Maximum chirality of THz metasurfaces with quasi-bound states in the continuum.

Metasurfaces hold great promise for terahertz (THz) chiral-optical devices. Here, we proposed a chiral THz metasurface with quasi-bound state in the continuum (BIC) for maximum chirality. By exploiting structural perturbations of the dipole displacement and the diverging angle for the THz metasurface, the symmetry-protected BIC transforms into quasi-BIC. The critical coupling condition is satisfied by the introduction of graphene, enabling the theoretical maximum absorption of the quasi-BIC. Subsequently, the perturbations are balanced to obtain maximum chirality. The numerical simulations show that the THz metasurface exhibits strong linear chirality with the circular dichroism (CD) of 0.99 at the quasi-BIC. Additionally, the chiral third harmonic generation (THG) is achieved, characterized by high efficiency up to 19% and strong THG-CD as high as 0.99. It is expected that the THz metasurfaces has great potential for applications in chiral sensing and imaging.

Targeting EFHD2 inhibits interferon-γ signaling and ameliorates non-alcoholic steatohepatitis.

BACKGROUND & AIMS: The precise pathomechanisms underlying the development of non-alcoholic steatohepatitis (NASH, also known as metabolic dysfunction-associated steatohepatitis [MASH]) remain incompletely understood. In this study, we investigated the potential role of EF-hand domain family member D2 (EFHD2), a novel molecule specific to immune cells, in the pathogenesis of NASH. METHODS: Hepatic EFHD2 expression was characterized in patients with NASH and two diet-induced NASH mouse models. Single-cell RNA sequencing (scRNA-seq) and double-immunohistochemistry were employed to explore EFHD2 expression patterns in NASH livers. The effects of global and myeloid-specific EFHD2 deletion on NASH and NASH-related hepatocellular carcinoma were assessed. Molecular mechanisms underlying EFHD2 function were investigated, while chemical and genetic investigations were performed to assess its potential as a therapeutic target. RESULTS: EFHD2 expression was significantly elevated in hepatic macrophages/monocytes in both patients with NASH and mice. Deletion of EFHD2, either globally or specifically in myeloid cells, improved hepatic steatosis, reduced immune cell infiltration, inhibited lipid peroxidation-induced ferroptosis, and attenuated fibrosis in NASH. Additionally, it hindered the development of NASH-related hepatocellular carcinoma. Specifically, deletion of myeloid EFHD2 prevented the replacement of TIM4+ resident Kupffer cells by infiltrated monocytes and reversed the decreases in patrolling monocytes and CD4+/CD8+ T cell ratio in NASH. Mechanistically, our investigation revealed that EFHD2 in myeloid cells interacts with cytosolic YWHAZ (14-3-3ζ), facilitating the translocation of IFNγR2 (interferon-γ receptor-2) onto the plasma membrane. This interaction mediates interferon-γ signaling, which triggers immune and inflammatory responses in macrophages during NASH. Finally, a novel stapled α-helical peptide targeting EFHD2 was shown to be effective in protecting against NASH pathology in mice. CONCLUSION: Our study reveals a pivotal immunomodulatory and inflammatory role of EFHD2 in NASH, underscoring EFHD2 as a promising druggable target for NASH treatment. IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH) represents an advanced stage of non-alcoholic fatty liver disease (NAFLD); however, not all patients with NAFLD progress to NASH. A key challenge is identifying the factors that trigger inflammation, which propels the transition from simple fatty liver to NASH. Our research pinpointed EFHD2 as a pivotal driver of NASH, orchestrating the over-activation of interferon-γ signaling within the liver during NASH progression. A stapled peptide designed to target EFHD2 exhibited therapeutic promise in NASH mice. These findings support the potential of EFHD2 as a therapeutic target in NASH.

Comprehensive analysis of the prognostic value and immunological role of IDO1 gene in pan-cancer.

OBJECTIVE: It has been demonstrated that IDO1, a target of immune checkpoint inhibition, functions as an oncogene in the majority of human malignancies. IDO1's function in human pan-cancers hasn't been thoroughly studied, though. MATERIALS AND METHODS: The Kaplan-Meier (K-M) and COX analyses were applied to the survival analysis. Furthermore, we used Spearman's correlation analysis to examine the associations between IDO1 and microsatellite instability (MSI), DNA methyltransferases (DNMTs), tumor mutational burden (TMB), the associated genes of mismatch repair (MMR), and immune checkpoint biomarkers. Moreover, immunohistochemical analysis and qRT-PCR were used to evaluate IDO1's expression in pan-cancer cells. RESULTS: The findings of this study reveal that IDO1 has abnormal expression in a number of malignancies and is related to the prognosis for UVM, LGG, KIRP, GBM, LAML, OV, READ, MESO, SARC, SKCM, and HNSC. Furthermore, the aberrant IDO1 expression was connected to the TMB, MSI, MMR, drug sensitivity, immune cells infiltrating, and tumor immune microenvironment across a variety of cancer types. The PCR results showed that in contrast to normal cells, IDO1 was found to be significantly highly expressed in breast cancer cells and hepatocellular carcinoma cells, and significantly lowly expressed in gastric cancer cells. CONCLUSION: The clinical treatment of IDO1 is now better supported by a theoretical basis and guidelines provided by our study.

Rheumatoid arthritis: pathogenesis and therapeutic advances.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the unresolved synovial inflammation for tissues-destructive consequence, which remains one of significant causes of disability and labor loss, affecting about 0.2-1% global population. Although treatments with disease-modifying antirheumatic drugs (DMARDs) are effective to control inflammation and decrease bone destruction, the overall remission rates of RA still stay at a low level. Therefore, uncovering the pathogenesis of RA and expediting clinical transformation are imminently in need. Here, we summarize the immunological basis, inflammatory pathways, genetic and epigenetic alterations, and metabolic disorders in RA, with highlights on the abnormality of immune cells atlas, epigenetics, and immunometabolism. Besides an overview of first-line medications including conventional DMARDs, biologics, and small molecule agents, we discuss in depth promising targeted therapies under clinical or preclinical trials, especially epigenetic and metabolic regulators. Additionally, prospects on precision medicine based on synovial biopsy or RNA-sequencing and cell therapies of mesenchymal stem cells or chimeric antigen receptor T-cell are also looked forward. The advancements of pathogenesis and innovations of therapies in RA accelerates the progress of RA treatments.

Unidirectional asymmetry transmission based on quasi-accidental bound states in the continuum.

The unidirectional asymmetry transmission is demonstrated based on quasi-accidental bound states in the continuum by a one-dimensional chiral photonic crystal slab (CPhCs) composed of tilted silicon nano-pillars. The chirality breaks symmetries on the far field polarization and radiation Q-factor between the upward and downward radiation channels. Accordingly, the CPhCs only supports the unidirectional maximal asymmetry transmission at fixed incident and conical angles. The numerical simulation indicates that the CPhCs obtains a circular dichroism of 0.99 and Q-factor of 753.7 at λ = 1.565 µm. In addition, the handedness of polarization is also effectively converted between the incidence and transmission, and the handedness depends on the incident direction and conical angle. Our scheme provides a feasible route for applications in manipulating polarization and chiral sensing.

Constructing a novel signature and predicting the immune landscape of colon cancer using N6-methylandenosine-related lncRNAs.

Background: Colon cancer (CC) is a prevalent malignant tumor that affects people all around the world. In this study, N6-methylandenosine-related long non-coding RNAs (m6A-related lncRNAs) in 473 colon cancers and 41 adjacent tissues of CC patients from The Cancer Genome Atlas (TCGA) were investigated. Method: The Pearson correlation analysis was conducted to examine the m6A-related lncRNAs, and the univariate Cox regression analysis was performed to screen 38 prognostic m6A-related lncRNAs. The least absolute shrinkage and selection operator (LASSO) regression analysis were carried out on 38 prognostic lncRNAs to develop a 14 m6A-related lncRNAs prognostic signature (m6A-LPS) in CC. The availability of the m6A-LPS was evaluated using the Kaplan-Meier and Receiver Operating Characteristic (ROC) curves. Results: Three m6A modification patterns with significantly different N stages, survival time, and immune landscapes were identified. It has been discovered that the m6A-LPS, which is based on 14 m6A-related lncRNAs (TNFRSF10A-AS1, AC245041.1, AL513550.1, UTAT33, SNHG26, AC092944.1, ITGB1-DT, AL138921.1, AC099850.3, NCBP2-AS1, AL137782.1, AC073896.3, AP006621.2, AC147651.1), may represent a new, promising biomarker with great potential. It was re-evaluated in terms of survival rate, clinical features, tumor infiltration immune cells, biomarkers related to Immune Checkpoint Inhibitors (ICIs), and chemotherapeutic drug efficacy. The m6A-LPS has been revealed to be a novel potential and promising predictor for evaluating the prognosis of CC patients. Conclusion: This study revealed that the risk signature is a promising predictive indicator that may provide more accurate clinical applications in CC therapeutics and enable effective therapy strategies for clinicians.

Targeting KAT2A inhibits inflammatory macrophage activation and rheumatoid arthritis through epigenetic and metabolic reprogramming.

Epigenetic regulation of inflammatory macrophages governs inflammation initiation and resolution in the pathogenesis of rheumatoid arthritis (RA). Nevertheless, the mechanisms underlying macrophage-mediated arthritis injuries remain largely obscure. Here, we found that increased expression of lysine acetyltransferase 2A (KAT2A) in synovial tissues was closely correlated with inflammatory joint immunopathology in both RA patients and experimental arthritis mice. Administration of MB-3, the KAT2A-specific chemical inhibitor, significantly ameliorated the synovitis and bone destruction in collagen-induced arthritis model. Both pharmacological inhibition and siRNA silencing of KAT2A, not only suppressed innate stimuli-triggered proinflammatory gene (such as Il1b and Nlrp3) transcription but also impaired NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in vivo and in vitro. Mechanistically, KAT2A facilitated macrophage glycolysis reprogramming through suppressing nuclear factor-erythroid 2-related factor 2 (NRF2) activity as well as downstream antioxidant molecules, which supported histone 3 lysine 9 acetylation (H3K9ac) and limited NRF2-mediated transcriptional repression of proinflammatory genes. Our study proves that acetyltransferase KAT2A licenses metabolic and epigenetic reprogramming for NLRP3 inflammasome activation in inflammatory macrophages, thereby targeting KAT2A represents a potential therapeutic approach for patients suffering from RA and relevant inflammatory diseases.

IRG1 prevents excessive inflammatory responses and cardiac dysfunction after myocardial injury.

Acute myocardial infarction (MI) and chemotherapeutic drug administration can induce myocardial damage and cardiomyocyte cell death, and trigger the release of damage-associated molecular patterns (DAMPs) that initiate the aseptic inflammatory response. The moderate inflammatory response is beneficial for repairing damaged myocardium, while an excessive inflammatory response exacerbates myocardial injury, promotes scar formation, and results in a poor prognosis of cardiac diseases. Immune responsive gene 1 (IRG1) is specifically highly expressed in activated macrophages and mediates the production of tricarboxylic acid (TCA) cycle metabolite itaconate. However, the role of IRG1 in the inflammation and myocardial injury of cardiac stress-related diseases remains unknown. Here, we found that IRG1 knockout mice exhibited increased cardiac tissue inflammation and infarct size, aggravated myocardial fibrosis, and impaired cardiac function after MI and in vivo doxorubicin (Dox) administration. Mechanically, IRG1 deficiency enhanced the production of IL-6 and IL-1ß by suppressing the nuclear factor red lineage 2-related factor 2 (NRF2) and activating transcription factor 3 (ATF3) pathway in cardiac macrophages. Importantly, 4-octyl itaconate (4-OI), a cell-permeable derivative of itaconate, reversed the inhibited expression of NRF2 and ATF3 caused by IRG1 deficiency. Moreover, in vivo 4-OI administration inhibited the cardiac inflammation and fibrosis, and prevented adverse ventricle remodeling in IRG1 knockout mice with MI or Dox-induced myocardial injury. Our study uncovers the critical protective role of IRG1 in suppressing inflammation and preventing cardiac dysfunction under ischemic or toxic injury conditions, providing a potential target for the treatment of myocardial injury.

Histone demethylase KDM5B licenses macrophage-mediated inflammatory responses by repressing Nfkbia transcription.

Macrophages play a critical role in the immune homeostasis and host defense against invading pathogens. However, uncontrolled activation of inflammatory macrophages leads to tissue injury and even fuels autoimmunity. Hence the molecular mechanisms underlying macrophage activation need to be further elucidated. The effects of epigenetic modifications on the function of immune cells draw increasing attention. Here, we demonstrated that lysine-specific demethylase 5B (KDM5B), a classical transcriptional repressor in stem cell development and cancer, was required for the full activation of NF-κB signaling cascade and pro-inflammatory cytokine production in macrophages. KDM5B deficiency or inhibitor treatment protected mice from immunologic injury in both collagen-induced arthritis (CIA) model and endotoxin shock model. Genome-wide analysis of KDM5B-binding peaks identified that KDM5B was selectively recruited to the promoter of Nfkbia, the gene encoding IκBα, in activated macrophages. KDM5B mediated the H3K4me3 modification erasing and decreased chromatin accessibility of Nfkbia gene locus, coordinating the elaborate suppression of IκBα expression and the enhanced NF-κB-mediated macrophage activation. Our finding identifies the indispensable role of KDM5B in macrophage-mediated inflammatory responses and provides a candidate therapeutic target for autoimmune and inflammatory disorders.

Murine neonatal cardiac B cells promote cardiomyocyte proliferation and heart regeneration.

The irreversible loss of cardiomyocytes in the adult heart following cardiac injury leads to adverse cardiac remodeling and ventricular dysfunction. However, the role of B cells in cardiomyocyte proliferation and heart regeneration has not been clarified. Here, we found that the neonatal mice with B cell depletion showed markedly reduced cardiomyocyte proliferation, leading to cardiac dysfunction, fibrosis scar formation, and the complete failure of heart regeneration after apical resection. B cell depletion also significantly impaired heart regeneration and cardiac function in neonatal mice following myocardial infarction (MI). However, B cell depletion in adult mice suppressed tissue inflammation, inhibited myocardial fibrosis, and improved cardiac function after MI. Interestingly, B cell depletion partially restricted cardiomyocyte proliferation in adult mice post-MI. Single-cell RNA sequencing showed that cardiac B cells possessed a more powerful ability to inhibit inflammatory responses and enhance angiogenesis in the postnatal day 1 (P1) mice compared with P7 and adult mice. Besides, the proportion of cardioprotective B cell clusters with high expression levels of S100a6 (S100 calcium-binding protein A6) and S100a4 (S100 calcium-binding protein A4) was greatly decreased in adult heart tissues compared with neonatal mice after cardiac damage. Thus, our study discovers that cardiac B cells in neonatal mice are required for cardiomyocyte proliferation and heart regeneration, while adult B cells promote inflammation and impair cardiac function after myocardial injury.

Enhanced chirality in a dielectric metasurface without breaking symmetry.

We propose a dielectric metasurface constructed by quadrumer silicon nano-disks with crossed slots in the middle. This metasurface can support the excitation of bound states in the continuum which are closely related to the toroidal dipole resonance. After introducing chiral enantiomers with weak chirality into the surrounding medium, due to the bound states in the continuum, the chiroptical effect of the metasurface can be greatly enhanced. In particular, this metasurface breaks neither the in-plane nor out-plane symmetry, which has lower requirements of spatial processing capabilities. The proposed metasurface can be used in the trace analysis of chiral enantiomers and may lead to potential applications for tailored phase control and ultra-integrated molar chiral sensing metadevices.

Single-cell transcriptome atlas reveals protective characteristics of COVID-19 mRNA vaccine.

Messenger RNA (mRNA) vaccines are promising alternatives to conventional vaccines in many aspects. We previously developed a lipopolyplex (LPP)-based mRNA vaccine (SW0123) that demonstrated robust immunogenicity and strong protective capacity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in mice and rhesus macaques. However, the immune profiles and mechanisms of pulmonary protection induced by SW0123 remain unclear. Through high-resolution single-cell analysis, we found that SW0123 vaccination effectively suppressed SARS-CoV-2-induced inflammatory responses by inhibiting the recruitment of proinflammatory macrophages and increasing the frequency of polymorphonuclear myeloid-derived suppressor cells. In addition, the apoptotic process in both lung epithelial and endothelial cells was significantly inhibited, which was proposed to be one major mechanism contributing to vaccine-induced lung protection. Cell-cell interaction in the lung compartment was also altered by vaccination. These data collectively unravel the mechanisms by which the SW0123 protects against lung damage caused by SARS-CoV-2 infection.

Loss of KDM5B ameliorates pathological cardiac fibrosis and dysfunction by epigenetically enhancing ATF3 expression.

Excessive cardiac fibrosis is central to adverse cardiac remodeling and dysfunction leading to heart failure in many cardiac diseases. Histone methylation plays a crucial role in various pathophysiological events. However, the role of histone methylation modification enzymes in pathological cardiac fibrosis needs to be fully elucidated. Here, we identified lysine demethylase 5B (KDM5B), a histone H3K4me2/me3 demethylase, as a key epigenetic mediator of pathological cardiac fibrosis. KDM5B expression was upregulated in cardiac fibroblasts and myocardial tissues in response to pathological stress. KDM5B deficiency markedly ameliorated cardiac fibrosis, improved cardiac function, and prevented adverse cardiac remodeling following myocardial infarction (MI) or pressure overload. KDM5B knockout or inhibitor treatment constrained the transition of cardiac fibroblasts to profibrogenic myofibroblasts and suppressed fibrotic responses. KDM5B deficiency also facilitated the transformation of cardiac fibroblasts to endothelial-like cells and promoted angiogenesis in response to myocardial injury. Mechanistically, KDM5B bound to the promoter of activating transcription factor 3 (Atf3), an antifibrotic regulator of cardiac fibrosis, and inhibited ATF3 expression by demethylating the activated H3K4me2/3 modification, leading to the enhanced activation of TGF-ß signaling and excessive expression of profibrotic genes. Our study indicates that KDM5B drives pathological cardiac fibrosis and represents a candidate target for intervention in cardiac dysfunction and heart failure.

Plasmonic characteristics of the structure with double graphene layers immersed in chiral media and applications in detection of chirality.

The propagating behavior of surface plasmons in chiral media is different from that in achiral media. By comparing the propagation behavior of SPPs, the chirality of the environment can be evaluated. We theoretically reveal the features of SPPs in a structure with two individual graphene sheets surrounded by chiral environment. A more universal dispersion relation covering the achiral cases is obtained. The effects of the chirality of medium and the chemical potential of graphene on the SPPs are explored. Besides, a novel method of detecting the chirality of the environment based on the lateral optical force and torque is proposed. The characteristics of the structure may enrich the surface plasmonic wave theory on the waveguides with multiple graphene sheets and provide new opportunities for the design of more compact nanophotonic functional devices and novel biosensors.

Lower lip recurrent keratoacanthoma: A case report.

BACKGROUND: This paper introduces a case of recurrent keratoacanthoma (KA). KA is a self-healing disease. Recurrence after surgical resection is rare. In this case, the local application of retinoic acid ointment after the second operation achieved a good prognosis after 2 years of follow-up. CASE SUMMARY: A 76-year-old male patient was admitted to the hospital for "lower lip rupture and scab for 3 mo". Treatment: A rectangular incision was made in the healthy tissue about 3 mm outside the periphery of the lower lip mass, and a modified Bernard sliding flap was designed to completely remove the mass. Pathology showed (lower lip) KA. When the patient returned 6 mo after surgery, the middle mucosa of the lower lip had a bulge with a diameter of about 0.5 cm. The boundary was still clear, the surface was ulcerated. A recurrence of lower lip KA was suspected and a fan-shaped incision was performed in the healthy tissue about 5 mm outside the lesion to completely resect. Pathological showed lower lip KA had recurred. Topical application of tretinoin cream was applied once a day for 3 mo. The lower lip wounds were clean at the 2-year postoperative follow-up and the mucosa was normal. CONCLUSION: Adjuvant retinoic acid treatment after KA surgical resection can achieve good results.

Loss of BTK ameliorates the pathological cardiac fibrosis and dysfunction.

Cardiac fibrosis is a common irreversible pathological feature of diverse heart disorders. Uncontrolled cardiac fibrosis contributes to maladaptive cardiac remodeling and eventually heart failure. However, the molecular determinants of ischemic and non-ischemic pathological cardiac fibrosis remain largely unknown. Here, we investigated the role of Bruton's tyrosine kinase (BTK) in cardiac fibrosis and remodeling of mice under various pathological conditions. BTK expression was increased in myocardium of mice after pressure overload or myocardial infarction (MI). BTK was mainly located in cardiac fibroblasts of myocardium, and its expression in isolated cardiac fibroblasts was also upregulated following TGF-ß treatment. The deficiency or pharmacological inhibition of BTK with the second-generation inhibitor Acalabrutinib attenuated cardiac fibrosis, preserved cardiac function and prevented adverse cardiac remodeling, which protected against heart failure in mice following pressure overload or MI. BTK deficiency or inhibitor treatment significantly decreased the expression of pro-fibrotic molecules in isolated cardiac fibroblasts and inhibited the transition of fibroblasts to myofibroblasts in response to diverse pathological stresses. BTK directly bound and phosphorylated TGF-ß receptor Ⅰ (TßRⅠ) at tyrosine 182, and then promoted the activation of downstream SMAD-dependent or -independent TGF-ß signaling, leading to the enhanced transition of fibroblasts to pro-fibrotic myofibroblasts and the excessive extracellular matrix gene expression. Our finding uncovers a driving role of BTK in cardiac fibrosis and dysfunction following pressure overload and MI stress, and highlights novel pathogenic mechanisms in ischemic and non-ischemic maladaptive cardiac remodeling, which presents as a promising target for the development of anti-fibrotic therapy.

Analysis of Cutting Stability of a Composite Variable-Section Boring Bar with a Large Length-to-Diameter Ratio Considering Internal Damping.

Chattering in composite deep-hole boring can directly affect surface processing quality and efficiency and has always been a research hotspot in machining mechanics. In this study, based on Euler-Bernoulli beam theory, the fine control equations for the cutting stability of composite variable-section boring bars were established using the Hamilton principle, in which the sectional change and internal damping of the material were considered. Next, using the Galerkin method and semi-discrete method, the effects of the taper ratio, damping ratio, length-to-diameter ratio, and ply angle on the free vibration characteristics and cutting stability were analyzed in detail. The results show that at a low damping ratio, both the first-order inherent frequency and boring stability can be enhanced with the increase in the taper ratio; at a large damping ratio, increasing the taper ratio can reduce the first-order inherent frequency and boring stability. Finally, the effects of the sectional change on the inherent frequency, displacement response, and convergence were analyzed. A numerical simulation was performed for the model reliability validation. The present research results can provide a theoretical basis and technical guidance for analyzing the cutting stability and fine control of composite variable-section boring bars with large length-to-diameter ratios.