777 research outputs found
Derivation of outcome-dependent dietary patterns for low-income women obtained from survey data using a Supervised Weighted Overfitted Latent Class Analysis
Full text linkPoor diet quality is a key modifiable risk factor for hypertension and
disproportionately impacts low-income women. \sw{Analyzing diet-driven
hypertensive outcomes in this demographic is challenging due to the complexity
of dietary data and selection bias when the data come from surveys, a main data
source for understanding diet-disease relationships in understudied
populations. Supervised Bayesian model-based clustering methods summarize
dietary data into latent patterns that holistically capture relationships among
foods and a known health outcome but do not sufficiently account for complex
survey design. This leads to biased estimation and inference and lack of
generalizability of the patterns}. To address this, we propose a supervised
weighted overfitted latent class analysis (SWOLCA) based on a Bayesian
pseudo-likelihood approach that integrates sampling weights into an
exposure-outcome model for discrete data. Our model adjusts for stratification,
clustering, and informative sampling, and handles modifying effects via
interaction terms within a Markov chain Monte Carlo Gibbs sampling algorithm.
Simulation studies confirm that the SWOLCA model exhibits good performance in
terms of bias, precision, and coverage. Using data from the National Health and
Nutrition Examination Survey (2015-2018), we demonstrate the utility of our
model by characterizing dietary patterns associated with hypertensive outcomes
among low-income women in the United States.Comment: 16 pages, 8 tables, 7 figure
A New Approach to the Use of Non-Primitive Variables in the Mechanics of Continuous Media
Get PDFThe problem of an approximate solution to hydrodynamic problems is the consideration of pressure. To exclude it from the equations, the transition to “non-primitive variables” (vortex and velocity vector divergence) is made. In this case, there are difficulties in the algorithmization of new equations for solving the inverse problem of hydrodynamics and a lot of internal iterative calculations. The object of this study includes equations in “non-primitive” variables. The research methods are based on the transformation without simplifications and assumptions of hydrodynamic equations into a form containing “non-primitive” variables and the demonstration of the possibilities of solving the equations. The GAMS programming language was used for approximate solutions for the first time. The aim of this paper is to demonstrate the possibility of solving the full equations in “non-primitive” variables for various conditions. The results showed the possibility of considering the compressibility of the medium when solving the inverse problem of hydrodynamics; the identity of solutions of the proposed system of equations and equations using the potential; and the possibility of using optimizing programming languages for hydrodynamics problems. The scientific novelty of this research consists of solving the full equations of hydrodynamics with the use of “non-primitive” variables but without the use of the current function. Doi: 10.28991/ESJ-2024-08-02-021 Full Text: PD
Magnetoresistive study of antiferromagnetic--weak ferromagnetic transition in single-crystal LaCuO
Full text linkThe resistive measurements were made to study the magnetic field-induced
antiferromagnetic (AF) - weak ferromagnetic (WF) transition in LaCuO
single-crystal. The magnetic field (DC or pulsed) was applied normally to the
CuO layers. The transition manifested itself in a drastic decrease of the
resistance in critical fields of ~5-7 T. The study is the first to display the
effect of the AF -WF transition on the conductivity of the LaCuO
single-crystal in the parallel - to - CuO layers direction. The results
provide support for the 3-dimensional nature of the hopping conduction of this
layered oxide.Comment: 8 pages, 7 figures, RevTe
Comparative characteristics of inducible NO synthase inhibitor and nitric oxide donor in endothelial dysfunction correction caused by osteoarthrosis under experimental conditions
Get PDFStudy have been carried out on white Wistar line rats (age – 3 months, weight – 180-220 g). According to the tasks the animals were divided into 7 groups. 1st group is intact (n = 20). 2nd group is rats, which were modeled osteoarthritis without further correction and were withdrawn from the experiment in the first stage (7th day) (n=40). 3rd group is rats, which were modeled osteoarthritis without further correction and removed from the experiment in the second stage (21st day) (n=40). 4th group is rats, in which experimental osteoarthritis was corrected with nonsteroidal anti-inflammatory drugs (NSAIDs) (Diclofenac) and aminoguanidine and removed from the experiment in the first stage (7th day) (n=20). 5th group is rats, in which experimental osteoarthritis was corrected with NSAIDs (Diclofenac) and aminoguanidine and withdrawn from the experiment in the second stage (21st day) (n=20). 6th group is rats, where experimental osteoarthritis was corrected
using NSAIDs and a 7% L-arginine solution and withdrawn from the experiment in the first stage (7th day) (n=20). 7th group is rats, in which experimental osteoarthritis was corrected with NSAIDs and 7% L-arginine solution and withdrawn from the experiment in the second stage (21st day) (n=20)
Animals were withdrawn from the experiment for the 7th day and the 21st day after the simulation of the pathological condition. NSAIDs (Diclofenac), aminoguanidine and L-arginine were administered from the beginning of the study.
We have obtained the following results:
The increase in the content of von Willebrand factor (VWF) in the animals blood proves that endothelial dysfunction is an important part of experimental osteoarthritis pathogenesis. It’s revealed the tendency which directed on normalization of the endothelial dysfunction investigated marker at correction by aminoguadine as a part of complex therapy. L-arginine involvement in the complex correction in experimental osteoarthritis more pronouncedly normalized the VWF level, which indicates the endothelial function normalization. The use of nitric oxide donor is more effective in comparison with the inhibition of inducible NO synthase also in the endothelial nitric oxide synthase activity analysis
The Reputational Consequences of Failed Replications and Wrongness Admission among Scientists
Get PDFScientists are dedicating more attention to replication efforts. While the scientific utility of replications is unquestionable, the impact of failed replication efforts and the discussions surrounding them deserve more attention. Specifically, the debates about failed replications on social media have led to worry, in some scientists, regarding reputation. In order to gain data-informed insights into these issues, we collected data from 281 published scientists. We assessed whether scientists overestimate the negative reputational effects of a failed replication in a scenario-based study. Second, we assessed the reputational consequences of admitting wrongness (versus not) as an original scientist of an effect that has failed to replicate. Our data suggests that scientists overestimate the negative reputational impact of a hypothetical failed replication effort. We also show that admitting wrongness about a non-replicated finding is less harmful to one’s reputation than not admitting. Finally, we discovered a hint of evidence that feelings about the replication movement can be affected by whether replication efforts are aimed one’s own work versus the work of another. Given these findings, we then present potential ways forward in these discussions
Structural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies different P-loop conformations
Get PDFThe human genome encodes two active Vaccinia-related protein kinases (VRK), VRK1 and VRK2. These proteins have been implicated in a number of cellular processes and linked to a variety of tumors. However, understanding the cellular role of VRKs and establishing their potential use as targets for therapeutic intervention has been limited by the lack of tool compounds that can specifically modulate the activity of these kinases in cells. Here we identified BI-D1870, a dihydropteridine inhibitor of RSK kinases, as a promising starting point for the development of chemical probes targeting the active VRKs. We solved co-crystal structures of both VRK1 and VRK2 bound to BI-D1870 and of VRK1 bound to two broad-spectrum inhibitors. These structures revealed that both VRKs can adopt a P-loop folded conformation, which is stabilized by different mechanisms on each protein. Based on these structures, we suggest modifications to the dihydropteridine scaffold that can be explored to produce potent and specific inhibitors towards VRK1 and VRK2
Structural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies different P-loop conformations
Get PDFThe human genome encodes two active Vaccinia-related protein kinases (VRK), VRK1 and VRK2. These proteins have been implicated in a number of cellular processes and linked to a variety of tumors. However, understanding the cellular role of VRKs and establishing their potential use as targets for therapeutic intervention has been limited by the lack of tool compounds that can specifically modulate the activity of these kinases in cells. Here we identified BI-D1870, a dihydropteridine inhibitor of RSK kinases, as a promising starting point for the development of chemical probes targeting the active VRKs. We solved co-crystal structures of both VRK1 and VRK2 bound to BI-D1870 and of VRK1 bound to two broad-spectrum inhibitors. These structures revealed that both VRKs can adopt a P-loop folded conformation, which is stabilized by different mechanisms on each protein. Based on these structures, we suggest modifications to the dihydropteridine scaffold that can be explored to produce potent and specific inhibitors towards VRK1 and VRK2
Multivalent Histone and DNA Engagement by a PHD/BRD/PWWP Triple Reader Cassette Recruits ZMYND8 to K14ac-Rich Chromatin
Get PDFElucidation of interactions involving DNA and histone post-translational-modifications (PTMs) is essential for providing insight into complex biological functions. Reader assemblies connected via flexible linkages facilitate avidity and increase affinity, however little is known of the contribution to the recognition process of multiple PTMs due to rigidity in the absence of conformational flexibility. We report here the high resolution crystal structure of the triple-reader module (PHD-Bromo-PWWP) of ZMYND8 which forms a stable unit capable of simultaneously recognizing multiple histone PTMs, while presenting a charged platform for association with DNA. Single domain disruptions destroy the functional network of interactions initiated by ZMYND8, impairing recruitment to sites of DNA damage. Our data establish proof-of-principle that rigidity can be compensated by concomitant DNA and histone PTM interactions, maintaining multivalent engagement of transient chromatin states, thus identifying an important underappreciated role for rigid multivalent reader modules in nucleosome binding and chromatin function
Cellular Radiosensitivity: How much better do we understand it?
Get PDFPurpose: Ionizing radiation exposure gives rise to a variety of lesions in DNA that result in genetic instability and potentially tumorigenesis or cell death. Radiation extends its effects on DNA by direct interaction or by radiolysis of H2O that generates free radicals or aqueous electrons capable of interacting with and causing indirect damage to DNA. While the various lesions arising in DNA after radiation exposure can contribute to the mutagenising effects of this agent, the potentially most damaging lesion is the DNA double strand break (DSB) that contributes to genome instability and/or cell death. Thus in many cases failure to recognise and/or repair this lesion determines the radiosensitivity status of the cell. DNA repair mechanisms including homologous recombination (HR) and non-homologous end-joining (NHEJ) have evolved to protect cells against DNA DSB. Mutations in proteins that constitute these repair pathways are characterised by radiosensitivity and genome instability. Defects in a number of these proteins also give rise to genetic disorders that feature not only genetic instability but also immunodeficiency, cancer predisposition, neurodegeneration and other pathologies.
Conclusions: In the past fifty years our understanding of the cellular response to radiation damage has advanced enormously with insight being gained from a wide range of approaches extending from more basic early studies to the sophisticated approaches used today. In this review we discuss our current understanding of the impact of radiation on the cell and the organism gained from the array of past and present studies and attempt to provide an explanation for what it is that determines the response to radiation
Predominance of null mutations in ataxia-telangiectasia
Get PDFAtaxia-telangiectasia (A-T) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity and cancer predisposition. The responsible gene, ATM, was recently identified by positional cloning and found to encode a putative 350 kDa protein with a PI 3-kinase-like domain, presumably involved in mediating cell cycle arrest in response to radiation-induced DNA damage. The nature and location of A-T mutations should provide insight into the function of the ATM protein and the molecular basis of this pleiotropic disease. Of 44 A-T mutations identified by us to date, 39 (89%) are expected to inactivate the ATM protein by truncating it, by abolishing correct initiation or termination of translation, or by deleting large segments. Additional mutations are four smaller in-frame deletions and insertions, and one substitution of a highly conserved amino acid at the PI 3-kinase domain. The emerging profile of mutations causing A-T is thus dominated by those expected to completely inactivate the ATM protein. ATM mutations with milder effects may result in phenotypes related, but not identical, to A-T
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