Selective Suppression of NF-kBp65 in Hepatitis Virus-Infected Pregnant Women Manifesting Severe Liver Damage and High Mortality

Fulminant hepatitis in Asian pregnant women is generally caused by hepatitis E virus infection, and extremely high mortality is most common in them. Decreased cell-mediated immunity is considered a major cause of death in these cases, but what exactly influences decreased immunity and high mortality specifically during pregnancy is not known. We used electrophoretic mobility shift assays, immunoblotting, and immunohistochemical analysis to study the expression and DNA binding activity of NF-kB p50 and NF-kB p65 in pregnant fulminant hepatic failure (FHF) patients and compared them with their nonpregnant counterparts. In both PBMC and postmortem liver biopsy specimens the DNA-binding activity of NF-kB was very high in samples from pregnant FHF patients compared with those from nonpregnant women as well as pregnant women with acute viral hepatitis (AVH) without FHF. Further dissection of the NF-kB complex in supershift assays demonstrated complete absence of p65 in the NF-kB complex, which is formed by homodimerization of the p50 component in pregnant FHF patients. Western blotting and immunohistochemical analysis of the expression of p50 and p65 proteins both showed higher levels of p50 expression and a complete absence or a minimal expression of p65, indicating its nonparticipation in NF-kB-dependent transactivation in pregnant FHF patients. We suggest that the exclusion of p65 from the NF-kB transactivation complex seems to be a crucial step that may cause deregulated immunity and severe liver damage, leading to the death of the patient. Our findings provide a molecular basis, for developing novel therapeutic approaches

Analytic approximate solutions for unsteady boundary-layer flow and heat transfer due to a stretching sheet by homotopy analysis method

In this work, the homotopy analysis method is applied to study the unsteady boundary-layer flow and heat transfer due to a stretching sheet. The analytic solutions of the system of nonlinear ordinary differential equations are constructed in the series form. The convergence of the obtained series solutions is carefully analyzed. The velocity and temperature profiles are shown and the influence of non-dimensional parameter on the heat transfer is discussed in detail. The validity of our solutions is verified by the numerical results

Predicting domain-domain interaction based on domain profiles with feature selection and support vector machines

<p>Abstract</p> <p>Background</p> <p>Protein-protein interaction (PPI) plays essential roles in cellular functions. The cost, time and other limitations associated with the current experimental methods have motivated the development of computational methods for predicting PPIs. As protein interactions generally occur via domains instead of the whole molecules, predicting domain-domain interaction (DDI) is an important step toward PPI prediction. Computational methods developed so far have utilized information from various sources at different levels, from primary sequences, to molecular structures, to evolutionary profiles.</p> <p>Results</p> <p>In this paper, we propose a computational method to predict DDI using support vector machines (SVMs), based on domains represented as interaction profile hidden Markov models (ipHMM) where interacting residues in domains are explicitly modeled according to the three dimensional structural information available at the Protein Data Bank (PDB). Features about the domains are extracted first as the Fisher scores derived from the ipHMM and then selected using singular value decomposition (SVD). Domain pairs are represented by concatenating their selected feature vectors, and classified by a support vector machine trained on these feature vectors. The method is tested by leave-one-out cross validation experiments with a set of interacting protein pairs adopted from the 3DID database. The prediction accuracy has shown significant improvement as compared to <it>InterPreTS </it>(Interaction Prediction through Tertiary Structure), an existing method for PPI prediction that also uses the sequences and complexes of known 3D structure.</p> <p>Conclusions</p> <p>We show that domain-domain interaction prediction can be significantly enhanced by exploiting information inherent in the domain profiles via feature selection based on Fisher scores, singular value decomposition and supervised learning based on support vector machines. Datasets and source code are freely available on the web at <url>http://liao.cis.udel.edu/pub/svdsvm</url>. Implemented in Matlab and supported on Linux and MS Windows.</p

Mesenchymal stem cells alleviate bacteria‐induced liver injury in mice by inducing regulatory dendritic cells

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102718/1/hep26670.pd

Signaling pathways involved in liver injury and regeneration in rabbit hemorrhagic disease, an animal model of virally-induced fulminant hepatic failure

Management of fulminant hepatic failure (FHF) continues to be one challenging problem, and experimental animal models resembling its clinical conditions are still needed. Rabbit hemorrhagic disease (RHD) fullfils many requirements of an animal model of FHF. This work investigated changes in MAPK, NF-κB, AP-1 and STAT pathways during RHD-induced liver injury. Rabbits were infected with 2 × 104 hemagglutination units of an RHD virus isolate. Apoptosis was documented by the presence of caspase-3 activity and substantial PARP proteolysis at 36 and 48 h postinfection (pi). Infection induced a marked and maintained expression of TNF-α from 12 h pi, while there was only a transitory increase in IL-6 expression. Expression of phosphorylated (p)-JNK, p-p38 and p-ERK1/2 was significantly elevated at 12 h pi. At 48 h pi p-JNK expression was maintained at a maximum level, while that of p-p38 returned to normality and there was no p-ERK1/2 expression. Activation of NF-κB and AP-1 and increased expression of VCAM-1 and COX-2 were observed. No significant changes were detected in activation of STAT1 and STAT3, while SOCS3 expression increased significantly. The current findings suggest that activation of JNK is an essential component in liver injury mediated by the RHD virus and that lack of activation of STAT3, probably mediated by SOCS3 over-expression, would contribute to the inhibition of the regenerative response. Data show the presence of molecular mechanisms contributing to liver damage and the lack of regeneration and they support the usefulness of this model to investigate novel therapeutical modalities in FHF

Flavors and Phases in Unparticle Physics

Inspired by the recent Georgi's unparticle proposal, we study the flavor structures of the standard model (SM) particles when they couple to unparticles. At a very high energy scale, we introduce \BZ charges for the SM particles, which are universal for each generation and allow \BZ fields to distinguish flavor generations. At the \Lambda_{\UP} scale, \BZ operators and charges are matched onto unparticle operators and charges, respectively. In this scenario, we find that tree flavor changing neutral currents (FCNCs) can be induced by the rediagonalizations of the SM fermions. As an illustration, we employ the Fritzsch ansatz to the SM fermion mass matrices and we find that the FCNC effects could be simplified to be associated with the mass ratios denoted by $\sqrt{m_{i}m_{j}/m^2_{3}}$, where $m_3$ is the mass of the heaviest particle in each type of fermion generations and $i, j$ are the flavor indices. In addition, we show that there is no new CP violating phase beside the unique one in the CKM matrix. We use $\bar B_{q}\to \ell^{+} \ell^{-}$ as examples to display the new FCNC effects. In particular, we demonstrate that the direct CP asymmetries in the decays can be $O(10$ due to the peculiar CP conserving phase in the unparticle propagator.Comment: 1+14 pages, 2 figures, version to appear in Phys. Lett.

Bulge- and Basal Layer-Specific Expression of Fibroblast Growth Factor-13 (FHF-2) in Mouse Skin

A variety of polypeptide growth factors are involved in the dynamic maintenance of the skin and hair. Here, we demonstrate the presence of high levels of fibroblast growth factor (FGF)-13 in the bulge region of hair follicles. Using real-time PCR, we found that expression of FGF-13 mRNA is comparable to, or higher than, that of other FGF known to regulate hair growth and wound healing. To gain additional insight into the function of FGF-13, we evaluated its distribution using in situ hybridization and immunohistochemical staining. Unlike other FGF, the distribution of FGF-13 mRNA and protein in adult mice was mainly restricted to cells in the bulge region of hair follicles, although lower levels were detected with less frequency in keratinocytes in the basal layer of the epidermis. FGF-13 protein was detectable in the bulge region throughout the hair growth cycle, but its distribution was especially wide during telogen and early anagen. During hair follicle morphogenesis in newborn mice, FGF-13 protein was first detected in the bulge region and basal layer keratinocytes 3 d after birth. These findings suggest that FGF-13 may play a role in regulating the function of cells in the bulge region and basal layer of the epidermis