Targeting p97-Npl4 interaction inhibits tumor Treg cell development to enhance tumor immunity.

Targeting tumor-infiltrating regulatory T (TI-Treg) cells is a potential strategy for cancer therapy. The ATPase p97 in complex with cofactors (such as Npl4) has been investigated as an antitumor drug target; however, it is unclear whether p97 has a function in immune cells or immunotherapy. Here we show that thonzonium bromide is an inhibitor of the interaction of p97 and Npl4 and that this p97-Npl4 complex has a critical function in TI-Treg cells. Thonzonium bromide boosts antitumor immunity without affecting peripheral Treg cell homeostasis. The p97-Npl4 complex bridges Stat3 with E3 ligases PDLIM2 and PDLIM5, thereby promoting Stat3 degradation and enabling TI-Treg cell development. Collectively, this work shows an important role for the p97-Npl4 complex in controlling Treg-TH17 cell balance in tumors and identifies possible targets for immunotherapy.

Potential prognostic indicators in dogs with advanced heart failure secondary to myxomatous mitral valve disease.

BACKGROUND: Advanced heart failure (AHF) secondary to myxomatous mitral valve disease (MMVD) in dogs has unclear predictive variables and survival time. METHODS: This retrospective study included 38 dogs with AHF and 38 with stable congestive heart failure (CHF), both due to MMVD. Predictive variables for AHF were analysed, and survival times were calculated using logistic regression and the Kaplan-Meier method. RESULTS: Left atrium to aortic root ratio, normalised left ventricular dimension at the end-diastole and end-systole, isovolumic relaxation time (IVRT) and early transmitral inflow velocity to IVRT ratio were associated with AHF progression. The median survival times were significantly longer in the stable group than in the AHF group. After AHF diagnosis, the median survival times for all-cause and cardiogenic mortality were 194 and 354 days, respectively. LIMITATIONS: This was a single-centre retrospective observational study. The study population was small, with breed bias (overrepresentation of Maltese dogs). Additionally, the treatment plans depended on clinical experience. CONCLUSIONS: AHF in dogs with CHF secondary to MMVD is linked to left heart chamber enlargement and increased left ventricular dimensions, significantly reducing survival time to around six months post-diagnosis. Early recognition and appropriate management may improve outcomes, highlighting the importance of advanced treatment strategies.

Multiple toroidal dipole Fano resonances from quasi-bound states in the continuum in an all-dielectric metasurface.

In this paper, a highly sensitive sensor consisting of a silicon nanorod and symmetric rings (SNSR) is presented. Theoretically, three Fano resonances with high Q-factors are excited in the near-infrared range by breaking the symmetry structure based on quasi-bound states in the continuum (Q-BICs). The electromagnetic near-field analysis confirms that the resonances are mainly controlled by toroidal dipole (TD) resonance. The structure is optimized by adjusting different geometrical parameters, and the maximum Q-factor of the Fano resonances can reach 7427. To evaluate the sensing performance of the structure, the sensitivity and the figure of merit (FOM) are calculated by adjusting the environmental refractive index: the maximum sensitivity of 474 nm/RIU and the maximum FOM of 3306 RIU-1. The SNSR can be fabricated by semiconductor-compatible processes, which is experimentally evaluated for changes in transmission spectra at different solution concentrations. The results show that the sensitivity and the Q-factor of the designed metasurface can reach 295 nm/RIU and 850, while the FOM can reach 235 RIU-1. Therefore, the metasurface of SNSR is characterized by high sensitivity and multi-wavelength sensing, which are current research hotspots in the field of optics and can be applied to biomedical sensing and multi-target detection.

High-Performance Refractive Index and Temperature Sensing Based on Toroidal Dipole in All-Dielectric Metasurface.

This article shows an all-dielectric metasurface consisting of "H"-shaped silicon disks with tilted splitting gaps, which can detect the temperature and refractive index (RI). By introducing asymmetry parameters that excite the quasi-BIC, there are three distinct Fano resonances with nearly 100% modulation depth, and the maximal quality factor (Q-factor) is over 104. The predominant roles of different electromagnetic excitations in three distinct modes are demonstrated through near-field analysis and multipole decomposition. A numerical analysis of resonance response based on different refractive indices reveals a RI sensitivity of 262 nm/RIU and figure of merit (FOM) of 2183 RIU-1. This sensor can detect temperature fluctuations with a temperature sensitivity of 59.5 pm/k. The proposed metasurface provides a novel method to induce powerful TD resonances and offers possibilities for the design of high-performance sensors.

Multi-function sensing applications based on high Q-factor multi-Fano resonances in an all-dielectric metastructure.

A multi-function sensor based on an all-dielectric metastructure for temperature and refractive index sensing simultaneously is designed and analyzed in this paper. The structure is composed of a periodic array of silicon dimers placed on the silicon dioxide substrate. By breaking the symmetry of the structure, the ideal bound states in the continuum can be converted to the quasi-bound states in the continuum, and three Fano resonances are excited in the near-infrared wavelength. Combining with the electromagnetic field distributions, the resonant modes of three Fano resonances are analyzed as magnetic dipole, magnetic toroidal dipole, and electric toroidal dipole, respectively. The proposed sensor exhibits an impressive maximal Q-factor of 9352, with a modulation depth approaching 100%. Our investigation into temperature and refractive index sensing properties reveals a maximum temperature sensitivity of 60 pm/K. Regarding refractive index sensing, the sensitivity and figure of merit are determined to be 279.5 nm/RIU and 2055.1 RIU-1, respectively. These findings underscore the potential of the all-dielectric metastructure for simultaneous multi-parameter measurements. The sensor's versatility suggests promising applications in biological and chemical sensing.

High-Q Fano resonances in all-dielectric metastructures for enhanced optical biosensing applications.

Fano resonance with high Q-factor is considered to play an important role in the field of refractive index sensing. In this paper, we theoretically and experimentally investigate a refractive index sensor with high performance, realizing a new approach to excite multiple Fano resonances of high Q-factor by introducing an asymmetric parameter to generate a quasi-bound state in the continuum (BIC). Combined with the electromagnetic properties, the formation mechanism of Fano resonances in multiple different excitation modes is analyzed and the resonant modes of the three resonant peaks are analyzed as toroidal dipole (TD), magnetic quadrupole (MQ), and magnetic dipole (MD), respectively. The simulation results show that the proposed metastructure has excellent sensing properties with a Q-factor of 3668, sensitivity of 350 nm/RIU, and figure of merit (FOM) of 1000. Furthermore, the metastructure has been fabricated and investigated experimentally, and the result shows that its maximum Q-factor, sensitivity and FOM can reach 634, 233 nm/RIU and 115, respectively. The proposed metastructure is believed to further contribute to the development of biosensors, nonlinear optics, and lasers.

SUN1/2 controls macrophage polarization via modulating nuclear size and stiffness.

Alteration of the size and stiffness of the nucleus triggered by environmental cues are thought to be important for eukaryotic cell fate and function. However, it remains unclear how context-dependent nuclear remodeling occurs and reprograms gene expression. Here we identify the nuclear envelope proteins SUN1/2 as mechano-regulators of the nucleus during M1 polarization of the macrophage. Specifically, we show that LPS treatment decreases the protein levels of SUN1/2 in a CK2-ßTrCP-dependent manner to shrink and soften the nucleus, therefore altering the chromatin accessibility for M1-associated gene expression. Notably, the transmembrane helix of SUN1/2 is solely required and sufficient for the nuclear mechano-remodeling. Consistently, SUN1/2 depletion in macrophages facilitates their phagocytosis, tissue infiltration, and proinflammatory cytokine production, thereby boosting the antitumor immunity in mice. Thus, our study demonstrates that, in response to inflammatory cues, SUN1/2 proteins act as mechano-regulators to remodel the nucleus and chromatin for M1 polarization of the macrophage.

Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS.

The discovery of small-molecule inhibitors requires suitable binding pockets on protein surfaces. Proteins that lack this feature are considered undruggable and require innovative strategies for therapeutic targeting. KRAS is the most frequently activated oncogene in cancer, and the active state of mutant KRAS is such a recalcitrant target. We designed a natural product-inspired small molecule that remodels the surface of cyclophilin A (CYPA) to create a neomorphic interface with high affinity and selectivity for the active state of KRASG12C (in which glycine-12 is mutated to cysteine). The resulting CYPA:drug:KRASG12C tricomplex inactivated oncogenic signaling and led to tumor regressions in multiple human cancer models. This inhibitory strategy can be used to target additional KRAS mutants and other undruggable cancer drivers. Tricomplex inhibitors that selectively target active KRASG12C or multiple RAS mutants are in clinical trials now (NCT05462717 and NCT05379985).

Deciphering the Influence of Anionic Electrons of Surface-Functionalized Two-Dimensional Electrides in Lithium-Sulfur Batteries.

Using transition metal compounds as sulfur hosts is regarded as a promising approach to suppress the polysulfide shuttle and accelerate redox kinetics for lithium-sulfur (Li-S) batteries. Herein, we report that a new kind of compound, electrides (exotic ionic crystalline materials in which electrons serve as anions), is efficient sulfur hosts for Li-S batteries for the first time. Based on the first-principles calculations, we found that two-dimensional (2D) electrides M2C (M = Sc, Y) exhibit unprecedentedly strong binding strength toward sulfur species and surface functionalization is necessary to passivate their activity. The 2D electrides modified with the F-functional group exhibit the best performance in terms of the adsorption energy and sulfur reduction process. A comparative study with a nonelectride reveals that the anionic electrons (AEs) of electrides aid in anchoring the soluble polysulfides. These results open an avenue for the application of electrides in Li-S batteries.

Excitation of multiple Fano resonances on all-dielectric nanoparticle arrays.

In this paper, an all-dielectric metasurface consisting of a unit cell containing a nanocube array and organized periodically on a silicon dioxide substrate is designed and analyzed. By introducing asymmetric parameters that can excite the quasi-bound states in the continuum, three Fano resonances with high Q-factor and high modulation depth may be produced in the near-infrared range. Three Fano resonance peaks are excited by magnetic dipole and toroidal dipole, respectively, in conjunction with the distributive features of electromagnetism. The simulation results indicate that the discussed structure can be utilized as a refractive index sensor with a sensitivity of around 434 nm/RIU, a maximum Q factor of 3327, and a modulation depth equal to 100%. The proposed structure has been designed and experimentally investigated, and its maximum sensitivity is 227 nm/RIU. At the same time, the modulation depth of the resonance peak at λ = 1185.81 nm is nearly 100% when the polarization angle of the incident light is 0 °. Therefore, the suggested metasurface has applications in optical switches, nonlinear optics, and biological sensors.

Pan-KRAS inhibitor disables oncogenic signalling and tumour growth.

KRAS is one of the most commonly mutated proteins in cancer, and efforts to directly inhibit its function have been continuing for decades. The most successful of these has been the development of covalent allele-specific inhibitors that trap KRAS G12C in its inactive conformation and suppress tumour growth in patients1-7. Whether inactive-state selective inhibition can be used to therapeutically target non-G12C KRAS mutants remains under investigation. Here we report the discovery and characterization of a non-covalent inhibitor that binds preferentially and with high affinity to the inactive state of KRAS while sparing NRAS and HRAS. Although limited to only a few amino acids, the evolutionary divergence in the GTPase domain of RAS isoforms was sufficient to impart orthosteric and allosteric constraints for KRAS selectivity. The inhibitor blocked nucleotide exchange to prevent the activation of wild-type KRAS and a broad range of KRAS mutants, including G12A/C/D/F/V/S, G13C/D, V14I, L19F, Q22K, D33E, Q61H, K117N and A146V/T. Inhibition of downstream signalling and proliferation was restricted to cancer cells harbouring mutant KRAS, and drug treatment suppressed KRAS mutant tumour growth in mice, without having a detrimental effect on animal weight. Our study suggests that most KRAS oncoproteins cycle between an active state and an inactive state in cancer cells and are dependent on nucleotide exchange for activation. Pan-KRAS inhibitors, such as the one described here, have broad therapeutic implications and merit clinical investigation in patients with KRAS-driven cancers.

Multiple Fano resonances on the metastructure of all-dielectric nanopore arrays excited by breaking two-different-dimensional symmetries.

We have designed and analyzed the high quality-factor (Q-factor), multiple Fano resonances device on the basis of the all-dielectric metastructure. The unit structure consists of two rectangular air holes etched within a silicon cube and periodically aligns on the substrate of silicon dioxide. The results demonstrate that four Fano resonances are achieved by integrating the theory of bound states in the continuum (BIC)and breaking the symmetry (width symmetry or depth symmetry) of two rectangle air holes, and the resonant wavelength can be modified by altering structural parameters. The sensing characteristics of the presented structure are studied. The sensitivity(S) of 304 nm/RIU, the maximal Q-factor of 2142 and the figure of merit (FOM) of 515.3 are achieved while width symmetry is broken. Meanwhile, the sensitivity of 280 nm/RIU, the maximal Q-factor of 2517 and the FOM of 560 are gotted through breaking depth symmetry. The proposed metastructures can be used for the lasers, biosensing and nonlinear optics.

InAs/GaAs quantum-dot lasers grown on on-axis Si (001) without dislocation filter layers.

InAs/GaAs quantum dot (QD) laser monolithically grown on silicon is one of the potential approaches to realizing silicon-based light sources. However, the mismatch between GaAs and Si generates a high density of threading dislocations (TDs) and antiphase boundaries (APBs), which trap carriers and adversely affect device performance. In this paper, we present a simple method to reduce the threading dislocation density (TDD) merely through GaAs buffer, eliminating the intricate dislocation filter layers (DFLs) as well as any intermediate buffer layers whose compositions are different from the target GaAs. An APB-free epitaxial 2.5 µm GaAs film was grown on exact Si (001) by metalorganic chemical vapor deposition (MOCVD) with a TDD of 9.4 × 106 cm-2. InAs/GaAs QDs with a density of 5.2 × 1010 cm-2 were grown on this GaAs/Si (001) virtual substrate by molecular beam epitaxy (MBE) system. The fabricated QD laser has achieved a single facet room temperature continuous-wave output power of 138 mW with a threshold current density of 397 A/cm2 and a lasing wavelength of 1306 nm. In this work, we propose a simplified method to fabricate high-power QD lasers, which is expected to promote the application of photonic integrated circuits.

MiRNA-144-5p down-modulates CDCA3 to regulate proliferation and apoptosis of lung adenocarcinoma cells.

BACKGROUND: Lung adenocarcinoma (LUAD) belongs to non-small cell lung cancer. In addition to surgical resection, chemotherapy and radiotherapy cause great side effects and low 5-year survival rates. MiRNAs are closely related to cancer development. This study aimed to analyze the molecular mechanism of miRNA-144-5p targeting CDCA3 to inhibit LUAD proliferation. METHODS: MiRNA and mRNA data were downloaded from TCGA-LUAD dataset for differential expression analysis. TargetScan and miRTarBase databases were adopted to predict the target genes of miRNA, and the signaling pathways involved were analyzed by gene set enrichment analysis. The functions of LUAD cells were analyzed by CCK-8, colony formation assay, stem cell spheroidization assay, and flow cytometry. The expression levels of CDCA3, p53, and cell cycle-associated proteins were evaluated by Western blot. RESULTS: The expression of miRNA-144-5p was significantly down-regulated in LUAD, but overexpression of it repressed proliferation and spheroidization, and promoted apoptosis of LUAD cells. By bioinformatics prediction and dual-luciferase reporter assay, miRNA-144-5p was validated to target CDCA3, thereby regulating proliferation of LUAD cells. Besides, the results of cell experiments showed that miRNA-144-5p targeting CDCA3 affected cell proliferation and apoptosis in LUAD by regulating cell cycles, and miRNA-144-5p/CDCA3 mediated the p53 signaling pathway to affect the growth of LUAD cells. SIGNIFICANCE: Through the study of the pathogenesis of miRNA-144-5p regulating LUAD, we can better understand the molecular mechanism underlying LUAD development.

A New Analytical Model for Deflection of Concrete Beams Reinforced by BFRP Bars and Steel Fibres under Cyclic Loading.

Basalt-fiber-reinforced plastic-bars-reinforced concrete beams (i.e., BFRP-RC beams) usually possess significant deformations compared to reinforced concrete beams due to the FRP bars having a lower Young's modulus. This paper investigates the effects of adding steel fibers into BFRP-RC beams to reduce their deflection. Ten BFRP-RC beams were prepared and tested to failure via four-point bending under cyclic loading. The experimental variables investigated include steel-fiber volume fraction and shape, BFRP reinforcement ratio, and concrete strength. The influences of steel fibers on ultimate moment capacity, service load moment, and deformation of the BFRP-RC beams were investigated. The results reveal that steel fibers significantly improved the ultimate moment capacity and service load moment of the BFRP-RC beams. The deflection and residual deflection of the BFRP-RC beams reinforced with 1.5% by volume steel fibers were 48.18% and 30.36% lower than their counterpart of the BFRP-RC beams without fibers. Under the same load, the deflection of the beams increased by 11% after the first stage of three loading and unloading cycles, while the deflection increased by only 8% after three unloading and reloading cycles in the second and third stages. Finally, a new analytical model for the deflection of the BFRP-RC beams with steel fibers under cyclic loading was established and validated by the experiment results from this study. The new model yielded better results than current models in the literature.

Flexural Performance of Concrete Beams Reinforced with Continuous FRP Bars and Discrete Steel Fibers under Cyclic Loads.

This research investigated the flexural behavior of high-strength concrete beams reinforced with continuous basalt fiber-reinforced polymer (BFRP) bars and discrete steel fibers. Five concrete beams with the dimensions of 150 × 300 × 2100 mm3 were constructed and tested to failure under four-point bending cyclic loading. The specimens consisted of four BFRP-reinforced concrete beams with various reinforcement ratios (ρf), namely, 0.56%, 0.77%, 1.15%, and 1.65%, and one conventional steel-reinforced concrete beam for comparison purposes. The cracking behavior, failure modes, load-deflection behavior, residual deformation, and stiffness degradation of the beams were studied. Additionally, a deformation-based approach was used to analyze the deformability of the beams. The results show that an increase in the ρf effectively restrained the crack widths, deflections, and residual deformation while also enhancing the flexural bearing capacity of the beams. In comparison to the first displacement cycle, the bearing capacity dropped by 10% on average in the third cycle. The stiffness exhibited a fast to slow degradation trend until failure. The residual stiffnesses were higher in beams with a higher ρf. The over-reinforced beams had superior deformability than the under-reinforced beams, according to the deformability factors.

Electrolyte formulation strategies for potassium-based batteries.

Potassium (K)-based batteries are viewed as the most promising alternatives to lithium-based batteries, owing to their abundant potassium resource, lower redox potentials (-2.97 V vs. SHE), and low cost. Recently, significant achievements on electrode materials have boosted the development of potassium-based batteries. However, the poor interfacial compatibility between electrode and electrolyte hinders their practical. Hence, rational design of electrolyte/electrode interface by electrolytes is the key to develop K-based batteries. In this review, the principles for formulating organic electrolytes are comprehensively summarized. Then, recent progress of various liquid organic and solid-state K+ electrolytes for potassium-ion batteries and beyond are discussed. Finally, we offer the current challenges that need to be addressed for advanced K-based batteries.

Diverse alterations associated with resistance to KRAS(G12C) inhibition.

Inactive state-selective KRAS(G12C) inhibitors1-8 demonstrate a 30-40% response rate and result in approximately 6-month median progression-free survival in patients with lung cancer9. The genetic basis for resistance to these first-in-class mutant GTPase inhibitors remains under investigation. Here we evaluated matched pre-treatment and post-treatment specimens from 43 patients treated with the KRAS(G12C) inhibitor sotorasib. Multiple treatment-emergent alterations were observed across 27 patients, including alterations in KRAS, NRAS, BRAF, EGFR, FGFR2, MYC and other genes. In preclinical patient-derived xenograft and cell line models, resistance to KRAS(G12C) inhibition was associated with low allele frequency hotspot mutations in KRAS(G12V or G13D), NRAS(Q61K or G13R), MRAS(Q71R) and/or BRAF(G596R), mirroring observations in patients. Single-cell sequencing in an isogenic lineage identified secondary RAS and/or BRAF mutations in the same cells as KRAS(G12C), where they bypassed inhibition without affecting target inactivation. Genetic or pharmacological targeting of ERK signalling intermediates enhanced the antiproliferative effect of G12C inhibitor treatment in models with acquired RAS or BRAF mutations. Our study thus suggests a heterogenous pattern of resistance with multiple subclonal events emerging during G12C inhibitor treatment. A subset of patients in our cohort acquired oncogenic KRAS, NRAS or BRAF mutations, and resistance in this setting may be delayed by co-targeting of ERK signalling intermediates. These findings merit broader evaluation in prospective clinical trials.

The G protein signaling regulator RGS3 enhances the GTPase activity of KRAS.

Recently reported to be effective in patients with lung cancer, KRASG12C inhibitors bind to the inactive, or guanosine diphosphate (GDP)­bound, state of the oncoprotein and require guanosine triphosphate (GTP) hydrolysis for inhibition. However, KRAS mutations prevent the catalytic arginine of GTPase-activating proteins (GAPs) from enhancing an otherwise slow hydrolysis rate. If KRAS mutants are indeed insensitive to GAPs, it is unclear how KRASG12C hydrolyzes sufficient GTP to allow inactive state­selective inhibition. Here, we show that RGS3, a GAP previously known for regulating G protein­coupled receptors, can also enhance the GTPase activity of mutant and wild-type KRAS proteins. Our study reveals an unexpected mechanism that inactivates KRAS and explains the vulnerability to emerging clinically effective therapeutics.

Relationship between Hyponatremia and Peripheral Neuropathy in Patients with Diabetes.

OBJECTIVES: Hyponatremia is a common complication of diabetes. However, the relationship between serum sodium level and diabetic peripheral neuropathy (DPN) is unknown. This study was aimed at investigating the relationship between low serum sodium level and DPN in Chinese patients with type 2 diabetes mellitus. METHODS: A retrospective study was performed on 1928 patients with type 2 diabetes between 2010 and 2018. The multivariate test was used to analyze the relationship between the serum sodium level and the nerve conduction function. A restricted cubic spline was used to flexibly model and visualize the relationship between the serum sodium level and DPN, followed by logistic regression with adjustment. RESULTS: As the serum sodium level increased, the prevalence of DPN had a reverse J-curve distribution with the serum sodium levels (69.6%, 53.7%, 49.6%, 43.9%, and 49.7%; P = 0.001). Significant differences existed between the serum sodium level and the motor nerve conduction velocity, sensory nerve conduction velocity, part of compound muscle action potential, and sensory nerve action potential of the participants. Compared with hyponatremia, the higher serum sodium level was a relative lower risk factor for DPN after adjusting for several potential confounders (OR = 0.430, 95%CI = 0.220-0.841; OR = 0.386, 95%CI = 0.198-0.755; OR = 0.297, 95%CI = 0.152-0.580; OR = 0.376, 95%CI = 0.190-0.743; all P < 0.05). Compared with low-normal serum sodium groups, the high-normal serum sodium level was also a risk factor for DPN (OR = 0.690, 95%CI = 0.526-0.905, P = 0.007). This relationship was particularly apparent in male participants, those aged <65 years, those with a duration of diabetes of <10 years, and those with a urinary albumin - to - creatinine ratio (UACR) < 30 mg/g. CONCLUSIONS: Low serum sodium levels were independently associated with DPN, even within the normal range of the serum sodium. We should pay more attention to avoid the low serum sodium level in patients with type 2 diabetes mellitus.