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991.
We examined whether the incorporation of a second amino group into the 1-aminoethyl pharmacophore of rimantadine 2 and into the piperidine pharmacophore of the heterocyclic rimantadine 4 was compatible with anti-influenza virus A activity. The new synthetic molecules are capable of forming two hydrogen bonds within the receptor. We identified molecules 8 and 16, bearing the adamantyl and 1,2-diaminoethyl groups, which are equipotent to rimantadine 2 bearing the adamantyl and 1-aminoethyl pharmacophore groups. Interestingly, diamino compound 16 is a 4-fold more potent inhibitor than its parent monoamino heterocyclic rimantadine 4 propably because of additional hydrogen bonding interactions with the M2 protein receptor.  相似文献   
992.
The nucleic acid binding channel of the hepatitis C virus RNA polymerase remains to be defined. Here we employed complementary footprinting techniques and show that the enzyme binds to a newly synthesized duplex of approximately seven to eight base pairs. Comparative analysis of surface topologies of free enzyme versus the nucleoprotein complex revealed certain lysines and arginines that are protected from chemical modification upon RNA binding. The protection pattern helps to define the trajectory of the nucleic acid substrate. Lys(81), Lys(98), Lys(100), Lys(106), Arg(158), Arg(386), and Arg(394) probably interact with the bound RNA. The selective protection of amino acids of the arginine-rich region in helix T points to RNA-induced conformational rearrangements. Together, these findings suggest that RNA-protein interaction through the entire substrate binding channel can modulate intradomain contacts at the C terminus.  相似文献   
993.
In all of the liver bile acid-binding proteins (L-BABPs) studied so far, it has been found that the stoichiometry of binding is of two cholate molecules per internal binding site. In this paper, we describe the expression, purification, crystallization, and three-dimensional structure determination of zebrafish (Danio rerio) L-BABP to 1.5A resolution, which is currently the highest available for a protein of this family. Since we have found that in zebrafish, the stoichiometry of binding in the protein cavity is of only one cholate molecule per wild type L-BABP, we examined the role of two crucial amino acids present in the binding site. Using site-directed mutagenesis, we have prepared, crystallized, and determined the three-dimensional structure of co-crystals of two mutants. The mutant G55R has the same stoichiometry of binding as the wild type protein, whereas the C91T mutant changes the stoichiometry of binding from one to two ligand molecules in the cavity and therefore appears to be more similar to the other members of the L-BABP family. Based on the presence or absence of a single disulfide bridge, it can be postulated that fish should bind a single cholate molecule, whereas amphibians and higher vertebrates should bind two. Isothermal titration calorimetry has also revealed the presence in the wild type protein and the G55R mutant of an additional binding site, different from the first and probably located on the surface of the molecule.  相似文献   
994.
The sclerophyllous forests of Quercus ilex (holm oak) possess a unique position in earth’s biosphere, existing only in countries of the Mediterranean basin. However, very little information exists about mushrooms associated with holm oak in east Mediterranean, including Greece, where Q. ilex appears mostly in relict forests and fragmented stands. A pertinent long-term investigation was undertaken in selected Q. ilex dominated habitats of Crete, Andros, Naxos and Ikaria islands (Aegean Archipelago) as well as in mountains of Attica. Specimens of xylotrophic basidiomycetes were collected and identified. As a result, 74 species were recorded; among them Hemimycena cephalotricha, Hyphoderma cremeoalbum, Hyphodontia radula, Irpex litschaueri, Mycena algeriensis, Phanerochaete martelliana, Phloeomana alba and Phlebia unica constitute new records for the Greek mycobiota, while 68 species are reported for the first time on Q. ilex in Greece. Moreover, the presence of Fomitiporia mediterranea on this host was evidenced through ITS sequencing, and comments are made about its relationship to F. punctata and F. pseudopunctata. The importance of findings is discussed in conjunction with their environmental value; five species could be assigned in the “Species of Special Interest” categories, and other five polypores are proposed as suitable indicators for Q. ilex habitat assessment and conservation.  相似文献   
995.
<正>Amino acids are biologically important molecules that serve as energy source, building blocks of proteins, precursors for metabolites and signaling compounds in all living cells.Transport of proteinogenic amino acids and related substances across biological membranes is mediated by membrane embedded proteins:the amino acid transporters. These membrane proteins belong to different solute carrier (SLC)families (http://slc.bioparadigms.org) and transfer amino acids in and out between compartments inside cells, between different cells and between organs. Amino acid transporters have diverse important physiological functions and their absence, overexpression and malfunction can lead to human diseases.  相似文献   
996.
In vitro studies suggested that nitrite may play a cytoprotective role in inflammation. The aim of the present clinical study was to investigate the relationship between the NO metabolites nitrite and nitrate and the biomarkers of oxidative stress 3-nitrotyrosine (3-NT) and 15(S)-iso-PGF in patients suffering from chronic inflammatory rheumatic diseases. In morning urine from 28 patients with different chronic inflammatory rheumatic diseases (23–82 years of age) and from 41 healthy persons of both genders, nitrite and nitrate were quantitated by GC-MS, and 3-NT and 15(S)-iso-PGF by GC-MS/MS. Mean creatinine-corrected urinary excretion rates of nitrite (1.1 versus 0.19 μmol/mmol, P = 0.00012) and 3-NT (1.2 versus 0.39 nmol/mmol, P = 0.01629), but not of nitrate (105 versus 106 μmol/mmol), were significantly elevated in rheumatism as compared to health. Urinary excretion rate of 15(S)-iso-PGF did not differ between patients and healthy subjects (65 versus 69 pmol/mmol creatinine, P = 0.48). In rheumatism, urinary 3-NT correlated closely with nitrite (R = 0.788, P < 0.0001) and moderately with nitrate (R = 0.45, P < 0.016), but did not correlate with 15(S)-iso-PGF (R = ?0.083, P = 0.68). In healthy persons there was no correlation between urinary 3-NT and nitrite or nitrate. Our study suggests that urinary nitrite may represent a novel specific biomarker of nitrative stress in chronic inflammatory rheumatic disease. In another eight patients with chronic inflammatory rheumatic diseases we found higher nitrite concentrations in synovial fluid as compared to serum (1.30 versus 0.35 μM). We hypothesize that in chronic inflammatory rheumatic diseases nitrite concentration is elevated in the inflamed joint and contributes to the inactivation of myeloperoxidase-catalyzed production of hypochloric acid by forming nitryl chloride which eventually nitrates tyrosine to form 3-NT.  相似文献   
997.
998.

Background

Recent evidence has underscored the role of hypoxia and angiogenesis in the pathogenesis of idiopathic fibrotic lung disease. Inhibitor of growth family member 4 (ING4) has recently attracted much attention as a tumor suppressor gene, due to its ability to inhibit cancer cell proliferation, migration and angiogenesis. The aim of our study was to investigate the role of ING4 in the pathogenesis of pulmonary fibrosis both in the bleomycin (BLM)-model and in two different types of human pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and cryptogenic organizing pneumonia (COP).

Methods

Experimental model of pulmonary fibrosis was induced by a single tail vein injection of bleomycin in 6- to 8-wk-old C57BL/6mice. Tissue microarrays coupled with qRT-PCR and immunohistochemistry were applied in whole lung samples and paraffin-embedded tissue sections of 30 patients with IPF, 20 with COP and 20 control subjects.

Results

A gradual decline of ING4 expression in both mRNA and protein levels was reported in the BLM-model. ING4 was also found down-regulated in IPF patients compared to COP and control subjects. Immunolocalization analyses revealed increased expression in areas of normal epithelium and in alveolar epithelium surrounding Masson bodies, in COP lung, whereas showed no expression within areas of active fibrosis within IPF and COP lung. In addition, ING4 expression levels were negatively correlated with pulmonary function parameters in IPF patients.

Conclusion

Our data suggest a potential role for ING4 in lung fibrogenesis. ING4 down-regulation may facilitate aberrant vascular remodelling and fibroblast proliferation and migration leading to progressive disease.  相似文献   
999.
1000.
Dopaminergic activity is expected to be altered in patients with Huntington’s disease (HD) and be related to factors like duration and severity of illness or patients’ specific symptomatology like dementia, depression, or psychotic features. We assessed plasma homovanillic acid (pHVA) and plasma prolactin (pPRL), two correlates of dopaminergic activity, in 116 subjects with CAG repeats expansion in the HD gene, 26 presymptomatic (18 females) and 90 with overt symptomatology (43 females). Patients were evaluated using the Unified HD Rating Scale and the Total Functional Capacity Scale. Presence of dementia, depression, and psychotic features were also assessed. The age range of the patients was 22–83 years, duration of illness from 0.5 to 27 years, and CAG repeat number from 34 to 66. A group of 60 age and sex matched healthy subjects served as control group. Plasma PRL in subjects at risk and in neuroleptic-free patients, evaluated separately for males and females, did not differ from controls. Plasma HVA levels did not differ from controls in the group of presymptomatic subjects, but were significantly higher in the patients group. This increase was positively associated mainly with severity of illness and functional capacity of the patients, and not with presence of depression or dementia. Plasma HVA levels may be proven to be a peripheral index of disease progression. Reducing dopaminergic activity may have not only symptomatic, but also neuroprotective effects in HD.  相似文献   
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