Protective effect of novel angiotensin receptor neprilysin inhibitor S086 on target organ injury in spontaneously hypertensive rats.

BACKGROUND: Hypertension is a clinical syndrome characterized by elevated systemic arterial blood pressure associated with injury to the heart, kidney, brain, and other organs. Angiotensin receptor neprilysin inhibitors (ARNi), including angiotensin receptor blockers (ARBs) and neprilysin inhibitors (NEPi), have been shown to be safe and effective at reducing blood pressure and alleviating development of target organ injury. This study was used to develop S086 as a novel ARNi and conducted preclinical studies in animal models to evaluate the protective effects of S086 on target organs. METHODS: This study used a 14-month-old spontaneously hypertensive rat (SHR) model to evaluate the protective effects of S086 on the cardiovascular system and organs such as heart and kidney by blood pressure monitoring, urine and blood examination, pathological examination, and immunological index detection. RESULTS: After administering S086 orally to the SHR, their blood pressure and levels of renal injury indicators such as serum creatinine and urinary microalbumin were reduced, and myocardial cell necrosis and cardiac fibrosis of the heart were significantly improved. In addition, there were also significantly improvements in the histological lesions of blood vessels and the kidneys. CONCLUSIONS: The findings showed that S086 effectively reduced the blood pressure of SHR and had effects on alleviating development of heart, blood vessels and kidney.

Approximate Autonomous Quantum Error Correction with Reinforcement Learning.

Autonomous quantum error correction (AQEC) protects logical qubits by engineered dissipation and thus circumvents the necessity of frequent, error-prone measurement-feedback loops. Bosonic code spaces, where single-photon loss represents the dominant source of error, are promising candidates for AQEC due to their flexibility and controllability. While existing proposals have demonstrated the in-principle feasibility of AQEC with bosonic code spaces, these schemes are typically based on the exact implementation of the Knill-Laflamme conditions and thus require the realization of Hamiltonian distances d≥2. Implementing such Hamiltonian distances requires multiple nonlinear interactions and control fields, rendering these schemes experimentally challenging. Here, we propose a bosonic code for approximate AQEC by relaxing the Knill-Laflamme conditions. Using reinforcement learning (RL), we identify the optimal bosonic set of code words (denoted here by RL code), which, surprisingly, is composed of the Fock states |2⟩ and |4⟩. As we show, the RL code, despite its approximate nature, successfully suppresses single-photon loss, reducing it to an effective dephasing process that well surpasses the break-even threshold. It may thus provide a valuable building block toward full error protection. The error-correcting Hamiltonian, which includes ancilla systems that emulate the engineered dissipation, is entirely based on the Hamiltonian distance d=1, significantly reducing model complexity. Single-qubit gates are implemented in the RL code with a maximum distance d_{g}=2.

IRE1α: from the function to the potential therapeutic target in atherosclerosis.

Inositol requiring enzyme 1 (IRE1) is generally thought to control the most conserved pathway in the unfolded protein response (UPR). Two isoforms of IRE1, IRE1α and IRE1ß, have been reported in mammals. IRE1α is a ubiquitously expressed protein whose knockout shows marked lethality. In contrast, the expression of IRE1ß is exclusively restricted in the epithelial cells of the respiratory and gastrointestinal tracts, and IRE1ß-knockout mice are phenotypically normal. As research continues to deepen, IRE1α was showed to be tightly linked to inflammation, lipid metabolism regulation, cell death and so on. Growing evidence also suggests an important role for IRE1α in promoting atherosclerosis (AS) progression and acute cardiovascular events through disrupting lipid metabolism balance, facilitating cells apoptosis, accelerating inflammatory responses and promoting foam cell formation. In addition, IRE1α was recognized as novel potential therapeutic target in AS prevention. This review provides some clues about the relationship between IRE1α and AS, hoping to contribute to further understanding roles of IRE1α in atherogenesis and to be helpful for the design of novel efficacious therapeutics agents targeting IRE1α-related pathways.

Nocardia seriolae mediates liver granulomatous chronic inflammation in Micropterus salmoides through pyroptosis.

Granulomatous diseases caused by Nocardia seriously endanger the health of cultured fish. These bacteria are widely distributed, but prevention and treatment methods are very limited. Chronic granulomatous inflammation is an important pathological feature of Nocardia infection. However, the molecular mechanisms of granuloma formation and chronic inflammation are still unclear. Constructing a granuloma infection model of Nocardia is the key to exploring the pathogenesis of the disease. In this study, we established a granuloma model in the liver of largemouth bass (Micropterus salmoides) and assessed the infection process of Nocardia seriolae at different concentrations by analysing relevant pathological features. By measuring the expression of pro-inflammatory cytokines, transcription factors and a pyroptosis-related protein, we revealed the close relationship between pyroptosis and chronic inflammation of granulomas. We further analysed the immunofluorescence results and the expression of pyroptosis-related protein of macrophage infected by N. seriolae and found that N. seriolae infection induced macrophage pyroptosis in vitro. These results were proved by flow cytometry analysis of infection experiment in vivo. Our results indicated that the pyroptosis effect may be the key to inducing chronic inflammation in the fish liver and further mediating granuloma formation. In this study, we explored the molecular mechanism underlying chronic inflammation of granulomas and developed research ideas for understanding the occurrence and development of granulomatous diseases in fish.

Role of Sp1 in atherosclerosis.

Specificity protein (Sp) is a famous family of transcription factors including Sp1, Sp2 and Sp3. Sp1 is the first one of Sp family proteins to be characterized and cloned in mammalian. It has been proposed that Sp1 acts as a modulator of the expression of target gene through interacting with a series of proteins, especially with transcriptional factors, and thereby contributes to the regulation of diverse biological processes. Notably, growing evidence indicates that Sp1 is involved in the main events in the development of atherosclerosis (AS), such as inflammation, lipid metabolism, plaque stability, vascular smooth muscle cells (VSMCs) proliferation and endothelial dysfunction. This review is designed to provide useful clues to further understanding roles of Sp1 in the pathogenesis of AS, and may be helpful for the design of novel efficacious therapeutics agents targeting Sp1.

Work statistics in non-Hermitian evolutions with Hermitian endpoints.

Non-Hermitian systems with specific forms of Hamiltonians can exhibit novel phenomena. However, it is difficult to study their quantum thermodynamical properties. In particular, the calculation of work statistics can be challenging in non-Hermitian systems due to the change of state norm. To tackle this problem, we modify the two-point measurement method in Hermitian systems. The modified method can be applied to non-Hermitian systems which are Hermitian before and after the evolution. In Hermitian systems, our method is equivalent to the two-point measurement method. When the system is non-Hermitian, our results represent a projection of the statistics in a larger Hermitian system. As an example, we calculate the work statistics in a non-Hermitian Su-Schrieffer-Heeger model. Our results reveal several differences between the work statistics in non-Hermitian systems and the one in Hermitian systems.

Angiopoietin-like proteins in atherosclerosis.

Atherosclerosis, as a chronic inflammatory disease within the arterial wall, is a leading cause of morbidity and mortality worldwide due to its role in myocardial infarction, stroke and peripheral artery disease. Additional evidence is emerging that the angiopoietin-like (ANGPTL) family of proteins participate in the pathology of this disease process via endothelial dysfunction, inflammation, dyslipidemia, calcification, foam cell formation and platelet activation. This review summarizes current knowledge on the ANGPTL family of proteins in atherosclerosis related pathological processes. Moreover, the potential value of ANGPTL family proteins as predictive biomarkers in atherosclerosis is discussed. Given the attractive role of ANGPTL3, ANGPTL4, ANGPTL8 in atherosclerotic dyslipidemia via regulation of lipoprotein lipase (LPL), antisense oligonucleotide or/and monoclonal antibody-based inactivation of these proteins represent potential atherosclerotic therapies.

HRD1 attenuates the high uptake of [18F]FDG in hepatocellular carcinoma PET imaging.

INTRODUCTION: Due to individual deviations in tumor tissue uptake, the role of [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) in hepatocellular carcinoma (HCC) diagnosis is limited. ß-Hydroxy ß-methylglutaryl-CoA reductase degradation 1 (HRD1) plays a key role in clearing misfolded proteins. This study is aimed to investigate the role and mechanism of HRD1 in [18F]FDG uptake for the diagnosis of HCC. METHODS: HRD1 expression level was detected using immunohistochemical (IHC) staining in 9 HCC patients. [18F]FDG PET/CT scans were conducted before treatment. [18F]FDG uptakes in HRD1 overexpressed and knockdown transgenic models were measured by γ-counter and microPET imaging. The GLUT1-HRD1 complex was examined by co-immunoprecipitation and IHC assays. GLUT1 expression in different cell lines, xenograft models and HCC patients was evaluated by Western blot and IHC assays. RESULTS: HRD1 was highly expressed in the HCC tumors of patients with low [18F]FDG uptake, while the HRD1 expression was obviously low in the higher [18F]FDG uptake group. Both in vitro and in vivo studies found that HRD1 significantly inhibited [18F]FDG uptake in HCC Huh7 cell lines and animal models. Furthermore, the co-location and interaction of HRD1 with GLUT1 were detected, and the results also indicate that HRD1 could induce the degradation of GLUT1 in vitro and in vivo. CONCLUSION: HRD1 inhibits the high uptake of [18F]FDG in HCC tumor cells by inducing degradation of GLUT1, which leads to decreased diagnostic efficiency of [18F]FDG PET imaging for HCC. ADVANCES IN KNOWLEDGE: This study suggests that HRD1 inhibits the high uptake of [18F]FDG in HCC tumor by inducing degradation of GLUT1. IMPLICATIONS FOR PATIENT CARE: HCC diagnosis with [18F]FDG PET should be accompanied by determination of HRD1 expression, and patients with high tumor HRD1 expression might be unsuitable for [18F]FDG PET.

Differentiating gastric cancer and gastric lymphoma using texture analysis (TA) of positron emission tomography (PET).

BACKGROUND: Texture analysis (TA) can quantify intra-tumor heterogeneity using standard medical images. The present study aimed to assess the application of positron emission tomography (PET) TA in the differential diagnosis of gastric cancer and gastric lymphoma. METHODS: The pre-treatment PET images of 79 patients (45 gastric cancer, 34 gastric lymphoma) between January 2013 and February 2018 were retrospectively reviewed. Standard uptake values (SUVs), first-order texture features, and second-order texture features of the grey-level co-occurrence matrix (GLCM) were analyzed. The differences in features among different groups were analyzed by the two-way Mann-Whitney test, and receiver operating characteristic (ROC) analysis was used to estimate the diagnostic efficacy. RESULTS: InertiaGLCM was significantly lower in gastric cancer than that in gastric lymphoma (4975.61 vs. 11,425.30, z = -3.238, P = 0.001), and it was found to be the most discriminating texture feature in differentiating gastric lymphoma and gastric cancer. The area under the curve (AUC) of inertiaGLCM was higher than the AUCs of SUVmax and SUVmean (0.714 vs. 0.649 and 0.666, respectively). SUVmax and SUVmean were significantly lower in low-grade gastric lymphoma than those in high grade gastric lymphoma (3.30 vs. 11.80, 2.40 vs. 7.50, z = -2.792 and -3.007, P = 0.005 and 0.003, respectively). SUVs and first-order grey-level intensity features were not significantly different between low-grade gastric lymphoma and gastric cancer. EntropyGLCM12 was significantly lower in low-grade gastric lymphoma than that in gastric cancer (6.95 vs. 9.14, z = -2.542, P = 0.011) and had an AUC of 0.770 in the ROC analysis of differentiating low-grade gastric lymphoma and gastric cancer. CONCLUSIONS: InertiaGLCM and entropyGLCM were the most discriminating features in differentiating gastric lymphoma from gastric cancer and low-grade gastric lymphoma from gastric cancer, respectively. PET TA can improve the differential diagnosis of gastric neoplasms, especially in tumors with similar degrees of fluorodeoxyglucose uptake.

Dark state with counter-rotating dissipative channels.

Dark state as a consequence of interference between different quantum states has great importance in the fields of chip-scale atomic clock and quantum information. For the Λ-type three-level system, this dark state is generally regarded as being dissipation-free because it is a superposition of two lowest states without dipole transition between them. However, previous studies are based on the rotating-wave approximation (RWA) by neglecting the counter-rotating terms in the system-environment interaction. In this work, we study non-Markovian quantum dynamics of the dark state in a Λ-type three-level system coupled to two bosonic baths and reveal the effect of counter-rotating terms on the dark state. In contrast to the dark state within the RWA, leakage of the dark state occurs even at zero temperature, as a result of these counter-rotating terms. Also, we present a method to restore the quantum coherence of the dark state by applying a leakage elimination operator to the system.

Occupational inhalational exposure and serum GM-CSF autoantibody in pulmonary alveolar proteinosis.

OBJECTIVES: Although the serum granulocyte-macrophage colony stimulating factor autoantibody (GMAb) levels have been recognised as a diagnostic marker in primary pulmonary alveolar proteinosis (PAP), their role in PAP with occupational inhalational exposure (PAPo) remains unclear. METHODS: Forty-five consecutive patients with PAP were enrolled. Each patient with PAP was assessed for baseline clinical characteristics, chest high-resolution CT (HRCT), serum GMAb and occupational exposure. Fifty healthy controls were included to define normal ranges for GMAb levels. Ninety-seven hospital controls with other respiratory diseases were included to establish prevalence of a history of occupational inhalation exposure. RESULTS: According to the serum GMAb cut-off value of 2.39 µg/mL, 84.4% of the recruited patients with PAP had positive serum GMAb with a median level of 28.7 µg/mL, defined as autoimmune PAP, and the remaining 15.6% had negative serum GMAb with a median level of 0.16 µg/mL, defined as non-autoimmune PAP. Also, 34.2% of patients with autoimmune PAP had a history of occupational inhalational exposure, which was not significantly higher than that of hospital controls (34.2% vs 19.6%, p=0.072). Four patients with PAPo showed negative GMAb. Their arterial oxygen tension, pulmonary function parameters and chest HRCT features were significantly different when compared with patients with autoimmune PAP (p<0.05). These four non-autoimmune occupational lung disease cases culminated in 3 deaths and a lung transplant. CONCLUSIONS: A number of patients with PAP who may have occupational inhalational exposure and negative serum GMAb represent a high possibility of silicoproteinosis and very poor survival.

Evaluation of apparent diffusion coefficient mappings in amnestic mild cognitive impairment using an image analysis software brain search.

BACKGROUND: The apparent diffusion coefficient (ADC) from diffusion-weighted imaging (DWI) can quantify alterations in water diffusivity resulting from microscopic structural changes from amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). PURPOSE: To investigate the ADC value for aMCI and AD using Brain Search (BS) software based on anatomical volumes of interest (AVOI). MATERIAL AND METHODS: In total, 174 aged people were screened, and 25 patients with AD, 26 patients with aMCI, and 18 normal controls (NCs) were recruited. DWI was performed at 1.5 T with a fluid-attenuated inversion recovery (FLAIR), and the independent ADC mapping was generated after imaging acquisition. Ninety regional parcellations were adopted in a Brain Search (BS) based on the automated anatomic labeling atlas. The gray scale intensities (water diffusivity) from the collected ADC mappings were analyzed with BS. The mean value of each anatomical brain region was compared among aMCI, AD, and NC. The statistically significant (P < 0.05) group differences are displayed in color. RESULTS: During the pathological process of AD, the changes of water diffusivity appeared first in the left hippocampus, then gradually progressed to the bilateral sides and eventually displayed right lateralization. The ADC values from aMCI were obviously elevated compared to the values from the NC group in the left limbic cortex. Between the AD and NC groups, the significantly different brain areas included the bilateral hippocampus, the Cingulum_Mid, the ParaHippocampal_R, and the Temporal and Frontal lobes. There was a negative correlation between the ADC values and the scores from MMSE, MoCA, the Digit test, Raven's IQ, and WAIS IQ. Additionally, the ADC values were positively correlated with the scores from CDR, ADL, and ADAS-Cog. CONCLUSION: The water diffusivity for aMCI and AD displays asymmetric anatomical lateralization. The water diffusivity alterations can be analyzed and visualized with our newly designed analytic imaging software, BS, which can be used as a good reference for examining and diagnosing aMCI and AD patients.