Impaired influenza A virus replication by the host restriction factor SAMHD1 which inhibited by PA-mediated dephosphorylation of the host transcription factor IRF3.

BACKGROUND: Influenza A virus (IAV) can cause severe and life-threatening illness in humans and animals. Therefore, it is important to search for host antiviral proteins and elucidate their antiviral mechanisms for the development of potential treatments. As a part of human innate immunity, host restriction factors can inhibit the replication of viruses, among which SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) can restrict the replication of viruses, such as HIV and enterovirus EV71. Viruses also developed countermeasures in the arms race with their hosts. There are few reports about whether SAMHD1 has a restriction effect on IAV. METHODS: To investigate the impact of IAV infection on SAMHD1 expression in A549 cells, we infected A549 cells with a varying multiplicity of infection (MOI) of IAV and collected cell samples at different time points for WB and RT-qPCR analysis to detect viral protein and SAMHD1 levels. The virus replication level in the cell culture supernatant was determined using TCID50 assay. Luciferase assay was used to reveal that H5N1 virus polymerase acidic protein (PA) affected the activity of the SAMHD1 promoter. To assess the antiviral capacity of SAMHD1, we generated a knockdown and overexpressed cell line for detecting H5N1 replication. RESULTS: In this study, we observed that SAMHD1 can restrict the intracellular replication of H5N1 and that the H5N1 viral protein PA can downregulate the expression of SAMHD1 by affecting SAMHD1 transcriptional promoter activity. We also found that SAMHD1's ability to restrict H5N1 is related to phosphorylation at 592-tyrosine. CONCLUSIONS: In conclusion, we found that SAMHD1 may affect the replication of IAVs as a host restriction factor and be countered by PA. Furthermore, SAMHD1 may be a potential target for developing antiviral drugs.

The genome of sheep ked (Melophagus ovinus) reveals potential mechanisms underlying reproduction and narrower ecological niches.

BACKGROUND: Melophagus ovinus is considered to be of great veterinary health significance. However, little is known about the information on genetic mechanisms of the specific biological characteristics and novel methods for controlling M. ovinus. RESULTS: In total, the de novo genome assembly of M. ovinus was 188.421 Mb in size (330 scaffolds, N50 Length: 10.666 Mb), with a mean GC content of 27.74%. A total of 13,372 protein-coding genes were functionally annotated. Phylogenetic analysis indicated that the diversification of M. ovinus and Glossina fuscipes took place 72.76 Mya within the Late Cretaceous. Gene family expansion and contraction analysis revealed that M. ovinus has 65 rapidly-evolving families (26 expansion and 39 contractions) mainly involved DNA metabolic activity, transposases activity, odorant receptor 59a/67d-like, IMD domain-containing protein, and cuticle protein, etc. The universal and tightly conserved list of milk protein orthologues has been assembled from the genome of M. ovinus. Contractions and losses of sensory receptors and vision-associated Rhodopsin genes were significant in M. ovinus, which indicate that the M. ovinus has narrower ecological niches. CONCLUSIONS: We sequenced, assembled, and annotated the whole genome sequence of M. ovinus, and launches into the preliminary genetic mechanisms analysis of the adaptive evolution characteristics of M. ovinus. These resources will provide insights to understand the biological underpinnings of this parasite and the disease control strategies.

Characterization of a reassortant H11N9 subtype avian influenza virus isolated from spot-billed duck in China.

H11N9 viruses in wild birds might have provided the NA gene of human H7N9 virus in early 2013 in China, which evolved with highly pathogenic strains in 2017 and caused severe fatalities. To investigate the prevalence and evolution of the H11N9 influenza viruses, 16,781 samples were collected and analyzed during 2016-2020. As a result, a novel strain of influenza A (H11N9) virus with several characteristics that increase virulence was isolated. This strain had reduced pathogenicity in chicken and mice and was able to replicate in mice without prior adaptation. Phylogenetic analyses showed that it was a sextuple-reassortant virus of H11N9, H3N8, H3N6, H7N9, H9N2, and H6N8 viruses present in China, similar to the H11N9 strains in Japan and Korea during the same period. This was the H11N9 strain isolated from China most recently, which add a record to viruses in wild birds. This study identified a new H11N9 reassortant in a wild bird with key mutation contributing to virulence. Therefore, comprehensive surveillance and enhanced biosecurity precautions are particularly important for the prediction and prevention of potential pandemics resulting from reassortant viruses with continuous evolution and expanding geographic distributions.

Infection of Trichinella spiralis Affects the Reproductive Capacity of ICR/CD-1 Male Mice by Reducing the Urine Pheromone Contents and Sperm Quality.

Female mice can discriminate the urinary odors of male mice due to their olfactory acuity. Parasitic infection or subclinical infection can decrease the odor attractiveness of male mice and finally lead to aversion or avoidance responses in odor selection for female mice. Trichinella spiralis is a kind of tissue-parasitizing nematode that causes trichinellosis, a zoonotic parasitic disease that spreads throughout the world. However, the reproductive injury caused by Trichinella spiralis infection was not fully revealed. In this study, we explored the effect of Trichinella spiralis infection on the reproductive capacity in ICR/CD-1 male mice. We identified eight volatile compounds in urine by GC-MS analysis, and the results indicated that the contents of dimethyl sulfone, Z-7-tetradecen-1-ol, 6-Hydroxy-6-methyl-3-heptanone and (S)-2-sec-butyl-4,5-dihydrothiazole were significantly downregulated after parasitic infection, which might lead to the reduction of attractiveness of male mice urine to females. On the other hand, parasitic infection decreased sperm quality and downregulated the expression levels of Herc4, Ipo11, and Mrto4, and these genes were strongly related to spermatogenesis. In summary, this study revealed that the reproductive injury caused by Trichinella spiralis infection in ICR/CD-1 male mice could be associated with a decrease in urine pheromone content and sperm quality.

DEC1 promotes progression of Helicobacter pylori-positive gastric cancer by regulating Akt/NF-κB pathway.

Helicobacter pylori (H. pylori) infection plays a crucial role in the initiation and progression of gastric cancer (GC). Differentiated embryo-chondrocyte expressed gene 1 (DEC1) is dysregulated in some cancers and may regulate cell proliferation in specific contexts. Of note, DEC1 is emerging as one of the important factors regulating cellular responses in microenvironment. However, the triggers and precise regulation mechanism for DEC1 during inflammatory carcinoma transformation of GC are unclear. In this study, we identified DEC1 was upregulated in both H. pylori-infected gastric tissues and GC cells. DEC1 expression was positively associated with H. pylori infection status and GC progression. DEC1-positive expression indicated a poorer prognosis in H. pylori-positive GC. DEC1 was required for H. pylori-induced GC cells proliferation. Mechanistically, H. pylori infection significantly activated Akt/NF-κB signal pathway and this induction depend on DEC1 expression level in GC cells. Importantly, their interaction pathway was further verified by H. pylori-positive gastritis mice model. Taken together, our findings identified a novel function of DEC1 in GC. H. pylori infection induce DEC1 expression, and which leading to the progression of GC through activating Akt/ NF-κB signalling pathway. Blocking DEC1/Akt/NF-κB, therefore, presents a promising novel therapeutic strategy for H. pylori-positive GC.

Statins Are Associated with Improved Survival of Patients with Gastric Cancer: A Systematic Review and Meta-Analysis.

Statins are associated with gastric cancer (GC) risk. The present study aimed to clarify the efficacy of statins on the overall survival (OS) benefits in patients with GC. Publications were retrieved from PubMed, Embase, and the Cochrane Library as of April 2022. Data from the eligible cohort, case-control studies, and randomized control trials (RCTs) were extracted for the meta-analysis. Hazard ratio (HR) and 95% confidence intervals (CI) were used to assess the association between statins users and OS in GC patients. Subgroup analysis was performed based on the study design (prospective vs. retrospective). A total of 6 studies encompassing 5693 GC patients were included. Statins added to the standard treatment prolonged the patient's OS outcome (HR (95% CI): 0.72 (0.53-0.97), p = 0.032; I 2 = 88.0%, p heterogeneity < 0.001). A prospective study did not find any statistically significant difference in OS between statins users vs. nonstatin users (HR (95% CI): 0.92 (0.68-1.26), p = 0.614; I 2 = 11.7%, p heterogeneity = 0.322), whereas the retrospective studies showed prolonged OS in statins users (HR (95% CI): 0.63 (0.42-0.961), p = 0.032; I 2 = 94.6%, p heterogeneity < 0.001). Statin users had significantly improved OS compared to nonstatin users in GC treatment. This long-term survival benefit was only observed in the pooled analysis of retrospective studies but not in prospective studies.

lncRNA DLEU2 promotes gastric cancer progression through ETS2 via targeting miR-30a-5p.

BACKGROUND: Gastric cancer (GC) remains an important cancer worldwide. Further understanding of the molecular mechanisms of gastric carcinogenesis will enhance the diagnosis and treatment of GC. METHODS: The expression of DLEU2 and ETS2 was analyzed in several GC cell lines using GEPIA online analyze, qRT-PCR and immunohistochemistry. The biological behavior of GC cells was detected by CCK8, clone formation, transwell, wound healing, western blot, and flow cytometry assay. More in-depth mechanisms were studied. RESULTS: DLEU2 was significantly up-regulated in GC tissues and cell lines. The expression of DLEU2 was significantly associated with pathological grading and TNM stage of GC patients. Furthermore, knockdown of DLEU2 inhibited the proliferation, migration, and invasion of AGS and MKN-45 cells, while overexpression of DLEU2 promoted the proliferation, migration, and invasion of HGC-27 cells. MiR-30a-5p could directly bind to the 3' UTR region of ETS2. Moreover, DLEU2 bound to miR-30a-5p through the same binding site, which facilitated the expression of ETS2. Knockdown of DLEU2 reduced the protein level of intracellular ETS2 and inhibited AKT phosphorylation, while overexpression of DLEU2 induced the expression of ETS2 and the phosphorylation of AKT. ETS2 was highly expressed in GC tissues. The expression of ETS2 was significantly associated with age, pathological grading, and TNM stage. ETS2 overexpression promoted cell proliferation and migration of AGS and MKN-45 cells. Furthermore, ETS2 overexpression rescued cell proliferation and migration inhibition induced by DLEU2 down-regulation and miR-30a-5p up-regulation in AGS and MKN-45 cells. CONCLUSIONS: DLEU2 is a potential molecular target for GC treatment.

Lethal infection caused by Tetratrichomonas gallinarum in black swans (Cygnus atratus).

BACKGROUND: Tetratrichomonas gallinarum is parasitic protozoa with a wide host range. However, its lethal infection is rare reported. CASE PRESENTATION: Here, we described the first lethal cases of T. gallinarum infection in black swans in China. Five black swans died within a week in succession without obvious symptoms except mild diarrhea. At necropsy, severe lesions were observed in caeca with thickened caecal walls and hemorrhages in the mucosa. A large number of moving trophozoites were found in the contents of the cecum by microscopic examination. The livers were enlarged with multiple bleeding spots on the surface. Histopathology of the livers showed mononuclear cell infiltration and moderate hyperplasia of fibrous tissue. The histopathology of the cecum showed that the villi of the cecum were edematous. Finally, the presence of T. gallinarum was determined by specific PCR andin-situ hybridization assay. Additionally, common pathogens that can cause similar symptoms were excluded. CONCLUSIONS: The death of the black swan was caused by T. gallinarum, suggesting that the parasite might be a new threat to the Cygnus birds.

ceRNA network construction and comparison of gastric cancer with or without Helicobacter pylori infection.

Gastric cancer (GC) is a lethal disease, and among its variety of etiological factors, Helicobacter pylori (H. pylori) infection is the strongest risk factor. However, the genetic and molecular mechanisms underlying H. pylori-related GC need further elucidation. We investigated the competing endogenous RNA (ceRNA) network differences between H. pylori (+) and H. pylori (-) GC. The long noncoding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA) expression data from 32 adjacent noncancerous samples and 18 H. pylori (+) and 141 H. pylori (-) stomach adenocarcinoma samples were downloaded from the TCGA database. After construction of lncRNA-miRNA-mRNA ceRNA networks of H. pylori (+) and H. pylori (-) GC, Panther and Kobas databases were used to analyze the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Finally, survival analysis was used to discover the key genes. In H. pylori (+) GC, we identified a total of 1,419 lncRNAs, 82 miRNAs, and 2,501 mRNAs with differentially expressed profiles. In H. pylori (-) GC, 2,225 lncRNAs, 130 miRNAs, and 3,146 mRNAs were differentially expressed. Furthermore, three unique pathways (cytokine-cytokine receptor interaction, HIF-1 signaling pathway, and Wnt signaling pathway) were enriched in H. pylori (+) GC. According to the overall survival analysis, three lncRNAs (AP002478.1, LINC00111, and LINC00313) and two mRNAs (MYB and COL1A1) functioned as prognostic biomarkers for patients with H. pylori (+) GC. In conclusion, our study has identified the differences in ceRNA regulatory networks between H. pylori (+) and H. pylori (-) GC and provides a rich candidate reservoir for future studies.

Forkhead box C1 promotes metastasis and invasion of non-small cell lung cancer by binding directly to the lysyl oxidase promoter.

Increasing evidence indicates that human forkhead box C1 (FOXC1) plays important roles in tumor development and metastasis. However, the underlying molecular mechanism of FOXC1 in non-small cell lung cancer (NSCLC) metastasis remains unclear. Here, we identified FOXC1 as an independent prognostic factor in NSCLC and showed clear biological implications in invasion and metastasis. FOXC1 overexpression enhanced the proliferation, migration and invasion of NSCLC cells, whereas FOXC1 silencing impaired the effects both in vitro and in vivo. Importantly, we found a positive correlation between FOXC1 expression and lysyl oxidase (LOX) expression in NSCLC cells and patient samples. Downregulation of LOX or LOX activity inhibition in NSCLC cells inhibited the FOXC1-driven effects on cellular migration and invasion. Xenograft models showed that inhibition of LOX activity by ß-aminopropionitrile monofumarate decreased the number of lung metastases. Mechanistically, we demonstrated a novel FOXC1-LOX mechanism that was involved in the invasion and metastasis of NSCLC. Dual-luciferase assay and ChIP identified that FOXC1 bound directly in the LOX promoter region and activated its transcription. Collectively, the present study offered new insight into FOXC1 in the mediation of NSCLC metastasis through interaction with the LOX promoter and further revealed that targeted inhibition of LOX protein activity could prevent lung metastasis in murine xenograft models. These data implicated FOXC1 as a potential therapeutic strategy for the treatment of NSCLC metastasis.

Overexpression of CD59 inhibits apoptosis of T-acute lymphoblastic leukemia via AKT/Notch1 signaling pathway.

BACKGROUND: T-acute lymphoblastic leukemia (T-ALL) was a hematological malignancy characterized by the accumulation of immature T cells in bone marrow and peripheral blood. In this study, we tried to explore the physiological role of CD59 in T-ALL. METHODS: In this study, we collected the bone marrow samples from 17 T-ALL patients and 38 healthy participants to find differences in CD59 expression patterns. Then, CD59 was over-expressed in T-ALL cell line Jurkat, and its biological functions were detected. In addition, in order to understand the active site of CD59, the Trp40 was mutated. Further, we constructed a mouse model by transplanting Jurkat cells into the nude mice to verify the function of CD59 in vitro. At last, mechanism studies were performed by western blot. RESULTS: We found that the proportion of T lymphocytes expressing CD59 in bone marrow of T-ALL patients was significantly higher than that of healthy individuals. Then, we found that the overexpression of CD59 in Jurkat cells was beneficial to the cell survival by inhibiting apoptosis and promoting IL-2 secretion. In this process, Trp40 of CD59 was a key functional site. Further, the high expression of CD59 inhibited apoptosis of bone marrow and peripheral blood cells, and promoted IL-2 secretion in mouse model. At last, mechanism studies showed that the activation of AKT, STAT5 and Notch1 signaling pathways in Jurkat cells, may be involved in the regulation of apoptosis by CD59; and mutation in the Trp40 affect the interaction of CD59 with these signaling pathways. CONCLUSIONS: In conclusion, CD59 inhibited apoptosis of T-ALL by regulating AKT/Notch1 signaling pathway, providing a new perspective for the treatment of T-ALL.

Genes and transcription factors related to the adverse effects of maternal type I diabetes mellitus on fetal development.

PURPOSE: Maternal type I diabetes mellitus (T1DM) increases the risk of adverse pregnancy outcomes, but the corresponding mechanism is unclear. This study aims to investigate the mechanism underlying the adverse pregnancy outcomes of maternal T1DM. METHODS: Gene expression microarray (GSE51546) was down-loaded from the Gene Expression Omnibus. This dataset included 12 umbilical cord samples from the newborns of T1DM mothers (T1DM group, N = six) and non-diabetic mothers (control group, N = six). RESULTS: Consequently, 1051 differentially expressed genes (DEGs) were found between the two groups. The up-regulated DEGs enriched in 30 KEGG pathways. HLA-DPA1, HLA-DMA, HLA-DMB, HLA-DQA1, HLA-DQA2 and HLA-DRA enriched in "Type I diabetes mellitus". This pathway was strongly related to 14 pathways, most of which were associated with diseases. Then, a protein-protein interaction network was constructed, and 45 potential key DEGs were identified. The 45 DEGs enriched in pathways such as "Rheumatoid arthritis", "Chemokine signaling pathway" and "Cytokine-cytokine receptor interaction" (e.g. CXCL12 and CCL5). Transcription factors (TFs) of key DEGs were predicted, and a TF-DEG regulatory network was constructed. CONCLUSIONS: Some genes (e.g. CXCL12 and CCL5) and their TFs were significantly and abnormally regulated in the umbilical cord tissue from the pregnancies of T1DM mothers compared to that from non-T1DM mothers.

The protective effect of kaempferol on heart via the regulation of Nrf2, NF-κß, and PI3K/Akt/GSK-3ß signaling pathways in isoproterenol-induced heart failure in diabetic rats.

This study was designed to delineate the effect of kaempferol (KF) on heart failure (HF) in diabetic rats. Streptozotocin-induced male diabetic rats received KF orally at 10 and 20 mg/kg for 42 consecutive days. In last 2 days of the experimental period, isoproterenol was subcutaneously injected at 85 mg/kg to induce HF. The hearts were processed for hemodynamic, biochemical, molecular, and histological investigations. Systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure were elevated in KF-treated HF-induced diabetic rats. Moreover, KF treatment resulted in decreased fasting blood glucose and glycosylated hemoglobin levels with increased serum insulin levels. Besides, serum cardiac injury markers like troponin-I, creatine kinase-muscle/brain, lactate dehydrogenase, and brain natriuretic peptide levels were significantly reduced in KF treatment. KF treatment has shown decrease in cardiac heme oxygenase-1, nuclear factor erythroid 2-related factor 2 (Nrf-2), and γ-glutamylcysteine synthetase with increased Keap1 mRNA levels. The cardioprotection of KF was improved by inhibition of apoptosis via blocking phosphorylation of Akt/glycogen synthase kinase (GSK)-3ß and p38 mitogen-activated protein-kinase/extracellular signal-regulated kinases signaling pathways in HF-induced diabetic rats. Moreover, reduced cardiac apoptosis in KF treatment was confirmed by decreased terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) positive cells, histopathological changes in HF-induced diabetic rats. Therefore, the cardioprotective effect of KF is attributed to the regulation of Nrf2, nuclear factor kappa-light-chain-enhancer of activated B cells, and Akt/GSK-3ß signaling pathways in HF-induced diabetic rats.

Ginkgolide B ameliorates oxidized low-density lipoprotein-induced endothelial dysfunction via modulating Lectin-like ox-LDL-receptor-1 and NADPH oxidase 4 expression and inflammatory cascades.

The current study was undertaken to delineate the protective effect of Ginkgolide B, a phyto-constituent from Ginkgo biloba, on oxidized (ox)-LDL-induced endothelial dysfunction via targeting Lectin-like ox-LDL-receptor-1 (LOX-1), NADPH oxidase 4 (NOX-4), and other inflammatory proteins. Our results have shown that Ginkgolide B downregulated the expression of LOX-1 in ox-LDL-treated human umbilical vein endothelial cells (HUVECs) and RAW246.7 murine macrophages which ultimately resulted in decreased cholesterol deposits in HUVECs and RAW264.7. Moreover, Ginkgolide B suppressed the enhanced NOX4 expression, which was associated with attenuation of ROS generation in ox-LDL-stimulated HUVECs and RAW264.7 cells. Ginkgolide B also ameliorated the endothelial dysfunction by inhibiting the augmented expression of monocyte chemotactic protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in ox-LDL-activated HUVECs. Furthermore, the enhanced expression of many inflammatory cytokines in ox-LDL-induced RAW264.7 macrophages, both at transcription and protein level, was significantly down-regulated after Ginkgolide B treatment. Ginkgolide B also illustrated atheroprotective property via suppressing the augmented expression of matrix metalloproteinase-1 and cyclooxygenase-2 in ox-LDL-stimulated RAW264.7 macrophages. In summary, our study has established that Ginkgolide B ameliorates endothelial dysfunction via targeting LOX-1, NOX-4, MCP-1, ICAM-1, and VCAM-1 along with the markers associated with inflammatory cascades and thus could be promoted as a valuable therapeutic agent in prevention and management of atherosclerosis.

Effect of Enteromorpha polysaccharides on gut-lung axis in mice infected with H5N1 influenza virus.

Enteromorpha polysaccharides (EPPs) have been reported to have antiviral and anti-inflammatory properties. To explore the effect of EPPs on H5N1-infected mice, mice were pretreated with EPPs before being infected with the H5N1 influenza virus intranasally. H5N1 infection resulted in body-weight loss, pulmonary and intestinal damage, and an imbalance of gut microbiota in mice. As a result of the inclusion of EPPs, the body weight of mice recovered and pathological damage to the lung and intestine was reduced. EPPs also diminished inflammation by drastically lowering the expression of proinflammatory cytokines in lungs and intestines. H5N1 infection reduced bacterial diversity, and the abundance of pathogenic bacteria such as Desulfovibrio increased. However, the beneficial bacteria Alistipes rebounded in the groups which received EPPs before the infection. The modulation of the gut-lung axis may be related to the mechanism of EPPs in antiviral and anti-inflammatory responses. EPPs have shown potential in protecting the host from the influenza A virus infection.

Enterococcus faecalis provides protection during scavenging in carrion crow ( Corvus corone).

The gut microbiota significantly influences host physiology and provides essential ecosystem services. While diet can affect the composition of the gut microbiota, the gut microbiota can also help the host adapt to specific dietary habits. The carrion crow ( Corvus corone), an urban facultative scavenger bird, hosts an abundance of pathogens due to its scavenging behavior. Despite this, carrion crows infrequently exhibit illness, a phenomenon related to their unique physiological adaptability. At present, however, the role of the gut microbiota remains incompletely understood. In this study, we performed a comparative analysis using 16S rRNA amplicon sequencing technology to assess colonic content in carrion crows and 16 other bird species with different diets in Beijing, China. Our findings revealed that the dominant gut microbiota in carrion crows was primarily composed of Proteobacteria (75.51%) and Firmicutes (22.37%). Significant differences were observed in the relative abundance of Enterococcus faecalis among groups, highlighting its potential as a biomarker of facultative scavenging behavior in carrion crows. Subsequently, E. faecalis isolated from carrion crows was transplanted into model mice to explore the protective effects of this bacterial community against Salmonella enterica infection. Results showed that E. faecalis down-regulated the expression of pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), and interleukin 6 (IL-6), prevented S. enterica colonization, and regulated the composition of gut microbiota in mice, thereby modulating the host's immune regulatory capacity. Therefore, E. faecalis exerts immunoregulatory and anti-pathogenic functions in carrion crows engaged in scavenging behavior, offering a representative case of how the gut microbiota contributes to the protection of hosts with specialized diets.

Therapeutic role of miR-19a/b protection from influenza virus infection in patients with coronary heart disease.

Patients with pre-existing medical conditions are at a heightened risk of contracting severe acute respiratory syndrome (SARS), SARS-CoV-2, and influenza viruses, which can result in more severe disease progression and increased mortality rates. Nevertheless, the molecular mechanism behind this phenomenon remained largely unidentified. Here, we found that microRNA-19a/b (miR-19a/b), which is a constituent of the miR-17-92 cluster, exhibits reduced expression levels in patients with coronary heart disease in comparison to healthy individuals. The downregulation of miR-19a/b has been observed to facilitate the replication of influenza A virus (IAV). miR-19a/b can effectively inhibit IAV replication by targeting and reducing the expression of SOCS1, as observed in cell-based and coronary heart disease mouse models. This mechanism leads to the alleviation of the inhibitory effect of SOCS1 on the interferon (IFN)/JAK/STAT signaling pathway. The results indicate that the IAV employs a unique approach to inhibit the host's type I IFN-mediated antiviral immune responses by decreasing miR-19a/b. These findings provide additional insights into the underlying mechanisms of susceptibility to flu in patients with coronary heart disease. miR-19a/b can be considered as a preventative/therapy strategy for patients with coronary heart disease against influenza virus infection.

Loss of cytoskeletal transport during egress critically attenuates ectromelia virus infection in vivo.

Egress of wrapped virus (WV) to the cell periphery following vaccinia virus (VACV) replication is dependent on interactions with the microtubule motor complex kinesin-1 and is mediated by the viral envelope protein A36. Here we report that ectromelia virus (ECTV), a related orthopoxvirus and the causative agent of mousepox, encodes an A36 homologue (ECTV-Mos-142) that is highly conserved despite a large truncation at the C terminus. Deleting the ECTV A36R gene leads to a reduction in the number of extracellular viruses formed and to a reduced plaque size, consistent with a role in microtubule transport. We also observed a complete loss of virus-associated actin comets, another phenotype dependent on A36 expression during VACV infection. ECTV ΔA36R was severely attenuated when used to infect the normally susceptible BALB/c mouse strain. ECTV ΔA36R replication and spread from the draining lymph nodes to the liver and spleen were significantly reduced in BALB/c mice and in Rag-1-deficient mice, which lack T and B lymphocytes. The dramatic reduction in ECTV ΔA36R titers early during the course of infection was not associated with an augmented immune response. Taken together, these findings demonstrate the critical role that subcellular transport pathways play not only in orthopoxvirus infection in an in vitro context but also during orthopoxvirus pathogenesis in a natural host. Furthermore, despite the attenuation of the mutant virus, we found that infection nonetheless induced protective immunity in mice, suggesting that orthopoxvirus vectors with A36 deletions may be considered another safe vaccine alternative.

Dexamethasone induces osteogenesis via regulation of hedgehog signalling molecules in rat mesenchymal stem cells.

PURPOSE: Hedgehog signalling plays an important role during the development of tissues and organs, including bone and limb. Dexamethasone (DEX), a synthetic and widely used glucocorticoid, affects osteogenesis of bone marrow mesenchymal stem cells (MSCs), while the signalling pathway by which DEX affects osteoblast differentiation remains obscure. This study aimed to investigate expressions of hedgehog signalling molecules Shh, Ihh and Gli1 during DEX-induced osteogenesis of rat MSCs in vitro. METHODS: DEX promoted osteoblast differentiation of MSCs at 10(-8) mol/L from seven days to 21 days, demonstrated by enhancing alkaline phosphatase (ALP) activity and osteoblast-associated marker type I collagen expression during osteoblastic differentiation. Gene and protein expressions of hedgehog signalling molecules, Shh, Ihh and Gli1 were tested by RT-PCR and western blot analysis during osteoblast differentiation. RESULTS: Shh expression was increased compared to the control while Ihh and Gli1 expressions were decreased on both mRNA and protein level during DEX-induced osteoblast differentiation of MSCs from seven days to 21 days. Altogether, these data demonstrate that DEX can enhance Shh expression via a Gli1-independent mechanism during osteoblast differentiation of MSCs. CONCLUSIONS: These results indicate that different patterns of hedgehog signalling are involved in DEX-induced osteogenesis and these findings provide insights into the mechanistic link between glucocorticoid-induced osteogenesis and hedgehog signalling pathway.

[Genetic polymorphisms of 19 STR loci in Shandong Han population].

OBJECTIVE: To investigate the genetic polymorphisms of 19 STR Loci in Shandong Han population in order to provide the genetic data for paternity testing. METHODS: The genotypes of 205 unrelated individuals in Shandong Han population were typed by Goldeneye 20A kit to get the allele frequencies and population genetic parameters of 19 STR loci. Four kits, Identifiler kit, SinoFiler kit, PowerPlex 16 kit, and Goldeneye 20A kit, were compared with each other and used in the analysis of a special paternity test case. RESULTS: The population genetic parameters of 19 STR loci in Shandong Han Population were obtained. The cumulative discrimination power (CDP) and cumulative probability of exclusion (CPE) ranked from high to low were Goldeneye 20A kit, SinoFiler kit, PowerPlex 16 kit and Identifiler kit, respectively. As duo case, the result of the real case showed that Identifiler kit had no excluding loci, and none of the SinoFiler kit, PowerPlex 16 kit or Goldeneye 20A kit could exclude fatherhood. CONCLUSION: Compared with Identifiler kit, SinoFiler kit, and PowerPlex 16 kit, Goldeneye 20A kit shows the higher efficiency than the others, but is not completely satisfied for duo cases.