ResearchPad - thermodynamics https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[How global DNA unwinding causes non-uniform stress distribution and melting of DNA]]> https://www.researchpad.co/article/elastic_article_14712 DNA unwinding is an important process that controls binding of proteins, gene expression and melting of double-stranded DNA. In a series of all-atom MD simulations on two DNA molecules containing a transcription start TATA-box sequence we demonstrate that application of a global restraint on the DNA twisting dramatically changes the coupling between helical parameters and the distribution of deformation energy along the sequence. Whereas only short range nearest-neighbor coupling is observed in the relaxed case, long-range coupling is induced in the globally restrained case. With increased overall unwinding the elastic deformation energy is strongly non-uniformly distributed resulting ultimately in a local melting transition of only the TATA box segment during the simulations. The deformation energy tends to be stored more in cytidine/guanine rich regions associated with a change in conformational substate distribution. Upon TATA box melting the deformation energy is largely absorbed by the melting bubble with the rest of the sequences relaxing back to near B-form. The simulations allow us to characterize the structural changes and the propagation of the elastic energy but also to calculate the associated free energy change upon DNA unwinding up to DNA melting. Finally, we design an Ising model for predicting the local melting transition based on empirical parameters. The direct comparison with the atomistic MD simulations indicates a remarkably good agreement for the predicted necessary torsional stress to induce a melting transition, for the position and length of the melted region and for the calculated associated free energy change between both approaches.

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<![CDATA[Conservation laws by virtue of scale symmetries in neural systems]]> https://www.researchpad.co/article/elastic_article_14657 Considerations of the way in which a dynamical system changes under transformation of scale offer insight into its operational principles. Scale freeness is a paradigm that has been observed in a variety of physical and biological phenomena and describes a situation in which appropriately scaling the space and time coordinates of any evolution of the system yields another possible evolution. In the brain, scale freeness has drawn considerable attention, as it has been associated with optimal information transmission capabilities. Scale symmetry describes a special case of scale freeness, in which a system is perfectly unchanged under transformation of scale. Noether’s theorem tells us that in a system that possesses such a symmetry, an associated conservation law must also exist. Here we show that scale symmetry can be identified, and the related conserved quantities measured, in both simulations and real-world data. We achieve this by deriving a generalised equation of motion that leaves the action invariant under spatiotemporal scale transformations and using a modified version of Noether’s theorem to write the associated family of conservation laws. Our contribution allows for the first such statistical characterisation of the quantity that is conserved purely by virtue of scale symmetry.

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<![CDATA[Dysregulated biodynamics in metabolic attractor systems precede the emergence of amyotrophic lateral sclerosis]]> https://www.researchpad.co/article/Nd64c8bc4-d849-4cf6-88a9-792b4ee4d346

Evolutionarily conserved mechanisms maintain homeostasis of essential elements, and are believed to be highly time-variant. However, current approaches measure elemental biomarkers at a few discrete time-points, ignoring complex higher-order dynamical features. To study dynamical properties of elemental homeostasis, we apply laser ablation inductively-coupled plasma mass spectrometry (LA-ICP-MS) to tooth samples to generate 500 temporally sequential measurements of elemental concentrations from birth to 10 years. We applied dynamical system and Information Theory-based analyses to reveal the longest-known attractor system in mammalian biology underlying the metabolism of nutrient elements, and identify distinct and consistent transitions between stable and unstable states throughout development. Extending these dynamical features to disease prediction, we find that attractor topography of nutrient metabolism is altered in amyotrophic lateral sclerosis (ALS), as early as childhood, suggesting these pathways are involved in disease risk. Mechanistic analysis was undertaken in a transgenic mouse model of ALS, where we find similar marked disruptions in elemental attractor systems as in humans. Our results demonstrate the application of a phenomological analysis of dynamical systems underlying elemental metabolism, and emphasize the utility of these measures in characterizing risk of disease.

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<![CDATA[Chemical profile of Lippia thymoides, evaluation of the acetylcholinesterase inhibitory activity of its essential oil, and molecular docking and molecular dynamics simulations]]> https://www.researchpad.co/article/5c8c194fd5eed0c484b4d3c7

The essential oils of the fresh and dry flowers, leaves, branches, and roots of Lippia thymoides were obtained by hydrodistillation and analyzed using gas chromatography (GC) and GC–mass spectrometry (MS). The acetylcholinesterase inhibitory activity of the essential oil of fresh leaves was investigated on silica gel plates. The interactions of the key compounds with acetylcholinesterase were simulated by molecular docking and molecular dynamics studies. In total, 75 compounds were identified, and oxygenated monoterpenes were the dominant components of all the plant parts, ranging from 19.48% to 84.99%. In the roots, the main compounds were saturated and unsaturated fatty acids, having contents varying from 39.5% to 32.17%, respectively. In the evaluation of the anticholinesterase activity, the essential oils (detection limit (DL) = 0.1 ng/spot) were found to be about ten times less active than that of physostigmine (DL = 0.01ng/spot), whereas thymol and thymol acetate presented DL values each of 0.01 ng/spot, equivalent to that of the positive control. Based on the docking and molecular dynamics studies, thymol and thymol acetate interact with the catalytic residues Ser203 and His447 of the active site of acetylcholinesterase. The binding free energies (ΔGbind) for these ligands were -18.49 and -26.88 kcal/mol, demonstrating that the ligands are able to interact with the protein and inhibit their catalytic activity.

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<![CDATA[Detailed characterization of the solution kinetics and thermodynamics of biotin, biocytin and HABA binding to avidin and streptavidin]]> https://www.researchpad.co/article/5c818e96d5eed0c484cc260a

The high affinity (KD ~ 10−15 M) of biotin for avidin and streptavidin is the essential component in a multitude of bioassays with many experiments using biotin modifications to invoke coupling. Equilibration times suggested for these assays assume that the association rate constant (kon) is approximately diffusion limited (109 M-1s-1) but recent single molecule and surface binding studies indicate that they are slower than expected (105 to 107 M-1s-1). In this study, we asked whether these reactions in solution are diffusion controlled, which reaction model and thermodynamic cycle describes the complex formation, and if there are any functional differences between avidin and streptavidin. We have studied the biotin association by two stopped-flow methodologies using labeled and unlabeled probes: I) fluorescent probes attached to biotin and biocytin; and II) unlabeled biotin and HABA, 2-(4’-hydroxyazobenzene)-benzoic acid. Both native avidin and streptavidin are homo-tetrameric and the association data show no cooperativity between the binding sites. The kon values of streptavidin are faster than avidin but slower than expected for a diffusion limited reaction in both complexes. Moreover, the Arrhenius plots of the kon values revealed strong temperature dependence with large activation energies (6–15 kcal/mol) that do not correspond to a diffusion limited process (3–4 kcal/mol). Accordingly, we propose a simple reaction model with a single transition state for non-immobilized reactants whose forward thermodynamic parameters complete the thermodynamic cycle, in agreement with previously reported studies. Our new understanding and description of the kinetics, thermodynamics, and spectroscopic parameters for these complexes will help to improve purification efficiencies, molecule detection, and drug screening assays or find new applications.

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<![CDATA[Haralick texture feature analysis for quantifying radiation response heterogeneity in murine models observed using Raman spectroscopic mapping]]> https://www.researchpad.co/article/5c706766d5eed0c4847c6fbd

Tumour heterogeneity plays a large role in the response of tumour tissues to radiation therapy. Inherent biological, physical, and even dose deposition heterogeneity all play a role in the resultant observed response. We here implement the use of Haralick textural analysis to quantify the observed glycogen production response, as observed via Raman spectroscopic mapping, of tumours irradiated within a murine model. While an array of over 20 Haralick features have been proposed, we here concentrate on five of the most prominent features: homogeneity, local homogeneity, contrast, entropy, and correlation. We show that these Haralick features can be used to quantify the inherent heterogeneity of the Raman spectroscopic maps of tumour response to radiation. Furthermore, our results indicate that Haralick-calculated textural features show a statistically significant dose dependent variation in response heterogeneity, specifically, in glycogen production in tumours irradiated with clinically relevant doses of ionizing radiation. These results indicate that Haralick textural analysis provides a quantitative methodology for understanding the response of murine tumours to radiation therapy. Future work in this area can, for example, utilize the Haralick textural features for understanding the heterogeneity of radiation response as measured by biopsied patient tumour samples, which remains the standard of patient tumour investigation.

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<![CDATA[Metal based donepezil analogues designed to inhibit human acetylcholinesterase for Alzheimer’s disease]]> https://www.researchpad.co/article/5c76fe06d5eed0c484e5b2cd

Among neurodegenerative disorders, Alzheimer’s disease (AD) is one of the most common disorders showing slow progressive cognitive decline. Targeting acetylcholinesterase (AChE) is one of the major strategies for AD therapeutics, as cholinergic pathways in the cerebral cortex and basal forebrain are compromised. Herein, we report the design of some copper and other metal based donepezil derivatives, employing density functional theory (DFT). All designed compounds are optimized at the B3LYP/SDD level of theory. Dipole moments, electronic energie, enthalpies, Gibbs free energies, and HOMO-LUMO gaps of these modified compounds are also investigated in the subsequent analysis. The molecules were then subjected to molecular docking analysis with AChE to study the molecular interactions broadly. Ensemble based docking and molecular dynamics (MD) simulations of the best candidates were also performed. Docking and MD simulation reveal that modified drugs are more potent than unmodified donepezil, where Trp86, Tyr337, Phe330 residues play some important roles in drug-receptor interactions. According to ensemble based docking, D9 shows greater binding affinity compared to the parent in most conformations obtained from protein data bank and MD simulation. In addition, it is observed that the π- π stacking with the residues of Trp86, Tyr337, Tyr341, Tyr124 and Trp286 may be required for strong ligand binding. Moreover, ADME/T analysis suggests that modified derivatives are less toxic and have improved pharmacokinetic properties than those of the parent drug. These results further confirm the ability of metal-directed drugs to bind simultaneously to the active sites of AChE and support them as potential candidates for the future treatment of Alzheimer’s disease.

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<![CDATA[Predicting change: Approximate inference under explicit representation of temporal structure in changing environments]]> https://www.researchpad.co/article/5c5ca27ed5eed0c48441e4cc

In our daily lives timing of our actions plays an essential role when we navigate the complex everyday environment. It is an open question though how the representations of the temporal structure of the world influence our behavior. Here we propose a probabilistic model with an explicit representation of state durations which may provide novel insights in how the brain predicts upcoming changes. We illustrate several properties of the behavioral model using a standard reversal learning design and compare its task performance to standard reinforcement learning models. Furthermore, using experimental data, we demonstrate how the model can be applied to identify participants’ beliefs about the latent temporal task structure. We found that roughly one quarter of participants seem to have learned the latent temporal structure and used it to anticipate changes, whereas the remaining participants’ behavior did not show signs of anticipatory responses, suggesting a lack of precise temporal expectations. We expect that the introduced behavioral model will allow, in future studies, for a systematic investigation of how participants learn the underlying temporal structure of task environments and how these representations shape behavior.

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<![CDATA[A low-threshold potassium current enhances sparseness and reliability in a model of avian auditory cortex]]> https://www.researchpad.co/article/5c58d63bd5eed0c484031922

Birdsong is a complex vocal communication signal, and like humans, birds need to discriminate between similar sequences of sound with different meanings. The caudal mesopallium (CM) is a cortical-level auditory area implicated in song discrimination. CM neurons respond sparsely to conspecific song and are tolerant of production variability. Intracellular recordings in CM have identified a diversity of intrinsic membrane dynamics, which could contribute to the emergence of these higher-order functional properties. We investigated this hypothesis using a novel linear-dynamical cascade model that incorporated detailed biophysical dynamics to simulate auditory responses to birdsong. Neuron models that included a low-threshold potassium current present in a subset of CM neurons showed increased selectivity and coding efficiency relative to models without this current. These results demonstrate the impact of intrinsic dynamics on sensory coding and the importance of including the biophysical characteristics of neural populations in simulation studies.

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<![CDATA[Dynamical analogues of rank distributions]]> https://www.researchpad.co/article/5c61e933d5eed0c48496f97e

We present an equivalence between stochastic and deterministic variable approaches to represent ranked data and find the expressions obtained to be suggestive of statistical-mechanical meanings. We first reproduce size-rank distributions N(k) from real data sets by straightforward considerations based on the assumed knowledge of the background probability distribution P(N) that generates samples of random variable values similar to real data. The choice of different functional expressions for P(N): power law, exponential, Gaussian, etc., leads to different classes of distributions N(k) for which we find examples in nature. Then we show that all of these types of functions can be alternatively obtained from deterministic dynamical systems. These correspond to one-dimensional nonlinear iterated maps near a tangent bifurcation whose trajectories are proved to be precise analogues of the N(k). We provide explicit expressions for the maps and their trajectories and find they operate under conditions of vanishing or small Lyapunov exponent, therefore at or near a transition to or out of chaos. We give explicit examples ranging from exponential to logarithmic behavior, including Zipf’s law. Adoption of the nonlinear map as the formalism central character is a useful viewpoint, as variation of its few parameters, that modify its tangency property, translate into the different classes for N(k).

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<![CDATA[Kinetic and thermodynamic insights into sodium ion translocation through the μ-opioid receptor from molecular dynamics and machine learning analysis]]> https://www.researchpad.co/article/5c536a92d5eed0c484a47639

The differential modulation of agonist and antagonist binding to opioid receptors (ORs) by sodium (Na+) has been known for decades. To shed light on the molecular determinants, thermodynamics, and kinetics of Na+ translocation through the μ-OR (MOR), we used a multi-ensemble Markov model framework combining equilibrium and non-equilibrium atomistic molecular dynamics simulations of Na+ binding to MOR active or inactive crystal structures embedded in an explicit lipid bilayer. We identify an energetically favorable, continuous ion pathway through the MOR active conformation only, and provide, for the first time: i) estimates of the energy differences and required timescales of Na+ translocation in inactive and active MORs, ii) estimates of Na+-induced changes to agonist binding validated by radioligand measurements, and iii) testable hypotheses of molecular determinants and correlated motions involved in this translocation, which are likely to play a key role in MOR signaling.

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<![CDATA[Activity painting: PET images of freely defined activity distributions applying a novel phantom technique]]> https://www.researchpad.co/article/5c57e684d5eed0c484ef3523

The aim of this work was to develop a novel phantom that supports the construction of highly reproducible phantoms with arbitrary activity distributions for PET imaging. It could offer a methodology for answering questions related to texture measurements in PET imaging. The basic idea is to move a point source on a 3-D trajectory in the field of view, while continuously acquiring data. The reconstruction results in a 3-D activity concentration map according to the pathway of the point source. A 22Na calibration point source was attached to a high precision robotic arm system, where the 3-D movement was software controlled. 3-D activity distributions of a homogeneous cube, a sphere, a spherical shell and a heart shape were simulated. These distributions were used to measure uniformity and to characterize reproducibility. Two potential applications using the lesion simulation method are presented: evaluation in changes of textural properties related to the position in the PET field of view; scanner comparison based on visual and quantitative evaluation of texture features. A lesion with volume of 50x50x50 mm3 can be simulated during approximately 1 hour. The reproducibility of the movement was found to be >99%. The coefficients of variation of the voxels within a simulated homogeneous cube was 2.34%. Based on 5 consecutive and independent measurements of a 36 mm diameter hot sphere, the coefficient of variation of the mean activity concentration was 0.68%. We obtained up to 18% differences within the values of investigated textural indexes, when measuring a lesion in different radial positions of the PET field of view. In comparison of two different human PET scanners the percentage differences between heterogeneity parameters were in the range of 5–55%. After harmonizing the voxel sizes this range reduced to 2–16%. The general activity distributions provided by the two different vendor show high similarity visually. For the demonstration of the flexibility of this method, the same pattern was also simulated on a small animal PET scanner giving similar results, both quantitatively and visually. 3-D motion of a point source in the PET field of view is capable to create an irregular shaped activity distribution with high reproducibility.

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<![CDATA[Thioguanine-based DENV-2 NS2B/NS3 protease inhibitors: Virtual screening, synthesis, biological evaluation and molecular modelling]]> https://www.researchpad.co/article/5c536b8fd5eed0c484a48cc8

Dengue virus Type 2 (DENV-2) is predominant serotype causing major dengue epidemics. There are a number of studies carried out to find its effective antiviral, however to date, there is still no molecule either from peptide or small molecules released as a drug. The present study aims to identify small molecules inhibitor from National Cancer Institute database through virtual screening. One of the hits, D0713 (IC50 = 62 μM) bearing thioguanine scaffold was derivatised into 21 compounds and evaluated for DENV-2 NS2B/NS3 protease inhibitory activity. Compounds 18 and 21 demonstrated the most potent activity with IC50 of 0.38 μM and 16 μM, respectively. Molecular dynamics and MM/PBSA free energy of binding calculation were conducted to study the interaction mechanism of these compounds with the protease. The free energy of binding of 18 calculated by MM/PBSA is -16.10 kcal/mol compared to the known inhibitor, panduratin A (-11.27 kcal/mol), which corroborates well with the experimental observation. Results from molecular dynamics simulations also showed that both 18 and 21 bind in the active site and stabilised by the formation of hydrogen bonds with Asn174.

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<![CDATA[Mutant T4 DNA polymerase for easy cloning and mutagenesis]]> https://www.researchpad.co/article/5c5217bad5eed0c484794479

The advent of high-fidelity DNA polymerases that can be used to linearize and amplify whole plasmids by PCR opened the door to greatly simplified cloning and mutagenesis protocols. Commercially available kits work well, but often have been optimized using undisclosed or proprietory components. Here we show that a mutant T4 DNA polymerase (Y320A) with attenuated 3’-exonuclease activity is uniquely suited to generate single-stranded DNA overhangs of uniform length in a more easily controllable manner than the wild-type enzyme, and this can be used to increase the yields of colonies containing correctly modified plasmids in cloning and mutagenesis experiments, which is particularly useful when E. coli cells are of relatively low competency. Standard protocols using the mutant T4 DNA polymerase are provided for the sequence and ligation independent cloning (SLIC) method and a modified QuikChange method, where the mutant enzyme enhances the yield of correctly mutated plasmid and further suppresses parental plasmid during digestion with DpnI. Single-stranded DNA overhangs generated by the mutant T4 DNA polymerase facilitate subsequent plasmid circularization, annealing and ligation in E. coli.

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<![CDATA[Subarctic singers: Humpback whale (Megaptera novaeangliae) song structure and progression from an Icelandic feeding ground during winter]]> https://www.researchpad.co/article/5c52181ad5eed0c48479736e

Humpback whale songs associated with breeding behaviors are increasingly reported outside of traditional low latitude breeding grounds. Songs from a subarctic feeding ground during the winter were quantitatively characterized to investigate the structure and temporal changes of the songs at such an atypical location. Recordings were collected from 26. January to 12. March, 2011, using bottom mounted recorders. Humpback songs were detected on 91% of the recording days with peak singing activities during 9.–26. February. The majority of the recordings included multiple chorusing singers. The songs were characterized by a) common static themes which transitioned consistently to predictable themes, b) shifting themes which occurred less predictably and c) rare themes. A set median sequence was found for four different periods (sets) of recordings (approximately 1 week each). The set medians were highly similar and formed a single cluster indicating that the sequences of themes sung in this area belonged to a single cluster of songs despite of the variation caused by the shifting themes. These subarctic winter songs could, thus, represent a characteristic song type for this area which is comparable to extensively studied songs from traditional low latitude breeding grounds. An increase in the number of themes per sequence was observed throughout the recording period including minor changes in the application of themes in the songs; indicating a gradual song progression. The results confirm that continual singing of sophisticated songs occur during the breeding season in the subarctic. In addition to being a well-established summer feeding ground the study area appears to be an important overwintering site for humpback whales delaying or canceling their migration where males engage in active sexual displays, i.e. singing. Importantly, such singing activity on a shared feeding ground likely aids the cultural transmission of songs in the North Atlantic.

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<![CDATA[Crystal structure of a Thermus aquaticus diversity-generating retroelement variable protein]]> https://www.researchpad.co/article/5c40f7b0d5eed0c484386634

Diversity-generating retroelements (DGRs) are widely distributed in bacteria, archaea, and microbial viruses, and bring about unparalleled levels of sequence variation in target proteins. While DGR variable proteins share low sequence identity, the structures of several such proteins have revealed the C-type lectin (CLec)-fold as a conserved scaffold for accommodating massive sequence variation. This conservation has led to the suggestion that the CLec-fold may be useful in molecular surface display applications. Thermostability is an attractive feature in such applications, and thus we studied the variable protein of a DGR encoded by a prophage of the thermophile Thermus aquaticus. We report here the 2.8 Å resolution crystal structure of the variable protein from the T. aquaticus DGR, called TaqVP, and confirm that it has a CLec-fold. Remarkably, its variable region is nearly identical in structure to those of several other CLec-fold DGR variable proteins despite low sequence identity among these. TaqVP was found to be thermostable, which appears to be a property shared by several CLec-fold DGR variable proteins. These results provide impetus for the pursuit of the DGR variable protein CLec-fold in molecular display applications.

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<![CDATA[Locus Coeruleus tracking of prediction errors optimises cognitive flexibility: An Active Inference model]]> https://www.researchpad.co/article/5c390b8dd5eed0c48491d307

The locus coeruleus (LC) in the pons is the major source of noradrenaline (NA) in the brain. Two modes of LC firing have been associated with distinct cognitive states: changes in tonic rates of firing are correlated with global levels of arousal and behavioural flexibility, whilst phasic LC responses are evoked by salient stimuli. Here, we unify these two modes of firing by modelling the response of the LC as a correlate of a prediction error when inferring states for action planning under Active Inference (AI). We simulate a classic Go/No-go reward learning task and a three-arm ‘explore/exploit’ task and show that, if LC activity is considered to reflect the magnitude of high level ‘state-action’ prediction errors, then both tonic and phasic modes of firing are emergent features of belief updating. We also demonstrate that when contingencies change, AI agents can update their internal models more quickly by feeding back this state-action prediction error–reflected in LC firing and noradrenaline release–to optimise learning rate, enabling large adjustments over short timescales. We propose that such prediction errors are mediated by cortico-LC connections, whilst ascending input from LC to cortex modulates belief updating in anterior cingulate cortex (ACC). In short, we characterise the LC/ NA system within a general theory of brain function. In doing so, we show that contrasting, behaviour-dependent firing patterns are an emergent property of the LC that translates state-action prediction errors into an optimal balance between plasticity and stability.

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<![CDATA[Characterization and performance of castor bean lineages and parents at the UFRB germplasm bank]]> https://www.researchpad.co/article/5c3d0120d5eed0c48403885a

The objective of this work was to characterize 203 lineages and five parents of Ricinus communis L. from the germplasm bank at the Federal University of Recôncavo da Bahia (UFRB), which was established by the Genetic Improvement and Biotechnology Program (NBIO) at the Center for Agrarian, Environmental and Biological Sciences. The study used 35 morpho-agronomic descriptors, proposed by the Ministry of Agriculture, Livestock and Supply, and 12 quantitative descriptors suggested by NBIO. The experiment was conducted in a randomized block design, composed of four blocks, in the experimental field at UFRB in 2014. The frequency and entropy level of the qualitative descriptors were estimated with the Renyi procedure, and an analysis of variance was used for the quantitative descriptors. The analyses were made with the statistical program R. Of the qualitative morpho-agronomic descriptors evaluated, 22.86% had a high level of entropy (above 1.0), and all 12 quantitative descriptors showed significant differences. This indicates genetic variability in the germplasm bank and a satisfactory performance for most of the descriptors evaluated, as well as the possibility of direct and indirect use of the lineages and parents in genetic improvement programs of the species.

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<![CDATA[Energy landscape for the insertion of amphiphilic nanoparticles into lipid membranes: A computational study]]> https://www.researchpad.co/article/5c3fa610d5eed0c484cabadc

Amphiphilic, monolayer-protected gold nanoparticles (NPs) have been shown to enter cells via a non-endocytic, non-disruptive pathway that could be valuable for biomedical applications. The same NPs were also found to insert into a series of model cell membranes as a precursor to cellular uptake, but the insertion mechanism remains unclear. Previous simulations have demonstrated that an amphiphilic NP can insert into a single leaflet of a planar lipid bilayer, but in this configuration all charged end groups are localized to one side of the bilayer and it is unknown if further insertion is thermodynamically favorable. Here, we use atomistic molecular dynamics simulations to show that an amphiphilic NP can reach the bilayer midplane non-disruptively if charged ligands iteratively “flip” across the bilayer. Ligand flipping is a favorable process that relaxes bilayer curvature, decreases the nonpolar solvent-accessible surface area of the NP monolayer, and increases attractive ligand-lipid electrostatic interactions. Analysis of end group hydration further indicates that iterative ligand flipping can occur on experimentally relevant timescales. Supported by these results, we present a complete energy landscape for the non-disruptive insertion of amphiphilic NPs into lipid bilayers. These findings will help guide the design of NPs to enhance bilayer insertion and non-endocytic cellular uptake, and also provide physical insight into a possible pathway for the translocation of charged biomacromolecules.

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<![CDATA[Alpha desynchronization during simple working memory unmasks pathological aging in cognitively healthy individuals]]> https://www.researchpad.co/article/5c3667dfd5eed0c4841a6755

Our aim is to explore if cognitive challenge combined with objective physiology can reveal abnormal frontal alpha event-related desynchronization (ERD), in early Alzheimer’s disease (AD). We used quantitative electroencephalography (qEEG) to investigate brain activities during N-back working memory (WM) processing at two different load conditions (N = 0 or 2) in an aging cohort. We studied 60–100 year old participants, with normal cognition, and who fits one of two subgroups from cerebrospinal fluid (CSF) proteins: cognitively healthy (CH) with normal amyloid/tau ratio (CH-NAT, n = 10) or pathological amyloid/tau ratio (CH-PAT, n = 14). We recorded behavioral performances, and analyzed alpha power and alpha spectral entropy (SE) at three occasions: during the resting state, and at event-related desynchronization (ERD) [250 ~ 750 ms] during 0-back and 2-back. During 0-back WM testing, the behavioral performance was similar between the two groups, however, qEEG notably differentiated CH-PATs from CH-NATs on the simple, 0-back testing: Alpha ERD decreased from baseline only in the parietal region in CH-NATs, while it decreased in all brain regions in CH-PATs. Alpha SE did not change in CH-NATs, but was increased from baseline in the CH-PATs in frontal and left lateral regions (p<0.01), and was higher in the frontal region (p<0.01) of CH-PATs compared to CH-NATs. The alpha ERD and SE analyses suggest there is frontal lobe dysfunction during WM processing in the CH-PAT stage. Additional power and correlations with behavioral performance were also explored. This study provide pilot information to further evaluate whether this biomarker has clinical significance.

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