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In situ intercellular strains in the outer annulus fibrosus of bovine caudal discs were determined under two states of biaxial strain. Confocal microscopy was used to track and capture images of fluorescently labelled nuclei at applied Lagrangian strains in the axial direction (E(A)(S)) of 0%, 7.5% and 15% while the circumferential direction (E(C)(S)) was constrained to either 0% or -2.5%. The position of the nuclear centroids were calculated in each image and used to investigate the in situ intercellular mechanics of both lamellar and interlamellar cells. The intercellular Lagrangian strains measured in situ were non-uniform and did not correspond with the biaxial Lagrangian strains applied to the tissue. A row-oriented analysis of intercellular unit displacements within the lamellar layers found that the magnitudes of unit displacements between cells along a row (delta;(II)) were small (|delta;(IIavg)|=1.6% at E(C)(S)=0%, E(A)(S)=15%; |delta;(IIavg)|=3.0% at E(C)(S)=-2.5%, E(A)(S)=15%) with negative unit displacements occurring greater than one-third of the time. Evidence of interlamellar shear and increased intercellular Lagrangian strains among the cells within the interlamellar septa suggested that their in situ mechanical environment may be more complex. The in situ intercellular strains of annular cells were strongly dependent upon the local structure and behaviour of the extracellular matrix and did not correspond with applied tissue strains. This knowledge has immediate relevance for in vitro investigations of disc mechanobiology, and will also provide a base to investigate the mechanical implications of disc degeneration at the cellular level. 相似文献
13.
Robert A Terkeltaub H Ralph Schumacher John D Carter Herbert SB Baraf Robert R Evans Jian Wang Shirletta King-Davis Steven P Weinstein 《Arthritis research & therapy》2013,15(1):R25
Introduction
In phase-3 clinical trials, the interleukin (IL-1) blocker, rilonacept (IL-1 Trap), demonstrated efficacy for gout flare prevention during initiation of urate-lowering therapy. This trial evaluated rilonacept added to a standard-of-care, indomethacin, for treatment of acute gout flares.Methods
Adults, aged 18-70 years, with gout presenting within 48 hours of flare onset and having at least moderate pain as well as swelling and tenderness in the index joint were randomized to subcutaneous (SC) rilonacept 320 mg at baseline plus oral indomethacin 50 mg TID for 3 days followed by 25 mg TID for up to 9 days (n = 74); SC placebo at baseline plus oral indomethacin as above (n = 76); or SC rilonacept 320 mg at baseline plus oral placebo (n = 75). The primary efficacy endpoint was change in pain in the index joint (patient-reported using a Likert scale (0 = none; 4 = extreme)) from baseline to the average of values at 24, 48 and 72 hours (composite time point) for rilonacept plus indomethacin versus indomethacin alone. Comparison of rilonacept monotherapy with indomethacin monotherapy was dependent on demonstration of significance for the primary endpoint. Safety evaluation included clinical laboratory and adverse event (AE) assessments.Results
Patient characteristics were comparable among the groups; the population was predominantly male (94.1%), white (75.7%), with mean ± SD age of 50.3 ± 10.6 years. All treatment groups reported within-group pain reductions from baseline (P < 0.0001). Although primary endpoint pain reduction was greater with rilonacept plus indomethacin (-1.55 ± 0.92) relative to indomethacin alone (-1.40 ± 0.96), the difference was not statistically significant (P = 0.33), so formal comparison between monotherapy groups was not performed. Pain reduction over the 72-hour period with rilonacept alone (-0.69 ± 0.97) was less than that in the other groups, but pain reduction was similar among groups at 72 hours. Treatment with rilonacept was well-tolerated with no reported serious AEs related to rilonacept. Across all groups, the most frequent AEs were headache and dizziness.Conclusions
Although generally well-tolerated, rilonacept in combination with indomethacin and rilonacept alone did not provide additional pain relief over 72 hours relative to indomethacin alone in patients with acute gout flare.Trial registration
ClinicalTrials.gov registration number . NCT00855920相似文献14.
Chunman Li Xiaomin Luo Shan Zhao Gavin KY Siu Yongheng Liang Hsiao Chang Chan Ayano Satoh Sidney SB Yu 《The EMBO journal》2017,36(4):441-457
The transport protein particle (TRAPP) was initially identified as a vesicle tethering factor in yeast and as a guanine nucleotide exchange factor (GEF) for Ypt1/Rab1. In mammals, structures and functions of various TRAPP complexes are beginning to be understood. We found that mammalian TRAPPII was a GEF for both Rab18 and Rab1. Inactivation of TRAPPII‐specific subunits by various methods including siRNA depletion and CRISPR–Cas9‐mediated deletion reduced lipolysis and resulted in aberrantly large lipid droplets. Recruitment of Rab18 onto lipid droplet (LD) surface was defective in TRAPPII‐deleted cells, but the localization of Rab1 on Golgi was not affected. COPI regulates LD homeostasis. We found that the previously documented interaction between TRAPPII and COPI was also required for the recruitment of Rab18 to the LD. We hypothesize that the interaction between COPI and TRAPPII helps bring TRAPPII onto LD surface, and TRAPPII, in turn, activates Rab18 and recruits it on the LD surface to facilitate its functions in LD homeostasis. 相似文献
15.
Evidence for independent recruitment of zeta-crystallin/quinone reductase (CRYZ) as a crystallin in camelids and hystricomorph rodents 总被引:3,自引:2,他引:1
Zeta-crystallin/quinone reductase (CRYZ) is an NADPH oxidoreductase
expressed at very high levels in the lenses of two groups of mammals:
camelids and some hystricomorph rodents. It is also expressed at very low
levels in all other species tested. Comparative analysis of the mechanisms
mediating the high expression of this enzyme/crystallin in the lens of the
Ilama (Lama guanacoe) and the guinea pig (Cavia porcellus) provided
evidence for independent recruitment of this enzyme as a lens crystallin in
both species and allowed us to elucidate for the first time the mechanism
of lens recruitment of an enzyme- crystallin. The data presented here show
that in both species such recruitment most likely occurred through the
generation of new lens promoters from nonfunctional intron sequences by the
accumulation of point mutations and/or small deletions and insertions.
These results further support the idea that recruitment of CRYZ resulted
from an adaptive process in which the high expression of CRYZ in the lens
provides some selective advantage rather than from a purely neutral
evolutionary process.
相似文献
16.
D Purnomosari T Aryandono K Setiaji SB Nugraha G Pals 《Biotechnic & histochemistry》2013,88(2-3):79-85
The HER-2/neu transmembrane tyrosine kinase receptor is both a prognostic marker and a therapeutic target for breast cancer. Accurate determination of HER-2/neu status is a prerequisite for selecting breast tumors for HER-2/neu immunotherapy or for taxan based chemotherapy. Unfortunately, there is no consensus concerning how this determination should be reached. We compared assessment of HER-2/neu status using Multiplex ligation-dependent probe amplification (MLPA) and immunohistochemistry (IHC). The patient group comprised 60 Indonesian breast cancers patients. IHC was performed on paraffin sections using the CB11 antibody from Novocastra. Results were scored according to the Hercept test. For MLPA, DNA was extracted from frozen samples, PCR amplified with a probe set containing three hemi-primer sets for the HER-2 locus and another nine control probes spread over chromosome 17 and other chromosomes, and analyzed on a gene scanner. A ratio above two for at least two HER-2 locus probes compared to the control probes was regarded as amplification. IHC for HER-2/neu was negative in 36 cases, and 24 cases (40%) showed expression. Seven, eight and nine of the latter cases were 1+, 2+ and 3+ positive, respectively. Forty-seven cases showed no amplification by MLPA, and 13 cases (22%) were amplified. Comparison of IHC and MPLA showed that none of the 36 IHC-negative or seven IHC 1+ cases was amplified. Five of the eight (63%) 2+ cases were amplified, and eight of nine (89%) of the IHC 3+ tumors showed gene amplification by MLPA assay. For HER-2/neu, there is a good correlation between gene amplification detected by MLPA and overexpression by IHC in invasive breast cancer. It appears that MLPA can detect the HER-2 amplified cases in the IHC 2+ class. Because MLPA is quick and inexpensive, it is an attractive method for detecting HER-2/neu amplification in daily laboratory practice. 相似文献
17.
Evidence of independent gene duplications during the evolution of archaeal and eukaryotic family B DNA polymerases 总被引:1,自引:0,他引:1
Eukaryotes and archaea both possess multiple genes coding for family B DNA
polymerases. In animals and fungi, three family B DNA polymerases, alpha,
delta, and epsilon, are responsible for replication of nuclear DNA. We used
a PCR-based approach to amplify and sequence phylogenetically conserved
regions of these three DNA polymerases from Giardia intestinalis and
Trichomonas vaginalis, representatives of early-diverging eukaryotic
lineages. Phylogenetic analysis of eukaryotic and archaeal paralogs
suggests that the gene duplications that gave rise to the three replicative
paralogs occurred before the divergence of the earliest eukaryotic
lineages, and that all eukaryotes are likely to possess these paralogs. One
eukaryotic paralog, epsilon, consistently branches within archaeal
sequences to the exclusion of other eukaryotic paralogs, suggesting that an
epsilon-like family B DNA polymerase was ancestral to both archaea and
eukaryotes. Because crenarchaeote and euryarchaeote paralogs do not form
monophyletic groups in phylogenetic analysis, it is possible that archaeal
family B paralogs themselves evolved by a series of gene duplications
independent of the gene duplications that gave rise to eukaryotic paralogs.
相似文献
18.
Duan-Ren Wen Dave SB Hoon Cindy Chang Alistair J. Cochran 《Cancer immunology, immunotherapy : CII》1989,30(5):277-282
Summary Individual lymph nodes draining tumors vary in their degree of immunological activity. Cell suspensions from tumor-free nodes located relatively near to tumors are spontaneously less reactive and respond poorly to exogenous stimulation by mitogens and lymphokines. Diminished spontaneous uptake of tritiated thymidine by lymph node cells not exposed to exogenous stimulation suggests that tumor-proximate immune suppression exists in vivo and is not purely a laboratory artefact. The present study was undertaken to explore that possibility further. Fluid in which cell suspensions from tumor-free nodes were prepared, and supernatants from short-term cultures of nodes located at different distances from tumors were compared for their capacity to inhibit the in vitro migration of the human lymphoblastoid cell line QIMR-WIL. Inhibitory activity of fluids from individual nodes was related to their position relative to the tumor and their immune competence, assessed by the responses to mitogens of cell suspensions prepared from them. Cell suspension fluids from 92/111 nodes (83%) significantly inhibited the migration of QIMR-WIL, at a level similar (44±14%) to that induced by the supernatants of mixed lymphocyte cultures (43±17%). Fluids from the nodes of melanoma patients were more inhibitory than those from breast cancer patients (49±12% and 37±13%, respectively,P = 0.003). The inhibitory activity of the different nodes of individual node groups varied significantly in 25 of 33 patients (76%), the node nearest the tumor generating least inhibitory activity (indexing the greatest immune suppression) in 20 of these 25 patients (80%). The strength of migration-inhibitory activity was concordant with the responsiveness to mitogen stimulation in up to 14 of 18 patients (78%). Studies of molecular size and heat stability indicated that the inhibitory factors had characteristics consistent with common migration-inhibitory lymphokines such as leukocyte-migration-inhibitory factor, macrophage-inhibitory factor and interleukin-2. Our findings further support the hypothesis that lymph nodes nearest to tumors are relatively immune-suppressed in vivo.Supported by grants CA 29938 and CA 43658, awarded by the National Cancer Institute, DHHS and a grant from the Candle Foundation, Los Angeles 相似文献
19.
Higher-level snake phylogeny inferred from mitochondrial DNA sequences of 12S rRNA and 16S rRNA genes 总被引:3,自引:0,他引:3
Portions of two mitochondrial genes (12S and 16S ribosomal RNA) were
sequenced to determine the phylogenetic relationships among the major
clades of snakes. Thirty-six species, representing nearly all extant
families, were examined and compared with sequences of a tuatara and three
families of lizards. Snakes were found to constitute a monophyletic group
(confidence probability [CP] = 96%), with the scolecophidians (blind
snakes) as the most basal lineages (CP = 99%). This finding supports the
hypothesis that snakes underwent a subterranean period early in their
evolution. Caenophidians (advanced snakes), excluding Acrochordus, were
found to be monophyletic (CP = 99%). Among the caenophidians, viperids were
monophyletic (CP = 98%) and formed the sister group to the elapids plus
colubrids (CP = 94%). Within the viperids, two monophyletic groups were
identified: true vipers (CP = 98%) and pit vipers plus Azemiops (CP = 99%).
The elapids plus Atractaspis formed a monophyletic clade (CP = 99%). Within
the paraphyletic Colubridae, the largely Holarctic Colubrinae was found to
be a monophyletic assemblage (CP = 98%), and the Xenodontinae was found to
be polyphyletic (CP = 91%). Monophyly of the henophidians (primitive
snakes) was neither supported nor rejected because of the weak resolution
of relationships among those taxa, except for the clustering of Calabaria
with a uropeltid, Rhinophis (CP = 94%).
相似文献
20.
Monophyly of the order Rodentia inferred from mitochondrial DNA sequences of the genes for 12S rRNA, 16S rRNA, and tRNA-valine 总被引:1,自引:2,他引:1
A recent analysis of amino acid sequence data (Graur et al.) suggested that
the mammalian order Rodentia is polyphyletic, in contrast to most
morphological data, which support rodent monophyly. At issue is whether the
hystricognath rodents, such as the guinea pig, represent an independent
evolutionary lineage within mammals, separate from the sciurognath rodents.
To resolve this problem, we sequenced a region (2,645 bp) of the
mitochondrial genome of the guinea pig containing the complete 12S
ribosomal RNA, 16S ribosomal RNA, and transfer RNA(VAL) genes for
comparison with the available sciurognath and other mammalian sequences.
Several methods of analysis and statistical tests of the data all show
strong support for rodent monophyly (91%-98% bootstrap probability, or BP).
Calibration with the mammalian fossil record suggests a Cretaceous date
(107 mya) for the divergence of sciurognaths and hystricognaths. An older
date (38 mya) for the controversial Mus- Rattus divergence also is
supported by these data. Our neighbor-joining analyses of all available
sequence data (25 genes) confirm that some individual genes support rodent
polyphyly but that tandem analysis of all data does not. We propose that
the conflicting results are due to several compounding factors. The unique
biochemical properties of some hystricognath metabolic proteins, largely
responsible for generating this controversy, may have a single explanation:
a cascade effect resulting from inactivation of the zinc-binding abilities
of insulin. After excluding six genes possibly affected by insulin
inactivation, analyses of all available sequence data (7,117 nucleotide
sites, 3,099 amino acid sites) resulted in strong support for rodent
monophyly (94% BP for DNA sequences, 90% for protein sequences), which
lends support to the insulin-cascade hypothesis.
相似文献