Hydrogen/deuterium exchange monitored by mass spectrometry is a promising technique for rapidly fingerprinting structural and dynamical properties of proteins. The time-dependent change in the mass of any fragment of the polypeptide chain depends uniquely on the rate of exchange of its amide hydrogens, but determining the latter from the former is generally not possible. Here, we show that, if time-resolved measurements are available for a number of overlapping peptides that cover the whole sequence, rate constants for each amide hydrogen exchange (or equivalently, their protection factors) may be extracted and the uniqueness of the solutions obtained depending on the degree of peptide overlap. However, in most cases, the solution is not unique, and multiple alternatives must be considered. We provide a statistical method that clusters the solutions to further reduce their number. Such analysis always provides meaningful constraints on protection factors and can be used in situations in which obtaining more refined experimental data is impractical. It also provides a systematic way to improve data collection strategies to obtain unambiguous information at single-residue level (e.g., for assessing protein structure predictions at atomistic level).

• MeSH
• amidy chemie   MeSH
• deuterium chemie   MeSH
• hmotnostní spektrometrie metody   normy   MeSH
• komplement C3 chemie   MeSH
• peptidy chemie   MeSH
• vodíková vazba MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• matematika MeSH
• metoda nejmenších čtverců MeSH
• Publikační typ
• monografie MeSH

• Konspekt
• Kombinatorika. Teorie grafů. Matematická statistika. Operační výzkum. Matematické modelování
• NLK Obory
• statistika, zdravotnická statistika

Prediction methods have become an integral part of biomedical and biotechnological research. However, their clinical interpretations are largely based on biochemical or molecular data, but not clinical data. Here, we focus on improving the reliability and clinical applicability of prediction algorithms. We assembled and curated two large non-overlapping large databases of clinical phenotypes. These phenotypes were caused by missense variations in 44 and 63 genes associated with Mendelian diseases. We used these databases to establish and validate the model, allowing us to improve the predictions obtained from EVmutation, SNAP2 and PoPMuSiC 2.1. The predictions of clinical effects suffered from a lack of specificity, which appears to be the common constraint of all recently used prediction methods, although predictions mediated by these methods are associated with nearly absolute sensitivity. We introduced evidence-based tailoring of the default settings of the prediction methods; this tailoring substantially improved the prediction outcomes. Additionally, the comparisons of the clinically observed and theoretical variations led to the identification of large previously unreported pools of variations that were under negative selection during molecular evolution. The evolutionary variation analysis approach described here is the first to enable the highly specific identification of likely disease-causing missense variations that have not yet been associated with any clinical phenotype.

• MeSH
• algoritmy MeSH
• ektodysplasiny genetika   MeSH
• fenotyp MeSH
• genetická variace MeSH
• genetické nemoci vrozené genetika   MeSH
• genomika MeSH
• glukosa-6-fosfátdehydrogenasa genetika   MeSH
• hemoglobiny genetika   MeSH
• hepatocytární jaderný faktor 4 genetika   MeSH
• lidé MeSH
• missense mutace MeSH
• modely genetické * MeSH
• molekulární evoluce MeSH
• mutace * MeSH
• pravděpodobnostní funkce MeSH
• proteomika MeSH
• tyrosinfosfatasa nereceptorového typu 11 genetika   MeSH
• výpočetní biologie metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

PURPOSE: Despite advancements in radiation techniques, concerns persist regarding the adverse effects of radiation therapy, particularly cardiotoxicity or radiation-induced heart disease. Recently, arrhythmogenic toxicity has come to the forefront-the impact of radiation therapy on the cardiac conduction system. Our objective was to conduct a dosimetric study and subsequently investigate the feasibility of optimizing the sinoatrial (SA) and atrioventricular (AV) nodes as organs at risk (OARs) in proton radiation therapy for non-small cell lung cancer with N3 disease. PATIENTS AND METHODS: Thirty-two non-small cell lung cancer patients with N3 disease undergoing proton radiation therapy were included. Sinoatrial and AV nodes, along with standard OARs, were delineated. Dosimetric analysis and optimization were performed using intensity-modulated proton therapy. RESULTS: Patients surpassing a predefined SA node dose threshold underwent dose optimization. Proton radiation therapy with pencil beam scanning demonstrated a significant reduction in SA and AV node doses without compromising target volume coverage or significant shift in the dose to other monitored OARs. CONCLUSION: Dose reduction to the SA and AV nodes for pencil beam scanning is a relatively simple task, and the reduction can be very substantial. Larger cohort studies and diverse radiotherapeutic modalities are needed for further validation and refinement of dose constraints.

• Publikační typ
• časopisecké články MeSH

Murid rodents (Rodentia: Muridae) represent the most diverse and abundant mammalian family. In this study, we provide a refined set of fossil calibrations which is used to reconstruct a dated phylogeny of the family using a multilocus dataset (six nuclear and nine mitochondrial gene fragments) encompassing 161 species representing 82 murid genera from four extant subfamilies (Deomyinae, Gerbillinae, Lophiomyinae and Murinae). In comparison with previous studies on murid or muroid rodents, our work stands out for the implementation of nine robust fossil constraints within the Muridae thanks to a thorough review of the fossil record. Before being assigned to specific nodes of the phylogeny, all potential fossil constraints were carefully assessed; they were also subjected to several cross-validation analyses. The resulting phylogeny is consistent with previous phylogenetic studies on murids, and recovers the monophyly of all sampled murid subfamilies and tribes. Based on nine controlled fossil calibrations, our inferred temporal timeframe indicates that the murid family likely originated in the course of the Early Miocene, 22.0-17.0 million years ago (Ma), and that most major lineages (i.e. tribes) started diversifying ca. 10 Ma. Historical biogeography analyses support the tropical origin for the family, with an initial internal split (vicariance event) between Afrotropical and Oriental (Indomalaya and Philippines) lineages. During the course of their diversification, the biogeographic pattern of murids is marked by several dispersal events toward the Australasian and the Palearctic regions. The Afrotropical region was also secondarily colonized at least three times from the Indomalaya, indicating that the latter region has acted as a major centre of diversification for the family.

• MeSH
• Bayesova věta MeSH
• časové faktory MeSH
• fylogeneze * MeSH
• fylogeografie MeSH
• kalibrace MeSH
• Muridae klasifikace   MeSH
• zkameněliny * MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Despite the increasing use of remote measurement technologies (RMT) such as wearables or biosensors in health care programs, challenges associated with selecting and implementing these technologies persist. Many health care programs that use RMT rely on commercially available, "off-the-shelf" devices to collect patient data. However, validation of these devices is sparse, the technology landscape is constantly changing, relative benefits between device options are often unclear, and research on patient and health care provider preferences is often lacking. OBJECTIVE: To address these common challenges, we propose a novel device selection framework extrapolated from human-centered design principles, which are commonly used in de novo digital health product design. We then present a case study in which we used the framework to identify, test, select, and implement off-the-shelf devices for the Remote Assessment of Disease and Relapse-Central Nervous System (RADAR-CNS) consortium, a research program using RMT to study central nervous system disease progression. METHODS: The RADAR-CNS device selection framework describes a human-centered approach to device selection for mobile health programs. The framework guides study designers through stakeholder engagement, technology landscaping, rapid proof of concept testing, and creative problem solving to develop device selection criteria and a robust implementation strategy. It also describes a method for considering compromises when tensions between stakeholder needs occur. RESULTS: The framework successfully guided device selection for the RADAR-CNS study on relapse in multiple sclerosis. In the initial stage, we engaged a multidisciplinary team of patients, health care professionals, researchers, and technologists to identify our primary device-related goals. We desired regular home-based measurements of gait, balance, fatigue, heart rate, and sleep over the course of the study. However, devices and measurement methods had to be user friendly, secure, and able to produce high quality data. In the second stage, we iteratively refined our strategy and selected devices based on technological and regulatory constraints, user feedback, and research goals. At several points, we used this method to devise compromises that addressed conflicting stakeholder needs. We then implemented a feedback mechanism into the study to gather lessons about devices to improve future versions of the RADAR-CNS program. CONCLUSIONS: The RADAR device selection framework provides a structured yet flexible approach to device selection for health care programs and can be used to systematically approach complex decisions that require teams to consider patient experiences alongside scientific priorities and logistical, technical, or regulatory constraints.

• MeSH
• lidé MeSH
• technologie MeSH
• telemedicína * MeSH
• zdravotnický personál MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Laboratory colonies of phlebotomine sand flies are necessary for experimental study of their biology, behaviour and mutual relations with disease agents and for testing new methods of vector control. They are indispensable in genetic studies and controlled observations on the physiology and behaviour of sand flies, neglected subjects of high priority. Colonies are of particular value for screening insecticides. Colonized sand flies are used as live vector models in a diverse array of research projects, including xenodiagnosis, that are directed toward control of leishmaniasis and other sand fly-associated diseases. Historically, labour-intensive maintenance and low productivity have limited their usefulness for research, especially for species that do not adapt well to laboratory conditions. However, with growing interest in leishmaniasis research, rearing techniques have been developed and refined, and sand fly colonies have become more common, enabling many significant breakthroughs. Today, there are at least 90 colonies representing 21 distinct phlebotomine sand fly species in 35 laboratories in 18 countries worldwide. The materials and methods used by various sand fly workers differ, dictated by the availability of resources, cost or manpower constraints rather than choice. This paper is not intended as a comprehensive review but rather a discussion of methods and techniques most commonly used by researchers to initiate, establish and maintain sand fly colonies, with emphasis on the methods proven to be most effective for the species the authors have colonized. Topics discussed include collecting sand flies for colony stock, colony initiation, maintenance and mass-rearing procedures, and control of sand fly pathogens in colonies.

• MeSH
• bydlení zvířat klasifikace   normy   MeSH
• doprava metody   MeSH
• hmyz - vektory klasifikace   růst a vývoj   parazitologie   fyziologie   MeSH
• kladení vajíček MeSH
• králíci MeSH
• křečci praví MeSH
• kur domácí MeSH
• morčata MeSH
• myši MeSH
• Psychodidae klasifikace   růst a vývoj   parazitologie   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• křečci praví MeSH
• morčata MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Indie MeSH

• MeSH
• molekulární biologie MeSH
• proteiny MeSH
• Publikační typ
• monografie MeSH

• Konspekt
• Biochemie. Molekulární biologie. Biofyzika
• NLK Obory
• biochemie
• molekulární biologie, molekulární medicína

• MeSH
• matematika MeSH
• teorie her MeSH
• Publikační typ
• monografie MeSH

• Konspekt
• Matematika
• NLK Obory
• přírodní vědy