV-B14 were and induced milder apoptosis. Finally, thermal sensitivity analysis revealed that HAdV-B55 exhibited lower thermostability than did either HAdV-B11 or HAdV-B14, which may limit the transmission of HAdV-B55 in humans. Together, the findings described here expand current knowledge about this re-emerging recombinant HAdV, shedding light on the pathogenesis of HAdV-B55. [ABSTRACT FROM AUTHOR]

Human enterovirus 71 (HEV71) has emerged as the leading cause of viral encephalitis in children in most Asian countries. The roles of host miRNAs in the neurological pathogenesis of HEV71 infection remain unknown. In the present study, comprehensive miRNA expression profiling in HEV71-infected human neuroblastoma SH-SY5Y cells was performed using the Affymetrix Gene Chip microarray assay and was validated using real-time RT-PCR. Among the 69 differentially expressed miRNAs, miR-1246 was specifically induced by HEV71 infection in human neuroblastoma cells, but inhibition of miR-1246 failed to affect HEV71 replication. Parallel mRNA and microRNA profiling based on the 35 K Human Genome Array identified 182 differentially regulated genes. Target prediction of miR-1246 and network modeling revealed 14 potential target genes involved in cell death and cell signaling. Finally, a combined analysis of the results from mRNA profiling and miR-1246 target predication led to the identification of disc-large homolog 3 (DLG3), which is associated with neurological disorders, for further validation. Sequence alignment and luciferase reporter assay showed that miR-1246 directly bound with the 3′-UTR of DLG3 gene. Down-regulation of miR-1246 induced significant changes in DLG3 expression levels in HEV71-infected SHSY5Y cells. Together, these results suggested that miR-1246 might play a role in neurological pathogenesis of HEV71 by regulating DLG3 gene in infected cells. These findings provide new information on the miRNA and mRNA profiles of HEV71-infected neuroblastoma cells. The biological significance of miR-1246 and DLG3 during the course of HEV71 infection deserves further investigation. [ABSTRACT FROM AUTHOR]

The worldwide expansion of four serotypes of dengue virus (DENV) poses great risk to global public health. Several vaccine candidates are under development. However, none is yet available for humans. In the present study, a novel strategy to produce tetravalent DENV vaccine based on envelope protein domain III (EDIII) was proposed. Tandem EDIIIs of two serotypes (type 1–2 and type 3–4) of DENV connected by a Gly-Ser linker ((Gly4Ser)3) were expressed in E. coli, respectively. Then, the two bivalent recombinant EDIIIs were equally mixed to form the tetravalent vaccine candidate MixBiEDIII, and used to immunize BALB/c mice. The results showed that specific IgG and neutralizing antibodies against all four serotypes of DENV were successfully induced in the MixBiEDIII employing Freund adjuvant immunized mice. Furthermore, in the suckling mouse model, sera from mice immunized with MixBiEDIII provided significant protection against four serotypes of DENV challenge. Our data demonstrated that MixBiEDIII, as a novel form of subunit vaccine candidates, might have the potential to be further developed as a tetravalent dengue vaccine in the near future. [ABSTRACT FROM AUTHOR]

Hand, foot, and mouth disease (HFMD) has caused significant morbidity and mortality in the Asia-Pacific regions, particularly in infants and young children. Coxsackievirus A16 (CA16) represents one of the major causative agents for HFMD, and the development of a safe and effective vaccine preventing CA16 infections has become a public health priority. In this study, we have developed a yeast system for the production of virus-like particles (VLPs) for CA16 by co-expressing P1 and 3CD of CA16 in Saccharomyces cerevisiae. These VLPs exhibit similarity in both protein composition and morphology as empty particles from CA16-infected cells. Immunization with CA16 VLPs in mice potently induced CA16-specific IgG and neutralization antibodies in a dose-dependent manner. IgG subclass isotyping revealed that IgG1 and lgG2b were dominantly induced by VLPs. Meanwhile, cytokine profiling demonstrated that immunization with VLPs significantly induced the secretion of IFN-γ, indicating potent cellular immune response. Furthermore, in vivo challenge experiments showed that passive immunization with anti-VLPs sera conferred full protection against lethal CA16 challenge in neonate mice. Taken together, our data demonstrated that VLPs produced in yeast might have the potential to be further developed as a vaccine candidate against HFMD. [ABSTRACT FROM AUTHOR]

Physiological and pathological changes to the anisotropic mechanical properties of skeletal muscle are still largely unknown, with only a few studies quantifying changes in vivo. This study used the noninvasive MR elastography (MRE) technique, in combination with diffusion tensor imaging (DTI), to measure shear modulus anisotropy in the human skeletal muscle in the lower leg. Shear modulus measurements parallel and perpendicular to the fibre direction were made in 10 healthy subjects in the medial gastrocnemius, soleus and tibialis anterior muscles. The results showed significant differences in the medial gastrocnemius ( μ| =0.86 ± 0.15 kPa; μ⊥ = 0.66 ± 0.19 kPa, P < 0.001), soleus ( μ| = 0.83 ± 0.22 kPa; μ⊥ = 0.65 ± 0.13 kPa, P < 0.001) and the tibialis anterior ( μ| = 0.78 ± 0.24 kPa; μ⊥ = 0.66 ± 0.16 kPa, P = 0.03) muscles, where the shear modulus measured in the direction parallel is greater than that measured in the direction perpendicular to the muscle fibres. No significant differences were measured across muscle groups. This study provides the first direct estimates of the anisotropic shear modulus in the triceps surae muscle group, and shows that the technique may be useful for the probing of mechanical anisotropy changes caused by disease, aging and injury. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Human enterovirus type 71 (EV71) is the major pathogen of hand-foot-and-mouth disease (HFMD) and has been associated with severe neurological disease and even death in infants and young children. The pathogenesis of EV71 infection in the human central nervous system remains unclear. In this study, human whole genome microarray was employed to perform transcriptome profiling in SH-SY5Y human neuroblastoma cells infected with EV71. The results indicated that EV71 infection lead to altered expression of 161 human mRNAs, including 74 up-regulated genes and 87 down-regulated genes. Bioinformatics analysis indicated the possible roles of the differentially regulated mRNAs in selected pathways, including cell cycle/proliferation, apoptosis, and cytokine/chemokine responses. Finally, the microarray results were validated using real-time RT-PCR with high identity. Overall, our results provided fundamental information regarding the host response to EV71 infection in human neuroblastoma cells, and this finding will help explain the pathogenesis of EV71 infection and virus-host interaction. [ABSTRACT FROM AUTHOR]

The emerging human enterovirus 71 (EV71) represents a growing threat to public health, and no vaccine or specific antiviral is currently available. Human intravenous immunoglobulin (IVIG) is clinical used in treating severe EV71 infections. However, the discovery of antibody dependent enhancement (ADE) of EV71 infection illustrates the complex roles of antibody in controlling EV71 infection. In this study, to identify the distinct role of each IgG subclass on neutralization and enhancement of EV71 infection, different lots of pharmaceutical IVIG preparations manufactured from Chinese donors were used for IgG subclass fractionation by pH gradient elution with the protein A-conjugated affinity column. The neutralization and ADE capacities on EV71 infection of each purified IgG subclass were then assayed, respectively. The neutralizing activity of human IVIG is mainly mediated by IgG1 subclass and to less extent by IgG2 subclass. Interestingly, IgG3 fraction did not have neutralizing activity but enhanced EV71 infection in vitro. These results revealed the different roles of human IgG subclasses on EV71 infection, which is of critical importance for the rational design of immunotherapy and vaccines against severe EV71 diseases. [ABSTRACT FROM AUTHOR]

Background: Viral self-replicating sub-genomic replicons represent a powerful tool for studying viral genome replication, antiviral screening and chimeric vaccine development. Many kinds of flavivirus replicons have been developed with broad applications. Findings: The replicon system of JEV live vaccine strain SA14-14-2 was successfully developed in this study. Two kinds of replicons that express enhanced green fluorescent protein (EGFP) and Renilla luciferase (R.luc) were constructed under the control of SP6 promoter, respectively. Robust EGFP and R.luc signals could be detected in the replicon-transfected BHK-21 cells. Furthermore, the potential effects of selected amino acids in the C-terminal of envelope protein on replication were characterized using the replicon system. Conclusions: Our results provide a useful platform not only for the study of JEV replication, but also for antiviral screening and chimeric vaccine development. [ABSTRACT FROM AUTHOR]

Gene therapy provides a promising approach to curing diabetes. However, an effective route for islet-specific targeting has yet to be established. Toward this end, the pancreatic blood circulation system in Balb/c mice was determined by the injection of rhodamine-containing beads. The efficiency of islet targeting was then measured by the injection of adenoviral vectors carrying a green fluorescence gene via the celiac trunk (C.T.). The results showed that >95% of islets and about 60% of β cells within the pancreatic body and tail could be labeled 3 days after surgery. α-Cell labeling was not as efficient, whereas labeling of nonendocrine tissues was barely detectable. For proof of principle, adenoviral vectors carrying a Sirtuin transgene were injected similarly to test the islet protection effect in the streptozotocin (STZ)-induced type 1 diabetic model. The results demonstrated that overexpression of Sirtuin in STZ-treated mice reduced the level of β-cell death and extent of glucose intolerance. This study reports on efficient islet-specific targeting by using adenoviral injection. This procedure could be invaluable to the treatment of diabetes and the study of islet biology. [ABSTRACT FROM AUTHOR]

Background: Patients with endotracheal intubation or tracheostomy are subject to benign tracheal stenosis (TS), for which current therapies are unsatisfactory. We conducted a preliminary investigation of drugs and drug combinations for the prevention and treatment of TS in a rabbit model. Methods: Fifty-four rabbits were apportioned into nine groups according to treatment: sham-operated control; untreated TS model; amikacin; budesonide; erythromycin; penicillin; amikacin + budesonide; erythromycin + budesonide; and penicillin + budesonide. TS was induced by abrasion during surgery. The drugs were applied for 7 days before and 10 days after the surgery. Rabbits were killed on the eleventh day. Tracheal specimens were processed for determining alterations in the thicknesses of tracheal epithelium and lamina propria via hematoxylin and eosin. The tracheal mRNA (assessed by real-time quantitative polymerase chain reaction) expressions of the following fibrotic-related factors were determined: transforming growth factor-β1 (TGF- β1), collagen type I (COL1A1), collagen type III (COL3A1), and interleukin-17 (IL-17). The protein levels of TGF-β1, COL1A1, and COL3A1 were determined through immunohistochemistry and integrated optical densities. Results: Compared with all other groups, the untreated TS model had significantly thicker tracheal epithelium and lamina propria, and higher mRNA and protein levels of all targeted fibrotic factors. The mRNA and protein levels of the targeted fibrotic factors in all the drug-treated groups were lower than those of the untreated TS model, and differences were most significant in the erythromycin + budesonide group. Conclusions: Erythromycin combined with budesonide may reduce inflammation and modify fibrosis progression in TS after tracheal injury.

Rabies remains a major public health concern in many developing countries. The precise neuropathogenesis of rabies is unknown, though it is hypothesized to be due to neuronal death or dysfunction. Mice that received intranasal inoculation of an attenuated rabies virus (RABV) strain HEP-Flury exhibited subtle clinical signs, and eventually recovered, which is different from the fatal encephalitis caused by the virulent RABV strain CVS-11. To understand the neuropathogenesis of rabies and the mechanisms of viral clearance, we applied RNA sequencing (RNA-Seq) to compare the brain transcriptomes of normal mice versus HEP-Flury or CVS-11 intranasally inoculated mice. Our results revealed that both RABV strains altered positively and negatively the expression levels of many host genes, including genes associated with innate and adaptive immunity, inflammation and cell death. It is found that HEP-Flury infection can activate the innate immunity earlier through the RIG-I/MDA-5 signaling, and the innate immunity pre-activated by HEP-Flury or Newcastle disease virus (NDV) infection can effectively prevent the CVS-11 to invade central nervous system (CNS), but fails to clear the CVS-11 after its entry into the CNS. In addition, following CVS-11 infection, genes implicated in cell adhesion, blood vessel morphogenesis and coagulation were mainly up-regulated, while the genes involved in synaptic transmission and ion transport were significantly down-regulated. On the other hand, several genes involved in the MHC class II-mediated antigen presentation pathway were activated to a greater extent after the HEP-Flury infection as compared with the CVS-11 infection suggesting that the collaboration of CD4+ T cells and MHC class II-mediated antigen presentation is critical for the clearance of attenuated RABV from the CNS. The differentially regulated genes reported here are likely to include potential therapeutic targets for expanding the postexposure treatment window for RABV infection.

The activation of neuromast supporting cell (SC) proliferation leads to hair cell (HC) regeneration in the zebrafish lateral line. Epigenetic mechanisms have been reported that regulate HC regeneration in the zebrafish lateral line, but the role of H3K9me2 in HC regeneration after HC loss remains poorly understood. In this study, we focused on the role of H3K9me2 in HC regeneration following neomycin-induced HC loss. To investigate the effects of H3K9me2 in HC regeneration, we took advantage of the G9a/GLP-specific inhibitor BIX01294 that significantly reduces the dimethylation of H3K9. We found that BIX01294 significantly reduced HC regeneration after neomycin-induced HC loss in the zebrafish lateral line. BIX01294 also significantly reduced the proliferation of neuromast cells and led to fewer SCs in the lateral line. In situ hybridization showed that BIX01294 significantly down-regulated the Wnt and Fgf signaling pathways, which resulted in reduced SC proliferation and HC regeneration in the neuromasts of the lateral line. Altogether, our results suggest that down-regulation of H3K9me2 significantly decreases HC regeneration after neomycin-induced HC loss through inactivation of the Wnt/β-catenin and Fgf signaling pathways. Thus H3K9me2 plays a critical role in HC regeneration.

Metabolic disease subclinical hypothyroidism (SCH) is closely associated with depression-like behavior both in human and animal studies, and our previous studies have identified the antidepressant effect of resveratrol (RES) in stressed rat model. The aim of this study was to investigate whether RES would manifest an antidepressant effect in SCH rat model and explore the possible mechanism. A SCH rat model was induced by hemi-thyroid electrocauterization, after which the model rats in the RES and LT4 groups received a daily intragastric injection of RES at the dose of 15 mg/kg or LT4 at the dose of 60 μg/kg for 16 days, respectively. The rats’ plasma concentrations of thyroid hormones were measured. Behavioral performance and hypothalamic-pituitary-adrenal (HPA) activity were evaluated. The protein expression levels of the Wnt/β-catenin in the hippocampus were detected by western blot. The results showed that RES treatment down-regulated the elevated plasma thyroid stimulating hormone (TSH) concentration and the hypothalamic mRNA expression of thyrotropin releasing hormone (TRH) in the SCH rats. RES-treated rats showed increased rearing frequency and distance in the OFT, increased sucrose preference in the SPT, and decreased immobility in the FST compared with SCH rats. The ratio of the adrenal gland weight to body weight, the plasma corticosterone levels and the hypothalamic CRH mRNA expression were reduced in the RES-treated rats. Moreover, RES treatment up-regulated the relative ratio of phosphorylated-GSK3β (p-GSK3β)/GSK3β and protein levels of p-GSK3β, cyclinD1 and c-myc, while down-regulating the relative ratio of phosphorylated-β-catenin (p-β-catenin)/β-catenin and expression of GSK3β in the hippocampus. These findings suggest that RES exerts anxiolytic- and antidepressant-like effect in SCH rats by down-regulating hyperactivity of the HPA axis and regulating both the HPT axis and the Wnt/β-catenin pathway.

Preeclampsia (PE) and its complications have become the leading cause of maternal and fetal morbidity and mortality in the world. And the development of PE is still barely predictable and thus challenging to prevent and manage clinically. Oxidative stress contributes to the development of the disease. Our previous study demonstrated that exogenous Alpha-1 antitrypsin (AAT) played a cytoprotective role in vascular endothelial cell by suppressing oxidative stress. In this study, we aim to investigate whether AAT contributes to the development of PE, and to identify the mechanism behind these effects. We found that AAT levels were significantly decreased in placenta tissues from women with PE compared that of healthy women. Notably, we demonstrate that AAT injection is able to relieve the high blood pressure and reduce urine protein levels in a dose-dependent manner in PE mice. In addition, our results showed that AAT injection exhibited an anti-oxidative stress role by significantly reducing PE mediated-upregulation of ROS, MMP9 and MDA, and increasing the levels of SOD, eNOS and GPx with increased dosage of AAT. Furthermore, we found that AAT injection inactivated PE mediated activation of PAK/STAT1/p38 signaling. These findings were confirmed in human samples. In conclusion, our study suggests that exogenous AAT injection increases the antioxidants and suppresses oxidative stress, and subsequent prevention of PE development through inactivation of STAT1/p38 signaling. Thus, AAT would become a potential strategy for PE therapy.

Wheat plants are very sensitive to high temperature stress during grain filling. Effects of heat priming applied to the first generation on tolerance of the successive generation to post-anthesis high temperature stress were investigated. Compared with the progeny of non-heat primed plants (NH), the progeny of heat-primed plants (PH) possessed higher grain yield, leaf photosynthesis and activities of antioxidant enzymes and lower cell membrane damage under high temperature stress. In the transcriptome profile, 1430 probes showed obvious difference in expression between PH and NH. These genes were related to signal transduction, transcription, energy, defense, and protein destination and storage, respectively. The gene encoding the lysine-specific histone demethylase 1 (LSD1) which was involved in histone demethylation related to epigenetic modification was up-regulated in the PH compared with NH. The proteome analysis indicated that the proteins involved in photosynthesis, energy production and protein destination and storage were up-regulated in the PH compared with NH. In short, thermos-tolerance was induced through heritable epigenetic alternation and signaling transduction, both processes further triggered prompt modifications of defense related responses in anti-oxidation, transcription, energy production, and protein destination and storage in the progeny of the primed plants under high temperature stress. It was concluded that trans-generation thermo-tolerance was induced by heat priming in the first generation, and this might be an effective measure to cope with severe high-temperature stresses during key growth stages in wheat production.