BACKGROUND: Chronic kidney disease (CKD) contributes to global morbidity and mortality. Early, targeted intervention can help mitigate its impact. CK273 is a urinary peptide classifier previously validated in a prospective clinical trial for the early detection of nephropathy. We hypothesized that drug-induced molecular changes in the urinary peptidome could be predicted in silico and guide selecting interventions for individual patients. METHODS: The efficacy of the urinary peptidomic classifier CKD273 in predicting major adverse kidney events (≥ 40% decline in estimated glomerular filtration rate or kidney failure -median follow-up: 1.50 (95%CI 0.35, 5.0) years), was confirmed in a retrospective cohort of 935 participants. In silico prediction of treatment effects from four drug-based interventions (Mineralocorticoid receptor antagonist, Sodium-glucose co-transporter 2 inhibitor, Glucagon-like peptide-1 receptor agonist, and Angiotensin receptor blocker), dietary intervention (olive oil), and exercise was performed based on: a) individual baseline urinary peptide profiles, and b) previously defined fold changes in peptide abundance after treatment in clinical trials. Following recalibration to align with outcomes of these trials, CKD273 scores were calculated for each patient after in silico treatment. For combination treatments, the effects of multiple interventions were combined. RESULTS: Simulated interventions demonstrated a significant reduction in median CKD273 scores, from 0.57 (IQR: 0.19-0.81) before to 0.039 (IQR: -0.192-0.363) after the most beneficial intervention (paired Wilcoxon test, P < 0.0001). The combination of all available treatments was not the most frequently predicted optimal intervention. Patients with higher baseline CKD273 scores required more complex intervention combinations to achieve the greatest score reduction. CONCLUSIONS: This study supports the feasibility of in silico predicting effects of therapeutic interventions on CKD progression. By identifying the most beneficial treatment combinations for individual patients, this approach paves the way for precision medicine trials in CKD. A prospective study is currently being planned to validate the in silico-guided intervention approach and determine its exact benefits on patient-relevant outcomes.
- Klíčová slova
- Chronic kidney disease, Clinical proteomics, Drug response prediction, Optimizing intervention, Urine peptides,
- MeSH
- chronická renální insuficience * moč terapie patofyziologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- peptidy moč MeSH
- počítačová simulace * MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- peptidy MeSH
To obtain materials with desired properties, material compositions are primarily altered, whereas thin films offer additional unique avenues. By combining state-of-the-art first-principles calculations and experimental investigations of thin films of strontium titanate as an exemplary representative of a broad class of perovskite oxides and the extensive family of ferroelectrics, a novel approach is presented to achieving superior material responses to external stimuli. The findings reveal that substrate-imposed deformations, or strains, significantly alter the frequencies and magnitudes of atomic vibrations in thin films. Consequently, material-specific response-stimulus coefficients can become strain-dependent. The strain-dependent Curie constant, which characterizes the dielectric response to thermal stimuli, is theoretically justified and experimentally validated. Given that atomic vibrations fundamentally govern various response coefficients in a wide range of materials, and that thin films are typically deformed by substrates, it is anticipated that unprecedented responses can be generally attained through substrate-induced control of atomic vibrations in thin films.
- Klíčová slova
- computational methods, condensed matter physics, ferroelectrics, physics & engineering,
- Publikační typ
- časopisecké články MeSH
Open science is now established as an important paradigm for publicly funded research. The main principle being that to ensure best use of research data and integrity of the scientific process the information from experiments should be made widely and freely available. However, dedicated technical infrastructure to enable useful access to comprehensive experimental information in molecular biophysics is lacking, in particular in regard to repositories for raw measurement data. The Molecular Biophysics Database (MBDB) was created to fill this gap. The MBDB provides a common and extensible framework to store and access raw measurement data from a growing number of biophysical methods, currently including bio-layer interferometry, isothermal titration calorimetry, surface plasmon resonance, and microscale thermophoresis, with additional methods planned for the future. Alongside the raw measurement data from these methods, a rich set of metadata to enable data reuse is captured in accordance with the FAIR data management principles. An overview of the data models and technologies that were used to create the MBDB is presented here.
- Klíčová slova
- Database, FAIR principles, Metadata model, Molecular biophysics, Raw data, Repository,
- Publikační typ
- časopisecké články MeSH
The hippocampus is a key brain region for memory and cognitive functions, which consists of distinct subregions with different developmental trajectories throughout adolescence. However, trajectories of hippocampal subfield change in young adulthood remain uncharacterized, as is their potential relationship with cortical brain aging and cognitive ability during this time. We conducted two magnetic resonance imaging (MRI) follow-ups of a prenatal birth cohort in young adulthood and studied the effects of chronological age and cortical brain age on the volume of hippocampal subfields in the early 20s (n = 109; 51% men) and late 20s (n = 251; 53% men) and how these age-related volumetric changes might relate to full-scale IQ (FSIQ). We showed that CA1 and CA4DG subfields continue to grow in the third decade of life and that this growth can be observed both at the level of chronological age as well as estimated cortical brain age at both MRI timepoints. Moreover, in men, a larger size of these age-related subfields was associated with higher FSIQ, and the deviations between cortical brain age and chronological age mediated the relationships between right CA1 and FSIQ, as well as right CA4DG and FSIQ. These findings reveal that coordinated patterns of advanced cortical brain aging and hippocampal maturation may confer a cognitive advantage in young adulthood.
- Klíčová slova
- CA1, CA4DG, brain aging, full‐scale IQ, hippocampal subfields, young adulthood,
- MeSH
- dospělí MeSH
- hipokampus * růst a vývoj diagnostické zobrazování anatomie a histologie MeSH
- inteligence fyziologie MeSH
- kognice * fyziologie MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mladiství MeSH
- mladý dospělý MeSH
- stárnutí * fyziologie MeSH
- velikost orgánu MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Motion Capture (MoCap) is rapidly growing in the sports, biomechanics, healthcare, and medicine segments, where accuracy is crucial. Current research studies are concurrently confirming that the accuracy can be determined only for the specific analyzed configuration and thus recommending performing your own accuracy verification on your specific setup. However, it is often hard to perform since it requires significant effort, time, knowledge of statistical data analysis and often equipment and tools that are not commonly available. This paper deals with this by creating a standardized setup with carefully evaluated accuracy, substituting the on-site validation process (in case of using such a setup) or providing the worst-case accuracy (when a more advanced setup is used). The setup is designed to be low-cost, easily reproducible and cover a wide range of applications - thus VICON setup with five VERO v1.3 cameras is used. The accuracy was evaluated using the robotic manipulator EPSON C3, determining that the absolute positioning accuracy of such a standardized setup is 0.65 mm on average (SD = 0.48, with maximal error of 2.47 mm) and rotation accuracy 0.40° (SD = 0.35, with maximal error of 2.0°), which is negligible considering the experimental diameter of 1.4 m and full angular span. The major source of error was specific to particular spatial and rotational positions; other systematic and other random errors were noticeably smaller. If the standardized setup is used and all its requirements are met, a similar accuracy as validated above can be expected without the need to explicitly validate the specific configuration, which is time-consuming and resource-intensive.
- Klíčová slova
- Accuracy assessment, Motion capture, Standardization, VICON, Validation,
- Publikační typ
- časopisecké články MeSH
Thyroid hormones (TH) are essential for vertebrate development, growth, and metabolism. The increasing prevalence of anthropogenic chemicals with TH-disrupting potential highlights the urgent need for advanced methods to assess their impact on TH homeostasis. Inhibition of the sodium-iodide symporter (NIS) has been identified as a key molecular initiating event disrupting the TH system across species, with significant relevance for diagnostic and therapeutic applications in various carcinomas. This study presents in vitro bioassays for evaluating the effects of compounds on iodide uptake into cells, a critical step in TH production mediated by NIS. Two novel stably transfected human cell lines overexpressing human NIS were employed along with a rat thyroid cell model FRTL-5, using colorimetric Sandell-Kolthoff (SK) reaction for iodide detection. The results from 23 model compounds demonstrate comparability across various in vitro models and radioactivity-based assays. To enhance physiological relevance, an external biotransformation system (BTS) was integrated and optimized for live-cell compatibility without inducing cytotoxicity or interfering with the assay. Compounds identified as NIS inhibitors were evaluated using the BTS-augmented assay, which revealed that metabolic activity mitigated the inhibitory effects of some chemicals. The augmented assay exhibited strong concordance with in vivo and in silico biotransformation data. Protein sequence alignment confirmed high conservation of NIS functional domains across vertebrates, reinforcing the cross-species applicability of the findings. The SK-based NIS assay, with optional BTS integration, represents a sensitive, robust, and high-throughput amendable alternative to radioactivity-based methods, for characterizing the impacts of individual compounds and complex environmental mixtures on TH homeostasis.
- Klíčová slova
- Biotransformation, NIS, Sandell–Kolthoff reaction, SeqAPASS, Thyroid hormone,
- MeSH
- biotest metody MeSH
- biotransformace MeSH
- buněčné linie MeSH
- endokrinní disruptory * toxicita MeSH
- hormony štítné žlázy metabolismus MeSH
- jodidy * metabolismus MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- štítná žláza metabolismus účinky léků cytologie MeSH
- symportéry * antagonisté a inhibitory metabolismus genetika MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- endokrinní disruptory * MeSH
- hormony štítné žlázy MeSH
- jodidy * MeSH
- sodium-iodide symporter MeSH Prohlížeč
- symportéry * MeSH
A honeybee colony is a complex and dynamic system that emerges out of the interactions of thousands of individuals within a seemingly chaotic and heterogeneous environment. At the figurative core of this system is the honeybee queen, responsible for the growth and reproduction of the eusocial superorganism. In this study, we examine the interaction between the queen and her surrounding environment by analyzing her movement patterns using mathematical models and computational approaches. We employed a visual tracking system to observe three queens of Apis mellifera within their colonies over a three-week period and analyzed sets of quality tracklets to provide observational evidence regarding the queens' motion-related decision-making. Contrary to expectations, we found that the queen's short-term motion characteristics-such as speed and turning-were remarkably invariant across distinct hive regions, suggesting a lack of direct environmental modulation at short timescales. Yet, long-term patterns showed structured and strategic behavior. Inter-stop distances followed a power-law distribution, and queens repeatedly revisited specific spatial zones over multi-day timescales. These results indicate a dual-scale movement strategy that is not captured by standard random walk models, highlighting internal state or memory-based navigation. Our findings suggest that queen movement is shaped by temporally layered processes that may support brood nest stability, efficient egg-laying, and colony cohesion.
- MeSH
- chování zvířat * fyziologie MeSH
- pohyb fyziologie MeSH
- sociální chování MeSH
- včely fyziologie MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Mitochondrial energy can be stored as ATP or released as heat by uncoupling protein 1 (UCP1) during non-shivering thermogenesis in brown adipose tissue. UCP1, located in the inner mitochondrial membrane, reduces the proton gradient in the presence of long-chain fatty acids (FA). FA act as weak, protein-independent uncouplers, with the transport of the FA anion across the membrane being the rate-limiting step. According to the fatty acid cycling hypothesis, UCP1 catalyzes this step through an as-yet-undefined mechanism. METHODS: We used computational and experimental techniques, including all-atom molecular dynamics (MD) simulations, membrane conductance measurements, and site-directed mutagenesis. RESULTS: We identified two novel pathways for fatty acid anion translocation (sliding) at the UCP1 protein-lipid interface, ending at key arginine residues R84 and R183 in a nucleotide-binding region. This region forms a stable complex with fatty acid anion, which is crucial for anion transport. Mutations of these two arginines reduced membrane conductance, consistent with the MD simulation prediction that the arachidonic acid anion slides between helices H2-H3 and H4-H5, terminating at R84 and R183. Protonation of the arachidonic acid anion predicts its release from the protein-lipid interface, allowing it to move to either cytosolic or matrix leaflets of the membrane. CONCLUSION: We provide a novel, detailed mechanism by which UCP1 facilitates fatty acid anion transport, as part of the fatty acid cycling process originally proposed by Skulachev. The residues involved in this transport are conserved in other SLC25 proteins, suggesting the mechanism may extend beyond UCP1 to other members of the superfamily.
- Klíčová slova
- anion transporter, cardiolipin, fatty acid cycling, mitochondrial SLC25 family, molecular dynamics simulations, proton transport mechanism,
- MeSH
- iontové kanály * metabolismus chemie genetika MeSH
- iontový transport fyziologie MeSH
- lidé MeSH
- mastné kyseliny * metabolismus MeSH
- mitochondriální proteiny * metabolismus chemie genetika MeSH
- mutageneze cílená MeSH
- simulace molekulární dynamiky * MeSH
- uncoupling protein 1 MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- iontové kanály * MeSH
- mastné kyseliny * MeSH
- mitochondriální proteiny * MeSH
- uncoupling protein 1 MeSH
Pesticides can have adverse effects on soil microorganisms, but they are underrepresented in the currently required OECD 216 test for environmental risk assessment of plant protection products (PPP). The guideline monitors soil microbial nitrogen transformation over 28 days, potentially missing long-term effects of persistent pesticides. Additionally, nitrate alone may be not sensitive enough to detect disruptions in microbial functions. We investigated whether functional gene analysis could provide a more sensitive bioindicator of pesticide impact. To compare this method with the standard test, we conducted a microcosm experiment following the OECD 216 experimental setup. To capture long-term effects beyond the typical test period, we extended the incubation duration to 56 days. Four different concentrations of the persistent fungicide boscalid were added based on predicted environmental concentration. We also assessed microbial responses to fungicide exposure by measuring classical soil microbial parameters. According to the standard test, boscalid had no harmful long-term effects on soil microbiota. In contrast, our analysis of functional genes found an overall reduction in the acid phosphatase-encoding phoN gene abundance on Day 56, and correspondingly, in acid phosphatase activity in the highest fungicide treatment. Simultaneously, we observed a tendency towards lower fungal abundance based on measured copy numbers of an ITS region of nuclear ribosomal DNA (rDNA) and increased cumulative CO2 production. These results indicate a fungicide-related response of the microbial community and impaired microbial phosphorus cycling. Extending the experimental period to 56 days revealed long-term effects that would have otherwise been undetected under the typical 28-day test duration.
- Klíčová slova
- Boscalid, Non-target soil microorganisms, OECD 216, Pesticide risk assessment, phoN,
- Publikační typ
- časopisecké články MeSH
Metal metabolism in plant-galler interactions is largely unknown. We hypothesise that the mites manipulate metal distribution by sequestration of excessive levels and differential regulation of metalloproteins to support the main functions of gall-nutrition, protection and microenvironment. Using the Tilia cordata-eriophyid mites system, we aimed to reveal the role of metals in galls by investigating their distribution, speciation, gene expression and metabolome profiling. Complementary spectroscopy techniques (μXRF and μXANES tomographies, electron paramagnetic resonance), histochemical, metabolomic and transcriptomic analyses were employed. Mn was the most abundant micronutrient in the galls. Differential cell-specific Mn accumulation (idioblasts vs nutritive tissue) and speciation are essential for its homeostasis. Mn(II)-aquo complex, co-localised with Ca, sequestered in idioblasts, while Mn bound to stronger ligands including enzymes accumulated in the nutritive tissue. Zn, Cu and Fe predominately accumulated in the nutritive tissue to support intensive metabolic processes such as secondary and lipid metabolism, protein N-glycosylation and redox regulation. The slower rate of redox-sensitive spin probes' decay in the galls indicated a lower amount of antioxidants than in the leaf. We reveal essential functions of micronutrients in the galls, supporting the developmental and chemical changes in the host plant, and the nutrition of the galler.
- Klíčová slova
- Mn speciation, Tilia cordata galls, biotic stress, eriophyid mites, metal metabolism, micro‐XANES tomography, micro‐XRF tomography, nutritive tissue,
- MeSH
- kovy * metabolismus MeSH
- listy rostlin * metabolismus parazitologie MeSH
- metabolom MeSH
- nádory rostlin * parazitologie MeSH
- regulace genové exprese u rostlin MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- kovy * MeSH
