The Circadian Clock Component RORA Increases Immunosurveillance in Melanoma by Inhibiting PD-L1 Expression.

Circadian clock perturbation frequently occurs in cancer and facilitates tumor progression by regulating malignant growth and shaping the immune microenvironment. Emerging evidence has indicated that clock genes are disrupted in melanoma and linked to immune escape. Here, we found that the expression of retinoic acid receptor-related orphan receptor-α (RORA) is downregulated in melanoma patients and that patients with higher RORA expression have a better prognosis after immunotherapy. Additionally, RORA was significantly positively correlated with T-cell infiltration and recruitment. Overexpression or activation of RORA stimulated cytotoxic T-cell-mediated antitumor responses. RORA bound to the CD274 promoter and formed an inhibitory complex with HDAC3 to suppress PD-L1 expression. In contrast, the DEAD-box helicase family member DDX3X competed with HDAC3 for binding to RORA, and DDX3X overexpression promoted RORA release from the suppressive complex and thereby increased PD-L1 expression to generate an inhibitory immune environment. The combination of a RORA agonist with an anti-CTLA4 antibody synergistically increased T-cell antitumor immunity in vivo. A score based on the combined expression of HDAC3, DDX3X and RORA correlated with immunotherapy response in melanoma patients. Together, this study elucidates a mechanism of clock component-regulated antitumor immunity, which will help inform the use of immunotherapy and lead to improved outcomes for melanoma patients receiving combined therapeutic treatments.

Intrinsic and Extrinsic Contributors to the Cardiac Benefits of Exercise.

Among its many cardiovascular benefits, exercise training improves heart function and protects the heart against age-related decline, pathological stress, and injury. Here, we focus on cardiac benefits with an emphasis on more recent updates to our understanding. While the cardiomyocyte continues to play a central role as both a target and effector of exercise's benefits, there is a growing recognition of the important roles of other, noncardiomyocyte lineages and pathways, including some that lie outside the heart itself. We review what is known about mediators of exercise's benefits-both those intrinsic to the heart (at the level of cardiomyocytes, fibroblasts, or vascular cells) and those that are systemic (including metabolism, inflammation, the microbiome, and aging)-highlighting what is known about the molecular mechanisms responsible.

Graphene-based iron single-atom catalysts for electrocatalytic nitric oxide reduction: a first-principles study.

The electrocatalytic NO reduction reaction (NORR) emerges as an intriguing strategy to convert harmful NO into valuable NH3. Due to their unique intrinsic properties, graphene-based Fe single-atom catalysts (SACs) have gained considerable attention in electrocatalysis, while their potential for NORR and the underlying mechanism remain to be explored. Herein, using constant-potential density functional theory calculations, we systematically investigated the electrocatalytic NORR on the graphene-based Fe SACs. By changing the local coordination environment of Fe single atoms, 26 systems were constructed. Theoretical results show that, among these systems, the Fe SAC coordinated with four pyrrole N atoms and that co-coordinated with three pyridine N atoms and one O atom exhibit excellent NORR activity with low limiting potentials of -0.26 and -0.33 V, respectively, as well as have high selectivity toward NH3 by inhibiting the formation of byproducts, especially under applied potential. Furthermore, electronic structure analyses indicate that NO molecules can be effectively adsorbed and activated via the electron "donation-backdonation" mechanism. In particular, the d-band center of the Fe SACs was identified as an efficient catalytic activity descriptor for NORR. Our work could stimulate and guide the experimental exploration of graphene-based Fe SACs for efficient NORR toward NH3 under ambient conditions.

Simplified expression for transverse mode instability threshold in high power fiber lasers.

In this work, we propose an analytical expression for calculating the transverse mode instability (TMI) threshold power, which clearly shows the role of various fiber parameters and system parameters. The TMI threshold expression is obtained by solving the heat conduction equation and the nonlinear coupling equation using the fundamental mode fitted by Gaussian functions. The calculation results of the proposed TMI threshold expression are consistent with the experimental phenomena and simulation results from the well-recognized theoretical model. The influence of some special parameters on the TMI threshold and the power scaling is also investigated. This work will be helpful for fiber design and TMI mitigation of high-power fiber lasers.

Unlocking the dark matter: noncoding RNAs and RNA modifications in cardiac aging.

Cardiac aging is a multifaceted process that encompasses structural and functional alterations culminating in heart failure. As the elderly population continues to expand, there is a growing urgent need for interventions to combat age-related cardiac functional decline. Noncoding RNAs have emerged as critical regulators of cellular and biochemical processes underlying cardiac disease. This review summarizes our current understanding of how noncoding RNAs function in the heart during aging, with particular emphasis on mechanisms of RNA modification that control their activity. Targeting noncoding RNAs as potential novel therapeutics in cardiac aging is also discussed.

Serum proteome profiling reveals heparanase as a candidate biomarker for chronic thromboembolic pulmonary hypertension.

Determining novel biomarkers for early identification of chronic thromboembolic pulmonary hypertension (CTEPH) could improve patient outcomes. We used the isobaric tag for relative and absolute quantitation approach to compare the serum protein profiles between CTEPH patients and the controls. Bioinformatics analyses and ELISA were also performed. We identified three proteins including heparanase (HPSE), gelsolin (GSN), and secreted protein acidic and rich in cysteine (SPARC) had significant changes in CTEPH. The receiver operating characteristic curve analysis showed that the areas under the curve of HPSE in CTEPH diagnosis were 0.988. Furthermore, HPSE was correlated with multiple parameters of right ventricular function. HPSE concentrations were significantly higher in patients with a low TAPSE/sPAP ratio (≤0.31 mm/mmHg) (65.4 [60.5,68.0] vs. 59.9 [35.9,63.2] ng/mL, p < 0.05). The CTEPH patients treated by balloon pulmonary angioplasty had significantly lower HPSE levels. The study demonstrates that HPSE may be a promising biomarker for noninvasive detection of CTEPH.

Interfacial Engineering of Zn Metal via a Localized Conjugated Layer for Highly Reversible Aqueous Zinc Ion Battery.

Aqueous zinc-ion batteries are regarded as promising and efficient energy storage systems owing to remarkable safety and satisfactory capacity. Nevertheless, the instability of zinc metal anodes, characterized by issues such as dendrite growth and parasitic side reactions, poses a significant barrier to widespread applications. Herein, we address this challenge by designing a localized conjugated structure comprising a cyclic polyacrylonitrile polymer (CPANZ), induced by a Zn2+-based Lewis acid (zinc trifluoromethylsulfonate) at a temperature of 120 °C. The CPANZ layer on the Zn anode, enriched with appropriate pyridine nitrogen-rich groups (conjugated cyclic -C=N-), exhibits a notable affinity for Zn2+ with ample deposition sites. This zincophilic skeleton not only serves as a protective layer to guide the deposition of Zn2+ but also functions as proton channel blocker, regulating the proton flux to mitigate the hydrogen evolution. Additionally, the strong adhesion strength of the CPANZ layer guarantees its sustained protection to the Zn metal during long-term cycling. As a result, the modified zinc electrode demonstrates long cycle life and high durability in both half-cell and pouch cells. These findings present a feasible approach to designing high performance aqueous anodes by introducing a localized conjugated layer.

Safety and efficacy of balloon pulmonary angioplasty for technically operable chronic thromboembolic pulmonary hypertension.

Balloon pulmonary angioplasty (BPA) has been proven effective for addressing technically inoperable chronic thromboembolic pulmonary hypertension (CTEPH). However, the effectiveness of BPA in technically operable CTEPH patients who, for various reasons, did not undergo the procedure remains an area requiring exploration. This study sought to assess the safety and efficacy of BPA in such cases. We collected and reviewed data from CTEPH patients who underwent BPA in a consecutive manner. Following multidisciplinary team (MDT) decisions, patients were classified into two groups: technically inoperable (group A) and operable (group B). Group B comprised patients deemed technically suitable for pulmonary endarterectomy (PEA) but who did not undergo the procedure for various reasons. All patients underwent a comprehensive diagnostic work-up, including right heart categorization at baseline and the last intervention. This study compared changes in hemodynamic parameters, functional capacity, and quality of life between the two groups. In total, 161 patients underwent 414 procedures at our center, with Group A comprising 112 patients who underwent 282 BPA sessions and group B comprising 49 patients who underwent 132 BPA sessions. Significantly, both groups exhibited improvements in hemodynamics, functional capacity, and quality of life. The occurrence rate of complications, including hemoptysis and lung injury, was similar [12 (63.2%) vs. 7 (36.8%), p = 0.68]. BPA demonstrated favorable outcomes in patients with proximal CTEPH who did not undergo pulmonary endarterectomy. However, the clinical impact of BPA in technically operable CTEPH was found to be less significant than in inoperable cases.

Thermal multiferroics in all-inorganic quasi-two-dimensional halide perovskites.

Multiferroic materials, particularly those possessing simultaneous electric and magnetic orders, offer a platform for design technologies and to study modern physics. Despite the substantial progress and evolution of multiferroics, one priority in the field remains to be the discovery of unexplored materials, especially those offering different mechanisms for controlling electric and magnetic orders1. Here we demonstrate the simultaneous thermal control of electric and magnetic polarizations in quasi-two-dimensional halides (K,Rb)3Mn2Cl7, arising from a polar-antipolar transition, as evidenced using both X-ray and neutron powder diffraction data. Our density functional theory calculations indicate a possible polarization-switching path including a strong coupling between the electric and magnetic orders in our halide materials, suggesting a magnetoelectric coupling and a situation not realized in oxide analogues. We expect our findings to stimulate the exploration of non-oxide multiferroics and magnetoelectrics to open access to alternative mechanisms, beyond conventional electric and magnetic control, for coupling ferroic orders.

Interpretable machine learning-assisted screening of perovskite oxides.

Perovskite oxides are extensively utilized in energy storage and conversion. However, they are conventionally screened via time-consuming and cost-intensive experimental approaches and density functional theory. Herein, interpretable machine learning is applied to identify perovskite oxides from virtual perovskite-type combinations by constructing classification and regression models to predict their thermodynamic stability and energy above the convex hull (Eh), respectively, and interpreting the models using SHapley Additive exPlanations. The highest occupied molecular orbital energy and the elastic modulus of the B-site elements of perovskite oxides are the top two features for stability prediction, whereas the Stability Label and features involving the elastic modulus and ionic radius are crucial for Eh regression. A classification model, which displays an accuracy of 0.919, precision of 0.937, F1-score of 0.932, and recall of 0.935, screens 682 143 stable perovskite oxides from 1 126 668 virtual perovskite-type combinations. The Eh values of the predicted stable perovskites are forecasted by a regression model with a coefficient of determination of 0.916, and root mean square error of 24.2 meV atom-1. Good agreement is observed between the regression model predicted and density functional theory-calculated Eh values.

miR-222 inhibits pathological cardiac hypertrophy and heart failure.

AIMS: Physiological cardiac hypertrophy occurs in response to exercise and can protect against pathological stress. In contrast, pathological hypertrophy occurs in disease and often precedes heart failure. The cardiac pathways activated in physiological and pathological hypertrophy are largely distinct. Our prior work demonstrated that miR-222 increases in exercised hearts and is required for exercise-induced cardiac hypertrophy and cardiomyogenesis. Here, we sought to define the role of miR-222 in pathological hypertrophy. METHODS AND RESULTS: We found that miR-222 also increased in pathological hypertrophy induced by pressure overload. To assess its functional significance in this setting, we generated a miR-222 gain-of-function model through cardiac-specific constitutive transgenic miR-222 expression (TgC-miR-222) and used locked nucleic acid anti-miR specific for miR-222 to inhibit its effects. Both gain- and loss-of-function models manifested normal cardiac structure and function at baseline. However, after transverse aortic constriction (TAC), miR-222 inhibition accelerated the development of pathological hypertrophy, cardiac dysfunction, and heart failure. Conversely, miR-222-overexpressing mice had less pathological hypertrophy after TAC, as well as better cardiac function and survival. We identified p53-up-regulated modulator of apoptosis, a pro-apoptotic Bcl-2 family member, and the transcription factors, Hmbox1 and nuclear factor of activated T-cells 3, as direct miR-222 targets contributing to its roles in this context. CONCLUSION: While miR-222 is necessary for physiological cardiac growth, it inhibits cardiac growth in response to pressure overload and reduces adverse remodelling and cardiac dysfunction. These findings support the model that physiological and pathological hypertrophy are fundamentally different. Further, they suggest that miR-222 may hold promise as a therapeutic target in pathological cardiac hypertrophy and heart failure.

Oriented polyaniline/poly-l-lactic acid/gelatin nanofiber scaffolds promote outgrowth of spiral ganglion neurons.

Sensorineural hearing loss (SNHL) is caused by the loss of sensory hair cells (HCs) and/or connected spiral ganglion neurons (SGNs). The current clinical conventional treatment for SNHL is cochlear implantation (CI). The principle of CI is to bypass degenerated auditory HCs and directly electrically stimulate SGNs to restore hearing. However, the effectiveness of CI is limited when SGNs are severely damaged. In the present study, oriented nanofiber scaffolds were fabricated using electrospinning technology to mimic the SGN spatial microenvironment in the inner ear. Meanwhile, different proportions of polyaniline (PANI), poly-l-lactide (PLLA), gelatin (Gel) were composited to mimic the composition and mechanical properties of auditory basement membrane. The effects of oriented PANI/PLLA/Gel biomimetic nanofiber scaffolds for neurite outgrowth were analyzed. The results showed the SGNs grew in an orientation along the fiber direction, and the length of the protrusions increased significantly on PANI/PLLA/Gel scaffold groups. The 2% PANI/PLLA/Gel group showed best effects for promoting SGN adhesion and nerve fiber extension. In conclusion, the biomimetic oriented nanofiber scaffolds can simulate the microenvironment of SGNs as well as promote neurite outgrowth in vitro, which may provide a feasible research idea for SGN regeneration and even therapeutic treatments of SNHL in future.

A comprehensive multimodal dataset for contactless lip reading and acoustic analysis.

Small-scale motion detection using non-invasive remote sensing techniques has recently garnered significant interest in the field of speech recognition. Our dataset paper aims to facilitate the enhancement and restoration of speech information from diverse data sources for speakers. In this paper, we introduce a novel multimodal dataset based on Radio Frequency, visual, text, audio, laser and lip landmark information, also called RVTALL. Specifically, the dataset consists of 7.5 GHz Channel Impulse Response (CIR) data from ultra-wideband (UWB) radars, 77 GHz frequency modulated continuous wave (FMCW) data from millimeter wave (mmWave) radar, visual and audio information, lip landmarks and laser data, offering a unique multimodal approach to speech recognition research. Meanwhile, a depth camera is adopted to record the landmarks of the subject's lip and voice. Approximately 400 minutes of annotated speech profiles are provided, which are collected from 20 participants speaking 5 vowels, 15 words, and 16 sentences. The dataset has been validated and has potential for the investigation of lip reading and multimodal speech recognition.

Large-capacity AC superimposed DC power supply for the degradation evaluation of DC-link capacitors.

The DC-link capacitor, whose operating voltage is a periodic irregular waveform, is a key device in the converter. A large-capacity DC/AC superimposed experimental power supply above 100 kVA is an important piece of equipment that must be used in the aging research of DC-link capacitors. The irregular periodic operating voltage of the DC support capacitor is equivalent in the form of DC voltage superimposed with multiple harmonics based on the Fast Fourier transform analysis. The power supply is mainly divided into four parts: an AC module, a DC module, a protection module, and an isolation component. The composited harmonics are output by the IGBT (Insulated Gate Bipolar Transistor) inverter of the AC module. The soft start method is applied to the AC module in order to ensure the long-term reliable operation of the power supply. The kV-level high-voltage is output by four inverter units connected in series. The amplitude and phase control of harmonic decomposition is adopted, and the inverter is controlled by Sinusoidal Pulse Width Modulation. The output voltage of the power supply is close to the operating voltage of the capacitor. Based on the designed power supply, the degradation experiment was carried out. The temperature rise and aging characteristics of DC-link capacitors under different AC/DC ratios were studied.

Machine Learning Confirms the Formation Mechanism of a Single-Atom Catalyst via Infrared Spectroscopic Analysis.

Single-atom catalysts (SACs) offer significant potential across various applications, yet our understanding of their formation mechanism remains limited. Notably, the pyrolysis of zeolitic imidazolate frameworks (ZIFs) stands as a pivotal avenue for SAC synthesis, of which the mechanism can be assessed through infrared (IR) spectroscopy. However, the prevailing analysis techniques still rely on manual interpretation. Here, we report a machine learning (ML)-driven analysis of the IR spectroscopy to unravel the pyrolysis process of Pt-doped ZIF-67 to synthesize Pt-Co3O4 SAC. Demonstrating a total Pearson correlation exceeding 0.7 with experimental data, the algorithm provides correlation coefficients for the selected structures, thereby confirming crucial structural changes with time and temperature, including the decomposition of ZIF and formation of Pt-O bonds. These findings reveal and confirm the formation mechanism of SACs. As demonstrated, the integration of ML algorithms, theoretical simulations, and experimental spectral analysis introduces an approach to deciphering experimental characterization data, implying its potential for broader adoption.

Carbamazepine regulates USP10 through miR-20a-5p to affect the deubiquitination of SKP2 and inhibit osteogenic differentiation.

BACKGROUND: Antiepileptic drugs (AEDs) harm bone health and are significantly associated with osteoporosis development. In this study, we aimed to explore the mechanisms involved in carbamazepine (CBZ) and microRNA (miR)-20a-5p/ubiquitin-specific peptidase 10 (USP10)/S-phase kinase-associated protein 2 (SKP2) axis in osteoporosis. METHODS: Human bone marrow mesenchymal stem cells (BMSCs) were treated with different concentrations of CBZ. Knocking down or overexpressing miR-20a-5p, USP10, and SKP2 cell lines were constructed. The expressions of miR-20a-5p, USP10, SKP2, runt-related transcription factor 2 (Runx2), Alkaline phosphatase (ALP), Osterix (Osx), osteocalcin (OCN) and Collagen I were detected with western blot (WB) and reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR). Alizarin Red S (ARS) staining was performed to measure calcium deposition. Dual-luciferase assay and RNA immunoprecipitation (RIP) were applied to verify the binding relationship between miR-20a-5p and USP10. USP10 and SKP2 combination was verified by Co-Immunopurification (Co-IP). The stability of the SKP2 protein was verified by Cycloheximide chase assay. RESULTS: CBZ could reduce cell activity. ALP activity and ARS staining were enhanced in the osteogenic induction (OM) group. The expressions of Runx2, ALP, Osx, OCN and Collagen I were increased. CBZ reduced miR-20a-5p expressions. Verification experiments showed miR-20a-5p could target USP10. USP10 increased SKP2 stability and promoted SKP2 expression. CBZ regulated miR-20a-5p/USP10/SPK2 and inhibited BMSCs osteogenic differentiation. CONCLUSIONS: CBZ regulated USP10 through miR-20a-5p to affect the deubiquitination of SKP2 and inhibit osteogenic differentiation, which provided a new idea for osteoporosis treatment.

Berberine protects against neomycin-induced ototoxicity by reducing ROS generation and activating the PI3K/AKT pathway.

In mammals, aminoglycoside antibiotic-induced injury to hair cells (HCs) and associated spiral ganglion neurons (SGNs) is irreversible and eventually leads to permanent hearing loss. Efforts have been directed towards the advancement of efficacious therapeutic treatments to protect hearing loss, but the ideal substance for treating the damaged cochlear sensory epithelium has yet to be identified. Berberine (BBR), a quaternary ammonium hydroxide extracted from Coptis chinensis, has been found to display potential anti-oxidant and neuroprotective properties. However, its involvement in aminoglycoside antibiotic-induced ototoxicity has yet to be explored or assessed. In the present study, we explored the possible anti-oxidative properties of BBR in mitigating neomycin-triggered ototoxicity. An improved survival of HCs and SGN nerve fibers (NFs) in organ of Corti (OC) explants after neomycin with BBR co-treatment was observed, and BBR treatment attenuated reactive oxygen species (ROS) generation and reduced cleaved caspase-3 signaling by activating six phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling relative subtypes, and the addition of PI3K/AKT suppressor LY294002 resulted in a decrease in the protective effect. The protective effect of BBR against ototoxicity was also evident in a neomycin-injured animal model, as evidenced by the preservation of HC and SGN in mice administered subcutaneous BBR for 7 days. In summary, all results suggest that BBR has potential as a new and effective otoprotective agent, operating via the PI3K/AKT signaling pathway.

Large Perpendicular Magnetic Anisotropy Induced by an Intersite Charge Transfer in Strained EuVO2H Films.

Perovskite oxides ABO3 continue to be a major focus in materials science. Of particular interest is the interplay between A and B cations as exemplified by intersite charge transfer (ICT), which causes novel phenomena including negative thermal expansion and metal-insulator transition. However, the ICT properties were achieved and optimized by cationic substitution or ordering. Here we demonstrate an anionic approach to induce ICT using an oxyhydride perovskite, EuVO2H, which has alternating layers of EuH and VO2. A bulk EuVO2H behaves as a ferromagnetic insulator with a relatively high transition temperature (TC) of 10 K. However, the application of external pressure to the EuIIVIIIO2H bulk or compressive strain from the substrate in the thin films induces ICT from the EuIIH layer to the VIIIO2 layer due to the extended empty V dxy orbital. The ICT phenomenon causes the VO2 layer to become conductive, leading to an increase in TC that is dependent on the number of carriers in the dxy orbitals (up to a factor of 4 for 10 nm thin films). In addition, a large perpendicular magnetic anisotropy appears with the ICT for the films of <100 nm, which is unprecedented in materials with orbital-free Eu2+, opening new perspectives for applications. The present results provide opportunities for the acquisition of novel functions by alternating transition metal/rare earth layers with heteroanions.

Tailoring the coordination environment of double-atom catalysts to boost electrocatalytic nitrogen reduction: a first-principles study.

Tailoring the coordination environment is an effective strategy to modulate the electronic structure and catalytic activity of atomically dispersed transition-metal (TM) catalysts, which has been widely investigated for single-atom catalysts but received less attention for emerging double-atom catalysts (DACs). Herein, based on first-principles calculations, taking the commonly studied N-coordinated graphene-based DACs as references, we explored the effect of coordination engineering on the catalytic behaviors of DACs towards the electrocatalytic nitrogen reduction reaction (NRR), which is realized through replacing one N atom by the B or O atom to form B, N or O, N co-coordinated DACs. We found that B, N or O, N co-coordination could significantly strengthen N2 adsorption and alter the N2 adsorption pattern of the TM dimer active center, which greatly facilitates N2 activation. Moreover, on the studied DACs, the linear scaling relationship between the binding strengths of key intermediates can be attenuated. Consequently, the O, N co-coordinated Mn2 DACs, exhibiting an ultralow limiting potential of -0.27 V, climb to the peak of the activity volcano. In addition, the experimental feasibility of this DAC system was also identified. Overall, benefiting from the coordination engineering effect, the chemical activity and catalytic performance of the DACs for NRR can be significantly boosted. This phenomena can be understood from the adjusted electronic structure of the TM dimer active center due to the changes of its coordination microenvironment, which significantly affects the binding strength (pattern) of key intermediates and changes the reaction pathways, leading to enhanced NRR activity and selectivity. This work highlights the importance of coordination engineering in developing DACs for the electrocatalytic NRR and other important reactions.