The Relationship between Viral Replication and the Severity of Hepatic Necroinflammatory Damage Changed before HBeAg Loss in Patients with Chronic Hepatitis B Virus Infection.

Background and Aims: Disease progression of chronic hepatitis B virus (HBV) infection is driven by the interactions between viral replication and the host immune response against the infection. This study aimed to clarify the relationship between HBV replication and hepatic inflammation during disease progression. Methods: Two cross-sectional, one validation cohort, and meta-analyses were used to explore the relationship between HBV replication and liver inflammation. Spearman analysis, multiple linear regression, and logistic regression were used to explore the relationship between variables. Results: In the cross-sectional cohorts A and B including 1,350 chronic hepatitis B patients, Spearman analysis revealed a negative relationship between HBV replication (such as HBV DNA) and liver inflammation (such as ALT) in HBeAg-positive patients with higher HBV DNA >2×106 IU/mL (rho=-0.160 and -0.042) which turned to be positive in HBeAg-positive patients with HBV DNA ≤2×106 IU/mL (rho=0.278 and 0.260) and HBeAg-negative patients (rho=0.450 and 0.363). After adjustment for sex, age, and anti-HBe, results from logistic regression and multiple linear regression showed the opposite relationship still existed in HBeAg-positive patients with different DNA levels; the opposite relationship in HBeAg-positive patients with different DNA levels was validated in a third cohort; the opposite relationship in patients with different HBeAg status was partially confirmed by meta-analysis (overall R: -0.004 vs 0.481). Conclusions: These results suggested a negative relationship between viral replication and liver inflammation in HBeAg-positive patients with high HBV DNA, which changed to a positive relationship for those HBeAg-positive patients with DNA less than 2×106 IU/mL and HBeAg-negative patients.

Association of HBV serological markers with host antiviral immune response relevant hepatic inflammatory damage in chronic HBV infection.

The natural progression of chronic hepatitis B virus (HBV) infection is dynamic, but the longitudinal landscape of HBV serological markers with host antiviral immune response relevant hepatic inflammatory damage remains undetermined. To this issue, we studied the association of HBV serological markers with the severity of hepatic inflammatory damage and enumerated HBV-specific T cells using the cultured enzyme-linked immune absorbent spot (ELISpot). Five hundred and twenty-four treatment-naïve chronic HBV infection patients were enrolled. The Spearman correlation analysis revealed that in hepatitis B e antigen (HBeAg)-positive patients, all HBV virologic indicators negatively correlated with liver inflammatory damage and fibrosis (p < 0.01). Stronger correlations were accessed in the subgroup of HBeAg-positive patients with HBV DNA > 2 × 106 IU/mL (p < 0.01), whereas negative correlations disappeared in patients with HBV DNA ≤ 2 × 106 IU/mL. Surprisingly, in HBeAg-negative patients, the HBV DNA level was positively correlated with the hepatic inflammatory damage (p < 0.01). The relationship between type Ⅱ interferon genes expression and HBV DNA levels also revealed a direct shift from the initial negative to positive in HBeAg-positive patients with HBV DNA declined below 2 × 106 IU/mL. The number of HBV-specific T cells were identified by interferon γ ELISpot assays and showed a significant increase from HBeAg-positive to HBeAg-negative group. The host's anti-HBV immunity remains effective in HBeAg-positive patients with HBV DNA levels exceeding 2 × 106 IU/mL, as it efficiently eliminates infected hepatocytes and inhibits HBV replication. However, albeit the increasing number of HBV-specific T cells, the host antiviral immune response shifts towards dysfunctional when the HBV DNA load drops below this threshold, which causes more pathological damage and disease progression.

Association of a single amino acid replacement with dorsal pigmentation in a lizard from the Qinghai-Tibetan Plateau.

Reptiles can evolve adaptive colors in different environments, but relatively little is known about the genetic mechanisms. Here, we identified the MC1R gene and its association with intraspecific color variation in the lizard Phrynocephalus erythrurus. Analysis of the MC1R sequence in 143 individuals from dark South Qiangtang Plateau (SQP) and light North Qiangtang plateau (NQP) populations, revealed two amino acid sites that showed significant differences in frequency between two areas. One SNP, corresponding to Glu183Lys residue, was found to be a highly significant outlier and differentially fixed for SQP and NQP populations. This residue is located in an extracellular area in the second small extracellular loop within the secondary structure of MC1R, which represents an "attachment pocket" part of the 3D structure. Cytological expression of MC1R alleles with the Glu183Lys replacement showed a 39 % increase in intracellular agonist-induced cyclic AMP levels and a 23.18 % greater cell surface expression of MC1R protein in the SQP relative to the NQP allele. Further in silico 3D modeling and in vitro binding experiments indicated a higher MC1R-α-MSH binding for the SQP allele, and elevated melanin synthesis. We provide an overview of how a single amino acid replacement leads to fundamental changes in MC1R function, and hence shapes variation in dorsal pigmentation in lizards from different environments.

Relationship between the Level of Serum Golgi Protein 73 and the Risk of Short-term Death in Patients with ALD-ACLF.

Background and Aims: As a hepatocellular carcinoma biomarker, serum Golgi protein 73 (GP73) is reportedly related to inflammation. Acute-on-chronic liver failure (ACLF) is characterized by severe systemic inflammation. In this study, we aimed to explore the association between the GP73 level and short-term mortality in patients with alcohol-associated liver disease-related ACLF (ALD-ACLF). Methods: This retrospective cohort study involved 126 Chinese adults with ALD-ACLF. Baseline serum GP73 level was measured using enzyme-linked immunosorbent assay. Patients were followed-up for 90 d and outcomes were assessed. Data were analyzed using multivariate Cox regression and piecewise linear regression analyses. The predictive value of GP73 and classic models for the short-term prognosis of participants were evaluated and compared using receiver operating characteristic curves. Results: The serum GP73 level was independently associated with an increased mortality risk in patients with ALD-ACLF. Compared with the lowest tertile, the highest serum GP73 level predisposed patients with ALD-ACLF to a higher mortality risk in the fully adjusted model [at 28 days: hazard ratio (HR): 4.29 (0.99-18.54), p=0.0511; at 90 days: HR: 3.52 (1.15-10.79), p=0.0276]. Further analysis revealed a positive linear association. GP73 significantly improved the accuracy of the Child-Turcotte-Pugh score, model for end-stage liver disease score, and model for end-stage liver disease-sodium score in predicting short-time prognosis of patients with ALD-ACLF. Conclusions: The serum GP73 level is a significant predictor of the subsequent risk of death in patients with ALD-ACLF. GP73 improved the predictive value of classic prognostic scores.

A review: The detection of cancer cells in histopathology based on machine vision.

Machine vision is being employed in defect detection, size measurement, pattern recognition, image fusion, target tracking and 3D reconstruction. Traditional cancer detection methods are dominated by manual detection, which wastes time and manpower, and heavily relies on the pathologists' skill and work experience. Therefore, these manual detection approaches are not convenient for the inheritance of domain knowledge, and are not suitable for the rapid development of medical care in the future. The emergence of machine vision can iteratively update and learn the domain knowledge of cancer cell pathology detection to achieve automated, high-precision, and consistent detection. Consequently, this paper reviews the use of machine vision to detect cancer cells in histopathology images, as well as the benefits and drawbacks of various detection approaches. First, we review the application of image preprocessing and image segmentation in histopathology for the detection of cancer cells, and compare the benefits and drawbacks of different algorithms. Secondly, for the characteristics of histopathological cancer cell images, the research progress of shape, color and texture features and other methods is mainly reviewed. Furthermore, for the classification methods of histopathological cancer cell images, the benefits and drawbacks of traditional machine vision approaches and deep learning methods are compared and analyzed. Finally, the above research is discussed and forecasted, with the expected future development tendency serving as a guide for future research.

Grating Interferometer with Redundant Design for Performing Wide-Range Displacement Measurements.

Grating interferometers that use large two-dimensional grating splice modules for performing wide-range measurements have significant advantages for identifying the position of the wafer stage. However, the manufacturing process of large two-dimensional grating splice modules is very difficult. In contrast to existing redundant designs in the grating line dimension, we propose a novel interferometric reading head with a redundant design for obtaining wide-range displacement measurements. This interferometric reading head uses a one-dimensional grating splice module, and it was observed to be compatible with two orthogonal gratings. We designed a grating interferometer system composed of four reading heads to achieve a wide range of measurements and verified it using ZEMAX simulation. By conducting experiments, we were able to verify the compatibility of the reading head with gratings possessing different grating line directions; the measurement noise was found to be less than 0.3 nm.

Diagnostic Value of Serum Golgi Protein 73 for Liver Inflammation in Patients with Autoimmune Hepatitis and Primary Biliary Cholangitis.

BACKGROUND: There is lack of reliable serum biomarkers to reflect the severity of liver necroinflammation for those who suffer autoimmune liver diseases (AILDs). In this study, a previously established patient cohort was used to explore the potential of serum Golgi protein 73 (GP73) as a noninvasive marker of AILD-related liver necroinflammation. METHODS: Serum GP73 concentration was measured in a retrospective cohort of 168 AILD patients, which included 74 patients with autoimmune hepatitis (AIH) and 94 with primary biliary cholangitis (PBC) who had undergone liver biopsy. Spearman's correlation and multivariate analysis were used to evaluate the relationship between serum GP73 and liver necroinflammation. A receiver operating characteristic curve was constructed to evaluate the value of GP73 for the prediction of moderate or severe liver necroinflammation. The diagnostic value of serum GP73 was also compared with that of alkaline phosphatase (ALP) in patients with PBC. Histologically, immunohistochemical analysis was performed to assess hepatic GP73 expression. RESULTS: Both the serum level and hepatic tissue expression of GP73 protein were aberrantly elevated and correlated well with the severity of necroinflammation in both AIH (rho = 0.655, P < 0.001) and PBC (rho = 0.547, P < 0.001) patients. The results here suggested that serum GP73 could be an independent biomarker to reflect the severity of liver necroinflammation. The AUROCs for GP73 to predict moderate necroinflammation (≥G2) and severe necroinflammation (≥G3) in patients with AIH were 0.828 and 0.832, respectively. Moreover, the AUROCs of serum GP73 for the identification of moderate necroinflammation (≥G2) (AUROC = 0.820, P < 0.001) and severe necroinflammation (≥G3) (AUROC = 0.803, P < 0.001) were superior to those of ALP (≥G2: AUROC = 0.607, P = 0.028 and ≥G3: AUROC = 0.559, P = 0.357) in patients with PBC. Mechanically, interlukin-6 (IL-6), the proinflammatory and prohepatic regenerating cytokine, could transcriptionally upregulate GP73 gene expression. CONCLUSION: Serum GP73 is a potential noninvasive biomarker to evaluate the severity of liver necroinflammation in patients with AILDs.

Method for measuring the relative phases among the three beams in the case of homodyne three-beam interference.

A method for measuring the relative phases (RPs) among the three beams in the case of homodyne three-beam interference (TBI) is proposed and verified by the ZEMAX simulation in this paper. The method requires that the interference beams are not on the same plane, that is, any two of the three beams interfere at an angle in different planes. Based on the phase delay of the beam in space, the inclined beams have different phases at different positions within the beams' range. By arranging the photodetector array within the interference area, the RPs can be calculated using the intensity of the interference light received by specific photodetector units. The application of the algorithm for the displacement measurement of the homodyne three-beam interferometer (TBIR) has been verified by simulation. The beam number of three-beam interference is one less than that of two two-beam interference when measuring two relative phases. Compared with the two-beam interferometer, the TBIR applied to two-degree-of-freedom displacement measurement is more compact in structure due to the more compact phase measurement components.

Integrating chemical engineering and crystallographic texturing design strategy for the realization of practically viable lead-free sodium bismuth titanate-based incipient piezoceramics.

Off-resonance actuators utilizing lead-free incipient piezoelectric materials have recently gained extensive attention because of their exceptionally high electromechanical strain. However, current incipient piezoelectric materials have three critical challenges, namely, high driving field required for producing potentially high strains, high frequency dependence, and relatively poor fatigue resistance, which seriously restrict the implementation of lead-free incipient piezoelectrics in high-efficiency actuator applications. Herein, we demonstrate that the integration of chemical engineering and crystallographic texturing design strategies into a Bi0.5Na0.5TiO3-based system provides a highly effective approach to address these challenges. Novel 〈00l〉-oriented 0.97(0.94Bi0.5Na0.5TiO3-0.06BaTiO3)-0.03NN, as an exemplary incipient piezoelectric ceramic, was fabricated to experimentally demonstrate this design concept. A low field-driven large strain response (∼0.32% at 50 kV cm-1, ∼0.46% at 75 kV cm-1), excellent frequency dependence (∼0.42% at 65 kV cm-1, <5% variation from 0.1 Hz to 100 Hz), and superior fatigue endurance (S > 0.4%, <10% change up to 105 cycles) were simultaneously achieved in the manufactured textured ceramic, which is superior to that reported previously in most lead-free perovskite ceramics. These outstanding actuator performances can be mainly ascribed to the considerably easy ergodic relaxor to ferroelectric phase transition due to the formation of an oriented microstructure, which promotes domain switching and mobility, as confirmed by PFM measurements. This study offers a feasible and reproducible design methodology, i.e., chemical engineering and crystallographic texturing, to develop viable incipient piezoceramics and will guide future efforts in this field.

Analysis of the Errors Caused by Disturbed Multimode Fibers in the Interferometer with Fiber-Coupled Delivery.

In this paper, the errors of the displacement measurement interferometer with multi-mode fiber-coupled delivery are analyzed when the fibers are disturbed. Simulation results show that the characteristic frequency of the measurement error is consistent with that of disturbance, and the error has higher order frequency components. The experiments are designed for the effect of fringe contrast on the measurement error. The experimental results show that the measurement error is rather sensitive to the interference angle between the measurement arm and the reference arm in the multi-mode fibers, but not to the irradiance ratio of the measurement arm and the reference arm. In an interferometer with multimode fiber, the interference angle between the measurement arm and the reference arm needs to be restricted. This conclusion provides a theoretical basis for designing an interferometer measurement system with interference angle that is adaptive to wider application.

Serum Golgi Protein 73 as a Potential Biomarker for Hepatic Necroinflammation in Population with Nonalcoholic Steatohepatitis.

AIMS: Persistent hepatic necroinflammatory damage almost always results in fibrosis/cirrhosis or even hepatocellular carcinoma. Therefore, the presence of active necroinflammation in the liver suggests that nonalcoholic fatty liver disease (NAFLD) patients are in urgent need of treatment. Unfortunately, alanine transaminase (ALT), a routine indicator of liver inflammatory damage, showed a poor performance in nonalcoholic steatohepatitis (NASH) patients. Thus, it will be valuable to find an alternative indicator to identify patients with hepatic necroinflammatory damage. In this study, we evaluated the diagnostic value of serum Golgi protein 73 (GP73) for hepatic necroinflammatory damage in patients with NASH. METHODS: The clinical data of 201 patients with NASH diagnosed by liver biopsy according to the Brunt staging system were collected retrospectively. The in situ expression of GP73 protein was measured by immunohistochemistry. The receiver operating characteristic (ROC) curve was used to calculate the area under the ROC curve (AUROC) of serum GP73 for diagnosing hepatic necroinflammatory damage. RESULTS: The serum GP73 levels of NASH patients increased with the aggravation of liver necroinflammation. The median levels significantly increased from 49.98 ng/ml (31.49, 75.05) for G0-1 to 76.61 ng/ml (48.68, 110.03) for G2 and to 116.44 ng/ml (103.41, 162.17) for G3 patients (G0-1 vs. G2, P < 0.0001; G2 vs. G2, P < 0.0001; G2. CONCLUSIONS: GP73 is a valuable alternative serum marker reflecting the severity of hepatic necroinflammation in NASH patients.

Exploring the Diagnostic Potential of Serum Golgi Protein 73 for Hepatic Necroinflammation and Fibrosis in Chronic HCV Infection with Different Stages of Liver Injuries.

BACKGROUND AND AIM: Serum Golgi protein 73 (GP73) is a promising alternative biomarker of chronic liver diseases, but most data are from patients with HBV infection rather than HCV. MATERIALS AND METHODS: Two independent cohorts of chronic hepatitis C (CHC) patients from the 5th Medical Centre of the Chinese PLA General Hospital (n = 174) and Beijing Youan Hospital (n = 120) with different histories of HCV infection were enrolled. The correlations between serum GP73 and other biochemical indices, as well as its correlations with different stages of liver disease progression, were investigated. The receiver operating characteristic (ROC) curve was employed to evaluate the diagnostic potential of serum GP73 for liver necroinflammation and fibrosis, and comparisons of the diagnostic efficiency with traditional indices of hepatic liver injuries were further investigated. RESULTS: Levels of serum GP73 were found significantly elevated in patients with moderate to severe inflammatory grade (G ≥ 2) and/or with advanced fibrotic stages (F ≥ 3) in both cohorts (P < 0.05, respectively), as compared to those with a normal or mild liver lesion. Further ROC analysis demonstrated that serum GP73 was comparable to serum ALT and AST in diagnosing the liver necroinflammation grade at G ≥ 2, but its diagnostic values for advanced fibrosis (F ≥ 3) and cirrhosis (F = 4) were limited when compared to APRI and FIB-4, and FIB-4 exhibited the best performance. Notably, an obvious elevation of serum GP73 was observed after patients received PEG-IFN and ribavirin treatment. CONCLUSIONS: Serum GP73 is an important biomarker in evaluating and monitoring the disease progression including liver necroinflammation and fibrosis in patients with chronic HCV infection, but the value is limited for diagnosing advanced fibrosis and cirrhosis in comparison with APRI and FIB-4.

Two Degree-of-Freedom Fiber-Coupled Heterodyne Grating Interferometer with Milli-Radian Operating Range of Rotation.

In the displacement measurement of the wafer stage in lithography machines, signal quality is affected by the relative angular position between the encoder head and the grating. In this study, a two-degree-of-freedom fiber-coupled heterodyne grating interferometer with large operating range of rotation is presented. Fibers without fiber couplers are utilized to receive the interference beams for high-contrast signals under the circumstances of large angular displacement and ZEMAX ray tracing software simulation and experimental validation have been carried out. Meanwhile, a reference beam generated inside the encoder head is adopted to suppress the thermal drift of the interferometer. Experimental results prove that the proposed grating interferometer could realize sub-nanometer displacement measurement stability in both in-plane and out-of-plane directions, which is 0.246 nm and 0.465 nm of 3σ value respectively within 30 s.

Zika virus NS3 is a canonical RNA helicase stimulated by NS5 RNA polymerase.

Zika virus is a positive single-strand RNA virus whose replication involved RNA unwinding and synthesis. ZIKV NS3 contains a helicase domain, but its enzymatic activity is not fully characterized. Here, we established a dsRNA unwinding assay based on the FRET effect to study the helicase activity of ZIKV NS3, which provided kinetic information in real time. We found that ZIKV NS3 specifically unwound dsRNA/dsDNA with a 3' overhang in the 3' to 5' direction. The RNA unwinding ability of NS3 significantly decreased when the duplex was longer than 18 base pairs. The helicase activity of NS3 depends on ATP hydrolysis and binding to RNA. Mutations in the ATP binding region or the RNA binding region of NS3 impair its helicase activity, thus blocking viral replication in the cell. Furthermore, we showed that ZIKV NS5 interacted with NS3 and stimulated its helicase activity. Disrupting NS3-NS5 interaction resulted in a defect in viral replication, revealing the tight coupling of RNA unwinding and synthesis. We suggest that NS3 helicase activity is stimulated by NS5; thus, viral replication can be carried out efficiently. Our work provides a molecular mechanism of ZIKV NS3 unwinding and novel insights into ZIKV replication.

Tailoring frequency-insensitive large field-induced strain and energy storage properties in (Ba0.85Ca0.15)(Zr0.1Ti0.9)O3-modified (Bi0.5Na0.5)TiO3 lead-free ceramics.

Lead-free (Bi0.5Na0.5)TiO3-based relaxor ferroelectrics are attracting growing research interest due to their very large field-induced strain response and excellent energy storage performance. While extensive explorations have been made of these performances separately, being able to optimize both field-induced strain and energy storage performance of polycrystalline materials together, and hence achieve a synergistic result, would also be highly desirable for their practical applications. Herein, lead-free relaxor-ferroelectric (Ba0.85Ca0.15)(Zr0.1Ti0.9)O3-modified (Bi0.5Na0.5)TiO3 (BNT-BCZT) ceramics were designed and demonstrated to be feasible candidates for both actuator and pulsed power capacitors. Optimal field-induced strain performances were realized in 0.92BNT-0.08BCZT ceramics with not only a high strain of 0.46% but also an impressive frequency stability (0.5 Hz-100 Hz), superior to those of other reported BNT-based materials under a similar frequency range. Moreover, the 0.5BNT-0.5BCZT compositions in the complete ER region delivered a relatively high Wrec of 0.95 J cm-3 and η of 69%, while still remaining insensitive to changes in temperature, frequency, and cycle number. More importantly, a short discharge time (of ∼0.41 µs) was also measured for this composition. Introducing BCZT into the composition was found to promote a non-ergodic-to-ergodic relaxor (NR-ER) phase transition and the formation of dynamic polar nanoregions (PNRs), generating the high strain responses and superior energy storage performances of the given compositions. These features may offer a new strategy to simultaneously tailor lead-free relaxor ferroelectrics toward high field-induced strain and superior energy storage performance for ceramics actuators and capacitor applications.

Ultraprecision Real-Time Displacements Calculation Algorithm for the Grating Interferometer System.

Grating interferometry is an environmentally stable displacement measurement technique that has significant potential for identifying the position of the wafer stage. A fast and precise algorithm is required for real-time calculation of six degrees-of-freedom (DOF) displacement using phase shifts of interference signals. Based on affine transformation, we analyze diffraction spot displacement and changes in the internal and external effective optical paths of the grating interferometer caused by the displacement of the wafer stage (DOWS); then, we establish a phase shift-DOWS model. To solve the DOWS in real time, we present a polynomial approximation algorithm that uses the frequency domain characteristics of nonlinearities to achieve model reduction. The presented algorithm is verified by experiment and ZEMAX simulation.