TFEB overexpression through GFAP promoter disrupts neuronal lamination by dysregulating neurogenesis during embryonic development.

INTRODUCTION: Transcription factor EB (TFEB), a key regulator of autophagy and lysosomal biogenesis, has diverse roles in various physiological processes. Enhancing lysosomal function by TFEB activation has recently been implicated in restoring neural stem cells (NSCs) function. Overexpression of TFEB can inhibit the cell cycle of newborn cortical NSCs. It has also been found that TFEB regulates the pluripotency transcriptional network in mouse embryonic stem cells independent of autophagy lysosomal biogenesis. This study aims to explore the effects of TFEB activation on neurogenesis in vivo through transgenic mice. METHODS: We developed a GFAP-driven TFEB overexpression mouse model (TFEB GoE) by crossing the floxed TFEB overexpression mice and hGFAP-cre mice. We performed immunohistochemical and fluorescence staining on brain tissue from newborn mice to assess neurogenesis changes, employing markers such as GFAP, Nestin, Ki67, DCX, Tbr1 and Neun to trace different stages of neural development and cell proliferation. RESULTS: TFEB GoE mice exhibited premature mortality, dying at 10-20 days after birth. Immunohistochemical analysis revealed significant abnormalities, including disrupted hippocampal structure and cortical layering. Compared to control mice, TFEB GoE mice showed a marked increase in radial glial cells (RGCs) in the hippocampus and cortex, with Ki67 staining indicating these cells were predominantly in a quiescent state. This suggests that TFEB overexpression suppresses RGCs proliferation. Additionally, abnormal distributions of migrating neurons and mature neurons were observed, highlighted by DCX, Tbr1 and Neun staining, indicating a disruption in normal neurogenesis. CONCLUSION: This study, using transgenic animals in vivo, revealed that GFAP-driven TFEB overexpression leads to abnormal neural layering in the hippocampus and cortex by dysregulating neurogenesis. Our study is the first to discover the detrimental impact of TFEB overexpression on neurogenesis during embryonic development, which has important reference significance in future TFEB overexpression interventions in NSCs for treatment.

Myocardial deformation characteristics assessed by cardiovascular magnetic resonance feature tracking in a healthy Chinese population.

Purpose: To explore global/regional myocardial deformation across various layers, vascular distributions, specific levels and distinct walls in healthy individuals using cardiovascular magnetic resonance feature tracking (CMR-FT). Methods: We selected a cohort of 55 healthy participants and CMR cine images were used to obtain the left ventricular (LV) peak longitudinal, circumferential, radial strains (LS, CS, RS). The characteristics of normal LV strain in various layers (endocardium, myocardium, epicardium), territories [left anterior descending artery (LAD), left circumflex artery (LCX), and right coronary artery (RCA)], levels (basal, middle, apical) and walls (anterior, septum, inferior, lateral) were compared. Results: The absolute values of the LV global LS and CS gradually decreased from endocardium to epicardium. The absolute LV global RS (65.7 ± 47.7%) was maximum relative to LS (-22.0 ± 10.8%) and CS (-22.8 ± 7.7%). The absolute values of the LCX territorial strain were the largest compared with the LAD and RCA territorial strains. Regional RS, endo-CS and endo-LS gradually increased from the basal to the apical level. The LV lateral walls had the highest strain values (CS, LS, and RS). Conclusions: Variations in normal LV strain values across various layers, territories, levels, and walls were observed, suggesting the necessity for careful clinical interpretation of these strain values. These findings also partially revealed the complexity of normal cardiac mechanics.

PQR309, a dual PI3K/mTOR inhibitor, synergizes with gemcitabine by impairing the GSK-3ß and STAT3/HSP60 signaling pathways to treat nasopharyngeal carcinoma.

End-stage nasopharyngeal carcinoma (NPC) has unsatisfactory survival. The limited benefit of chemotherapy and the scarcity of targeted drugs are major challenges in NPC. New approaches to treat late-stage NPC are urgently required. In this study, we explored whether the dual PI3K/mTOR inhibitor, PQR309, exerted a favorable antineoplastic effect and sensitized the response to gemcitabine in NPC. We observed that PI3K expression was positive and elevated in 14 NPC cell lines compared with that in normal nasopharygeal cell lines. Patients with NPC with higher PI3K levels displayed poorer prognosis. We subsequently showed that PQR309 alone effectively decreased the viability, invasiveness, and migratory capability of NPC cells and neoplasm development in mice xenograft models, and dose-dependently induced apoptosis. More importantly, PQR309 remarkably strengthened the anti-NPC function of gemcitabine both in vivo and in vitro. Mechanistically, PQR309 sensitized NPC to gemcitabine by increasing caspase pathway-dependent apoptosis, blocking GSK-3ß and STAT3/HSP60 signaling, and ablating epithelial-mesenchyme transition. Thus, targeting PI3K/mTOR using PQR309 might represent a treatment option to promote the response to gemcitabine in NPC, and provides a theoretical foundation for the study of targeted drugs combined with chemotherapy for NPC.

Preclinical characterization and phase 1 results of ADG106 in patients with advanced solid tumors and non-Hodgkin's lymphoma.

ADG106, a ligand-blocking agonistic antibody targeting CD137 (4-1BB), exhibits promising results in preclinical studies, demonstrating tumor suppression in various animal models and showing a balanced profile between safety and efficacy. This phase 1 study enrolls 62 patients with advanced malignancies, revealing favorable tolerability up to the 5.0 mg/kg dose level. Dose-limiting toxicity occurs in only one patient (6.3%) at 10.0 mg/kg, resulting in grade 4 neutropenia. The most frequent treatment-related adverse events include leukopenia (22.6%), neutropenia (22.6%), elevated alanine aminotransferase (22.6%), rash (21.0%), itching (17.7%), and elevated aspartate aminotransferase (17.7%). The overall disease control rates are 47.1% for advanced solid tumors and 54.5% for non-Hodgkin's lymphoma. Circulating biomarkers suggest target engagement by ADG106 and immune modulation of circulating T, B, and natural killer cells and cytokines interferon γ and interleukin-6, which may affect the probability of clinical efficacy. ADG106 has a manageable safety profile and preliminary anti-tumor efficacy in patients with advanced cancers (this study was registered at ClinicalTrials.gov: NCT03802955).

High salt diet exacerbates cognitive deficits and neurovascular abnormalities in APP/PS1 mice and induces AD-like changes in wild-type mice.

High salt diet (HSD) is a risk factor of hypertension and cardiovascular disease. Although clinical data do not clearly indicate the relationship between HSD and the prevalence of Alzheimer's disease (AD), animal experiments have shown that HSD can cause hyperphosphorylation of tau protein and cognition impairment. However, whether HSD can accelerate the progression of AD by damaging the function of neurovascular unit (NVU) in the brain is unclear. Here, we fed APP/PS1 mice (an AD model) or wild-type mice with HSD and found that the chronic HSD feeding increased the activity of enzymes related to tau phosphorylation, which led to tau hyperphosphorylation in the brain. HSD also aggravated the deposition of Aß42 in hippocampus and cortex in the APP/PS1 mice but not in the wild-type mice. Simultaneously, HSD caused the microglia proliferation, low expression of Aqp-4, and high expression of CD31 in the wild-type mice, which were accompanied with the loss of pericytes (PCs) and increase in blood brain barrier (BBB) permeability. As a result, wild-type mice fed with HSD performed poorly in Morris Water Maze and object recognition test. In the APP/PS1 mice, HSD feeding for 8 months worsen the cognition and accompanied the loss of PCs, the activation of glia, the increase in BBB permeability, and the acceleration of calcification in the brain. Our data suggested that HSD feeding induced the AD-like pathology in wild-type mice and aggravated the development of AD-like pathology in APP/PS1 mice, which implicated the tau hyperphosphorylation and NVU dysfunction.

The BCL-2 inhibitor APG-2575 resets tumor-associated macrophages toward the M1 phenotype, promoting a favorable response to anti-PD-1 therapy via NLRP3 activation.

The main challenges in the use of immune checkpoint inhibitors (ICIs) are ascribed to the immunosuppressive tumor microenvironment and the lack of sufficient infiltration of activated CD8+ T cells. Transforming the tumor microenvironment (TME) from "cold" to "hot" and thus more likely to potentiate the effects of ICIs is a promising strategy for cancer treatment. We found that the selective BCL-2 inhibitor APG-2575 can enhance the antitumor efficacy of anti-PD-1 therapy in syngeneic and humanized CD34+ mouse models. Using single-cell RNA sequencing, we found that APG-2575 polarized M2-like immunosuppressive macrophages toward the M1-like immunostimulatory phenotype with increased CCL5 and CXCL10 secretion, restoring T-cell function and promoting a favorable immunotherapy response. Mechanistically, we demonstrated that APG-2575 directly binds to NF-κB p65 to activate NLRP3 signaling, thereby mediating macrophage repolarization and the activation of proinflammatory caspases and subsequently increasing CCL5 and CXCL10 chemokine production. As a result, APG-2575-induced macrophage repolarization could remodel the tumor immune microenvironment, thus improving tumor immunosuppression and further enhancing antitumor T-cell immunity. Multiplex immunohistochemistry confirmed that patients with better immunotherapeutic efficacy had higher CD86, p-NF-κB p65 and NLRP3 levels, accompanied by lower CD206 expression on macrophages. Collectively, these data provide evidence that further study on APG-2575 in combination with immunotherapy for tumor treatment is required.

Predictive value of immunotherapy-induced inflammation indexes: dynamic changes in patients with nasopharyngeal carcinoma receiving immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have achieved substantial advancements in clinical care. However, there is no strong evidence for identified biomarkers of ICIs in NPC. METHODS: In this retrospective study, 284 patients were enrolled into a training or validation cohort. Inflammatory indexes based on peripheral blood parameters were evaluated, including the systemic immune-inflammation index (SII), the neutrophil-lymphocyte ratio (NLR), the platelet-lymphocyte ratio (PLR), the lymphocyte-to-C-reactive protein ratio (LCR), and the lymphocyte-monocyte ratio (LMR). The optimum cut-off value for patient stratification was identified using X-tile. The Kaplan-Meier method and Cox's proportional regression analyses were used to identify prognostic factors. RESULTS: Immunotherapy significantly changed the levels of SII, NLR, PLR, LCR and LMR in NPC patients. Patients with lower SII, NLR, and PLR, as well as those with higher LCR and LMR, before immunotherapy had superior PFS (all p < 0.05). Moreover, PFS in the decreased SII, reduced NLR and increased LMR group was significantly longer than in the opposite group (all p < 0.05). Both univariate and multivariate analyses validated that baseline SII and LMR, and the immunotherapy-related SII reduction and LMR elevation were independent prognostic factors for PFS in advanced NPC patients receiving ICIs. CONCLUSIONS: Immune checkpoint inhibitor treatments significantly changed the levels of SII, NLR, PLR, LCR and LMR in NPC patients treated with immunotherapy. A lower baseline SII and a higher baseline LMR, and a reduction in SII and an elevation in LMR after immunotherapy are favorable factors for predicting survival among advanced NPC patients.

There is no strong evidence for identified biomarkers of immune checkpoint inhibitors (ICIs) in nasopharyngeal carcinoma (NPC).Lower baseline SII and higher baseline LMR were related to better PFS. The dynamic changes of SII and LMR were independent prognostic factors for the survival of NPC patients receiving ICIs.Neutrophils, platelets, lymphocytes, and monocytes can be used as cheap and valuable biomarkers for predicting tumor response in NPC on immunotherapy.

Evaluation of left ventricular diastolic function in patients with coronary microvascular dysfunction via cardiovascular magnetic resonance feature tracking.

Background: Coronary microvascular dysfunction (CMD) has been suggested to be one of the pathologic mechanisms contributing to heart failure with preserved left ventricular ejection fraction (LVEF) and left ventricular (LV) diastolic dysfunction. We therefore aimed to evaluate LV diastolic function in patients with CMD using cardiovascular magnetic resonance feature tracking (CMR-FT). Methods: We prospectively enrolled 115 patients referred to cardiology clinics for chest pain assessment who subsequently underwent coronary computed tomography angiogram and stress perfusion CMR. CMD was defined as the presence of subendocardial inducible ischemia detected through visual assessment. LV diastolic function was evaluated using CMR-derived volume-time curves and CMR-FT parameters. The former included early peak filling rate (PFR) and time to PFR; the latter included LV global/regional peak longitudinal diastolic strain rate (LDSR), circumferential diastolic strain rate (CDSR), and radial diastolic strain rate (RDSR). Results: A total of 92 patients with 1,312 segments were eventually included. Of these, 19 patients were classified as non-CMD (48.8±11.2 years; 63.2% male) and 73 as with CMD (52.3±11.9 years; 54.8% male). The LVEFs were similar and preserved in both groups (P=0.266). At the per-patient level, no differences were observed in PFR, time to PFR, or LV global diastolic strain rates between the two groups. At the per-segment level, 51% (665/1,312) of the myocardial segments were classified as CMD, whereas 49% (647/1,312) were classified as non-CMD. CMD segments showed significantly lower regional CDSR (P=0.019) and RDSR (P=0.006) compared with non-CMD segments. Conclusions: Despite normal LV ejection fraction in CMD patients, decreased LV diastolic function in CMD myocardial segments indicates early diastolic impairment.

A series of fluorescent dyes based on 4-phenylacetylene-1,8-naphthalimide: Synthesis, theoretical calculations, photophysical properties and application in two-color imaging and dynamic behavior monitoring of lipid droplets and lysosomes.

A series of fluorescent dyes (NapPAs) based on 4-phenylacetylene-1,8-naphthalimide were synthesized and characterized, whose conjugated structures were extended by the introduction of phenylethynyl. Furthermore, changes in the photophysical properties of the dyes when substituents with varying electron richness were introduced at the p-position of phenylacetylene were studied. The theoretical calculation of the dye molecules was carried out by B3LYP functional and 6-31G(d,p) basis set, and the effects of different substituents at the p-position of phenylacetylene on the electronic structure and photophysical properties of the dyes were studied by theoretical calculation results. Theoretical calculations provided a reliable means of predicting the properties of dyes, which could help in the design of more efficient and novel dyes. To verify the practicability of the dyes, two dyes with excellent photophysical properties (large Stokes shift, high polarity-viscosity sensitivity, good biocompatibility) were selected as fluorescent probes for visualization of LDs and two-color imaging of LDs and lysosomes. Cell imaging showed that NapPA-LDs and NapPA-LDs-Lyso serve as excellent imaging tools to monitor the dynamic changes, movements, and behaviors of LDs and lysosomes in real time. Notably, NapPA-LDs-Lyso held promise as a potential tool to study the interaction between LDs and lysosomes.

Three-Dimensional-Network-Structured Bismuth-Based Silica Aerogel Fiber Felt for Highly Efficient Immobilization of Iodine.

The effective capture and deposition of radioactive iodine in the spent fuel reprocessing process is of great importance for nuclear safety and environmental protection. Three-dimensional (3D) fiber felt with structural diversity and tunability is applied as an efficient adsorbent with easy separation for iodine capture. Here, a bismuth-based silica aerogel fiber felt (Bi@SNF) was synthesized using a facile hydrothermal method. Abundant and homogeneous Bi nanoparticles greatly enhanced the adsorption and immobilization of iodine. Notably, Bi@SNF demonstrated a high capture capacity of 982.9 mg/g by forming stable BiI3 and Bi5O7I phases, which was about 14 times higher than that of the unloaded material. Fast uptake kinetics and excellent resistance to nitric acid and radiation were exhibited as a result of the 3D porous interconnected network and silica aerogel fiber substrate. Adjustable size and easy separation and recovery give the material potential as a radioactive iodine gas capture material.

π-Extended BTD Derivatives: Synthesis, Photophysical Properties, and Applications in Biological Systems Imaging for Discriminating Living and Dead Cells.

Here, π-Extended BTD derivatives were successfully synthesized by Heck coupling reaction, which exhibited the the advantages of simplicity and efficiency, wild substrate scope, easily available substrates and high yield. The fluorescent probe PEG-BTDAr targeting LDs was successfully prepared by the nucleophilic substitution reaction between the Heck coupling reaction product 3 h and Amino polyethylene glycol monomethyl ether (Mn=2000). PEG-BTDAr exhibited the advantages of high selectivity, good stability and pH resistance. The use of PEG as a substrate gave PEG-BTDAr good biocompatibility. It was worth mentioning that PEG-BTDAr could not only track LDs in cells under different physiological conditions, but also distinguish between living and dead cells in biological systems.

Genotypic and Phenotypic Characterization of Some psms Hypervirulent Clinical Isolates of Staphylococcus aureus in a Tertiary Hospital in Hefei, Anhui.

Background: Staphylococcus aureus is a highly successful pathogen that can cause various infectious diseases, from relatively mild skin infections to life-threatening severe systemic diseases. The widespread pathogenicity of S. aureus is mainly due to its ability to produce many virulence factors that help destroy various host cells, causing disease. Our primary goal in this study was to explore the genes of highly virulent strains, to identify genes closely associated with high virulence, and to provide ideas for the treatment of infection by highly virulent clinical strains. Results: This study collected 221 clinical strains from The First Affiliated Hospital Of The University of Science and Technology of China (USTC); their hemolytic abilities were tested. Eight isolates were selected based on their highly hemolytic ability and tested their hemolytic activity again; their phenotypes and gene sequences were also explored. Whole-genome sequencing (WGS) showed six plasmids (pN315, pNE131, pSJH901, pSJH101, SAP106B, and MSSA476), eight antibiotic resistance genes [blaR1, blaI, blaZ, mecA, erm(C), erm(T), tet(38), and fosB-Saur] and seventy-two virulence related genes. Three highly virulent strains, namely X21111206, 21092239, and 21112607, were found according the Galleria mellonella infection model. Therefore, we selected 10 representative virulence genes for qRT-PCR: psmα, psmß, hlgA, hlgB, hlgC, hla, clfA, clfB, spa, and sak. Among them, the expression levels of psmα and psmß, the three isolates, were significantly higher than the positive control NCTC8325. Conclusion: Significant differences appear in the expression of virulence genes in the highly virulent strains, particularly the psmα and psmß, It may be that the high expression of psm gene is the cause of the high virulence of Staphylococcus aureus. We can reduce the pathogenicity of Staphylococcus aureus by inhibiting the expression of psm gene, which may provide a strong basis for psm as a new target for clinical treatment of S. aureus infection.

HbA1c is related to microcirculation blood perfusion in patients with coronary microvascular disease using stress perfusion cardiac magnetic resonance: An observational study.

BACKGROUND: In coronary microvascular disease (CMD) patients, the incidence of major adverse cardiovascular events (MACEs) in patients with myocardial perfusion reserve index (MPRI) ≤ 1.47 is three times higher than that in MPRI > 1.47. We investigated whether the increase of glycated hemoglobin A1c (HbA1c) could increase the risk of MPRI ≤1.47 in diabetic and non-diabetic patients. METHODS: From November 2019, patients with ischemic symptoms but without obstructive coronary disease were screened. Use MPRI measured by stress perfusion cardiac magnetic resonance (CMR) to reflect microcirculation blood perfusion, and MPRI <2.5 were included. The patients were divided into two groups based on MPRI was greater or <1.47. The risk factors for CMD were explored using logistic regression analysis. RESULTS: A total of 80 patients with an MPRI of 1.69 ± 0.79 were included. CMD patients with an MPRI of ≤1.47(n = 33) were higher than MPRI of >1.47(n = 47) in age, presence of diabetes mellitus, fasting blood glucose levels and HbA1c levels (P < 0.05). In non-diabetic patients, increased HbA1c was associated with the risk of MPRI≤1.47 (OR = 0.017, 95%CI: 0.050-1.107, P = 0.045). Compared with non-diabetic patients with HbA1c < 6.0, non-diabetic patients with HbA1c ≥ 6.0 increased the risk of MPRI of ≤1.47 (OR = 0.219, 95%CI: 0.069-0.697, P = 0.010). In diabetic patients, HbA1c was not associated with the risk of MPRI of ≤1.47 (OR = 1.043, 95%CI: 0.269, 4.044, P = 0.952). And compared with non-diabetic patients with HbA1c <6.0, diabetic patients with HbA1c <6.0 (OR = 0.917, 95%CI: 0.233-3.610, P = 0.901) or ≥6.0 (OR = 0.326, 95%CI: 0.073-1.446, P = 0.140), the risk of MPRI ≤ 1.47 was not further increased. CONCLUSIONS: In non-diabetic patients, elevated HbA1c is related to MPRI≤1.47(a value increased incidence of MACEs). Therefore, in patients with undiagnosed diabetes, early management of glycosylated hemoglobin is very important. TRIAL REGISTRATION: This clinical trial has been registered in the Chinese clinical Trial Registry with an identifier: ChiCTR1900025810.

ß-arrestin2 Mediates the Arginine Vasopressin-Induced Expression of IL-1ß in Murine Hearts.

BACKGROUND: Circulating levels of arginine vasopressin (AVP) are elevated during cardiac stress and this could be a factor in cardiac inflammation and fibrosis. Herein, we studied the effects of AVP on interleukin-1ß (IL-1ß) production and the role(s) of ß-arrestin2-dependent signaling in murine heart. METHODS: The levels of IL-1ß mRNA and protein in adult rat cardiofibroblasts (ARCFs) was measured using quantitative PCR and ELISA, respectively. The activity of ß-arrestin2 was manipulated using either pharmacologic inhibitors or through recombinant ß-arrestin2 over-expression. These experiments were conducted to determine the roles of ß-arrestin2 in the regulation of AVP-induced IL-1ß and NLRP3 inflammasome production. The phosphorylation and activation of NF-κB induced by AVP was measured by immunoblotting. ß-arrestin2 knockout (KO) mice were used to investigate whether ß-arrestin2 mediated the AVP-induced production of IL-1ß and NLRP3, as well as the phosphorylation of the NF-κB p65 subunitin mouse myocardium. Prism GraphPad software(version 8.0), was used for all statistical analyses. RESULTS: AVP induced the expression of IL-1ß in a time-dependent manner in ARCFs but not in cultured adult rat cardiomyocytes (ARCMs). The inhibition of NF-κB with pyrrolidinedithiocarbamic acid (PDTC) prevented the AVP-induced phosphorylation of NF-κB and production of IL-1ß and NLRP3 in ARCFs. The deletion of ß-arrestin2 blocked the phosphorylation of p65 and the expression of NLRP3 and IL-1ß induced by AVP in both mouse hearts and in ARCFs. CONCLUSIONS: AVP promotes IL-1ß expression through ß-arrestin2-mediated NF-κB signaling in murine heart.

Molecular Epidemiology of Staphylococcus aureus in a Tertiary Hospital in Anhui, China: ST59 Remains a Serious Threat.

Purpose: This study aimed to investigate the molecular characteristics, antimicrobial resistance and hemolytic phenotype of Staphylococcus aureus isolated from Anhui, China. Results: From August 2021 to January 2022, 214 S. aureus isolates were collected from the Anhui Provincial Hospital. This study identified 117 methicillin-resistant S. aureus and 97 methicillin-sensitive S. aureus isolates, and the detection rate of methicillin-resistant isolates was 1.8-fold higher than the average isolates reported in China (53.9% vs 30.5%). S. aureus isolates share identity at five or more of the seven MLST-based housekeeping loci, referred to as the clonal complex (CC). Forty ST types were found in 214 clinical S. aureus isolates, with the most extensive distribution of ST59 and ST6697 typing numbers and higher CC5 detection rates than any other clonal group. (The ST typing is the result of the MLST typing website query.) To detect the virulence of ST types of S. aureus, hemolysis experiments were performed on 214 clinical isolates, and it was concluded that ST59 had a relatively robust hemolytic capacity. Conclusion: Anhui S. aureus isolates have unique molecular and antibiotic resistance profiles. The antibiotic resistance profile may be related to the random use of antibiotics.

Motion artefact reduction in coronary CT angiography images with a deep learning method.

BACKGROUND: The aim of this study was to investigate the ability of a pixel-to-pixel generative adversarial network (GAN) to remove motion artefacts in coronary CT angiography (CCTA) images. METHODS: Ninety-seven patients who underwent single-cardiac-cycle multiphase CCTA were retrospectively included in the study, and raw CCTA images and SnapShot Freeze (SSF) CCTA images were acquired. The right coronary artery (RCA) was investigated because its motion artefacts are the most prominent among the artefacts of all coronary arteries. The acquired data were divided into a training dataset of 40 patients, a verification dataset of 30 patients and a test dataset of 27 patients. A pixel-to-pixel GAN was trained to generate improved CCTA images from the raw CCTA imaging data using SSF CCTA images as targets. The GAN's ability to remove motion artefacts was evaluated by the structural similarity (SSIM), Dice similarity coefficient (DSC) and circularity index. Furthermore, the image quality was visually assessed by two radiologists. RESULTS: The circularity was significantly higher for the GAN-generated images than for the raw images of the RCA (0.82 ± 0.07 vs. 0.74 ± 0.11, p < 0.001), and there was no significant difference between the GAN-generated images and SSF images (0.82 ± 0.07 vs. 0.82 ± 0.06, p = 0.96). Furthermore, the GAN-generated images achieved the SSIM of 0.87 ± 0.06, significantly better than those of the raw images 0.83 ± 0.08 (p < 0.001). The results for the DSC showed that the overlap between the GAN-generated and SSF images was significantly higher than the overlap between the GAN-generated and raw images (0.84 ± 0.08 vs. 0.78 ± 0.11, p < 0.001). The motion artefact scores of the GAN-generated CCTA images of the pRCA and mRCA were significantly higher than those of the raw CCTA images (3 [4-3] vs 4 [5-4], p = 0.022; 3 [3-2] vs 5[5-4], p < 0.001). CONCLUSIONS: A GAN can significantly reduce the motion artefacts in CCTA images of the middle segment of the RCA and has the potential to act as a new method to remove motion artefacts in coronary CCTA images.

Rotenone aggravates PD-like pathology in A53T mutant human α-synuclein transgenic mice in an age-dependent manner.

Multiple factors such as genes, environment, and age are involved in developing Parkinson's disease (PD) pathology. However, how various factors interact to cause PD remains unclear. Here, 3-month and 9-month-old hα-syn+⁣/- mice were treated with low-dose rotenone for 2 months to explore the mechanisms that underline the environment-gene-age interaction in the occurrence of PD. We have examined the behavior of mice and the PD-like pathologies of the brain and gut. The present results showed that impairments of the motor function and olfactory function were more serious in old hα-syn+/- mice with rotenone than that in young mice. The dopaminergic neuron loss in the SNc is more in old hα-syn+/- mice with rotenone than in young mice. Expression of hα-syn+/- is increased in the SNc of hα-syn+/- mice following rotenone treatment for 2 months. Furthermore, the number of activated microglia cells increased in SNc and accompanied the high expression of inflammatory cytokines, namely, TNF-α and IL-18 in the midbrain of old hα-syn+/- mice treated with rotenone. Meanwhile, we found that after treatment with rotenone, hα-syn positive particles deposited in the intestinal wall, intestinal microflora, and T lymphocyte subtypes of Peyer's patches changed, and intestinal mucosal permeability increased. Moreover, these phenomena were age-dependent. These findings suggested that rotenone aggravated the PD-like pathologies and affected the brain and gut of human α-syn+/- transgenic mice in an age-dependent manner.

Cardiac Protection of a Novel Lupane-Type Triterpenoid from Injuries Induced by Hypoxia-Reperfusion.

Myocardial ischemia-reperfusion injury (MIRI) leads to cardiac remodeling and heart failure associated with acute myocardial infarction, which is one of the leading causes of death worldwide. Betulinic acid (BA), a widely distributed lupane-type triterpenoid, has been reported to possess antioxidative activity and inhibit apoptosis in MIRI. Due to the low bioavailability and water insolubility of BA, a previous study found a series of BA-derivative compounds by microbial transformation. In this study, we observe whether there are anti-MIRI effects of BTA07, a BA derivative, on cardiac injuries induced by hypoxia/reoxygenation (H/R) in adult rat cardiomyocytes in vitro and in Langendorff-perfused hearts ex vivo, and further explore its mechanism of cardioprotection to find more efficient BA derivatives. The hemodynamic parameters of isolated hearts were monitored and recorded by a Lab Chart system. The markers of oxidative stress and apoptosis in isolated hearts and adult rat cardiomyocytes (ARCMs) were evaluated. The expression levels of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X (Bax), protein kinase B (Akt) and phospho-Akt (pAkt, Ser473) induced by H/R were detected via Western blot. The Langendorff experiments showed that BTA07 improves hemodynamic parameters, reduces myocardium damage and infarct size, inhibits levels of myocardial tissue enzymes lactate dehydrogenase (LDH) and creatine kinase (CK) in the coronary outflow and reduces oxidative stress and the activation of caspase-3 in the myocardium. In vitro, BTA07 reduced cell death and caspase-3 activation and inhibited reactive oxygen species (ROS) generation. Furthermore, the protective effects of BTA07 were attenuated by inhibition of the PI3K/Akt signaling pathway with LY294002 in ARCMs. BTA07 protects ARCMs and isolated hearts from hypoxia-reperfusion partly by inhibiting oxidative stress and cardiomyocyte apoptosis.

Risk factors associated with hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation.

Hemorrhagic cystitis (HC) is a common complication of allogeneic hematopoietic stem cell transplantation (HSCT). The incidence is about 7% to 68%, and some patients have to suffer a long period of frequent, urgent, and painful urination, which brings great pain. This study aimed to analyze risk factors of HC and its effect on patient survival. We collected the medical records of 859 patients who underwent HSCT at our hospital between August 2016 and August 2020. Patients with and without HC were matched using propensity score matching at a 1:1 ratio based on sex, age, and diagnosis, and logistic regression analyses were used to identify factors associated with HC. We used Kaplan-Meier curves to analyze the survival rates of patients in the HC and non-HC groups. We also analyzed the relationship between BK viral load and the occurrence of HC using receiver operating characteristic curve (ROC) analysis. After propensity score matching, there were 131 patients each in the HC and non-HC groups. In the HC group, 89 patients (67.9%) had mild HC (stage II°) and 43 (32.1%) had severe HC (stage III-IV). The median interval between stem cell transplantation and HC development was 31 (3-244) days. Univariate analysis indicated that donor age, hematopoietic stem cell source, HLA, acute graft-versus-host disease, busulfan, anti-thymocyte globulin (ATG), total body irradiation, cytomegalovirus (CMV) (urine), and BK polyomavirus (BKV) (urine) were significantly associated with HC. ATG, CMV (urine), and BKV (urine) were independent risk factors for HC based on the multivariate analysis. The Kaplan-Meier survival analysis showed no significant difference between the HC and non-HC groups (P = .14). The 1- and 2-year survival rates in the HC group were 78.4% and 69.6%, respectively, and the corresponding rates in the non-HC group were 84.4% and 80.7%, respectively. ROC analysis indicated that a urine BKV load of 1 × 107 copies/mL was able to stratify the risk of HC. In conclusion, when the BKV load is >1 × 107, we need to be aware of the potential for the development of HC.