Oxidative stress is two sided: Whereas excessive oxidant challenge causes damage to biomolecules, maintenance of a physiological level of oxidant challenge, termed oxidative eustress, is essential for governing life processes through redox signaling. Recent interest has focused on the intricate ways by which redox signaling integrates these converse properties. Redox balance is maintained by prevention, interception, and repair, and concomitantly the regulatory potential of molecular thiol-driven master switches such as Nrf2/Keap1 or NF-κB/IκB is used for system-wide oxidative stress response. Nonradical species such as hydrogen peroxide (H2O2) or singlet molecular oxygen, rather than free-radical species, perform major second messenger functions. Chemokine-controlled NADPH oxidases and metabolically controlled mitochondrial sources of H2O2 as well as glutathione- and thioredoxin-related pathways, with powerful enzymatic back-up systems, are responsible for fine-tuning physiological redox signaling. This makes for a rich research field spanning from biochemistry and cell biology into nutritional sciences, environmental medicine, and molecular knowledge-based redox medicine.
Applied Biochemistry and Bioengineering.Vol. 1: Immobilized Enzyme Principles. Edited byL. B. Wingard Jr E. Katchalski-Katzir and L. Goldstein. Pp. xi + 364. (Academic: New York and London, 1976.) $29.50; £20.95.
Abstract Metastasis is the main cause of cancer-related deaths, yet the underlying mechanisms remain elusive. Here, using clear cell renal cell carcinoma (ccRCC), a tumor type with frequent lung metastases, we conduct an in vivo genome-wide CRISPR-Cas9 screen and identify HLF as a potent suppressor of lung metastasis. HLF depletion enhances ccRCC cell migration and lung metastasis, whereas HLF overexpression abrogates these effects. In ccRCC patients, HLF expression is reduced at metastatic sites and associates with epigenetic silencing mediated by the SWI/SNF ATPase subunit BRG1. HLF levels negatively correlate with migration potential in collagen. Mechanistically, HLF regulates LPXN expression, modulating the integration of collagen’s mechanical cues with the actin cytoskeleton through Paxillin, thereby suppressing cancer cell migration and lung metastasis. Overexpression of HLF or pharmacological inhibition of BRG1 reduces cell invasion across multiple cancer types. Our findings suggest that targeting the BRG1-HLF axis offers a promising therapeutic strategy for combating metastatic cancers.
Francesco Gucci†, Andrea Iudica†, Andres Valladares Y Tacchi†
et al.
Ultrafast chiro-optical spectroscopy provides unique access to the structural dynamics of molecules, spin-valley relaxation in semiconductors, and the non-equilibrium optical response of chiral nanophotonic systems. Yet, because chiral signals are intrinsically weak and time-resolved spectroscopy probes small photoinduced changes, transient chiro-optical responses are often difficult to isolate from parasitic achiral contributions. Here, we introduce a broadband ultrafast chiro-optical spectroscopy technique that integrates a birefringent common-path interferometer with an optical polarization bridge to sensitively detect photoinduced changes in the polarization state of light. Phase-sensitive self-heterodyned detection enables simultaneous measurement of transient circular dichroism and optical rotatory dispersion across a broad spectral range with ultrafast temporal resolution. Balanced detection suppresses excess laser noise, enabling exceptional sensitivity (<50 $μ$deg) close to shot-noise limit. We demonstrate this approach on an array of gold nano-helicoids, supported by a full-wave time-resolved model of the spatiotemporal dynamics of plasmonic non-equilibrium carriers and their associated optical nonlinearities. The model traces the system's transient chiro-optical response back to photoinduced modulations of the electric-magnetic dipole interaction in the nano-helicoid, elucidating the connection of near- and far-field dynamics in the non-equilibrium regime. We further investigate spin excitation, thermalization, and relaxation in a lead halide perovskite, establishing a novel approach to broadband time-resolved Faraday rotation. The simplicity, sensitivity, and wide applicability of this detection scheme provide a powerful platform for broadband ultrafast chiro-optical spectroscopy, opening new opportunities in biochemistry, solid-state physics, and nanophotonics.
Simulation of the time-dynamics of fermionic many-body systems has long been predicted to be one of the key applications of quantum computers. Such simulations -- for which classical methods are often inaccurate -- are critical to advancing our knowledge and understanding of quantum chemistry and materials, underpinning a wide range of fields, from biochemistry to clean-energy technologies and chemical synthesis. However, the performance of all previous digital quantum simulations of fermions has been matched by classical methods, and it has thus far remained unclear whether near-term, intermediate-scale quantum hardware could offer any computational advantage in this area. Here, we implement an efficient quantum simulation algorithm on Quantinuum's System Model H2 trapped-ion quantum computer for the time dynamics of a 56-qubit system that is too complex for exact classical simulation. We focus on the periodic spinful 2D Fermi-Hubbard model and present evidence of spin-charge separation, where the elementary electron's charge and spin decouple. In the limited cases where ground truth is available through exact classical simulation, we find that it agrees with the results we obtain from the quantum device. Employing long-range Wilson operators to study deconfinement of the effective gauge field between spinons and the effective potential between charge carriers, we find behaviour that differs from predictions made by classical tensor network methods. Our results herald the use of quantum computing for simulating strongly correlated electronic systems beyond the capacity of classical computing.
Aims: Nutritional vitamin B12 deficiency remains a significant public health issue. This study aimed to compare the efficacy of an oral combination of thiamine, pyridoxine, cyanocobalamin, and parenteral cyanocobalamin treatment among adolescents with nutritional vitamin B12 deficiency.
Methods: This retrospective study included patients aged 12-18 years who applied to University of Health Sciences Türkiye, Gülhane Training and Research Hospital General Pediatrics Polyclinic between 2018 and 2019, and serum vitamin B12 levels were measured before and after parenteral or oral combination of thiamine, pyridoxine, and cyanocobalamin treatment.
Results: Of the subjects with post-treatment serum vitamin B12 levels above the target level of 200 pg/mL, parenteral cyanocobalamin was given to 34 patients with a median age of 16 years [interquartile range (IQR), 14 to 16 years], and girls (52.9%), and oral cyanocobalamin was given to 51 patients with a median age of 15 years (IQR, 13 to 16 years), and girls (58.8%). The mean serum vitamin B12 levels before parenteral and oral cyanocobalamin treatment were 150.32±6.49 pg/mL parenteral and 132.35±4.67 pg/mL in oral replacement groups (p>0.05). The mean serum vitamin B12 levels after parenteral and oral cyanocobalamin treatments were 566.0±62.77 pg/mL and 463.1±36.97 pg/mL, respectively (p>0.05). Both parenteral and oral cyanobalamin treatments caused a significant increase in serum vitamin B12 levels compared with before treatment (p<0.001 for both).
Conclusions: In adolescents with nutritional vitamin B12 deficiency, an oral combination of thiamine, pyridoxine, and cyanocobalamin may be preferred to parenteral cyanocobalamin because it is non-invasive and provides an increase in serum vitamin B12 levels similar to parenteral cyanocobalamin treatment.
Hannah Wapenaar, Gillian Clifford, Willow Rolls
et al.
Abstract DNA methyltransferase 3A (DNMT3A) plays a critical role in establishing and maintaining DNA methylation patterns in vertebrates. Here we structurally and biochemically explore the interaction of DNMT3A1 with diverse modified nucleosomes indicative of different chromatin environments. A cryo-EM structure of the full-length DNMT3A1-DNMT3L complex with a H2AK119ub nucleosome reveals that the DNMT3A1 ubiquitin-dependent recruitment (UDR) motif interacts specifically with H2AK119ub and makes extensive contacts with the core nucleosome histone surface. This interaction facilitates robust DNMT3A1 binding to nucleosomes, and previously unexplained DNMT3A disease-associated mutations disrupt this interface. Furthermore, the UDR-nucleosome interaction synergises with other DNMT3A chromatin reading elements in the absence of histone ubiquitylation. H2AK119ub does not stimulate DNMT3A DNA methylation activity, as observed for the previously described H3K36me2 mark, which may explain low levels of DNA methylation on H2AK119ub marked facultative heterochromatin. This study highlights the importance of multivalent binding of DNMT3A to histone modifications and the nucleosome surface and increases our understanding of how DNMT3A1 chromatin recruitment occurs.
Renata de Souza Mendes, Pedro Leme Silva, Chiara Robba
et al.
Abstract This narrative review delves into the intricate interplay between the lungs and the kidneys, with a focus on elucidating the pathogenesis of diseases influenced by immunological factors, acid–base regulation, and blood gas disturbances, as well as assessing the effects of various therapeutic modalities on these interactions. Key disorders, such as anti-glomerular basement membrane (anti-GBM) disease, the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and Anti-neutrophil Cytoplasmic Antibodies (ANCA) associated vasculitis (AAV), are also examined to shed light on their underlying mechanisms. This review also explores the relationship between acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI), emphasizing how inflammatory mediators can lead to systemic damage and impact multiple organs. In ARDS, fluid overload exacerbates pulmonary edema, while imbalances in blood volume, such as hypovolemia or hypervolemia, can precipitate renal dysfunction. The review highlights how mechanical ventilation strategies can compromise renal blood flow, trigger systemic inflammation, and induce hemodynamic and neurohormonal alterations, all contributing to lung and kidney damage. The impact of extracorporeal membrane oxygenation (ECMO) on lung–kidney interactions is evaluated, highlighting its role in severe respiratory failure and its renal implications. Emerging therapies, such as mesenchymal stem cells and extracellular vesicles, are discussed as promising avenues to mitigate organ damage and enhance outcomes in critically ill patients. Overall, this review offers a nuanced exploration of lung–kidney dynamics, bridging historical insights with contemporary perspectives. It underscores the clinical significance of these interactions in critically ill patients and advocates for integrated management approaches to optimize patient outcomes.
Medical emergencies. Critical care. Intensive care. First aid
Purines and pyrimidines, crucial building blocks in biological systems, have attracted significant interest across molecular physics, biochemistry, pharmacology, and chemistry. Extensive spectroscopies have been employed for characterization, while the temperature and potential tautomeric effects can complicate the interpretation of underlying physics and chemistry. Here, we conducted first-principles simulations to analyze the vibrationally-resolved O1s X-ray photoelectron spectra of 6 common biomolecules at different temperatures, comprising 3 purine (xanthine, caffeine, and hypoxanthine) and 3 pyrimidine (thymine, 5F-uracil, and uracil) derivatives, and the tautomeric effect of hypoxanthine at varying temperatures. Using both time-independent (TI) and time-dependent (TD) methods under the Franck-Condon approximation, we obtained theoretical spectra that exhibited excellent agreement with experiments. Our analysis of these systems, all featuring carbonyl oxygens, unveiled distinctive characteristics of oxygen in N-CO-N (O2) compared to that within a N-CO-C structure (O1), showcasing higher O1s binding energy and total vibrational reorganization energy. We observed small differences in the zero-point vibration energies between the core-ionized and ground states, indicating a weak Duschinsky rotation effect. We consistently found that O1s ionization resulted in elongation of the O*=C bond length. The TI method facilitated the assignment of experimental spectra to different atoms or tautomers, where the atom-specific vibronic profiles of all 6 molecules exhibited similarity, with the 0-2 transitions dominating. TD enabled a more comprehensive exploration of the temperature effect, and the tautomeric effect of hypoxanthine by incorporating the Boltzmann population ratios of tautomers. We observed significant temperature dependence in the vibronic features present in these spectra.
Mihael Erakovic, Freek Witteveen, Dylan Harley
et al.
Quantum computers can accurately compute ground state energies using phase estimation, but this requires a guiding state that has significant overlap with the true ground state. For large molecules and extended materials, it becomes difficult to find guiding states with good ground state overlap for growing molecule sizes. Additionally, the required number of qubits and quantum gates may become prohibitively large. One approach for dealing with these challenges is to use a quantum embedding method, which allows a reduction to one or multiple smaller quantum cores embedded in a larger quantum region. In such situations it is unclear how the embedding method affects the hardness of constructing good guiding states. In this work, we therefore investigate the preparation of guiding states in the context of quantum embedding methods. We extend previous work on quantum impurity problems, a framework in which we can rigorously analyze the embedding of a subset of orbitals. While there exist results for optimal active orbital space selection in terms of energy minimization, we rigorously demonstrate how the same principles can be used to define selected orbital spaces for state preparation in terms of the overlap with the ground state. Moreover, we perform numerical studies of molecular systems relevant to biochemistry, one field in which quantum embedding methods are required due to the large size of biomacromolecules such as proteins and nucleic acids. We investigate two different embedding strategies which can exhibit qualitatively different orbital entanglement. In all cases we demonstrate that the easy-to-obtain mean-field state will have a sufficiently high overlap with the target state to perform quantum phase estimation.
The flow of a $k$-cooperative system maps the set of vectors with up to~$(k-1)$ sign variations to itself. Strongly $2$-cooperative systems satisfy a strong \Poincare-Bendixson property: any bounded solution that evolves in a compact set containing no equilibria converges to a periodic orbit. For $3$-dimensional strongly $2$-cooperative nonlinear systems, we provide a simple sufficient condition that guarantees the existence, in the state space, of an invariant compact set that includes no equilibrium points. Thus, any solution emanating from this set converges to a periodic orbit. We characterize explicitly the set of initial conditions from which the trajectory converges to a periodic solution. We demonstrate our theoretical results on two well-known models in biochemistry: a 3D Goodwin oscillator model and the 3D Field-Noyes ordinary-differential-equation (ODE) model for the Belousov-Zhabotinskii reaction.
Vachirapong Charoennitiwat, Kittipong Chaisiri, Sumate Ampawong
et al.
The parasitic nematode Paracapillaria (Ophidiocapillaria) najae De, 1998, found in the Indian cobra Naja naja is redescribed and re-illustrated in the present study. The monocled cobra Naja kaouthia was discovered to be a new host for this parasite in central Thailand. A comprehensive description extending the morphological and molecular characteristics of the parasites is provided to aid species recognition in future studies. The morphometric characters of 41 parasites collected from 5 cobra specimens are compared with those described in the original studies. Phylogenetic analyses using mitochondrial cytochrome c oxidase subunit 1 and nuclear 18S ribosomal RNA genes were performed to provide novel information on the systematics of P. najae. Similar characteristics were observed in the examined nematode samples, despite being found in different hosts, confirming their identity as P. najae. The molecular genetic results support the species status of P. najae, indicating P. najae is well defined and separated from other related nematode species in the family Capillariidae. Morphological descriptions, genetic sequences, evolutionary relationships among capillariids and new host and distribution records of P. najae are discussed. Paracapillaria najae specimens found in the Thai cobra had some morphological variation, and sexual size dimorphism was also indicated. Paracapillaria najae was found to infect various cobra host species and appeared to be common throughout the Oriental regions, consistent with its hosts' distribution.
Víctor Gutiérrez-González, Gisela Gerardi, Pilar Muñiz
et al.
Hyperglycemia is a significant risk factor in metabolic syndrome, contributing to the development of cardiovascular diseases and diabetes mellitus. Hyperglycemia increases ROS (reactive oxygen species) production via glucose oxidation and protein glycosylation, leading to cell damage. Our previous studies have highlighted the antioxidant properties of wine pomace products (wWPPs), a co-product of winemaking, and their ability to modulate oxidative stress. The objective of this study was to evaluate the protective effect of wWPPs against oxidative stress in hyperglycemic Caco-2 cells. They were treated with 1.5 μg GAE/mL of wWPP bioaccessible fractions, obtained from gastrointestinal digestion (WPGI) and colonic fermentation (WPF), under normoglycemic or hyperglycemic (35 mM glucose) conditions. After 24 h of treatment, cell viability, oxidative stress biomarkers and the expression of transcription factors and enzymes involved in cellular oxidation balance were evaluated. Hyperglycemia induced a 30% reduction in cell viability, which was restored to normoglycemic levels by WPF treatment. The bioaccessible fractions were able to counteract hyperglycemia-induced oxidative stress in intestinal cells, as evidenced by significant decreases in carbonyl groups and MDA levels (10 and 40%, respectively). Furthermore, hyperglycemia-induced NF-κB overexpression was also significantly reduced by WPGI and WPF pre-treatment (between 15 and 53%), modulating the redox activity. In conclusion, the bioaccessible fractions of wWPP, particularly WPF, demonstrated significant potential in mitigating hyperglycemia-induced oxidative stress and enhancing cell viability in Caco-2 cells.
Zeinab Asgarian, Marcio Guiomar Oliveira, Agata Stryjewska
et al.
There is a large diversity of inhibitory interneurons in the mammalian cerebral cortex. How this emerges during embryogenesis remains unclear. Here, the authors identify MTG8 as a co-factor of LHX6 and a new regulator of cortical interneuron development.
Marta Balog, Allison Anderson, Thiago C. Genaro-Mattos
et al.
Polypharmacy, or the simultaneous use of multiple drugs to treat a single patient, is a common practice in psychiatry. Unfortunately, data on the health effects of commonly used combinations of medications are very limited. In this study, we therefore investigated the effects and interactions between two commonly prescribed psychotropic medications with sterol inhibiting side effects, trazodone (TRZ), an antidepressant, and aripiprazole (ARI), an antipsychotic. In vitro cell culture experiments revealed that both medications alone disrupted neuronal and astroglial sterol biosynthesis in dose-dependent manners. Furthermore, when ARI and TRZ were combined, exposure resulted in an additive 7-dehydrocholesterol (7-DHC) increase, as well as desmosterol (DES) and cholesterol decreases in both cell types. In adult mice, at baseline, we found that the three investigated sterols showed significant differences in distribution across the eight assessed brain regions. Furthermore, experimental mice treated with ARI or TRZ, or a combination of both medications for 8 days, showed strong sterol disruption across all brain regions. We show ARI or TRZ alone elevated 7-DHC and decreased DES levels in all brain regions, but with regional differences. However, the combined utilization of these two medications for 8 days did not lead to additive changes in sterol disturbances. Based on the complex roles of 7-DHC derived oxysterols, we conclude that individual and potentially simultaneous use of medications with sterol biosynthesis-inhibiting properties might have undesired side effects on the adult brain, with as yet unknown long-term consequences on mental or physical health.