sequence randomization
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Intrinsically disordered proteins (IDPs) represent a distinct class of proteins and are distinguished from globular proteins by conformational plasticity, high evolvability and a broad functional repertoire. Some of their properties are reminiscent of early proteins, but their abundance in eukaryotes, functional properties and compositional bias suggest that IDPs appeared at later evolutionary stages. The spectrum of IDP properties and their determinants are still not well defined. This study compares rudimentary physicochemical properties of IDPs and globular proteins using bioinformatic analysis on the level of their native sequences and random sequence permutations, addressing the contributions of composition versus sequence as determinants of the properties. IDPs have, on average, lower predicted secondary structure contents and aggregation propensities and biased amino acid compositions. However, our study shows that IDPs exhibit a broad range of these properties. Induced fold IDPs exhibit very similar compositions and secondary structure/aggregation propensities to globular proteins, and can be distinguished from unfoldable IDPs based on analysis of these sequence properties. While amino acid composition seems to be a major determinant of aggregation and secondary structure propensities, sequence randomization does not result in dramatic changes to these properties, but for both IDPs and globular proteins seems to fine-tune the tradeoff between folding and aggregation.
- Klíčová slova
- IDP, IDR, aggregation propensity, secondary structure prediction, sequence randomization,
- Publikační typ
- časopisecké články MeSH
All grass species evolved from an ancestor that underwent a whole-genome duplication (WGD) approximately 70 million years ago. Interestingly, the short arms of rice chromosomes 11 and 12 (and independently their homologs in sorghum) were found to be much more similar to each other than other homeologous regions within the duplicated genome. Based on detailed analysis of rice chromosomes 11 and 12 and their homologs in seven grass species, we propose a mechanism that explains the apparently 'younger' age of the duplication in this region of the genome, assuming a small number of reciprocal translocations at the chromosome termini. In each case the translocations were followed by unbalanced transmission and subsequent lineage sorting of the involved chromosomes to offspring. Molecular dating of these translocation events also allowed us to date major chromosome 'fusions' in the evolutionary lineages that led to Brachypodium and Triticeae. Furthermore, we provide evidence that rice is exceptional regarding the evolution of chromosomes 11 and 12, inasmuch as in other species the process of sequence exchange between homeologous chromosomes ceased much earlier than in rice. We presume that random events rather than selective forces are responsible for the observed high similarity between the short arm ends of rice chromosomes 11 and 12.
- Klíčová slova
- genome evolution, grass ancestor, inter-homeolog recombination, reciprocal translocation, whole-genome duplication,
- MeSH
- časové faktory MeSH
- chromozomy rostlin genetika MeSH
- druhová specificita MeSH
- duplikace genu MeSH
- fylogeneze MeSH
- genetická variace MeSH
- genom rostlinný genetika MeSH
- lipnicovité klasifikace genetika MeSH
- molekulární evoluce * MeSH
- molekulární sekvence - údaje MeSH
- rekombinace genetická MeSH
- sekvence nukleotidů MeSH
- sekvenční analýza DNA MeSH
- sekvenční homologie nukleových kyselin MeSH
- selekce (genetika) MeSH
- syntenie MeSH
- translokace genetická MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Harmonic elastic constants of 3-11 bp duplex DNA fragments were evaluated using four 5 ns unrestrained molecular dynamics simulation trajectories of 17 bp duplexes with explicit inclusion of solvent and counterions. All simulations were carried out with the Cornell et al. force-field and particle mesh Ewald method for long-range electrostatic interactions. The elastic constants including anisotropic bending and all coupling terms were derived by analyzing the correlations of fluctuations of structural properties along the trajectories. The following sequences have been considered: homopolymer d(ApA)(n) and d(GpG)(n), and alternating d(GPC)(n) and d(APT)(n). The calculated values of elastic constants are in very good overall agreement with experimental values for random sequences. The atomic-resolution molecular dynamics approach, however, reveals a pronounced sequence-dependence of the stretching and torsional rigidity of DNA, while sequence-dependence of the bending rigidity is smaller for the sequences considered. The earlier predicted twist-bend coupling emerged as the most important cross-term for fragments shorter than one helical turn. The calculated hydrodynamic relaxation times suggest that damping of bending motions may play a role in molecular dynamics simulations of long DNA fragments. A comparison of elasticity calculations using global and local helicoidal analyses is reported. The calculations reveal the importance of the fragment length definition. The present work shows that large-scale molecular dynamics simulations represent a unique source of data to study various aspects of DNA elasticity including its sequence-dependence.
- MeSH
- algoritmy MeSH
- anizotropie MeSH
- DNA chemie genetika metabolismus MeSH
- konformace nukleové kyseliny * MeSH
- oligodeoxyribonukleotidy chemie genetika metabolismus MeSH
- párování bází MeSH
- počítačová simulace MeSH
- pohyb těles MeSH
- pružnost MeSH
- rozpouštědla MeSH
- sekvence nukleotidů MeSH
- statická elektřina MeSH
- termodynamika MeSH
- voda metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- DNA MeSH
- oligodeoxyribonukleotidy MeSH
- rozpouštědla MeSH
- voda MeSH
BACKGROUND: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses. METHODS: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects. RESULTS: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk. CONCLUSIONS: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.
- Klíčová slova
- Mendelian Randomization, TERT, chromosome 5p15.33, lung cancer, mediation analysis, telomere length,
- MeSH
- adenokarcinom plic epidemiologie MeSH
- dlaždicobuněčné karcinomy hlavy a krku epidemiologie MeSH
- homeostáza telomer genetika MeSH
- leukocyty metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- lidské chromozomy, pár 5 genetika MeSH
- mendelovská randomizace MeSH
- nádory hlavy a krku epidemiologie MeSH
- nádory plic epidemiologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- spinocelulární karcinom epidemiologie MeSH
- telomery metabolismus MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
BACKGROUND: Rapid sequence induction (RSI) is a standard procedure, which should be implemented in all patients with a risk of aspiration/regurgitation during anaesthesia induction. OBJECTIVE: The primary aim was to evaluate clinical practice in RSI, both in adult and paediatric populations. DESIGN: Online survey. SETTINGS: A total of 56 countries. PARTICIPANTS: Members of the European Society of Anaesthesiology. MAIN OUTCOME MEASURES: The aim was to identify and describe the actual clinical practice of RSI related to general anaesthesia. RESULTS: From the 1921 respondents, 76.5% (n=1469) were qualified anaesthesiologists. When anaesthetising adults, the majority (61.7%, n=1081) of the respondents preoxygenated patients with 100% O2 for 3 min and 65.9% (n=1155) administered opioids during RSI. The Sellick manoeuvre was used by 38.5% (n=675) and was not used by 37.4% (n=656) of respondents. First-line medications for a haemodynamically stable adult patient were propofol (90.6%, n=1571) and suxamethonium (56.0%, n=932). Manual ventilation (inspiratory pressure <12 cmH2O) was used in 35.5% (n=622) of respondents. In the majority of paediatric patients, 3 min of preoxygenation (56.6%, n=817) and opioids (54.9%, n=797) were administered. The Sellick manoeuvre and manual ventilation (inspiratory pressure <12 cmH2O) in children were used by 23.5% (n=340) and 35.9% (n=517) of respondents, respectively. First-line induction drugs for a haemodynamically stable child were propofol (82.8%, n=1153) and rocuronium (54.7%, n=741). CONCLUSION: We found significant heterogeneity in the daily clinical practice of RSI. For patient safety, our findings emphasise the need for international RSI guidelines. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03694860.
- MeSH
- celková anestezie MeSH
- crush úvod do anestezie * MeSH
- dítě MeSH
- dospělí MeSH
- intratracheální intubace * MeSH
- lidé MeSH
- průzkumy a dotazníky MeSH
- sukcinylcholin MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- sukcinylcholin MeSH
Computational design of new proteins is often performed by optimizing the amino acid sequence. This sequence is characterized by an energy (lower energy means better propensity to form the desired 3D structure) that is sampled and minimized. Here, we use the parallel tempering algorithm to accelerate this task. ESMfold was used to predict the structures of the sampled proteins and calculate energy. Starting from random amino acid sequences, each sequence was sampled using the Monte Carlo method at one of a series of temperatures, and these replicas were being exchanged by the parallel tempering method. A series of 100 or 200 residue proteins was designed to maximize confidence in structure prediction and globularity and minimize surface hydrophobic residues. We show that parallel tempering is a viable alternative to Monte Carlo sampling without replica exchanges and simulated annealing or related energy-based protein design methods, especially in the situation where a continuous flow of designed sequences is desired.
- Klíčová slova
- ESMfold, Monte Carlo, machine learning, parallel tempering, protein design, replica exchange,
- MeSH
- algoritmy * MeSH
- hydrofobní a hydrofilní interakce MeSH
- konformace proteinů MeSH
- metoda Monte Carlo MeSH
- molekulární modely MeSH
- proteinové inženýrství * metody MeSH
- proteiny * chemie genetika MeSH
- sekvence aminokyselin MeSH
- termodynamika MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- proteiny * MeSH
- MeSH
- crush úvod do anestezie * MeSH
- klinické kompetence * MeSH
- lidé MeSH
- průzkumy a dotazníky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- dopisy MeSH
- komentáře MeSH
De novo gene emergence provides a route for new proteins to be formed from previously non-coding DNA. Proteins born in this way are considered random sequences and typically assumed to lack defined structure. While it remains unclear how likely a de novo protein is to assume a soluble and stable tertiary structure, intersecting evidence from random sequence and de novo-designed proteins suggests that native-like biophysical properties are abundant in sequence space. Taking putative de novo proteins identified in human and fly, we experimentally characterize a library of these sequences to assess their solubility and structure propensity. We compare this library to a set of synthetic random proteins with no evolutionary history. Bioinformatic prediction suggests that de novo proteins may have remarkably similar distributions of biophysical properties to unevolved random sequences of a given length and amino acid composition. However, upon expression in vitro, de novo proteins exhibit moderately higher solubility which is further induced by the DnaK chaperone system. We suggest that while synthetic random sequences are a useful proxy for de novo proteins in terms of structure propensity, de novo proteins may be better integrated in the cellular system than random expectation, given their higher solubility.
- MeSH
- lidé MeSH
- proteiny * chemie MeSH
- proteomika * MeSH
- výpočetní biologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- proteiny * MeSH
This study examined the sequences of the two rRNA (rrn) operons of pathogenic non-cultivable treponemes, comprising 11 strains of T. pallidum ssp. pallidum (TPA), five strains of T. pallidum ssp. pertenue (TPE), two strains of T. pallidum ssp. endemicum (TEN), a simian Fribourg-Blanc strain and a rabbit T. paraluiscuniculi (TPc) strain. PCR was used to determine the type of 16S-23S ribosomal intergenic spacers in the rrn operons from 30 clinical samples belonging to five different genotypes. When compared with the TPA strains, TPc Cuniculi A strain had a 17 bp deletion, and the TPE, TEN and Fribourg-Blanc isolates had a deletion of 33 bp. Other than these deletions, only 17 heterogeneous sites were found within the entire region (excluding the 16S-23S intergenic spacer region encoding tRNA-Ile or tRNA-Ala). The pattern of nucleotide changes in the rrn operons corresponded to the classification of treponemal strains, whilst two different rrn spacer patterns (Ile/Ala and Ala/Ile) appeared to be distributed randomly across species/subspecies classification, time and geographical source of the treponemal strains. It is suggested that the random distribution of tRNA genes is caused by reciprocal translocation between repetitive sequences mediated by a recBCD-like system.
- MeSH
- DNA bakterií chemie genetika MeSH
- fylogeneze MeSH
- genetická variace MeSH
- genom bakteriální MeSH
- genotyp MeSH
- mezerníky ribozomální DNA genetika MeSH
- molekulární sekvence - údaje MeSH
- RNA ribozomální 16S genetika MeSH
- RNA ribozomální 23S genetika MeSH
- rRNA operon * MeSH
- sekvence nukleotidů MeSH
- sekvenční analýza DNA MeSH
- sekvenční delece MeSH
- Treponema pallidum klasifikace genetika MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- DNA bakterií MeSH
- mezerníky ribozomální DNA MeSH
- RNA ribozomální 16S MeSH
- RNA ribozomální 23S MeSH