Case Report: Chronic hepatitis E virus Infection in an individual without evidence for immune deficiency.

Chronic hepatitis E virus (HEV) infection occurs mainly in immunosuppressed populations. We describe an investigation of chronic HEV infection of genotype 3a in an individual without evidence for immune deficiency who presented hepatitis with significant HEV viremia and viral shedding. We monitored HEV RNA in plasma and stools, and assessed anti-HEV specific immune responses. The patient was without apparent immunodeficiency based on quantified results of white blood cell, lymphocyte, neutrophilic granulocyte, CD3+ T cell, CD4+ T cell, and CD8+ T cell counts and CD4/CD8 ratio, as well as total serum IgG, IgM, and IgA, which were in the normal range. Despite HEV specific cellular response and strong humoral immunity being observed, viral shedding persisted up to 109 IU/mL. After treatment with ribavirin combined with interferon, the indicators of liver function in the patient returned to normal, accompanied by complete suppression and clearance of HEV. These results indicate that HEV chronicity can also occur in individuals without evidence of immunodeficiency.

[Analysis of clinical characteristics of 87 patients with cochlear migraine].

Objective:The aim of this study is to analyze the clinical features of cochlear migraine. Methods:The clinical data of cases of cochlear migraine were collected, and the clinical symptoms and hearing examination results were analyzed. Results:The ratio of male to female patients with cochlear migraine was 1∶3.1; the peak incidence was between 30 to 60 years old; the clinical symptoms were tinnitus in 61 people（70%）, mild hearing loss in 52 people（60%）, aural fullness in hyperacusis in 13 people（15%）, auditory allergy in 9 people（10%） and otalgia in 5 people（6%）; the audiology characteristic was that 61.5%（32/52） of patients with hearing loss showed mild high-frequency neurological hearing loss, 34.6%（18/52） of patients showed mild low-frequency neurological hearing loss, and 3.8%（2/52） of patients showed full-frequency mild neurological hearing loss; the effective rate of tinnitus treatment was 57.4%, the effective rate of hearing loss was 71.2%, and the effective rate of aural fullness was 69.2%, the effective rate of hyperacusis is 66.7% and the effective rate of otalgia is 60.0%. Conclusion:The clinical characteristics of cochlear migraine are summarized, which provides a basis for the intervention of anti-migraine treatment programs for inner ear diseases.

[Genotype and clinical phenotype analysis of 42 patients with delayed nonsyndromic hearing loss].

Objective:The aim of this study is to analyze the mutation characteristics of GJB2 and SLC26A4 gene in patients with delayed non-syndromic hearing loss, which is beneficial to the early detection and intervention of delayed deafness. Methods:Sanger sequencing technology was used to detect two common genes in 139 patients with non-syndromic deafness, six hot spot mutations in GJB2 gene and SLC26A4 gene, and single heterozygous mutations found in GJB2 gene and SLC26A4 gene were detected by whole exome sequencing. Results:Among the 25 patients with deafness caused by GJB2 gene mutation, 12 of them passed universal newborn hearing screening and then developed delayed extremely severe hearing loss. The onset time of hearing loss was 6-48 months. All the genotypes were homozygous or compound heterozygous mutation of c. 235delC, especially genotype of GJB2 c. 235delC homozygous and c. 235delC/c. 299-300 delAT compound heterozygous mutations, and the CT manifestations were normal. Among the 42 patients with deafness caused by SLC26A4 gene mutation, 30 of them passed universal newborn hearing screening and developed delayed deafness. The onset time of hearing loss was three months to ten years old. Among them, the genotypes of 21 patients were compound heterozygous mutation, and 9 patients were homozygous mutation of c. 919-2A>G, especially genotypes were SLC26A4 c. 919-2A>G/c. 665G>T and c. 919-2A>G /c. 2027T>A compound heterozygous mutation. The CT findings of 19 cases showed single enlarged vestibular aqueduct, and 11 cases showed enlarged vestibular aqueduct with Mondini malformation. Conclusion:For the children who have passed universal newborn hearing screening, the genotypes detected are GJB2 c. 235delC homozygous, SLC26A4 c. 919-2A>G homozygous or compound heterozygous mutations, especially genotypes GJB2 c. 235delC homozygous, c. 235delC/c. 299-300delAT compound heterozygous mutations and SLC26A4 c. 919-2A>G/c. 665G>T and c. 919-2A>G/c. 2027T>A compound heterozygous mutation. Attention should be paid to the hearing problems of children all the time, and the possibility of delayed deafness in the future should be considered.

Ab initio predictions for the reaction mechanism and orbital topological properties of the formation of Neptunimine, Plutonimine, and its side products.

Exploring the different mechanisms involved in the application of actinide is necessary to obtain a more comprehensive understanding of actinide science. In this study, the mechanisms of gas-phase Np and Pu atoms dissociating NH3 molecules forming Neptunimine and Plutonimine complexes were systematically investigated using different approaches of density functional theory. A new dehydrogenation channel was discovered. The results reveal that the intermediates HAn-NH2 are the lowest energy in the overall reaction, and the direct planar evolution dehydrogenations are the lowest energy reaction path. Besides, the mechanism of the initial complexation process is discussed on the electron localization function, atoms-in-molecules, atomic dipole moment corrected Hirshfeld atomic charges, and electron density difference analysis. The results indicate that An-N in complex I exhibits a very weak covalent interaction, and it comes down to pulling the original dipole moment of the NH3 molecule and stretched between An atom and three H atoms. Graphical abstract.

The Clinical Significance of PD-L1/PD-1 Expression in Gastroenteropancreatic Neuroendocrine Neoplasia.

PURPOSE: This study examined the tumor expression of programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) in patients with GEP-NEN. This study aims to reveal the relationship of their expression with clinicopathological characteristics and prognosis. METHODS: PD1 and PD-L1 expression in tumors from 120 GEP-MEN patients was evaluated using immunohistochemistry. The correlations of the expression of PDL1/PD1 and clinicopathological features were assessed. RESULTS: Immunohistochemical staining indicated that PD-L1 was expressed in the tumor cells of 52.5% patients with GEP-NENs, and PD-L1 expression was positively correlated with the World Health Organization (WHO) classification, American Joint Committee on Cancer (AJCC) stage, lymphatic metastasis and prognosis. Meanwhile, PD-1 was expressed in tumor infiltrating lymphocytes within 55.8% tumor samples, and PD-1 expression was positively correlated with AJCC stage and GEP-NENs prognosis. Moreover, survival analysis indicated that the overall median survival of patients with PD-L1/PD-1-positive tumors significantly differed from that of patients with PD-L1/PD-1-negative tumors. Multivariate analysis confirmed that AJCC stage and Chromogranin A expression in tumor tissues were independent prognostic factors for overall survival. In conclusion, PDL1 was an independent prognostic factor for patients with GEP-NENs. Our results suggested that patients with GEP-NENs might be appropriate for PD1/PDL1-targeted therapy. CONCLUSIONS: Our findings show that the expression of PD-L1 and PD-1 correlates with patient prognosis, and may thus serve as potential pathological prognostic markers of GEP-NENs. Immunotherapy using PD-1/PD-L1 inhibitors may be a promising strategy for GEP-NENs patients with PD-L1/PD-1 positively expressed.

MTA1 promotes epithelial to mesenchymal transition and metastasis in non-small-cell lung cancer.

The present study assessed the role of metastasis-associated protein 1 (MTA1) in epithelial to mesenchymal transition (EMT) and metastasis in non-small-cell lung cancer (NSCLC) cells using a normal lung epithelium cell line, three NSCLC cell lines, a mouse NSCLC model, and 56 clinical NSCLC samples. We observed that MTA1 overexpression decreased cellular adhesion, promoted migration and invasion, and changed cytoskeletal polarity. MTA1 knockdown had the opposite effects. MTA1 overexpression decreased E-cadherin, Claudin-1, and ZO-1 levels and increased Vimentin expression in vitro and in vivo, through activation of AKT/GSK3ß/ß-catenin signaling. However, treatment with the AKT inhibitor MK2206 did not completely rescue effects associated with MTA1 expression changes, indicating that pathways other than the AKT/GSK3ß/ß-catenin pathway could be involved in MTA1-induced EMT. Compared with normal lung tissues, MTA1 expression was elevated in NSCLC patient tissues and was correlated with American Joint Committee on Cancer stage, T stage, lymphatic metastasis, and patient overall survival. Additionally, MTA1 expression was positively associated with p-AKT and cytoplasmic ß-catenin levels. These findings indicate MTA1 promotes NSCLC cell EMT and metastasis via AKT/GSK3ß/ß-catenin signaling, which suggests MTA1 may be an effective anti-NSCLC therapeutic target.

Systematic analysis of structural and spectroscopic properties of neptunimine (HN=NpH2) and plutonimine (HN=PuH2).

The structures, stabilities, nature of bonding, and spectroscopic properties of the new actinide imine molecules, neptunimine (HN=NpH2) and plutonimine (HN=PuH2), in the gas phase have been systematically explored at different levels of theory. Our calculation indicates that HN=AnH2 (An=Np, Pu) should be nonplanar and have a quartet ([Formula: see text]) and quintet ([Formula: see text]) ground state, respectively. The nature of the chemical bonding in these molecules were investigated by employing topological methods including electron localization function (ELF), atoms in molecules (AIM) as well as natural bond orbital analysis (NBO). The results showed that these actinide complexes possess relatively strong An=N multiple bonds between the An 6d-5f hybrid orbitals with N 2s-2p orbitals. The charge decomposition analysis (CDA) diagram demonstrated that the transition of electrons mainly happened inside the AnH2 of HN=AnH2. Total and partial density of state (TDOS and PDOS) and also overlap population density of state (OPDOS) diagrams analysis were implemented. The IR and Raman spectra were theoretically simulated as a convenient way to confirm the existence of the actinide imine complexes in further experiments.

Reaction of Np atom with H2O in the gas phase: reaction mechanisms and ab initio molecular dynamics study.

The gas-phase reaction of an Np atom with H2O was investigated using density functional theory and ab initio molecular dynamics. The reaction mechanisms and the corresponding potential energy profiles for different possible spin states were analyzed. Three reaction channels were found in the mechanism study: the isomerization channel, the H2 elimination channel, and the H atom elimination channel. The latter two were observed in the dynamics simulation. It was found that the branching ratio of the title reaction depends on the initial kinetic energy along the transition vector. Product energy distributions for the reaction were evaluated by performing direct classical trajectory calculations on the lowest sextet potential energy surface. The results indicate that most of the available energy appears as the translational energy of the products. The overall results indicate that the H2 elimination channel with low kinetic energy is thermodynamically favored but competes with the H atom elimination channel with higher kinetic energy.

Water O-H bond activation by gas-phase plutonium atoms: reaction mechanisms and ab initio molecular dynamics study.

A thorough description of the reaction mechanisms, taking into account different possible spin states, offers insights into the gas-phase reaction of plutonium atoms with water. Two possible reactions (isomerization and dehydrogenation) are presented. These reactions are found to be exothermic, with the best thermochemical conditions observed for the dehydrogenation reaction at around 23.5 kcal mol(-1). The nature of the chemical-bonding evolution along the reaction pathways are investigated by employing various methods including electron localization function, atoms in molecules, and Mayer bond order. Total, partial, and overlap population density of state diagrams and analyses are also presented. Reaction rates at elevated temperatures (T=298-2 000 K) are calculated by using variational transition-state theory with one-dimensional tunneling effects. In dynamics simulations, only the dehydrogenation reaction is observed, and found to be in good agreement with experimental values.

Structures, spectroscopic and thermodynamic properties of U2On (n = 0 ∼ 2, 4) molecules: a density functional theory study.

The equilibrium structures, spectroscopic and thermodynamic parameters [entropy (S), internal energy (E), heat capacity (C p)] of U2, U2O, U2O2 and U2O4 uranium oxide molecules were investigated systematically using density functional theory (DFT). Our computations indicated that the ground electronic state of U2 is the septet state and the equilibrium bond length is 2.194 Å; the ground electronic state of U2O and U2O2 were found to be X³Φ and X³Σ(g) with stable C(∞v) and D(∞h) linear structures, respectively. The bridge-bonded structure with D(2h) symmetry and X³B1(g) state is the most stable configuration for the U2O4 molecule. Mulliken population analyses show that U atoms always lose electrons to become the donor and O atoms always obtain electrons as the acceptor. Molecular orbital analyses demonstrated that the frontier orbitals of the title molecules were contributed mostly by 5f atomic orbitals of U atoms. Vibrational frequencies analyses indicate that the maximum absorption peaks stem from the stretching mode of U-O bonds in U2O, U2O2 and U2O4. In addition, thermodynamic data of U2O(n) (n = 0 ∼ 4) molecules at elevated temperatures of 293.0 K to 393.0 K was predicted.

Ab initio molecular dynamics study of the reaction of U+ and U2+ with H2O in the gas phase: direct classical trajectory calculations.

The gas phase reactions of U(+) and U(2+) with H2O were investigated using an ab initio molecular dynamics method. All of the information along the minimum energy path were calculated with density functional theory (DFT) and coupled cluster methods. For U(+) with H2O, the molecular dynamics simulations yield a branching ratio of 86% for the H2 elimination channel to 14% for the H atomic elimination channel in agreement with the quadruple ion trap mass spectrometry (QIT/MS) experimental ratio of 91% to 9%. In the case of U(2+) + H2O, there is a crossing of the potential energy surfaces (PES) after the first transition state. Crossing seams between the PES and possible spin inversion processes were studied by means of the intrinsic reaction coordinate (IRC) approach. For U(2+) with H2O, all trajectories are corresponds to H atom elimination channel, this is consistent with the Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) experimental results. The chemical bonding evolution along the reaction pathways was discussed by using topological methodologies of the electron localization function (ELF).