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71.
Klemens Högenauer Klaus Hinterding Peter Nussbaumer 《Bioorganic & medicinal chemistry letters》2010,20(5):1485-1487
Various carboxylic acids, phosphonic acids, sulfonic acids, tetrazoles as well as sulfonylhydantoins were prepared as phosphate mimics of the chiral aminophosphate 1-P to act as agonists on the S1P1 receptor. It was found that amino phosphonates and amino carboxylates are potent S1P1 binders. β-Amino acid 11 could be shown to reversibly reduce blood lymphocyte counts in rats after po administration. 相似文献
72.
The effect of relaxed functional constraints on the photosynthetic gene rbcL in photosynthetic and nonphotosynthetic parasitic plants 总被引:1,自引:0,他引:1
The photosynthetic gene rbcL has been lost or dramatically altered in some
lineages of nonphotosynthetic parasitic plants, but the dynamics of these
events following loss of photosynthesis and whether rbcL has sustained
functionally significant changes in photosynthetic parasitic plants are
unknown. To assess the changes to rbcL associated with the loss of
functional constraints for photosynthesis, nucleotide sequences from
nonparasitic and parasitic plants of Scrophulariales were used for
phylogeny reconstruction and character analysis. Plants in this group
display a broad range of parasitic abilities, from photosynthetic
("hemiparasites") to nonphotosynthetic ("holoparasites"). With the
exception of Conopholis (Orobanchaceae), the rbcL locus is present in all
parasitic plants of Scrophulariales examined. Several holoparasitic genera
included in this study, including Boschniakia, Epifagus, Orobanche, and
Hyobanche, have rbcL pseudogenes. However, the holoparasites Alectra
orobanchoides, Harveya capensis, Harveya purpurea, Lathraea clandestina,
Orobanche corymbosa, O. fasciculata, and Striga gesnerioides have intact
open reading frames (ORFs) for the rbcL gene. Phylogenetic hypotheses based
on rbcL are largely in agreement with those based on sequences of the
nonphotosynthetic genes rps2 and matK and show a single origin of
parasitism, and loss of photosynthesis and pseudogene formation have been
independently derived several times in Scrophulariales. The mutations in
rbcL in nonparasitic and hemiparasitic plants would result in largely
conservative amino acid substitutions, supporting the hypothesis that
functional proteins can experience only a limited range of changes, even in
minimally photosynthetic plants. In contrast, ORFs in some holoparasites
had many previously unobserved missense substitutions at functionally
important amino acid residues, suggesting that rbcL genes in these plants
have evolved under relaxed or altered functional constraints.
相似文献
73.
Alternative splicing and protein function 总被引:1,自引:0,他引:1
AD?Neverov II?Artamonova RN?Nurtdinov D?Frishman MS?GelfandEmail author AA?Mironov 《BMC bioinformatics》2005,6(1):266
Background
Alternative splicing is a major mechanism of generating protein diversity in higher eukaryotes. Although at least half, and probably more, of mammalian genes are alternatively spliced, it was not clear, whether the frequency of alternative splicing is the same in different functional categories. The problem is obscured by uneven coverage of genes by ESTs and a large number of artifacts in the EST data. 相似文献74.
Allogeneic dendritic cell vaccination against metastatic renal cell carcinoma with or without cyclophosphamide 总被引:3,自引:0,他引:3
Höltl L Ramoner R Zelle-Rieser C Gander H Putz T Papesh C Nussbaumer W Falkensammer C Bartsch G Thurnher M 《Cancer immunology, immunotherapy : CII》2005,54(7):663-670
In this phase I/II study, we evaluated the feasibility, safety and efficacy of allogeneic dendritic cells (DCs) with or without cyclophosphamide in the treatment of patients with metastatic renal cell carcinoma (RCC). Immunomagnetic beads were used to isolate CD14+ monocytes from healthy donor leukapheresis products, and CD83+ antigen-pulsed monocyte-derived DCs (moDCs) loaded with tumor lysate and keyhole limpet hemocyanin (KLH) were generated. Twelve patients were treated with allogeneic moDCs alone, while ten patients also received cyclophosphamide on days 4 and 3 prior to vaccination. Of the 22 patients enrolled, 20 received full treatment consisting of at least three vaccinations at monthly intervals. Two mixed responses with substantial tumor regression were observed. In 3 patients, disease stabilization occurred, in 13 patients disease progressed and 4 patients were lost to follow-up. Overall, immune responses against KLH and tumor lysate were weak or absent; however, the strongest increases in antigen-independent and KLH-specific responses were observed in the 2 patients with mixed responses. In addition, 1 of them showed a substantial increase in oncofetal antigen (OFA)-specific IFN- production. Importantly, the 2 mixed responders and 1 patient with stable disease belonged to the cyclophosphamide group. Median overall survival in the cyclophosphamide group was 23.2 and 20.3 months in the group that received allogeneic moDCs alone. Allogeneic immunotherapy with moDCs is feasible and well tolerated. However, the immunogenicity of allogeneic moDCs is clearly less pronounced than that of autologous moDC immunotherapy. Cyclophosphamide may have the capacity to augment DC-induced antitumor immunity. 相似文献
75.
The aim of the present study was to simulate the input system and the motoneuron (MN) pool of the MN pool–muscle complex
(MNPMC). Input fibers, which can originate from command centers in the central nervous system or from sensory organs, activate
the MN pool. They generate sequences of action potentials, the frequency of which is proportional to a time-dependent activation
factor (which is an input to the model). Different connection patterns between the input fibers and motor units (MUs) are
allowed. For simplicity and since no precise experimental data are available, 70 input fibers and 4 boutons per fiber and
MN are simulated (this corresponds approximately to the monosynaptic group-Ia input of the cat medial gastrocnemius muscle).
Each bouton generates the same conductance change in the postsynaptic membrane. The MNs are modeled with a single compartment
and a homogenous membrane. According to experimental data, the membrane leakage conductance and capacitance are MU dependent.
Since the precise relation is unknown: (a) the computed relation between MU contraction force and the MN leakage conductance
was taken from a steady-state MNPMC model, and (b) the capacitance was assumed to be proportional to the leakage conductance.
The MN membrane includes time- and voltage-dependent ionic channels (fast and slow K+ and low- and high-threshold Ca2+ channels). The density and time constant of the slow K+ channels and the density of the Ca2+ channels were fitted to approximate afterhyperpolarization characteristics and frequency-injected current relations of type-identified
cat MNs. If the membrane reaches a voltage threshold the MNs generate action potentials, which were simulated by voltage pulses.
The activation of the MN pool of the human first dorsal interosseus muscle was simulated with injected and synaptic currents
in order to illustrate the size principle, synaptic noise, and other features of muscle activation. It is concluded that the
present model reproduces the main properties of the input–output relations of different MN types within a muscle. Together
with the simulation of the muscle force and the surface EMG, which will be published in subsequent papers, it will be a powerful
tool for reproducing experiments on the motor system and investigating functional mechanisms of motor control.
Received: 17 April 2001 / Accepted in revised form: 6 November 2001 相似文献
76.
Aiming at new drugs to efficiently treat diseases, in which either increased or decreased levels of active vitamin D are desirable, we have designed some 400 structurally different azole-type inhibitors and examined their capacity to selectively block vitamin D metabolism by CYP24 or synthesis by CYP27B, in human keratinocytes. Based on resulting data, we built pharmacophore models of the active sites using commercial software. The overlay of potent selective compounds indicated similar docking modes in the two-substrate pockets and allowed for identification of bioactive conformations. Superimposing these bioactive conformations with low energy conformers of 25(OH)D(3) suggested that the substrate-mimicked by strong inhibitors in size, shape and lipophilic character-binds to both enzymes in 6s-trans configuration. Pharmacophoric models implied a similar geometry of the substrate sites, nevertheless specific features of CYP24 and CYP27B could be defined. Bulky substituents in alpha-position to the azole caused selectivity for CYP24, whereas bulky substituents in beta-position could result in selectivity for CYP27B. Moreover, studies with small sterically restricted inhibitors revealed a probable location of the 3-OH-group of 25(OH)D(3) in CYP27B. In the absence of crystal structures, our inhibitors are valuable tools to model and understand the active sites of vitamin D hydroxylases, resulting in the design of powerful, selective therapeutics. 相似文献
77.
Billich A Meingassner JG Nussbaumer P Desrayaud S Lam C Winiski A Schreiner E 《The Journal of steroid biochemistry and molecular biology》2004,92(1-2):29-37
Steroid sulfatase (STS) offers a new target for the treatment of steroid hormone-dependent diseases, such as breast and prostate cancer and androgen-dependent skin diseases. We here characterize a novel non-estrogenic inhibitor of the enzyme, namely 6-[2-(adamantylidene)-hydroxybenzoxazole]-O-sulfamate (AHBS), with special attention to its potential use in the treatment of acne. The compound blocks STS activity in homogenates of human skin with IC(50)=16 nM. Following a single oral dose (5 mg/kg) in rats, the compound blocks STS in the skin by 95% at 8 h, followed by recovery of activity over 5 days. Following topical application to the skin, both in vitro and in vivo, AHBS passes through the stratum corneum leading to inhibition of STS activity in the dermal compartment with rapid onset and long duration. Topical application of AHBS to G?ttingen minipigs for a period of 2 weeks does not induce symptoms of ichthyosis as seen in STS-deficient human subjects, but leads to a reduction of sebum secretion to the skin surface. Based on these data, clinical studies with AHBS in acne patients are warranted, in order to verify the hypothesis on the importance of the sulfatase pathway in androgen-dependent skin diseases. 相似文献
78.
The components of hard tissues including dentin, enamel, cementum, bone and other calcified deposits, and mature and immature collagen pose problems for identification in routine hematoxylin and eosin (H & E) stained sections. Use of combinations of stains can demonstrate the components of hard tissues and soft tissues distinctly. We assessed the efficacy of the Verde Luz-orange G-acid fuchsin (VOF) stain for differentiating hard and soft connective tissues and compared results with other histochemical staining techniques. Eighty tissue sections comprising developing tooth (30), ossifying fibroma (30) and miscellaneous pathologies (20) expected to contain varying types of calcified tissues were stained with H & E, VOF, and Masson's trichrome (MT). In developing tooth, VOF demonstrated better differentiation of hard tissues, while it was comparable to MT for ossifying fibroma and miscellaneous pathologies. The intensity of staining was greater with VOF than with the other stains studied. VOF stains hard tissue components distinctly and gives good contrast with the surrounding connective tissue. VOF is comparable to MT, but has added advantages including single step staining, rapid and easy procedures, and it distinguishes the maturity of the tissues. 相似文献
79.
The method of affinity coelectrophoresis was used to study the binding of
nine representative glycosaminoglycan (GAG)-binding proteins, all thought
to play roles in nervous system development, to GAGs and proteoglycans
isolated from developing rat brain. Binding to heparin and non-neural
heparan and chondroitin sulfates was also measured. All nine
proteins-laminin-1, fibronectin, thrombospondin-1, NCAM, L1, protease
nexin-1, urokinase plasminogen activator, thrombin, and fibroblast growth
factor-2-bound brain heparan sulfate less strongly than heparin, but the
degree of difference in affinity varied considerably. Protease nexin-1
bound brain heparan sulfate only 1.8- fold less tightly than heparin
(Kdvalues of 35 vs. 20 nM, respectively), whereas NCAM and L1 bound heparin
well (Kd approximately 140 nM) but failed to bind detectably to brain
heparan sulfate (Kd>3 microM). Four proteins bound brain chondroitin
sulfate, with affinities equal to or a few fold stronger than the same
proteins displayed toward cartilage chondroitin sulfate. Overall, the
highest affinities were observed with intact heparan sulfate proteoglycans:
laminin-1's affinities for the proteoglycans cerebroglycan (glypican-2),
glypican-1 and syndecan-3 were 300- to 1800-fold stronger than its affinity
for brain heparan sulfate. In contrast, the affinities of fibroblast growth
factor-2 for cerebroglycan and for brain heparan sulfate were similar.
Interestingly, partial proteolysis of cerebroglycan resulted in a >400-
fold loss of laminin affinity. These data support the views that (1)
GAG-binding proteins can be differentially sensitive to variations in GAG
structure, and (2) core proteins can have dramatic, ligand-specific
influences on protein-proteoglycan interactions.
相似文献