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131.
Multiple nanosecond duration molecular dynamics simulations on the pore-lining M2 helix of the nicotinic acetylcholine receptor reveal how its structure and dynamics change as a function of environment. In water, the M2 helix partially unfolds to form a molecular hinge in the vicinity of a central Leu residue that has been implicated in the mechanism of ion channel gating. In a phospholipid bilayer, either as a single transmembrane helix, or as part of a pentameric helix bundle, the M2 helix shows less flexibility, but still exhibits a kink in the vicinity of the central Leu. The single M2 helix tilts relative to the bilayer normal by 12 degrees, in agreement with recent solid state NMR data (Opella et al., Nat Struct Biol 6:374-379, 1999). The pentameric helix bundle, a model for the pore domain of the nicotinic receptor and for channels formed by M2 peptides in a bilayer, is remarkably stable over a 2-ns MD simulation in a bilayer, provided one adjusts the pK(A)s of ionizable residues to their calculated values (when taking their environment into account) before starting the simulation. The resultant transbilayer pore shows fluctuations at either mouth which transiently close the channel. Proteins 2000;39:47-55. 相似文献
132.
A mercury-hyperresistant strain of Pseudomonas aeruginosa PU21 harboring plasmid Rip64 was utilized to develop bioprocesses able to detoxify and recover soluble mercuric ions in aquatic systems. The kinetics of mercury detoxification was investigated to determine the parameters needed for the design of the bioprocesses. Batch, fed-batch, and continuous bioreactors were utilized to evaluate the efficiency and feasibility of each mode of operation. The results showed that the specific mercury detoxification rate was dependent on cell growth phases, as well as the initial mercury concentrations. Cells at the lag growth phase exhibited the best specific detoxification rate of approximately 1.1 x 10(-6) microg Hg/cell/h, and the rate was optimal at an initial mercury concentration of 8 mg/L. In batch operations with initial mercuric ions ranging from 2 to 10 mg/L, the mercuric ions added were rapidly volatilized from the media in less than 2-3 h. With periodic feeding of 3 or 5 mg Hg/L at fixed time intervals, the fed-batch processes had mercury removal efficiencies of 2.9 and 3.3 mg Hg/h/L, respectively. For continuous operations, the effluent cell concentration (Xe) was essentially invariant at 527 and 523 mg/L with the dilution rates (D) of 0.18 and 0.325 h-1, respectively. The increase in mercury feeding concentrations (Hgf) from 1.0 to 6.15 mg Hg2+/L did not affect the steady-state cell concentration (Xe) but forced the effluent mercury concentration (Hge) to increase. The decrease in the dilution rate, however, resulted in lower Hge values. It was also found that sequential mercury vapor absorption columns recovered over 80% of the Hg degrees released from the bioreactor while the residual mercury vapor was subsequently immobilized by an activated carbon trap in the down stream of the absorption column. 相似文献
133.
Amino acid changes S180A (S-->A at site 180), H197Y, Y277F, T285A, and
A308S are known to shift the maximum wavelength of absorption (lambda max)
of red and green visual pigments toward blue, essentially in an additive
fashion. To test the generality of this "five-sites" rule, we have
determined the partial amino acid sequences of red and green pigments from
five mammalian orders (Artiodactyla, Carnivora, Lagomorpha, Perissodactyla,
and Rodentia). The result suggests that cat (Felis catus), dog (Canis
familiaris), and goat (Capra hircus) pigments all with AHYTA at the five
critical sites have lambda max values of approximately 530 nm, whereas rat
(Rattus norvegicus) pigment with AYYTS has a lambda max value of
approximately 510 nm, which is accurately predicted by the five-sites rule.
However, the observed lambda max values of the orthologous pigments of
European rabbit (Oryctolagus cuniculus), white-tailed deer (Odocoileus
virginianus), gray squirrel (Sciurus carolinensis), and guinea pig (Cavia
procellus) are consistently more than 10 nm higher than the predicted
values, suggesting the existence of additional molecular mechanisms for red
and green color vision. The inferred amino acid sequences of ancestral
organisms suggest that the extant mammalian red and green pigments appear
to have evolved from a single ancestral green-red hybrid pigment by
directed amino acid substitutions.
相似文献
134.
W. Bartels B. S. Law F. Geiser 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》1998,168(3):233-239
Little is known about torpor in the tropics or torpor in megachiropteran species. We investigated thermoregulation, energetics
and patterns of torpor in the northern blossom-bat Macroglossus minimus (16 g) to test whether physiological variables may explain why its range is limited to tropical regions. Normothermic bats
showed a large variation in body temperature (T
b) (33 to 37 °C) over a wide range of ambient temperatures (T
as) and a relatively low basal metabolic rate (1.29 ml O2 g−1 h−1). Bats entered torpor frequently in the laboratory at T
as between 14 and 25 °C. Entry into torpor always occurred when lights were switched on in the morning, independent of T
a. MRs during torpor were reduced to about 20–40% of normothermic bats and T
bs were regulated at a minimum of 23.1 ± 1.4 °C. The duration of torpor bouts increased with decreasing T
a in non-thermoregulating bats, but generally terminated after 8 h in thermoregulating torpid bats. Both the mean minimum T
b and MR of torpid M. minimus were higher than that predicted for a 16-g daily heterotherm and the T
b was also about 5 °C higher than that of the common blossom-bat Syconycteris australis, which has a more subtropical distribution. These observations suggest that variables associated with torpor are affected
by T
a and that the restriction to tropical areas in M. minimus to some extent may be due to their ability to enter only very shallow daily torpor.
Accepted: 22 September 1997 相似文献
135.
Carsten Höltke Marilyn P. Law Stefan Wagner Klaus Kopka Andreas Faust Hans-Jörg Breyholz Otmar Schober Christoph Bremer Burkhard Riemann Michael Schäfers 《Bioorganic & medicinal chemistry》2009,17(20):7197-7208
The expression and function of endothelin (ET) receptors is abnormal in cardiovascular diseases, tumor progression, and tumor metastasis. In this study, we prepared two [18F]-fluorinated derivatives of the non-peptide ETA receptor antagonist PD 156707 and evaluated their ET receptor binding potencies. Ex vivo as well as in vivo biodistribution studies in mice were performed, as well as the metabolism of the radiotracer, which was examined by metabolite analysis in mice and rats. All tested derivatives of PD 156707 exhibited potent in vitro pharmacological characteristics with Ki values comparable to that of the lead compound. The biodistribution studies showed a high accumulation of the tracer in bile and intestine. In vivo we were able to show that the visualization of the heart as a major target organ with high ETAR expression is possible. 相似文献
136.
137.
Yat Ming Lau Tak Hong Cheung Winnie Yeo Frankie Mo Mei Yung Yu Kun Min Lee Wendy C. S. Ho Apple C. M. Yeung Priscilla T. Y. Law Paul K. S. Chan 《PloS one》2015,10(4)
High-risk human papillomavirus (HPV) types are associated with cervical cancer. It is well established that individual HPV types vary in oncogenicity, but current data on their prognostic implication remain controversial. We examined the association between HPV types/species and the survival of 236 Chinese women aged 26–87 (mean 54.4) years after receiving primary treatment for cervical cancer. Overall, 45.8% were of FIGO stage I, 41.9% stage II, and 12.3% stage III. The four most prevalent types found were HPV-16 (60.2%), HPV-18 (21.6%), HPV-52 (11.9%), and HPV-58 (9.3%). Overall, 19.5% of patients had multiple-type infections, 78.4% harboured one or more alpha-9 species, and 28.8% harboured one or more alpha-7 species. After a median follow-up of 8.0 years, 156 (66.1%) patients survived. The 3-year overall survival rate was 75.5%. Factors independently associated with a poorer 3-year overall survival were age >60 years, tumour size >4 cm, lymph node involvement and treatment with radiotherapy+/-chemotherapy. Univariate analysis showed HPV-16 single-type infection was associated with a marginally poorer disease-specific survival (71.6% vs. 87.0%, HR: 1.71, 95% CI = 1.01–2.90), whereas non-HPV-16 alpha-9 species was associated with a better disease-specific survival (90.0% vs. 76.2%, HR: 0.36, 95% CI = 0.16–0.79). However, on multivariate analysis, HPV infection status irrespective of different grouping methods, including individual types, species, single-type or co-infection, did not carry any significant prognostic significance. In conclusion, we did not observe any association between infection with a particular HPV type/species and survival. An HPV type-based stratification in treatment and follow-up plan could not be recommended. 相似文献
138.
Lui Ng Timothy Ming-Hun Wan Colin Siu-Chi Lam Ariel Ka-Man Chow Sunny Kit-Man Wong Johnny Hon-Wai Man Hung-Sing Li Nathan Shiu-Man Cheng Ryan Chung-Hei Pak Alvin Ho-Kwan Cheung Thomas Chung-Cheung Yau Oswens Siu-Hung Lo Dominic Chi-Chung Foo Jensen Tung-Chung Poon Ronnie Tung-Ping Poon Roberta Wen-Chi Pang Wai-Lun Law 《PloS one》2015,10(5)
BackgroundThe overall prognosis of colorectal cancer (CRC) patients is unsatisfactory due to cancer metastasis after operation. This study aims to investigate the clinical significance of plasma osteopontin (OPN) levels as minimally invasive, predictive, and surrogate biomarkers for prognosis of CRC patients.MethodsThis randomized study design consists of pre-operative and post-operative plasma samples from a total of 79 patients. We determined plasma levels of OPN by ELISA and examined their correlation with the clinicopathological parameters of CRC patients. The effects of endogenous and exogenous OPN on CRC metastasis were investigated by examination of the effect on regulators of epithelial to messenchymal transition and migration assay.ResultsOur findings demonstrated for the first time the clinical correlation of plasma OPN with metastasis of CRC patients. High post-operative plasma OPN level (>153.02 ng/ml) associated with development of metastasis after curative resection (p<0.001). Moreover, post-operative plasma OPN level correlated with disease-free survival of CRC patients (p=0.009) and was an independent factor for predicting development of metastasis in CRC patients after curative resection (p=0.036). Our in vitro model showed that OPN ectopic expression induced DLD1 cell migration through Snail and Twist1 overexpression and E-cadherin repression, and secretory OPN level enhanced cell migration.ConclusionsThe results of the current study suggest that post-operative plasma OPN correlated with post-operative metastasis, suggesting that it is a potential non-invasive biomarker for the development of future metastasis in CRC patients. In addition, OPN was shown to be involved in the metastatic process and thus inhibition of OPN is a potential therapeutic approach to treat CRC patients. 相似文献
139.
During neural circuit development, attractive or repulsive guidance cue molecules direct growth cones (GCs) to their targets by eliciting cytoskeletal remodeling, which is reflected in their morphology. The experimental power of in vitro neuronal cultures to assay this process and its molecular mechanisms is well established, however, a method to rapidly find and quantify multiple morphological aspects of GCs is lacking. To this end, we have developed a free, easy to use, and fully automated Fiji macro, Conographer, which accurately identifies and measures many morphological parameters of GCs in 2D explant culture images. These measurements are then subjected to principle component analysis and k-means clustering to mathematically classify the GCs as “collapsed” or “extended”. The morphological parameters measured for each GC are found to be significantly different between collapsed and extended GCs, and are sufficient to classify GCs as such with the same level of accuracy as human observers. Application of a known collapse-inducing ligand results in significant changes in all parameters, resulting in an increase in ‘collapsed’ GCs determined by k-means clustering, as expected. Our strategy provides a powerful tool for exploring the relationship between GC morphology and guidance cue signaling, which in particular will greatly facilitate high-throughput studies of the effects of drugs, gene silencing or overexpression, or any other experimental manipulation in the context of an in vitro axon guidance assay. 相似文献
140.
Daniel D. Murray Kazuo Suzuki Matthew Law Jonel Trebicka Jacquie Neuhaus Deborah Wentworth Margaret Johnson Michael J. Vjecha Anthony D. Kelleher Sean Emery INSIGHT ESPRIT SMART Study Groups 《PloS one》2015,10(10)