Generative learning facilitated discovery of high-entropy ceramic dielectrics for capacitive energy storage.

Dielectric capacitors offer great potential for advanced electronics due to their high power densities, but their energy density still needs to be further improved. High-entropy strategy has emerged as an effective method for improving energy storage performance, however, discovering new high-entropy systems within a high-dimensional composition space is a daunting challenge for traditional trial-and-error experiments. Here, based on phase-field simulations and limited experimental data, we propose a generative learning approach to accelerate the discovery of high-entropy dielectrics in a practically infinite exploration space of over 1011 combinations. By encoding-decoding latent space regularities to facilitate data sampling and forward inference, we employ inverse design to screen out the most promising combinations via a ranking strategy. Through only 5 sets of targeted experiments, we successfully obtain a Bi(Mg0.5Ti0.5)O3-based high-entropy dielectric film with a significantly improved energy density of 156 J cm-3 at an electric field of 5104 kV cm-1, surpassing the pristine film by more than eight-fold. This work introduces an effective and innovative avenue for designing high-entropy dielectrics with drastically reduced experimental cycles, which could be also extended to expedite the design of other multicomponent material systems with desired properties.

Core-Alkynylated Fluorescent Flippers: Altered Ultrafast Photophysics to Track Thick Membranes.

Fluorescent flippers have been introduced as small-molecule probes to image membrane tension in living systems.  This study describes the design, synthesis, spectroscopic and imaging properties of flippers that are elongated by one and two alkynes inserted between the push and the pull dithienothiophene domains.  The resulting mechanophores combine characteristics of flippers, reporting on physical compression in the ground state, and molecular rotors, reporting on torsional motion in the excited state, to take their photophysics to new level of sophistication.  Intensity ratios in broadened excitation bands from differently twisted conformers of core-alkynylated flippers thus report on mechanical compression.  Lifetime boosts from ultrafast excited-state planarization and lifetime drops from competitive intersystem crossing into triplet states report on viscosity.  In standard lipid bilayer membranes, core-alkynylated flippers are too long for one leaflet and tilt or extend into disordered interleaflet space, which preserves rotor-like torsional disorder and thus weak, blue-shifted fluorescence.  Flipper-like planarization occurs only in highly ordered membranes of matching leaflet thickness, where they light up and selectively report on these thick membranes with red-shifted, sharpened excitation maxima, high intensity and long lifetime.

Progress in the treatment of advanced hepatocellular carcinoma with immune combination therapy.

Advanced hepatocellular carcinoma (HCC) is a severe malignancy that poses a serious threat to human health. Owing to challenges in early diagnosis, most patients lose the opportunity for radical treatment when diagnosed. Nonetheless, recent advancements in cancer immunotherapy provide new directions for the treatment of HCC. For instance, monoclonal antibodies against immune checkpoint inhibitors (ICIs) such as programmed cell death protein 1/death ligand-1 inhibitors and cytotoxic t-lymphocyte associated antigen-4 significantly improved the prognosis of patients with HCC. However, tumor cells can evade the immune system through various mechanisms. With the rapid development of genetic engineering and molecular biology, various new immunotherapies have been used to treat HCC, including ICIs, chimeric antigen receptor T cells, engineered cytokines, and certain cancer vaccines. This review summarizes the current status, research progress, and future directions of different immunotherapy strategies in the treatment of HCC.

MATR3 pathogenic variants differentially impair its cryptic splicing repression function.

Matrin-3 (MATR3) is an RNA-binding protein implicated in neurodegenerative and neurodevelopmental diseases. However, little is known regarding the role of MATR3 in cryptic splicing within the context of functional genes and how disease-associated variants impact this function. We show that loss of MATR3 leads to cryptic exon inclusion in many transcripts. We reveal that ALS-linked S85C pathogenic variant reduces MATR3 solubility but does not impair RNA binding. In parallel, we report a novel neurodevelopmental disease-associated M548T variant, located in the RRM2 domain, which reduces protein solubility and impairs RNA binding and cryptic splicing repression functions of MATR3. Altogether, our research identifies cryptic events within functional genes and demonstrates how disease-associated variants impact MATR3 cryptic splicing repression function.

Subphthalocyanine-flipper dyads for selective membrane staining.

The design, synthesis and evaluation of a subphthalocyanine-flipper (SubPc-Flipper) amphiphilic dyad is reported. This dyad combines two fluorophores that function in the visible region (420-800 nm) for the simultaneous sensing of both ordered and disordered lipidic membranes. The flipper probes part of the dyad possesses mechanosensitivity, long fluorescence lifetimes (τ = 3.5-5 ns) and selective staining of ordered membranes. On the other hand, subphthalocyanines (SubPc) are short-lifetime (τ = 1-2.5 ns) fluorophores that are insensitive to membrane tension. As a result of a Förster Resonance Energy Transfer (FRET) process, the dyad not only retains the mechanosensitivity of flippers but also demonstrates high selectivity and emission in different kinds of lipidic membranes. The dyad exhibits high emission and sensitivity to membrane tension (Δτ = 3.5 ns) when tested in giant unilamellar vesicles (GUVs) with different membrane orders. Overall, the results of this study represent a significant advancement in the applications of flippers and dyads in mechanobiology.

Comparative severe dermatologic toxicities of immune checkpoint inhibitors in malignant melanoma: A systematic review and network meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have advanced the therapeutic landscape for malignant melanoma patients. However, they can cause permanent and irreversible dermatologic immune-related adverse events (irAEs) that may lead to interruption of ICI treatment or become life-threatening. To assess the risk of severe dermatologic irAEs (grade 3 or higher) among ICIs for advanced melanoma, we conducted a network meta-analysis (NMA). METHODS: Phase II/III randomized controlled clinical trials (RCTs) involving ICIs were retrieved from various databases, including PubMed, Embase, Cochrane Library, and Web of Science. These trials were published from the inception of databases to October 15, 2022. In addition, the risk of severe dermatologic irAEs associated with ICI types and doses was evaluated and compared by NMA. RESULTS: This study included 20 Phase II/III RCTs with a total of 10 575 patients. The results indicated that ICIs carry a higher risk of severe dermatologic irAEs compared to chemotherapy. Additionally, the combinational therapy of Nivolumab + Ipilimumab was associated with a higher risk than ICI monotherapy. Comparatively, the latest treatment option involving dual ICI therapy with Relatlimab + Nivolumab showed a lower toxicity risk, but higher than Ipilimumab alone. Lastly, Nivolumab, at a dose of 3 mg/kg every 2 weeks, was observed as the lowest-risk dosing regimen for severe dermatologic irAEs in patients with advanced melanoma. CONCLUSION: The findings suggest that Nivolumab (1 mg/kg) + Ipilimumab (3 mg/kg) administered every 3 weeks should be used cautiously in patients with advanced melanoma at high risk for dermatologic irAEs. While we recommend the preferred regimen of Nivolumab (dose = 3 mg/kg, every 2 weeks).

[Clinical, genetic, and pathological analysis in 165 children with disorders of sex development]. / 165ä¾‹å„¿ç«¥æ€§å‘è‚²å¼‚å¸¸ç–¾ç— çš„ä¸´åºŠã€é—ä¼ å­¦ä¸Žç— ç†å­¦åˆ†æž.

OBJECTIVES: To investigate the clinical phenotypes, genetic characteristics, and pathological features of children with disorders of sex development (DSD). METHODS: A retrospective analysis was conducted on epidemiological, clinical phenotype, chromosomal karyotype, gonadal pathology, and genotype data of 165 hospitalized children with DSD at Children's Hospital of Hebei Province and Tangshan Maternal and Child Health Hospital from August 2008 to December 2022. RESULTS: Among the 165 children with DSD, common presenting symptoms were short stature (62/165, 37.6%), clitoromegaly (33/165, 20.0%), cryptorchidism (28/165, 17.0%), hypospadias (24/165, 14.5%), and skin pigmentation abnormalities/exteriorized pigmented labia majora (19/165, 11.5%). Chromosomal karyotype analysis was performed on 127 cases, revealing 36 cases (28.3%) of 46,XX DSD, 34 cases (26.8%) of 46,XY DSD, and 57 cases (44.9%) of sex chromosome abnormalities. Among the sex chromosome abnormal karyotypes, the 45,X karyotype (11/57, 19%) and 45,X/other karyotype mosaicism (36/57, 63%) were more common. Sixteen children underwent histopathological biopsy of gonadal tissues, resulting in retrieval of 25 gonadal tissues. The gonadal tissue biopsies revealed 3 cases of testes, 3 cases of dysplastic testes, 6 cases of ovaries, 11 cases of ovotestes, and 1 case each of streak gonad and agenesis of gonads. Genetic testing identified pathogenic/likely pathogenic variants in 23 cases (23/36, 64%), including 12 cases of 21-hydroxylase deficiency congenital adrenal hyperplasia caused by CYP21A2 pathogenic variants. CONCLUSIONS: Short stature, clitoromegaly, cryptorchidism, hypospadias, and skin pigmentation abnormalities are common phenotypes in children with DSD. 45,X/other karyotype mosaicism and CYP21A2 compound heterozygous variants are major etiological factors in children with DSD. The most commonly observed gonadal histopathology in children with DSD includes ovotestes, ovaries, and testes/dysgenetic testes.

Double-slit interference experimental platform based on a Sagnac interferometer.

In this paper, we build a Young's double-slit experimental platform with adjustable multiparameters by inserting a single slit in a Sagnac interferometer. Our experiment proves that this platform can easily control the parameters related to double slits. In addition, a new, to the best of our knowledge, type of double-slit experiment is performed on the platform. Our approach provides a detailed conceptual and experimental analysis for wave-particle duality and will be useful for research on quantum optics.

Fluorogenic In Situ Thioacetalization: Expanding the Chemical Space of Fluorescent Probes, Including Unorthodox, Bifurcated, and Mechanosensitive Chalcogen Bonds.

Progress with fluorescent flippers, small-molecule probes to image membrane tension in living systems, has been limited by the effort needed to synthesize the twisted push-pull mechanophore. Here, we move to a higher oxidation level to introduce a new design paradigm that allows the screening of flipper probes rapidly, at best in situ. Late-stage clicking of thioacetals and acetals allows simultaneous attachment of targeting units and interfacers and exploration of the critical chalcogen-bonding donor at the same time. Initial studies focus on plasma membrane targeting and develop the chemical space of acetals and thioacetals, from acyclic amino acids to cyclic 1,3-heterocycles covering dioxanes as well as dithiolanes, dithianes, and dithiepanes, derived also from classics in biology like cysteine, lipoic acid, asparagusic acid, DTT, and epidithiodiketopiperazines. From the functional point of view, the sensitivity of membrane tension imaging in living cells could be doubled, with lifetime differences in FLIM images increasing from 0.55 to 1.11 ns. From a theoretical point of view, the complexity of mechanically coupled chalcogen bonding is explored, revealing, among others, intriguing bifurcated chalcogen bonds.

Activation of the cGAS-STING pathway by a mitochondrial DNA-targeted emissive rhodium(iii) metallointercalator.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon (STING) pathway is a key mediator of innate immunity involved in cancer development and treatment. The roles of mitochondrial DNA (mtDNA) in cancer immunotherapy have gradually emerged. Herein, we report a highly emissive rhodium(iii) complex (Rh-Mito) as the mtDNA intercalator. Rh-Mito can specifically bind to mtDNA to cause the cytoplasmic release of mtDNA fragments to activate the cGAS-STING pathway. Moreover, Rh-Mito activates the mitochondrial retrograde signaling by disturbing the key metabolites involved in epigenetic modifications, which alters the nuclear genome methylation landscape to influence the expression of genes related to immune signaling pathways. Finally, we demonstrate that ferritin-encapsulated Rh-Mito elicits potent anticancer activities and evokes intense immune responses in vivo by intravenous injection. Overall, we report for the first time that small molecules targeting mtDNA can activate the cGAS-STING pathway, which gives insights into the development of biomacromolecule-targeted immunotherapeutic agents.

Eosinophilic granuloma of the clavicle in an 11-year-old Chinese girl: A case report.

RATIONALE: Eosinophilic granuloma (EG) - the most common form of Langerhans cell histiocytosis - occurs rarely, and manifestations with only rib and clavicle involvement are extremely rare. EG symptoms often include pain, swelling, and soft tissue mass. The clinical diagnosis of bone EG is complex, and the differential diagnosis includes Ewing sarcoma, tuberculosis, multiple myeloma, lymphoma, primary bone malignancy, and other osteolytic lesions. PATIENTS CONCERN: The patient was an 11-year-old female who found a subcutaneous mass at the junction of the right clavicle and sternum 2 days before presenting at the clinic without apparent triggers. Initially, we considered a subcutaneous cyst or inflammatory mass. Color ultrasound and computed tomography examination revealed osteomyelitis. Finally, the patient was diagnosed with EG after a pathological tissue biopsy, and the child recovered after surgery and anti-infective treatment. DIAGNOSIS: The patient underwent surgery to remove the tumor at a specialist hospital and was diagnosed with EG by pathological examination. INTERVENTION: The patient went to a specialist hospital for surgery to remove the mass and underwent anti-infective treatment. OUTCOMES: The patient recovered after surgical resection and antibiotic treatment. LESSONS: In this report, we emphasize that the clinical presentation of EG in children is not specific. Furthermore, examining age, history, presence of symptoms, and the number of sites is essential to make a correct diagnosis, and a histological examination is necessary to confirm the diagnosis.

Chromosome-level de novo genome assembly of two conifer-parasitic wasps, Megastigmus duclouxiana and Megastigmus sabinae, reveals genomic imprints of adaptation to hosts.

Conifers make up about one third of global forests but are threatened by seed parasitoid wasp species. Many of these wasps belong to the genus Megastigmus, yet little is known about their genomic background. In this study, we provide chromosome-level genome assemblies for two oligophagous conifer parasitoid species of Megastigmus, which represent the first two chromosome-level genomes of the genus. The assembled genomes of Megastigmus duclouxiana and M. sabinae are 878.48 Mb (scaffold N50 of 215.60 Mb) and 812.98 Mb (scaffold N50 of 139.16 Mb), respectively, which are larger than the genome size of most hymenopterans due to the expansion of transposable elements. Expanded gene families highlight the difference in sensory-related genes between the two species, reflecting the difference in their hosts. We further found that these two species have fewer family members but more single-gene duplications than polyphagous congeners in the gene families of ATP-binding cassette transporter (ABC), cytochrome P450 (P450) and olfactory receptors (OR). These findings shed light on the pattern of adaptation to a narrow spectrum of hosts in oligophagous parasitoids. Our findings suggest potential drivers underlying genome evolution and parasitism adaptation, and provide valuable resources for understanding the ecology, genetics and evolution of Megastigmus, as well as for the research and biological control of global conifer forest pests.

Fluorescent Flippers: Small-Molecule Probes to Image Membrane Tension in Living Systems.

Flipper probes have been introduced as small molecule fluorophores to image physical forces, that is, membrane tension in living systems. Their emergence over one decade is described, from evolution in design and synthesis to spectroscopic properties. Responsiveness to physical compression in equilibrium at the ground state is identified as the ideal origin of mechanosensitivity to image membrane tension in living cells. A rich collection of flippers is described to deliver and release in any subcellular membrane of interest in a leaflet-specific manner. Chalcogen-bonding cascade switching and dynamic covalent flippers are developed for super-resolution imaging and dual-sensing of membrane compression and hydration. Availability and broad use in the community validate flipper probes as a fine example of the power of translational supramolecular chemistry, moving from fundamental principles to success on the market.

Multiple primary malignancies - hepatocellular carcinoma combined with splenic lymphoma: A case report.

BACKGROUND: Primary liver cancer is one of the most common malignant tumours, while primary splenic lymphoma is a rare malignancy. Thus, cases of hepatocellular carcinoma (HCC) combined with splenic lymphoma are extremely rare. CASE SUMMARY: We present a 62-year-old woman who was admitted to the Interventional Radiology Department with a lump in the spleen and liver as well as multiple enlarged lymph nodes visible by ultrasound. Contrast-enhanced computed of the abdomen revealed a circular, low-density, shallow mass (approximately 2.6 cm in diameter) in the left intrahepatic lobe and multiple round, low-density shadows in the spleen with clear boundaries (maximum diameter 7.6 cm). Based on the characteristic clinical symptoms and explicit radiological findings, the clinical diagnosis was HCC with metastasis to the liver portal, retroperitoneal lymph nodes, and spleen. After transcatheter arterial chemoembolization and sequential radiofrequency ablation, the -fetoprotein level returned to the normal range, and the hepatitis B cirrhosis improved. In addition, splenic tumour biopsy confirmed the diagnosis of primary malignant lymphoma, which went into remission after chemotherapy. CONCLUSION: HCC with primary splenic non-Hodgkin lymphoma is extremely rare and easily misdiagnosed. Better understanding would facilitate early diagnosis, treatment and prognosis.

In vivo imaging of heart failure with preserved ejection fraction by simultaneous monitoring of cardiac nitric oxide and glutathione using a three-channel fluorescent probe.

The pathophysiology of heart failure with preserved ejection fraction (HFpEF) remains unclear, making the diagnosis and treatment challenging. Cardiac oxidative and nitrative stress are strongly implicated in the pathogenesis of HFpEF. Herein, we present a unique three-channel fluorescent probe for evaluating cardiac oxidative and nitrative stress in HFpEF by simultaneous detection of NO and GSH. The probe exhibits a native green fluorescence (probe channel), while the presence of GSH and NO can sensitively turn the native green fluorescence into red fluorescence (GSH channel) and near-infrared fluorescence (NO channel), respectively. The probe clearly reveals that both GSH and NO levels are upregulated in cardiomyocytes and heart tissue with HFpEF. Moreover, it uncovers that the enhancement in NO and GSH levels are closely associated with increased level of iNOS (inducible nitric oxide synthase) and activation of the Keap1 (Kelch-like ECH-associated protein 1)/Nrf2 (nuclear factor erythroid 2-related factor 2)/ARE (antioxidant response element) signaling pathway in cardiomyocytes, respectively. This work proposes a promising approach for distinguishing normal heart and HFpEF heart by in vivo noninvasive imaging of both GSH and NO, and greatly contributing to the improvement of the diagnosis and treatment of HFpEF.

[Research on function of Feilike Mixture in stopping cough, eliminating phlegm and relieving asthma based on animal experiments and network pharmacology].

This study observed the pharmacological effects of Feilike Mixture(FLKM) in stopping cough, eliminating phlegm, and relieving asthma through animal experiments, and explored its mechanism using network pharmacology. The antitussive effect was detected by citric acid-induced guinea pig cough model, the expectorant effect by mouse phenol red excretion experiment and lipopolysaccharide-induced mucus hypersecretion rat model, and the antiasthmatic effect by histamine phosphate-induced guinea pig asthma model. The chemical components of FLKM were collected by TCMSP, TCMID, TCMIP, and BATMAN-TCM databases and literature search, and the potential active components were screened through ADMETlab 2.0. The targets of FLKM were obtained by STITCH, SwissTargetPrediction, and TCMSP, and the symptom targets of cough, phlegm, and asthma were acquired through SymMap database. After taking the intersection of FLKM targets and symptom targets, this study used the OECloud tool to perform Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis. RESULTS:: demonstrated that FLKM 0.43-1.74 g·kg~(-1) reduced the number of coughs in guinea pigs within 3 min(P<0.05, P<0.01), and FLKM 6-12 g·kg~(-1) increased the tracheal phenol red excretion in mice(P<0.01). Moreover, FLKM 2-8 g·kg~(-1) inhibited the number of goblet cells(P<0.05, P<0.01), and FLKM 7-11.2 g·kg~(-1) prolonged the incubation period of asthma(P<0.05). A total of 115 potential active components and 910 targets of FLKM were obtained through network pharmacological analysis. FLKM had 27, 12, and 7 targets for stopping cough, eliminating phlegm, and relieving asthma, respectively. The GO and KEGG enrichment analysis found that there were commonalities and characteristics, among which cytokine-cytokine receptor interaction and infectious disease-related signaling pathway were shared. FLKM has a good effect of stopping cough, eliminating phlegm, and relieving asthma through animal experiments and network pharmacology.

Study on the relationship between SLCO1B1 and ApoE gene polymorphisms and the risk of coronary heart disease in the Mongolian population.

Objective This study aimed to analyze the influence of SLCO1B1 and APOE gene polymorphisms on coronary heart disease in Mongolian population who living in Ordos area. Methods From January 2019 to June 2020, 200 Mongolian patients with coronary heart disease admitted to our hospital and other banner hospitals were selected as the case group. At the same time, 150 randomly selected healthy Mongolian people from medical examination centers comprised the control group. The polymorphisms of SLCO1B1 (388A>G, 521 T > C) and ApoE (388 T > C, 526 C > t) were detected by real-time polymerase chain reaction. Combined with environmental data, the effect of gene polymorphism on coronary heart disease was explored. Results Both SLCO1B1 and ApoE polymorphisms satisfied Hardy-Weinberg equilibrium. The SLCO1B1 genotype *1a/*1b showed the highest frequency in the case group, accounting for 35.0%, while The SLCO1B1 genotype *1b/*1b showed the highest frequency in the control group, accounting for 32.0%. Allele *1b was the most commonly seen allele in both the case group and control group (57.8% and 53.7%, respectively). Meanwhile, The difference in the distribution of SLCO1B1 *1a/*15 genotype between the two groups was statistically significant (P < .05). Conclusion The results showed that the SLCO1B *1a/*15 genotype, ApoE ε3 /ε3 genotype, and ε3 allele reduced the risk of coronary disease in the Mongolian population, making them protective genes against this disease, while the ApoE ε4 allele increased the risk of coronary disease, making it a coronary disease risk factor.

MATR3 F115C knock-in mice do not exhibit motor defects or neuropathological features of ALS.

The F115C mutation in the MATR3 gene has been linked to amyotrophic lateral sclerosis (ALS). To determine the pathogenicity of the F115C mutation and the mechanism by which this mutation causes ALS, we generated mice that harbor the F115C mutation in the endogenous murine Matr3 locus. Heterozygous or homozygous MATR3 F115C knock-in mice were viable and did not exhibit motor deficits up to 2 years of age. The mutant mice showed no significant differences in the number of Purkinje cells or motor neurons compared to wild-type littermates. Neuropathological examination revealed an absence of MATR3 and TDP-43 pathology in Purkinje cells and motor neurons in the mutant mice. Together, our results suggest that the F115C mutation in MATR3 may not confer pathogenicity.

Diabetic mastopathy in an elderly woman misdiagnosed as breast cancer: A case report and review of the literature.

BACKGROUND: Diabetic mastopathy is a rare benign disease in clinical practice that mainly occurs in young and middle-aged women with type 1 diabetes. It has also been reported that this disease can be found in patients with type 2 diabetes and other autoimmune diseases, such as Hashimoto's thyroiditis, as well as in men. The pathogenesis of diabetic mastopathy is not yet clear, and it is easily confused with breast cancer due to their similar clinical manifestations and imaging features. CASE SUMMARY: A 69-year-old female patient was admitted because of painless breast masses, with a history of type 2 diabetes. The imaging and physical examination suggested a high risk of breast cancer. Further histopathological analysis showed dense lymphocytes infiltrating around the lobules of the breast, and extensive fibrosis of the surrounding stroma. Finally, diabetic mastopathy was diagnosed. CONCLUSION: The diagnosis of diabetic mastopathy in elderly patients with painless breast masses is difficult to distinguish from breast cancer, and its imaging manifestations are not specific.

Visualizing the Underlying Signaling Pathway Related to Nitric Oxide and Glutathione in Cardiovascular Disease Therapy by a Sequentially Activated Fluorescent Probe.

Clarifying the signaling pathway associated with nitric oxide (NO) and glutathione (GSH) in cardiovascular disease therapy is important for understanding its physiological and pathological processes but is challenging due to the lack of efficient analytical techniques. Herein, we report a BODIPY-based fluorescent probe for recognition of NO and GSH in sequence with high sensitivity and selectivity. The probe exhibits turn-on fluorescence triggered by NO, followed by red-shifted emission in the presence of GSH. The sequentially activated mechanism allows the visualization of NO-induced GSH upregulation in drug-treated endothelial cells and zebrafish for the first time, revealing a signal pathway during the therapy. We hope that it can be used as a convenient and efficient tool for the study of the interplay between NO and GSH and for the screening of effective drugs for cardiovascular disease therapy.