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101.
Perturbations of the denatured state ensemble: modeling their effects on protein stability and folding kinetics. 下载免费PDF全文
By considering the denatured state of a protein as an ensemble of conformations with varying numbers of sequence-specific interactions, the effects on stability, folding kinetics, and aggregation of perturbing these interactions can be predicted from changes in the molecular partition function. From general considerations, the following conclusions are drawn: (1) A perturbation that enhances a native interaction in denatured state conformations always increases the stability of the native state. (2) A perturbation that promotes a non-native interaction in the denatured state always decreases the stability of the native state. (3) A change in the denatured state ensemble can alter the kinetics of aggregation and folding. (4) The loss (or increase) in stability accompanying two mutations, each of which lowers (or raises) the free energy of the denatured state, will be less than the sum of the effects of the single mutations, except in cases where both mutations affect the same set of partially folded conformations. By modeling the denatured state as the ensemble of all non-native conformations of hydrophobic-polar (HP) chains configured on a square lattice, it can be shown that the stabilization obtained from enhancement of native interactions derives in large measure from the avoidance of non-native interactions in the D state. In addition, the kinetic effects of fixing single native contacts in the denatured state or imposing linear gradients in the HH contact probabilities are found, for some sequences, to significantly enhance the efficiency of folding by a simple hydrophobic zippering algorithm. Again, the dominant mechanism appears to be avoidance of non-native interactions. These results suggest stabilization of native interactions and imposition of gradients in the stability of local structure are two plausible mechanisms involving the denatured state that could play a role in the evolution of protein folding and stability. 相似文献
102.
Free energies of pairwise hydrophobic association are simulated in aqueous solutions of urea at concentrations ranging from 0-8 M. Consistent with the expectation that hydrophobic interactions are weakened by urea, the association of relatively large nonpolar solutes is destabilized by urea. However, the association of two small methane-sized nonpolar solutes in water has the opposite tendency of being slightly strengthened by the addition of urea. Such size effects and the dependence of urea-induced stability changes on the configuration of nonpolar solutes are not predicted by solvent accessible surface area approaches based on energetic parameters derived from bulk-phase solubilities of model compounds. Thus, to understand hydrophobic interactions in proteins, it is not sufficient to rely solely on transfer experiment data that effectively characterize a single nonpolar solute in an aqueous environment but not the solvent-mediated interactions among two or more nonpolar solutes. We find that the m-values for the rate of change of two-methane association free energy with respect to urea concentration is a dramatically nonmonotonic function of the spatial separation between the two methanes, with a distance-dependent profile similar to the corresponding two-methane heat capacity of association in pure water. Our results rationalize the persistence of residual hydrophobic contacts in some proteins at high urea concentrations and explain why the heat capacity signature (DeltaC(P)) of a compact denatured state can be similar to DeltaC(P) values calculated by assuming an open random-coil-like unfolded state. 相似文献
103.
PHILIP S WANG MATTHIAS ANGERMEYER GUILHERME BORGES RONNY BRUFFAERTS WAI TAT CHIU GIOVANNI DE GIROLAMO JOHN FAYYAD OYE GUREJE JOSEP MARIA HARO YUEQIN HUANG RONALD C KESSLER VIVIANE KOVESS DAPHNA LEVINSON YOSHIBUMI NAKANE MARK A OAKLEY BROWN JOHAN H ORMEL JOSé POSADA-VILLA SERGIO AGUILAR-GAXIOLA JORDI ALONSO SING LEE STEVEN HEERINGA BETH-ELLEN PENNELL SOMNATH CHATTERJI T. BEDIRHAN üSTüN 《World psychiatry》2007,6(3):177-185
Data are presented on patterns of failure and delay in making initial treatment
contact after first onset of a mental disorder in 15 countries in the World
Health Organization (WHO)''s World Mental Health (WMH) Surveys. Representative
face-to-face household surveys were conducted among 76,012 respondents aged
18 and older in Belgium, Colombia, France, Germany, Israel, Italy, Japan,
Lebanon, Mexico, the Netherlands, New Zealand, Nigeria, People''s Republic
of China (Beijing and Shanghai), Spain, and the United States. The WHO Composite
International Diagnostic Interview (CIDI) was used to assess lifetime DSM-IV
anxiety, mood, and substance use disorders. Ages of onset for individual disorders
and ages of first treatment contact for each disorder were used to calculate
the extent of failure and delay in initial help seeking. The proportion of
lifetime cases making treatment contact in the year of disorder onset ranged
from 0.8 to 36.4% for anxiety disorders, from 6.0 to 52.1% for mood disorders,
and from 0.9 to 18.6% for substance use disorders. By 50 years, the proportion
of lifetime cases making treatment contact ranged from 15.2 to 95.0% for anxiety
disorders, from 7.9 to 98.6% for mood disorders, and from 19.8 to 86.1% for
substance use disorders. Median delays among cases eventually making contact
ranged from 3.0 to 30.0 years for anxiety disorders, from 1.0 to 14.0 years
for mood disorders, and from 6.0 to 18.0 years for substance use disorders.
Failure and delays in treatment seeking were generally greater in developing
countries, older cohorts, men, and cases with earlier ages of onset. These
results show that failure and delays in initial help seeking are pervasive
problems worldwide. Interventions to ensure prompt initial treatment contacts
are needed to reduce the global burdens and hazards of untreated mental disorders. 相似文献
104.
105.
Restoration ecology is a young academic field, but one with enough history to judge it against past and current expectations of the science's potential. The practice of ecological restoration has been identified as providing ideal experimental settings for tests of ecological theory; restoration was to be the 'acid test' of our ecological understanding. Over the past decade, restoration science has gained a strong academic foothold, addressing problems faced by restoration practitioners, bringing new focus to existing ecological theory and fostering a handful of novel ecological ideas. In particular, recent advances in plant community ecology have been strongly linked with issues in ecological restoration. Evolving models of succession, assembly and state-transition are at the heart of both community ecology and ecological restoration. Recent research on seed and recruitment limitation, soil processes, and diversity–function relationships also share strong links to restoration. Further opportunities may lie ahead in the ecology of plant ontogeny, and on the effects of contingency, such as year effects and priority effects. Ecology may inform current restoration practice, but there is considerable room for greater integration between academic scientists and restoration practitioners. 相似文献
106.
Nahum J. Duker 《Chemico-biological interactions》1986,60(3):265-273
Hydrolytic damages to DNA can occur at physiological conditions. The possible role of DNA conformation on the distribution of such alterations of pyrimidines was investigated. Model compounds used were the synthetic alternating copolymer poly(dG-dC):poly(dG-dC) and the homopolymer poly(dG):poly(dC). Base damages were assayed by paper chromatography using polymers radioactively labeled in cytosine. Conformational changes were assayed by circular dichroic spectral changes. Incubation and heating of the polymers in 1 mM MnCl2 caused the spectral shift reported for the left-handed Z-DNA conformation in the alternating copolymer and the change reported for the triple helix in the homopolymer. After incubation in 85°C, incidences of base damages were compared between the polymers. The presence of manganese reduced depyrimidination in both polymers. Rates of cytosine deamination to uracil were substantial and did not vary among the various conformational states. 相似文献
107.
Enhancement of VOC without Loss of JSC in Organic Solar Cells by Modification of Donor/Acceptor Interfaces 下载免费PDF全文
Yufei Zhong Akira Tada Seiichiro Izawa Kazuhito Hashimoto Keisuke Tajima 《Liver Transplantation》2014,4(5)
Organic solar cells (OSCs) are promising low‐cost devices for generating electricity. In addition to fill factor, the short circuit current density (JSC) and the open circuit voltage (VOC) are two key factors that have critical influence on the device performance. The energy levels of the donor and acceptor materials are crucial for achieving a high JSC and VOC. However, the interfacial structures between the organic materials substantially affect the JSC and VOC through the energy of the charge transfer (CT) states and the charge separation and recombination reaction kinetics. Here, it is reported that separating the donor and acceptor layer in bilayer OSCs with a thin insulating layer increases the energy of the CT state by weakening the Coulomb interaction at the interface and this also suppresses photoinduced CT and recombination. Although these effects usually increase VOC and decrease JSC, the trade‐off is avoided by doping the insulating layer with a dye to utilize the energy transfer process. The increase in VOC without the reduction in JSC enhances the conversion efficiency of the OSCs by 30%. 相似文献
108.
Margreet ten Have Marlous Tuithof Saskia van Dorsselaer Frederiek Schouten Annemarie I. Luik Ron de Graaf 《World psychiatry》2023,22(2):275-285
Up-to-date information on the prevalence and trends of common mental disorders is relevant to health care policy and planning, owing to the high burden associated with these disorders. In the first wave of the third Netherlands Mental Health Survey and Incidence Study (NEMESIS-3), a nationally representative sample was interviewed face-to-face from November 2019 to March 2022 (6,194 subjects; 1,576 interviewed before and 4,618 during the COVID-19 pandemic; age range: 18-75 years). A slightly modified version of the Composite International Diagnostic Interview 3.0 was used to assess DSM-IV and DSM-5 diagnoses. Trends in 12-month prevalence rates of DSM-IV mental disorders were examined by comparing these rates between NEMESIS-3 and NEMESIS-2 (6,646 subjects; age range: 18-64 years; interviewed from November 2007 to July 2009). Lifetime DSM-5 prevalence estimates in NEMESIS-3 were 28.6% for anxiety disorders, 27.6% for mood disorders, 16.7% for substance use disorders, and 3.6% for attention-deficit/hyperactivity disorder. Over the last 12 months, prevalence rates were 15.2%, 9.8%, 7.1%, and 3.2%, respectively. No differences in 12-month prevalence rates before vs. during the COVID-19 pandemic were found (26.7% pre-pandemic vs. 25.7% during the pandemic), even after controlling for differences in socio-demographic characteristics of the respondents interviewed in these two periods. This was the case for all four disorder categories. From 2007-2009 to 2019-2022, the 12-month prevalence rate of any DSM-IV disorder significantly increased from 17.4% to 26.1%. A stronger increase in prevalence was found for students, younger adults (18-34 years) and city dwellers. These data suggest that the prevalence of mental disorders has increased in the past decade, but this is not explained by the COVID-19 pandemic. The already high mental disorder risk of young adults has particularly further increased in recent years. 相似文献
109.
Toru Hiratsuka Kalle H Sipilä Julio M Belmonte Seyedeh Atefeh Mobasseri Christina Philippeos Rui Dilão Fiona M Watt 《Molecular systems biology》2018,14(8)
Murine dermis contains functionally and spatially distinct fibroblast lineages that cease to proliferate in early postnatal life. Here, we propose a model in which a negative feedback loop between extracellular matrix (ECM) deposition and fibroblast proliferation determines dermal architecture. Virtual‐tissue simulations of our model faithfully recapitulate dermal maturation, predicting a loss of spatial segregation of fibroblast lineages and dictating that fibroblast migration is only required for wound healing. To test this, we performed in vivo live imaging of dermal fibroblasts, which revealed that homeostatic tissue architecture is achieved without active cell migration. In contrast, both fibroblast proliferation and migration are key determinants of tissue repair following wounding. The results show that tissue‐scale coordination is driven by the interdependence of cell proliferation and ECM deposition, paving the way for identifying new therapeutic strategies to enhance skin regeneration. 相似文献
110.
Solution structure of the His12 --> Cys mutant of the N-terminal zinc binding domain of HIV-1 integrase complexed to cadmium. 下载免费PDF全文
M. Cai Y. Huang M. Caffrey R. Zheng R. Craigie G. M. Clore A. M. Gronenborn 《Protein science : a publication of the Protein Society》1998,7(12):2669-2674
The solution structure of His12 --> Cys mutant of the N-terminal zinc binding domain (residues 1-55; IN(1-55)) of HIV-1 integrase complexed to cadmium has been solved by multidimensional heteronuclear NMR spectroscopy. The overall structure is very similar to that of the wild-type N-terminal domain complexed to zinc. In contrast to the wild-type domain, however, which exists in two interconverting conformational states arising from different modes of coordination of the two histidine side chains to the metal, the cadmium complex of the His12 --> Cys mutant exists in only a single form at low pH. The conformation of the polypeptide chain encompassing residues 10-18 is intermediate between the two forms of the wild-type complex. 相似文献