Conformational transitions and activation of the adhesion receptor CD97.

Adhesion G protein-coupled receptors (aGPCRs) are evolutionarily ancient receptors involved in a variety of physiological and pathophysiological processes. Modulators of aGPCR, particularly antagonists, hold therapeutic promise for diseases like cancer and immune and neurological disorders. Hindered by the inactive state structural information, our understanding of antagonist development and aGPCR activation faces challenges. Here, we report the cryo-electron microscopy structures of human CD97, a prototypical aGPCR that plays crucial roles in immune system, in its inactive apo and G13-bound fully active states. Compared with other family GPCRs, CD97 adopts a compact inactive conformation with a constrained ligand pocket. Activation induces significant conformational changes for both extracellular and intracellular sides, creating larger cavities for Stachel sequence binding and G13 engagement. Integrated with functional and metadynamics analyses, our study provides significant mechanistic insights into the activation and signaling of aGPCRs, paving the way for future drug discovery efforts.

Phase separation of PML/RARα and BRD4 coassembled microspeckles governs transcriptional dysregulation in acute promyelocytic leukemia.

In acute promyelocytic leukemia (APL), the promyelocytic leukemia-retinoic acid receptor alpha (PML/RARα) fusion protein destroys PML nuclear bodies (NBs), leading to the formation of microspeckles. However, our understanding, largely learned from morphological observations, lacks insight into the mechanisms behind PML/RARα-mediated microspeckle formation and its role in APL leukemogenesis. This study presents evidence uncovering liquid-liquid phase separation (LLPS) as a key mechanism in the formation of PML/RARα-mediated microspeckles. This process is facilitated by the intrinsically disordered region containing a large portion of PML and a smaller segment of RARα. We demonstrate the coassembly of bromodomain-containing protein 4 (BRD4) within PML/RARα-mediated condensates, differing from wild-type PML-formed NBs. In the absence of PML/RARα, PML NBs and BRD4 puncta exist as two independent phases, but the presence of PML/RARα disrupts PML NBs and redistributes PML and BRD4 into a distinct phase, forming PML/RARα-assembled microspeckles. Genome-wide profiling reveals a PML/RARα-induced BRD4 redistribution across the genome, with preferential binding to super-enhancers and broad-promoters (SEBPs). Mechanistically, BRD4 is recruited by PML/RARα into nuclear condensates, facilitating BRD4 chromatin binding to exert transcriptional activation essential for APL survival. Perturbing LLPS through chemical inhibition (1, 6-hexanediol) significantly reduces chromatin co-occupancy of PML/RARα and BRD4, attenuating their target gene activation. Finally, a series of experimental validations in primary APL patient samples confirm that PML/RARα forms microspeckles through condensates, recruits BRD4 to coassemble condensates, and co-occupies SEBP regions. Our findings elucidate the biophysical, pathological, and transcriptional dynamics of PML/RARα-assembled microspeckles, underscoring the importance of BRD4 in mediating transcriptional activation that enables PML/RARα to initiate APL.

The adaptive mechanisms of the marine diatom Thalassiosira weissflogii to long-term high CO2 and warming.

While it is known that increased dissolved CO2 concentrations and rising sea surface temperature (ocean warming) can act interactively on marine phytoplankton, the ultimate molecular mechanisms underlying this interaction on a long-term evolutionary scale are relatively unexplored. Here, we performed transcriptomics and quantitative metabolomics analyses, along with a physiological trait analysis, on the marine diatom Thalassiosira weissflogii adapted for approximately 3.5 years to warming and/or high CO2 conditions. We show that long-term warming has more pronounced impacts than elevated CO2 on gene expression, resulting in a greater number of differentially expressed genes (DEGs). The largest number of DEGs was observed in populations adapted to warming + high CO2, indicating a potential synergistic interaction between these factors. We further identified the metabolic pathways in which the DEGs function and the metabolites with significantly changed abundances. We found that ribosome biosynthesis-related pathways were upregulated to meet the increased material and energy demands after warming or warming in combination with high CO2. This resulted in the upregulation of energy metabolism pathways such as glycolysis, photorespiration, the tricarboxylic acid cycle, and the oxidative pentose phosphate pathway, as well as the associated metabolites. These metabolic changes help compensate for reduced photochemical efficiency and photosynthesis. Our study emphasizes that the upregulation of ribosome biosynthesis plays an essential role in facilitating the adaptation of phytoplankton to global ocean changes and elucidates the interactive effects of warming and high CO2 on the adaptation of marine phytoplankton in the context of global change.

RUNX1::ETO and CBFß::MYH11 converge on aberrant activation of BCAT1 to confer a therapeutic vulnerability in core-binding factor-acute myeloid leukaemia.

Effectively targeting transcription factors in therapeutic interventions remains challenging, especially in core-binding factor-acute myeloid leukaemia (CBF-AML) characterized by RUNX1::ETO and CBFß::MYH11 fusions. However, recent studies have drawn attention towards aberrant amino acid metabolisms as actionable therapeutic targets. Here, by integrating the expression profile and genetic makeup in AML cohort, we found higher BCAT1 expression in CBF-AML patients compared with other subtypes. Metabolic profiling revealed that high BCAT1 expression led to reprogrammed branch amino acid metabolism in CBF-AML and was associated with sphingolipid pathway relating to the fitness of leukaemia cells, supported by transcriptomic profiling. Mechanistically, we demonstrated in cell lines and primary patient samples that BCAT1 was directly activated by RUNX1::ETO and CBFß::MYH11 fusion proteins similarly in a RUNX1-dependent manner through rewiring chromatin conformation at the BCAT1 gene locus. Furthermore, BCAT1 inhibition resulted in blunted cell cycle, enhanced apoptosis and myeloid differentiation of CBF-AML cells in vitro, and alleviated leukaemia burden and prolonged survival in vivo. Importantly, pharmacological inhibition of BCAT1 using the specific inhibitor Gabapentin demonstrated therapeutic effects, as evidenced by delayed leukaemia progression and improved survival in vivo. In conclusion, our study uncovers BCAT1 as a genetic vulnerability and a promising targeted therapeutic opportunity for CBF-AML.

Unraveling the rhizobial infection thread.

Most legumes can form an endosymbiotic association with soil bacteria called rhizobia, which colonize specialized root structures called nodules where they fix nitrogen. To colonize nodule cells, rhizobia must first traverse the epidermis and outer cortical cell layers of the root. In most legumes, this involves formation of the infection thread, an intracellular structure that becomes colonized by rhizobia, guiding their passage through the outer cell layers of the root and into the newly formed nodule cells. In this brief review, we recount the early research milestones relating to the rhizobial infection thread and highlight two relatively recent advances in the symbiotic infection mechanism, the eukaryotically conserved 'MYB-AUR1-MAP' mitotic module, which links cytokinesis mechanisms to intracellular infection, and the discovery of the 'infectosome' complex, which guides infection thread growth. We also discuss the potential intertwining of the two modules and the hypothesis that cytokinesis served as a foundation for intracellular infection of symbiotic microbes.

Independent ultrahigh-Q dual-band resonances via coating a resonator on a BIC-driven metasurface.

Traditional designs driven by symmetry-protected bound states in the continuum (SP-BICs) hardly support independent dual-band resonances, and they require extremely small perturbations to obtain an ultrahigh-Q. Here, we propose an SP-BIC-driven structure composed of a metasurface and a resonator, which supports independent dual-band resonances and enables ultrahigh-Q at large perturbations. The underlying mechanism enabling this is to form reasonable eigenfield distributions of two BICs by coating a dielectric layer on the metasurface. One eigenfield is confined within the metasurface and the bottom of the resonator, while the other one concentrates at the top of the resonator. Thus, two resonances with different originations can be supported, and the effect of metasurface perturbations on the eigenfields is weakened. This work provides a promising pathway for unlocking the potential of SP-BICs, enhancing light trapping and manipulation across diverse applications.

Manipulation and applications of ultrafast all-optical switching based on transient absorption and dispersion in KTN crystals.

Potassium tantalate niobate (KTN) represents a noteworthy category of optical crystals known for their superior nonlinear optical properties. In this study, we conducted measurements of femtosecond time-resolved transient absorption (TA) spectra in KTa0.57Nb0.43O3 crystals. Notably, a rapid and pronounced "plateau" phase, ∼1.5 ps in duration, was detected at the onset of the TA kinetics and succeeded by two distinct decay components, exhibiting lifetimes of ∼140 ps and over 10 ns, respectively. We attribute these observations to a decay process involving two-photon absorption, dispersion characteristics, and excited state absorption. Based on this unique TA characteristic of KTN crystals, an all-optical switching strategy was proposed and utilized to measure the ultrafast lasing dynamics of single-crystal CH3NH3PbBr3 nanowires. This polarization-independent TA gate approach offers an adjustable gate width combining ps and ns time scales and introduces a versatile tool for advanced optical applications.

Quantum Light Generation Based on GaN Microring toward Fully On-Chip Source.

An integrated quantum light source is increasingly desirable in large-scale quantum information processing. Despite recent remarkable advances, a new material platform is constantly being explored for the fully on-chip integration of quantum light generation, active and passive manipulation, and detection. Here, for the first time, we demonstrate a gallium nitride (GaN) microring based quantum light generation in the telecom C-band, which has potential toward the monolithic integration of quantum light source. In our demonstration, the GaN microring has a free spectral range of 330 GHz and a near-zero anomalous dispersion region of over 100 nm. The generation of energy-time entangled photon pair is demonstrated with a typical raw two-photon interference visibility of 95.5±6.5%, which is further configured to generate a heralded single photon with a typical heralded second-order autocorrelation g_{H}^{(2)}(0) of 0.045±0.001. Our results pave the way for developing a chip-scale quantum photonic circuit.

Model-based precision dosing and remedial dosing recommendations for delayed or missed doses of isoniazid in Chinese patients with tuberculosis.

AIMS: Isoniazid (INH) has been used as a first-line drug to treat tuberculosis (TB) for more than 50 years. However, large interindividual variability was found in its pharmacokinetics, and effects of nonadherence to INH treatment and corresponding remedy regime remain unclear. This study aimed to develop a population pharmacokinetic (PPK) model of INH in Chinese patients with TB to provide model-informed precision dosing and explore appropriate remedial dosing regimens for nonadherent patients. METHODS: In total, 1012 INH observations from 736 TB patients were included. A nonlinear mixed-effects modelling was used to analyse the PPK of INH. Using Monte Carlo simulations to determine optimal dosage regimens and design remedial dosing regimens. RESULTS: A 2-compartmental model, including first-order absorption and elimination with allometric scaling, was found to best describe the PK characteristics of INH. A mixture model was used to characterize dual rates of INH elimination. Estimates of apparent clearance in fast and slow eliminators were 28.0 and 11.2 L/h, respectively. The proportion of fast eliminators in the population was estimated to be 40.5%. Monte Carlo simulations determined optimal dosage regimens for slow and fast eliminators with different body weight. For remedial dosing regimens, the missed dose should be taken as soon as possible when the delay does not exceed 12 h, and an additional dose is not needed. delay for an INH dose exceeds 12 h, the patient only needs to take the next single dose normally. CONCLUSION: PPK modelling and simulation provide valid evidence on the precision dosing and remedial dosing regimen of INH.

Host-Host Interactions Enhanced the Structural Rigidity in a 6-Fold Interpenetrated Diamondoid Metal-Organic Framework Exhibiting C2H2/C2H4 Separation.

Multi-interpenetrated metal-organic frameworks (MOFs) have exhibited excellent performance in selective adsorption due to the variable post-interspersed flexibility, but the design and control remain challenging. Herein, two anthracene-based ligands, 4,4'-(anthracene-9,10-diyl)dibenzoic acid (H2L1) and 9,10-di(pyridin-4-yl)anthracene (L2), are used to construct a new three-dimensional 6-fold interpenetrated MOF [Zn(L1)(L2)]n (NBU-X1), which exhibits multiple C-H···π interactions that enhance the structural rigidity, thereby entangling with a C2H2/C2H4 separation performance. In this material, the incorporation of abundant anthracene rings within the framework not only partitions and restricts the pore window size to a quasi-double pore but also stabilizes it through host-host interactions. The structural stability upon heating or guest displacement/removal has been investigated by single-crystal X-ray diffraction and in situ variable-temperature powder X-ray diffraction, in contrast to the extreme flexibility of most multi-interpenetrated MOFs. The performance of purifying C2H4 from C2H2/C2H4 mixtures has been proved by dynamic breakthrough tests.

Off-axis bifocal metalens for displacement measurement.

Metasurface is a new type of micro-optical element developed in recent years. It can intelligently modulate electromagnetic waves by adjusting the geometrical parameters and arrangement of dielectric structures. In this paper, a bifocal metalens based on modulation of propagation phase was designed for the potential application in displacement measurement. The phase of the bifocal lens is designed by the optical holography-like method, which is verified by the scalar diffraction theory. We designed a square aperture lens with a side length of 200µm to realize two focal spots with focal lengths of 900 and 1100µm. The two focal spots aren't on one optical axis. The polarization insensitive TiO2cylinders are chosen as structure units. Four structures with different radius were selected to achieve the four phase steps. We fabricated the designed bifocal metalens using electron beam lithography and atomic layer deposition techniques, and measured the light intensity in the areas near the two foci in the direction of the longitudinal axis. The differential signal was calculated, from which we obtained a linear interval. It demonstrates the ability of bifocal differential measurement to be applied to displacement measurement. Because the metasurfaces production process is semiconductor compatible, the bifocal lens is easy to integrate and can be used for miniaturized displacement measurements, micro-resonators, acceleration measurements, and so on.

The effect of incorporating domain knowledge with deep learning in identifying benign and malignant gastric whitish lesions: A retrospective study.

BACKGROUND AND AIM: Early whitish gastric neoplasms can be easily misdiagnosed; differential diagnosis of gastric whitish lesions remains a challenge. We aim to build a deep learning (DL) model to diagnose whitish gastric neoplasms and explore the effect of adding domain knowledge in model construction. METHODS: We collected 4558 images from two institutions to train and test models. We first developed two sole DL models (1 and 2) using supervised and semi-supervised algorithms. Then we selected diagnosis-related features through literature research and developed feature-extraction models to determine features including boundary, surface, roundness, depression, and location. Then predictions of the five feature-extraction models and sole DL model were combined and inputted into seven machine-learning (ML) based fitting-diagnosis models. The optimal model was selected as ENDOANGEL-WD (whitish-diagnosis) and compared with endoscopists. RESULTS: Sole DL 2 had higher sensitivity (83.12% vs 68.67%, Bonferroni adjusted P = 0.024) than sole DL 1. Adding domain knowledge, the decision tree performed best among the seven ML models, achieving higher specificity than DL 1 (84.38% vs 72.27%, Bonferroni adjusted P < 0.05) and higher accuracy than DL 2 (80.47%, Bonferroni adjusted P < 0.001) and was selected as ENDOANGEL-WD. ENDOANGEL-WD showed better accuracy compared with 10 endoscopists (75.70%, P < 0.001). CONCLUSIONS: We developed a novel system ENDOANGEL-WD combining domain knowledge and traditional DL to detect gastric whitish neoplasms. Adding domain knowledge improved the performance of traditional DL, which provided a novel solution for establishing diagnostic models for other rare diseases potentially.

Planting halophytes increases the rhizosphere ecosystem multifunctionality via reducing soil salinity.

Soil salinization poses a significant global challenge, exerting adverse effects on both agriculture and ecosystems. Planting halophytes has the potential ability to improve saline-alkali land and enhance ecosystem multifunctionality (EMF). However, it remains unclear which halophytes are effective in improving saline-alkali land and what impact they have on the rhizosphere microbial communities and EMF. In this study, we evaluated the Na+ absorption capability of five halophytes (Grubovia dasyphylla, Halogeton glomeratus, Suaeda salsa, Bassia scoparia, and Reaumuria songarica) and assessed their rhizosphere microbial communities and EMF. The results showed that S. salsa possessed the highest shoot (3.13 mmol g-1) and root (0.92 mmol g-1) Na+ content, and its soil Na+ absorption, along with B. scoparia, was significantly higher than that of other plants. The soil pH, salinity, and Na+ content of the halophyte rhizospheres decreased by 6.21%, 23.49%, and 64.29%, respectively, when compared to the bulk soil. Extracellular enzymes in the halophyte rhizosphere soil, including α-glucosidase, ß-glucosidase, ß-1,4-N-acetyl-glucosaminidase, neutral phosphatase, and alkaline phosphatase, increased by 70.1%, 78.4%, 38.5%, 79.1%, and 64.9%, respectively. Furthermore, the halophyte rhizosphere exhibited higher network complexity of bacteria and fungi and EMF than bulk soil. The relative abundance of the dominant phyla Proteobacteria, Firmicutes, and Ascomycota in the halophyte rhizosphere soil increased by 9.4%, 8.3%, and 22.25%, respectively, and showed higher microbial network complexity compared to the bulk soil. Additionally, keystone taxa, including Muricauda, Nocardioides, and Pontibacter, were identified with notable effects on EMF. This study confirmed that euhalophytes are the best choice for saline-alkali land restoration. These findings provided a theoretical basis for the sustainable use of saline-alkali cultivated land.

Oral administration of Robinia pseudoacacia L. flower exosome-like nanoparticles attenuates gastric and small intestinal mucosal ferroptosis caused by hypoxia through inhibiting HIF-1α- and HIF-2α-mediated lipid peroxidation.

The prevention and treatment of gastrointestinal mucosal injury caused by a plateau hypoxic environment is a clinical conundrum due to the unclear mechanism of this syndrome; however, oxidative stress and microbiota dysbiosis may be involved. The Robinia pseudoacacia L. flower, homologous to a functional food, exhibits various pharmacological effects, such as antioxidant, antibacterial, and hemostatic activities. An increasing number of studies have revealed that plant exosome-like nanoparticles (PELNs) can improve the intestinal microbiota and exert antioxidant effects. In this study, the oral administration of Robinia pseudoacacia L. flower exosome-like nanoparticles (RFELNs) significantly ameliorated hypoxia-induced gastric and small intestinal mucosal injury in mice by downregulating hypoxia-inducible factor-1α (HIF-1α) and HIF-2α expression and inhibiting hypoxia-mediated ferroptosis. In addition, oral RFELNs partially improved hypoxia-induced microbial and metabolic disorders of the stomach and small intestine. Notably, RFELNs displayed specific targeting to the gastrointestinal tract. In vitro experiments using gastric and small intestinal epithelial cell lines showed that cell death caused by elevated HIF-1α and HIF-2α under 1% O2 mainly occurred via ferroptosis. RFELNs obviously inhibited HIF-1α and HIF-2α expression and downregulated the expression of NOX4 and ALOX5, which drive reactive oxygen species production and lipid peroxidation, respectively, suppressing ferroptosis under hypoxia. In conclusion, our findings underscore the potential of oral RFELNs as novel, naturally derived agents targeting the gastrointestinal tract, providing a promising therapeutic approach for hypoxia-induced gastric and small intestinal mucosal ferroptosis.

Mechanism of Ferulic Acid in PI3K/AKT Pathway and Research in Glioblastoma.

Phenolic acids and their analogues in nature exist in many diseases of oxidative stress with beneficial effects on human health (such as cancer). Phenolic acids possess a variety of pharmacological activities, with anti-inflammatory, anticancer and cytotoxic, antioxidant, immunomodulatory, antimicrobial, insecticidal and other biological activities. Numerous in vitro and in vivo studies have shown that because phenolic acids have antioxidant capacity, they can reflect their strong anticancer potential by regulating cell growth and metastasis and promoting cancer cell death. Studies have shown that the consumption of natural polyphenols can significantly reduce the risk of cancer metastasis. A combination of phenolic acids with traditional chemoradiation or other polyphenols may be effective in reducing cancer spread.Ferulic acid is ubiquitous, and widely found in plants, such as angelica, chuanxiong, cohote, three, edge, reed root, tomato, sweet corn, and rice are produced by the metabolism of phenylalanine and tyrosine. It is the most abundant hydroxyl cassia bark-acid acid in the plant kingdom, with anti-inflammatory, antidiabetic, anticancer and antioxidant activity, and polyphenols composed of hydroxyl cassia bark-acid derivatives, flavone-3-alcohol and flavonol retain non-cancer-cells-and-significantly-inhibit glioblastoma viability in a dose-dependent manner, which deserves further investigation as potential anticancer drugs. This paper summarizes the role of ferulic acid in the PI3K / AKT pathway and its mechanism in glioblastoma resistance.

Neurotoxicity from long-term exposure to 6-PPDQ: Recent advances.

The recent acceleration of industrialization and urbanization has brought significant attention to N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6-PPDQ), an emerging environmental pollutant from tire wear, due to its long-term effects on the environment and organisms. Recent studies suggest that 6-PPDQ can disrupt neurotransmitter synthesis and release, impact receptor function, and alter signaling pathways, potentially causing oxidative stress, inflammation, and apoptosis. This review investigates the potential neurotoxic effects of prolonged 6-PPDQ exposure, the mechanisms underlying its cytotoxicity, and the associated health risks. We emphasize the need for future research, including precise exposure assessments, identification of individual differences, and development of risk assessments and intervention strategies. This article provides a comprehensive overview of 6-PPDQ's behavior, impact, and neurotoxicity in the environment, highlighting key areas and challenges for future research.

Green preparation of CaO-based CO2 adsorbent by calcium-induced hydrogenation of shell wastes at room/moderate temperature.

Capturing CO2 using clamshell/eggshell-derived CaO adsorbent can not only reduce carbon emissions but also alleviate the impact of trash on the environment. However, organic acid was usually used, high-temperature calcination was often performed, and CO2 was inevitably released during preparing CaO adsorbents from shell wastes. In this work, CaO-based CO2 adsorbent was greenly prepared by calcium-induced hydrogenation of clamshell and eggshell wastes in one pot at room/moderate temperature. CO2 adsorption experiments were performed in a thermogravimetric analyzer (TGA). The adsorption performance of the adsorbents obtained from the mechanochemical reaction (BM-C/E-CaO) was superior to that of the adsorbents obtained from the thermochemical reaction (Cal-C/E-CaO). The CO2 adsorption capacity of BM-C-CaO at 650 °C is up to 36.82 wt%, but the adsorption decay rate of the sample after 20 carbonation/calcination cycles is only 30.17%. This study offers an alternative energy-saving method for greenly preparing CaO-based adsorbent from shell wastes.

General In Situ Engineering of Carbon-Based Materials on Carbon Fiber for In Vivo Neurochemical Sensing.

Developing real-time, dynamic, and in situ analytical methods with high spatial and temporal resolutions is crucial for exploring biochemical processes in the brain. Although in vivo electrochemical methods based on carbon fiber (CF) microelectrodes are effective in monitoring neurochemical dynamics during physiological and pathological processes, complex post modification hinders large-scale productions and widespread neuroscience applications. Herein, we develop a general strategy for the in situ engineering of carbon-based materials to mass-produce functional CFs by introducing polydopamine to anchor zeolitic imidazolate frameworks as precursors, followed by one-step pyrolysis. This strategy demonstrates exceptional universality and design flexibility, overcoming complex post-modification procedures and avoiding the delamination of the modification layer. This simplifies the fabrication and integration of functional CF-based microelectrodes. Moreover, we design highly stable and selective H+, O2, and ascorbate microsensors and monitor the influence of CO2 exposure on the O2 content of the cerebral tissue during physiological and ischemia-reperfusion pathological processes.