Effects of Telbivudine Treatment on the Circulating CD4+ T-Cell Subpopulations in Chronic Hepatitis B Patients

CD4+ T cells serve as master regulators of the adaptive immune response to HBV. However, CD4+ T-cell subsets are heterogeneous, and it remains unknown how the antiviral agents affect the different CD4+ T cell subtypes. To this end, the expressions of signature transcription factors and cytokines of CD4+ T-cell subtypes were examined in hepatitis B patients before and after treatment with telbivudine. Results showed that, upon the rapid HBV copy decrease induced by telbivudine treatment, the frequencies and related cytokines of Th17 and Treg cells were dramatically decreased, while those for Th2 cells were dramatically increased. No obvious changes were observed in Th1 cell frequencies; although, IFN-γ expression was upregulated in response to telbivudine treatment, suggesting another cell source of IFN-γ in CHB patients. Statistical analyses indicated that Th17 and Tr1 (a Treg subtype) cells were the most sensitive subpopulations of the peripheral blood CD4+ T cells to telbivudine treatment over 52 weeks. Thus, Th17 and Tr1 cells may represent a suitable and effective predictor of responsiveness during telbivudine therapy. These findings not only improve our understanding of hepatitis pathogenesis but also can aid in future development of appropriate therapeutic strategies to control viral hepatitis

Poly[[diaqua­{N-[1-(3-pyrid­yl)ethyl­idene]-4H-1,2,4-triazol-4-amine}zinc(II)] bis­(perchlorate)]

In the title compound, {[Zn(C9H9N5)2(H2O)2](ClO4)2}n, the ZnII ion lies on an inversion center and is coordinated by two triazolyl N atoms and two pyridyl N atoms from four symmetry-related N-1-(3-pyrid­yl)ethyl­idene-4H-1,2,4-triazol-4-amine (L) ligands and two O atoms from coordinated water mol­ecules in a slightly distorted octa­hedral environment. Each L ligand bridges symmetry-related ZnII ions, forming a two-dimensional layer with a (4,4) grid. In the crystal structure, inter­molecular O—H⋯O hydrogen bonds connect perchlorate counter-anions to the layers

Hepatitis B virus pre-genomic RNA and hepatitis B core-related antigen reductions at week 4 predict favourable hepatitis B surface antigen response upon long-term nucleos(t)ide analogue in chronic hepatitis B

Background/Aims We investigated the dynamics of serum HBV pre-genomic RNA (pgRNA) and hepatitis B core-related antigen (HBcrAg) in patients receiving nucleos(t)ide analogues (NAs) and their predictability for favourable suppression of serum hepatitis B surface antigen (HBsAg). Methods Serum viral biomarkers were measured at baseline, weeks 4, 12, 24, 36, and 48 of treatment. Patients were followed up thereafter and serum HBsAg level was measured at end of follow-up (EOFU). Favourable HBsAg response (FHR) was defined as ≤100 IU/mL or HBsAg seroclearance upon EOFU. Results Twenty-eight hepatitis B e antigen (HBeAg)-positive and 36 HBeAg-negative patients (median, 38.2 years old; 71.9% male) were recruited with median follow-up duration of 17.1 years (interquartile range, 12.8–18.2). For the entire cohort, 22/64 (34.4%) achieved FHR. For HBeAg-positive patients, serum HBV pgRNA decline at week 4 was significantly greater for patients with FHR compared to non-FHR (5.49 vs. 4.32 log copies/mL, respectively; P=0.016). The area under the receiver-operating-characteristic curve (AUROC) for week 4 HBV pgRNA reduction to predict FHR in HBeAg-positive patients was 0.825 (95% confidence interval [CI], 0.661–0.989). For HBeAg-negative patients, instead of increase in serum HBcrAg in non-FHR patients, FHR patients had median reduction in HBcrAg at week 4 (increment of 1.75 vs. reduction of 2.98 log U/mL; P=0.023). The AUROC for week 4 change of HBcrAg to predict FHR in HBeAg-negative patients was 0.789 (95% CI, 0.596–0.982). Conclusions Early on-treatment changes of serum HBV pgRNA and HBcrAg at 4 weeks predict HBsAg seroclearance or ≤100 IU/mL in NA-treated CHB patients upon long-term FU

Substrate Trapping Proteomics Reveals Targets of the βTrCP2/FBXW11 Ubiquitin Ligase

Defining the full complement of substrates for each ubiquitin ligase remains an important challenge. Improvements in mass spectrometry instrumentation and computation and in protein biochemistry methods have resulted in several new methods for ubiquitin ligase substrate identification. Here we used the parallel adapter capture (PAC) proteomics approach to study βTrCP2/FBXW11, a substrate adaptor for the SKP1–CUL1–F-box (SCF) E3 ubiquitin ligase complex. The processivity of the ubiquitylation reaction necessitates transient physical interactions between FBXW11 and its substrates, thus making biochemical purification of FBXW11-bound substrates difficult. Using the PAC-based approach, we inhibited the proteasome to “trap” ubiquitylated substrates on the SCFFBXW11E3 complex. Comparative mass spectrometry analysis of immunopurified FBXW11 protein complexes before and after proteasome inhibition revealed 21 known and 23 putatively novel substrates. In focused studies, we found that SCFFBXW11bound, polyubiquitylated, and destabilized RAPGEF2, a guanine nucleotide exchange factor that activates the small GTPase RAP1. High RAPGEF2 protein levels promoted cell-cell fusion and, consequently, multinucleation. Surprisingly, this occurred independently of the guanine nucleotide exchange factor (GEF) catalytic activity and of the presence of RAP1. Our data establish new functions for RAPGEF2 that may contribute to aneuploidy in cancer. More broadly, this report supports the continued use of substrate trapping proteomics to comprehensively define targets for E3 ubiquitin ligases. All proteomic data are available via ProteomeXchange with identifier PXD001062

Proteomics Reveals Novel Drosophila Seminal Fluid Proteins Transferred at Mating

Across diverse taxa, seminal fluid proteins (Sfps) transferred at mating affect the reproductive success of both sexes. Such reproductive proteins often evolve under positive selection between species; because of this rapid divergence, Sfps are hypothesized to play a role in speciation by contributing to reproductive isolation between populations. In Drosophila, individual Sfps have been characterized and are known to alter male sperm competitive ability and female post-mating behavior, but a proteomic-scale view of the transferred Sfps has been missing. Here we describe a novel proteomic method that uses whole-organism isotopic labeling to detect transferred Sfps in mated female D. melanogaster. We identified 63 proteins, which were previously unknown to function in reproduction, and confirmed the transfer of dozens of predicted Sfps. Relative quantification of protein abundance revealed that several of these novel Sfps are abundant in seminal fluid. Positive selection and tandem gene duplication are the prevailing forces of Sfp evolution, and comparative proteomics with additional species revealed lineage-specific changes in seminal fluid content. We also report a proteomic-based gene discovery method that uncovered 19 previously unannotated genes in D. melanogaster. Our results demonstrate an experimental method to identify transferred proteins in any system that is amenable to isotopic labeling, and they underscore the power of combining proteomic and evolutionary analyses to shed light on the complex process of Drosophila reproduction

A solar wind-derived water reservoir on the Moon hosted by impact glass beads

The past two decades of lunar exploration have seen the detection of substantial quantities of water on the Moon’s surface. It has been proposed that a hydrated layer exists at depth in lunar soils, buffering a water cycle on the Moon globally. However, a reservoir has yet to be identified for this hydrated layer. Here we report the abundance, hydrogen isotope composition and core-to-rim variations of water measured in impact glass beads extracted from lunar soils returned by the Chang’e-5 mission. The impact glass beads preserve hydration signatures and display water abundance profiles consistent with the inward diffusion of solar wind-derived water. Diffusion modelling estimates diffusion timescales of less than 15 years at a temperature of 360 K. Such short diffusion timescales suggest an efficient water recharge mechanism that could sustain the lunar surface water cycle. We estimate that the amount of water hosted by impact glass beads in lunar soils may reach up to 2.7 × 1014 kg. Our direct measurements of this surface reservoir of lunar water show that impact glass beads can store substantial quantities of solar wind-derived water on the Moon and suggest that impact glass may be water reservoirs on other airless bodies

Cooperativity and allosterism in the ligand -receptor and subunit interaction of the serine receptor for bacterial chemotaxis

The dissertation is focused on the role of chemotaxis receptor played in the transmembrane signaling. The first project accomplished was to study the interaction between serine receptor and methyltransferase. As an effort to probe the regulation mechanism of methyltransferase CheR, Isothermal Titration Calorimetry (ITC) was applied to characterize any possible regulation associated allosteric effect between methyltransferase CheR\u27s multiple interactions. It was found that methyltransferase CheR binds to its receptor docking site and substrate SAH independently, further experiments are proposed to explore the interaction between the receptor methylation region and methyltransferase, CheR. It is speculated that conformational change in the receptor upon ligand binding controls the accessibility of the receptor methylation region to methyltransferase. The second project was carried out as a continued effort to determine the receptor ligand binding activity in the ternary complex with the adaptor protein CheW and the histidine kinase CheA, and it was expected that some cooperativity between receptor dimers would be observed. Surprisingly, in the absence of the cytoplasmic signaling proteins, CheW and CheA, serine receptors exhibited negative cooperativity in ligand binding between dimers, and the negative cooperavtivity disappeared in detergent solution. For the first time, direct evidence was found as a strong support the transmembrane signaling mechanism that involves receptor clusters. Chemoreceptors form patches at the poles of bacteria in the presence and absence of signaling proteins, and the active interaction between receptor dimers could play a significant role in information integration when passing through the bacterial membrane. Experiments are also designed for further clarify the function of receptor cluster in the future

Infinitely many solutions for quasilinear Schrödinger equations under broken symmetry situation

In this paper, we study the existence of infinitely many solutions for the quasilinear Schrödinger equations $$\begin{cases} -\Delta u-\Delta(|u|^{\alpha})|u|^{\alpha-2}u=g(x,u)+h(x,u) &\text{for } x\in \Omega,\\ u=0 &\text{for } x\in \partial\Omega, \end{cases}$$ where $\alpha\geq 2$, $g, h\in C(\Omega\times \mathbb{R}, \mathbb{R})$. When $g$ is of superlinear growth at infinity in $u$ and $h$ is not odd in $u$, the existence of infinitely many solutions is proved in spite of the lack of the symmetry of this problem, by using the dual approach and Rabinowitz perturbation method. Our results generalize some known results and are new even in the symmetric situation

Economic losses and willingness to pay for haze: the data analysis based on 1123 residential families in Jiangsu province, China

Contains fulltext : 220174.pdf (publisher's version ) (Closed access)Haze pollution is a key obstacle for environmental management faced by China and many other developing countries. The survey on residential families’ economic losses and willingness to pay (WTP) are regarded as an essential reference for the implementation of environmental policies for haze treatment. For Jiangsu province of China, the authors of this paper first conducted three qualitative interviews with respectively meteorologists, meteorological administrators, and residents, a questionnaire was then elaborately designed, and subsequent surveys of 1123 families were administered in Jiangsu province. Further, the authors investigated measurements of direct economic losses by using the contingent valuation method (CVM) and explored influential factors of WTP by utilizing the binary logistic regression. From this survey, the estimated total economic loss incurred by haze disasters and total treatment cost for haze-related diseases were respectively 22.38 billion (in RMB) and 8.4 billion for Jiangsu province. 55.9% of residential families were willing to pay 11.6 billion RMB annually (51.97% of total loss) for haze treatment, leaving a shortage of 11.05 billion RMB, which the government is responsible to pay. These findings provide empirical information reflecting the opinions of communities and residential families, useful for the governments and industrial sectors to design environmental policies to meet the requirements of the public and control environmental pollution in an effective way to achieve sustainable development.11 maart 202014 p