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Mirror symmetry for higher genus curves is usually formulated and studied in terms of Landau–Ginzburg models; however the critical locus of the superpotential is arguably of greater intrinsic relevance to mirror symmetry than the whole Landau–Ginzburg model. Accordingly, we propose a new approach to the A-model of the mirror, viewed as a trivalent configuration of rational curves together with some extra data at the nodal points. In this context, we introduce a version of Lagrangian Floer theory and the Fukaya category for trivalent graphs, and show that homological mirror symmetry holds, namely, that the Fukaya category of a trivalent configuration of rational curves is equivalent to the derived category of a non-Archimedean generalized Tate curve. To illustrate the concrete nature of this equivalence, we show how explicit formulas for theta functions and for the canonical map of the curve arise naturally under mirror symmetry. [ABSTRACT FROM AUTHOR]

The hazards of pollution are highlighted by gas exposure, and creating effective adsorbents is essential for maintaining clean air, the environment, and human health. In our study, employing the DFT/M062x/def2svp level of theory, the potentials of metal-doped (Na, Zn, and Al) fullerene surfaces as efficient adsorbents for CN, CNCl, and NO2 gases were evaluated. Investigation revealed that the introduction of metal dopants has visible impacts on the structural and electronic properties of fullerene surfaces. Specifically, a slight increase in the bond length of C–C bonds, with protruded bonds forming between the doped atoms and carbon atoms, was observed. The obtained energy gap (Eg) demonstrated a consistent reduction across the doped surfaces, indicative of heightened sensitivity toward the gas analytes. C59Al exhibited a higher Eg (3.876 eV), while C59Zn displayed a lower value (3.103 eV) compared to C59Na. Topology analysis using the quantum theory of atoms in molecules (QTAIM) predicted non-covalent interactions between gas analytes and metal-doped fullerene surfaces, a finding that was further substantiated by the analysis of non-covalent interactions. Focusing on CN gas adsorption, distinct behaviors emerged, where C59Na exhibited strong adsorption (Eads = −2.67 eV), surpassing C59Al (−1.82 eV) and C59Zn (−0.64 eV). A similar trend was observed for CNCl and NO2 gas adsorption, with C59Na consistently showing higher adsorption energies. This alignment was corroborated by frontier molecular orbital (FMO) and natural bond orbital (NBO) analyses. The results for dipole moment and recovery time emulated those of adsorption energy, emphasizing the stability and uniformity in adsorbed states. This collective evidence highlights the potential of doped surfaces to effectively adsorb specific gas molecules, offering insights into their applicability in gas sensing and environmental remediation. [ABSTRACT FROM AUTHOR]

The antimicrobial resistance crisis along with challenges of antimicrobial discovery revealed the vital necessity to develop new antibiotics. Many of the animal proline-rich antimicrobial peptides (PrAMPs) inhibit the process of bacterial translation. Genome projects allowed to identify immune-related genes encoding animal host defense peptides. Here, using genome mining approach, we discovered a family of proline-rich cathelicidins, named rumicidins. The genes encoding these peptides are widespread among ruminant mammals. Biochemical studies indicated that rumicidins effectively inhibited the elongation stage of bacterial translation. The cryo-EM structure of the Escherichia coli 70S ribosome in complex with one of the representatives of the family revealed that the binding site of rumicidins span the ribosomal A-site cleft and the nascent peptide exit tunnel interacting with its constriction point by the conservative Trp23-Phe24 dyad. Bacterial resistance to rumicidins is mediated by knockout of the SbmA transporter or modification of the MacAB-TolC efflux pump. A wide spectrum of antibacterial activity, a high efficacy in the animal infection model, and lack of adverse effects towards human cells in vitro make rumicidins promising molecular scaffolds for development of ribosome-targeting antibiotics. The antimicrobial resistance crisis calls for development of new classes of antibiotics. Here, authors use genome mining approach to discover a distinct family of ribosome-targeting proline rich antimicrobial peptides. [ABSTRACT FROM AUTHOR]

This review provides a survey of computational methods generally used in the evaluation of the corrosion inhibition evaluation of metallic materials in various environments. Herein a general overview of corrosion inhibition is given, thereafter, a discussion of the most widely used computational methods is given which include; molecular dynamics (MD) simulations, Monte Carlo (MC) simulations, density functional theory (DFT), Semi-empirical methods and first-principles calculations and Ab initio (Hartree Fock) calculations. A comparison of comparative analysis of experimental and computational approaches in corrosion inhibition studies was given after which the prospects of the use of computational methods in corrosion science were discussed. Overall, each of these methods has its strengths and limitations, but when used in combination, they are capable of providing a holistic understanding of corrosion inhibition mechanisms. [ABSTRACT FROM AUTHOR]

The Murun massif (Aldan shield, Russia) is particularly intriguing due to its group of alkali Ca-(K)-(Na) silicates, which includes many new and rare species. Additionally, it is also of interest for its beryllium mineralization. One of the unique beryllium Ca-(K)-(Na) silicates, odintsovite K2Na4Ca3Ti2Be4Si12O38, was investigated in this study. The aim of this study is to provide new insights into the crystal chemistry and spectroscopic properties of odintsovite. DFT modelling was used to interpret the experimental IR and Raman spectra. Determining the crystal-chemical formula of odintsovite is challenging due to the presence of atoms in different structural positions with varying valence states. The distribution of cations was determined by combining electron probe microanalysis with the results of crystal structure refinement. Luminescence of Eu3+ was observed in odintsovite upon excitation at around 532 nm. Analysis of the luminescence band splitting is related to the 4f–4f transitions in Eu3+ ions. Additionally, upon excitation at around 370 nm, luminescence with a peak at around 410 nm, associated with 5d–4f transitions in Ce3+ ions, was observed. [ABSTRACT FROM AUTHOR]

This comprehensive review delves into recent advancements in lithium, magnesium, zinc, and iron-air batteries, which have emerged as promising energy delivery devices with diverse applications, collectively shaping the landscape of energy storage and delivery devices. Lithium-air batteries, renowned for their high energy density of 1910 Wh/kg and long life cycle, have seen remarkable improvements in performance and safety measures, making them the go-to choose for portable electronics and electric vehicles. Lithium-air batteries have promising safer and more efficient energy storage solution. However, their reliance on limited lithium resources has driven research into alternative chemistries. Magnesium-air batteries, characterized by high theoretical capacity and reduced flammability risks, have garnered significance due to their potential of high energy density (700 Wh/kg). Magnesium-air batteries also offer compelling prospects due to their abundance and environmentally friendly resource. Meanwhile, zinc air batteries having energy density (1087 Wh/kg), low cost, abundant material availability, and impressive cycle life offer an attractive solution for grid-scale energy storage. Additionally, iron-air batteries have emerged as eco-friendly options with energy efficiency of 50%, harnessing iron's abundance and oxygen from the air. This review extracts recent research developments, offering insights into the strengths, challenges, and promising pathways for these battery systems, paving the way for a more diversified an environmentally conscious energy delivery landscape. While challenges such as electrode materials, electrolyte design, and safety concerns persist, the progress in these battery technologies presents exciting for more efficient and sustainable energy delivery systems, with potential benefits spanning from consumer electronics to renewable energy integration and beyond. [ABSTRACT FROM AUTHOR]

The stress-protective effect of melatonin (N-acetyl-5-methoxytryptamine) on plant cells is mediated by key signaling mediators, in particular calcium ions and reactive oxygen species (ROS). However, the links between changes in calcium and redox homeostasis and the formation of adaptive responses of cultivated cereals (including wheat) to the action of high temperatures have not yet been studied. In the present study, we investigated the possible involvement of ROS and calcium ions as signaling mediators in developing heat resistance in wheat (Triticum aestivum L.) seedlings and activating their antioxidant system. Treatment of 3-day-old etiolated seedlings with melatonin solutions at concentrations 0.01–10 µM increased their survival after exposure to 45 °C for 10 min. The most significant stress-protective effect was exerted by melatonin treatment at 1 µM concentration. Under the influence of melatonin, a transient enhancement of superoxide anion radical (O2•–) generation and an increase in hydrogen peroxide content were observed in roots, with a maximum at 1 h. Four hours after treatment with melatonin, the activity of catalase and guaiacol peroxidase increased in roots, while the activity of superoxide dismutase did not change significantly. After exposure to 45 °C, the activity of catalase and guaiacol peroxidase was higher in the roots of melatonin-treated wheat seedlings, and the indices of ROS generation, content of the lipid peroxidation product malonic dialdehyde, and cell membrane damage were lower than in control seedlings. Melatonin-induced changes in root ROS generation and antioxidant enzyme activities were eliminated by pretreatment with the hydrogen peroxide scavenger dimethylthiourea (DMTU), NADPH oxidase inhibitor imidazole, and calcium antagonists (the extracellular calcium chelator EGTA and phospholipase C inhibitor neomycin). Treatment with DMTU, imidazole, EGTA, and neomycin also abolished the melatonin-induced increase in survival of wheat seedlings after heat stress. The role of calcium ions and ROS, generated with the participation of NADPH oxidase, as signaling mediators in the melatonin-induced antioxidant system and heat stress resistance of wheat seedlings have been demonstrated. [ABSTRACT FROM AUTHOR]

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Purpose of Review: The endotracheal intubation of patients with pulmonary arterial hypertension (PAH) in respiratory distress is a highly morbid procedure that can precipitate hemodynamic collapse. Here we review our strategy for confronting this difficult clinical situation. Recent findings: There are no clinical trials that explore best practices in the management of patients with PAH and respiratory failure. Summary: Here we provide a practical approach to respiratory support, inopressor and pulmonary vasodilator selection, hemodynamic considerations, point-of-care ultrasound monitoring, and endotracheal intubation in patients with PAH in respiratory failure. [ABSTRACT FROM AUTHOR]

Identifying high-affinity antibodies in human serum is challenging due to extremely low number of circulating B cells specific to the desired antigens. Delays caused by a lack of information on the immunogenic proteins of viral origin hamper the development of therapeutic antibodies. We propose an efficient approach allowing for enrichment of high-affinity antibodies against pathogen proteins with simultaneous epitope mapping, even in the absence of structural information about the pathogenic immunogens. To screen therapeutic antibodies from blood of recovered donors, only pathogen transcriptome is required to design an antigen polypeptide library, representing pathogen proteins, exposed on the bacteriophage surface. We developed a two-dimensional screening approach enriching lentiviral immunoglobulin libraries from the convalescent or vaccinated donors against bacteriophage library expressing the overlapping set of polypeptides covering the spike protein of SARS-CoV-2. This platform is suitable for pathogen-specific immunoglobulin enrichment and allows high-throughput selection of therapeutic human antibodies. The authors present a 2D screening approach using antibody libraries against a panel of antigen fragments exposed on the phage surface, which facilitates the mapping of monoclonal antibodies to panels of diverse antigens, even with unknown immunogens. [ABSTRACT FROM AUTHOR]

Kainate receptors, a subclass of ionotropic glutamate receptors, are tetrameric ligand-gated ion channels that mediate excitatory neurotransmission1–4. Kainate receptors modulate neuronal circuits and synaptic plasticity during the development and function of the central nervous system and are implicated in various neurological and psychiatric diseases, including epilepsy, depression, schizophrenia, anxiety and autism5–11. Although structures of kainate receptor domains and subunit assemblies are available12–18, the mechanism of kainate receptor gating remains poorly understood. Here we present cryo-electron microscopy structures of the kainate receptor GluK2 in the presence of the agonist glutamate and the positive allosteric modulators lectin concanavalin A and BPAM344. Concanavalin A and BPAM344 inhibit kainate receptor desensitization and prolong activation by acting as a spacer between the amino-terminal and ligand-binding domains and a stabilizer of the ligand-binding domain dimer interface, respectively. Channel opening involves the kinking of all four pore-forming M3 helices. Our structures reveal the molecular basis of kainate receptor gating, which could guide the development of drugs for treatment of neurological disorders.Structures of the kainate receptor GluK2 with and without concanavilin A and BPAM344 show how these ligands modulate channel activity and reveal the molecular basis of kainate receptor gating. [ABSTRACT FROM AUTHOR]

Structural biology is solving an ever-increasing number of snapshots of ion channel conformational ensembles. Deciphering ion channel mechanisms, however, requires understanding the ensemble dynamics beyond the static structures. Here, we present a molecular modeling-based approach characterizing the ion channel structural intermediates, or their "dynamic molecular portraits", by assessing water and ion conductivity along with the detailed evaluation of pore hydrophobicity and residue packing. We illustrate the power of this approach by analyzing structures of few vanilloid-subfamily transient receptor potential (TRPV) channels. Based on the pore architecture, there are three major states that are common for TRPVs, which we call α-closed, π-closed, and π-open. We show that the pore hydrophobicity and residue packing for the open state is most favorable for the pore conductance. On the contrary, the α-closed state is the most hydrophobic and always non-conducting. Our approach can also be used for structural and functional classification of ion channels. Ion channels are known to be important actors in cellular signaling, and their functions correlate to their conformational states, however, detailed function–conformation relationships remain underexplored. Here, the authors use a molecular modeling-based approach to assess water and ion conductivity along with pore hydrophobicity and residue packing to characterize the ion channel structural intermediates, revealing three major states of vanilloid-subfamily transient receptor potential channels. [ABSTRACT FROM AUTHOR]

Each connected graded, graded-commutative algebra A of finite type over a field k of characteristic zero defines a complex of finitely generated, graded modules over a symmetric algebra, whose homology graded modules are called the (higher) Koszul modules of A. In this note, we investigate the geometry of the support loci of these modules, called the resonance schemes of the algebra. When A = k ⟨ Δ ⟩ is the exterior Stanley–Reisner algebra associated to a finite simplicial complex Δ , we show that the resonance schemes are reduced. We also compute the Hilbert series of the Koszul modules and give bounds on the regularity and projective dimension of these graded modules. This leads to a relationship between resonance and Hilbert series that generalizes a known formula for the Chen ranks of a right-angled Artin group. [ABSTRACT FROM AUTHOR]

In this work, we investigate collective electronic fluctuations and, in particular, the possibility of the charge density wave ordering in an infinite-layer NdNiO2. We perform advanced many-body calculations for the ab-initio three-orbital model by taking into account local correlation effects, nonlocal charge and magnetic fluctuations, and the electron-phonon coupling. We find that in the considered material, electronic correlations are strongly orbital- and momentum-dependent. Notably, the charge density wave and magnetic instabilities originate from distinct orbitals. In particular, we show that the correlation effects lead to the momentum-dependent hybridization between different orbitals, resulting in the splitting and shifting of the flat part of the Ni- d z 2 band. This strong renormalization of the electronic spectral function drives the charge density wave instability that is related to the intraband Ni- d z 2 correlations. Instead, the magnetic instability stems from the Ni- d x 2 − y 2 orbital, which remains half-filled through the redistribution of the electronic density between different bands even upon hole doping. Consequently, the strength of the magnetic fluctuations remains nearly unchanged for the considered doping levels. We argue that this renormalization is not inherent to the stoichiometric case but can be induced by hole doping. [ABSTRACT FROM AUTHOR]

Pancreatic intraepithelial neoplasias (PanINs) are the most common precursors of pancreatic cancer, but their small size and inaccessibility in humans make them challenging to study1. Critically, the number, dimensions and connectivity of human PanINs remain largely unknown, precluding important insights into early cancer development. Here, we provide a microanatomical survey of human PanINs by analysing 46 large samples of grossly normal human pancreas with a machine-learning pipeline for quantitative 3D histological reconstruction at single-cell resolution. To elucidate genetic relationships between and within PanINs, we developed a workflow in which 3D modelling guides multi-region microdissection and targeted and whole-exome sequencing. From these samples, we calculated a mean burden of 13 PanINs per cm3 and extrapolated that the normal intact adult pancreas harbours hundreds of PanINs, almost all with oncogenic KRAS hotspot mutations. We found that most PanINs originate as independent clones with distinct somatic mutation profiles. Some spatially continuous PanINs were found to contain multiple KRAS mutations; computational and in situ analyses demonstrated that different KRAS mutations localize to distinct cell subpopulations within these neoplasms, indicating their polyclonal origins. The extensive multifocality and genetic heterogeneity of PanINs raises important questions about mechanisms that drive precancer initiation and confer differential progression risk in the human pancreas. This detailed 3D genomic mapping of molecular alterations in human PanINs provides an empirical foundation for early detection and rational interception of pancreatic cancer.Quantitative multimodal 3D reconstruction of human pancreatic tissue at single-cell resolution reveals a high burden of multifocal, genetically heterogeneous pancreatic intraepithelial neoplasias in the normal adult pancreas. [ABSTRACT FROM AUTHOR]

Graphene/hBN/graphene tunnel devices offer promise as sensitive mid-infrared photodetectors but the microscopic origin underlying the photoresponse in them remains elusive. In this work, we investigated the photocurrent generation in graphene/hBN/graphene tunnel structures with localized defect states under mid-IR illumination. We demonstrate that the photocurrent in these devices is proportional to the second derivative of the tunnel current with respect to the bias voltage, peaking during tunneling through the hBN impurity level. We revealed that the origin of the photocurrent generation lies in the change of the tunneling probability upon radiation-induced electron heating in graphene layers, in agreement with the theoretical model that we developed. Finally, we show that at a finite bias voltage, the photocurrent is proportional to either of the graphene layers heating under the illumination, while at zero bias, it is proportional to the heating difference. Thus, the photocurrent in such devices can be used for accurate measurements of the electronic temperature, providing a convenient alternative to Johnson noise thermometry. [ABSTRACT FROM AUTHOR]

Purpose: Patients with pancreatic ductal adenocarcinoma (PDAC) have yet to experience significant benefits from targeted therapy. Olaparib is currently the only active substance in BRCA-mutated PDACs that successfully influences the DNA repair of carcinoma cells. H2AX belongs to the histone family and is known as a part of the DNA repair system. The inhibition of γ-H2AX could lead to the inhibition of mitotically active tumor cells. Therefore, we aimed to evaluate the predictive value of the γ-H2AX in patients with PDAC. Methods: All included patients (n = 311) received a pancreatic resection with curative intention in one of our PANCALYZE study centers. Subsequently, they were enrolled in a standardized follow-up protocol. Immunohistochemical stainings for γ-H2AX were conducted on tissue microarrays. Results: Patients exhibiting high levels of γ-H2AX expression experience more frequent R1 resections, indicating advanced tumor stages in this subgroup. Additionally, patients with high γ-H2AX expression demonstrated significantly poorer survival compared to those with low expression (median OS: 15 vs. 25 months, p < 0.001). In multivariate analyses, high γ-H2AX expression could be identified as an independent risk factor for worse patient survival. Moreover, high γ-H2AX expression could be more frequently observed in the more aggressive basal-like subtype. Conclusion: γ-H2AX can be characterized as a predictive biomarker for poorer patient survival. Consequently, upcoming clinical trials focused on the efficacy of targeted therapies influencing the DNA repair system and radiotherapy should evaluate γ-H2AX as a potential biomarker for therapy response. Furthermore, γ-H2AX may serve as a viable target for treatment in the future. [ABSTRACT FROM AUTHOR]

CoMOF-BTA, a new metal-organic framework with inherent corrosion inhibition ability was prepared via a one-step solvothermal process and characterized using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and thermal analyses. Immersion and polarization tests were conducted to evaluate the ability of CoMOF-BTA to resist corrosion on AA2024-T3 alloy in NaCl solution. In addition, CoMOF-BTA particles were incorporated into polyurethane coatings to produce active anti-corrosion coatings, whose corrosion protection capabilities were assessed using electrochemical methods and salt spray analysis. The impedance results show that polyurethane coatings containing CoMOF-BTA have coating resistances (Rcoat) that are around two orders of magnitude higher than that without the CoMOF-BTA particles. The salt spray analysis also indicates the corrosion protection ability of coatings containing CoMOF-BTA particles after a long period of exposure. The results demonstrate that CoMOF-BTA improved the ability of AA2024-T3 to resist corrosion and confirm the anti-corrosion properties of CoMOF-BTA-laden coatings by the controlled release of BTA molecules in NaCl solution. This study offers a new anti-corrosion MOF material and active coating for the protection of aluminum alloys against corrosion. [ABSTRACT FROM AUTHOR]

We have developed a strong-coupling perturbation scheme for a general doped Hubbard model around a particle-hole-symmetric reference system, which is free from the fermionic sign problem. Our approach is based on the lattice determinantal Quantum Monte Carlo (QMC) method in both continuous and discrete time versions for large periodic clusters in a fermionic bath. By considering the first-order perturbation in the shift of the chemical potential and the second-neighbor hopping, we are able to obtain an accurate electronic spectral function for a range of parameters that correspond to optimally doped cuprate systems at temperatures of up to T = 0.1t, which are challenging to access using straightforward lattice QMC calculations. We also discuss the formation of the pseudogap and the nodal-antinodal dichotomy for a doped Hubbard system with the interaction parameter U equal to the bandwidth and the optimal value of the next-nearest-neighbor hopping parameter t ′ for high-temperature superconducting cuprates. [ABSTRACT FROM AUTHOR]

In spite of the fact that photons do not interact with an external magnetic field unless nonlinearity of QED is taken into account, the latter field may indirectly affect photons in the presence of a charged environment. This opens up an interesting possibility to continuously control the entanglement of photon beams without using any crystalline devices. We study this possibility in the framework of an adequate QED model. In an approximation it was discovered that such entanglement has a resonant nature, namely, a peak behavior at certain magnetic field strengths, depending on characteristics of photon beams direction of the magnetic field and parameters of the charged medium. Numerical calculations illustrating the above-mentioned resonant behavior of the entanglement measure and some concluding remarks are presented. [ABSTRACT FROM AUTHOR]

Cephalopods are harvested in increasingly large quantities but understanding how to control and manage their stocks, and tracking the routes of the consumption that exploits them, lag behind what has been developed for exploiting finfish. This review attempts to redress the imbalance by considering the status of the major cephalopod stock species and the traceability of cephalopod seafood along the trade value chain. It begins with a general overview of the most important exploited cephalopods, their stock status and their market. Four major cephalopod resources are identified: the three squid species Todarodes pacificus, Dosidicus gigas and Illex argentinus; and one species of octopus, Octopus vulgaris. The techniques and problems of stock assessment (to assess sustainability) are reviewed briefly and the problems and possible solutions for assessing benthic stock such as those of octopuses are considered. An example of a stock well managed in the long term is presented to illustrate the value of careful monitoring and management: the squid Doryteuthis gahi available in Falkland Islands waters. Issues surrounding identification, mislabelling and illegal, unreported and unregulated (IUU) fishing are then reviewed, followed by a discussion of approaches and techniques of traceability as applied to cephalopods. Finally, some of the mobile apps currently available and in development for tracking seafood are compared. This review concludes with observations on the necessity for the strengthening and international coordination of legislation, and more rigorous standards for seafood labelling and for taxonomic curation of DNA sequences available in public databases for use in seafood identification. [ABSTRACT FROM AUTHOR]

We introduce orthogonal ring patterns consisting of pairs of concentric circles generalizing circle patterns. We show that orthogonal ring patterns are governed by the same equation as circle patterns. For every ring pattern there exists a one parameter family of patterns that interpolates between a circle pattern and its dual. We construct ring patterns analogues of the Doyle spiral, Erf and z α functions. We also derive a variational principle and compute ring patterns based on Dirichlet and Neumann boundary conditions. [ABSTRACT FROM AUTHOR]

Layered antiferromagnetic materials have recently emerged as an intriguing subset of the two-dimensional family providing a highly accessible regime with prospects for layer-number-dependent magnetism. Furthermore, transition metal phosphorus trichalcogenides, MPX3 (M = transition metal; X = chalcogen) provide a platform on which to investigate fundamental interactions between magnetic and lattice degrees of freedom and further explore the developing fields of spintronics and magnonics. Here, we use a combination of temperature dependent Raman spectroscopy and density functional theory to explore magnetic-ordering-dependent interactions between the manganese spin degree of freedom and lattice vibrations of the non-magnetic sub-lattice via a Kramers-Anderson super-exchange pathway in both bulk, and few-layer, manganese phosphorus triselenide (MnPSe3). We observe a nonlinear temperature-dependent shift of phonon modes predominantly associated with the non-magnetic sub-lattice, revealing their non-trivial spin-phonon coupling below the Néel temperature at 74 K, allowing us to extract mode-specific spin-phonon coupling constants. [ABSTRACT FROM AUTHOR]

Geometric frustration commonly occurs in materials where magnetic rare-earth ions are arranged on a two-dimensional triangular lattice. These compounds have been gaining significant attention lately, as they hold the promise of revealing unique quantum states of matter. However, little attention has been devoted to cases where spin- 1 2 rare-earth ions are substituted with ions exhibiting higher spin multiplicities. Here, we successfully synthesize high-quality single crystal samples of Ba3Er(BO3)3, which is part of the family of triangular lattice compounds. In our experiments, conducted at extremely low temperatures (around 100 millikelvin), we observe two sublattice exchange interactions in Ba3Er(BO3)3, resulting in the hexagonal lattice spins exhibiting a mixture of ferromagnetic and antiferromagnetic tendencies. Our theoretical analysis suggest that this behavior may be attributed to the distinct positions of magnetic ions within the crystal lattice. However, the presence of quantum effects adds an extra layer of complexity to our findings, calling for further exploration. Materials hosting magnetic rare-earth ions sitting on a two-dimensional triangular lattices are ideal candidates to realize spin liquid states. In this work, the authors synthesize a high-quality single crystal sample of an erbium based triangular lattice compound, that exhibits a mixture of ferromagnetic and antiferromagnetic behaviour. [ABSTRACT FROM AUTHOR]

Reactive halogen species (RHS) are highly reactive compounds that are normally required for regulation of immune response, inflammatory reactions, enzyme function, etc. At the same time, hyperproduction of highly reactive compounds leads to the development of various socially significant diseases – asthma, pulmonary hypertension, oncological and neurodegenerative diseases, retinopathy, and many others. The main sources of (pseudo)hypohalous acids are enzymes from the family of heme peroxidases – myeloperoxidase, lactoperoxidase, eosinophil peroxidase, and thyroid peroxidase. Main targets of these compounds are proteins and peptides, primarily methionine and cysteine residues. Due to the short lifetime, detection of RHS can be difficult. The most common approach is detection of myeloperoxidase, which is thought to reflect the amount of RHS produced, but these methods are indirect, and the results are often contradictory. The most promising approaches seem to be those that provide direct registration of highly reactive compounds themselves or products of their interaction with components of living cells, such as fluorescent dyes. However, even such methods have a number of limitations and can often be applied mainly for in vitro studies with cell culture. Detection of reactive halogen species in living organisms in real time is a particularly acute issue. The present review is devoted to RHS, their characteristics, chemical properties, peculiarities of interaction with components of living cells, and methods of their detection in living systems. Special attention is paid to the genetically encoded tools, which have been introduced recently and allow avoiding a number of difficulties when working with living systems. [ABSTRACT FROM AUTHOR]

The plastids of algae and plants originated on a single occasion from an endosymbiotic cyanobacterium at least a billion years ago. Despite the divergent evolution that characterizes the plastids of different lineages, many traits such as membrane organization and means of fission are universal—they pay tribute to the cyanobacterial origin of the organelle. For one such trait, the peptidoglycan (PG) layer, the situation is more complicated. Our view on its distribution keeps on changing and little is known regarding its molecular relevance, especially for land plants. Here, we investigate the extent of PG presence across the Chloroplastida using a phylogenomic approach. Our data support the view of a PG layer being present in the last common ancestor of land plants and its remarkable conservation across bryophytes that are otherwise characterized by gene loss. In embryophytes, the occurrence of the PG layer biosynthetic toolkit becomes patchier and the availability of novel genome data questions previous predictions regarding a functional coevolution of the PG layer and the plastid division machinery-associated gene FtsZ3. Furthermore, our data confirm the presence of penicillin-binding protein (PBP) orthologs in seed plants, which were previously thought to be absent from this clade. The 5-7 nm thick, and seemingly unchanged, PG layer armoring the plastids of glaucophyte algae might still provide the original function of structural support, but the same can likely not be said about the only recently identified PG layer of bryophyte and tracheophyte plastids. There are several issues to be explored regarding the composition, exact function, and biosynthesis of the PG layer in land plants. These issues arise from the fact that land plants seemingly lack certain genes that are believed to be crucial for PG layer production, even though they probably synthesize a PG layer. [ABSTRACT FROM AUTHOR]

Purpose of Review: Cardiogenic shock (CS) is a time-sensitive and often fatal condition. To address this issue, many centers have developed multidisciplinary shock teams with a common goal of expediting the recognition and treatment of CS. In this review, we examine the mission, structure, implementation, and outcomes reported by these early shock teams. Recent Findings: To date, there have been four observational shock team analyses, each providing unique insight into the utility of the shock team. Summary: The limited available data supports that shock teams are associated with improved CS mortality. However, there is considerable operational heterogeneity among shock teams, and randomized data assessing their value and best practices in both local and regional care models are needed. [ABSTRACT FROM AUTHOR]

This paper confirms the regularities of the formation of increased concentrations of strontium (Sr) in fresh groundwater used for drinking water supply, depending on the time they are residen in the carbonate deposits of the aquifer. On average, every thousand years, the Sr concentration increases by 2.1–3.5 mg L−1. In addition, high strontium content is positively correlated with altitude and well depth and negatively correlated with redox conditions in the aquifer. Large relief elevations are associated with the development of marginal moraine deposits from the Last Glacial Period composed predominantly of clay, which contributes to a decrease in water exchange. The high Sr content is associated with the dissolution of significant formations of celestite and strontianite, up to their ore occurrences. For this reason, the saturation indices (SIs) for celestite and strontianite correlate with TDS and rise to − 1.42 and 2.05, respectively. Low Sr values do not correlate with the residence time of groundwater in the aquifer or the depth of wells and tend to depressions in the relief, with a virtual absence of overlying sediments and positive Eh values, which indicates an active water exchange. The low level of Sr is associated with the dissolution of gypsum, calcite, and dolomite containing strontium as an impurity. This causes the SIs for gypsum, calcite, and dolomite to correlate with TDS, while for celestite and strontianite, the SI drops to − 5.02 and − 0.92, respectively. The established patterns make it possible to more reasonably choose places for the construction of water wells to obtain drinking water of standard quality. [ABSTRACT FROM AUTHOR]

Across jurisdictions, the use of 'leverage' to promote adherence to mental health treatment is widespread. However, little research exists on the possible association between the application of leverage and personal recovery. We examined the prevalence of various forms of leverage in a Canadian context and compared these rates with those in other jurisdictions. Additionally, we examined the relationship between two prominent forms of leverage (financial and housing) and the experience of personal recovery. Structured interviews were conducted with people receiving community-based mental health care in Toronto, Canada. Rates of overall leverage in our sample were similar to rates reported in other jurisdictions. Personal recovery was negatively associated with financial leverage but was not associated with housing leverage. Our results highlight the importance of separately examining the relationship of specific forms of leverage and personal recovery and raise questions for future research about the possible effect of financial leverage on recovery. [ABSTRACT FROM AUTHOR]

Understanding the nature and origin of collective excitations in materials is of fundamental importance for unraveling the underlying physics of a many-body system. Excitation spectra are usually obtained by measuring the dynamical structure factor, S(Q, ω), using inelastic neutron or x-ray scattering techniques and are analyzed by comparing the experimental results against calculated predictions. We introduce a data-driven analysis tool which leverages 'neural implicit representations' that are specifically tailored for handling spectrographic measurements and are able to efficiently obtain unknown parameters from experimental data via automatic differentiation. In this work, we employ linear spin wave theory simulations to train a machine learning platform, enabling precise exchange parameter extraction from inelastic neutron scattering data on the square-lattice spin-1 antiferromagnet La2NiO4, showcasing a viable pathway towards automatic refinement of advanced models for ordered magnetic systems. Analysis of experimental data in condensed matter is often challenging due to system complexity and slow character of physical simulations. The authors propose a framework that combines machine learning with theoretical calculations to enable real-time analysis for electron, neutron, and x-ray spectroscopies. [ABSTRACT FROM AUTHOR]

The CCT/TRiC chaperonin is found in the cytosol of all eukaryotic cells and assists protein folding in an ATP-dependent manner. The heterozygous double mutation T400P and R516H in subunit CCT2 is known to cause Leber congenital amaurosis (LCA), a hereditary congenital retinopathy. This double mutation also renders the function of subunit CCT2, when it is outside of the CCT/TRiC complex, to be defective in promoting autophagy. Here, we show using steady-state and transient kinetic analysis that the corresponding double mutation in subunit CCT2 from Saccharomyces cerevisiae reduces the off-rate of ADP during ATP hydrolysis by CCT/TRiC. We also report that the ATPase activity of CCT/TRiC is stimulated by a non-folded substrate. Our results suggest that the closed state of CCT/TRiC is stabilized by the double mutation owing to the slower off-rate of ADP, thereby impeding the exit of CCT2 from the complex that is required for its function in autophagy. Potential insights into a hereditary congenital retinopathy are gained by kinetic analysis of a double mutation in the CCT2 subunit of the CCT chaperonin in Saccharomyces cerevisiae. [ABSTRACT FROM AUTHOR]

Many strongly correlated transition metal insulators are colored, even though they have band gaps much larger than the highest energy photons from the visible light. An adequate explanation for the color requires a theoretical approach able to compute subgap excitons in periodic crystals, reliably and without free parameters—a formidable challenge. The literature often fails to disentangle two important factors: what makes excitons form and what makes them optically bright. We pick two archetypal cases as examples: NiO with green color and MnF2 with pink color, and employ two kinds of ab initio many body Green's function theories; the first, a perturbative theory based on low-order extensions of the GW approximation, is able to explain the color in NiO, while the same theory is unable to explain why MnF2 is pink. We show its color originates from higher order spin-flip transitions that modify the optical response, which is contained in dynamical mean-field theory (DMFT). We show that symmetry lowering mechanisms may determine how 'bright' these excitons are, but they are not fundamental to their existence. Strongly correlated transition metal insulators are often coloured. Understanding the underlying optical response from first-principles calculations is challenging. Now, ab initio many body Green's function theories are shown to reproduce the colours of NiO and MnF2. [ABSTRACT FROM AUTHOR]

The interplay between magnetism and electronic band topology enriches topological phases and has promising applications. However, the role of topology in magnetic fluctuations has been elusive. Here, we report evidence for topology stabilized magnetism above the magnetic transition temperature in magnetic Weyl semimetal candidate CeAlGe. Electrical transport, thermal transport, resonant elastic X-ray scattering, and dilatometry consistently indicate the presence of locally correlated magnetism within a narrow temperature window well above the thermodynamic magnetic transition temperature. The wavevector of this short-range order is consistent with the nesting condition of topological Weyl nodes, suggesting that it arises from the interaction between magnetic fluctuations and the emergent Weyl fermions. Effective field theory shows that this topology stabilized order is wavevector dependent and can be stabilized when the interband Weyl fermion scattering is dominant. Our work highlights the role of electronic band topology in stabilizing magnetic order even in the classically disordered regime. Recently, rich condensed matter physics has emerged from the interplay between band topology and magnetic order. Here, the authors characterize the magnetic Weyl semimetal CeAlGe and find evidence for the role of Weyl fermions in stabilizing the magnetic order above the local transition temperature. [ABSTRACT FROM AUTHOR]

Purpose: Rising incidence of pancreatic ductal adenocarcinoma (PDAC) bind with insufficient therapy options showcases a great medical challenge. Further biomarkers are required to identify patients, who will benefit from more aggressive therapy. Methods: 320 patients were included by the PANCALYZE study group. Cytokeratin 6 (CK6) immunohistochemical staining as a putative marker for the basal-like subtype of PDAC was performed. The correlation between CK6 expression patterns and survival data, as well as various markers of the (inflammatory) tumor microenvironment, were analyzed. Results: We divided the study population based on the expression pattern of CK6. Patients with a high CK6 tumor expression had a significantly shorter survival (p = 0.013), confirmed in a multivariate cox regression model. CK6-expression is an independent marker for a decreased overall survival (HR = 1.655, 95% CI 1.158–2.365, p = 0.006). In addition, the CK6-positive tumors showed significantly less plasma cell infiltration and more cancer-associated fibroblasts (CAFs) expressing Periostin and SMA. Conclusions: CK6 could be considered as an independent biomarker for a shorter overall survival. CK6 is a clinically easily accessible biomarker for the identification of the basal-like subtype of PDAC. Therefore, it could be taken into consideration in deciding for the more aggressive therapy regimes. Prospectively, studies addressing the chemosensitive characteristics of this subtype are required. [ABSTRACT FROM AUTHOR]

The calcium-selective oncochannel TRPV6 is an important driver of cell proliferation in human cancers. Despite increasing interest of pharmacological research in developing synthetic inhibitors of TRPV6, natural compounds acting at this channel have been largely neglected. On the other hand, pharmacokinetics of natural small-molecule antagonists optimized by nature throughout evolution endows these compounds with a medicinal potential to serve as potent and safe next-generation anti-cancer drugs. Here we report the structure of human TRPV6 in complex with tetrahydrocannabivarin (THCV), a natural cannabinoid inhibitor extracted from Cannabis sativa. We use cryo-electron microscopy combined with electrophysiology, calcium imaging, mutagenesis, and molecular dynamics simulations to identify THCV binding sites in the portals that connect the membrane environment surrounding the protein to the central cavity of the channel pore and to characterize the allosteric mechanism of TRPV6 inhibition. We also propose the molecular pathway taken by THCV to reach its binding site. Our study provides a foundation for the development of new TRPV6-targeting drugs. Neuberger et al. report the structure of human channel TRPV6 in complex with a cannabinoid inhibitor tetrahydrocannabivarin (THCV) and explore the pathway taken by the drug to reach binding sites in the portals that connect the membrane environment to the central cavity of the ion channel pore. [ABSTRACT FROM AUTHOR]

The prediction of knockout tournaments represents an area of large public interest and active academic as well as industrial research. Here, we show how one can leverage the computational analogies between calculating the phylogenetic likelihood score used in the area of molecular evolution to efficiently calculate, instead of approximate via simulations, the exact per-team tournament win probabilities, given a pairwise win probability matrix between all teams. We implement and make available our method as open-source code and show that it is two orders of magnitude faster than simulations and two or more orders of magnitude faster than calculating the exact per-team win probabilities naïvely, without taking into account the substantial computational savings induced by the tournament tree structure. Furthermore, we showcase novel prediction approaches that now become feasible due to this order of magnitude improvement in calculating tournament win probabilities. We demonstrate how to quantify prediction uncertainty by calculating 100,000 distinct tournament win probabilities for a tournament with 16 teams under slight variations of a reasonable pairwise win probability matrix within one minute on a standard laptop. We also conduct an analogous analysis for a tournament with 64 teams. [ABSTRACT FROM AUTHOR]

Engineered cardiac microtissues were fabricated using pluripotent stem cells with a hypertrophic cardiomyopathy associated c. 2827 C>T; p.R943x truncation variant in myosin binding protein C (MYBPC3+/−). Microtissues were mounted on iron-incorporated cantilevers, allowing manipulations of cantilever stiffness using magnets, enabling examination of how in vitro afterload affects contractility. MYPBC3+/− microtissues developed augmented force, work, and power when cultured with increased in vitro afterload when compared with isogenic controls in which the MYBPC3 mutation had been corrected (MYPBC3+/+(ed)), but weaker contractility when cultured with lower in vitro afterload. After initial tissue maturation, MYPBC3+/− CMTs exhibited increased force, work, and power in response to both acute and sustained increases of in vitro afterload. Together, these studies demonstrate that extrinsic biomechanical challenges potentiate genetically-driven intrinsic increases in contractility that may contribute to clinical disease progression in patients with HCM due to hypercontractile MYBPC3 variants. [ABSTRACT FROM AUTHOR]

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is currently one of the leading causes of cancer death worldwide. Therefore, building further subgroups as well as enabling individual patient therapy and diagnostics are needed. X-linked inhibitor of apoptosis protein (XIAP) is known to modulate apoptotic and inflammatory pathways. Its expression was found to correlate with patients' survival in other tumor entities. This study aims to examine the role of XIAP in patients with PDAC in relation to the inflammatory microenvironment. Methods: The PANCALYZE multicenter study group included 257 patients with PDAC. Paraffin-embedded tumor samples were stained immunohistochemically for CD3, CD20, CD38, CD56, CD66b, CD117, and CD163 and XIAP. These stainings were further analyzed digitally with QuPath and survival analyses were done. Results: XIAP-positive patients with T-cell, respectively, neutrophil enriched tumors survived significantly longer compared to XIAP-negative patients (CD3: 37.6 vs. 24.6 months, p = 0.028; CD66b: 34.1 vs. 14.9 months, p = 0.027). Additionally, XIAP-positive patients showed better survival in the lymph node-negative population (48.4 vs. 24.2 months, p = 0.019). Regarding the total population, our findings did not show a correlation between XIAP expression and survival. In multivariate cox regression analyzes XIAP proves to be an independent factor for better survival in the identified subgroups (CD3: p = 0.043; CD66b: p = 0.012, N0: p = 0.040). Conclusion: We found XIAP-positive subgroups with significantly better survival in patients with PDAC in T-cell-rich, neutrophil-rich, or lymph node-negative cohorts. This could lead to further individualized cancer treatment with less aggressive therapy protocols for XIAP-positive tumors or more intensive follow-up for XIAP-negative tumors. [ABSTRACT FROM AUTHOR]

Nonlinear interactions between excitons strongly coupled to light are key for accessing quantum many-body phenomena in polariton systems. Atomically-thin two-dimensional semiconductors provide an attractive platform for strong light-matter coupling owing to many controllable excitonic degrees of freedom. Among these, the recently emerged exciton hybridization opens access to unexplored excitonic species, with a promise of enhanced interactions. Here, we employ hybridized interlayer excitons (hIX) in bilayer MoS2 to achieve highly nonlinear excitonic and polaritonic effects. Such interlayer excitons possess an out-of-plane electric dipole as well as an unusually large oscillator strength allowing observation of dipolar polaritons (dipolaritons) in bilayers in optical microcavities. Compared to excitons and polaritons in MoS2 monolayers, both hIX and dipolaritons exhibit ≈ 8 times higher nonlinearity, which is further strongly enhanced when hIX and intralayer excitons, sharing the same valence band, are excited simultaneously. This provides access to an unusual nonlinear regime which we describe theoretically as a mixed effect of Pauli exclusion and exciton-exciton interactions enabled through charge tunnelling. The presented insight into many-body interactions provides new tools for accessing few-polariton quantum correlations. In semiconductors, accessing nonlinear interactions between excitons strongly coupled to light will be key for quantum technologies. Here, in atomic bilayers of MoS2, new types of excitons are discovered showing strong inter-excitonic interactions. [ABSTRACT FROM AUTHOR]

Transient receptor potential (TRP) channel TRPV4 is a polymodal cellular sensor that responds to moderate heat, cell swelling, shear stress, and small-molecule ligands. It is involved in thermogenesis, regulation of vascular tone, bone homeostasis, renal and pulmonary functions. TRPV4 is implicated in neuromuscular and skeletal disorders, pulmonary edema, and cancers, and represents an important drug target. The cytoskeletal remodeling GTPase RhoA has been shown to suppress TRPV4 activity. Here, we present a structure of the human TRPV4-RhoA complex that shows RhoA interaction with the membrane-facing surface of the TRPV4 ankyrin repeat domains. The contact interface reveals residues that are mutated in neuropathies, providing an insight into the disease pathogenesis. We also identify the binding sites of the TRPV4 agonist 4α-PDD and the inhibitor HC-067047 at the base of the S1-S4 bundle, and show that agonist binding leads to pore opening, while channel inhibition involves a π-to-α transition in the pore-forming helix S6. Our structures elucidate the interaction interface between hTRPV4 and RhoA, as well as residues at this interface that are involved in TRPV4 disease-causing mutations. They shed light on TRPV4 activation and inhibition and provide a template for the design of future therapeutics for treatment of TRPV4-related diseases. Nadezhdin et al. present structures of human TRPV4 in complex with the GTPase RhoA, in the apo, agonist 4α-PDD and antagonist HC-067047 bound states, uncovering the mechanisms of channel activation, inhibition and disease-causing mutations. [ABSTRACT FROM AUTHOR]

We develop an asymptotic control theory for one of the simplest distributed (infinite-dimensional) oscillating systems, namely, for a closed string under a bounded load applied to a single distinguished point. We give a precise description of the classes of string states that admit complete damping, and find an asymptotically exact value of the required time. By using approximate reachable sets instead of the exact ones, we design a feedback control, which turns out to be asymptotically optimal. The main results are exact algebraic formulas for the asymptotic shape of the reachable sets, for the asymptotically optimal time of motion, and for the asymptotically optimal control thus constructed. [ABSTRACT FROM AUTHOR]

Water-soluble fullerene derivatives are good candidates for various biological applications such as anticancer or antimicrobial therapy, cytoprotection, enzyme inhibition, and many others. Their toxicity, both in tissue culture and in vivo, is a critical characteristic for the development and restriction of these applications. The effects of six water-soluble cationic and anionic polysubstituted fullerene derivatives on cytochrome c oxidase activity in rat brain mitochondria and the possibility of cytochrome c binding were studied. We found that the ability of these fullerene derivatives to bind with cytochrome c oxidase and charged molecules like eosin Y strongly depends on their electrostatic charge. As was shown, the cationic fullerene derivative inhibits cytochrome c oxidase that has the overall negative electrostatic potential completely, unlike anionic derivatives. Thus, it confirms the essential role of electrostatic interactions in the interaction of fullerene derivatives with the active site of enzymes. The results explore how cationic fullerene derivatives play a role in mitochondrial dysfunction, oxidative stress, and cytotoxicity. [ABSTRACT FROM AUTHOR]

This article is a tribute to the life and accomplishments of Dr. Bob V. Conger, who passed away on October 31, 2022. Bob was a longstanding member of the Tissue Culture Association and the Society for In Vitro Biology. This tribute is written by his students and Post Docs who were in his lab from the 1970s to the 2000s. [ABSTRACT FROM AUTHOR]

Lanthanides in the trivalent oxidation state are typically described using an ionic picture that leads to localized magnetic moments. The hierarchical energy scales associated with trivalent lanthanides produce desirable properties for e.g., molecular magnetism, quantum materials, and quantum transduction. Here, we show that this traditional ionic paradigm breaks down for praseodymium in the tetravalent oxidation state. Synthetic, spectroscopic, and theoretical tools deployed on several solid-state Pr4+-oxides uncover the unusual participation of 4f orbitals in bonding and the anomalous hybridization of the 4f1 configuration with ligand valence electrons, analogous to transition metals. The competition between crystal-field and spin-orbit-coupling interactions fundamentally transforms the spin-orbital magnetism of Pr4+, which departs from the Jeff = 1/2 limit and resembles that of high-valent actinides. Our results show that Pr4+ ions are in a class on their own, where the hierarchy of single-ion energy scales can be tailored to explore new correlated phenomena in quantum materials. Trivalent lanthanides are typically described using an ionic picture that leads to localized magnetic moments. Here authors show that the "textbook" description of lanthanides fails for Pr4+ ions where the hierarchy of single-ion energy scales can be tailored to explore correlated phenomena in quantum materials. [ABSTRACT FROM AUTHOR]

Calcium-selective oncochannel TRPV6 is the major driver of cell proliferation in human cancers. While significant effort has been invested in the development of synthetic TRPV6 inhibitors, natural channel blockers have been largely neglected. Here we report the structure of human TRPV6 in complex with the plant-derived phytoestrogen genistein, extracted from Styphnolobium japonicum, that was shown to inhibit cell invasion and metastasis in cancer clinical trials. Despite the pharmacological value, the molecular mechanism of TRPV6 inhibition by genistein has remained enigmatic. We use cryo-EM combined with electrophysiology, calcium imaging, mutagenesis, and molecular dynamics simulations to show that genistein binds in the intracellular half of the TRPV6 pore and acts as an ion channel blocker and gating modifier. Genistein binding to the open channel causes pore closure and a two-fold symmetrical conformational rearrangement in the S4–S5 and S6-TRP helix regions. The unprecedented mechanism of TRPV6 inhibition by genistein uncovers new possibilities in structure-based drug design. The authors report the structure of human oncochannel TRPV6 in complex with the plant derived phytoestrogen genistein. The structure provides insights into genistein binding in the channel pore, and how it acts as blocker and gating modifier, suggesting a mechanism of inhibition that can be explored for the structure-based drug design. [ABSTRACT FROM AUTHOR]

The transient receptor potential channel TRPM7 is a master regulator of the organismal balance of divalent cations that plays an essential role in embryonic development, immune responses, cell mobility, proliferation, and differentiation. TRPM7 is implicated in neuronal and cardiovascular disorders, tumor progression and has emerged as a new drug target. Here we use cryo-EM, functional analysis, and molecular dynamics simulations to uncover two distinct structural mechanisms of TRPM7 activation by a gain-of-function mutation and by the agonist naltriben, which show different conformational dynamics and domain involvement. We identify a binding site for highly potent and selective inhibitors and show that they act by stabilizing the TRPM7 closed state. The discovered structural mechanisms provide foundations for understanding the molecular basis of TRPM7 channelopathies and drug development. Authors present the structural mechanisms of TRPM7 spontaneous and agonist-induced opening and inhibition by potent and selective antagonists. [ABSTRACT FROM AUTHOR]

Proteorhodopsins (PRs), bacterial light-driven outward proton pumps comprise the first discovered and largest family of rhodopsins, they play a significant role in life on the Earth. A big remaining mystery was that up-to-date there was no described bacterial rhodopsins pumping protons at acidic pH despite the fact that bacteria live in different pH environment. Here we describe conceptually new bacterial rhodopsins which are operating as outward proton pumps at acidic pH. A comprehensive function-structure study of a representative of a new clade of proton pumping rhodopsins which we name "mirror proteorhodopsins", from Sphingomonas paucimobilis (SpaR) shows cavity/gate architecture of the proton translocation pathway rather resembling channelrhodopsins than the known rhodopsin proton pumps. Another unique property of mirror proteorhodopsins is that proton pumping is inhibited by a millimolar concentration of zinc. We also show that mirror proteorhodopsins are extensively represented in opportunistic multidrug resistant human pathogens, plant growth-promoting and zinc solubilizing bacteria. They may be of optogenetic interest. Summary: Proteorhodopsins act as light-driven outward proton pumps mainly at neutral and alkaline pH, however, mirror proteorhodopsins are known to operate only at acidic pH. Here, the authors report the detailed structural and functional characterization of pH mirror proteorhodopsin SpaR as well as its diverse biological roles. [ABSTRACT FROM AUTHOR]

Pain therapy has remained conceptually stagnant since the opioid crisis, which highlighted the dangers of treating pain with opioids. An alternative addiction-free strategy to conventional painkiller-based treatment is targeting receptors at the origin of the pain pathway, such as transient receptor potential (TRP) ion channels. Thus, a founding member of the vanilloid subfamily of TRP channels, TRPV1, represents one of the most sought-after pain therapy targets. The need for selective TRPV1 inhibitors extends beyond pain treatment, to other diseases associated with this channel, including psychiatric disorders. Here we report the cryo-electron microscopy structures of human TRPV1 in the apo state and in complex with the TRPV1-specific nanomolar-affinity analgesic antagonist SB-366791. SB-366791 binds to the vanilloid site and acts as an allosteric hTRPV1 inhibitor. SB-366791 binding site is supported by mutagenesis combined with electrophysiological recordings and can be further explored to design new drugs targeting TRPV1 in disease conditions. Small molecules targeting transient receptor potential (TRP) channels might be used to control pain. Here, Neuberger et al. report cryo-EM structures of human TRPV1 in the absence of added ligands or in the presence of the TRPV1-specific antagonist SB-366791, providing insights for the design of new promising analgesics. [ABSTRACT FROM AUTHOR]