A new novel mutation in FBN1 causes autosomal dominant Marfan syndrome in a Chinese family

Purpose: Screening of mutations in the fibrillin-1 (FBN1) gene in a Chinese family with autosomal dominant Marfan syndrome (MFS). Methods: It has been reported that FBN1 mutations account for approximately 90% of Autosomal Dominant MFS. FBN1 mutations were analyzed in a Chinese family of 36 members including 13 MFS patients. The genomic DNAs from blood leukocytes of the patients and their relatives were isolated and the entire coding region of FBN1 was amplified by PCR. The sequence of FBN1 was dertermined with an ABI 3100 Genetic Analyzer. Results: A previously unreported the missense mutation G214S (caused by a 640 A -> G heterozygous change) in FBN1 was identified in the Chinese family. The mutation was associated with the disease phenotype in patients, but not detected in their relatives or in the 100 normal controls. Conclusions: This is the first report of molecular characterization of FBN1 in the MFS family of Chinese origin. Our results expand the spectrum of FBN1 mutations causing MFS and further confirm the role of FBN1 in the pathogenesis of MFS. Direct sequencing of the mutation in FBN1 may be used for diagnosis of MFS.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000301238300001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701Biochemistry & Molecular BiologyOphthalmologySCI(E)PubMed10ARTICLE10-1181-861

Application of Industrial Standard Methods for Detection of Horse- and Donkey-Derived Ingredients for Detecting Mule Meat

Both horse- and donkey-derived ingredients have been detected in mule meat by real-time polymerase chain reaction (PCR) as described in China’s industry standards for detection of horse (SN/T 3730.5-2013) and donkey (SN/T 3730.4-2013) ingredients in food and feed, respectively. This contradicts the theory of strict maternal inheritance of mitochondrial DNA (mtDNA). Therefore, in this study, 3 horse meat samples, 3 donkey meat samples and 3 mule meat samples were detected by mitochondrial gene and nuclear gene sequencing based on PCR and the China’s industry standard methods for horse and donkey ingredients, respectively, and the results of the SN/T 3730.4-2013 method for mule meat were analyzed. According to the results of mitochondrial gene and nuclear gene sequencing, all 3 mule meat samples were derived from mules. Both donkey and horse ingredients were detected in the 3 mule meat samples by the SN/T 3730.4-2013 and SN/T 3730.5-2013 methods. The cycle threshold (Ct) of the SN/T 3730.5-2013 method for horse ingredient was in the range of ≤ 20.00, and that of the SN/T 3730.4-2013 method for donkey ingredient were in the range of 25.00-35.00. The sequencing results of PCR products using the primers described in the SN/T 3730.4-2013 method showed that the 3 mule meat samples had no homology with horse or donkey meat. This might be because the SN/T 3730.4-2013 target sequence appeared in the form of nuclear mitochondrial DNA segments in low repeat numbers in the mule nuclear genome, and some base insertions and deletions occurred. The possibility that mule ingredient may be present should be considered when the Ct value of the SN/T 3730.4-2013 is ≤ 20.00, while the Ct value of the SN/T 3730.5-2013 is in the range of 25.00-35.00 for horse and donkey ingredients in known samples of single animal-derived ingredients, respectively

Immune-modulation by polyclonal IgM treatment reduces atherosclerosis in hypercholesterolemic apoE−/− mice

AbstractObjectiveGamma-globulin treatment reduces experimental atherosclerosis by modulating immune function; however the effect of IgM on atherosclerosis is not known. We investigated the effect of serum-derived, non-immune polyclonal IgM (Poly-IgM) on atherosclerosis in mice with advanced disease and also assessed its immune-modulatory effects.Methods and resultsAortic atherosclerosis was assessed in apoE−/− mice fed atherogenic diet starting at 6 weeks of age. In addition, mice were also subjected to perivascular cuff injury to the carotid artery at 25 weeks of age to induce accelerated atherosclerosis. At the time of injury, the mice were treated weekly with a commercially available Poly-IgM (0.4mg/mouse) or PBS for 4 weeks and euthanized at 29 weeks of age. Poly-IgM reduced aortic atherosclerosis, and reduced lesion size in the aortic sinus and injured carotid artery, without significant changes in serum cholesterol levels. Poly-IgM treatment was associated with increased anti-oxLDL IgG titers and a reduction in the % splenic CD4+ T cells compared to controls. The splenic CD4+ T cell cultured from the Poly-IgM treated mice had reduced proliferation in vitro compared with controls.ConclusionPoly-IgM treatment reduced aortic and accelerated carotid atherosclerosis in apoE−/− mice in association with increased anti-oxLDL IgG titers, and reduced number and proliferative function of splenic CD4+ T cells. Our study identifies a novel athero-protective and immunomodulatory role for non-immune polyclonal IgM

Impaired tolerance to the autoantigen LL-37 in acute coronary syndrome

BackgroundLL-37 is the only member of the cathelicidin family of antimicrobial peptides in humans and is an autoantigen in several autoimmune diseases and in acute coronary syndrome (ACS). In this report, we profiled the specific T cell response to the autoimmune self-antigen LL-37 and investigated the factors modulating the response in peripheral blood mononuclear cells (PBMCs) of healthy subjects and ACS patients.Methods and resultsThe activation induced marker (AIM) assay demonstrated differential T cell profiles characterized by the persistence of CD134 and CD137, markers that impair tolerance and promote immune effector and memory response, in ACS compared to Controls. Specifically, CD8+CD69+CD137+ T cells were significantly increased by LL-37 stimulation in ACS PBMCs. T effector cell response to LL-37 were either HLA dependent or independent as determined by blocking with monoclonal antibody to either Class-I HLA or Class-II HLA. Blocking of immune checkpoints PD-1 and CTLA-4 demonstrated the control of self-reactive T cell response to LL-37 was modulated predominantly by CTLA-4. Platelets from healthy controls down-modulated CD8+CD69+CD137+ T cell response to LL-37 in autologous PBMCs. CD8+CD69+CD137+ T cell AIM profile negatively correlated with platelet count in ACS patients.ConclusionsOur report demonstrates that the immune response to the autoantigen LL-37 in ACS patients is characterized specifically by CD8+CD69+CD137+ T cell AIM profile with persistent T cell activation and the generation of immunologic memory. The results provide potentially novel insight into mechanistic pathways of antigen-specific immune signaling in ACS

CD8+ T Cells Mediate the Athero-Protective Effect of Immunization with an ApoB-100 Peptide

Immunization of hypercholesterolemic mice with selected apoB-100 peptide antigens reduces atherosclerosis but the precise immune mediators of athero-protection remain unclear. In this study we show that immunization of apoE (-/-) mice with p210, a 20 amino acid apoB-100 related peptide, reduced aortic atherosclerosis compared with PBS or adjuvant/carrier controls. Immunization with p210 activated CD8+ T cells, reduced dendritic cells (DC) at the site of immunization and within the plaque with an associated reduction in plaque macrophage immunoreactivity. Adoptive transfer of CD8+ T cells from p210 immunized mice recapitulated the athero-protective effect of p210 immunization in naïve, non-immunized mice. CD8+ T cells from p210 immunized mice developed a preferentially higher cytolytic response against p210-loaded dendritic cells in vitro. Although p210 immunization profoundly modulated DCs and cellular immune responses, it did not alter the efficacy of subsequent T cell dependent or independent immune response to other irrelevant antigens. Our data define, for the first time, a role for CD8+ T cells in mediating the athero-protective effects of apoB-100 related peptide immunization in apoE (-/-) mice

A Novel SALL4/OCT4 Transcriptional Feedback Network for Pluripotency of Embryonic Stem Cells

Background: SALL4 is a member of the SALL gene family that encodes a group of putative developmental transcription factors. Murine Sall4 plays a critical role in maintaining embryonic stem cell (ES cell) pluripotency and self-renewal. We have shown that Sall4 activates Oct4 and is a master regulator in murine ES cells. Other SALL gene members, especially Sall1 and Sall3 are expressed in both murine and human ES cells, and deletions of these two genes in mice lead to perinatal death due to developmental defects. To date, little is known about the molecular mechanisms controlling the regulation of expressions of SALL4 or other SALL gene family members. Methodology/Principal Findings: This report describes a novel SALL4/OCT4 regulator feedback loop in ES cells in balancing the proper expression dosage of SALL4 and OCT4 for the maintenance of ESC stem cell properties. While we have observed that a positive feedback relationship is present between SALL4 and OCT4, the strong self-repression of SALL4 seems to be the “break” for this loop. In addition, we have shown that SALL4 can repress the promoters of other SALL family members, such as SALL1 and SALL3, which competes with the activation of these two genes by OCT4. Conclusions/Significance: Our findings, when taken together, indicate that SALL4 is a master regulator that controls its own expression and the expression of OCT4. SALL4 and OCT4 work antagonistically to balance the expressions of other SALL gene family members. This novel SALL4/OCT4 transcription regulation feedback loop should provide more insight into the mechanism of governing the “stemness” of ES cells

Enhanced Neointima Formation Following Arterial Injury in Immune Deficient Rag-1−/− Mice Is Attenuated by Adoptive Transfer of CD8+ T cells

T cells modulate neointima formation after arterial injury but the specific T cell population that is activated in response to arterial injury remains unknown. The objective of the study was to identify the T cell populations that are activated and modulate neointimal thickening after arterial injury in mice. Arterial injury in wild type C57Bl6 mice resulted in T cell activation characterized by increased CD4+CD44hi and CD8+CD44hi T cells in the lymph nodes and spleens. Splenic CD8+CD25+ T cells and CD8+CD28+ T cells, but not CD4+CD25+ and CD4+CD28+ T cells, were also significantly increased. Adoptive cell transfer of CD4+ or CD8+ T cells from donor CD8−/− or CD4−/− mice, respectively, to immune-deficient Rag-1−/− mice was performed to determine the T cell subtype that inhibits neointima formation after arterial injury. Rag-1−/− mice that received CD8+ T cells had significantly reduced neointima formation compared with Rag-1−/− mice without cell transfer. CD4+ T cell transfer did not reduce neointima formation. CD8+ T cells from CD4−/− mice had cytotoxic activity against syngeneic smooth muscle cells in vitro. The study shows that although both CD8+ T cells and CD4+ T cells are activated in response to arterial injury, adoptive cell transfer identifies CD8+ T cells as the specific and selective cell type involved in inhibiting neointima formation

Is Treatment with Trimetazidine Beneficial in Patients with Chronic Heart Failure?

<div><p>Background</p><p>Whether additional benefit can be achieved with the use of trimetazidine (TMZ) in patients with chronic heart failure (CHF) remains controversial. We therefore performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the effects of TMZ treatment in CHF patients.</p><p>Methods</p><p>We searched PubMed, EMBASE, and Cochrane databases through October 2013 and included 19 RCTs involving 994 CHF patients who underwent TMZ or placebo treatment. Risk ratio (RR) and weighted mean differences (WMD) were calculated using fixed or random effects models.</p><p>Results</p><p>TMZ therapy was associated with considerable improvement in left ventricular ejection fraction (WMD: 7.29%, 95% CI: 6.49 to 8.09, p<0.01) and New York Heart Association classification (WMD: −0.55, 95% CI: −0.81 to −0.28, p<0.01). Moreover, treatment with TMZ also resulted in significant decrease in left ventricular end-systolic volume (WMD: −17.09 ml, 95% CI: −20.15 to −14.04, p<0.01), left ventricular end-diastolic volume (WMD: −11.24 ml, 95% CI: −14.06 to −8.42, p<0.01), hospitalization for cardiac causes (RR: 0.43, 95% CI: 0.21 to 0.91, p = 0.03), B-type natriuretic peptide (BNP; WMD: −157.08 pg/ml, 95% CI: −176.55 to −137.62, p<0.01) and C-reactive protein (CRP; WMD: −1.86 mg/l, 95% CI: −2.81 to −0.90, p<0.01). However, there were no significant differences in exercise duration and all-cause mortality between patients treated with TMZ and placebo.</p><p>Conclusions</p><p>TMZ treatment in CHF patients may improve clinical symptoms and cardiac function, reduce hospitalization for cardiac causes, and decrease serum levels of BNP and CRP.</p></div

Moderate wetting and drying increases rice yield and reduces water use, grain arsenic level, and methane emission

To meet the major challenge of increasing rice production to feed a growing population under increasing water scarcity, many water-saving regimes have been introduced in irrigated rice, such as an aerobic rice system, non-flooded mulching cultivation, and alternate wetting and drying (AWD). These regimes could substantially enhance water use efficiency (WUE) by reducing irrigation water. However, such enhancements greatly compromise grain yield. Recent work has shown that moderate AWD, in which photosynthesis is not severely inhibited and plants can rehydrate overnight during the soil drying period, or plants are rewatered at a soil water potential of −10 to −15 kPa, or midday leaf potential is approximately −0.60 to −0.80 MPa, or the water table is maintained at 10 to 15 cm below the soil surface, could increase not only WUE but also grain yield. Increases in grain yield WUE under moderate AWD are due mainly to reduced redundant vegetative growth; improved canopy structure and root growth; elevated hormonal levels, in particular increases in abscisic acid levels during soil drying and cytokinin levels during rewatering; and enhanced carbon remobilization from vegetative tissues to grain. Moderate AWD could also improve rice quality, including reductions in grain arsenic accumulation, and reduce methane emissions from paddies. Adoption of moderate AWD with an appropriate nitrogen application rate may exert a synergistic effect on grain yield and result in higher WUE and nitrogen use efficiency. Further research is needed to understand root–soil interaction and evaluate the long-term effects of moderate AWD on sustainable agriculture