Infection by hepatitis B virus (HBV) accounts for 50-80% of hepatocellular carcinoma (HCC) development worldwide, in which the HBV-encoded X protein (HBx) has critical role in the induction of ...carcinogenesis. Several studies have shown that thyroid hormone (TH) suppresses HCC development and protects hepatocytes from HBx-induced damage, thus it is of interest to examine whether TH can protect hepatocytes from HBx-induced carcinogenesis. By treating HBx- transgenic mice with or without TH, we confirmed the protective effects of TH on HBx-induced hepatocarcinogenesis, which was achieved via reduction of reactive oxygen species (ROS) inflicted DNA damage. We further found that TH induced biogenesis of mitochondria (MITO) and autophagy of HBx-targeted MITO simultaneously, consequently leading to suppression of HBx-promoted ROS and carcinogenesis. Using microarray data analysis, this protective effect of TH was found to be mediated via activation of PTEN-induced kinase 1 (PINK1) in hepatocytes. PINK1, in turn, activated and recruited Parkin, an E3 ligase, to ubiquitinate MITO-associated HBx protein and trigger selective mitophagy. The pathological significance of the TH/PINK1 pathway in liver protection was confirmed by the concomitant decrease in expression of both TR and PINK1 in matched HCC tumor tissues and negatively correlated with aggressive progression of cancer and poor prognosis. Our data indicate that TH/PINK1/Parkin pathway has a critical role in protecting hepatocytes from HBx-induced carcinogenesis. Notably, several liver-targeting therapeutic derivatives of TH facilitating prevention or therapy of steatosis have been identified. Furthermore, our proof-of-concept experiments suggest that application of T
constitutes an effective novel therapeutic or preventive option for HCC. Thus, the utilization of the agonists of TRs could be the meaningful strategy in liver relative diseases, ranging from simple hepatic steatosis to HCC.
The Red River shear zone (RRSZ) is a major left‐lateral strike‐slip shear zone, containing a ductilely deformed metamorphic core bounded by brittle strike‐slip and normal faults, which stretches for ...>1000 km from Tibet through Yunnan and North Vietnam to the South China Sea. The RRSZ exposes four high‐grade metamorphic core complexes along its length. Various lithologies from the southernmost core complex, the Day Nui Con Voi (DNCV), North Vietnam, provide new constraints on the tectonic and metamorphic evolution of this region prior to and following the initial India–Asia collision. Analysis of a weakly deformed anatectic paragneiss using P–T pseudosections constructed in the MnO–Na2O–CaO–K2O–FeO–MgO–Al2O3–SiO2–H2O–TiO2–O (MnNCKFMASHTO) system provides prograde, peak and retrograde metamorphic conditions, and in situ U–Th–Pb geochronology of metamorphic monazite yields texturally controlled age constraints. Tertiary metamorphism and deformation, overprinting earlier Triassic metamorphism associated with the Indosinian orogeny and possible Cretaceous metamorphism, are characterized by peak metamorphic conditions of ~805 °C and ~8.5 kbar between c. 38 and 34 Ma. Exhumation occurred along a steep retrograde P–T path with final melt crystallizing at the solidus at ≥~5.5 kbar at ~790 °C. Further exhumation at ~640–700 °C and ~4–5 kbar at c. 31 Ma occurred at subsolidus conditions. U–Pb geochronological analysis of monazite from a strongly deformed pre‐kinematic granite dyke from the flank of the DNCV provides further evidence for exhumation at this time. Magmatic grains suggest initial emplacement at 66.0 ± 1.0 Ma prior to the India–Asia collision, whereas grains with metamorphic characteristics indicate later growth at 30.6 ± 0.4 Ma. Monazite grains from a cross‐cutting post‐kinematic dyke within the core of the DNCV antiform provide a minimum age constraint of 25.2 ± 1.4 Ma for the termination of fabric development. A separate and significant episode of monazite growth at c. 83–69 Ma is suggested to be the result of fluid‐assisted recrystallization following the emplacement of magmatic units.
Psoriasis is a chronic inflammatory skin disorder that affects ~2%–3% of the worldwide population. Inappropriate and excessive activation of endosomal Toll-like receptors 7, 8, and 9 (TLRs 7–9) at ...the psoriatic site has been shown to play a pathogenic role in the onset of psoriasis. Macrophage is a major inflammatory cell type that can be differentiated into phenotypes M1 and M2. M1 macrophages produce proinflammatory cytokines, and M2 macrophages produce anti-inflammatory cytokines. The balance between these two types of macrophages determines the progression of various inflammatory diseases; however, whether macrophage polarization plays a role in psoriatic inflammation activated by endosomal TLRs has not been investigated. In this study, we investigated the function and mechanism of macrophages related to the pathogenic role of TLRs 7–9 in the progression of psoriasis. Analysis of clinical data in database revealed significantly increased expression of macrophage markers and inflammatory cytokines in psoriatic tissues over those in normal tissues. In animal studies, depletion of macrophages in mice ameliorated imiquimod, a TLR 7 agonist-induced psoriatic response. Imiquimod induced expression of genes and cytokines that are signature of M1 macrophage in the psoriatic lesions. In addition, treatment with this TLR 7 agonist shifted macrophages in the psoriatic lesions to a higher M1/M2 ratio. Both of the exogenous and endogenous TLR 7–9 ligands activated M1 macrophage polarization. M1 macrophages expressed higher levels of proinflammatory cytokines and TLRs 7–9 than M2 macrophages. These results suggest that by rendering macrophages into a more inflammatory status and capable of response to their ligands in the psoriatic sites, TLR 7–9 activation drives them to participate in endosomal TLR-activated psoriatic inflammation, resulting in an amplified inflammatory response. Our results also suggest that blocking M1 macrophage polarization could be a strategy which enables inhibition of psoriatic inflammation activated by these TLRs.
Differentiating tumor growth from posttreatment radiation effect (PTRE) remains a common problem in neuro-oncology practice. To our knowledge, useful threshold relative cerebral blood volume (rCBV) ...values that accurately distinguish the 2 entities do not exist. Our prospective study uses image-guided neuronavigation during surgical resection of MR imaging lesions to correlate directly specimen histopathology with localized dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging (DSC) measurements and to establish accurate rCBV threshold values, which differentiate PTRE from tumor recurrence.
Preoperative 3T gradient-echo DSC and contrast-enhanced stereotactic T1-weighted images were obtained in patients with high-grade glioma (HGG) previously treated with multimodality therapy. Intraoperative neuronavigation documented the stereotactic location of multiple tissue specimens taken randomly from the periphery of enhancing MR imaging lesions. Coregistration of DSC and stereotactic images enabled calculation of localized rCBV within the previously recorded specimen locations. All tissue specimens were histopathologically categorized as tumor or PTRE and were correlated with corresponding rCBV values. All rCBV values were T1-weighted leakage-corrected with preload contrast-bolus administration and T2/T2*-weighted leakage-corrected with baseline subtraction integration.
Forty tissue specimens were collected from 13 subjects. The PTRE group (n = 16) rCBV values ranged from 0.21 to 0.71, tumor (n = 24) values ranged from 0.55 to 4.64, and 8.3% of tumor rCBV values fell within the PTRE group range. A threshold value of 0.71 optimized differentiation of the histopathologic groups with a sensitivity of 91.7% and a specificity of 100%.
rCBV measurements obtained by using DSC and the protocol we have described can differentiate HGG recurrence from PTRE with a high degree of accuracy.
Some individuals show abnormal reactions to extreme fear and life-threatening situations, including tonic immobility (TI) and peri-traumatic dissociation (PTD). We aimed to investigate the ...association of TI and PTD with posttraumatic stress disorder (PTSD) in women who experienced sexual violence and the risk factors for PTD occurrence. We compared PTSD severity in 86 young adult women with PTSD after a sexual violence exposure grouped according to the presence of PTD and TI. In addition, we investigated whether PTD is associated with depression and anxiety symptoms and assessed potential risk factors for PTD reaction. We found a significant positive correlation between PTSD severity and PTD occurrence (R2 = .132; p = .001). PTD was also positively correlated with all clusters of PTSD symptoms except the Clinician-Administered PTSD Scale avoidance cluster (p = .058). PTD was strongly correlated with anxiety (R2 = .619; p < .001) and depressive symptoms (R2 = .547; p < .001). Multiple logistic regression showed that history of physical abuse (odds ratio OR: 1.386; p = .011) and sexual abuse (OR: 1.947; p = .004) during childhood were associated with PTD occurrence. Other risk factors for PTD were having less years of study (OR: 0.216; p = .016) and lower income (OR: 7.403; p = .028). TI measures were available for a subsample of 29 women. We found no association between TI and PTSD severity. PTD, but not TI, is significantly associated with more severe PTSD, depressive, and anxiety symptoms. Less-educated women with a history of childhood abuse and a lower income are at risk of PTD occurrence during a sexual violence episode.
Background The risk of hepatocellular carcinoma (HCC) increases with increasing level of hepatitis B virus (HBV) in serum (viral load). However, it is unclear whether genetic characteristics of HBV, ...including HBV genotype and specific genetic mutations, contribute to the risk of HCC. We examined the HCC risk associated with HBV genotypes and common variants in the precore and basal core promoter (BCP) regions. Methods From January 5, 1991, to December 21, 1992, baseline blood samples were collected from 2762 Taiwanese men and women who were seropositive for HBV surface antigen but had not been diagnosed with HCC; the samples were tested for HBV viral load by real-time polymerase chain reaction and genotyped by melting curve analysis. Participants who had a baseline serum HBV DNA level greater than 104 copies/mL (n = 1526) were tested for the precore G1896A and BCP A1762T/G1764A mutants by direct sequencing. Incident cases of HCC were ascertained through follow-up examinations and computerized linkage to the National Cancer Registry and death certification profiles. A Cox proportional hazards model was used to estimate the risk of HCC associated with HBV genotype and precore and BCP mutants after adjustment for other risk factors. All statistical tests were two-sided. Results A total of 153 HCC cases occurred during 33 847 person-years of follow-up. The HCC incidence rates per 100 000 person-years for participants infected with HBV genotype B or C were 305.6 (95% confidence interval CI = 236.9 to 388.1) and 785.8 (95% CI = 626.8 to 972.9), respectively. Among participants with a baseline HBV DNA level of at least 104 copies/mL, HCC incidence per 100 000 person-years was higher for those with the precore G1896 (wild-type) variant than for those with the G1896A variant (955.5 95% CI = 749.0 to 1201.4 vs 269.4 95% CI = 172.6 to 400.9) and for those with the BCP A1762T/G1764A double mutant than for those with BCP A1762/G1764 (wild-type) variant (1149.2 95% CI = 872.6 to 1485.6 vs 358.7 95% CI = 255.1 to 490.4). The multivariable-adjusted hazard ratio of developing HCC was 1.76 (95% CI = 1.19 to 2.61) for genotype C vs genotype B, 0.34 (95% CI = 0.21 to 0.57) for precore G1896A vs wild type, and 1.73 (95% CI = 1.13 to 2.67) for BCP A1762T/G1764A vs wild type. Risk was highest among participants infected with genotype C HBV and wild type for the precore 1896 variant and mutant for the BCP 1762/1764 variant (adjusted hazard ratio = 2.99, 95% CI = 1.57 to 5.70, P < .001). Conclusions HBV genotype C and specific alleles of BCP and precore were associated with risk of HCC. These associations were independent of serum HBV DNA level.
This study was undertaken to establish reference values of exhaled nitric oxide fraction (F(eNO)) and its determinants in healthy Asian children. 693 healthy Asian children aged 5-18 yrs were ...assessed using a single-breath online F(eNO) measurement (exhaled flow 50 mL·s(-1)), questionnaires, anthropometric measurements, spirometry and total and specific immunoglobulin (Ig) E. Geometric mean F(eNO) and the upper 95% CI were 13.7 ppb and 49.7 ppb, respectively, for healthy children, and 11.2 ppb and 30.2 ppb, respectively, for those without allergic sensitisation. F(eNO) was positively associated with age, allergic sensitisation, total IgE, ambient nitric oxide, measurement in the afternoon, and drinking water within 1 h before testing, and was negatively associated with weight. In healthy children without allergic sensitisation, age was the single best explanatory variable. The F(eNO) predicted values were 1-2 ppb higher in Asian than in Caucasian children in earlier studies, while the upper 95% CI were 9-10 ppb higher. In conclusion, the upper limits of normal F(eNO) in Asian children depend on age, from 21 ppb in young children to 39 ppb in adolescents. Ethnicity, age, allergic sensitisation, total IgE, ambient nitric oxide, time of testing, drinking water and weight are important determinants.
We report on the first coherent excitation of the highly forbidden S21/2→F27/2 electric octupole (E3) transition in a single trapped Yb+172 ion, an isotope without nuclear spin. Using the transition ...in Yb+171 as a reference, we determine the transition frequency to be 642 116 784 950 887.6(2.4) Hz. We map out the magnetic field environment using the forbidden S21/2→D25/2 electric quadrupole (E2) transition and determine its frequency to be 729 476 867 027 206.8(4.4) Hz. Our results are a factor of 1×105 (3×105) more accurate for the E2 (E3) transition compared to previous measurements. The results open up the way to search for new physics via precise isotope shift measurements and improved tests of local Lorentz invariance using the metastable F27/2 state of Yb+.
Abstract
Excess infrared flux from white dwarf stars is likely to arise from a dusty debris disk or a cool companion. In this work, we present near-infrared spectroscopic observations with ...Keck/MOSFIRE, Gemini/GNIRS, and Gemini/Flamingos-2 of seven white dwarfs with infrared excesses identified in previous studies. We confirmed the presence of dust disks around four white dwarfs (Gaia J0611–6931, Gaia J0006+2858, Gaia J2100+2122, and WD 0145+234) as well as two new white dwarf–brown dwarf pairs (Gaia J0052+4505 and Gaia J0603+4518). In three of the dust disk systems, we detected for the first time near-infrared metal emissions (Mg
i
, Si I, and possibly Fe I) from a gaseous component of the disk. We developed a new Markov Chain Monte Carlo framework to constrain the geometric properties of each dust disk. In three systems, the dust disk and the gas disk appear to coincide spatially. For the two brown dwarf–white dwarf pairs, we identified broad molecular absorption features typically seen in L dwarfs. The origin of the infrared excess around Gaia J0723+6301 remains a mystery. Our study underlines how near-infrared spectroscopy can be used to determine sources of infrared excess around white dwarfs, which has now been detected photometrically in hundreds of systems.
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