Magnetic sensitivity of cryptochrome 4 from a migratory songbird.

Night-migratory songbirds are remarkably proficient navigators1. Flying alone and often over great distances, they use various directional cues including, crucially, a light-dependent magnetic compass2,3. The mechanism of this compass has been suggested to rely on the quantum spin dynamics of photoinduced radical pairs in cryptochrome flavoproteins located in the retinas of the birds4-7. Here we show that the photochemistry of cryptochrome 4 (CRY4) from the night-migratory European robin (Erithacus rubecula) is magnetically sensitive in vitro, and more so than CRY4 from two non-migratory bird species, chicken (Gallus gallus) and pigeon (Columba livia). Site-specific mutations of ErCRY4 reveal the roles of four successive flavin-tryptophan radical pairs in generating magnetic field effects and in stabilizing potential signalling states in a way that could enable sensing and signalling functions to be independently optimized in night-migratory birds.

Cellular and molecular mechanisms of gastrointestinal cancer liver metastases and drug resistance.

Distant metastases and drug resistance account for poor survival of patients with gastrointestinal (GI) malignancies such as gastric cancer, pancreatic cancer, and colorectal cancer. GI cancers most commonly metastasize to the liver, which provides a unique immunosuppressive tumour microenvironment to support the development of a premetastatic niche for tumor cell colonization and metastatic outgrowth. Metastatic tumors often exhibit greater resistance to drugs than primary tumors, posing extra challenges in treatment. The liver metastases and drug resistance of GI cancers are regulated by complex, intertwined, and tumor-dependent cellular and molecular mechanisms that influence tumor cell behavior (e.g. epithelial-to-mesenchymal transition, or EMT), tumor microenvironment (TME) (e.g. the extracellular matrix, cancer-associated fibroblasts, and tumor-infiltrating immune cells), tumor cell-TME interactions (e.g. through cytokines and exosomes), liver microenvironment (e.g. hepatic stellate cells and macrophages), and the route and mechanism of tumor cell dissemination (e.g. circulating tumor cells). This review provides an overview of recent advances in the research on cellular and molecular mechanisms that regulate liver metastases and drug resistance of GI cancers. We also discuss recent advances in the development of mechanism-based therapy for these GI cancers. Targeting these cellular and molecular mechanisms, either alone or in combination, may potentially provide novel approaches to treat metastatic GI malignancies.

Rhabdomyosarcomas are oncogene addicted to the activation of AVIL.

Rhabdomyosarcoma (RMS) is one of the most common pediatric soft-tissue cancer. Previously, we discovered a gene fusion, MARS-AVIL formed by chromosomal inversion in RMS. Suspecting that forming a fusion with a housekeeping gene may be one of the mechanisms to dysregulate an oncogene, we investigated AVIL expression and its role in RMS. We first showed that MARS-AVIL translates into an in-frame fusion protein, which is critical for RMS cell tumorigenesis. Besides forming a gene fusion with the housekeeping gene, MARS, the AVIL locus is often amplified, and its RNA and protein expression are overexpressed in the majority of RMSs. Tumors with AVIL dysregulation exhibit evidence of oncogene addiction: Silencing MARS-AVIL in cells harboring the fusion, or silencing AVIL in cells with AVIL overexpression, nearly eradicated the cells in culture, as well as inhibited in vivo xenograft growth in mice. Conversely, gain-of-function manipulations of AVIL led to increased cell growth and migration, enhanced foci formation in mouse fibroblasts, and most importantly transformed mesenchymal stem cells in vitro and in vivo. Mechanistically, AVIL seems to serve as a converging node functioning upstream of two oncogenic pathways, PAX3-FOXO1 and RAS, thus connecting two types of RMS associated with these pathways. Interestingly, AVIL is overexpressed in other sarcoma cells as well, and its expression correlates with clinical outcomes, with higher levels of AVIL expression being associated with worse prognosis. AVIL is a bona fide oncogene in RMS, and RMS cells are addicted to its activity.

Identification of Sodium- and Chloride-Sensitive Sites in the Slack Channel.

The Slack channel (KCNT1, Slo2.2) is a sodium-activated and chloride-activated potassium channel that regulates heart rate and maintains the normal excitability of the nervous system. Despite intense interest in the sodium gating mechanism, a comprehensive investigation to identify the sodium-sensitive and chloride-sensitive sites has been missing. In the present study, we identified two potential sodium-binding sites in the C-terminal domain of the rat Slack channel by conducting electrophysical recordings and systematic mutagenesis of cytosolic acidic residues in the rat Slack channel C terminus. In particular, by taking advantage of the M335A mutant, which results in the opening of the Slack channel in the absence of cytosolic sodium, we found that among the 92 screened negatively charged amino acids, E373 mutants could completely remove sodium sensitivity of the Slack channel. In contrast, several other mutants showed dramatic decreases in sodium sensitivity but did not abolish it altogether. Furthermore, molecular dynamics (MD) simulations performed at the hundreds of nanoseconds timescale revealed one or two sodium ions at the E373 position or an acidic pocket composed of several negatively charged residues. Moreover, the MD simulations predicted possible chloride interaction sites. By screening predicted positively charged residues, we identified R379 as a chloride interaction site. Thus, we conclude that the E373 site and the D863/E865 pocket are two potential sodium-sensitive sites, while R379 is a chloride interaction site in the Slack channel.SIGNIFICANCE STATEMENT The research presented here identified two distinct sodium and one chloride interaction sites located in the intracellular C-terminal domain of the Slack (Slo2.2, KCNT1) channel. Identification of the sites responsible for the sodium and chloride activation of the Slack channel sets its gating property apart from other potassium channels in the BK channel family. This finding sets the stage for future functional and pharmacological studies of this channel.

eLIMS: Ensemble Learning-Based Spatial Segmentation of Mass Spectrometry Imaging to Explore Metabolic Heterogeneity.

Spatial segmentation is an essential processing method for image analysis aiming to identify the characteristic suborgans or microregions from mass spectrometry imaging (MSI) data, which is critical for understanding the spatial heterogeneity of biological information and function and the underlying molecular signatures. Due to the intrinsic characteristics of MSI data including spectral nonlinearity, high-dimensionality, and large data size, the common segmentation methods lack the capability for capturing the accurate microregions associated with biological functions. Here we proposed an ensemble learning-based spatial segmentation strategy, named eLIMS, that combines a randomized unified manifold approximation and projection (r-UMAP) dimensionality reduction module for extracting significant features and an ensemble pixel clustering module for aggregating the clustering maps from r-UMAP. Three MSI datasets are used to evaluate the performance of eLIMS, including mouse fetus, human adenocarcinoma, and mouse brain. Experimental results demonstrate that the proposed method has potential in partitioning the heterogeneous tissues into several subregions associated with anatomical structure, i.e., the suborgans of the brain region in mouse fetus data are identified as dorsal pallium, midbrain, and brainstem. Furthermore, it effectively discovers critical microregions related to physiological and pathological variations offering new insight into metabolic heterogeneity.

Progression of hippocampal subfield atrophy and asymmetry in Alzheimer's disease.

Alzheimer's disease (AD) affects the hippocampus during its progression, but the specific observable changes of hippocampal subfields during disease progression remain poorly understood. In this study, we employed an event-based model (EBM) to determine the sequence of occurrence of hippocampal subfield atrophy in mild cognitive impairment (MCI) and AD cohorts. Subjects (207) were included: 86 MCI, 53 AD, and 68 healthy controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants underwent structural magnetic resonance imaging (MRI) scans to analyse the hippocampal subfields. We assigned each patient to a specific EBM stage, based on the number of their abnormal subfields. A combination of 2-year follow-up MRI scans were applied to demonstrate the longitudinal consistency and utility of the model's staging system. The model estimated that the earliest atrophy occurs in the hippocampal fissure, then spreading to other subregions in both MCI and AD. We identified a marked divergence between the sequences of left and right hippocampal subfields atrophy, so inter-hemispheric asymmetry pattern was further analysed. The sequence of asymmetry index (AI) increases beginning in the molecular and granule cell layers of the dentate gyrus (GC-ML-DG), cornus ammonis (CA) 4, and the molecular layer (ML). Longitudinal analysis confirms the efficacy of the model. In addition, the model stages were significantly correlated with patients' memory scores (p < .05). Collectively, we used a data-driven method to provide new insight into AD hippocampal progression. The present model could aid in understanding of the disease stages, as well as tracking memory decline.

Therapeutic vaccine-induced plasma cell differentiation is defective in the presence of persistently high HBsAg levels.

BACKGROUND & AIMS: Mechanisms behind the impaired response of antigen-specific B cells to therapeutic vaccination in chronic hepatitis B virus (HBV) infection remain unclear. The development of vaccines or strategies to overcome this obstacle is vital for advancing the management of chronic hepatitis B. METHODS: A mouse model, denominated as E6F6-B, was engineered to feature a knock-in of a B-cell receptor (BCR) that specifically recognizes HBsAg. This model served as a valuable tool for investigating the temporal and spatial dynamics of humoral responses following therapeutic vaccination under continuous antigen exposure. Using a suite of immunological techniques, we elucidated the differentiation trajectory of HBsAg-specific B cells post-therapeutic vaccination in HBV carrier mice. RESULTS: Utilizing the E6F6-B transfer model, we observed a marked decline in antibody-secreting cells 2 weeks after vaccination. A dysfunctional and atypical pre-plasma cell population (BLIMP-1+ IRF4+ CD40- CD138- BCMA-) emerged, manifested by sustained BCR signaling. By deploying an antibody to purge persistent HBsAg, we effectively prompted the therapeutic vaccine to provoke conventional plasma cell differentiation. This resulted in an enhanced anti-HBs antibody response and facilitated HBsAg clearance. CONCLUSIONS: Sustained high levels of HBsAg limit the ability of therapeutic hepatitis B vaccines to induce the canonical plasma cell differentiation necessary for anti-HBs antibody production. Employing a strategy combining antibodies with vaccines can surmount this altered humoral response associated with atypical pre-plasma cells, leading to improved therapeutic efficacy in HBV carrier mice. IMPACT AND IMPLICATIONS: Therapeutic vaccines aimed at combatting HBV encounter suboptimal humoral responses in clinical settings, and the mechanisms impeding their effectiveness have remained obscure. Our research, utilizing the innovative E6F6-B mouse transfer model, reveals that the persistence of HBsAg can lead to the emergence of an atypical pre-plasma cell population, which proves to be relevant to the potency of therapeutic HBV vaccines. Targeting the aberrant differentiation process of these atypical pre-plasma cells stands out as a critical strategy to amplify the humoral response elicited by HBV therapeutic vaccines in carrier mouse models. This discovery suggests a compelling avenue for further study in the context of human chronic hepatitis B. Encouragingly, our findings indicate that synergistic therapy combining HBV-specific antibodies with vaccines offers a promising approach that could significantly advance the pursuit of a functional cure for HBV.

DeepION: A Deep Learning-Based Low-Dimensional Representation Model of Ion Images for Mass Spectrometry Imaging.

Mass spectrometry imaging (MSI) is a high-throughput imaging technique capable of the qualitative and quantitative in situ detection of thousands of ions in biological samples. Ion image representation is a technique that produces a low-dimensional vector embedded with significant spectral and spatial information on an ion image, which further facilitates the distance-based similarity measurement for the identification of colocalized ions. However, given the low signal-to-noise ratios inherent in MSI data coupled with the scarcity of annotated data sets, achieving an effective ion image representation for each ion image remains a challenge. In this study, we propose DeepION, a novel deep learning-based method designed specifically for ion image representation, which is applied to the identification of colocalized ions and isotope ions. In DeepION, contrastive learning is introduced to ensure that the model can generate the ion image representation in a self-supervised manner without manual annotation. Since data augmentation is a crucial step in contrastive learning, a unique data augmentation strategy is designed by considering the characteristics of MSI data, such as the Poisson distribution of ion abundance and a random pattern of missing values, to generate plentiful ion image pairs for DeepION model training. Experimental results of rat brain tissue MSI show that DeepION outperforms other methods for both colocalized ion and isotope ion identification, demonstrating the effectiveness of ion image representation. The proposed model could serve as a crucial tool in the biomarker discovery and drug development of the MSI technique.

Identification of HK3 as a promising immunomodulatory and prognostic target in sepsis-induced acute lung injury.

BACKGROUND: Sepsis is a life-threatening global disease with a significant impact on human health. Acute lung injury (ALI) has been identified as one of the primary causes of mortality in septic patients. This study aimed to identify candidate genes involved in sepsis-induced ALI through a comprehensive approach combining bioinformatics analysis and experimental validation. METHODS: The datasets GSE65682 and GSE32707 obtained from the Gene Expression Omnibus database were merged to screen for sepsis-induced ALI related differentially expressed genes (DEGs). Functional enrichment and immune infiltration analyses were conducted on DGEs, with the construction of protein-protein interaction (PPI) networks to identify hub genes. In vitro and in vivo models of sepsis-induced ALI were used to study the expression and function of hexokinase 3 (HK3) using various techniques including Western blot, real-time PCR, immunohistochemistry, immunofluorescence, Cell Counting Kit-8, Enzyme-linked immunosorbent assay, and flow cytometry. RESULTS: The results of bioinformatics analysis have identified HK3, MMP9, and S100A8 as hub genes with diagnostic and prognostic significance for sepsis-induced ALI. The HK3 has profound effects on sepsis-induced ALI and exhibits a correlation with immune regulation. Experimental results showed increased HK3 expression in lung tissue of septic mice, particularly in bronchial and alveolar epithelial cells. In vitro studies demonstrated upregulation of HK3 in lipopolysaccharide (LPS)-stimulated lung epithelial cells, with cytoplasmic localization around the nucleus. Interestingly, following the knockdown of HK3 expression, lung epithelial cells exhibited a significant decrease in proliferation activity and glycolytic flux, accompanied by an increase in cellular inflammatory response, oxidative stress, and cell apoptosis. CONCLUSIONS: It was observed for the first time that HK3 plays a crucial role in the progression of sepsis-induced ALI and may be a valuable target for immunomodulation and therapy.Bioinformatics analysis identified HK3, MMP9, and S100A8 as hub genes with diagnostic and prognostic relevance in sepsis-induced ALI. Experimental findings showed increased HK3 expression in the lung tissue of septic mice, particularly in bronchial and alveolar epithelial cells. In vitro experiments demonstrated increased HK3 levels in lung epithelial cells stimulated with LPS, with cytoplasmic localization near the nucleus. Knockdown of HK3 expression resulted in decreased proliferation activity and glycolytic flux, increased inflammatory response, oxidative stress, and cell apoptosis in lung epithelial cells.

I-KCKT allows dissection-free RNA profiling of adult Drosophila intestinal progenitor cells.

The adult Drosophila intestinal epithelium is a model system for stem cell biology, but its utility is limited by current biochemical methods that lack cell type resolution. Here, we describe a new proximity-based profiling method that relies upon a GAL4 driver, termed intestinal-kickout-GAL4 (I-KCKT-GAL4), that is exclusively expressed in intestinal progenitor cells. This method uses UV crosslinked whole animal frozen powder as its starting material to immunoprecipitate the RNA cargoes of transgenic epitope-tagged RNA binding proteins driven by I-KCKT-GAL4 When applied to the general mRNA-binder, poly(A)-binding protein, the RNA profile obtained by this method identifies 98.8% of transcripts found after progenitor cell sorting, and has low background noise despite being derived from whole animal lysate. We also mapped the targets of the more selective RNA binder, Fragile X mental retardation protein (FMRP), using enhanced crosslinking and immunoprecipitation (eCLIP), and report for the first time its binding motif in Drosophila cells. This method will therefore enable the RNA profiling of wild-type and mutant intestinal progenitor cells from intact flies exposed to normal and altered environments, as well as the identification of RNA-protein interactions crucial for stem cell function.

Flexible Anionic Groups-Activated Structure Dissymmetry for Strong Nonlinearity in Ln2 Ae3 MIV 3 S12 Family.

Structural dissymmetry and strong second-harmonic generation (SHG) responses are key conditions for nonlinear optical (NLO) crystals, and targeted combinatorial screening of suitable anionic groups has become extremely effective. Herein, optimal combination of flexible SnSn (n = 5, 6) groups and highly electropositive cations (lanthanides (Ln3+ ) and alkaline earth (Ae2+ : Sr, Ca) metals) affords the successful synthesis of 12 NLO thiostannates including Ln2 Sr3 Sn3 S12 (Pmc21 ) and Ln2 Ca3 Sn3 S12 (P-62m); whereas 17 rigid GeS4 or SiS4 tetrahedra-constructed Ln2 Ae3 Ge3 S12 and Ln2 Ae3 Si3 S12 crystallize in the centrosymmetric (CS) Pnma. This unprecedented CS to noncentrosymmetric (NCS) structural transformation (Pnma to P-62m to Pmc21 ) in the Ln2 Ae3 MIV 3 S12 family indicates that chemical substitution of the tetrahedral GeS4 /SiS4 units with SnSn breaks the original symmetry to form the requisite NCS structures. Remarkably, strong polarization anisotropy and hyperpolarizability of the Sn(4+) S5 unit afford huge performance improvement from the nonphase-matching (NPM) SHG response (1.4 × AgGaS2 and Δn = 0.008) of La2 Ca3 Sn3 S12 to the strong phase-matching (PM) SHG effect (3.0 × AgGaS2 and Δn = 0.086) of La2 Sr3 Sn3 S12 . Therefore, Sn(4+) S5 is proven to be a promising "NLO-active unit." This study verifies that the coupling of flexible SnSn building blocks into structures opens a feasible path for designing targeted NCS crystals with strong nonlinearity and optical anisotropy.

microRNA-125b-5p alleviated CCI-induced neuropathic pain and modulated neuroinflammation via targeting SOX11.

BACKGROUND: Increasing evidence demonstrated the involvement of microRNAs (miRNAs) in the onset and development of neuropathic pain (NP). Exploring the molecular mechanism underlying NP and identifying key molecules could provide potential targets for the therapy of NP. The function and mechanism of miR-125b-5p in regulating NP have been studied, aiming to find a potential therapeutic target for NP. METHODS: NP rat models were established by the chronic constriction injury (CCI) method. The paw withdrawal threshold and paw withdrawal latency were assessed to evaluate the establishment and recovery of rats. Highly aggressive proliferating immortalized (HAPI) micoglia cell, a rat microglia cell line, was treated with lipopolysaccharide (LPS). The M1/M2 polarization and inflammation were evaluated by enzyme-linked immunosorbent assay and western blotting. RESULTS: Decreasing miR-125b-5p and increasing SOX11 were observed in CCI rats and LPS-induced HAPI cells. Overexpressing miR-125b-5p alleviated mechanical allodynia and thermal hyperalgesia and suppressed inflammation in CCI rats. LPS induced M1 polarization and inflammation of HAPI cells, which was attenuated by miR-125b-5p overexpression. miR-125-5p negatively regulated the expression of SOX11 in CCI rats and LPS-induced HAPI cells. Overexpressing SOX11 reversed the protective effects of miR-125b-5p on mechanical pain in CCI rats and the polarization and inflammation in HAPI cells, which was considered the mechanism underlying miR-125b-5p. CONCLUSION: miR-125b-5p showed a protective effect on NP by regulating inflammation and polarization of microglia via negatively modulating SOX11.

Association between frozen embryo transfer and childhood allergy: a retrospective cohort study.

RESEARCH QUESTION: Does frozen embryo transfer (FET) increase the risk of allergic diseases in offspring? DESIGN: This study followed up 653 singleton children: 166 born through FET and 487 born through natural conception. Demographic characteristics, perinatal information and allergic diseases of children and their parents were collected through clinical medical systems and questionnaires. Among these 653 children, allergen-specific immunoglobulin E (IgE) testing was performed using peripheral blood samples collected from 207 children: 145 in the FET group and 62 in the natural conception group. The prevalence of allergic diseases and positive rates of allergen-specific IgE testing were compared between the two groups with adjustments for confounding factors. RESULTS: The prevalence of food allergy was significantly higher in children born through FET compared with children born through natural conception (adjusted OR = 3.154, 95% CI 1.895-5.250; P < 0.001). In addition, positive rates of food allergen sensitization were higher in children in the FET group compared with children in the natural conception group (adjusted OR = 5.769, 95% CI 2.859-11.751, P < 0.001). Children in the FET group had a higher positive sensitization rate to at least one allergen compared with children in the natural conception group (adjusted OR = 3.127, 95% CI 1.640-5.961, P < 0.001). No association was observed between FET and other allergic diseases, including asthma (P = 0.136), atopic dermatitis (P = 0.130) and allergic rhinitis (P = 0.922). Allergen sensitization IgE testing indicated no differences between the two groups in terms of positive sensitization rates of other common allergens, including animal and insect allergens (P = 0.627), inhaled outdoor allergens (P = 0.915) and inhaled outdoor allergens (P = 0.544). CONCLUSION: This study suggests that children born through FET have increased risk of developing food allergy in early childhood.

M2 tumor-associated macrophage promoted DNA methylation in lung cancer metastasis via intensifying EZH2.

This study aimed to explore the interaction between the tumor-associated macrophage (TAM) and enhancer of zeste homolog 2 (EZH2) in tumor microenvironment of lung cancer are obscure. M2 type of TAM was induced by interleukin-4 (IL-4) and interleukin-13 (IL-13) in RAW264.7 cells. Subsequently, the co-culture system of the M2 RAW264.7 treating LLC-1 cells were constructed to evaluate the cell proliferation, migration and invasion abilities. On top of that, the M2 RAW264.7 was injected into the LLC-1 cells-bearing mice. Tumor growth and the number of metastatic nodes were observed. Moreover, DNA methylation, EZH2 expression, target genes of EZH2 and the M2 type TAM-related markers were detected in vivo and in vitro . Further experiments of EZH2 function in lung cancer were carried out by the addition of EZH2 inhibitor (GSK126) and si-EZH2. M2 type of TAM was induced with IL-4 and IL-13 with increased expression of CD206, CD68, CD163 and Arg1. Following co-culture with M2 type TAM, the proliferative, invasive, migrative abilities, tumor growth and metastasis, and the DNA methylation, EZH2 level were strengthened whereas the target genes of EZH2, including p21, CDKN2A, CDKN2B were reduced in LLC-1 cells and LLC-1 cell-bearing mice. Of note, GSK126 and si-EZH2 offset the M2 type TAM's effects, and inhibited the LLC-1 cell metastasis, DNA methylation and tumor growth. M2 type TAM promoted DNA methylation in LLC-1 cells and LLC-1 cell-bearing mice, which is related to the intensified EZH2.

When is the best time and grade to start ruxolitinib in corticosteroid-refractory acute graft-versus-host-disease: A multi-center research.

OBJECTIVE: Ruxolitinib was recently approved to treat corticosteroid-resistant acute graft-versus-host disease (GvHD). However, it is unknown as to whether starting ruxolitinib at a lower versus higher acute GvHD grade or earlier versus later affected outcomes. This study identified the impact of starting acute GvHD grade and start time after declaring corticosteroid resistance and the effect on complete and overall response rates to ruxolitinib therapy. METHODS: Retrospective, observational multi-center study. We divided cohorts into starting ruxolitinib ≤ 7 days (N = 45) versus at > 7 days after declaring corticosteroid resistance (N = 24). RESULTS: In ≤ 7 days cohort complete response (CR) rates at day 28 were 69% (54, 81%) versus 25% (11, 47%; p = .001) in > 7 days cohort, and overall response (OR) rates were 91% (78, 96%) versus 80% (48, 92%; p = .25). CONCLUSIONS: Our data suggest that starting ruxolitinib in ≤ 7 days of declaring corticosteroid failure regardless of G vHD grade improves complete response rate but not OR rates. Starting ruxolitinib at grade I and within 7 days may get a more significant response.

Influence of Cation-Size Effects of Alkaline Earth (Ae) Metals on Dimensionality and Optical Anisotropy Regulation in K4AeP2S8 Thiophosphates.

Cationic substitution demonstrates significant potential for regulating structural dimensionality and physicochemical performance owing to the cation-size effect. Leveraging this characteristic, this study synthesized a new family of K4AeP2S8 (Ae = alkaline earth elements: Mg, Ca, Sr, and Ba) thiophosphates, involving the substitution of Ae2+ cations. The synthesized compounds crystallized in distinct space groups, monoclinic P2/c (Ae = Mg) versus orthorhombic Ibam (Ae = Ca, Sr, and Ba), exhibiting intriguing dimensionality transformations from zero-dimensional (0D) [Mg2P4S16]8- clusters in K4MgP2S8 to 1D ∞[AeP2S8]4- chains in other K4AeP2S8 thiophosphates owing to the varying ionic radii of Ae2+ cations, Ae-S bond lengths, and coordination numbers of AeSn (Mg: n = 6 versus other: n = 8). Experimental investigations revealed that K4AeP2S8 thiophosphates featured wide optical bandgaps (3.37-3.64 eV), and their optical absorptions were predominantly influenced by the S 3p and P 3s orbitals, with negligible contributions from the K and Ae cations. Notably, within the K4AeP2S8 series, birefringence (Δn) increased from K4MgP2S8 (Δn = 0.034) to other K4AeP2S8 (Δn = 0.050-0.079) compounds, suggesting that infinite 1D chains more significantly influence Δn origins than 0D clusters, thus offering a feasible approach for enhancing optical anisotropy and exploring potential new birefringent materials.

MDI versus CSII in Chinese adults with type 1 diabetes in a real-world situation: based on propensity score matching method.

BACKGROUND: Compared with multiple daily insulin injections (MDI), continuous subcutaneous insulin infusion (CSII) is significantly more expensive and has not been widely used in Chinese type 1 diabetes mellitus (T1DM) patients. So there are still significant knowledge gaps regarding clinical and patient-reported outcomes in China. AIMS: This study aims to compare the glycated hemoglobin (HbA1C), insulin therapy related quality of life (ITR-QOL), fear of hypoglycemia (FOH) of adult T1DM patients treated with MDI and CSII based on propensity score matching in real-world conditions in China. METHODS: Four hundred twenty adult T1DM patients who were treated with MDI or CSII continuously for more than 12 months in a national metabolic center from June 2021 to June 2023 were selected as the study subjects. Their QOL and FOH were evaluated with Insulin Therapy Related Quality of Life Measure Questionnaire-Chinese version (ITR-QOL-CV) and the Chinese Version Hypoglycemia Fear Survey-Worry Scale (CHFSII-WS), and their HbA1C were collected at the same time. Potential confounding variables between the two groups were matched using propensity score matching. RESULTS: Of the 420 patients included in the study, 315 were in MDI group and 105 were in CSII group. 102 pairs were successfully matched. After matching, the total score of ITR-QOL-CV scale in CSII group was significantly higher than that in MDI group (87.08 ± 13.53 vs. 80.66 ± 19.25, P = 0.006). Among them, the dimensions of daily life, social life, and psychological state were all statistically different (P < 0.05). The scores of CHFSII-WS (8.33 ± 3.49 vs. 11.77 ± 5.27, P = 0.003) and HbA1C (7.19 ± 1.33% vs. 7.71 ± 1.93%, P = 0.045) in CSII group were lower than those in MDI group. CONCLUSIONS: 25.0% of T1DM adults are treated with CSII. Compared with adult T1DM patients treated with MDI, those treated with CSII have higher ITR-QOL, less FoH, and better control of HbA1C in real-world conditions in China. Therefore, regardless of economic factors, CSII is recommended for adult T1DM patients to optimize the therapeutic effect and outcomes.

Developing a risk model for early diagnosis of metabolic syndrome in Chinese adults aged 40 years and above based on BMI/HDL-C: a cross-sectional study.

BACKGROUND: This study aimed to compare the diagnostic accuracy of four indicators, including waist-to-height ratio (WHTR), vascular adiposity index (VAI), TG/HDL-C, and BMI/HDL-C for metabolic syndrome (MS) in Chinese adults aged 40 years and above. Additionally, the study aimed to develop an efficient diagnostic model displayed by a nomogram based on individual's BMI and circulating HDL-C level. METHODS: A cross-sectional study was conducted on 699 participants aged 40 years and above. Quartiles of BMI/HDL-C, TG/HDL-C, VAI, and WHTR were used as independent variables, and metabolic syndrome was used as the dependent variable. Logistic regression was conducted to explore the impact of each parameter on the risk of MS. The areas under the receiver operating characteristics were compared to determine the accuracy of the indicators in diagnosing MS in the participants. Logistic regression was run to construct the nomograms, and the performance of the nomogram was assessed by a calibration curve. RESULTS: MS subjects had higher levels of BMI, BFM, PBF, VFA, AMC, WC, SCR, TG, and insulin, but lower LDH and HDL-C levels than the subjects without MS. The BMI/HDL-C ratio was positively correlated with the prevalence of MS and its components. The final diagnostic model included five variables: gender, BFM, WC, TG, and BMI/HDL-C. The model showed good calibration and discrimination power with an AUC of 0.780. The cut-off value for the nomogram was 0.623 for diagnosing MS. CONCLUSIONS: BMI/HDL-C ratio was an independent risk factor for MS in Chinese adults. BMI/HDL-C was significantly correlated with MS and its components. BMI/HDL-C was the most powerful diagnostic indicator compared to other indicators, including TG/HDL-C, VAI and WHTR for diagnosing MS. The nomogram drawn based on the diagnostic model provided a practical tool for diagnosing MS in Chinese adults.

Urolithin A promotes atherosclerotic plaque stability by limiting inflammation and hypercholesteremia in Apolipoprotein E-deficient mice.

Urolithin A (UroA), a dietary phytochemical, is produced by gut bacteria from fruits rich in natural polyphenols ellagitannins (ETs). The efficiency of ETs metabolism to UroA in humans depends on gut microbiota. UroA has shown a variety of pharmacological activities. In this study we investigated the effects of UroA on atherosclerotic lesion development and stability. Apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat and high-cholesterol diet for 3 months to establish atherosclerosis model. Meanwhile the mice were administered UroA (50 mg·kg-1·d-1, i.g.). We showed that UroA administration significantly decreased diet-induced atherosclerotic lesions in brachiocephalic arteries, macrophage content in plaques, expression of endothelial adhesion molecules, intraplaque hemorrhage and size of necrotic core, while increased the expression of smooth muscle actin and the thickness of fibrous cap, implying features of plaque stabilization. The underlying mechanisms were elucidated using TNF-α-stimulated human endothelial cells. Pretreatment with UroA (10, 25, 50 µM) dose-dependently inhibited TNF-α-induced endothelial cell activation and monocyte adhesion. However, the anti-inflammatory effects of UroA in TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) were independent of NF-κB p65 pathway. We conducted RNA-sequencing profiling analysis to identify the differential expression of genes (DEGs) associated with vascular function, inflammatory responses, cell adhesion and thrombosis in UroA-pretreated HUVECs. Human disease enrichment analysis revealed that the DEGs were significantly correlated with cardiovascular diseases. We demonstrated that UroA pretreatment mitigated endothelial inflammation by promoting NO production and decreasing YAP/TAZ protein expression and TEAD transcriptional activity in TNF-α-stimulated HUVECs. On the other hand, we found that UroA administration modulated the transcription and cleavage of lipogenic transcription factors SREBP1/2 in the liver to ameliorate cholesterol metabolism in ApoE-/- mice. This study provides an experimental basis for new dietary therapeutic option to prevent atherosclerosis.

Association between multiple inflammatory biomarkers and remnant cholesterol levels in patients with percutaneous coronary intervention: A large-scale real-world study.

BACKGROUND AND AIM: Remnant cholesterol (RC) has garnered increasing attention recently due to its association with adverse cardiovascular events. However, the relationship between RC levels and inflammation remains unclear. The goal of this study was to investigate and compare the predictive value of multiple inflammatory biomarkers for high RC in patients with percutaneous coronary intervention (PCI). METHODS AND RESULTS: Initially, a total of 10,724 consecutive individuals hospitalized for PCI at Fu Wai Hospital in 2013 were enrolled. Finally, 9983 patients receiving dual antiplatelet therapy and drug-eluting stent were selected for analysis. The inflammatory biomarkers included high-sensitivity C-reactive protein (hs-CRP), hs-CRP-to-albumin ratio (CAR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), lymphocyte-to-hs-CRP ratio (LCR), and systemic immune-inflammation index (SII). Patients were divided into higher RC and lower RC groups based on the median RC level. Multivariate logistic regression showed that hs-CRP (OR per SD: 1.254), CAR (OR per SD: 1.245), PLR (OR per SD: 1.139), and SII (OR per SD: 1.077) were associated with high RC (≥median), while LCR (OR per SD: 0.792) was associated with low RC (