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1.  Effects of Grazing Intensity and Environmental Factors on Species Composition and Diversity in Typical Steppe of Inner Mongolia, China 
PLoS ONE  2012;7(12):e52180.
In the present study, we aim to analyze the effect of grazing, precipitation and temperature on plant species dynamics in the typical steppe of Inner Mongolia, P.R. China. By uncoupling biotic and abiotic factors, we provide essential information on the main drivers determining species composition and species diversity. Effects of grazing by sheep were studied in a controlled experiment along a gradient of seven grazing intensities (from ungrazed to very heavily grazed) during six consecutive years (2005–2010). The results show that plant species composition and diversity varied among years but were little affected by grazing intensity, since the experimental years were much dryer than the long term average, the abiotic constraints may have overridden any grazing effect. Among-year differences were predominantly determined by the abiotic factors of precipitation and temperature. Most of the variation in species dynamics and coexistence between C3 and C4 species was explained by seasonal weather conditions, i.e. precipitation and temperature regime during the early-season (March-June) were most important in determining vegetation dynamics. The dominant C3 species Stipa grandis was highly competitive in March-June, when the temperature levels were low and rainfall level was high. In contrast, the most common C4 species Cleistogenes squarrosa benefited from high early-season temperature levels and low early-season rainfall. However, biomass of Stipa grandis was positively correlated with temperature in March, when effective mean temperature ranges from 0 to 5°C and thus promotes vernalization and vegetative sprouting. Our results suggest that, over a six-year term, it is temporal variability in precipitation and temperature rather than grazing that determines vegetation dynamics and species co-existence of grazed steppe ecosystems. Furthermore, our data support that the variability in the biomass of dominant species, rather than diversity, determine ecosystem functioning. The present study provides fundamental knowledge on the complex interaction of grazing – vegetation – climate.
doi:10.1371/journal.pone.0052180
PMCID: PMC3528763  PMID: 23284925
2.  Classification of DNA sequences based on thermal melting profiles 
Bioinformation  2010;4(10):463-467.
A new classification scheme based on the melting profile of DNA sequences simulated thermal melting profiles. This method was applied in the classification of (a) several species of mammalian ­ β globin and (b) α­chain class II MHC genes. Comparison of the thermal melting profile with the molecular phylogenetic trees constructed using the sequences shows that the melting temperature based approach is able to reproduce most of the major features of the sequence based evolutionary tree. Melting profile method takes into account the inherent structure and dynamics of the DNA molecule, does not require sequence alignment prior to tree construction, and provides a means to verify the results experimentally. Therefore our results show that melting profile based classification of DNA sequences could be a useful tool for sequence analysis.
PMCID: PMC2951702  PMID: 21042401
DNA; hybridization; melting profiles; classification
3.  Further optimization of a hybrid united-atom and coarse-grained force field for folding simulations: Improved backbone hydration and interactions between charged side chains 
PACE, a hybrid force field which couples united-atom protein models with coarse-grained (CG) solvent, has been further optimized, aiming to improve itse ciency for folding simulations. Backbone hydration parameters have been re-optimized based on hydration free energies of polyalanyl peptides through atomistic simulations. Also, atomistic partial charges from all-atom force fields were combined with PACE in order to provide a more realistic description of interactions between charged groups. Using replica exchange molecular dynamics (REMD), ab initio folding using the new PACE has been achieved for seven small proteins (16 – 23 residues) with different structural motifs. Experimental data about folded states, such as their stability at room temperature, melting point and NMR NOE constraints, were also well reproduced. Moreover, a systematic comparison of folding kinetics at room temperature has been made with experiments, through standard MD simulations, showing that the new PACE may speed up the actual folding kinetics 5-10 times. Together with the computational speedup benefited from coarse-graining, the force field provides opportunities to study folding mechanisms. In particular, we used the new PACE to fold a 73-residue protein, 3D, in multiple 10 – 30 μs simulations, to its native states (Cα RMSD ~ 0.34 nm). Our results suggest the potential applicability of the new PACE for the study of folding and dynamics of proteins.
doi:10.1021/ct300696c
PMCID: PMC3507460  PMID: 23204949
4.  Commentary: Fatalismo Reconsidered: A Cautionary Note for Health-Related Research and Practice with Latino Populations 
Ethnicity & disease  2007;17(1):153-158.
Over recent years, interest has grown in studying whether fatalismo (fatalism) deters Latinos from engaging in various health promotion and disease detection behaviors, especially with regard to cancer screening. This commentary presents problematic issues posed by the concept of fatalism, focusing on research on Latinos and cancer screening. We discuss key findings in the literature, analyze methodologic and conceptual problems, and highlight structural contexts and other barriers to health care as critical to the fatalism concept. Although the need to better understand the role of fatalistic beliefs on health is great, we discuss the public health implications of reaching premature conclusions concerning the effect of fatalism on Latinos’ cancer screening behaviors.
PMCID: PMC3617551  PMID: 17274225
Cancer Screening; Fatalism; Latino
5.  Academic Commentary Faculty Development: Some Thoughts About the Process and Content 
Canadian Family Physician  1979;25:631-634.
Faculty development, particularly that aspect of it concerned with increasing the educational and teaching skills of faculty members, is currently a major issue for medicine in general—and family medicine in particular. This article presents the author's views about what might be aspects of the guiding philosophy and content of such a program of faculty development, where it is concerned with increasing teaching skills.
These views have been distilled over several years of personal growth and development, whilst working in this area as an educator within the RACGP's family medicine program, as a participant and facilitator in international workshops examining related topics, and most recently as a visiting professor within the McGill Department of Family Medicine at Jewish General Hospital, Montreal.
PMCID: PMC2383099  PMID: 21297745
6.  Kinetic nanofriction: a mechanism transition from quasi-continuous to ballistic-like Brownian regime 
Nanoscale Research Letters  2012;7(1):148.
Surface diffusion of mobile adsorbates is not only the key to control the rate of dynamical processes on solid surfaces, e.g. epitaxial growth, but also of fundamental importance for recent technological applications, such as nanoscale electro-mechanical, tribological, and surface probing devices. Though several possible regimes of surface diffusion have been suggested, the nanoscale surface Brownian motion, especially in the technologically important low friction regimes, remains largely unexplored. Using molecular dynamics simulations, we show for the first time, that a C60 admolecule on a graphene substrate exhibits two distinct regimes of nanoscale Brownian motion: a quasi-continuous and a ballistic-like. A crossover between these two regimes is realized by changing the temperature of the system. We reveal that the underlying physical origin for this crossover is a mechanism transition of kinetic nanofriction arising from distinctive ways of interaction between the admolecule and the graphene substrate in these two regimes due to the temperature change. Our findings provide insight into surface mass transport and kinetic friction control at the nanoscale.
doi:10.1186/1556-276X-7-148
PMCID: PMC3366869  PMID: 22353343
7.  On the Origins of the Weak Folding Cooperativity of a Designed ββα Ultrafast Protein FSD-1 
PLoS Computational Biology  2010;6(11):e1000998.
FSD-1, a designed small ultrafast folder with a ββα fold, has been actively studied in the last few years as a model system for studying protein folding mechanisms and for testing of the accuracy of computational models. The suitability of this protein to describe the folding of naturally occurring α/β proteins has recently been challenged based on the observation that the melting transition is very broad, with ill-resolved baselines. Using molecular dynamics simulations with the AMBER protein force field (ff96) coupled with the implicit solvent model (IGB = 5), we shed new light into the nature of this transition and resolve the experimental controversies. We show that the melting transition corresponds to the melting of the protein as a whole, and not solely to the helix-coil transition. The breadth of the folding transition arises from the spread in the melting temperatures (from ∼325 K to ∼302 K) of the individual transitions: formation of the hydrophobic core, β-hairpin and tertiary fold, with the helix formed earlier. Our simulations initiated from an extended chain accurately predict the native structure, provide a reasonable estimate of the transition barrier height, and explicitly demonstrate the existence of multiple pathways and multiple transition states for folding. Our exhaustive sampling enables us to assess the quality of the Amber ff96/igb5 combination and reveals that while this force field can predict the correct native fold, it nonetheless overstabilizes the α-helix portion of the protein (Tm = ∼387K) as well as the denatured structures.
Author Summary
The protein folding process, in which a linear chain of amino acids reaches its biologically active three-dimensional shape, is fundamental to life. Small “ultrafast” folders, proteins that fold in microseconds, have received considerable attention, because these proteins serve as model systems for the folding of larger proteins, and thus permit a testing of the accuracy of computational models as well as an assessment of protein folding theories. FSD-1, a designed small ultrafast folder with a ββα fold, has been actively studied in the last few years as a model system for mixed α/β fold proteins. The suitability of this protein to describe the folding of naturally occurring proteins has however recently been challenged based on the observation that the melting transition is very broad, with ill-resolved baselines. Prior simulations have not been successful in providing an interpretation of this broad melting transition. In the present study, our extensive molecular dynamics simulations using the AMBER protein force field (ff96) coupled with the implicit solvent model (IGB = 5) shed new light on the nature of the folding transition of this protein, as well as reveal the strengths and weaknesses of the force field in predicting the thermodynamics and kinetics of folding.
doi:10.1371/journal.pcbi.1000998
PMCID: PMC2987907  PMID: 21124953
8.  Strain-induced high ferromagnetic transition temperature of MnAs epilayer grown on GaAs (110) 
Nanoscale Research Letters  2011;6(1):125.
MnAs films are grown on GaAs surfaces by molecular beam epitaxy. Specular and grazing incidence X-ray diffractions are used to study the influence of different strain states of MnAs/GaAs (110) and MnAs/GaAs (001) on the first-order magnetostructural phase transition. It comes out that the first-order magnetostructural phase transition temperature Tt, at which the remnant magnetization becomes zero, is strongly affected by the strain constraint from different oriented GaAs substrates. Our results show an elevated Tt of 350 K for MnAs films grown on GaAs (110) surface, which is attributed to the effect of strain constraint from different directions.
PACS: 68.35.Rh, 61.50.Ks, 81.15.Hi, 07.85.Qe
doi:10.1186/1556-276X-6-125
PMCID: PMC3211171  PMID: 21711651
9.  Linear Relationship between Deformability and Thermal Stability of 2′-O-Modified RNA Hetero Duplexes 
The Journal of Physical Chemistry. B  2010;114(7):2517-2524.
We describe the relationship between the experimentally determined melting temperatures of 2′-O-modified-RNA/RNA duplexes and their deformability estimated from molecular dynamics simulations. To clarify this relationship, we synthesized several fully modified oligoribonucleotides such as 2′-O-cyanoethyl RNAs and 2′-O-methoxyethyl RNAs and compared the actual melting temperatures of the duplexes with their calculated deformabilities. An increase of the melting temperatures by 2′-O-modifications was found to correlate strongly with an increase of the helical elastic constants in U14/A14, (CU)7/(AG)7, and (GACU)3/(AGUC)3 sequences. Linear regression analyses could be used to estimate the melting temperature with an accuracy of ±2.0 °C in our model case. Although the strong correlation was observed in the same base sequence, the linear regression functions were different from each base sequence. Our results indicated the possibility of predicting the thermal stability of 2′-O-modified duplexes at the computer-aided molecular design stage.
doi:10.1021/jp909851j
PMCID: PMC2825091  PMID: 20108976
10.  Mice left out in the cold: commentary on the phenotype of TRPM8-nulls 
Molecular Pain  2007;3:23.
Detection of innocuous temperatures allows an organism to select an appropriate environmental climate, while the ability to recognize noxious temperature extremes warns of impending tissue damage. For temperatures considered cold, the menthol receptor TRPM8 is activated when temperatures drop below ~26°C, thus making it an intriguing candidate as the molecular mediator of cold perception. However, confirmation of this hypothesis in vivo has eluded researchers until recently. Three independent research groups have reported that mice lacking this single gene are severely impaired in their ability to detect cold temperatures. Remarkably, these animals are deficient in many diverse aspects of cold signaling, including cool and noxious cold perception, injury-evoked sensitization to cold, and cooling-induced analgesia. These animals provide a great deal of insight into the molecular signaling pathways that participate in the detection of cold and painful stimuli.
doi:10.1186/1744-8069-3-23
PMCID: PMC1988789  PMID: 17705869
11.  Global Nanotribology Research Output (1996–2010): A Scientometric Analysis 
PLoS ONE  2013;8(12):e81094.
This study aims to assess the nanotribology research output at global level using scientometric tools. The SCOPUS database was used to retrieve records related to the nanotribology research for the period 1996–2010. Publications were counted on a fractional basis. The level of collaboration and its citation impact were examined. The performance of the most productive countries, institutes and most preferred journals is assessed. Various visualization tools such as the Sci2 tool and Ucinet were employed. The USA ranked top in terms of number of publications, citations per paper and h-index, while Switzerland published a higher percentage of international collaborative papers. The most productive institution was Tsinghua University followed by Ohio State University and Lanzhou Institute of Chemical Physics, CAS. The most preferred journals were Tribology Letters, Wear and Journal of Japanese Society of Tribologists. The result of author keywords analysis reveals that Molecular Dynamics, MEMS, Hard Disk and Diamond like Carbon are major research topics.
doi:10.1371/journal.pone.0081094
PMCID: PMC3855179  PMID: 24339900
12.  Conformational changes below the Tm: Molecular dynamics studies of the thermal pretransition of ribonuclease A† 
Biochemistry  2007;47(3):880-892.
Recent work suggests that some native conformations of proteins can vary with temperature. To obtain an atomic-level description of this structural and conformational variation, we have performed all-atom, explicit-solvent molecular dynamics simulations of bovine pancreatic ribonuclease A (RNase A) up to its melting temperature (Tm ≈ 337 K). RNase A has a thermal pretransition near 320 K [Stelea, S.D, Pancoska, P., Benight, A.S., Keiderling, T.A. (2001) Prot. Sci. 10, 970—978]. Our simulations identify a conformational change that coincides with this pretransition. Between 310 and 320 K, there is a small but significant decrease in the number of native contacts, β-sheet hydrogen bonding, and deviation of backbone conformation from the starting structure, and an increase in nonnative contacts. Native contacts are lost in β-sheet regions and in α1, partially due to movement of α1 away from the β-sheet core. At 330 and 340 K, a nonnative helical segment forms at residues 15–20, corresponding to a helix observed in the N-terminal domain-swapped dimer [Liu Y.S., Hart, P.J., Schulnegger, M.P., Eisenberg, D. (1998) Proc. Natl. Acad. Sci. USA, 95, 3437—3432]. The conformations observed at the higher temperatures possess native-like topology and overall conformation, with many native contacts, but they have a disrupted active site. We propose that these conformations may represent the native state at elevated temperature, or the N′ state. These simulations show that subtle, functionally important changes in protein conformation can occur below the Tm.
doi:10.1021/bi701565b
PMCID: PMC2532537  PMID: 18161991
13.  Microscopic reversibility of protein folding in molecular dynamics simulations of the engrailed homeodomain† 
Biochemistry  2008;47(27):7079-7089.
The principle of microscopic reversibility states that at equilibrium the number of molecules entering a state by a given path must equal those exiting the state via the same path under identical conditions, or in structural terms, that the conformations along the two pathways are the same. There has been some indirect evidence indicating that protein folding is such a process, but there have been few conclusive findings. In this study, we performed molecular dynamics simulations of an ultra-fast unfolding and folding protein at its melting temperature in order to observe, on an atom-by-atom basis, the pathways the protein followed as it unfolded and folded within a continuous trajectory. In a total of 0.67 μs of simulation in water, we found 6 transient denaturing events near the melting temperature (323K and 330K) and an additional refolding event following a previously identified unfolding event at high-temperature (373K). In each case unfolding and refolding transition state ensembles were identified, and they agreed well with experiment based on comparison of S- and Φ-values. Based on several structural properties, these 13 transition state ensembles agreed very well with each other and with 4 previously identified transition states from high-temperature denaturing simulations. Thus, not only were the unfolding and refolding transition states part of the same ensemble, but in five of the seven cases, the pathway the protein took as it unfolded was nearly identical to the subsequent refolding pathway. These events provide compelling evidence that protein folding is a microscopically reversible process. In the other two cases, the folding and unfolding transition states were remarkably similar to each other, but the paths deviated.
doi:10.1021/bi800118b
PMCID: PMC2905463  PMID: 18553935
14.  Dynamics of the Gel to Fluid Phase Transformation in Unilamellar DPPC Vesicles 
The journal of physical chemistry. B  2012;116(46):13749-13756.
The dynamics of the gel to fluid phase transformation in 100 nm large unilamellar vesicles (LUV) of 1,2-dipalmitoyl(d62)-sn-glycero-3-phosphocholine (d62-DPPC), has been studied by laser-induced temperature-jump initiation coupled with time-resolved infrared spectroscopy and by MD simulations. The infrared transients that characterize the temperature dependent phase transformation are complex, extending from the nanosecond to the millisecond time scales. An initial fast (submicrosecond) component can be modeled by partial melting of the gel domains, initiated at pre-existing defects at the edges of the faceted structure of the gel phase. Molecular dynamics simulations support the model of fast melting from edge defects. The extent of melting during the fast phase is limited by the area expansion on melting, which leads to a surface pressure that raises the effective melting temperature. Subsequent melting is observed to follow highly stretched exponential kinetics, consistent with collective relaxation of the surface pressure through a hierarchy of surface undulations with different relaxation times. The slowest step is water diffusion through the bilayer to allow the vesicle volume to grow along with its expanded surface area. The results demonstrate that the dominant relaxation in the gel to fluid phase transformation in response to a large T-jump perturbation (compared to the transition width) is fast (submicrosecond), which has important practical and fundamental consequences.
doi:10.1021/jp309832u
PMCID: PMC3508262  PMID: 23130986
15.  A commentary on evidenced-based parenting programs: redressing misconceptions of the empirical support for Triple P 
BMC Medicine  2012;10:145.
A meta-analytic review of the Triple P-Positive Parenting program by Wilson et al., recently published in BMC Medicine, claimed to demonstrate that although Triple P is widely disseminated and adopted, the evidence attesting to the effectiveness of the program is not as convincing as it may appear. Although this review addresses the important issue of evaluation and reporting methods within evidence-based interventions, we contend that the Wilson et al. review contains a number of significant conceptual, methodological and interpretational inadequacies that render the key conclusions of their review problematic.
doi:10.1186/1741-7015-10-145
PMCID: PMC3532235  PMID: 23173559
Triple P; Public Health; Parenting; Evidence
16.  Exploring the Energy Landscape of Protein Folding using Replica-Exchange and Conventional Molecular Dynamics Simulations 
Journal of structural biology  2006;157(3):514-523.
Two independent replica-exchange molecular dynamics (REMD) simulations with an explicit water model were performed of the Trp-cage mini-protein. In the first REMD simulation, the replicas started from the native conformation, while in the second they started from a nonnative conformation. Initially, the first simulation yielded results qualitatively similar to those of two previously published REMD simulations: the protein appeared to be over-stabilized, with the predicted melting temperature 50–150 K higher than the experimental value of 315 K. However, as the first REMD simulation progressed, the protein unfolded at all temperatures. In our second REMD simulation, which starts from a nonnative conformation, there was no evidence of significant folding. Transitions from the unfolded to the folded state did not occur on the timescale of these simulations, despite the expected improvement in sampling of REMD over conventional molecular dynamics (MD) simulations. The combined 1.42 μs of simulation time was insufficient for REMD simulations with different starting structures to converge. Conventional MD simulations at a range of temperatures were also performed. In contrast to REMD, the conventional MD simulations provide an estimate of Tm in good agreement with experiment. Furthermore, the conventional MD is a fraction of the cost of REMD and continuous, realistic pathways of the unfolding process at atomic resolution are obtained.
doi:10.1016/j.jsb.2006.10.002
PMCID: PMC1945213  PMID: 17113307
Replica exchange; molecular dynamics; protein folding; protein dynamics; Trp-cage; all-atom; explicit solvent
17.  THE MELTING MECHANISM OF DNA TETHERED TO A SURFACE 
The details of melting of DNA immobilized on a chip or nanoparticle determines the sensitivity and operating characteristics of many analytical and synthetic biotechnological devices. Yet, little is known about the differences in how the DNA melting occurs between a homogeneous solution and that on a chip. We used molecular dynamics simulations to explore possible pathways for DNA melting on a chip. Simulation conditions were chosen to ensure that melting occurred in a submicrosecond timescale. The temperature was set to 400 K and the NaCl concentration was set to 0.1 M. We found less symmetry than in the solution case where for oligomeric double-stranded nucleic acids both ends melted with roughly equal probability. On a prepared silica surface we found melting is dominated by fraying from the end away from the surface. Strand separation was hindered by nonspecific surface adsorption at this temperature. At elevated temperatures the melted DNA was attracted to even uncharged organically coated surfaces demonstrating surface fouling. While hybridization is not the simple reverse of melting, this simulation has implications for the kinetics of hybridization.
PMCID: PMC2755589  PMID: 19802357
DNA; melting; and microarray
18.  Soy isoflavones, estrogen therapy, and breast cancer risk: analysis and commentary 
Nutrition Journal  2008;7:17.
There has been considerable investigation of the potential for soyfoods to reduce risk of cancer, and in particular cancer of the breast. Most interest in this relationship is because soyfoods are essentially a unique dietary source of isoflavones, compounds which bind to estrogen receptors and exhibit weak estrogen-like effects under certain experimental conditions. In recent years the relationship between soyfoods and breast cancer has become controversial because of concerns – based mostly on in vitro and rodent data – that isoflavones may stimulate the growth of existing estrogen-sensitive breast tumors. This controversy carries considerable public health significance because of the increasing popularity of soyfoods and the commercial availability of isoflavone supplements. In this analysis and commentary we attempt to outline current concerns regarding the estrogen-like effects of isoflavones in the breast focusing primarily on the clinical trial data and place these concerns in the context of recent evidence regarding estrogen therapy use in postmenopausal women. Overall, there is little clinical evidence to suggest that isoflavones will increase breast cancer risk in healthy women or worsen the prognosis of breast cancer patients. Although relatively limited research has been conducted, and the clinical trials often involved small numbers of subjects, there is no evidence that isoflavone intake increases breast tissue density in pre- or postmenopausal women or increases breast cell proliferation in postmenopausal women with or without a history of breast cancer. The epidemiologic data are generally consistent with the clinical data, showing no indication of increased risk. Furthermore, these clinical and epidemiologic data are consistent with what appears to be a low overall breast cancer risk associated with pharmacologic unopposed estrogen exposure in postmenopausal women. While more research is required to definitively allay concerns, the existing data should provide some degree of assurance that isoflavone exposure at levels consistent with historical Asian soyfood intake does not result in adverse stimulatory effects on breast tissue.
doi:10.1186/1475-2891-7-17
PMCID: PMC2443803  PMID: 18522734
19.  The problems of meta-analysis for antibiotic treatment of chronic obstructive pulmonary disease, a heterogeneous disease: a commentary on Puhan et al 
BMC Medicine  2008;6:29.
Exacerbations are a major cause of morbidity and mortality in chronic obstructive pulmonary disease. Exacerbations can be of bacterial, viral or mixed etiology, with bacteria involved in 50% of exacerbations. Consequently, current management of exacerbations frequently involves the use of antibiotics. The paper by Puhan et al published this month in BMC Medicine examines the benefit of antibiotics in placebo-controlled trials in mild to moderate outpatient exacerbations. The authors use a meta-analytic approach and rightly conclude that more trials are needed in this area. However, the heterogeneity of chronic obstructive pulmonary disease patients and exacerbations and the limited end-points in past trials do not allow firm conclusions to be drawn about antibiotic use in outpatient exacerbations based on this meta-analysis. Future trials need to take into account this heterogeneity as well as incorporate novel end-points to address this important issue.
doi:10.1186/1741-7015-6-29
PMCID: PMC2569059  PMID: 18847482
20.  Localizing internal friction along the reaction coordinate of protein folding by combining ensemble and single-molecule fluorescence spectroscopy 
Nature Communications  2012;3:1195-.
Theory, simulations and experimental results have suggested an important role of internal friction in the kinetics of protein folding. Recent experiments on spectrin domains provided the first evidence for a pronounced contribution of internal friction in proteins that fold on the millisecond timescale. However, it has remained unclear how this contribution is distributed along the reaction and what influence it has on the folding dynamics. Here we use a combination of single-molecule Förster resonance energy transfer, nanosecond fluorescence correlation spectroscopy, microfluidic mixing and denaturant- and viscosity-dependent protein-folding kinetics to probe internal friction in the unfolded state and at the early and late transition states of slow- and fast-folding spectrin domains. We find that the internal friction affecting the folding rates of spectrin domains is highly localized to the early transition state, suggesting an important role of rather specific interactions in the rate-limiting conformational changes.
Internal friction affects the kinetics of protein folding. Borgia et al. investigate how this friction affects the folding dynamics of the protein spectrin, revealing a potential role in the rate-limiting conformational changes.
doi:10.1038/ncomms2204
PMCID: PMC3514500  PMID: 23149740
21.  Prediction of Selected Physical and Mechanical Properties of a Telechelic Polybenzoxazine by Molecular Simulation 
PLoS ONE  2013;8(4):e61179.
Molecular simulation is becoming an important tool for both understanding polymeric structures and predicting their physical and mechanical properties. In this study, temperature ramped molecular dynamics simulations are used to predict two physical properties (i.e., glass transition temperature and thermal degradation temperature) of a previously synthesised and published telechelic benzoxazine. Plots of simulated density versus temperature show decreases in density within the same temperature range as experimental values for the thermal degradation. The predicted value for the thermal degradation temperature for the cured polybenzoxazine based on the telechelic polyetherketone (PEK) monomer was ca. 400°C, in line with the experimental thermal degradation temperature range of 450°C to 500°C. Mechanical Properties of both the unmodified PEK and the telechelic benzoxazines are simulated and compared to experimental values (where available). The introduction of the benoxazine moieties are predicted to increase the elastic moduli in line with the increase of crosslinking in the system.
doi:10.1371/journal.pone.0061179
PMCID: PMC3620114  PMID: 23577206
22.  Solution Structures, Dynamics, and Ice Growth Inhibitory Activity of Peptide Fragments Derived from an Antarctic Yeast Protein 
PLoS ONE  2012;7(11):e49788.
Exotic functions of antifreeze proteins (AFP) and antifreeze glycopeptides (AFGP) have recently been attracted with much interest to develop them as commercial products. AFPs and AFGPs inhibit ice crystal growth by lowering the water freezing point without changing the water melting point. Our group isolated the Antarctic yeast Glaciozyma antarctica that expresses antifreeze protein to assist it in its survival mechanism at sub-zero temperatures. The protein is unique and novel, indicated by its low sequence homology compared to those of other AFPs. We explore the structure-function relationship of G. antarctica AFP using various approaches ranging from protein structure prediction, peptide design and antifreeze activity assays, nuclear magnetic resonance (NMR) studies and molecular dynamics simulation. The predicted secondary structure of G. antarctica AFP shows several α-helices, assumed to be responsible for its antifreeze activity. We designed several peptide fragments derived from the amino acid sequences of α-helical regions of the parent AFP and they also showed substantial antifreeze activities, below that of the original AFP. The relationship between peptide structure and activity was explored by NMR spectroscopy and molecular dynamics simulation. NMR results show that the antifreeze activity of the peptides correlates with their helicity and geometrical straightforwardness. Furthermore, molecular dynamics simulation also suggests that the activity of the designed peptides can be explained in terms of the structural rigidity/flexibility, i.e., the most active peptide demonstrates higher structural stability, lower flexibility than that of the other peptides with lower activities, and of lower rigidity. This report represents the first detailed report of downsizing a yeast AFP into its peptide fragments with measurable antifreeze activities.
doi:10.1371/journal.pone.0049788
PMCID: PMC3509122  PMID: 23209600
23.  Losartan and diabetic nephropathy: commentaries on the RENAAL study 
The RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) study is a multinational, double-blind, randomized, placebo controlled trial which was recently published. It was aimed to evaluate the effect of the angiotensin receptor blocker losartan in patients with diabetic nephropathy. The primary efficacy measure was the time to the first event of the composite end point of a doubling of serum creatinine, end-stage renal disease, or death. The conclusion was that losartan led to significant improvement in renal outcomes, that was beyond that attributable to blood pressure control in patients with type 2 diabetes and nephropathy.
The perusal of the report raises concern, regarding to both the patient population as well as the outcome measures. At randomization, the placebo group included more patients with angina, myocardial infarction and lipid disorders than the losartan group. Information on glucose metabolism was disregarded, and data on antihyperglycemic therapy – which may have undesirable influences on cardiac performance – were not included in a multivariate analysis. In addition, only data on first hospitalization were reported, whilst information on total specific-cause hospitalizations was disregarded, thus potentially masking further unfavorable events. Furthermore, creatinine seems not to be a reliable surrogate end point. Based on its mechanism of action, losartan may possess favorable renoprotective properties. However, due to the methodological flaws and the incomplete data in the RENAAL study, the question of the effectiveness and safety of this drug in diabetic nephropathy remains yet unanswered.
doi:10.1186/1475-2840-1-2
PMCID: PMC116616  PMID: 12119058
Angiotensin receptor blockers; Clinical trials; Diabetes mellitus; Losartan; Nephropathy; RENAAL study
24.  Commentary: The Relative Research Unit: An Approach to Measuring and Encouraging Clinician Participation in Research Activities 
Recent nationwide initiatives to accelerate clinical and translational research, including comparative effectiveness research, increasingly will require clinician participation in research-related activities at the point-of-care, activities such as participant recruitment for clinical research studies and systematic data collection. A key element to the success of such initiatives that has not yet been adequately addressed is how to provide incentives to clinicians for the time and effort that such participation will require. Models to calculate the value of clinical care services are commonly used to compensate clinicians, and similar models have been proposed to calculate and compensate researchers’ efforts. However, to the authors’ knowledge, no such model has been proposed for calculating the value of research-related activities performed by non-investigator clinicians, be they in academic or community settings. In this commentary, the authors propose a new model for doing just that. They describe how such a relative research unit model could be used to provide both direct and indirect incentives for clinician participation in research activities. Direct incentives could include financial compensation, while indirect incentives could include credit towards promotion and tenure and towards the maintenance of specialty board certification. The authors discuss the principles behind this relative research unit approach as well as ethical, funding, and other considerations to fully developing and deploying such a model, across academic environments first and then more broadly across the health care community.
doi:10.1097/ACM.0b013e31823a8d99
PMCID: PMC3914136  PMID: 22201633
25.  Mapping of plasmonic resonances in nanotriangles 
Summary
Plasmonic resonances in metallic nano-triangles have been investigated by irradiating these structures with short laser pulses and imaging the resulting ablation and melting patterns. The triangular gold structures were prepared on Si substrates and had a thickness of 40 nm and a side length of ca. 500 nm. Irradiation was carried out with single femtosecond and picosecond laser pulses at a wavelength of 800 nm, which excited higher order plasmon modes in these triangles. The ablation distribution as well as the local melting of small parts of the nanostructures reflect the regions of large near-field enhancement. The observed patterns are reproduced in great detail by FDTD simulations with a 3-dimensional model, provided that the calculations are not based on idealized, but on realistic structures. In this realistic model, details like the exact shape of the triangle edges and the dielectric environment of the structures are taken into account. The experimental numbers found for the field enhancement are typically somewhat smaller than the calculated ones. The results demonstrate the caveats for FDTD simulations and the potential and the limitations of “near field photography” by local ablation and melting for the mapping of complex plasmon fields and their applications.
doi:10.3762/bjnano.4.66
PMCID: PMC3817793  PMID: 24205453
ablation; FDTD simulations; field enhancement; nanotriangles; near field; surface plasmons

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