The structure and function of platelet-activating factor acetylhydrolases

Platelet-activating factor acetylhydrolases (PAF-AHs, EC 3.1.1.47) constitute a unique and biologically important family of phospholipase A2s. They are related to neither the well-characterized secretory nor cytosolic PLA2s, and unlike them do not require Ca2+ for catalytic activity. The distinguishing property of PAF-AHs is their unique substrate specificity: they act on the phospholipid platelet-activating factor (PAF), and in some cases on proinflammatory polar phospholipids, from which they remove a short acyl moiety--acetyl in the case of PAF--located at the sn-2 position. Because PAF is found both in the plasma and in the cytosol of many tissues, PAF-acetylhydrolases are equally widely distributed in an animal organism. Recent crystallographic studies shed new light on the complex structure-function relationships in PAF-AHs.     

有限精度时间自动机的可达性检测

为了缓解状态空间爆炸问题,减小模型检测过程中生成的状态空间,加快模型检测速度,引入有限精度时间自动机(finite precision timed automata,简称FPTA)作为实时系统的形式模型,并提出了一种数据结构SDS(series of delay sequence)符号化表示状态空间中的状态集.FPTA只记录时钟变量的整数值及时钟变化的先后次序,从而减小生成的状态空间.在一定的时间约束下,Alur与Dill提出的时间自动机的可达性检测可简化为FPTA的可达性检测.举例描述了状态空间的生成过程和表示方法.最后,列出部分初步的实验结果,分析了SDS的特点及不足.     

Dyslipidemias and autoimmune diseases

The paper summarizes the results of over 30-year studies dealt with dyslipidemias and autoimmune diseases. The teaching of the antiphospholipid syndrome (APS) has aroused interest in the problem. The experience gained shows changes in the blood cholesterol transport system. Patients with systemic lupus erythematosus (SLE) have higher levels of low density lipoprotein cholesterol and lower concentrations of high density lipoprotein (HDL) cholesterol, apolipoprotein A than the controls. The quantitative and qualitative changes in particles result in decreased acceptance of cholesterol from the membrane of a cell and tissues, which promotes the development of vascular diseases. Lipoprotein (a) may be an additional risk factor for thrombosis chiefly of coronary arteries, in patients with SLE and APS. Increased levels of oxidized low density proteins having atherogenic activity were found mainly in patients with SLE. The use of corticosteroids causes the changes in the spectrum of blood lipids, which together with other factors (thrombosis, vasculopathy, thrombocytopenia, etc.) create good conditions for the development of atherosclerosis, which determines the necessity of correcting the parameters of blood lipid transport not only to prevent vascular disorders but to improve the general life prognosis in SLE patients.     

Improved exercise tolerance following enhanced external counterpulsation: cardiac or peripheral effect?

Tissue damage, inflammation and necrosis are hallmarks of myocardial infarction. In the present study significant elevations of serum alpha-1-antitrypsin were noted in coronary artery disease and angina cases. Interestingly chronic rheumatic heart disease which is also characterized by tissue injury. Inflammation revealed normal levels of serum alpha-1-antitrypsin. The level in chronic rheumatic heart disease was 3.37 +/- 0.57 mumol/mt/ml (control level was 3.37 +/- 0.54 mumol/mt/ml). The corollary of these observations is that in heart diseases acute phase response in terms of enhanced levels of alpha-1-antitrypsin differ depending on the causative factors. Except chronic rheumatic heart disease, in all other stressful states studied there is (to a certain degree) an altered systemic homeostasis and haemostasis. On the other hand chronic rheumatic heart disease encompass certain amount of acute phase status in terms of tissue damage and inflammation does exist unaccompanied by altered systemic homeostasis and haemostasis. However, bacteriological etiologies predominate the triggered immune responses. It is hypothesised that serum alpha-1-antitrypsin enhancement will not occur even though acute phase state exists if specific immune responses are also a part of the disease manifestation.     

Acute hemodynamic effects of estrogen administration in postmenopausal women

The hemodynamic effects of estrogens in replacement doses have not been fully clarified; therefore, we studied the acute hemodynamic changes after 0.625 and 1.25 mg of conjugated estrogens, administered intravenously, using a thermodilution catheter, in postmenopausal women without structural heart disease. Pulmonary and systemic pressures and resistances and stroke volume did not change compared with baseline, but heart rate and cardiac output decreased significantly, which may be associated with estrogen's previously described calcium-blocking effect or with a more recently contemplated beta-blocking action.     

Agmatine--a novel endogenous ligand of imidazoline receptors

Hyperalgesia is known to depend on neuroplastic changes chiefly represented by long-term potentiation. These phenomena are proved to depend on excitatory amino acids (EAAs) action at the level of NMDA receptors. This action is known to be related to nitric oxide (NO) release. We found a visceral/vascular hyperalgesia state in migraine (M) sufferers as well as an inheritable systemic hyperalgesia in healthy subjects who are first-degree consanguineous with M sufferers; this type was labelled 'third hyperalgesia'. We discovered that a hyper-increase of plasma L-citrulline, equimolar co-product in the synthesis of NO, characterizes both M sufferers and their first-degree relatives who are exempt from primary headache. A similar pattern never occurred in healthy subjects having both a personal and family history negative for primary headache. We conclude that both 'third hyperalgesia' and a pattern of NO synthase (NOS) hyperactivity seems to be inheritable and can constitute, at least in part, a ground for developing headache. Morphine, proved to be unable to relieve M attack, was given in low doses that caused pain and side-effects in M sufferers only. This outcome seemingly indicates that M sufferers are characterized by a set-up of opioid receptor subtypes different from that of healthy headache-exempts. Following a period of morphine addiction and a withdrawal period, 65.07% of a group of 63 opiate addicts developed M syndrome. All these subjects were first-degree consanguineous relatives of primary headache sufferers. Discussion topics concern the activity of morphine in NO release and the role of NO in sensory transmission of both controls and hyperalgesia sufferers. It is suggested that the inheritable couple consisting of hyperalgesia and NOS hyperactivity can play some role in setting off the pain occurring following morphine in M sufferers.     

Brain acetylhydrolase that inactivates platelet-activating factor is a G-protein-like trimer

The platelet-activating factor PAF (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a potent lipid first messenger active in general cell activation, fertilization, inflammatory and allergic reactions, asthma, HIV pathogenesis, carcinogenesis, and apoptosis. There is substantial evidence that PAF is involved in intracellular signalling, but the pathways are poorly understood. Inactivation of PAF is carried out by specific intra- and extracellular acetylhydrolases (PAF-AHs), a subfamily of phospholipases A2 that remove the sn-2 acetyl group. Mammalian brain contains at least three intracellular isoforms, of which PAF-AH(Ib) is the best characterized. This isoform contains a heterodimer of two homologous catalytic subunits alpha1 and alpha2, each of relative molecular mass 26K, and a non-catalytic 45K beta-subunit, a homologue of the beta-subunit of trimeric G proteins. We now report the crystal structure of the bovine alpha1 subunit of PAF-AH(Ib) at 1.7 A resolution in complex with a reaction product, acetate. The tertiary fold of this protein is closely reminiscent of that found in p21(ras) and other GTPases. The active site is made up of a trypsin-like triad of Ser 47, His 195 and Asp 192. Thus, the intact PAF-AH(Ib) molecule is an unusual G-protein-like (alpha1/alpha2)beta trimer.