Immune-related GTPase M (IRGM1) regulates neuronal autophagy in a mouse model of stroke

Autophagy is an important cellular recycling mechanism through self-digestion in responses to cellular stress such as starvation. Studies have shown that autophagy is involved in maintaining the homeostasis of the neural system during stroke. However, molecular mechanisms underlying neuronal autophagy in ischemic stroke remain poorly understood. Previously, we and others have shown that immune-related GTPase M (IRGM; termed IRGM1 in the mouse nomenclature) can regulate the survival of immune cells through autophagy in response to infections and autoimmune conditions. Here, using a permanent middle cerebral artery occlusion (pMCAO) mouse model, we found that IRGM1 was upregulated in the ischemic side of the brain, which was accompanied by a significant autophagic response. In contrast, neuronal autophagy was almost complete lost in Irgm1 knockout (KO) mice after pMCAO induction. In addition, the infarct volume in the Irgm1-KO pMCAO mice was significantly increased as compared to wild-type mice. Histological studies suggested that, at the early stage (within 24 h) of ischemia, the IRGM1-dependent autophagic response is associated with a protection of neurons from necrosis in the ischemic core but a promotion of neuronal apoptosis in the penumbra area. These data demonstrate a novel role of IRGM1 in regulating neuronal autophagy and survival during ischemic stroke.     

Design, synthesis and biological activity of 6-substituted carbamoyl benzimidazoles as new nonpeptidic angiotensin II AT₁ receptor antagonists

A series of 6-substituted carbamoyl benzimidazoles were designed and synthesised as new nonpeptidic angiotensin II AT(1) receptor antagonists. The preliminary pharmacological evaluation revealed a nanomolar AT(1) receptor binding affinity for all compounds in the series, and a potent antagonistic activity in an isolated rabbit aortic strip functional assay for compounds 6f, 6g, 6h and 6k was also demonstrated. Furthermore, evaluation in spontaneous hypertensive rats and a preliminary toxicity evaluation showed that compound 6g is an orally active AT(1) receptor antagonist with low toxicity.     

Design, synthesis and biological evaluation of novel amino acid ureido derivatives as aminopeptidase N/CD13 inhibitors

A series of amino acid ureido derivatives as aminopeptidase N (APN/CD13) inhibitors were synthesized and evaluated for their APN inhibitory activities and anti-cancer effects. The results showed that most of these amino acid ureido derivatives exhibited good inhibition against APN, several of which were better than Bestatin. The most active compound 12j (IC(50) = 1.1 μM, compared with Bestatin IC(50) = 8.1 μM) not only possessed much better APN inhibitory activity and anti-proliferation effect on cancer cells, but also exhibited significant block effect of human cancer cell invasion compared with the positive control, Bestatin. These amino acid ureido derivatives could be possibly developed as new APN inhibitors for cancer chemotherapy in the future.     

转录因子Ets-1与β1,3 N-乙酰氨基葡萄糖基转移酶基因启动子结合活性分析

β1,3-N-乙酰氨基葡萄糖转移酶-2,-8（β3GnT-2, β3GnT-8）共同参与多聚N-乙酰氨基乳糖(［Galβ1→4GlcNAcβ1→3］n)的合成,从而使得细胞表面的相应糖链结 构延长进而影响细胞的恶性转化.已有研究表明,在全反式维甲酸诱导人白血病细胞株 HL-60分化过程中β3GnT-2,-8的表达上调,但其分子机制不明.本文旨在探讨ATRA诱导 HL-60分化过程中,转录因子Ets-1对β3GnT-2,-8表达调控的分子机制.采用10-6 mol/L ATRA 诱导人白血病细胞株HL-60向粒系分化,RT-PCR检测到细胞中Ets-1的表达 明显增加;进一步采用染色质免疫沉淀（ChIP）结合电泳迁移率变动实验（EMSA）检测 证实,有活化的Ets-1结合至β3GnT-2/-8基因调控区. 以上结果表明,转录因子Ets-1对 人白血病细胞株HL-60分化过程中β3GnT-2,-8基因有表达调控作用.     

Cofilin 与肿瘤

Cofilin是肌动蛋白相关蛋白,对肌动蛋白动力学特性的调节很重要。近年发现Cofilin活化与肿瘤细胞的恶性侵袭性质有关。Cofilin的局部激活可以诱导片状伪足的形成,并影响肿瘤细胞运动的方向,从而增强肿瘤细胞的运动和迁移;抑制Cofilin的活性可以减少肿瘤细胞的运动和迁移。本文对Cofilin的结构、功能、调控机制和与肿瘤的关系进行综述。     

Endothelium-specific SIRT1 overexpression inhibits hyperglycemia-induced upregulation of vascular cell senescence

The rapidly increasing prevalence of diabetes mellitus worldwide is one of the most serious and challenging health problems in the 21st century. Mammalian sirtuin 1 (SIRT1) has been shown to decrease high-glucose-induced endothelial cell senescence in vitro and prevent hyperglycemia-induced vascular dysfunction. However, a role for SIRT1 in prevention of hyperglycemia-induced vascular cell senescence in vivo remains unclear. We used endothelium-specific SIRT1 transgenic (SIRT1-Tg) mice and wild-type (WT) mice to construct a 40-week streptozotocin (STZ)-induced diabetic mouse model. In this mode, 42.9% of wild-type (WT) mice and 38.5% of SIRT1-Tg mice were successfully established as diabetic. Forty weeks of hyperglycemia induced significant vascular cell senescence in aortas of mice, as indicated by upregulation of expression of senescence-associated markers including p53, p21 and plasminogen activator inhibitor-1 (PAI-1). However, SIRT1-Tg diabetic mice displayed dramatically decreased expression of p53, p21 and PAI-1 compared with diabetic WT mice. Moreover, manganese superoxide dismutase expression (MnSOD) was significantly downregulated in the aortas of diabetic WT mice, but was preserved in diabetic SIRT1-Tg mice. Furthermore, expression of the oxidative stress adaptor p66Shc was significantly decreased in aortas of SIRT1-Tg diabetic mice compared with WT diabetic mice. Overall, these findings suggest that SIRT1-mediated inhibition of hyperglycemia-induced vascular cell senescence is mediated at least partly through the reduction of oxidative stress.     

On optimal control policy for probabilistic Boolean network: a state reduction approach

Background

Probabilistic Boolean Network (PBN) is a popular model for studying genetic regulatory networks. An important and practical problem is to find the optimal control policy for a PBN so as to avoid the network from entering into undesirable states. A number of research works have been done by using dynamic programming-based (DP) method. However, due to the high computational complexity of PBNs, DP method is computationally inefficient for a large size network. Therefore it is natural to seek for approximation methods.

Results

Inspired by the state reduction strategies, we consider using dynamic programming in conjunction with state reduction approach to reduce the computational cost of the DP method. Numerical examples are given to demonstrate both the effectiveness and the efficiency of our proposed method.

Conclusions

Finding the optimal control policy for PBNs is meaningful. The proposed problem has been shown to be ${\sum }_2^p\mathsf{\text{ - hard}}$. By taking state reduction approach into consideration, the proposed method can speed up the computational time in applying dynamic programming-based algorithm. In particular, the proposed method is effective for larger size networks.

     

HCV and HIV Infection among Heroin Addicts in Methadone Maintenance Treatment (MMT) and Not in MMT in Changsha and Wuhan,China

Objective

To compare HCV and HIV infection among heroin addicts in MMT and not in MMT in two large cities in central China.

Methods

A total of 541 heroin addicts were recruited from MMT clinics and voluntary detoxification centers in Changsha and Wuhan, China. Structured questionnaires collected data on their socio-demographics, clinical status, risk behaviors, and their knowledge of HIV. Their HIV serostatus and Hepatitis C virus (HCV) serostatus were determined by testing antibodies in blood serum.

Results

We observed a higher prevalence of HCV infection among MMT heroin addicts (82.3%) than that in the non-MMT group (50.6%). However, our findings indicated that the heroin addicts in MMT had less drug or sexual HIV/HCV risk behaviors and more knowledge about HIV than non-MMT addicts. The heroin addicts in MMT had a significantly higher percentage of individuals who always used condoms (44.9%) compared with patients in the non-MMT group (14.6%, p = 0.039), and they had more knowledge about HIV than non-MMT individuals (p<.001). The percentage of HIV-positive addicts in the MMT group (0.7%) and non-MMT group (0.8%) were almost same.

Conclusion

Our study indicated that the rate of HCV infection among heroin addicts among MMT or non-MMT settings in central China is very high. The non-MMT heroin addicts have higher risk of becoming infected with HCV in the future, while at present they have lower rates of HCV infection than MMT heroin addicts. Although rates of HIV infection among MMT and non-MMT heroin addicts are low now, they are all at great risk of becoming infected with HIV in the future, especially for non-MMT heroin addicts. We should use the MMT sites as a platform to improve the control of HCV and HIV infection in heroin addicts.     

High Resolution Size Analysis of Fetal DNA in the Urine of Pregnant Women by Paired-End Massively Parallel Sequencing

Background

Fetal DNA in maternal urine, if present, would be a valuable source of fetal genetic material for noninvasive prenatal diagnosis. However, the existence of fetal DNA in maternal urine has remained controversial. The issue is due to the lack of appropriate technology to robustly detect the potentially highly degraded fetal DNA in maternal urine.

Methodology

We have used massively parallel paired-end sequencing to investigate cell-free DNA molecules in maternal urine. Catheterized urine samples were collected from seven pregnant women during the third trimester of pregnancies. We detected fetal DNA by identifying sequenced reads that contained fetal-specific alleles of the single nucleotide polymorphisms. The sizes of individual urinary DNA fragments were deduced from the alignment positions of the paired reads. We measured the fractional fetal DNA concentration as well as the size distributions of fetal and maternal DNA in maternal urine.

Principal Findings

Cell-free fetal DNA was detected in five of the seven maternal urine samples, with the fractional fetal DNA concentrations ranged from 1.92% to 4.73%. Fetal DNA became undetectable in maternal urine after delivery. The total urinary cell-free DNA molecules were less intact when compared with plasma DNA. Urinary fetal DNA fragments were very short, and the most dominant fetal sequences were between 29 bp and 45 bp in length.

Conclusions

With the use of massively parallel sequencing, we have confirmed the existence of transrenal fetal DNA in maternal urine, and have shown that urinary fetal DNA was heavily degraded.