Molecular study of hypersensitivity to spores in adults and children from Castile & Leon

Introduction and objectivesBiological aerosols play a vital role in the interactions between the atmosphere, biosphere, climate and public health and fungal spores are a component with allergic importance.We constructed a database in Castile & Leon (Spain) and carry out molecular-level component-resolved diagnosis to complete the air quality study carried out since 2006 by our aerobiological network (RACYL) to aid clinical diagnosis and treatment.MethodsWe reviewed a database of 19,774 patients (adults and children) with allergic respiratory disease treated in our unit during the last 12 years. We also made a component-resolved diagnosis of the molecules involved in the pathology in a randomly selected population of 150 patients.ResultsThe dimeric glycoprotein Alt a1 from Alternaria is the most prevalent and most useful allergen in the diagnosis of patients with allergy to fungi in our area (94.4%), followed by enolase Alt a 6 (Alternaria), ribonuclease Asp f 1 of Aspergillus and mannitol dehydrogenase from Cla h 8 (Cladosporium).ConclusionsOur results have helped determine which spore molecules are most-closely associated with allergies. Molecular analysis will be useful to determine more accurate and useful immunotherapy in these patients.     

Mechanisms mediating the brain stem control of somatosensory transmission in the dorsal horn of the cat's spinal cord: an intracellular analysis

Summary The effect of brainstem stimulation was studied on neurones recorded intracellularly in the superficial and deeper laminae of the lumbosacral dorsal horn of the spinal cord in anaesthetised cats. Stimulation in the nucleus locus coeruleus (LC) produced a hyperpolarisation in 4/13 multireceptive neurones and produced a biphasic action consisting of a hyperpolarisation which was followed by a depolarisation in 3/13 neurones. These actions were produced irrespective of whether the multireceptive neurone was located in the superficial or deeper laminae of the dorsal horn. Stimulation failed to produce postsynaptic potentials in the remaining 6/13 multireceptive neurones. The amplitude of hyperpolarisation was increased by the passage of depolarising pulses through the recording microelectrode and decreased by hyperpolarising pulses. Stimulation in other brainstem areas such as, the lateral (FTL), paralemniscal (FTP) and central (FTC) divisions of the tegmental field and the nuclei raphe magnus (NRM) and reticularis magnocellularis (RMc) also hyperpolarised neurones in the dorsal horn. The polarity of hyperpolarisation evoked from some brainstem areas (FTP, FTC, RMc) could be reversed to depolarisation by the passive diffusion of ions from the recording microelectrode containing 3M-KCl. Brainstem (LC, NRM, FTP, FTL) stimulation generated long lasting (700 ms) hyperpolarisation on 4/4 selectively nocireceptive neurones of lamina I. There was, however, no effect on the activity of 5/5 neurones recorded in laminae I/II which in addition to receiving excitatory cutaneous inputs were inhibited by heat stimuli. Stimulation in LC also produced dorsal root potentials (DRPs) and reduced the amplitude of simultaneously recorded excitatory postsynaptic potentials (EPSPs) generated by the activation of primary afferent fibres in 3 multireceptive neurones. It is concluded that inhibition of nociceptive transmission in the spinal cord from LC and other brainstem areas may involve both pre- and postsynaptic mechanisms.     

黄芩中四种主要黄酮成分与环氧酶-2的分子对接研究

目的:黄芩中四种主要黄酮与COX-2进行分子对接。方法:采用软件Molegro Virtual Docker(MVD),以选择性COX-2抑制剂SC-558和6COX共结晶复合物作为受体模板,建立COX-2的活性位点,并对黄芩苷等四种黄酮进行分子对接。结果:黄芩苷、汉黄芩苷、黄芩素、汉黄芩素与6COX发生分子对接的MVD分值分别为-121.64KJ/moL、-124.76KJ/moL、-96.11KJ/moL和-96.68KJ/moL。黄芩苷、汉黄芩苷以及SC-558均能作用于以Leu352,Phe518,Gly526,Val523,Ala527和Ser353等氨基酸残基组成的活性位点。结论:黄芩苷等四种黄酮与COX-2能够成功进行分子对接,其对接位点信息有助于该类化合物抑制COX-2的活性机制的阐释。     

Molecular targeted therapy for advanced hepatocellular carcinoma

Systemic anticancer therapy for hepatocellular carcinoma (HCC) is limited by intrinsic drug resistance and accompanying liver dysfunction. However, recent advances in molecular targeted therapy (MTT) have shed light on the treatment of advanced HCC. A recent randomized, placebo-controlled trial demonstrated that sorafenib, a multi-target tyrosine kinase inhibitor, prolonged overall survival and time-to-progression in patients with advanced HCC. This breakthrough highlights the potential of MTT targeting hepatocarcinogenic pathways, such as the Raf/MAPK/ERK pathway, angiogenic pathways and the EGFR signaling pathway. This review discusses the current status and the potential of developing novel MTTs for advanced HCC.     

The nature of polymorphism of the HLA-DRB intron sequences is lineage specific

Abstract: The sequence database of HLA-DRB genes is mainly derived from mRNA analysis or has focused exclusively on the polymorphism of the 2nd exon. Little is known about the non-coding sequences of the different DRB alleles which represent about 94% of the genes. In this study we have determined the sequence of the 3' 500 bp intron 1 fragment adjacent to exon 2 in all serologically defined HLA-DRB genes and their most frequent allelic subtypes. The intron sequences turned out to be highly polymorphic. Similar to the class I introns, this variability was not characterized by random point mutations but by a highly systematic diversity reflecting the lineage-specific relationship of the HLA-DR alleles. With a few exceptions in DRB1*15, 13 and 08 as well as DRB 4 and 5, the variability mirrors the serological diversity. As well as delivering insight into the genetic relationship between the different DRB alleles, these sequences will provide an extremely valuable basis for developing advanced DRB sequencing strategies for clinical purposes.     

Morphological and biochemical correlates of chemical induced injury in the lung

We have reviewed some of the factors which contribute to lung damage by various toxicants. These include disposition of the chemical, its metabolism, individual cell type susceptibility and the potential for the tissue to repair. We have discussed the use of biochemical parameters to measure the functional activity of individual cell types in order to predict the damage to specific cell types and concluded that careful morphological analysis of lung tissue is likely to provide a more sensitive and informative measure of specific cell type injury. However, in order to investigate the mechanism of toxicity of pulmonary toxicants it is essential to establish the primary biochemical event that leads to cell damage and morphological change. The importance of separating the relevant biochemical change(s) from the cascade of biochemical events associated with dead and dying cells and the reparative response of the lung is emphasised.This report results from a discussion sponsored and organised by the Advisory Subgroup in Toxicology (AST) of the European Science Foundation's Standing Committee for the European Medical Research Councils and held at the Medical Research Council Toxicology Unit, Carshalton, U. K. Those taking part were: W. N. Aldridge (AST; as above); J. Bignon (Unit for Research in Renal and Pulmonary Pathology, University of Paris, Creteil, France); P. H. Burri (Section of Developmental Biology, Institute of Anatomy, University of Berne, Switzerland); G. M. Cohen (as above); D. Dinsdale (MRC Toxicology Unit, Carshalton U. K.); P. Hedqvist (Dept. of Physiology, Karolinska Institute, Stockholm, Sweden); D. Henschler (AST; Dept. of Toxicology and Pharmacology, University of Wurzburg, FDR); G. J. Laurent (Biochemistry Unit, Cardiothoracic Institute, University of London, London, U. K.); R. Lauwerys (AST Industrial and Medical Toxicology Unit, University of Louvain, Brussels, Belgium); F. Lembeck (AST; Dept. for Experimental and Clinical Pharmacology, University of Graz, Austria); N. Lery (AST; Poison Control Centre, Lyon, France); P. Moldeus (Dept. of Forensic Medicine, Karolinska Institute, Stockholm, Sweden); B. Nemery (MRC Toxicology Unit, Carshalton, U. K.); A. Saria (Dept. for Experimental and Clinical Pharmacology, University of Graz, Austria); L. L. Smith (as above);B. Terracini (AST; Dept. of Pathology and Cancer Epidemiology, University of Turin, Italy)     

Expression, purification and molecular modeling of recombinant fibrinogenase [IV], a metalloproteinase from Deinakistrodon acutus venom.

A novel metalloproteinase, recombinant fibrinogenase IV (rFIV(a)), was expressed and purified from Deinakistrodon acutus venom. It was a single chain protein with an apparent molecular weight 27 kDa and an isoeletric point of pH 7.1. RFIV(a) cleaved preferentially the Aalpha-chain and also cleaved Bbeta, gamma-chains of fibrinogen when the incubation time was prolonged. The proteolytic activity was inhibited by EDTA, l-cysteine, and DTT, indicating rFIV(a) was a metalloproteinase requiring disulfide bonds for its activity. It kept above 85% of the initial activity from pH 4.5-11, showed an equal maximum activity at the temperature range from 30 to 50 degrees C, and was inactivated by Zn2+, Cu2+ and Cd2+. Homology modeling of rFIV(a) showed that two highly conserved disulfide bonds (Cys159-Cys164 and Cys117-Cys197) was maintained from its structure, and it exhibited the characteristic conserved motif H142E143XXH146XXGXXH152, whose three histidine residues were involved in binding of the catalytically essential zinc ion. This work demonstrates the expression, purification and characterization of recombinant fibrinogenase IV, which belongs to class P-I metalloproteinase from D. acutus venom.     

脊髓损伤后中枢性疼痛的实验模型和机制研究进展

中枢性疼痛(central pain,CP)是脊髓损伤(spi-nal cord injury,SCI)的顽固性合并症,为患者主观上感到损伤平面以下皮肤痛觉消失区一种以自发痛为主的疼痛,发生率为11%~94%,严重者为5%~30%。近年来其发生率逐年增高,使很多患者陷于抑郁、药物成瘾、甚至自杀的悲惨境地。许多疼痛