Drugs to cure avian influenza infection – multiple ways to prevent cell death

New treatments and new drugs for avian influenza virus (AIV) infection are developed continually, but there are still high mortality rates. The main reason may be that not all cell death pathways induced by AIV were blocked by the current therapies. In this review, drugs for AIV and associated acute respiratory distress syndrome (ARDS) are summarized. The roles of antioxidant (vitamin C) and multiple immunomodulators (such as Celecoxib, Mesalazine and Eritoran) are discussed. The clinical care of ARDS may result in ischemia reperfusion injury to poorly ventilated alveolar cells. Cyclosporin A should effectively inhibit this kind of damages and, therefore, may be the key drug for the survival of patients with virus-induced ARDS. Treatment with protease inhibitor Ulinastatin could also protect lysosome integrity after the infection. Through these analyses, a large drug combination is proposed, which may hypothetically greatly reduce the mortality rate.     

55岁以下急性冠状动脉综合征的影响因素分析

目的:探究55岁以下急性冠状动脉综合征(Acute coronary syndrome,ACS)患者的影响因素。方法:选择2010年3月至2013年3月于我院就诊的180例55岁以下ACS患者为研究对象,按照其性别将其区分为男性组(101例)和女性组(79例)。收集和比较两组患者一般临床资料,血清血红蛋白(Hemoglobin,HGB)、甘油三酯(Triglyceride,TG)、胆固醇(Cholesterol,TC)、低密度脂蛋白胆固醇(Low density lipoprotein cholesterol,LDL-C)、高密度脂蛋白胆固醇(High density lipoprotein cholesterol,HDL-C)、血尿酸水平。对两组患者进行5年随访,对比两组患者心血管不良事件(Major adverse cardiovas-cular events,MACE)的发生率、死亡率及再发病率。结果:(1)女性组平均发病年龄高于男性组,女性组伴发高血压、糖尿病、脑卒中比率高于男性组,男性组吸烟史比率高于女性组(P<0.05),两组BMI、心血管病家族史对比差异无统计学意义(P>0.05);(2)女性组TC、TG、LDL-C、HDL-C水平均高于男性组(P<0.05),女性组血尿酸水平低于男性组(P<0.05);(3)对比5年预后,男性组MACE发生率为9.90%(10/101),女性组MACE发生率为11.39%(9/79),男性组死亡率为1.98%(2/101),女性组为1.27%(1/79),再发病率男性组为5.94%(6/101),女性组为6.33%(5/79),两组上述指标对比差异均无统计学意义(P>0.05)。结论:女性ACS患者发病年龄高于男性患者,糖尿病、高血压等病对女性患者影响更为明显,而吸烟则对男性影响更大,女性ACS患者血脂、血尿酸等指标异常程度甚于男性患者,但女性与男性患者远期预后相当。     

The Down syndrome-related protein kinase DYRK1A phosphorylates p27Kip1 and Cyclin D1 and induces cell cycle exit and neuronal differentiation

A fundamental question in neurobiology is how the balance between proliferation and differentiation of neuronal precursors is maintained to ensure that the proper number of brain neurons is generated. Substantial evidence implicates DYRK1A (dual specificity tyrosine-phosphorylation-regulated kinase 1A) as a candidate gene responsible for altered neuronal development and brain abnormalities in Down syndrome. Recent findings support the hypothesis that DYRK1A is involved in cell cycle control. Nonetheless, how DYRK1A contributes to neuronal cell cycle regulation and thereby affects neurogenesis remains poorly understood. In the present study we have investigated the mechanisms by which DYRK1A affects cell cycle regulation and neuronal differentiation in a human cell model, mouse neurons, and mouse brain. Dependent on its kinase activity and correlated with the dosage of overexpression, DYRK1A blocked proliferation of SH-SY5Y neuroblastoma cells within 24 h and arrested the cells in G₁ phase. Sustained overexpression of DYRK1A induced G₀ cell cycle exit and neuronal differentiation. Furthermore, we provide evidence that DYRK1A modulated protein stability of cell cycle-regulatory proteins. DYRK1A reduced cellular Cyclin D1 levels by phosphorylation on Thr286, which is known to induce proteasomal degradation. In addition, DYRK1A phosphorylated p27^Kip1 on Ser10, resulting in protein stabilization. Inhibition of DYRK1A kinase activity reduced p27^Kip1 Ser10 phosphorylation in cultured hippocampal neurons and in embryonic mouse brain. In aggregate, these results suggest a novel mechanism by which overexpression of DYRK1A may promote premature neuronal differentiation and contribute to altered brain development in Down syndrome.     

Effects of micronutrients on the growth form of two families of Pinus radiata (D.Don) seedlings

Micro-element deficiencies have been implicated in the development of poor stem form in Pinus radiata plantations. Cu, Mn and B have been implicated in previous studies as influencing tree form and/or the process of lignification in plants. Therefore an experiment was initiated to examine the individual and interactive effects exhibited by these trace elements on stem form and lignification.The investigation showed that Cu deficiency reduced both lignification and stem form in seedlings. Mn, competing with Cu for uptake, enhanced the symptoms of Cu deficiency. Boron addition did not alleviate the expression of deformity or increase levels of lignification. There was a clear family influence on the development of seedling stem form in response to variations in mineral nutrition.     

Identification of differentially expressed genes in primary Sjögren's syndrome

Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune disease that affects exocrine glands. To study the molecular mechanism and identify crucial genes/pathways in pSS pathogenesis, the microarray-based whole-genome gene expression profiles from salivary glands of patients with pSS and non-sicca controls were retrieved. After normalization and subsequent batch effect adjustment, significance analysis of microarrays method was applied to five available datasets, and 379 differentially expressed genes (DEGs) were identified. The 300 upregulated DEGs were enriched in Gene Ontology terms of immune and inflammatory responses, including antigen processing and presentation, interferon-mediated signaling pathway, and chemotaxis. Previously reported pSS-associated genes, including HLA-DRA, TAP2, PRDM1, and IFI16, were found to be significantly upregulated. The downregulated DEGs were enriched in pathways of salivary secretion, carbohydrate digestion and absorption, and starch and sucrose metabolism, implying dysfunction of salivary glands during pathogenesis. Next, a protein-protein interaction network was constructed, and B2M, an upregulated DEG, was shown to be a hub, suggesting its potential involvement in pSS development. In summary, we found the activation of pSS-associated genes in pathogenesis, and provide clues for salivary glands dysfunction. Experimental investigation on the identified DEGs in this study will deepen our understanding on pSS.     

The diet-induced metabolic syndrome is accompanied by whole-genome epigenetic changes

Consuming a high-fat/high-fructose diet (HFD) starting at a young age leads to the development of obesity and to the progression of metabolic syndrome (MS). We are interested in the relationship between MS and DNA methylation as a mediator of the metabolic memory and the early appearance of these diseases in the progeny. To this end, Wistar rats were fed a HFD for 1 year, and every 12 weeks, biochemical analyses were performed. After 24 weeks, animals fed the HFD showed alterations related to MS such as elevated blood levels of fasting glucose, triglycerides, and insulin compared with their littermate controls. During the experimental period, the control females exhibited a 40 % lower 5-methylcytosine (5-mC) level compared to the control males. The HFD affected the 5-mC levels in males and females differently. The HFD induced a 20 % decrease in the 5-mC levels in males and a 15 % increase in females. We found that the HFD induces an early presentation of MS in the progeny of treated animals and that the DNA methylation was altered in the F₁ generation. The presentation of MS is positively associated with changes in the global percentage of 5-mC in the DNA.     

Mitochondrial purine and pyrimidine metabolism and beyond

ABSTRACT

Carefully balanced deoxynucleoside triphosphate (dNTP) pools are essential for both nuclear and mitochondrial genome replication and repair. Two synthetic pathways operate in cells to produce dNTPs, e.g., the de novo and the salvage pathways. The key regulatory enzymes for de novo synthesis are ribonucleotide reductase (RNR) and thymidylate synthase (TS), and this process is considered to be cytosolic. The salvage pathway operates both in the cytosol (TK1 and dCK) and the mitochondria (TK2 and dGK). Mitochondrial dNTP pools are separated from the cytosolic ones owing to the double membrane structure of the mitochondria, and are formed by the salvage enzymes TK2 and dGK together with NMPKs and NDPK in postmitotic tissues, while in proliferating cells the mitochondrial dNTPs are mainly imported from the cytosol produced by the cytosolic pathways. Imbalanced mitochondrial dNTP pools lead to mtDNA depletion and/or deletions resulting in serious mitochondrial diseases. The mtDNA depletion syndrome is caused by deficiencies not only in enzymes in dNTP synthesis (TK2, dGK, p53R2, and TP) and mtDNA replication (mtDNA polymerase and twinkle helicase), but also in enzymes in other metabolic pathways such as SUCLA2 and SUCLG1, ABAT and MPV17. Basic questions are why defects in these enzymes affect dNTP synthesis and how important is mitochondrial nucleotide synthesis in the whole cell/organism perspective? This review will focus on recent studies on purine and pyrimidine metabolism, which have revealed several important links that connect mitochondrial nucleotide metabolism with amino acids, glucose, and fatty acid metabolism.