The optical blue filter with the suitable bandwidth, high transmittance and large acceptance angle is usually regarded as a critical optical component for a variety of applications. Here, we propose ...a polarization-insensitive angle-tolerant hybrid plasmonic blue filter incorporating two-dimensional aluminum (Al) nanodisks on the top of planar waveguide. The proposed plasmonic filter works via hybridization of surface plasmon polariton (SPP) mode, the localized Fabry–Perot resonance and waveguide mode, thus enables high peak transmittance up to 70% with the bandwidth of 30 nm and large acceptance angle up to 20°.
This study investigates the problem of designing unimodular waveform with spectral compatibility for multiple-input multiple-output radar in the presence of multiple targets and the signal-dependent ...interferences. A new approach is proposed to optimise the spectrally compatible radar waveform subject to not only the constant modulus constraint and the similarity constraint but also the signal-to-interference-plus-noise ratio (SINR) requirements for targets, aiming at suppressing the radar energy in some space-frequency areas occupied by other cooperative communication systems. However, the formulated optimisation problem is NP-hard because of the existence of the non-convex constraints. Based on the dual ascent framework, the authors develop an iterative algorithm to solve this challenging problem. The receive filter is obtained at the beginning of each iteration with the off-the-shelf technique and an innovative method termed phase-only dual ascent method is proposed to get the desired waveform. Additionally, they analyse the performance of the waveforms designed under the global SINR constraint and the local SINR constraint, respectively. Moreover, the convergence of the proposed algorithm is discussed concretely. Finally, the numerical simulations are provided to show the validity of the proposed approach.
Serum samples identified as positive for total anti-HBc, but negative for both HBsAg and anti-HBs, are referred to as anti-HBc alone. This serological response is compatible with acute, resolved, and ...chronic hepatitis B virus (HBV)infection but might also signify occult HBV infection. Once the anti-HBc alone pattern is detected, false-positive reactivity should be ruled out and further analyses can resolve the clinical status of the donor. The identification of anti-HBc positivity in the absence of HBsAg in organ transplant donors and in candidate patients for chemotherapy and immunosuppressive therapy requires further investigation because of the risk of HBV reactivation. False-positive detection, acute infection during the window phase, and resolved or chronic HBV infection are all possible and only distinguishable if the additional assays are done and measures of liver damage are taken into account. Measurement of serum anti-HBs responses after the administration of HBV vaccination can be useful to distinguish this serological profile. In view of the low risk of HBV reactivation in anti-HBc alone patients who are candidates for immunosuppressive treatment, such patients might not require pre-emptive antiviral therapy, but should be followed up on a monthly basis for alanine aminotransferase followed by quantitative HBV DNA testing in those with alanine aminotransferase increase. According to specific guidelines, nucleoside analogue prophylaxis is recommended in anti-HBc-positive liver allograft recipients and anti-HBc alone individuals who receive chemotherapy or biological therapy and should be continued for 6-12 months after discontinuation of such immunosuppressive therapies to protect against HBV reactivation.
Myosins belong to a large superfamily of actin-dependent molecular motors. Nonmuscle myosin II (NM II) is involved in the morphology and function of neurons, but little is known about how NM II ...activity is regulated. Brain-derived neurotrophic factor (BDNF) is a prevalent neurotrophic factor in the brain that encourages growth and differentiation of neurons and synapses. In this study, we report that BDNF upregulates the phosphorylation of myosin regulatory light chain (MLC2), to increases the activity of NM II. The role of BDNF on modulating the phosphorylation of MLC2 was validated by using Western blotting in primary cultured hippocampal neurons. This result was confirmed by injecting BDNF into the dorsal hippocampus of mice and detecting the phosphorylation level of MLC2 by Western blotting. We further perform coimmunoprecipitation assay to confirm that this process depends on the activation of the LYN kinase through binding with tyrosine kinase receptor B, the receptor of BDNF, in a kinase activity-dependent manner. LYN kinase subsequently phosphorylates MLCK, further promoting the phosphorylation of MLC2. Taken together, our results suggest a new molecular mechanism by which BDNF regulates MLC2 activity, which provides a new perspective for further understanding the functional regulation of NM II in the nervous system.
Macrophages are key elements in the pathogenesis of cholestatic liver diseases. Arid3a plays a prominent role in the biologic properties of hematopoietic stem cells, B lymphocytes and tumor cells, ...but its ability to modulate macrophage function during cholestasis remains unknown.
Gene and protein expression and cellular localization were assessed by q-PCR, immunohistochemistry, immunofluorescence staining and flow cytometry. We generated myeloid-specific Arid3a knockout mice and established three cholestatic murine models. The transcriptome was analyzed by RNA-seq. A specific inhibitor of the Mertk receptor was used in vitro and in vivo. Promoter activity was determined by chromatin immunoprecipitation-seq against Arid3a and a luciferase reporter assay.
In cholestatic murine models, myeloid-specific deletion of Arid3a alleviated cholestatic liver injury (accompanied by decreased accumulation of macrophages). Arid3a-deficient macrophages manifested a more reparative phenotype, which was eliminated by in vitro treatment with UNC2025, a specific inhibitor of the efferocytosis receptor Mertk. Efferocytosis of apoptotic cholangiocytes was enhanced in Arid3a-deficient macrophages via upregulation of Mertk. Arid3a negatively regulated Mertk transcription by directly binding to its promoter. Targeting Mertk in vivo effectively reversed the protective phenotype of Arid3a deficiency in macrophages. Arid3a was upregulated in hepatic macrophages and circulating monocytes in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Mertk was correspondingly upregulated and negatively correlated with Arid3a expression in PBC and PSC. Mertk
cells were located in close proximity to cholangiocytes, while Arid3a
cells were scattered among immune cells with greater spatial distances to hyperplastic cholangiocytes in PBC and PSC.
Arid3a promotes cholestatic liver injury by impairing Mertk-mediated efferocytosis of apoptotic cholangiocytes by macrophages during cholestasis. The Arid3a-Mertk axis is a promising novel therapeutic target for cholestatic liver diseases.
Macrophages play an important role in the pathogenesis of cholestatic liver diseases. This study reveals that macrophages with Arid3a upregulation manifest a pro-inflammatory phenotype and promote cholestatic liver injury by impairing Mertk-mediated efferocytosis of apoptotic cholangiocytes during cholestasis. Although we now offer a new paradigm to explain how efferocytosis is regulated in a myeloid cell autonomous manner, the regulatory effects of Arid3a on chronic liver diseases remain to be further elucidated.
Light-emitting diodes (LEDs) based visible light communication (VLC) can provide license-free bands, high data rates, and high security levels, which is a promising technique that will be extensively ...applied in future. Multi-band transmission color filters with enough peak transmittance and suitable bandwidth play a pivotal role for boosting signal-noise-ratio in VLC systems. In this paper, multi-band transmission color filters with bandwidth of dozens nanometers are designed by a simple analytical method. Experiment results of one-dimensional (1D) and two-dimensional (2D) tri-band color filters demonstrate the effectiveness of the multi-band transmission color filters and the corresponding analytical method.
•Multi-band transmission filters with dozens nanometers bandwidth are proposed.•An analytic method is used to design such multi-band transmission filters.•Both 1D and 2D tri-band filters are fabricated for RGB white light LEDs, respectively.•Experiment results demonstrate the effectiveness of the proposed analytical method.
Background and Aims:
Primary sclerosing cholangitis (PSC) is a chronic progressive liver disease characterized by the infiltration of intrahepatic tissue-resident memory CD8
+
T cells (T
RM
). ...Itaconate has demonstrated therapeutic potential in modulating inflammation. An unmet need for PSC is the reduction of biliary inflammation, and we hypothesized that itaconate may directly modulate pathogenic T
RM
.
Approach and Results:
The numbers of intrahepatic CD103
+
T
RM
were evaluated by immunofluorescence in PSC (n = 32), and the serum levels of itaconate in PSC (n = 64), primary biliary cholangitis (PBC) (n = 60), autoimmune hepatitis (AIH) (n = 49), and healthy controls (n = 109) were determined by LC-MS/MS. In addition, the frequencies and immunophenotypes of intrahepatic T
RM
using explants from PSC (n = 5) and healthy donors (n = 6) were quantitated by flow cytometry. The immunomodulatory properties of 4-octyl itaconate (4-OI, a cell-permeable itaconate derivative) on CD103
+
T
RM
were studied in vitro. Finally, the therapeutic potential of itaconate was studied by the administration of 4-OI and deficiency of immune-responsive gene 1 (encodes the aconitate decarboxylase producing itaconate) in murine models of PSC. Intrahepatic CD103
+
T
RM
was significantly expanded in PSC and was positively correlated with disease severity. Serum itaconate levels decreased in PSC. Importantly, 4-OI inhibited the induction and effector functions of CD103
+
T
RM
in vitro. Mechanistically, 4-OI blocked DNA demethylation of RUNX3 in CD8
+
T cells. Moreover, 4-OI reduced intrahepatic CD103
+
T
RM
and ameliorated liver injury in murine models of PSC.
Conclusions:
Itaconate exerted immunomodulatory activity on CD103
+
T
RM
in both in vitro and murine PSC models. Our study suggests that targeting pathogenic CD103
+
T
RM
with itaconate has therapeutic potential in PSC.
Background and Aims
The diverse inflammatory response found in the liver of patients with autoimmune hepatitis (AIH) is well established, but identification of potentially pathogenic subpopulations ...has proven enigmatic.
Approach and Results
We report herein that CD69+CD103+CD8+ tissue‐resident memory T cells (TRM) are significantly increased in the liver of patients with AIH compared to chronic hepatitis B, NAFLD, and healthy control tissues. In addition, there was a significant statistical correlation between elevation of CD8+ TRM cells and AIH disease severity. Indeed, in patients with successful responses to immunosuppression, the frequencies of such hepatic CD8+ TRM cells decreased significantly. CD69+CD8+and CD69+CD103+CD8+ T cells, also known as CD8+ TRM cells, reflect tissue residency and are well known to provide intense immune antigenic responses. Hence, it was particularly interesting that patients with AIH also manifest an elevated expression of IL‐15 and TGF‐β on inflammatory cells, and extensive hepatic expression of E‐cadherin; these factors likely contribute to the development and localization of CD8+ TRM cells. Based on these data and, in particular, the relationships between disease severity and CD8+ TRM cells, we studied the mechanisms involved with glucocorticoid (GC) modulation of CD8+ TRM cell expansion. Our data reflect that GCs in vitro inhibit the expansion of CD8+ TRM cells induced by IL‐15 and TGF‐β and with direct down‐regulation of the nuclear factor Blimp1 of CD8+ TRM cells.
Conclusions
Our data suggest that CD8+ TRM cells play a critical role in the pathogenesis of AIH, and GCs attenuate hepatic inflammation through direct inhibition of CD8+ TRM cell expansion.
Prolyl-4-hydroxylases (P4Hs) are key enzymes in collagen synthesis. The P4HA subunit (P4HA1, P4HA2, and P4HA3) contains a substrate binding and catalyzation domain. We postulated that P4HA2 would ...play a key role in the cholangiocyte pathology of cholestatic liver diseases.
We studied humans with primary biliary cholangitis (PBC) and Primary sclerosing cholangitis (PSC), P4HA2 -/- mice injured by DDC, and P4HA2 -/- /MDR2 -/- double knockout mice. A parallel study was performed in patients with PBC, PSC, and controls using immunohistochemistry and immunofluorescence. In the murine model, the level of ductular reaction and biliary fibrosis were monitored by histology, qPCR, immunohistochemistry, and Western blotting. Expression of Yes1 Associated Transcriptional Regulator (YAP) phosphorylation was measured in isolated mouse cholangiocytes. The mechanism of P4HA2 was explored in RBE and 293T cell lines by using qPCR, Western blot, immunofluorescence, and co-immunoprecipitation.
The hepatic expression level of P4HA2 was highly elevated in patients with PBC or PSC. Ductular reactive cholangiocytes predominantly expressed P4HA2. Cholestatic patients with more severe liver injury correlated with levels of P4HA2 in the liver. In P4HA2 -/- mice, there was a significantly reduced level of ductular reaction and fibrosis compared with controls in the DDC-induced chronic cholestasis. Decreased liver fibrosis and ductular reaction were observed in P4HA2 -/- /MDR2 -/- mice compared with MDR2 -/- mice. Cholangiocytes isolated from P4HA2 -/- /MDR2 -/- mice displayed a higher level of YAP phosphorylation, resulting in cholangiocytes proliferation inhibition. In vitro studies showed that P4HA2 promotes RBE cell proliferation by inducing SAV1 degradation, eventually resulting in the activation of YAP.
P4HA2 promotes hepatic ductular reaction and biliary fibrosis by regulating the SAV1-mediated Hippo signaling pathway. P4HA2 is a potential therapeutic target for PBC and PSC.
Background and Aim
Persistent hepatocellular secretory failure (PHSF) is a rare condition of severe cholestasis caused by drugs, toxins, infection, or temporary biliary obstruction. Real‐world data ...on rifampicin in cholestasis, particularly among patients with deep jaundice, are scarce. We aimed to expand the knowledge on the efficacy and safety of rifampicin treatment in PHSF patients.
Methods
Sixteen patients with PHSF who had received rifampicin treatment (150–300 mg/d) at our institution from September 2016 to July 2020 were included. Treatment efficacy was assessed by 20% improvement in serum total bilirubin (TBIL) concentration at 4 weeks. Follow‐up was continued until the concentration of TBIL returned to normal.
Results
Among the 16 enrolled patients, 12 had predisposing factors (drugs, infection, or transient biliary obstruction). ATP8B1 or ABCB11 mutations were detected in the other four patients without trigger events. UGT1A1 mutations were found in 7/10 patients. Before rifampicin treatment, the median TBIL level was 352 μmol/L (range 171–591 μmol/L). TBIL > 20% improvement was observed in 14 patients at 4 weeks. TBIL levels of 14 patients eventually returned to normal after 6–12 weeks of rifampicin treatment. The remaining two patients who did not respond to rifampicin finally recovered after nasobiliary drainage. Except for one patient with transient drug‐induced hepatitis, no other serious adverse events were observed.
Conclusions
Rifampicin could be a promising option for most PHSF patients. Most PHSF patients have UGT1A1 deficiency, which may be the target of rifampicin.
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