Browse Articles

Deciphering Ca ^<b>2+</b> permeation and valence selectivity in Ca _V 1: Molecular dynamics simulations reveal the three-ion knock-on mechanism

Voltage-gated calcium (Ca V ) channels are pivotal in cellular signaling due to their selective calcium ion permeation upon membrane depolarization. While previous studies have established the highly selective permeability of Ca V channels, the detailed molecular mechanism remains elusive. Here, we use extensive atomistic molecular dynamics simulations to elucidate the mechanisms governing ion permeation and valence selectivity in Ca V 1 channels. Employing the electronic continuum correction method, we simulated a calcium conductance of approximately 9 to 11 pS, aligning closely with experimental measurement. Our simulations uncovered a three-ion knock-on mechanism critical for efficient calcium ion permeation, necessitating the binding of at least two calcium ions within the selectivity filter (SF) and the subsequent entry of a third ion. In silico mutation simulations further validated the importance of multi-ion coordination in the SF for efficient ion permeation, identifying two critical residues, D706 and E1101, that are essential for the binding of two calcium ions in the SF. Moreover, we explored the competitive permeation of calcium and sodium ions and obtained a valence selectivity favoring calcium over sodium at a ratio of approximately 35:1 under the bication condition. This selectivity arises from the strong electrostatic interactions of calcium ions in the confined SF and the three-ion knock-on mechanism. Our findings provide quantitative insights into the molecular underpinnings of Ca V channel function, with implications for understanding calcium-dependent cellular processes.

Electrochemical, quantum chemical, and thermodynamic investigation of a Schiff base corrosion inhibitor for XC70 steel

Surface melting–driven hydrogen absorption for high-pressure polyhydride synthesis

The synthesis of new polyhydrides with high superconducting T c is challenging owing to the high pressures and temperatures required. In this study, we used machine-learning potential molecular dynamics simulations to investigate the initial stage of polyhydride formation in calcium hydrides. Upon contact with high-pressure H 2 , the surface of CaH 2 melts, leading to CaH 4 formation. This surface melting proceeds via CaH 4 liquid phase as an intermediate state. High pressure reduces not only the hydrogenation (CaH 2 (s) + H 2 (l) ↔ CaH 4 (s)) enthalpy but also the enthalpy for liquid polyhydride formation (CaH 2 (s) + H 2 (l) ↔ CaH 4 (l)). Consequently, this surface melting process becomes more favorable than the fusion of the polyhydride bulk. Thus, high pressure not only shifts the equilibrium toward the polyhydride product but also lowers the activation energy, thereby promoting the hydrogenation reaction. From these thermodynamic insights, we propose structure-search criteria for polyhydride synthesis that are both computationally effective and experimentally relevant. These criteria are based on bulk properties, such as polyhydride (product) melting temperature and pressure-dependent hydrogenation enthalpy, readily determined through supplementary calculations during structure prediction workflows.

Machine learning optimization of microwave-assisted extraction of phenolics and tannins from pomegranate peel

Histone variant H2A.W7 represses meiotic crossover formation in <i>Arabidopsis</i> heterochromatin

In eukaryotic genomes, DNA is packaged into nucleosomes to form chromatin. The incorporation of canonical or variant histones into nucleosomes confers different properties and influences chromatin structure to regulate cellular processes, including recombination. During meiosis, DNA double-strand breaks (DSBs) are formed and repaired as interhomolog crossovers. Nucleosome occupancy is generally associated with low crossover frequency, but it remains unclear which histone variants are involved in this process. In Arabidopsis , three variants of H2A coexist: H2A.X, H2A.Z, and H2A.W. Here, we show that H2A.W7 has a suppressive role on meiotic recombination. Genome-wide mapping of the crossover landscape revealed increased centromere-proximal recombination in h2a.w7 . Moreover, H2A.W7 can be recruited to the 3a crossover hotspot via 21-24-nucleotide siRNAs during RNA-directed DNA methylation, causing increased nucleosome occupancy and decreased crossover frequency. Cytological analysis reveals that H2A.W7 restricts heterochromatin clustering during meiosis, which can form a mechanism to limit interhomolog recombination. Conversely, the linker histone H1, of which its loading is known to be restricted by H2A.W, promotes heterochromatin clustering and crossover on a heterochromatic genetic interval. Our study reveals a role for H2A.W7 in repressing crossover formation in Arabidopsis .

Deep learning-based electrical impedance spectroscopy analysis for malignant and potentially malignant oral disorder detection

Abstract Electrical impedance spectroscopy (EIS) is a powerful tool used to investigate the properties of materials and biological tissues. This study presents one of the first applications of EIS for the detection and classification of oral potentially malignant disorders (OPMDs) and oral cancer. We aimed to apply EIS in conjunction with deep learning to assist the clinical diagnosis of OPMD and oral cancer as a non-invasive diagnostic technology. Currently, the diagnosis of OPMD and oral cancer relies on clinical examination and histopathological analysis of invasive scalpel tissue biopsies, which is stressful for patients, time-consuming for clinicians and subject to histopathological interobserver variation in diagnosis, although recent advances in artificial intelligence may circumvent discrepancy. Here we developed a novel deep learning convolutional neural network (CNN)-based method to automatically differentiate normal, OPMD and malignant oral tissues using EIS measurements. EIS readings were initially taken from untreated or glacial acetic acid-treated porcine oral mucosa and analyzed via CNN to determine if this method could discriminate between normal and damaged oral epithelium. CNN models achieved area under the curve (AUC) values of 0.92 ± 0.03, with specificity 0.95 and sensitivity 0.84, showing good discrimination. EIS data from ventral tongue and floor-of-the-mouth were collected from 51 healthy humans and 11 patients with OPMD and oral cancer. When a binary classification (low or high risk of malignancy) was applied, the best CNN model achieved an AUC 0.91 ± 0.1, with accuracy 0.91 ± 0.05, specificity 0.97 and sensitivity 0.74. These results demonstrate the considerable potential of EIS in combination with CNN models as an adjunctive non-invasive diagnostic tool for OPMD and oral cancer.

Microtubule dynamics are defined by conformations and stability of clustered protofilaments

Microtubules are dynamic cytoskeletal polymers that add and lose tubulin dimers at their ends. Microtubule growth, shortening, and transitions between them are linked to GTP hydrolysis. Recent evidence suggests that flexible tubulin protofilaments at microtubule ends adopt a variety of shapes, complicating structural analysis using conventional techniques. Therefore, the link between GTP hydrolysis, protofilament structure and microtubule polymerization state is poorly understood. Here, we investigate the conformational dynamics of microtubule ends using coarse-grained modeling supported by atomistic simulations and cryoelectron tomography. We show that individual bent protofilaments organize in clusters, transient precursors to the straight microtubule lattice, with GTP-bound ends showing elevated and more persistent cluster formation. Differences in the mechanical properties of GTP- and GDP-protofilaments result in differences in intracluster tension, determining both clustering propensity and protofilament length. We propose that conformational selection at microtubule ends favors long-lived clusters of short GTP-protofilaments that are more prone to forming a straight microtubule lattice and accommodating new tubulin dimers. Conversely, microtubule ends trapped in states with unevenly long and stiff GDP-protofilaments are more prone to shortening. We conclude that protofilament clustering is the key phenomenon that links the hydrolysis state of single tubulins to the polymerization state of the entire microtubule.

Differential expression of proliferation and immune response genes between children and adults influences survival of diffuse large B cell lymphoma

Abstract Diffuse large B-cell lymphoma (DLBCL) is a neoplasm affecting adults and children, with different clinical behaviors between age groups. To shed light on those differences, gene expression profiling was evaluated in 48 formalin-fixed paraffin-embedded biopsies of patients with DLBCL. Sixteen differentially expressed genes in pediatric DLBCL compared to adults were demonstrated, involving lymphocyte differentiation, oncogenic signaling and chemotaxis. Pathway analysis confirmed the enrichment in proliferation-related pathways. In addition, the increased presence of NKCD56dim cells in pediatric patients suggests a cytotoxic immune response in this group, perhaps explaining their better outcome. Exclusion of Epstein Barr virus (EBV) + DLBCL, NOS, showed, in pediatric cases, additional downregulated genes associated with immune regulators and checkpoint genes. This suggested EBV infection may have on the modulation of immune response in pediatric lymphomas. Survival analysis showed associations between genes such as MYC, NT5E and CD34, and event-free survival in pediatric patients. Furthermore, higher expression of MYC in children displayed higher risk of death or relapse, while lower expression of NT5E and CD34 was associated with lower risk. This study identifies distinct immune response and proliferation gene expression patterns in pediatric DLBCL compared to adults, and the interaction with tumor microenvironment, with potential implications for disease pathogenesis.

Molecular basis for ligand recognition and receptor activation of the prostaglandin D2 receptor DP1

The prostaglandin D2 receptor 1 (DP1), a rhodopsin-like Class A GPCR, orchestrates critical physiological and pathological processes, ranging from sleep regulation to inflammatory responses and cardiovascular function. Despite its therapeutic significance, structural insights into DP1 activation mechanisms have remained elusive. Here, using cryoelectron microscopy (cryo-EM), we determined high-resolution structures of human DP1 in both inactive and active states, with the latter captured in complex with its endogenous agonist PGD2 or the synthetic agonist BW245C, bound to the stimulatory G protein, Gs. Our structures, coupled with functional and mutagenesis studies, unveiled unique structural features of DP1, including an alternative activation mechanism, ligand-selectivity determinants, and G protein coupling characteristics. These molecular insights provide a rational framework for designing selective DP1-targeted therapeutics, both agonists and antagonists, with enhanced specificity and reduced off-target effects, opening broad avenues for treating DP1-associated disorders.

Investigation of flow-induced noise reduction in high-specific-speed centrifugal pumps using bionic blades

Ethanol induction of FGF21 in the liver is dependent on histone acetylation and ligand activation of ChREBP by glycerol-3-phosphate

Ethanol rapidly stimulates the liver to synthesize the hormone fibroblast growth factor 21 (FGF21), which then acts on the brain to elicit a multifaceted protective response. We show that in mice, this induction of FGF21 occurs at the level of gene transcription and is regulated by two byproducts of ethanol metabolism, glycerol-3-phosphate (G3P) and acetyl-CoA. Using cell-based reporter and thermal shift binding assays, we show that G3P binds to a conserved domain and activates the transcription factor carbohydrate-responsive element-binding protein (ChREBP), which regulates the Fgf21 gene promoter. The stimulation of Fgf21 gene transcription by ethanol also requires its metabolism to acetyl-CoA and correlates with histone acetylation. Accordingly, a p300/CBP histone acetyltransferase inhibitor blocks histone acetylation, ChREBP recruitment, and transcriptional activation at the Fgf21 promoter. Together, these findings reveal a dual regulatory mechanism driven by both G3P and acetyl-CoA that explains ethanol’s robust stimulatory effect on Fgf21 and possibly other ChREBP target genes in the liver.

Determinants of regenerative endodontic therapy use among pediatric and endodontic specialists in 13 countries

Manifold fitting reveals metabolomic heterogeneity and disease associations in UK Biobank populations

NMR-based metabolic biomarkers provide comprehensive insights into human metabolism; however, extracting biologically meaningful patterns from such high-dimensional data remains a significant challenge. In this study, we propose a manifold-fitting-based framework to analyze metabolic heterogeneity within the UK Biobank population, utilizing measurements of 251 NMR biomarkers from 212,853 participants. Initially, our method clusters these biomarkers into seven distinct metabolic categories that reflect the modular organization of human metabolism. Subsequent manifold fitting to each category unveils underlying low-dimensional structures, elucidating fundamental variations from basic energy metabolism to hormone-mediated regulation. Importantly, three of these manifolds clearly stratify the population, identifying subgroups with distinct metabolic profiles and associated disease risks. These subgroups exhibit consistent links with specific diseases, including severe metabolic dysregulation and its complications, as well as cardiovascular and autoimmune conditions, highlighting the intricate relationship between metabolic states and disease susceptibility. Supported by strong correlations with demographic factors, clinical measurements, and lifestyle variables, these findings validate the biological relevance of the identified manifolds. By utilizing a geometrically informed approach to dissect metabolic heterogeneity, our framework enhances the accuracy of population stratification and deepens our understanding of metabolic health, potentially guiding personalized interventions and preventive healthcare strategies.

Gender differences in the relationship between hearing and visual impairments, dual sensory impairment, and depression in middle-aged and elderly populations

An electrostatic network with strong connectivity is a phospho-sensor for regulating affinity of Syk–receptor association

Spleen tyrosine kinase (Syk) mediates early signaling events in immunity by coupling membrane receptors to immune responses. Syk comprises a tandem SH2 (tSH2) regulatory module—two SH2 domains connected by a structured linker—and a kinase domain. The association of tSH2 with a doubly tyrosine-phosphorylated motif (dpITAM) on membrane immunoreceptors is central to controlling Syk’s signaling activity. tSH2-dpITAM association is regulated by Y131-phosphorylation on linker A, distant from the Syk–immunoreceptor binding sites. A unique thermodynamic signature was reported to control this protein–protein interaction by phosphorylation, yet the molecular mechanism for the phosphorylation effect is unknown. Molecular dynamics (MD) simulation affords the detail needed to fill this knowledge deficiency. Long MD simulations revealed a highly correlated interdomain electrostatic network (distance correlation coefficients &gt; 0.75) that is lost upon Y131-phosphorylation. Some of the strongly correlated interdomain pairs carry the same charge or are separated by distances greater than a salt-bridge pair. The strong interdomain connectivity accounts for the single, narrow free energy basin in the domain-structure conformational landscape for unphosphorylated tSH2. Linker phosphorylation disrupts this network and yields a broader free energy landscape with multiple networks formed by the same group of residues adopting alternative interdomain conformations. A salt dependence of NMR rotational tumbling times substantiates the electrostatic nature of tSH2 domain–domain coupling. Syk tandem SH2 is thus a sensor whose conformational plasticity is sensitive to Y131 phosphorylation. This phospho-sensing response provides the basis for an entropically driven regulatory mechanism that is so-far unique to Syk–immunoreceptor protein–protein association.

Magnetization and superparamagnetic behavior of FeCu nanoalloys at room temperature via synthesis and simulation

Reversible molecular simulation for training classical and machine-learning force fields

The next generation of force fields for molecular dynamics will be developed using a wealth of data. Training systematically with experimental data remains a challenge, however, especially for machine-learning potentials. Differentiable molecular simulation calculates gradients of observables with respect to parameters through molecular dynamics trajectories. Here, we improve this approach by explicitly calculating gradients using a reverse-time simulation with effectively constant memory cost and a computation count similar to the forward simulation. The method is applied to learn all-atom water and gas diffusion models with different functional forms and to train a machine-learning potential for diamond from scratch. Comparison to ensemble reweighting indicates that reversible simulation can provide more accurate gradients and train to match time-dependent observables.

Impact of polyacrylic acid as soil amendment on soil microbial activity under different moisture regimes

Abstract Polyacrylic acid (PAA), a synthetic superabsorbent polymer (SAP), enhances the maximum water holding capacity (WHC max ), soil structural stability, and aeration of soil but may simultaneously affect soil microbiome by altering soil properties. However, its effects on microbial activity under different moisture regimes remain insufficiently understood. We examined the impact of PAA on soil microbial activity in a sand and loam treated with PAA at three concentrations (25, 250, 2500 mg kg − 1 dry soil) either incubated under constant moisture or subjected to ten drying-rewetting cycles. During incubation, soil WHC max , pH, and soil microbial activity via headspace CO 2 and MicroResp assay were measured. PAA increased WHC max in both soils, yet its effectiveness decreased in loam under static conditions. Initially, PAA acidified both soils, with pH shifts persisting in sand but dissipating in loam after one week. Drying–rewetting cycles counteracted acidification and partially maintained PAA swelling. In sand, high PAA concentrations consistently suppressed microbial respiration across substrate groups, whereas in loam, microbial responses were modulated by moisture dynamics: drying–rewetting enhanced, while static moisture reduced SIR under PAA treatment. Overall, PAA altered soil microbial activity in a concentration-, soil type-, and moisture-dependent manner, emphasizing the dual role of SAPs in improving soil water retention while potentially impairing microbial-mediated soil functions over time.

<i>Arabidopsis</i> HOOKLESS1 acts as a histone acetyltransferase to promote cotyledon greening during seedling de-etiolation

Greening immediately after etiolated-seedling’s emergence from the soil is critical for plants to initiate their autotrophic life cycle through photosynthesis. The greening process relies on a complex transcriptional network that fine-tunes the biosynthesis of chlorophyll and prevents premature development of chloroplasts. In this study, we identified the Arabidopsis HOOKLESS1 (HLS1) as a key regulator of light-induced cotyledon greening. Our results demonstrated that HLS1 is essential for the proper expression of greening-related genes controlling chlorophyll biosynthesis and chloroplast development. Loss of HLS1 severely disrupts the Pchlide-to-Chlide transition and impairs reactive oxygen species (ROS) scavenging in etiolated seedlings upon light exposure, leading to catastrophic ROS burst and even photobleaching. Biochemical assays revealed that HLS1 is a histone acetyltransferase mediating the deposition of H3K9ac and H3K27ac marks at multiple greening-related genes, thereby promoting their transcriptional activation. Genetic analysis further confirmed that HLS1’s promotive effect on the greening process is fully dependent on its histone acetyltransferase activity. Moreover, the loss of HLS1 also interrupts the promotive effect of ethylene signaling on the greening process by reducing the binding of ETHYLENE-INSENSITIVE 3 to the promoter region of POR genes, thus inhibiting the activation effect of ethylene signaling on the expression of PORs . Collectively, our study reveals that HLS1 acetylates histones to activate greening-related genes, optimizing chlorophyll biosynthesis and chloroplast development during dark-to-light transition in seedlings.

TiO2-doped borate glass and glass-ceramic: properties and prospects for biological and electrical applications

Abstract This study explores the synthesis, characterization, and potential applications of TiO2-doped borate glasses and their glass-ceramics, focusing on their biological and electrical properties. Examining the impact of varying the TiO2 content on the structural, electrical, and antimicrobial properties of the prepared samples was done. X-ray diffraction, Fourier-transform infrared spectroscopy (FTIR), density, and Field emission scanning electron microscope (FESEM) were employed to analyze the material’s structural integrity and phase transitions. The AC conductivity (σac) was measured within the frequency range of 0.042 kHz–1 MHz and at the temperature range of 298–573 (K). The estimated DC conductivity proved that incorporating of TiO2 at the expense of BaO results in higher conductivity values than those of the free glass and glass ceramic samples. The prepared samples exhibited a semiconducting nature. The dielectric constant (ɛʹ) values increase upon doping with TiO2. The incorporation of TiO2 improved the bioactivity (antimicrobial) of the studied glasses, making it suitable for biomedical applications such as drug delivery and tissue engineering. Also, the long-term stability and cytotoxicity were evaluated. The results indicate that TiO2-doped borate glasses and glass-ceramics present a promising avenue for the development of multifunctional materials that meet the demands of both biological and electrical applications.