Disruption of TNFα/TNFR1 function in resident skin cells impairs host immune response against cutaneous vaccinia virus infection

One strategy adopted by vaccinia virus (VV) to evade the host immune system is to encode homologs of TNF receptors (TNFR) that block TNFα function. The response to VV skin infection under conditions of TNFα deficiency, however, has not been reported. We found that TNFR1−/− mice developed larger primary lesions, numerous satellite lesions and higher skin virus levels after VV scarification. Following their recovery, these TNFR1−/− mice were fully protected against challenge with a lethal intranasal dose of VV, suggesting these mice developed an effective memory immune response. A functional systemic immune response of TNFR1−/− mice was further demonstrated by enhanced production of VV-specific IFNγ and VV-specific CD8+ T cells in spleens and draining lymph nodes. Interestingly, bone marrow (BM) reconstitution studies using WT BM in TNFR1−/− host mice, but not TNFR1−/− BM in WT host mice, reproduced the original results seen in TNFR1−/− mice, indicating that TNFR1 deficiency in resident skin cells, rather than hematopoietic cells, accounts for the impaired cutaneous immune response. Our data suggest that lack of TNFR1 leads to a skin-specific immune deficiency and that resident skin cells play a crucial role in mediating an optimal immune defense to VV cutaneous infection via TNFα/TNFR1 signaling

Preliminary safety assessment of oridonin in zebrafish

Context: Oridonin, isolated from the leaves of Isodon rubescens (Hemsl.) H.Hara (Lamiaceae), has good antitumor activity. However, its safety in vivo is still unclear. Objective: To investigate the preliminary safety of oridonin in zebrafish. Materials and methods: Embryo, larvae and adult zebrafish (n = 40) were used. Low, medium and high oridonin concentrations (100, 200 and 400 mg/L for embryo; 150, 300 and 600 mg/L for larvae; 200, 400 and 800 mg/L for adult zebrafish) and blank samples were administered. At specific stages of zebrafish development, spontaneous movement, heartbeat, hatching rate, etc., were recorded to assess the developmental effects of oridonin. VEGFA, VEGFR2 and VEGFR3 gene expression were also examined. Results: Low-dose oridonin increased spontaneous movement and hatching rate with median effective doses (ED50) of 115.17 mg/L at 24 h post-fertilization (hpf) and 188.59 mg/L at 54 hpf, but these values decreased at high doses with half maximal inhibitory concentrations (IC50) of 209.11 and 607.84 mg/L. Oridonin decreased heartbeat with IC50 of 285.76 mg/L at 48 hpf, and induced malformation at 120 hpf with half maximal effective concentration (EC50) of 411.94 mg/L. Oridonin also decreased body length with IC50 of 324.78 mg/L at 144 hpf, and increased swimming speed with ED50 of 190.98 mg/L at 120 hpf. The effects of oridonin on zebrafish embryo development may be attributed to the downregulation of VEGFR3 gene expression. Discussions and conclusions: Oridonin showed adverse effects at early stages of zebrafish development. We will perform additional studies on mechanism of oridonin based on VEGFR3

Significance of STAT3 in Immune Infiltration and Drug Response in Cancer

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor and regulates tumorigenesis. However, the functions of STAT3 in immune and drug response in cancer remain elusive. Hence, we aim to reveal the impact of STAT3 in immune infiltration and drug response comprehensively by bioinformatics analysis. The expression of STAT3 and its relationship with tumor stage were explored by Tumor Immune Estimation Resource (TIMER), Human Protein Altas (HPA), and UALCAN databases. The correlations between STAT3 and immune infiltration, gene markers of immune cells were analyzed by TIMER. Moreover, the association between STAT3 and drug response was evaluated by the Cancer Cell Line Encyclopedia (CCLE) and Cancer Therapeutics Response Portal (CTRP). The results suggested that the mRNA transcriptional level of STAT3 was lower in tumors than normal tissues and mostly unrelated to tumor stage. Besides, the protein expression of STAT3 decreased in colorectal and renal cancer compared with normal tissues. Importantly, STAT3 was correlated with immune infiltration and particularly regulated tumor-associated macrophage (TAM), M2 macrophage, T-helper 1 (Th1), follicular helper T (Treg), and exhausted T-cells. Remarkably, STAT3 was closely correlated with the response to specified inhibitors and natural compounds in cancer. Furthermore, the association between STAT3 and drug response was highly cell line type dependent. Significantly, the study provides thorough insight that STAT3 is associated with immunosuppression, as well as drug response in clinical treatment

Comparisons of Ramie and Corn Stover Silages: Effects on Chewing Activity, Rumen Fermentation, Microbiota and Methane Emissions in Goats

The study aimed to investigate the nutritional value of ramie (Boehmeria nivea) silage, and its consequences for chewing activity, rumen fermentation, and enteric methane (CH4) emissions in goats, by comparing it with corn stover (CS) silage. An in vitro ruminal experiment was firstly performed to investigate the substrate degradation and fermentation of CS and ramie silage. The ramie silage diet was formulated by replacing 60% of CS silage with ramie silage (dry matter (DM) basis). Eight female Xiangdong Black goats (a local breed in Southern China, 1 to 1.2 years of age) with BW of 21.0 ± 1.05 kg were used for this experiment and were randomly assigned to either one of the two dietary treatments in a cross-over design. The ramie silage had higher crude protein (CP) and ash content and lower hemicellulose content, together with decreased (p p p > 0.05), decreased (p p p p 4 concentration and enteric CH4 emissions (p p > 0.05) the population of bacteria, protozoa, and fungi; it increased the 16S rRNA gene copies of Ruminococcus flavefaciens (p p Lawsonibacter, Sedimentibacter, Saccharofermentans, Sediminibacterium, and Bifidobacterium (p 4 emissions in ruminants

Comparisons of Ramie and Corn Stover Silages: Effects on Chewing Activity, Rumen Fermentation, Microbiota and Methane Emissions in Goats

The study aimed to investigate the nutritional value of ramie (Boehmeria nivea) silage, and its consequences for chewing activity, rumen fermentation, and enteric methane (CH4) emissions in goats, by comparing it with corn stover (CS) silage. An in vitro ruminal experiment was firstly performed to investigate the substrate degradation and fermentation of CS and ramie silage. The ramie silage diet was formulated by replacing 60% of CS silage with ramie silage (dry matter (DM) basis). Eight female Xiangdong Black goats (a local breed in Southern China, 1 to 1.2 years of age) with BW of 21.0 ± 1.05 kg were used for this experiment and were randomly assigned to either one of the two dietary treatments in a cross-over design. The ramie silage had higher crude protein (CP) and ash content and lower hemicellulose content, together with decreased (p < 0.05) nutrient degradation and methane production and increased (p < 0.05) acetate molar percentage and acetate to propionate ratio through in vitro ruminal fermentation. Feeding the ramie silage diet did not alter feed intake (p > 0.05), decreased (p < 0.05) nutrient digestibility, and increased (p < 0.05) chewing activity and rumination activity, with reductions (p < 0.05) in eating activity and idle activity. Although feeding the ramie silage diet caused a greater (p < 0.05) molar percentage of acetate and lower molar percentage of propionate, it decreased the rumen-dissolved CH4 concentration and enteric CH4 emissions (p < 0.05). Feeding the ramie silage diet did not alter (p > 0.05) the population of bacteria, protozoa, and fungi; it increased the 16S rRNA gene copies of Ruminococcus flavefaciens (p < 0.05). Further 16SrRNA gene amplicon analysis indicated a distinct bacterial composition between the two treatments (p < 0.05). Feeding the ramie silage diet led to a lower abundance of genera Lawsonibacter, Sedimentibacter, Saccharofermentans, Sediminibacterium, and Bifidobacterium (p < 0.05). Ramie can be an alternative forage resource to stimulate chewing activity and reduce CH4 emissions in ruminants

Improved Antitumor Efficacy of Combined Vaccine Based on the Induced HUVECs and DC-CT26 Against Colorectal Carcinoma

Angiogenesis is essential for the development, growth, and metastasis of solid tumors. Vaccination with viable human umbilical vein endothelial cells (HUVECs) has been used for antitumor angiogenesis. However, the limited immune response induced by HUVECs hinders their clinical application. In the present study, we found that HUVECs induced by a tumor microenvironment using the supernatant of murine CT26 colorectal cancer cells exerted a better antiangiogenic effect than HUVECs themselves. The inhibitory effect on tumor growth in the induced HUVEC group was significantly better than that of the HUVEC group, and the induced HUVEC group showed a strong inhibition in CD31-positive microvessel density in the tumor tissues. Moreover, the level of anti-induced HUVEC membrane protein antibody in mouse serum was profoundly higher in the induced HUVEC group than in the HUVEC group. Based on this, the antitumor effect of a vaccine with a combination of induced HUVECs and dendritic cell-loading CT26 antigen (DC-CT26) was evaluated. Notably, the microvessel density of tumor specimens was significantly lower in the combined vaccine group than in the control groups. Furthermore, the spleen index, the killing effect of cytotoxic T lymphocytes (CTLs), and the concentration of interferon-γ in the serum were enhanced in the combined vaccine group. Based on these results, the combined vaccine targeting both tumor angiogenesis and tumor cells may be an attractive and effective cancer immunotherapy strategy

Annihilation of Nanoscale Inversion Domains in Nitrogen-Polar AlN under High-Temperature Annealing

Inversion domains (IDs) are common defects in N-polar III-nitride thin films grown on sapphire substrates. In this work, the atomic structure and lateral migration of the randomly distributed Al-polar nanoscale IDs in N-polar AlN films subjected to high-temperature thermal annealing are investigated. With the increasing annealing temperature and time, Al-polar AlN IDs gradually shrunk in sizes. The vertical stripes transformed into cone-shaped caps on top of the AlN columns and were completely removed at last. The annihilation of the IDs was explained in terms of the lateral migration of the inversion domain boundary (IDB) induced by the imbalance of the strain state on two sides of the IDB. This work clarifies the evolution mechanism of AlN IDs during high-temperature annealing, providing a promising approach in the realization of uniform-polar AlN template for the development of high-efficiency optoelectronic and electronic devices