Vitamin D Switches BAF Complexes to Protect ß Cells.

A primary cause of disease progression in type 2 diabetes (T2D) is ß cell dysfunction due to inflammatory stress and insulin resistance. However, preventing ß cell exhaustion under diabetic conditions is a major therapeutic challenge. Here, we identify the vitamin D receptor (VDR) as a key modulator of inflammation and ß cell survival. Alternative recognition of an acetylated lysine in VDR by bromodomain proteins BRD7 and BRD9 directs association to PBAF and BAF chromatin remodeling complexes, respectively. Mechanistically, ligand promotes VDR association with PBAF to effect genome-wide changes in chromatin accessibility and enhancer landscape, resulting in an anti-inflammatory response. Importantly, pharmacological inhibition of BRD9 promotes PBAF-VDR association to restore ß cell function and ameliorate hyperglycemia in murine T2D models. These studies reveal an unrecognized VDR-dependent transcriptional program underpinning ß cell survival and identifies the VDR:PBAF/BAF association as a potential therapeutic target for T2D.

Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy.

The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state, resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume, and a 57% increase in survival compared to chemotherapy alone. This work describes a molecular strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests vitamin D priming as an adjunct in PDA therapy. PAPERFLICK:

A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response.

Liver fibrosis is a reversible wound-healing response involving TGFß1/SMAD activation of hepatic stellate cells (HSCs). It results from excessive deposition of extracellular matrix components and can lead to impairment of liver function. Here, we show that vitamin D receptor (VDR) ligands inhibit HSC activation by TGFß1 and abrogate liver fibrosis, whereas Vdr knockout mice spontaneously develop hepatic fibrosis. Mechanistically, we show that TGFß1 signaling causes a redistribution of genome-wide VDR-binding sites (VDR cistrome) in HSCs and facilitates VDR binding at SMAD3 profibrotic target genes via TGFß1-dependent chromatin remodeling. In the presence of VDR ligands, VDR binding to the coregulated genes reduces SMAD3 occupancy at these sites, inhibiting fibrosis. These results reveal an intersecting VDR/SMAD genomic circuit that regulates hepatic fibrogenesis and define a role for VDR as an endocrine checkpoint to modulate the wound-healing response in liver. Furthermore, the findings suggest VDR ligands as a potential therapy for liver fibrosis.

Spectroscopic evidence of spin-state excitation in d-electron correlated semiconductor FeSb2.

Iron antimonide (FeSb2) has been investigated for decades due to its puzzling electronic properties. It undergoes the temperature-controlled transition from an insulator to an ill-defined metal, with a cross-over from diamagnetism to paramagnetism. Extensive efforts have been made to uncover the underlying mechanism, but a consensus has yet to be reached. While macroscopic transport and magnetic measurements can be explained by different theoretical proposals, the essential spectroscopic evidence required to distinguish the physical origin is missing. In this paper, through the use of X-ray absorption spectroscopy and atomic multiplet simulations, we have observed the mixed spin states of 3d 6 configuration in FeSb2. Furthermore, we reveal that the enhancement of the conductivity, whether induced by temperature or doping, is characterized by populating the high-spin state from the low-spin state. Our work constitutes vital spectroscopic evidence that the electrical/magnetical transition in FeSb2 is directly associated with the spin-state excitation.

Single-Cell Transcriptomic Analysis Links Nonmyelinating Schwann Cells to Proinflammatory Response in the Lung.

The lung is a barrier tissue with constant exposure to the inhaled environment. Therefore, innate immunity against particulates and pathogens is of critical importance to maintain tissue homeostasis. Although the lung harbors both myelinating and nonmyelinating Schwann cells (NMSCs), NMSCs represent the most abundant Schwann cell (SC) population in the lung. However, their contribution to lung physiology remains largely unknown. In this study, we used the human glial fibrillary acidic protein promoter driving tdTomato expression in mice to identify SCs in the peripheral nervous system and determine their location within the lung. Single-cell transcriptomic analysis revealed the existence of two NMSC populations (NMSC1 and NMSC2) that may participate in pathogen recognition. We demonstrated that these pulmonary SCs produce chemokines and cytokines upon LPS stimulation using in vitro conditions. Furthermore, we challenged mouse lungs with LPS and found that NMSC1 exhibits an enriched proinflammatory response among all SC subtypes. Collectively, these findings define the molecular profiles of lung SCs and suggest a potential role for NMSCs in lung inflammation.

The MuSK agonist antibody protects the neuromuscular junction and extends the lifespan in C9orf72-ALS mice.

The disassembly of the neuromuscular junction (NMJ) is an early event in amyotrophic lateral sclerosis (ALS), ultimately leading to motor dysfunction and lethal respiratory paralysis. The hexanucleotide GGGGCC repeat expansion in the C9orf72 gene is the most common genetic mutation, and the dipeptide repeat (DPR) proteins have been shown to cause neurodegeneration. While no drugs can treat ALS patients efficiently, new treatment strategies are urgently needed. Here, we report that a MuSK agonist antibody alleviates poly-PR-induced NMJ deficits in C9orf72-ALS mice. The HB9-PRF/F mice, which express poly-PR proteins in motor neurons, exhibited impaired motor behavior and NMJ deficits. Mechanistically, poly-PR proteins interacted with Agrin to disrupt the interaction between Agrin and Lrp4, leading to attenuated activation of MuSK. Treatment with a MuSK agonist antibody rescued NMJ deficits, and extended the lifespan of C9orf72-ALS mice. Moreover, impaired NMJ transmission was observed in C9orf72-ALS patients. These findings identify the mechanism by which poly-PR proteins attenuate MuSK activation and NMJ transmission, highlighting the potential of promoting MuSK activation with an agonist antibody as a therapeutic strategy to protect NMJ function and prolong the lifespan of ALS patients.

Proteomics and Metabolic Characteristics of Boar Seminal Plasma Extracellular Vesicles Reveal Biomarker Candidates Related to Sperm Motility.

Although seminal plasma extracellular vesicles (SPEVs) play important roles in sperm function, little is known about their metabolite compositions and roles in sperm motility. Here, we performed metabolomics and proteomics analysis of boar SPEVs with high or low sperm motility to investigate specific biomarkers affecting sperm motility. In total, 140 proteins and 32 metabolites were obtained through differentially expressed analysis and weighted gene coexpression network analysis (WGCNA). Seven differentially expressed proteins (DEPs) (ADIRF, EPS8L1, PRCP, CD81, PTPRD, CSK, LOC100736569) and six differentially expressed metabolites (DEMs) (adenosine, beclomethasone, 1,2-benzenedicarboxylic acid, urea, 1-methyl-l-histidine, and palmitic acid) were also identified in WGCNA significant modules. Joint pathway analysis revealed that three DEPs (GART, ADCY7, and NTPCR) and two DEMs (urea and adenosine) were involved in purine metabolism. Our results suggested that there was significant correlation between proteins and metabolites, such as IL4I1 and urea (r = 0.86). Furthermore, we detected the expression level of GART, ADCY7, and CDC42 in sperm of two groups, which further verified the experimental results. This study revealed that several proteins and metabolites in SPEVs play important roles in sperm motility. Our results offered new insights into the complex mechanism of sperm motility and identified potential biomarkers for male reproductive diseases.

Triglyceride-glucose index and clinical outcomes in sepsis: A retrospective cohort study of MIMIC-IV.

Although accumulating researches were done for investigating the relationship between triglyceride-glucose index (TyG index) and different diseases, none of the researches have been made in sepsis yet. In this study, we aimed to explore the relationship between TyG index and clinical outcomes in sepsis based on a large critical care public database. Sepsis patients in Medical Information Mart for Intensive Care IV (MIMIC-IV) Database were included. The exposure was TyG index, which was calculated by the equation: ln (TG (mg/dL) × FBG (mg/dL)/2). The outcomes were in-hospital mortality and 1-year mortality. The relationship between TyG index and outcomes was performed by Cox regression analysis. Smooth fitting curves were constructed by using generalized additive model. Kaplan-Meier analyses for cumulative hazard of 1-year mortality in different groups were done. 1103 sepsis patients were included with a median TyG index of 9.78. The mortalities of in-hospital and 1-year were 37.53% (n = 414) and 42.25% (n = 466), respectively. After adjusting confounders, there was a significantly negative relationship between TyG index and mortalities of in-hospital and 1-year. With the per unit increment in TyG index, the risk of in-hospital and 1-year mortality both decreased by 21% (HR = 0.79, 95% CI: 0.66-0.94, p = 0.0086 and HR = 0.79, 95% CI: 0.66-0.94, p = 0.0080, respectively). A negative relationship between TyG index and clinical outcomes in sepsis was found.

Pathogen stimulations and immune cells synergistically affect the gene expression profile characteristics of porcine peripheral blood mononuclear cells.

BACKGROUND: Pigs serve as a crucial source of protein in the human diet and play a fundamental role in ensuring food security. However, infectious diseases caused by bacteria or viruses are a major threat to effective global pig farming, jeopardizing human health. Peripheral blood mononuclear cells (PBMCs) are a mixture of immune cells that play crucial roles in immunity and disease resistance in pigs. Previous studies on the gene expression regulation patterns of PBMCs have concentrated on a single immune stimulus or immune cell subpopulation, which has limited our comprehensive understanding of the mechanisms of the pig immune response. RESULTS: Here, we integrated and re-analyzed RNA-seq data published online for porcine PBMC stimulated by lipopolysaccharide (LPS), polyinosinic acid (PolyI:C), and various unknown microorganisms (EM). The results revealed that gene expression and its functional characterization are highly specific to the pathogen, identifying 603, 254, and 882 pathogen-specific genes and 38 shared genes, respectively. Notably, LPS and PolyI:C stimulation directly triggered inflammatory and immune-response pathways, while exposure to mixed microbes (EM) enhanced metabolic processes. These pathogen-specific genes were enriched in immune trait-associated quantitative trait loci (QTL) and eGenes in porcine immune tissues and were implicated in specific cell types. Furthermore, we discussed the roles of eQTLs rs3473322705 and rs1109431654 in regulating pathogen- and cell-specific genes CD300A and CD93, using cellular experiments. Additionally, by integrating genome-wide association studies datasets from 33 complex traits and diseases in humans, we found that pathogen-specific genes were significantly enriched for immune traits and metabolic diseases. CONCLUSIONS: We systematically analyzed the gene expression profiles of the three stimulations and demonstrated pathogen-specific and cell-specific gene regulation across different stimulations in porcine PBMCs. These findings enhance our understanding of shared and distinct regulatory mechanisms of genetic variants in pig immune traits.

Tumor suppressive function of IGF2BP1 in gastric cancer through decreasing MYC.

Gastric cancer is one of the most common causes of cancer-related death worldwide. The N6 -methyladenosine (m6 A) reader IGF2BP1 (insulin-like growth factor-2 mRNA binding protein 1) has been reported to promote cancer progression by stabilizing oncogenic mRNAs through its m6 A-binding activity in some tumors. However, the role of IGF2BP1 in gastric carcinogenesis remains unclear. In this study, we found that IGF2BP1 is significantly downregulated in tumor tissues from patients with gastric cancer. Lower expression of IGF2BP1 is associated with poor prognosis. Gastric cancer cell proliferation is suppressed by IGF2BP1 in an m6 A-dependent manner. Additionally, IGF2BP1 is able to significantly attenuate tumor growth of gastric cancer cells. Further m6 A sequencing and m6 A-RNA immunoprecipitation assays show that MYC (c-myc proto-oncogene) mRNA is a target transcript of IGF2BP1 in gastric cancer cells. IGF2BP1 inhibits gastric cancer cell proliferation by reducing the mRNA and protein expression of MYC. Mechanistically, IGF2BP1 promotes the degradation of MYC mRNA and inhibits its translation efficiency. Taken together, these data suggest that IGF2BP1 plays a tumor-suppressive role in gastric carcinogenesis by downregulating MYC in an m6 A-dependent manner, thereby making the IGF2BP1-MYC axis a potential target for gastric cancer treatment.

Portable Hadamard-Transform Raman Spectrometer: A Powerful Analytical Tool for Point-of-Care Testing.

A portable Hadamard-transform Raman spectrometer with excellent performance was fabricated consisting of a 785 nm laser, an optical filter, an optical system, a control system, and a signal processing system. As the core of the spectrometer, the optical system was composed of a slit, collimator, optical grating, reflector, digital micromirror devices (DMD), lens system, and InGaAs photodetector. Compared with a conventional dispersive Raman spectrometer, the proposed Raman spectrometer adopted the DMD and corresponding controlling device (DLPC350 control chip) to collect the Raman spectrum. Thus, in our design, the gratings are fixed, while the full Raman spectrum was collected by the deflection of the micromirror. This design can greatly improve the vibration resistance ability of the spectrometer since the gratings are not rotating during the spectrum collecting. More importantly, Hadamard-transform was used as signal processing technology, which has the ability of faster calculation, the merits of high energy input, single detector multichannel simultaneous detection (imaging) ability, and high signal-to-noise ratio (SNR). Hence, the Hadamard-transform portable Raman spectrometer has the potential to be applied in the field of point-of-care testing (POCT).

Large Enhancement of Polarization in a Layered Hybrid Perovskite Ferroelectric Semiconductor via Molecular Engineering.

Switchable spontaneous polarization is the vital property of ferroelectrics, which leads to other key physical properties such as piezoelectricity, pyroelectricity, and nonlinear optical effects, etc. Recently, organic-inorganic hybrid perovskites with 2D layered structure have become an emerging branch of ferroelectric materials. However, most of the 2D hybrid ferroelectrics own relatively low polarizations (<15 µC cm-2 ). Here, a strategy to enhance the polarization of these hybrid perovskites by using ortho-, meta-, para-halogen substitution is developed. Based on (benzylammonium)2 PbCl4 (BZACL), the para-chlorine substituted (4-chlorobenzylammonium)2 PbCl4 (4-CBZACL) ferroelectric semiconductor shows a large spontaneous polarization (23.3 µC cm-2 ), which is 79% larger than the polarization of BZACL. This large enhancement of polarization is successfully explained via ab initio calculations. The study provides a convenient and efficient strategy to promote the ferroelectric property in the hybrid perovskite family.

Low-loss tantalum pentoxide photonics with a CMOS-compatible process.

We report a Ta2O5 photonic platform with a propagation loss of 0.49 dB/cm at 1550 nm, of 0.86 dB/cm at 780 nm, and of 3.76 dB/cm at 2000 nm. The thermal bistability measurement is conducted in the entire C-band for the first time to reveal the absorption loss of Ta2O5 waveguides, offering guidelines for further reduction of the waveguide loss. We also characterize the Ta2O5 waveguide temperature response, which shows favorable thermal stability. The fabrication process temperature is below 350°C, which is friendly to integration with active optoelectronic components.

Protective effects of engineered Lactobacillus crispatus strains expressing G-CSF on thin endometrium of mice.

STUDY QUESTION: Does recombinant Lactobacillus expressing granulocyte colony-stimulating factor (G-CSF) have a better protective effect than the current treatment of thin endometrium (TE)? SUMMARY ANSWER: This study suggested that the intrauterine injection of Lactobacillus crispastus (L. crispastus)-pPG612-G-CSF has a positive effect on preventing TE induced by 95% alcohol in mice. WHAT IS KNOWN ALREADY: TE has a negative impact on the success rate of ART in patients, and is usually caused by intrauterine surgery, endometrial infection, or hormone drugs. Exogenous G-CSF can promote endometrial vascular remodelling and increase endometrial receptivity and the embryo implantation rate. Moreover, Lactobacillus plays a crucial role in maintaining and regulating the local microecological balance of the reproductive tract, and it could be a delivery carrier of the endometrial repair drug G-CSF. STUDY DESIGN, SIZE, DURATION: We constructed engineered L. crispastus strains expressing G-CSF. The mice were divided into five groups: (i) Control group (C, n = 28), uteri were treated with preheated saline solution via intrauterine injection on the third and sixth day of oestrus; (ii) Model group (M, n = 35), where uteri were treated with 95% alcohol on the third day of oestrus and preheated saline solution on the sixth day of oestrus via intrauterine injection; (iii) L. crispatus-pPG612-treatment group (L, n = 45), where uteri were treated with 95% alcohol on the third day of oestrus and 0.1 ml × 108 CFU/ml L. crispatus-pPG612 on the sixth day of oestrus via intrauterine injection; (iv) L. crispatus-pPG612-treatment group (LG, n = 45), where uteri were treated with 95% alcohol on the third day of oestrus and 0.1 ml × 108 CFU/ml L. crispatus-pPG612-G-CSF on the sixth day of oestrus via intrauterine injection; (v) G-CSF-treatment group (G, n = 52), where uteri were treated with 95% alcohol on the third day of oestrus and 30 µg/kg G-CSF on the sixth day of oestrus via intrauterine injection. Then, we compared the effects of L. crispastus, L. crispatus-pPG612-G-CSF and G-CSF on endometrial thickness, angiogenesis, fibrosis, and inflammation in the TE mouse. PARTICIPANTS/MATERIALS, SETTING, METHODS: We collected uterine tissues for haematoxylin-eosin staining, immunohistochemical staining, Western blot and RT-PCR, as well as serum for ELISA and uterine flushing solution for high-throughput sequencing. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with those in the M group (the mice of the group were intrauterine injected 95% alcohol and treated with saline solution), the L. crispatus-pPG612-G-CSF strain increased the thickness of the endometrium (P < 0.001) and the number of blood vessels and glands (both P < 0.001), enhanced the expression of cytokeratin 19 (CK19) (P < 0.001), vimentin (Vim) (P < 0.001), vascular endothelial growth factor-A (P < 0.001), and CD34 (P < 0.001), and decreased fibrosis levels (P = 0.004). In addition, the high-throughput sequencing results indicated that the L. crispatus-pPG612-G-CSF strain could decrease the abundance of Pseudomonas (P = 0.044) and Actinomyces spp. (P = 0.094) in TE mice and increased the average number of embryos (P = 0.036). Finally, the L. crispatus-pPG612-G-CSF strain was preliminarily confirmed to activate the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signalling pathway and enhance the mRNA expression of hypoxia-inducible factor-1α (P < 0.001), vascular endometrial growth factor (P = 0.003), and endothelial cell nitric oxide synthase (P = 0.003) in mouse uterine tissue. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Therapy with the L. crispatus-pPG612-G-CSF strain has tremendous potential to accelerate the reparative processes of TE. However, we have reported only the expression of genes and proteins related to the PI3K/AKT pathway, and numerous other mechanisms may also be involved in the restoration of the endometrium by L. crispatus-pPG612-G-CSF. WIDER IMPLICATIONS OF THE FINDINGS: The results from the study provide new ideas and suggest new methods for TE treatment. STUDY FUNDING/COMPETING INTEREST(S): This work was financially supported by the Project of Science and Technology Development Plan of Jilin Province (grant number 20210101232JC), the Science and Technology Plan Item of Jilin Provincial Education Department (grant number JT53101022010), and the Doctoral Research Start-up Fund of Jilin Medical University (grant numbers JYBS2021014LK and 2022JYBS006KJ). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.

LHPP, a risk factor for major depressive disorder, regulates stress-induced depression-like behaviors through its histidine phosphatase activity.

Histidine phosphorylation (pHis), occurring on the histidine of substrate proteins, is a hidden phosphoproteome that is poorly characterized in mammals. LHPP (phospholysine phosphohistidine inorganic pyrophosphate phosphatase) is one of the histidine phosphatases and its encoding gene was recently identified as a susceptibility gene for major depressive disorder (MDD). However, little is known about how LHPP or pHis contributes to depression. Here, by using integrative approaches of genetics, behavior and electrophysiology, we observed that LHPP in the medial prefrontal cortex (mPFC) was essential in preventing stress-induced depression-like behaviors. While genetic deletion of LHPP per se failed to affect the mice's depression-like behaviors, it markedly augmented the behaviors upon chronic social defeat stress (CSDS). This augmentation could be recapitulated by the local deletion of LHPP in mPFC. By contrast, overexpressing LHPP in mPFC increased the mice's resilience against CSDS, suggesting a critical role of mPFC LHPP in stress-induced depression. We further found that LHPP deficiency increased the levels of histidine kinases (NME1/2) and global pHis in the cortex, and decreased glutamatergic transmission in mPFC upon CSDS. NME1/2 served as substrates of LHPP, with the Aspartic acid 17 (D17), Threonine 54 (T54), or D214 residue within LHPP being critical for its phosphatase activity. Finally, reintroducing LHPP, but not LHPP phosphatase-dead mutants, into the mPFC of LHPP-deficient mice reversed their behavioral and synaptic deficits upon CSDS. Together, these results demonstrate a critical role of LHPP in regulating stress-related depression and provide novel insight into the pathogenesis of MDD.

Understanding the Interface Enhancement Mechanisms of CFRP with the Polydopamine-Polyetheramine Interphase at the Molecular Level.

In this work, polydopamine (PDA) and polyetheramine D230 were selected to construct the PDA-D230 interphase between the carbon fiber (CF) and epoxy matrix. Density functional theory (DFT) and molecular dynamics (MD) simulations were performed to explore the interface enhancement mechanisms of a carbon fiber reinforced polymer (CFRP) with the PDA-D230 interphase from the molecular level. The adsorption characteristics of a PDA molecule on the CF surface were investigated using the DFT method. The results show that stronger π-π stacking interactions are formed due to the structure and orientation preference of the PDA molecule. The interfacial structures and properties of CFRP with the PDA-D230 interphase are derived from MD simulations. The PDA-D230 interphase on the CF surface induces stronger interfacial interaction energy, leading to the better load transfer between the CF and epoxy matrix. The existence of the PDA-D230 interphase on the CF surface can decrease the mean-square displacement (MSD) value and the free volume fraction of CFRP, which restricts the movement of epoxy atoms and inhibits the translational and rotational motion of epoxy chains. Compared with the epoxy using pristine CFs as reinforcement, the interfacial shear stress (ISS) of CFRP with the PDA-D230 interphase is improved by 13.1%. Our results provide valuable insights into the interface characteristics of CFRP with the PDA-D230 interphase, which are of great significance for exploring the strengthening mechanisms for CFRPs with the PDA-D230 interphase.

Unenhanced computed tomography radiomics help detect endoleaks after endovascular repair of abdominal aortic aneurysm.

OBJECTIVES: To explore the feasibility of unenhanced CT images for endoleak detection of abdominal aortic aneurysm (AAA) after endovascular repair (EVAR). METHODS: Patients who visited our hospital after EVAR from July 2014 to September 2021 were retrospectively collected. Two radiologists evaluated the presence or absence of endoleaks using the combination of contrast-enhanced and unenhanced CT as the referenced standard. After segmenting the aneurysm sac of the unenhanced CT, the radiomic features were automatically extracted from the region of interest. Histogram features of patients with and without endoleak were statistically analyzed to explore the differences between the two groups. Twelve common machine learning (ML) models based on radiomic features were constructed to evaluate the performance of endoleak detection with unenhanced CT images. RESULTS: The study included 216 patients (69 ± 8 years; 191 men) with AAA, including 64 patients with endoleaks. A total of 1955 radiomic features of unenhanced CT were extracted. Compared with patients without endoleak, the aneurysm sac outside the stent of patients with endoleak had higher CT attenuation (41.7 vs. 33.6, p < 0.001) with smaller dispersion (51.5 vs. 58.8, p < 0.001). The average area under the curve (AUC) of the ML models constructed with unenhanced CT radiomics was 0.86 ± 0.05, the accuracy was 81% ± 4, the sensitivity was 88% ± 10, and the specificity was 78% ± 5. When fixing the sensitivity to > 90% (92% ± 2), the models retained specificity at 72% ± 10. CONCLUSIONS: Unenhanced CT features exhibit significant differences between patients with and without endoleak and can help detect endoleaks in AAA after EVAR with high sensitivity. CLINICAL RELEVANCE STATEMENT: Unenhanced CT radiomics can help provide an alternative method of endoleak detection in patients who have adverse reactions to contrast media. This study further exploits the value of unenhanced CT examinations in the clinical management and surveillance of postoperative abdominal aortic aneurysm. KEY POINTS: • Unenhanced CT features of the aneurysm sac outside the stent exhibit significant differences between patients with and without endoleak. The endoleak group showed higher unenhanced CT attenuation (41.7 vs 33.6, p < .001) with smaller dispersion (51.5 vs 58.8, p < .001) than the nonendoleak group. • Unenhanced CT radiomics can help detect endoleaks after intervention. The average area under the curve (AUC) of twelve common machine learning models constructed with unenhanced CT radiomics was 0.86 ± 0.05, the average accuracy was 81% ± 4. • When fixing the sensitivity to > 90% (92% ± 2), the machine learning models retained average specificity at 72% ± 10.

Unveiling the role of ABI3 and hub senescence-related genes in macrophage senescence for atherosclerotic plaque progression.

BACKGROUND: Atherosclerosis, characterized by abnormal arterial lipid deposition, is an age-dependent inflammatory disease and contributes to elevated morbidity and mortality. Senescent foamy macrophages are considered to be deleterious at all stages of atherosclerosis, while the underlying mechanisms remain largely unknown. In this study, we aimed to explore the senescence-related genes in macrophages diagnosis for atherosclerotic plaque progression. METHODS: The atherosclerosis-related datasets were retrieved from the Gene Expression Omnibus (GEO) database, and cellular senescence-associated genes were acquired from the CellAge database. R package Limma was used to screen out the differentially expressed senescence-related genes (DE-SRGs), and then three machine learning algorithms were applied to determine the hub DE-SRGs. Next, we established a nomogram model to further confirm the clinical significance of hub DE-SRGs. Finally, we validated the expression of hub SRG ABI3 by Sc-RNA seq analysis and explored the underlying mechanism of ABI3 in THP-1-derived macrophages and mouse atherosclerotic lesions. RESULTS: A total of 15 DE-SRGs were identified in macrophage-rich plaques, with five hub DE-SRGs (ABI3, CAV1, NINJ1, Nox4 and YAP1) were further screened using three machine learning algorithms. Subsequently, a nomogram predictive model confirmed the high validity of the five hub DE-SRGs for evaluating atherosclerotic plaque progression. Further, the ABI3 expression was upregulated in macrophages of advanced plaques and senescent THP-1-derived macrophages, which was consistent with the bioinformatics analysis. ABI3 knockdown abolished macrophage senescence, and the NF-κB signaling pathway contributed to ABI3-mediated macrophage senescence. CONCLUSION: We identified five cellular senescence-associated genes for atherogenesis progression and unveiled that ABI3 might promote macrophage senescence via activation of the NF-κB pathway in atherogenesis progression, which proposes new preventive and therapeutic strategies of senolytic agents for atherosclerosis.

1-Trinitromethyl-3,5-dinitro-4-nitroaminopyrazole: Intramolecular Full Nitration and Strong Intermolecular H-Bonds toward Highly Dense Energetic Materials.

Full nitration is one of the most effective strategies used in synthesizing high-density energetic materials, but this strategy has reached its limit because the resultant compounds cannot be further functionalized. To overcome this limitation, we present the synergistic action of full nitration and strong intermolecular H-bonding in designing and synthesizing 1-trinitromethyl-3,5-dinitro-4-nitroaminopyrazole (DNTP) with a density that exceeds those of the reported monocyclic CHON compounds. The detonation velocity and specific impulse of DNTP exceed those of 1-trinitromethyl-3,4,5-trinitropyrazole (TTP), HMX, and ADN.

Suitability of reduced dose glucocorticoids therapy regimen for antibody-associated vasculitis patients with TB: a retrospective study.

INTENTION: Immunosuppressive therapy is the major treatment approach for patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). Due to impaired cellular immunological function and the use of glucocorticoids and immunosuppressants, AAV patients are predisposed to opportunistic infections, including tuberculosis (TB). This retrospective study aims to analyze the clinical characteristics of patients with AAV and TB and explore suitable glucocorticoid regimens for them. So as to provide a basis for future clinical guidelines and have important value for guiding clinical treatment. METHODS: This study retrospectively reviewed 58 AAV patients (18-80 years old) with TB admitted to Changsha Central Hospital Affiliated with the University of South China from 2016.1 to 2023.4 Patients were divided into standard-dose and reduced-dose glucocorticoid groups before retrospectively analyzing their medical records. RESULTS: A total of 58 AAV patients with TB were enrolled, with 15 dying throughout the monitoring period. Through analysis data, compared with the standard-dose group, the reduced group had less proteinuria and hematuria. In survival analysis, the reduced-dose glucocorticoid group had lower mortality than the standard-dose group (P = 0.03); however, no significant difference was noted in the use of immunoglobulin (P = 0.39), tuberculosis activity (P = 0.64), and age stratification (P = 0.40). The BVAS score before treatment and 6 months post-treatment suggest that the two regimens cause the same risk of ESKD (P > 0.05). CONCLUSION: In conclusion, the reduced glucocorticoid dose group can achieve the same curative effect as the standard dose group and has less damage to the kidney in hematuria and proteinuria. Therefore, the reduced glucocorticoid dose treatment regimen may be more suitable for AAV patients with TB.