Pathogenic human coronavirus infections, such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV), cause high morbidity and mortality 1,2 . Recently, a severe pneumonia-associated respiratory syndrome caused by a new coronavirus was reported at December 2019 (2019-nCoV) in the city Wuhan, Hubei province, China [3][4][5] , which was also named as pneumonia-associated respiratory syndrome (PARS) 6 . Up to 9th of February 2020, at least 37, 251 cases have been reported with 812 fatal cases according to the report from China CDC. However, the immune mechanism that potential orchestrated acute mortality from patients of 2019-nCoV is still unknown. Here we show that after the 2019-nCoV infection, CD4 + T lymphocytes are rapidly activated to become pathogenic T helper (Th) 1 cells and generate GM-CSF etc. The cytokines environment induces inflammatory CD14 + CD16 + monocytes with high expression of IL-6 and accelerates the inflammation. These aberrant and excessive immune cells may enter the pulmonary circulation in huge numbers and play an immune damaging role to causing lung functional disability and quick mortality. Our results demonstrate that excessive non-effective host immune responses by pathogenic T cells and inflammatory monocytes may associate with severe lung pathology. Therefore, we suggest that monoclonal antibody that targets the GM-CSF or interleukin 6 receptor may potentially curb immunopathology caused by 2019-nCoV and consequently win more time for virus clearance.Coronavirus, including SARS and MERS, has caused two large-scale pandemic in the last two decades 1,2 . Although viral evasion of host immune responses and virus-induced cytopathic effects are believed to be critical in disease severity, studies from humans who died of SARS and animal models suggested that an excessive and aberrant host immune response resulting in an exuberant immunopathology and lethal disease [7][8][9] . Similarly, patients infected with 2019-nCoV, that have been reported recently, have increased plasma concentrations of preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

BackgroundSub-acute ruminal acidosis (SARA) is a well-recognized digestive disorder found in particular in well-managed dairy herds. SARA can result in increased flow of fermentable substrates to the hindgut, which can increase the production of volatile fatty acids, alter the structure of the microbial community, and have a negative effect on animal health and productivity. However, little is known about changes in the structure of the microbial community and its relationship with fatty acids during SARA. Four cannulated primiparous (60 to 90 day in milk) Holstein dairy cows were assigned to two diets in a 2 × 2 crossover experimental design. The diets contained (on a dry matter basis): 40% (control diet, COD) and 70% (SARA induction diet, SAID) concentrate feeds. Samples of ruminal fluid and feces were collected on day 12, 15, 17 and 21 of the treatment period, and the pH was measured in the ruminal and fecal samples; the fecal microbiota was determined by pyrosequencing analysis of the V1–V3 region of amplified 16S ribosomal RNA (16S rRNA).ResultsSAID decreased ruminal and fecal pH and increased the propionate, butyrate and total volatile fatty acid (TVFA) concentration in feces when compared with the COD. A barcoded DNA pyrosequencing method was used to generate 2116 16S operational taxonomic units (OTUs). A total of 11 phyla were observed, distributed amongst all cattle on both diets; however, only 5 phyla were observed in all animals regardless of dietary treatment, and considerable animal to animal variation was revealed. The average abundance and its range of the 5 phyla were as follows: Firmicutes (63.7%, 29.1–84.1%), Proteobacteria (18.3%, 3.4–46.9%), Actinobacteria (6.8%, 0.4–39.9%), Bacteroidetes (7.6%, 2.2–17.7%) and Tenericutes (1.6%, 0.3–3%). Feeding the SAID resulted in significant shifts in the structure of the fecal microbial community when compared with the traditional COD. Among the 2116 OTUs detected in the present study, 88 OTUs were affected significantly by diet; and the proportion of these OTUs was 20.6% and 17.4% among the total number of sequences, respectively. Among the OTUs affected, the predominant species, including OTU2140 (G: Turicibacter), OTU1695 (G: Stenotrophomonas) and OTU8143 (F: Lachnospiraceae), were increased, while the abundance of OTU1266 (S: Solibacillus silvestris) and OTU2022 (G: Lysinibacillus) was reduced in the SAID group compared with the COD. Further, our results indicated that the fecal volatile fatty acid (VFA) concentrations were significantly related to presence of some certain species of Bacteroidetes and Firmicutes in the feces.ConclusionsThis is, to our knowledge, the first study that has used barcoded DNA pyrosequencing to survey the fecal microbiome of dairy cattle during SARA. Our results suggest that particular bacteria and their metabolites in the feces appear to contribute to differences in host health between those given SAID and traditional COD feeding. A better understanding of these microbial populations will allow for improved nutrient managem...

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Purpose This study aimed to understand the prognostic value of integrin β1 expression in head and neck squamous cell carcinoma (HNSCC) and the mechanism underlying its association with metastatic HNSCC. Experimental Design Archival HNSCC tissues including 99 non-metastatic primary tumors and 101 metastatic primary tumors were examined for the association of integrin β1 expression with metastasis and disease prognosis by appropriate statistical methods. Fluorescence activated cell sorting was used to separate the integrin β1high/+ cell population from the integrin β1low/− population in HNSCC cell lines. These two populations and integrin β1 shRNA knock-down HNSCC cells were examined for the effect of integrin β1 on invasion in vitro and on lymph node and lung metastases in a xenograft mouse model. Expression and activation of matrix metalloproteinases (MMPs) were examined by zymography. Results Statistical analysis showed that integrin β1 expression was significantly higher in the metastatic primary tumors than in the non-metastatic tumors (42.6% vs 24.8%, p<0.0001 and p<0.0001 by univariate and multivariate analyses, respectively). In patients with lymph node metastasis, integrin β1 expression was inversely correlated with overall survival (p=0.035). The integrin β1 knock-down or integrin β1low/− HNSCC cells showed a significant reduction in lymph node and lung metastases in vivo (p<0.001 and p<0.05, respectively). Significantly reduced matrigel invasion capability was also found in integrin β1 knock-down or integrin β1low/− HNSCC cells (p< 0.01). Finally, zymography results showed integrin β1 affected HNSCC invasion by regulating MMP-2 activation. Conclusion These findings indicate that integrin β1 has a major impact on HNSCC prognosis through its regulation of metastasis.

The results indicate that the ITB composed of nHAC/CSH and dBMPC may represent a useful strategy for the clinical reconstruction of bone defects around immediate implantation. However, further investigation is needed involving the use of human BMPC as well as possible use of stem cells.

Systemic delivery of siRNA to solid tumors remains challenging. In this study, we investigated the systemic delivery of an siRNA-nanoparticle targeting ribonucleotide reductase subunit M2 (RRM2), and evaluated its intratumoral kinetics, efficacy and mechanism of action. Knockdown of RRM2 by an RNAi mechanism strongly inhibited cell growth in head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) cell lines. In a mouse xenograft model of HNSCC, a single intravenous injection led to the accumulation of intact nanoparticles in the tumor that disassembled over a period of at least 3 days, leading to target gene knockdown lasting at least 10 days. A four-dose schedule of siRNA-nanoparticle delivering RRM2 siRNA targeted to HNSCC tumors significantly reduced tumor progression by suppressing cell proliferation and inducing apoptosis. These results show promise for the use of RRM2 siRNA-based therapy for HNSCC and possibly NSCLC.

BackgroundThe toll-like receptor (TLR)4-interleukin1β (IL1β) signaling pathway is involved in the monosodium urate (MSU)-mediated inflammation. The aim of this present study was to determine whether the TLR4 gene rs2149356 SNP is associated with gouty arthritis (GA) susceptibility and whether rs2149356 SNP impacts the TLR4-IL1β signaling pathway molecules expression.Methods and FindingsThe rs2149356 SNP was detected in 459 GA patients and 669 control subjects (containing 459 healthy and 210 hyperuricemic subjects). Peripheral blood mononuclear cells (PBMCs) TLR4 mRNA and serum IL1β were measured in different genotype carriers, and correlations between TLR4 gene SNP and TLR4 mRNA, IL1β were investigated. The frequencies of the genotype and allele were significantly different between the GA and control groups (P<0.01, respectively). The TT genotype was associated with a significantly increased risk of GA (OR = 1.88); this finding was not influenced by making adjustments for the components of possible confounders (adjusted OR = 1.96). TLR4 mRNA and IL1β were significantly increased in the TT genotype from acute GA patients (P<0.05, respectively), and lipids were significantly different among three genotypes in the GA patients (P<0.05, respectively).ConclusionsThe TLR4 gene rs2149356 SNP might be associated with GA susceptibility, and might participate in regulating immune, inflammation and lipid metabolism. Further studies are required to confirm these findings.

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