Transforming growth factor β-activated kinase 1 transcriptionally suppresses hepatitis B virus replication

Hepatitis B Virus (HBV) replication in hepatocytes is restricted by the host innate immune system and related intracellular signaling pathways. Transforming growth factor β-activated kinase 1 (TAK1) is a key mediator of toll-like receptors and pro-inflammatory cytokine signaling pathways. Here, we report that silencing or inhibition of endogenous TAK1 in hepatoma cell lines leads to an upregulation of HBV replication, transcription, and antigen expression. In contrast, overexpression of TAK1 significantly suppresses HBV replication, while an enzymatically inactive form of TAK1 exerts no effect. By screening TAK1-associated signaling pathways with inhibitors and siRNAs, we found that the MAPK-JNK pathway was involved in TAK1-mediated HBV suppression. Moreover, TAK1 knockdown or JNK pathway inhibition induced the expression of farnesoid X receptor α, a transcription factor that upregulates HBV transcription. Finally, ectopic expression of TAK1 in a HBV hydrodynamic injection mouse model resulted in lower levels of HBV DNA and antigens in both liver and serum. In conclusion, our data suggest that TAK1 inhibits HBV primarily at viral transcription level through activation of MAPK-JNK pathway, thus TAK1 represents an intrinsic host restriction factor for HBV replication in hepatocytes

Observations on the Hipparion Red Clays of the Loess Plateau

We discuss the history of exploration of Red Clay vertebrate fossils of the Loess Plateau, and record observations on “Hipparion Red Clay” localities of Shanxi and Gansu provinces. Red clay is widespread across the Loess Plateau, but misleading as a descriptive term because many deposits are neither red nor dominated by clay-size sediment. Many red clay sequences contain paleosols, but also water-laid deposits. Our survey includes well-known localities of Yushe Basin, Renjiagou and Leijiahe near Lingtai, and sites of Qingyang and Qin’an. We discuss fossils found at Renjiagou, a new discovery of micromammals (Pliopentalagus) from Yucun, and Pliocene burrows observed at Hu Jia Cun, both latter localities northeast of Lingtai. Observations are consistent with a high rate of supply of clay sized particles, likely air-fall origin, throughout the Loess Plateau during the late Miocene. In some areas where fluvial or lake processes dominate, red clay particles are replaced in part or completely by water-laid coarse-grained deposits. We saw no evidence for a dry Late Miocene-Early Pliocene, but rather hypothesize well-watered habitat of high productivity. Locally diverse vertebrate fossils attest to high terrestrial biomass for Hipparion faunas.Human Evolutionary Biolog

High L-Carnitine Levels Impede Viral Control in Chronic Hepatitis B Virus Infection

Persistent antigen exposure during chronic hepatitis B infection leads to exhausted immune responses, thus impeding viral control. In recent years, immunometabolism opens new therapeutic possibilities for the modulation of immune responses. Herein, we investigated the immunomodulatory effect of L-carnitine (L-Cn) on immune cells in chronic HBV infection. In this study, 141 treatment-naïve patients with chronic HBV infection, 38 patients who achieved HBsAg loss following antiviral treatment, and 47 patients who suffered from HBV-related HCC from real-life clinical practice were recruited. The plasma L-Cn levels were measured by ELISA. RNA sequencing was conducted to define the transcriptional profiles of peripheral blood mononuclear cells after L-Cn stimulation. In vitro assays were performed to assess the effect of L-Cn on immune cells; the frequencies and function of immune cells were analyzed by flow cytometry. We found that compared with patients with HBsAg loss, patients with HBsAg positivity and patients who suffered from HBV-related HCC had higher levels of L-Cn, and the plasma levels of L-Cn in the HBeAg-positive chronic hepatitis patients who had elevated ALT were significantly higher than that of HBeAg-negative chronic infection and HBsAg loss groups. Moreover, a positive correlation between plasma levels of L-Cn and HBsAg levels was found. Additionally, RNA sequencing analysis demonstrated that L-Cn altered the transcriptional profiles related to immune response. In vitro assays revealed that L-Cn suppressed the proliferation of and IFN-γ production by CD4+ and CD8+ T cells. It also down-regulated the proliferation and IgG production of B cells. Notably, L-Cn enhanced IL-10 secretion from regulatory T cells and up-regulated the expression of inhibitory receptors on T cells. Moreover, a variant in CPT2 (rs1799821) was confirmed to be associated with L-Cn levels as well as complete response in CHB patients following Peg-IFNα antiviral therapy. Taken together, the immunosuppressive properties of L-Cn may hinder the control of HBV in chronic HBV infection, implicating that L-Cn manipulation might influence the prognosis of patients with HBV infection

Characterization of deep sub-wavelength nanowells by imaging the photon state scattering spectra

Optical-matter interactions and photon scattering in a sub-wavelength space are of great interest in many applications, such as nanopore-based gene sequencing and molecule characterization. Previous studies show that spatial distribution features of the scattering photon states are highly sensitive to the dielectric and structural properties of the nanopore array and matter contained on or within them, as a result of the complex optical-matter interaction in a confined system. In this paper, we report a method for shape characterization of subwavelength nanowells using photon state spatial distribution spectra in the scattering near field. Far-field parametric images of the near-field optical scattering from sub-wavelength nanowell arrays on a SiN substrate were obtained experimentally. Finite-difference time-domain simulations were used to interpret the experimental results. The rich features of the parametric images originating from the interaction of the photons and the nanowells were analyzed to recover the size of the nanowells. Experiments on nanoholes modified with Shp2 proteins were also performed. Results show that the scattering distribution of modified nanoholes exhibits significant differences compared to empty nanoholes. This work highlights the potential of utilizing the photon status scattering of nanowells for molecular characterization or other virus detection applications

B^0-\bar{B}^0 mixing and B \to X_s \gamma decay in the third type 2HDM: effects of NLO QCD contributions

In this paper, we calculated the next-to-leading order (NLO) new physics contributions to the mass splitting \dmd and the branching ratio \brbxsga induced by the charged Higgs loop diagrams in the third type of two-Higgs-doublet models (model III) and draw the constraints on the free parameters of model III. For the model III under consideration, we found that (a) an upper limit |\ltt|\leq 1.7 is obtained from the precision data of \dmd=0.502 \pm 0.007 ps^{-1}, while |\ltt| \approx 0.5 is favored phenomenologicaly; (b) for $B \to X_s \gamma$ decay, the NLO QCD contributions tend to cancel the LO new physics contributions; (c) a light charged Higgs boson with a mass around or even less than 200 GeV is still allowed at NLO level by the measured branching ratio \brbxsga: numerically, 188 \leq \mh \leq 215 GeV for (|\ltt|,|\lbb|)=(0.5,18); (d) the NLO QCD contributions tend to cancel the LO contributions effectively, the lower limit on \mh is consequently decreased by about 200 GeV; (e) the allowed region of \mh will be shifted toward heavy mass end for a non-zero relative phase $\theta$ between the Yukawa couplings \ltt and \lbb. The numerical results for the conventional model II are also presented for the sake of a comparison.Comment: 42 pages, 18 eps figures, Revtex, new references adde

Specimen size effect on the fracture energy of architected stretchable materials

ABSTRACTArchitected stretchable materials with well-organized micro-architectures evolve very rapidly due to their potential in customizing mechanical properties and achieving exotic functions. In many applications, the architected stretchable materials are required to sustain large deformation, and their fracture is size-dependent. However, the size effect on the fracture of architected stretchable materials is still elusive. Here, we study this issue by experiment and finite element calculation. It is found that the fracture energy of architected stretchable materials increases with the specimen size ratio, H/h, within a range. When H/h reaches a transition ratio, Rt, the fracture energy approaches a plateau. This transition ratio differentiates the size-dependent and size-independent fracture behavior of architected stretchable materials. The mechanical properties of constituent material only have a minor effect on the transition ratio. The degree of constraint and stress concentration at the node, which are affected by the geometry of the unit-cell, dominate the specimen size effect. The result gives a practical guidance in choosing the specimen size to measure the steady state fracture energy of this class of materials. This work provides insights into the fracture of architected stretchable materials and design for fracture-resistant architected stretchable devices