Persistence of chronic hepatitis B (CHB) is attributed to maintenance of the intrahepatic pool of the viral covalently closed circular DNA (cccDNA), which serves as the transcriptional template for ...all viral gene products required for replication. Current nucleos(t)ide therapies for CHB prevent virus production and spread but have no direct impact on cccDNA or expression of viral genes. We describe a potential curative approach using a highly specific engineered ARCUS nuclease (ARCUS-POL) targeting the hepatitis B virus (HBV) genome. Transient ARCUS-POL expression in HBV-infected primary human hepatocytes produced substantial reductions in both cccDNA and hepatitis B surface antigen (HBsAg). To evaluate ARCUS-POL in vivo, we developed episomal adeno-associated virus (AAV) mouse and non-human primate (NHP) models containing a portion of the HBV genome serving as a surrogate for cccDNA. Clinically relevant delivery was achieved through systemic administration of lipid nanoparticles containing ARCUS-POL mRNA. In both mouse and NHP, we observed a significant decrease in total AAV copy number and high on-target indel frequency. In the case of the mouse model, which supports HBsAg expression, circulating surface antigen was durably reduced by 96%. Together, these data support a gene-editing approach for elimination of cccDNA toward an HBV cure.
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Transient delivery of a highly specific ARCUS gene-editing nuclease (ARCUS-POL) targeting HBV polymerase results in 85% cccDNA reduction and robust HBsAg loss in vitro. Utilizing novel mouse and non-human primate models, LNP delivery of ARCUS-POL mRNA results in high levels of gene editing and >95% reduction of HBsAg.
Zr-based bulk metallic glasses (BMGs) possess excellent unique properties, such as high mechanical properties, good corrosion resistance, long-term antimicrobial ability, and were considered as an ...ideal candidate for medical tools. In this study, self-made ZrCuAlAgSi BMG surgical blade and commercial martensitic steel blade with and without metallic glass thin film (MGTF) were carefully examined for their sharpness. The amorphous state of BMG and MGTF were ascertained by X-ray diffraction (XRD) and differential scanning carlorimetry (DSC) analysis. A specially designed indentation-cutting rig was established to evaluate the sharpness of each blade on cutting the soft rubber material. The sharpness was evaluated by the blade sharpness index (BSI) which represents the ratio of external work done by the load to the energy required to initiate a cut or crack inside given materials. Results of sharpness test reveal that both BMG blade and the MGTF coated blade exhibits much lower surface roughness at their tip-edge and smaller BSI values (0.25 and 0.23, respectively) than the commercial blade (∼0.34), which corresponds to 26.5% and 32% improvement on the sharpness, respectively.
A special test rig was designed for indentation-cutting test and to evaluate the sharpness of each blade on cutting the soft rubber material. The sharpness was evaluated by the blade sharpness index (BSI) which represents the ratio of external work done by the load to the energy required to initiate a cut or crack inside given materials. The upper-left insert is the blades studied in this research, including commercial blade, ZrCuAlAgSi MGTF coated blade, and ZrCuAlAgSi BMG blade (left to right). The lower-right insert is the whole set rig. Display omitted
► One special cutting device was designed to evaluate the BSI of each blade on cutting the soft substrate. ► The energy require to initiate a cut on a substrate can be defined as “blade sharpness index”(BSI). ► The interaction strength between blade and soft substrate were recorded for BSI calculation. ► The BSI value of blade is a significant index for evaluating cutting ability. ► BSI can be improved about 26.5% and 32% by ZrCuAlAgSi BMG blade and by MGTF blade, respectively.
This study investigated the gastroprotective effect of Lycium barbarum polysaccharides (LBP) and C-phycocyanin (C-PC) in rats with ethanol-induced gastric ulcer. Rats were divided into 5 groups: ...normal, ulcer, ulcer treated with 100 mg/kg bw LBP, ulcer treated with 50 mg/kg bw C-PC, and ulcer treated with 50 mg/kg bw LBP and 25 mg/kg bw C-PC. Pretreatment with LBP and/or C-PC was given a week before ulcer induction. Ulcer induction was produced by 50% ethanol administration orally every other day for 4 weeks. After 5-week treatment, the histopathological observation showed that LBP or C-PC attenuated the severity of gastric mucosal damage. LBP decreased serum malondialdehyde (MDA) levels and gastric interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1) levels, and myeloperoxidase (MPO) activity. C-PC decreased serum MDA levels and gastric tumor necrosis factor-α (TNF-α), IL-1β, IL-6, ICAM-1 levels, and MPO activity. Combined LBP and C-PC decreased serum MDA levels and gastric TNF-α, IL-1β, IL-6, and ICAM-1 levels. LBP and/or C-PC increased gastric heat shock protein 70 and non-protein sulfhydryl compounds. Rats with ulcer and treatment had enriched with the family Bacillaceae. Therefore, pretreatment with LBP and/or C-PC attenuated ethanol-induced gastric ulcer in rats via suppressing oxidation and inflammation and increasing gastroprotection.
The authors report the growth of crack-free GaN on Si(1
1
1) substrate with step-graded AlGaN intermediate layers all grown at 1120
°C. By preparing all these layers at high-temperature, we can ...simplify the growth proceduce and minimize the growth time. Using X-ray diffraction and transmission electron microscopy, it was found that the high-temperature step-graded AlGaN intermediate layers can effectively reduce the tensile stress on GaN epitaxial layers. Photoluminescence and Raman measurements also indicate that we can improve the crystal quality of GaN by inserting the step-graded AlGaN intermediate layers.
The effective treatment for hepatocellular carcinoma (HCC) with American Joint Committee on Cancer stage IIIB remains controversial and challenging because of the high recurrence rate after resection ...and low survival rate. The median survival of those with macroscopic portal vein tumor thrombus (PVTT) is short. We reported such a case which received liver transplantation (LT) after successful consecutive downstaging therapies. A 40-year-old man with alcohol related liver cirrhosis and repeated esophageal varices bleeding had HCC with tumor thrombi in right main portal vein and the second portal branch of segment VI (stage IIIB). The received percutaneous alcohol injection, radiofrequency ablation, 8 sessions of transcatheter hepatic arterial chemoembolization, radiotherapy, and target therapy with sorafenib. Computed tomography (CT) scan and magnetic resonance imaging after treatments showed no viable fragments in the tumor and revealed both the right main portal vein and V1 branch were patent. One month later, the patient received a deceased LT. The perioperative course was rather smooth. After discharge, the interval follow-up CT studies of the chest and liver and whole body bone scan showed no tumor recurrence or metastasis up to 20 months postoperation.
•The treatment of HCC portal vein tumor thrombus remains challenging.•Multimodal downstaging to meet the Milan criteria is successful.•The patient in the present case had received liver transplantation and presented tumor-free up to 20 months posttransplant.
Summary
This study investigated the influence of deformation on precipitation behaviour and microstructure change during annealing. Here, the prior deformation of high‐chromium stainless steel was ...tensile deformation of 3%, 6% and 10%, and the specimens were then annealed at 700˚C for 10 h. The specimens were subsequently analyzed using backscattered electron image and electron backscattering diffraction measurements with SEM. Compared with the deformation microstructure, the grains revealed no preferred orientation. The precipitates of TiN and NbC were formed homogenously in the grain interior and at grain boundaries after annealing. Fine Laves phase precipitates were observed in grains and along subgrain boundaries as the deformation increased. Furthermore, the volume fraction of Laves phase increased, but the average particle diameter of precipitate was reduced as the deformation increased.
Lay Description
Crofer 22 H ferritic steel with high chromium has been developed for interconnect applications in solid oxide fuel cell at high temperature above 620°C due to ecoenergy and CO2 reduction regulation. Thus, work hardening and solution strengthening are needed for the high‐temperature mechanical properties. Here, the formation of precipitates inhibits recrystallization and grain growth. For example, microalloying elements of Ti, V and Nb have been added to achieve precipitates in HSLA steel. In this study, we focused on the relationship between prior deformation and the behaviour of Laves phase precipitates in Crofer 22 H after annealing. In addition, the deformation microstructure was investigated during annealing using backscattered electron image and electron backscattering diffraction measurements with SEM.
Anxiety Disorders (ANX) such as panic disorder, generalized anxiety disorder, and phobias, are highly prevalent conditions that are moderately heritable. Evidence suggests that DNA methylation may ...play a role, as it is involved in critical adaptations to changing environments. Applying an enrichment-based sequencing approach covering nearly 28 million autosomal CpG sites, we conducted a methylome-wide association study (MWAS) of lifetime ANX in 1132 participants (618 cases/514 controls) from the Netherlands Study of Depression and Anxiety. Using epigenomic deconvolution, we performed MWAS for the main cell types in blood: granulocytes, T-cells, B-cells and monocytes. Cell-type specific analyses identified 280 and 82 methylome-wide significant associations (q-value < 0.1) in monocytes and granulocytes, respectively. Our top finding in monocytes was located in ZNF823 on chromosome 19 (p = 1.38 × 10
) previously associated with schizophrenia. We observed significant overlap (p < 1 × 10
) with the same direction of effect in monocytes (210 sites), T-cells (135 sites), and B-cells (727 sites) between this Discovery MWAS signal and a comparable replication dataset from the Great Smoky Mountains Study (N = 433). Overlapping Discovery-Replication MWAS signal was enriched for findings from published GWAS of ANX, major depression, and post-traumatic stress disorder. In monocytes, two specific sites in the FZR1 gene showed significant replication after Bonferroni correction with an additional 15 nominally replicated sites in monocytes and 4 in T-cells. FZR1 regulates neurogenesis in the hippocampus, and its knockout leads to impairments in associative fear memory and long-term potentiation in mice. In the largest and most extensive methylome-wide study of ANX, we identified replicable methylation sites located in genes of potential relevance for brain mechanisms of psychiatric conditions.
Because of the development of large-format, wide-field cameras, microlensing surveys are now able to monitor millions of stars with sufficient cadence to detect planets. These new discoveries will ...span the full range of significance levels including planetary signals too small to be distinguished from the noise. At present, we do not understand where the threshold is for detecting planets. MOA-2011-BLG-293Lb is the first planet to be published from the new surveys, and it also has substantial follow-up observations. This planet is robustly detected in survey+follow-up data ( Delta chi super(2) ~ 5400). The planet/host mass ratio is q = (5.3 + or - 0.2) x 10 super(-3). The best-fit projected separation is s = 0.548 + or - 0.005 Einstein radii. However, due to the s left right arrow s super(-1) degeneracy, projected separations of s super(-1) are only marginally disfavored at Delta chi super(2) = 3. A Bayesian estimate of the host mass gives ML = 0.43 super(+0.27) sub(-0.17) M sub(middot in circle), with a sharp upper limit of ML < 1.2 M sub(middot in circle) from upper limits on the lens flux. Hence, the planet mass is mp = 2.4 super(+1.5) sub(-0.9) M sub(Jup), and the physical projected separation is either r sub(perpendicular) Asymptotically = to 1.0 AU or r sub(perpendicular) Asymptotically = to 3.4 AU. We show that survey data alone predict this solution and are able to characterize the planet, but the Delta chi super(2) is much smaller ( Delta chi super(2) ~ 500) than with the follow-up data. The Delta chi super(2) for the survey data alone is smaller than for any other securely detected planet. This event suggests a means to probe the detection threshold, by analyzing a large sample of events like MOA-2011-BLG-293, which have both follow-up data and high-cadence survey data, to provide a guide for the interpretation of pure survey microlensing data.
Reaction of fluoride with waste oyster shell was studied. To enhance the stability and adsorption capacity, oyster shell was coated with Al(OH)3 and the adsorption behaviors were compared with the ...uncoated one. When at low fluoride concentration (<30 mg/L), fluoride removal efficiency decreased with increasing pH, and the adsorption could be modeled by Langmuir isotherm. At high fluoride concentration (>100 mg/L), linear adsorption isotherm fitted better, in which the adsorption capacity of fluoride increased linearly with increasing equilibrium fluoride concentration. The coated oyster shell showed higher adsorption capacity and wider workable pH range. From XPS analysis, the presence of CaF2 was confirmed by the peak at 684.7 eV when fluoride concentration increased. It was noted that magnesium content of waste oyster shell reacted with fluoride to form significant fractions of MgF2 whose corresponding peak was detected at 685.6–685.8 eV. For coated oyster shell, fluoride reacted with Ca, Mg, and Al. The reaction mechanism was mainly adsorption at low initial concentration, and precipitation-dominated at higher concentration.
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•Waste oyster shell coated with Al(OH)3 show higher fluoride adsorption.•The main reaction mechanism was adsorption at low fluoride concentration.•It was precipitation-dominated at high fluoride concentration.•Fluoride not only reacted with Ca but also with Mg to form MgF2 at significant fractions.•For coated oyster shell, fluoride reacted with Ca, Mg, and Al as revealed by XPS.
Chronic Kidney Disease (CKD), characterized by an impaired kidney function, is associated with low testosterone levels. This study investigated the association between dietary patterns, testosterone ...levels, and severity of impaired kidney function among middle-aged and elderly men.
This cross-sectional study used the database from a private health-screening institute in Taiwan between 2008 and 2010. Men aged 40 years old and older (n = 21,376) with estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m
and proteinuria were selected. Among 21,376 men, 256 men had available measurements of testosterone levels. Dietary assessment was conducted using a food frequency questionnaire and three dietary patterns (fried-processed, vege-seafood, and dairy-grain dietary patterns) were identified using principal component analysis.
Men in the lower tertiles (T1 and T2) of eGFR had significantly decreased testosterone levels by 0.8 (95% CI: - 1.40, - 0.20) and 0.9 nmol/L (95% CI: - 1.43, - 0.33). Furthermore, serum triglycerides (TG) levels were inversely associated with testosterone levels (β = - 0.51, 95% CI: - 0.77, - 0.24). Men in the higher tertile of fried-processed dietary pattern scores were associated with decreased testosterone levels by 0.8 nmol/L (95% CI: - 1.40, - 0.16), reduced testosterone-to-TG (T/TG) ratio by 1.8 units (95% CI: - 2.99, - 0.53), and increased risk of moderate/severe impaired kidney function (eGFR < 60 mL/min/1.73 m
) and proteinuria severity by 1.35 (95% CI: 1.15, 1.58) and 1.18 (95% CI: 1.02, 1.37) times respectively. In contrast, the vege-seafood dietary pattern was negatively associated with severity of impaired kidney function and proteinuria after multivariable adjustment, but had no association with testosterone levels and T/TG ratio.
The fried-processed dietary pattern is negatively associated with testosterone levels but positively associated with the severity of impaired kidney function. However, the vege-seafood and dairy-grain dietary patterns appear to have beneficial effects.
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