Susceptibility to leprosy is associated with PARK2 and PACRG

Leprosy is caused by Mycobacterium leprae and affects about 700,000 individuals each year. It has long been thought that leprosy has a strong genetic component, and recently we mapped a leprosy susceptibility locus to chromosome 6 region q25-q26 (ref. 3). Here we investigate this region further by using a systematic association scan of the chromosomal interval most likely to harbour this leprosy susceptibility locus. In 197 Vietnamese families we found a significant association between leprosy and 17 markers located in a block of approx. 80 kilobases overlapping the 5' regulatory region shared by the Parkinson's disease gene PARK2 and the co-regulated gene PACRG. Possession of as few as two of the 17 risk alleles was highly predictive of leprosy. This was confirmed in a sample of 975 unrelated leprosy cases and controls from Brazil in whom the same alleles were strongly associated with leprosy. Variants in the regulatory region shared by PARK2 and PACRG therefore act as common risk factors for leprosy.     

Lys751Gln polymorphism in ERCC2 gene is associated with lung cancer susceptibility in the Chinese population

The excision repair cross-complementing group 2 (ERCC2) gene encodes a DNA repair protein, which is absolutely necessary in nucleotide excision repair. A polymorphism in codon 751 that induces a Lys→Gln substitution has been suggested to reduce the DNA repair capacity. Therefore, we conducted a matched case-control study to investigate the role of ERCC2 Lys751Gln polymorphism in the development of lung cancer in the Chinese population. The genotype of ERCC2 gene was analyzed by di-allele-specific-amplification with artificially modified primers (diASA-AMP) in 200 original lung cancer cases and 200 controls. The results showed that carriers of Lys/Gln and Gln/Gln genotypes had a 3.32-fold higher risk of lung cancer compared with carriers of Lys/Lys genotype. Furthermore, the mutant genotype of 751Gln allele was found to be associated with an increased risk in both lung squamous cell carcinoma and lung adenocarcinoma. However, no significant interaction between 751Gln variants and smoking was observed after stratifying according to the smoking status in this study. The results suggest that the Lys751Gln polymorphism in ERCC2 gene is a potential biomarker for susceptibility of lung cancer in the Chinese population.     

Lys751Gln polymorphism in ERCC2 gene is associated with lung cancer susceptibility in the Chinese population

The excision repair cross-complementing group 2(ERCC2)gene encodes a DNA repair protein,which is absolutely necessary in nucleotide excision repair.A polymorphism in codon 751 that induces a Lys→Gln substitution has been suggested to reduce the DNA repair capacity.Therefore,we conducted a matched case-control study to investigate the role of ERCC2 Lys751Gln polymor- phism in the development of lung cancer in the Chinese population.The genotype of ERCC2 gene was analyzed by di-allele-specific-amplifi- cation with artificially modified primers(diASA-AMP)in 200 original lung cancer cases and 200 controls.The results showed that carriers of Lys/Gln and Gln/Gln genotypes had a 3.32-fold higher risk of lung cancer compared with carriers of Lys/Lys genotype.Furthermore, the mutant genotypa of 751Gln allele was found to be associated with an increased risk in both lung squamous cell carcinoma and lung ade- nocarcinoma.However,no significant interaction between 751Gln variants and smoking was observed after stratifying according to the smoking status in this study.The results suggest that the Lys751Gln polymorphism in ERCC2 gene is a potential biomarker for suscepti- bility of lung cancer in the Chinese population.     

Recovery of learning and memory is associated with chromatin remodelling

Neurodegenerative diseases of the central nervous system are often associated with impaired learning and memory, eventually leading to dementia. An important aspect in pre-clinical research is the exploration of strategies to re-establish learning ability and access to long-term memories. By using a mouse model that allows temporally and spatially restricted induction of neuronal loss, we show here that environmental enrichment reinstated learning behaviour and re-established access to long-term memories after significant brain atrophy and neuronal loss had already occurred. Environmental enrichment correlated with chromatin modifications (increased histone-tail acetylation). Moreover, increased histone acetylation by inhibitors of histone deacetylases induced sprouting of dendrites, an increased number of synapses, and reinstated learning behaviour and access to long-term memories. These data suggest that inhibition of histone deacetylases might be a suitable therapeutic avenue for neurodegenerative diseases associated with learning and memory impairment, and raises the possibility of recovery of long-term memories in patients with dementia.     

iRhom2Uncv 小鼠乳腺发育障碍的转录组分析

摘要:目的 研究 iRhom2Uncv 小鼠乳腺表型相关的差异表达基因,为深入研究 iRhom2Uncv 小鼠乳腺发育障碍的相关机制提供靶点信息。 方法 对 12 周龄的野生型和 iRhom2Uncv 小鼠的乳腺组织进行 whole-mounts 染色,分析乳腺发育形态,收集乳腺组织进行转录组测序,筛选差异表达基因,ELISA 检测血清激素水平。 结果 与野生型小鼠相比,iRhom2Uncv 小鼠乳腺侧枝导管较稀疏,差异最显著的 18 个基因中有 6 个在 iRhom2Uncv 小鼠中表达上调,12 个表达下调。 其中 3 个催乳素家族基因在 iRhom2Uncv 小鼠中不表达,且在血清中几乎检测不到催乳素表达,而血清中的雌激素水平相比野生型小鼠较高。 结论 iRhom2Uncv 突变的小鼠存在乳腺发育障碍,可能与 iRhom2Uncv 小鼠中催乳素和 Zfp281 的缺失表达有关,生物信息学分析发现,iRhom2Uncv 小鼠神经发育可能存在不同于野生型小鼠的表型。     

Long-term potentiation is associated with increases in quantal content and quantal amplitude.

Long-term potentiation (LTP) of synaptic transmission in CA1 neurons of the hippocampus, elicited by the conjunction of presynaptic firing and postsynaptic depolarization, is an important model of plasticity, which may underlie memory storage. Although induction of LTP takes place in the postsynaptic cell, it is not clear whether it is expressed through an enhancement of transmitter release or through an increased postsynaptic response to the same amount of transmitter. Analysis of the trial-to-trial amplitude fluctuations of synaptic signals, that is quantal analysis, gives an important insight into the probabilistic mechanisms of transmission, although attempts to apply it to the mode of expression of LTP have so far yielded inconsistent results, at least in part because they have relied on models of transmitter release that have not been confirmed experimentally. Here we report clear evidence for quantal fluctuation in a subset of cells. Induction of LTP in these cells causes abrupt increases in either quantal content or quantal amplitude, or both. This shows that two different mechanisms can underlie the maintenance of LTP.     

Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation

In near-physiological concentrations, glucocorticoid hormones cause the death of several types of normal and neoplastic lymphoid cell, but the mechanisms involved are unknown. One of the earliest structural changes in the dying cell is widespread chromatin condensation, of the type characteristic of apoptosis, the mode of death frequently observed where cell deletion seems to be 'programmed'. It is shown here that this morphological change is closely associated with excision of nucleosome chains from nuclear chromatin, apparently through activation of an intracellular, but non-lysosomal, endonuclease.     

Postconditioning of sevoflurane and propofol is associated with mitochondrial permeability transition pore

Background： Sevoflurane and propofol are effective cardioprotective anaesthetic agents, though the cardioprotection of propofol has not been shown in humans. Their roles and underlying mechanisms in anesthetic postconditioning are unclear. Mitochondrial permeability transition pore （MPTP） opening is a major cause of ischemia-reperfusion injury. Here we investigated sevoflurane- and propofol-induced postconditioning and their relationship with MPTP. Methods： Isolated perfused rat hearts were exposed to 40 min of ischemia followed by 1 h of reperfusion. During the first 15 min of reperfusion, hearts were treated with either control buffer （CTRL group） or buffer containing 20 μmol/L atractyloside （ATR group）, 3% （v/v） sevoflurane （SPC group）, 50 μmol/L propofol （PPC group）, or the combination of atractyloside with respective anesthetics （SPC＋ATR and PPC＋ATR groups）. Infarct size was determined by dividing the total necrotic area of the left ventricle by the total left ventricular slice area （percent necrotic area）. Results： Hearts treated with sevoflurane or propofol showed significantly better recovery of coronary flow, end-diastolic pressures, left ventricular developed pressure and derivatives compared with controls. Sevoflurane resulted in more protective alteration of hemodynamics at most time point of reperfusion than propofol. These improvements were paralleled with the reduction of lactate dehydrogenase release and the decrease of infarct size （SPC vs CTRL： （17.48±2.70）% vs （48.47±6.03）%, P〈0.05; PPC vs CTRL： （35.60±2.10）% vs （48.47±6.03）%,P〈0.05）. SPC group had less infarct size than PPC group （SPC vs PPC： （ 17.48±2.70）% vs （35.60±2.10）%,P〈0.05）. Atractyloside coadministration attenuated or completely blocked the cardioprotective effect of postconditioning of sevoflurane and propofol. Conclusion： Postconditioning of sevoflurane and propofol has cardio-protective effect against ischemia-reperfusion injury of heart     

Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor

Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. In contrast, it is unclear if the PACAP-PAC1 receptor pathway has a role in human psychological stress responses, such as post-traumatic stress disorder (PTSD). Here we find, in heavily traumatized subjects, a sex-specific association of PACAP blood levels with fear physiology, PTSD diagnosis and symptoms in females. We examined 44 single nucleotide polymorphisms (SNPs) spanning the PACAP (encoded by ADCYAP1) and PAC1 (encoded by ADCYAP1R1) genes, demonstrating a sex-specific association with PTSD. A single SNP in a putative oestrogen response element within ADCYAP1R1, rs2267735, predicts PTSD diagnosis and symptoms in females only. This SNP also associates with fear discrimination and with ADCYAP1R1 messenger RNA expression in human brain. Methylation of ADCYAP1R1 in peripheral blood is also associated with PTSD. Complementing these human data, ADCYAP1R1 mRNA is induced with fear conditioning or oestrogen replacement in rodent models. These data suggest that perturbations in the PACAP-PAC1 pathway are involved in abnormal stress responses underlying PTSD. These sex-specific effects may occur via oestrogen regulation of ADCYAP1R1. PACAP levels and ADCYAP1R1 SNPs may serve as useful biomarkers to further our mechanistic understanding of PTSD.     

甘黄疗法对肾阴虚和脾阳虚小鼠口腔溃疡的疗效分析

为了研究不同类型小鼠口腔溃疡在甘黄疗法下的效果,试验设计肾阴虚与脾阳虚两种常见的口腔溃疡模型,以甘草黄芪配合使用的甘黄疗法,以及口服黄芪粉为主要方法,冰硼散为反证方法,对两种类型的口腔溃疡进行治疗,以观察不同类型的溃疡在不同甘黄配比、单用以及使用冰硼散时的治疗效果.结果表明,肾阴虚型口腔溃疡小鼠并不适合甘黄疗法,在用药后2日起,病情加重伤口扩大至平均7 mm左右,同时病程较对照组而言平均延长3日.冰硼散对此类型溃疡的疗效较好,平均6日基本痊愈.而对脾阳虚小鼠进行治疗发现,甘黄疗法对其疗效甚佳,且在甘草黄芪配比为1∶2时效果最好.除此之外,任何配比以及单用均不如该配比效果好.冰硼散可加重该型口腔溃疡(伤口扩大至平均8mm左右),同时延长病程(较对照组延长2日).而进一步研究发现,在外用甘黄1∶2的同时内服黄芪粉,可进一步缩短病程(平均缩短1日).因此,甘黄疗法对脾阳虚型口腔溃疡小鼠效果明显好于肾阴虚型.另外,在外用甘黄药物的同时口服黄芪粉效果更加显著.     

Centractin is an actin homologue associated with the centrosome.

Actin is one of the most ubiquitous, abundant and well-conserved proteins of eukaryotes, participating in many crucial cellular processes including the maintenance of cell shape, motility and cell division. Actins from the most divergent sources still share amino-acid identities in excess of 70% (ref. 3). This may well explain why low-abundance homologues of actin have been difficult to isolate. Genes encoding distant relatives of actin in budding and fisson yeast have now been cloned. We report here the discovery of a vertebrate actin-like protein, which we name centractin. A full-length complementary DNA clone was isolated whose sequence reveals amino-acid identities with actin of over 50%, increasing to more than 70% when conservative amino-acid changes are considered. Northern analysis and western blotting indicate a ubiquitous tissue and species distribution. Morphological and biochemical criteria show that centractin is associated with centrosomes.     

Differential positioning of adherens junctions is associated with initiation of epithelial folding

During tissue morphogenesis, simple epithelial sheets undergo folding to form complex structures. The prevailing model underlying epithelial folding involves cell shape changes driven by myosin-dependent apical constriction. Here we describe an alternative mechanism that requires differential positioning of adherens junctions controlled by modulation of epithelial apical-basal polarity. Using live embryo imaging, we show that before the initiation of dorsal transverse folds during Drosophila gastrulation, adherens junctions shift basally in the initiating cells, but maintain their original subapical positioning in the neighbouring cells. Junctional positioning in the dorsal epithelium depends on the polarity proteins Bazooka and Par-1. In particular, the basal shift that occurs in the initiating cells is associated with a progressive decrease in Par-1 levels. We show that uniform reduction of the activity of Bazooka or Par-1 results in uniform apical or lateral positioning of junctions and in each case dorsal fold initiation is abolished. In addition, an increase in the Bazooka/Par-1 ratio causes formation of ectopic dorsal folds. The basal shift of junctions not only alters the apical shape of the initiating cells, but also forces the lateral membrane of the adjacent cells to bend towards the initiating cells, thereby facilitating tissue deformation. Our data thus establish a direct link between modification of epithelial polarity and initiation of epithelial folding.