A Score of the Ability of a Three-Dimensional Protein Model to Retrieve Its Own Sequence as a Quantitative Measure of Its Quality and Appropriateness

BACKGROUND: Despite the remarkable progress of bioinformatics, how the primary structure of a protein leads to a three-dimensional fold, and in turn determines its function remains an elusive question. Alignments of sequences with known function can be used to identify proteins with the same or similar function with high success. However, identification of function-related and structure-related amino acid positions is only possible after a detailed study of every protein. Folding pattern diversity seems to be much narrower than sequence diversity, and the amino acid sequences of natural proteins have evolved under a selective pressure comprising structural and functional requirements acting in parallel. PRINCIPAL FINDINGS: The approach described in this work begins by generating a large number of amino acid sequences using ROSETTA [Dantas G et al. (2003) J Mol Biol 332:449-460], a program with notable robustness in the assignment of amino acids to a known three-dimensional structure. The resulting sequence-sets showed no conservation of amino acids at active sites, or protein-protein interfaces. Hidden Markov models built from the resulting sequence sets were used to search sequence databases. Surprisingly, the models retrieved from the database sequences belonged to proteins with the same or a very similar function. Given an appropriate cutoff, the rate of false positives was zero. According to our results, this protocol, here referred to as Rd.HMM, detects fine structural details on the folding patterns, that seem to be tightly linked to the fitness of a structural framework for a specific biological function. CONCLUSION: Because the sequence of the native protein used to create the Rd.HMM model was always amongst the top hits, the procedure is a reliable tool to score, very accurately, the quality and appropriateness of computer-modeled 3D-structures, without the need for spectroscopy data. However, Rd.HMM is very sensitive to the conformational features of the models' backbone

A CLASP-modulated cell edge barrier mechanism drives cell-wide cortical microtubule organization in Arabidopsis

It is well known that the parallel order of microtubules in the plant cell cortex defines the direction of cell expansion, yet it remains unclear how microtubule orientation is controlled, especially on a cell-wide basis. Here we show through 4D imaging and computational modelling that plant cell polyhedral geometry provides spatial input that determines array orientation and heterogeneity. Microtubules depolymerize when encountering sharp cell edges head-on, whereas those oriented parallel to those sharp edges remain. Edge-induced microtubule depolymerization, however, is overcome by the microtubule-associated protein CLASP, which accumulates at specific cell edges, enables microtubule growth around sharp edges and promotes formation of microtubule bundles that span adjacent cell faces. By computationally modelling dynamic 'microtubules on a cube' with edges differentially permissive to microtubule passage, we show that the CLASP-edge complex is a 'tuneable' microtubule organizer, with the inherent flexibility to generate the numerous cortical array patterns observed in nature

A novel method to compare protein structures using local descriptors

<p>Abstract</p> <p>Background</p> <p>Protein structure comparison is one of the most widely performed tasks in bioinformatics. However, currently used methods have problems with the so-called "difficult similarities", including considerable shifts and distortions of structure, sequential swaps and circular permutations. There is a demand for efficient and automated systems capable of overcoming these difficulties, which may lead to the discovery of previously unknown structural relationships.</p> <p>Results</p> <p>We present a novel method for protein structure comparison based on the formalism of local descriptors of protein structure - DEscriptor Defined Alignment (DEDAL). Local similarities identified by pairs of similar descriptors are extended into global structural alignments. We demonstrate the method's capability by aligning structures in difficult benchmark sets: curated alignments in the SISYPHUS database, as well as SISY and RIPC sets, including non-sequential and non-rigid-body alignments. On the most difficult RIPC set of sequence alignment pairs the method achieves an accuracy of 77% (the second best method tested achieves 60% accuracy).</p> <p>Conclusions</p> <p>DEDAL is fast enough to be used in whole proteome applications, and by lowering the threshold of detectable structure similarity it may shed additional light on molecular evolution processes. It is well suited to improving automatic classification of structure domains, helping analyze protein fold space, or to improving protein classification schemes. DEDAL is available online at <url>http://bioexploratorium.pl/EP/DEDAL</url>.</p

Social disparities in food preparation behaviours: a DEDIPAC study

BACKGROUND: The specific role of major socio-economic indicators in influencing food preparation behaviours could reveal distinct socio-economic patterns, thus enabling mechanisms to be understood that contribute to social inequalities in health. This study investigated whether there was an independent association of each socio-economic indicator (education, occupation, income) with food preparation behaviours. METHODS: A total of 62,373 adults participating in the web-based NutriNet-Santé cohort study were included in our cross-sectional analyses. Cooking skills, preparation from scratch and kitchen equipment were assessed using a 0-10-point score; frequency of meal preparation, enjoyment of cooking and willingness to cook better/more frequently were categorical variables. Independent associations between socio-economic factors (education, income and occupation) and food preparation behaviours were assessed using analysis of covariance and logistic regression models stratified by sex. The models simultaneously included the three socio-economic indicators, adjusting for age, household composition and whether or not they were the main cook in the household. RESULTS: Participants with the lowest education, the lowest income group and female manual and office workers spent more time preparing food daily than participants with the highest education, those with the highest income and managerial staff (P < 0.0001). The lowest educated individuals were more likely to be non-cooks than those with the highest education level (Women: OR = 3.36 (1.69;6.69); Men: OR = 1.83 (1.07;3.16)) while female manual and office workers and the never-employed were less likely to be non-cooks (OR = 0.52 (0.28;0.97); OR = 0.30 (0.11;0.77)). Female manual and office workers had lower scores of preparation from scratch and were less likely to want to cook more frequently than managerial staff (P < 0.001 and P < 0.001). Women belonging to the lowest income group had a lower score of kitchen equipment (P < 0.0001) and were less likely to enjoy cooking meal daily (OR = 0.68 (0.45;0.86)) than those with the highest income. CONCLUSION: Lowest socio-economic groups, particularly women, spend more time preparing food than high socioeconomic groups. However, female manual and office workers used less raw or fresh ingredients to prepare meals than managerial staff. In the unfavourable context in France with reduced time spent preparing meals over last decades, our findings showed socioeconomic disparities in food preparation behaviours in women, whereas few differences were observed in men

Molecular biology of the blood-brain and the blood-cerebrospinal fluid barriers: similarities and differences

Efficient processing of information by the central nervous system (CNS) represents an important evolutionary advantage. Thus, homeostatic mechanisms have developed that provide appropriate circumstances for neuronal signaling, including a highly controlled and stable microenvironment. To provide such a milieu for neurons, extracellular fluids of the CNS are separated from the changeable environment of blood at three major interfaces: at the brain capillaries by the blood-brain barrier (BBB), which is localized at the level of the endothelial cells and separates brain interstitial fluid (ISF) from blood; at the epithelial layer of four choroid plexuses, the blood-cerebrospinal fluid (CSF) barrier (BCSFB), which separates CSF from the CP ISF, and at the arachnoid barrier. The two barriers that represent the largest interface between blood and brain extracellular fluids, the BBB and the BCSFB, prevent the free paracellular diffusion of polar molecules by complex morphological features, including tight junctions (TJs) that interconnect the endothelial and epithelial cells, respectively. The first part of this review focuses on the molecular biology of TJs and adherens junctions in the brain capillary endothelial cells and in the CP epithelial cells. However, normal function of the CNS depends on a constant supply of essential molecules, like glucose and amino acids from the blood, exchange of electrolytes between brain extracellular fluids and blood, as well as on efficient removal of metabolic waste products and excess neurotransmitters from the brain ISF. Therefore, a number of specific transport proteins are expressed in brain capillary endothelial cells and CP epithelial cells that provide transport of nutrients and ions into the CNS and removal of waste products and ions from the CSF. The second part of this review concentrates on the molecular biology of various solute carrier (SLC) transport proteins at those two barriers and underlines differences in their expression between the two barriers. Also, many blood-borne molecules and xenobiotics can diffuse into brain ISF and then into neuronal membranes due to their physicochemical properties. Entry of these compounds could be detrimental for neural transmission and signalling. Thus, BBB and BCSFB express transport proteins that actively restrict entry of lipophilic and amphipathic substances from blood and/or remove those molecules from the brain extracellular fluids. The third part of this review concentrates on the molecular biology of ATP-binding cassette (ABC)-transporters and those SLC transporters that are involved in efflux transport of xenobiotics, their expression at the BBB and BCSFB and differences in expression in the two major blood-brain interfaces. In addition, transport and diffusion of ions by the BBB and CP epithelium are involved in the formation of fluid, the ISF and CSF, respectively, so the last part of this review discusses molecular biology of ion transporters/exchangers and ion channels in the brain endothelial and CP epithelial cells

Validity of an online 24-h recall tool (myfood24) for dietary assessment in population studies: comparison with biomarkers and standard interviews

Background: Online dietary assessment tools can reduce administrative costs and facilitate repeated dietary assessment during follow-up in large-scale studies. However, information on bias due to measurement error of such tools is limited. We developed an online 24-hour recall (myfood24) and compared its performance with a traditional interviewer-administered multiple-pass 24-hour recall, assessing both against biomarkers. Methods: Metabolically stable adults were recruited and completed the new online dietary recall, an interviewer-based multiple pass recall and a suite of reference measures. Longer-term dietary intake was estimated from up to 3 x 24-hour recalls taken 2 weeks apart. Estimated intake of protein, potassium and sodium were compared with urinary biomarker concentrations. Estimated total sugar intake was compared with a predictive biomarker and estimated energy intake compared with energy expenditure measured by accelerometry and calorimetry. Nutrient intakes were also compared to those derived from an interviewer-administered multiple-pass 24-hour recall. Results: Biomarker samples were received from 212 participants on at least one occasion. Both self-reported dietary assessment tools led to attenuation compared to biomarkers. The online tools resulted in attenuation factors around 0.2 to 0.3 and partial correlation coefficients reflecting ranking intakes, of approximately 0.3 to 0.4. This was broadly similar to the more administratively burdensome interviewer-based tool. Other nutrient estimates derived from myfood24 were around 10-20% lower than from the interviewer-based tool, with wide limits of agreement. Intra-class correlation coefficients were approximately 0.4 to 0.5 indicating consistent moderate agreement. Conclusions: Our findings show that, whilst results from both measures of self-reported diet are attenuated compared to biomarker measures, the myfood24 online 24-hour recall is comparable to the more time-consuming and costly interviewer-based 24-hour recall across a range of measures

The complex variability of blazars: time-scales and periodicity analysis in S4 0954+65

Among active galactic nuclei, blazars show extreme variability properties. We here investigate the case of the BL Lac object S4 0954+65 with data acquired in 2019-2020 by the Transiting Exoplanet Survey Satellite (TESS) and by the Whole Earth Blazar Telescope (WEBT) Collaboration. The 2-min cadence optical light curves provided by TESS during three observing sectors of nearly 1 month each allow us to study the fast variability in great detail. We identify several characteristic short-term time-scales, ranging from a few hours to a few days. However, these are not persistent, as they differ in the various TESS sectors. The long-term photometric and polarimetric optical and radio monitoring undertaken by the WEBT brings significant additional information, revealing that (i) in the optical, long-term flux changes are almost achromatic, while the short-term ones are strongly chromatic; (ii) the radio flux variations at 37 GHz follow those in the optical with a delay of about 3 weeks; (iii) the range of variation of the polarization degree and angle is much larger in the optical than in the radio band, but the mean polarization angles are similar; (iv) the optical long-term variability is characterized by a quasi-periodicity of about 1 month. We explain the source behaviour in terms of a rotating inhomogeneous helical jet, whose pitch angle can change in time