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.

The Early On-treatment Stiffness Decline Attributed to the Improved Hepatic Inflammation in Fibrotic Chronic Hepatitis B.

OBJECTIVES: Hepatic inflammation, the driver of fibrosis progression in liver disease, can impact the accuracy of liver stiffness measurement (LSM). We wondered whether the decline in LSM value during the early antiviral phase was mainly attributed to the control of hepatic inflammation or the regression of fibrosis in patients with fibrotic/cirrhotic chronic hepatitis B (CHB). PATIENTS AND METHODS: The study cohort was composed of 82 patients with CHB who underwent antiviral and antifibrotic therapy at the Fifth Medical Center of PLA General Hospital. All patients had liver biopsies at both baseline and 72 weeks posttherapy. Liver pathology and clinical data, including the LSM value, were collected. RESULTS: After 72 weeks of treatment, both the histologic activity index score and fibrosis score, as well as the LSM value, were significantly decreased (P < 0.001), compared with their baseline values. The pretreatment correlation of LSM value with either histologic activity index score (r = 0.526 vs r = 0.286) or fibrosis score (r = 0.677 vs r = 0.587) was attenuated at 72 weeks. Notably, logistic regression analysis revealed that the improvement in inflammation (odds ratio = 1.018, 95% CI: 1.002-1.031, P = 0.023) but not fibrosis (odds ratio = 0.994, 95% CI: 0.980-1.009, P = 0.414), had an impact on the change in LSM values between baseline and at 72-week treatment. CONCLUSIONS: The findings of this study suggest that in patients with fibrotic CHB receiving antiviral medication, the early phase reduction in LSM value was related to improved hepatic inflammation rather than fibrosis regression.

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.

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.

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.

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.

Three-degrees-of-freedom laser interferometer based on differential wavefront sensing with wide angular measurement range.

We present a three-degrees-of-freedom laser interferometer based on differential wavefront sensing with a wide angular measurement range. To obtain measurement signals with a high AC/DC ratio and improve the linearity of differential wavefront sensing in a wide range angular displacement measurement, a fiber bundle instead of a quadrant photodiode is applied to receive the interference light. Meanwhile, a decoupled algorithm with quadratic correction derived by the ray tracing method and kinematic analysis is detailed in the case of the wide range angular displacement. The simulation and experimental results prove that the laser interferometer with the proposed structure could realize hundreds of microradian range of angular displacement measurement, which are expanded in the differential wavefront sensing.

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.

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.

Translational displacement computational algorithm of the grating interferometer without geometric error for the wafer stage in a photolithography scanner.

The translational displacement computational algorithm base on a novel phase-shift model is proposed eliminating the geometric error of the grating interferometer for precision positioning of a multi-degree-of-freedom motion stage. Firstly, the mechanism of the geometric error of the grating interferometer is analyzed, and the novel phase-shift model of the grating interferometer is constructed based on rigid body kinematics and affine geometry transformation. High accuracy of the model is demonstrated by ZEMAX simulation. Then, according to Taylor series expansion, the phase-shift model is simplified by polynomial regression to solve the problems of a large amount of computational effort and inability to derive the translational displacement computational algorithm. The availability and accuracy of the translational displacement computational algorithm are verified by ZEMAX simulation and experiment.

Sinusoidal phase-modulating laser diode interferometer for wide range displacement measurement.

A sinusoidal phase-modulating laser diode interferometer for wide range displacement measurement is proposed. To realize wide range displacement measurement, a signal processing method utilizing a look-up table to estimate the dynamic value of the effective sinusoidal phase-modulating depth is detailed, and the error caused by the residual amplitude modulation and the effective sinusoidal phase-modulating depth in wide range displacement measurement can be eliminated. It is discussed that the extended measurement range depends on the monotone intervals of several specific functions. The simulation and experimental results prove that the sinusoidal phase-modulating laser diode interferometer with the proposed method could realize centimeter level displacement measurement range.

[Correlation between red blood cell count and liver function status].

OBJECTIVE: To investigate the changes in red blood cell count in patients with different liver diseases and the correlation between red blood cell count and degree of liver damage. METHODS: The clinical data of 1427 patients with primary liver cancer, 172 patients with liver cirrhosis, and 185 patients with hepatitis were collected, and the Child-Pugh class was determined for all patients. The differences in red blood cell count between patients with different liver diseases were retrospectively analyzed, and the correlation between red blood cell count and liver function status was investigated. The Mann-Whitney U test, Kruskal-Wallis H test, rank sum test, Spearman rank sum correlation test, and chi-square test were performed for different types of data. RESULTS: Red blood cell count showed significant differences between patients with chronic hepatitis, liver cancer, and liver cirrhosis and was highest in patients with chronic hepatitis and lowest in patients with liver cirrhosis (P < 0.05). In the patients with liver cirrhosis, red blood cell count tended to decrease in patients with a higher Child-Pugh class (P < 0.05). CONCLUSION: For patients with liver cirrhosis, red blood cell count can reflect the degree of liver damage, which may contribute to an improved liver function prediction model for these patients.

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 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.

Image-inpainting and quality-guided phase unwrapping algorithm.

For the wrapped phase map with regional abnormal fringes, a new phase unwrapping algorithm that combines the image-inpainting theory and the quality-guided phase unwrapping algorithm is proposed. First, by applying a threshold to the modulation map, the valid region (i.e., the interference region) is divided into the doubtful region (called the target region during the inpainting period) and the reasonable one (the source region). The wrapped phase of the doubtful region is thought to be unreliable, and the data are abandoned temporarily. Using the region-filling image-inpainting method, the blank target region is filled with new data, while nothing is changed in the source region. A new wrapped phase map is generated, and then it is unwrapped with the quality-guided phase unwrapping algorithm. Finally, a postprocessing operation is proposed for the final result. Experimental results have shown that the performance of the proposed algorithm is effective.

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.

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.

An approximate closed-form link loss model for non-line-of-sight ultraviolet communication in noncoplanar geometry.

Non-line-of-sight UV communication link path loss models have been explored for both coplanar and noncoplanar geometries, and these typically require numerical evaluation. In this Letter, we propose a closed-form and easily applied model to describe link behavior, applicable to noncoplanar geometry. The model is compared with a recently reported analytical model and shows good agreement.