Spred2 controls the severity of Concanavalin A-induced liver damage by limiting interferon-gamma production by CD4(+) and CD8(+) T cells

Introduction: Mitogen-activated protein kinases (MAPKs) are involved in T cell-mediated liver damage. However, the inhibitory mechanism(s) that controls T cell-mediated liver damage remains unknown. Objectives: We investigated whether Spred2 (Sprouty-related, EVH1 domain-containing protein 2) that negatively regulates ERK-MAPK pathway has a biological impact on T cell-mediated liver damage by using a murine model. Methods: We induced hepatotoxicity in genetically engineered mice by intravenously injecting Concanavalin A (Con A) and analyzed the mechanisms using serum chemistry, histology, ELISA, qRT-PCR, Western blotting and flow cytometry. Results: Spred2-deficient mice (Spred2(-/-)) developed more sever liver damage than wild-type (WT) mice with increased interferon-gamma (IFNy) production. Hepatic ERK phosphorylation was enhanced in Spred2(-/-) mice, and pretreatment of Spred2(-/-) mice with the MAPK/ERK inhibitor U0126 markedly inhibited the liver damage and reduced IFN gamma production. Neutralization of IFNy abolished the damage with decreased hepatic Stat1 activation in Spred2(-/-) mice. IFN gamma was mainly produced from CD4(+) and CD8(+) T cells, and their depletion decreased liver damage and IFN gamma production. Transplantation of CD4(+) and/or CD8(+) T cells from Spred2(-/-) mice into RAG1(-/-) mice deficient in both T and B cells caused more severe liver damage than those from WT mice. Hepatic expression of T cell attractants, CXCL9 and CXCL10, was augmented in Spred2(-/-) mice as compared to WT mice. Conversely, liver damage, IFN gamma production and the recruitment of CD4(+) and CD8(+) T cells in livers after Con A challenge were lower in Spred2 transgenic mice, and Spred2-overexpressing CD4(+) and CD8(+) T cells produced lower levels of IFN gamma than WT cells upon stimulation with Con A in vitro. Conclusion: We demonstrated, for the first time, that Spred2 functions as an endogenous regulator of T cell IFNy production and Spred2-mediated inhibition of ERK-MAPK pathway may be an effective remedy for T cell-dependent liver damage

COVID-19 antibody responses in individuals with natural immunity and with vaccination-induced immunity:a systematic review and meta-analysis

Background: The COVID-19 pandemic has caused a large mortality and morbidity burden globally. For individuals, a strong immune response is the most effective means to block SARS-CoV-2 infection. To inform clinical case management of COVID-19, development of improved vaccines, and public health policy, a better understanding of antibody response dynamics and duration following SARS-CoV-2 infection and after vaccination is imperatively needed. Methods: We systematically analyzed antibody response rates in naturally infected COVID-19 patients and vaccinated individuals. Specifically, we searched all published and pre-published literature between 1 December 2019 and 31 July 2023 using MeSH terms and “all field” terms comprising “COVID-19” or “SARS-CoV-2,” and “antibody response” or “immunity response” or “humoral immune.” We included experimental and observational studies that provided antibody positivity rates following natural COVID-19 infection or vaccination. A total of 44 studies reporting antibody positivity rate changes over time were included. Results: The meta-analysis showed that within the first week after COVID-19 symptom onset/diagnosis or vaccination, antibody response rates in vaccinated individuals were lower than those in infected patients (p &lt; 0.01), but no significant difference was observed from the second week to the sixth month. IgG, IgA, and IgM positivity rates increased during the first 3 weeks; thereafter, IgG positivity rates were maintained at a relatively high level, while the IgM seroconversion rate dropped. Conclusions: Antibody production following vaccination might not occur as quickly or strongly as after natural infection, and the IgM antibody response was less persistent than the IgG response.</p

Internal kinematics of groups of galaxies in the Sloan Digital Sky Survey data release 7

We present measurements of the velocity dispersion profile (VDP) for galaxy groups in the final data release of the Sloan Digital Sky Survey (SDSS). For groups of given mass we estimate the redshift-space cross-correlation function (CCF) with respect to a reference galaxy sample, xi(r_p, pi), the projected CCF, w_p(r_p), and the real-space CCF, xi(r). The VDP is then extracted from the redshift distortion in xi(r_p, pi), by comparing xi(r_p, pi) with xi(r). We find that the velocity dispersion (VD) within virial radius (R_200) shows a roughly flat profile, with a slight increase at radii below ~0.3 R_200 for high mass systems. The average VD within the virial radius, sigma_v, is a strongly increasing function of central galaxy mass. We apply the same methodology to N-body simulations with the concordance Lambda cold dark matter cosmology but different values of the density fluctuation parameter sigma_8, and we compare the results to the SDSS results. We show that the sigma_v-M_* relation from the data provides stringent constraints on both sigma_8 and sigma_ms, the dispersion in log M_* of central galaxies at fixed halo mass. Our best-fitting model suggests sigma_8 = 0.86 +/- 0.03 and sigma_ms = 0.16 +/- 0.03. The slightly higher value of sigma_8 compared to the WMAP7 result might be due to a smaller matter density parameter assumed in our simulations. Our VD measurements also provide a direct measure of the dark matter halo mass for central galaxies of different luminosities and masses, in good agreement with the results obtained by Mandelbaum et al. (2006) from stacking the gravitational lensing signals of the SDSS galaxies.Comment: 17 pages, 10 figures, 1 table, accepted for publication in ApJ, text slightly changed, abstract substantially shortened, two new panels added to Figs. 2 and 3 showing w_p and VDP as functions of r_p/R_200 instead of r_

Preparation of Pullulan Polysaccharide/Thermoplastic Polyurethane Coaxial Electrospinning Film with Oregano Essential Oil as Core Material and Its Preservative Effect on the Quality of Lateolabrax japonicus Fillets

The use of plant essential oils as an antibacterial agent for food packaging has become a new trend. In order to obtain biodegradable films for the preservation of aquatic products, coaxial electrospinning films were prepared by electrospinning using the antimicrobial preservative oregano essential oil (OEO) or its main components as core material, pullulan (Pul) as film-forming substrate, and thermoplastic polyurethane (TPU) as shell material and were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy. Also, its thermal stability, physicochemical properties was determined as well as the release performance of the antimicrobial preservative from the coaxial electrospinning films and its efficacy in preserving the quality of refrigerated Lateolabrax japonicus fillets. The results showed that OEO was effectively encapsulated in the electrospinning fibers, improving the micromorphology, water vapor barrier properties and wettability and significantly reducing the tensile strength (TS), and swelling degree (SD) of the film (P < 0.05), but not changing the thermal stability of the film significantly. The fibers inside the film had a coaxial core-shell structure, and the release behavior of the preservative was a complex coupling of disintegration and dissolution, resulting in controlled OEO release for up to 60 h. In addition, the film effectively inhibited the growth of microorganisms, and thus had excellent preservative effect on fresh L. japonicus fillets. It effectively delayed the deterioration of the smell, texture and apparent quality of the fillets, and extended the shelf life from 8 to 12 d. This study can provide a theoretical basis and technical support for the development of biodegradable antibacterial packaging materials based on biological antibacterial agents

Mortality and Attrition Rates within the First Year of Antiretroviral Therapy Initiation among People Living with HIV in Guangxi, China: An Observational Cohort Study

Objective. To assess the mortality and attrition rates within the first year of antiretroviral therapy (ART) initiation among people living with human immunodeficiency virus (PLHIV) in rural Guangxi, China. Design. Observational cohort study. Setting. The core treatment indicators and data were collected with standard and essential procedures as per the Free ART Manual guidelines across all the rural health care centers of Guangxi. Participants. 58,115 PLHIV who were under ART were included in the study. Interventions. The data collected included sociodemographic characteristics that consist of age, sex, marital status, route of HIV transmission, CD4 cell count before ART, initial ART regimen, level of ART site, and year of ART initiation. Primary and Secondary Outcome Measures. Mortality and attrition rate following ART initiation. Results. The average mortality rate was 5.94 deaths, and 17.52 attritions per 100 person-years within the first year of ART initiation among PLHIV. The mortality rate was higher among intravenous drug users (Adjusted Hazard Ratio (AHR) 1.27, 95% Confidence Interval (CI) 1.14-1.43), prefecture as a level of ART site (AHR 1.14, 95% CI 1.02-1.28), and county as the level of ART site (AHR 2.12, 95% CI 1.90-2.37). Attrition was higher among intravenous drug users (AHR 1.87, 95% CI 1.75-2.00), the first-line ART containing AZT (AHR 1.09, 95% CI 1.03-1.16), and first-line ART containing LVP/r (AHR 1.34, 95% CI 1.23-1.46). Conclusion. The mortality and attrition rates were both at the highest level in the first year of post-ART; continued improvement in the quality of HIV treatment and care is needed

Genetic features of a pollen-part mutation suggest an inhibitory role for the Antirrhinum pollen self-incompatibility determinant

Abstract Self-incompatibility (SI), an important barrier to inbreeding in flowering plants, is controlled in many species by a single polymorphic S-locus. In the Solanaceae, two tightly linked S-locus genes, S-RNase and SLF (S-locus F-box)/SFB (S-haplotype-specific F-box), control SI expression in pistil and pollen, respectively. The pollen S-determinant appears to function to inhibit all but self S-RNase in the Solanaceae, but its genetic function in the closely-related Plantaginaceae remains equivocal. We have employed transposon mutagenesis in a member of the Plantaginaceae (Antirrhinum) to generate a pollen-part SI-breakdown mutant Pma1 (Pollen-part mutation in Antirrhinum1). Molecular genetic analyses showed that an extra telocentric chromosome containing AhSLF-S 1 is present in its self-compatible but not in its SI progeny. Furthermore, analysis of the effects of selection revealed positive selection acting on both SLFs and SFBs, but with a stronger purifying selection on SLFs. Taken together, our results suggest an inhibitor role of the pollen S in the Plantaginaceae (as represented by Antirrhinum), similar to that found in the Solanaceae. The implication of these findings is discussed in the context of S-locus evolution in flowering plants

Genome-wide association reveals three SNPs associated with sporadic amyotrophic lateral sclerosis through a two-locus analysis

<p>Abstract</p> <p>Background</p> <p>Amyotrophic lateral sclerosis (ALS) is a fatal, degenerative neuromuscular disease characterized by a progressive loss of voluntary motor activity. About 95% of ALS patients are in "sporadic form"-meaning their disease is not associated with a family history of the disease. To date, the genetic factors of the sporadic form of ALS are poorly understood.</p> <p>Methods</p> <p>We proposed a two-stage approach based on seventeen biological plausible models to search for two-locus combinations that have significant joint effects to the disease in a genome-wide association study (GWAS). We used a two-stage strategy to reduce the computational burden associated with performing an exhaustive two-locus search across the genome. In the first stage, all SNPs were screened using a single-marker test. In the second stage, all pairs made from the 1000 SNPs with the lowest p-values from the first stage were evaluated under each of the 17 two-locus models.</p> <p>Results</p> <p>we performed the two-stage approach on a GWAS data set of sporadic ALS from the SNP Database at the NINDS Human Genetics Resource Center DNA and Cell Line Repository <url>http://ccr.coriell.org/ninds/</url>. Our two-locus analysis showed that two two-locus combinations--rs4363506 (SNP1) and rs3733242 (SNP2), and rs4363506 and rs16984239 (SNP3) -- were significantly associated with sporadic ALS. After adjusting for multiple tests and multiple models, the combination of SNP1 and SNP2 had a p-value of 0.032 under the Dom∩Dom epistatic model; SNP1 and SNP3 had a p-value of 0.042 under the Dom × Dom multiplicative model.</p> <p>Conclusion</p> <p>The proposed two-stage analytical method can be used to search for joint effects of genes in GWAS. The two-stage strategy decreased the computational time and the multiple testing burdens associated with GWAS. We have also observed that the loci identified by our two-stage strategy can not be detected by single-locus tests.</p

Agrimol B inhibits colon carcinoma progression by blocking mitochondrial function through the PGC-1α/NRF1/TFAM signaling pathway

BackgroundThe activation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) stimulates the transcription of the downstream target proteins, mitochondrial transcription factor A (TFAM) and nuclear respiratory factor 1 (NRF1), which induces mitochondrial biogenesis and promotes colorectal tumorigenesis. Agrimol B (Agr) is a constituent of Agrimonia pilosa Ledeb. that exerts anticancer effects. Herein, we aimed to investigate the antitumor activity of Agr and its mechanism of action.MethodsThe interaction between Agr and PGC-1α was predicted by molecular docking. After the treatment with different concentrations of Agr (0, 144, 288, and 576 nM), the cell viability, migration rate, proliferation rate, and apoptosis rate of human colon cancer HCT116 cells were determined. Mitochondrial activity, cellular reactive oxygen species (ROS), and mitochondrial membrane potential were assessed to measure the regulatory effect of Agr on mitochondrial function. Western blotting (WB) assay was used to examine the expression of PGC-1α, NRF1, and TFAM, as well as of the pro-apoptotic proteins, Bax and Caspase-3, and the antiapoptotic protein (Bcl-2). Finally, subcutaneous tumor xenograft model mice were used to evaluate the effect of Agr on colorectal cancer (CRC) in vivo.ResultsThe molecular docking results revealed a high likelihood of Agr interacting with PGC-1α. Agr inhibited the proliferation and migration of HCT116 cells, promoted ROS production and mitochondrial oxidative stress, inhibited mitochondrial activity, and decreased mitochondrial membrane potential. Agr induced cell apoptosis and, in combination with PGC-1α, impaired mitochondrial biogenesis and suppressed the expression of NRF1 and TFAM. Agr also suppressed the expression of Bcl-2 and Cleaved-Caspase-3 and increased the expression of Bax and Caspase-3. In addition, the in vivo antitumor effect and mechanism of Agr were confirmed by using a subcutaneous tumor xenograft mouse model.ConclusionsOur findings demonstrated that Agr regulates the expression of PGC-1α, thereby inducing mitochondrial dysfunction and promoting tumor cell apoptosis. This work highlights the potential of Agr as a promising therapeutic candidate in CRC

The DNA/RNA-Dependent RNA Polymerase QDE-1 Generates Aberrant RNA and dsRNA for RNAi in a Process Requiring Replication Protein A and a DNA Helicase

The Neurospora RNA-dependent RNA polymerase QDE-1 is an RNA polymerase that can use both RNA and DNA as templates, suggesting a new mechanism for small RNA production