The immunoproteasome controls the availability of the cardioprotective pattern recognition molecule Pentraxin3

Cardiomyocyte death as a result of viral infection is an excellent model for dissecting the inflammatory stress response that occurs in heart tissue. We reported earlier that a specific proteasome isoform, the immunoproteasome, prevents exacerbation of coxsackievirus B3 (CVB3)‐induced myocardial destruction and preserves cell vitality in heart tissue inflammation. Following the aim to decipher molecular targets of immunoproteasome‐dependent proteolysis, we investigated the function and regulation of the soluble PRR Pentraxin3 (PTX3). We show that the ablation of PTX3 in mice aggravated CVB3‐triggered inflammatory injury of heart tissue, without having any significant effect on viral titers. Thus, there might be a role of PTX3 in preventing damage‐associated molecular pattern‐induced cell death. We found that the catalytic activity of the immunoproteasome subunit LMP7 regulates the timely availability of factors controlling PTX3 production. We report on immunoproteasome‐dependent alteration of ERK1/2 and p38MAPKs, which were both found to be involved in PTX3 expression control. Our finding of a cardioprotective function of immunoproteasome‐dependent PTX3 expression revealed a crucial mechanism of the stress‐induced damage response in myocardial inflammation. In addition to antigen presentation and cytokine production, proteolysis by the immunoproteasome can also regulate the innate immune response during viral infection.     

Neutrophil Function in Elderly Persons Assessed by Flow Cytometry

It is well known that the immune response declines with senescence and it is suggested that these changes render an individual susceptible to infection, autoimmune phenomena and cancer. Bacterial and viral infections are a major cause of illness and death amongst aged subjects, and once infection is established, the elderly also have a diminished capacity to prevent its spread (1). The cellular and molecular basis for this age-related decline in immuno-competence are still unknown and, possibly, are related to an alteration in cell transduction mechanisms (2).     

Neutrophil Function in Elderly Persons Assessed by Flow Cytometry

It is well known that the immune response declines with senescence and it is suggested that these changes render an individual susceptible to infection, autoimmune phenomena and cancer. Bacterial and viral infections are a major cause of illness and death amongst aged subjects, and once infection is established, the elderly also have a diminished capacity to prevent its spread (1). The cellular and molecular basis for this age-related decline in immuno-competence are still unknown and, possibly, are related to an alteration in cell transduction mechanisms (2).     

Effects of aging on slowing of motor-response generation.

The aim of the present study was to analyze different stages of central processing mechanisms during a choice reaction task and to evaluate their contribution to aging-related response slowing. Event-related potentials (ERPs) were recorded from two groups of subjects, young (mean 22 years) and older adults (mean 58 years), who performed a four-alternative choice-reaction task. The results showed the expected reaction time slowing in the older subjects. This behavioural slowing was not due to delays in stimulus processing (as reflected by latencies of early ERP components), or in response selection (as reflected by the onset of the lateralized readiness potential). Instead, this slowing was due to an alteration of movement-related components, particularly an amplitude enhancement and prolongation of the motor-related potential at the cortex contralateral to the responding hand. This alteration was reliable and of general nature since it was also found in a second study using a different choice-reaction task with a more direct stimulus-response relation. The results suggest that the overt response requires a higher activation level in older vs. young subjects; this extra-activation needs time and hence prolongs reaction time with aging.     

Cancer immune escape: MHC expression in primary tumours versus metastases

Tumours can escape T-cell responses by losing major histocompatibility complex (MHC)/ human leucocyte antigen (HLA) class I molecules. In the early stages of cancer development, primary tumours are composed of homogeneous HLA class I-positive cancer cells. Subsequently, infiltration of the tumour by T cells generates a vast diversity of tumour clones with different MHC class I expressions. A Darwinian type of T-cell-mediated immune selection results in a tumour composed solely of MHC class I-negative cells. Metastatic colonization is a highly complex phenomenon in which T lymphocytes and natural killer cells play a major role. We have obtained evidence that the MHC class I phenotype of metastatic colonies can be highly diverse and is not necessarily the same as that of the primary tumour. The molecular mechanisms responsible for MHC/HLA class I alterations are an important determinant of the clinical response to cancer immunotherapy. Hence, immunotherapy can successfully up-regulate MHC/HLA class I expression if the alteration is reversible (‘soft’), leading to T-cell-mediated tumour regression. In contrast, it cannot recover this expression if the alteration is irreversible (‘hard’), when tumour cells escape T-cell-mediated destruction with subsequent cancer progression. This review summarizes clinical and experimental data on the complexity of immune escape mechanisms used by tumour cells to avoid T and natural killer cell responses. We also provide in-depth analysis of the nature of MHC/HLA class I changes during metastatic colonization and contribute evidence of the enormous diversity of MHC/HLA class I phenotypes that can be produced by tumour cells during this process.     

Glutathione S-transferase pi gene methylation: the search for a molecular marker of prostatic adenocarcinoma

Glutathione S-transferase pi gene methylation has recently been described in prostatic adenocarcinoma. Aggregate data on 115 samples studied to date have found an 87% sensitivity and 92% specificity for prostate cancer diagnosis. The current literature about this new marker is herein summarized, and possible molecular mechanisms by which glutathione S-transferase pi may participate in prostatic carcinogenesis are reviewed. The possible clinical implications of this molecular alteration in the diagnosis of prostatic adenocarcinoma are also studied.     

Cytoplasmic bridges and gap junctions in an insect cell line (Aedes albopictus).

Cell pairs of an insect cell line (Aedes albopictus, clone C6/36) were used study simultaneously the diffusional and electrical properties of intercellular junctions. Diffusion studies involved injection of fluorescent molecules into one cell of a cell pair and visual inspection of their intercellular redistribution. Electrical measurements involved a dual voltage clamp method and whole-cell recording with patch pipette. The voltage clamp protocol was aimed at examining the dependency of the junctional conductance, gj, on membrane potential, Vm. Cell pairs exhibiting a voltage-dependent gj were found to allow intercellular diffusion of Lucifer Yellow CH (molecular mass, 443 Da), but not of FITC-dextran (molecular mass, 4,400 Da). This response pattern is consistent with the presence of gap junctions in the intercellular junctions. Cell pairs showing no voltage dependence of gj were found to permit intercellular diffusion of both Lucifer Yellow CH and FITC-dextran (dextran labelled with fluorescein isothiocyanate). This behaviour is compatible with the presence of cytoplasmic bridges connecting the two adjacent cells. Hence, in culture the cells investigated express two kinds of intercellular structures, gap junctions and cytoplasmic bridges.     

Targeted chemotherapy: chronic myelogenous leukemia as a model

Many of the therapeutic agents used for cancer chemotherapy today are based on decades-old agents which are highly cytotoxic but are nonselective for cancer cells. The hallmark of chronic myelogenous leukemia (CML) is the Philadelphia chromosome translocation t(9;22), which results in the bcr-abl fusion gene. As an alteration that is nearly universal in CML cells, bcr-abl presents a therapeutic target that is unique to the pathological cells in CML patients. Advances in the understanding of the molecular mechanisms which sustain leukemic cells in CML have enabled the development of selective therapies for this disease. We review here the molecular pathogenesis and current treatment of CML. We also discuss the development of imatinib mesylate, a selective inhibitor of Bcr-Abl which has shown promise in clinical trials with CML. This recent advance in CML therapy represents a novel approach to rational design and development of new anticancer drugs.     

Effect of malnutrition on K+ current in T lymphocytes

Severe malnutrition in children is frequently associated with infectious diseases. Animal models have been useful for studying the effects of malnutrition. One of the immunosuppressive mechanisms of malnutrition is inhibition of the activation of T lymphocytes. The voltage-dependent K(V) potassium channels are vital for the activation of T lymphocytes. The blockade of K(V) channels inhibits the activation of T lymphocytes. Malnutrition could affect the suitable synthesis of K(V) channels in T lymphocytes, producing changes in the magnitude and/or dependency of the voltage of the K+ current. We reported a significant decrease in the K+ current and activation to a 20 mV more positive membrane potential in T lymphocytes of rats with severe malnutrition. These results indicate that the diminution in the K+ conductance by alteration of K(V) channels in severe malnutrition is one of the mechanisms that inhibit the activation of T lymphocytes.     

Ionic current model of rabbit retinal horizontal cell

We propose a mathematical model of rabbit retinal horizontal cell based on the ionic current mechanisms. Five types of ionic currents in rabbit retinal horizontal cell, I(Na), I(Ca), I(Kv), I(A) and I(Ka), are described by Hodgkin-Huxley type equations based on voltage clamp measurements. In simulation the model reproduced similar responses to voltage and current clamp experiments. Under the current clamp experiment a repetitive action potential was found on A-type rabbit horizontal cells. Our result suggests that the repetitive action potential is generated by an interaction Of I(Ca) and I(Kv).     

Tropomyosin isoform expression in normal and neoplastic astrocytes.

Changes of tropomyosin isoforms have previously been found accompanying morphologic alterations such as those associated with neoplastic transformations in mammalian cells. To determine whether an isoform change is associated with the malignancy of brain tumors, we employed both polyclonal antibodies specific to high and low molecular weight tropomyosin isoforms. We found, by using immunocytochemistry and immunoblotting, that an alteration of tropomyosin isoforms is associated with human astrocytomas. Differential staining patterns were seen for normal, reactive, and neoplastic astrocytes. Characterization of the antibodies revealed an increase in the higher molecular weight tropomyosin in more anaplastic astrocytomas than in those that were well differentiated. We also observed that the different isoforms have specific subcellular localizations. These findings suggest that neoplastic transformation is associated with alteration of tropomyosin isoforms in astrocytomas. We speculate that this change may be related to morphologic transformation in which microfilament functions, such as cell shape, interaction, and recognition are altered.     

Magnetic resonance imaging of the bone marrow following treatment with recombinant human erythropoietin in patients with end-stage renal disease

We used magnetic resonance imaging (MRI) to study vertebral bone marrow in hemodialysis patients during treatment with recombinant human erythropoietin (rHuEPO). We found changes in T1 relaxation times and image contrast within 14 days after starting treatment, before any response was seen in the hemoglobin concentration in peripheral blood. The increase in T1 relaxation times, together with earlier reported changes observed with localized magnetic resonance spectroscopy, indicate an alteration in cellular composition of the hemopoietic bone marrow with an increase in the amount of hemopoietic active tissue. MRI may be a useful, non-invasive way of evaluating bone marrow response to different modes of rHuEPO administration and dosage.     

Innate Immunity and Inflammatory Response to Trichomonas vaginalis and Bacterial Vaginosis: Relationship to HIV Acquisition

Citation Thurman AR, Doncel GF. Innate immunity and inflammatory response to Trichomonas vaginalis and bacterial vaginosis: relationship to HIV acquisition. Am J Reprod Immunol 2011; 65: 89–98 Most women contract HIV‐1 through sexual intercourse with an infected partner. Highly prevalent, unreported and often asymptomatic lower genital tract infections, including bacterial vaginosis (BV) and trichomoniasis (Trichomonas vaginalis– TV), increase a woman’s susceptibility to HIV‐1 genital infection, given an exposure. A review of the literature from 1989 to the present was conducted. This article will review potential mechanisms by which BV and TV serve as HIV‐1‐enhancing cofactors including (i) initiation of a clinical or subclinical mucosal inflammatory response, (ii) alteration of innate mucosal immunity, (iii) alteration of normal vaginal microflora and pH, and (iv) weakening or breach of intact cervico‐vaginal mucosa. The transmission of HIV‐1, in the absence of cofactors, is poorly efficient. Understanding the mechanisms by which these infections enhance HIV‐1 acquisition is important to designing effective, safe and evidence‐based prevention modalities.     

Aortic lesion in Marfan syndrome: the ultrastructure of cystic medial degeneration

Areas of medial alteration (Erdheim cystic medionecrosis) in an aortic root aneurysm surgically removed from a patient with Marfan syndrome were studied with an electron microscope. The single striking morphologic abnormality was the disorganized, haphazard architecture of the media in these areas. This lesion is interpreted as being an abortive reparative response to hemodynamic stress in a condition with a molecular defect in the structural proteins of connective tissue.     

Functional categorization of gene expression changes in the cerebellum of a Cln3-knockout mouse model for Batten disease

Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten Disease) is the most common progressive neurodegenerative disorder of childhood. The disease is inherited in an autosomal recessive manner and is the result of mutations in the CLN3 gene. One brain region severely affected in Batten disease is the cerebellum. Using a mouse model for Batten disease which shares pathological similarities to the disease in humans we have used oligonucleotide arrays to profile approximately 19000 mRNAs in the cerebellum. We have identified reproducible changes of twofold or more in the expression of 756 gene products in the cerebellum of 10-week-old Cln3-knockout mice as compared to wild-type controls. We have subsequently divided these genes with altered expression into 14 functional categories. We report a significant alteration in expression of genes associated with neurotransmission, neuronal cell structure and development, immune response and inflammation, and lipid metabolism. An apparent shift in metabolism toward gluconeogenesis is also evident in Cln3-knockout mice. Further experimentation will be necessary to understand the contribution of these changes in expression to a disease state. Detailed analysis of the functional consequences of altered expression of genes in the cerebellum of the Cln3-knockout mice may provide valuable clues in understanding the molecular basis of the pathological mechanisms underlying Batten disease.     

Linkage of a tumor immune function and cell cycle de-regulation via a gene regulatory network subcircuit

Gene regulatory network (GRN) subcircuits have been described for cell fate progressions in animal development. The hallmark of these subcircuits is the integration of promoters, and positive- and negative-acting promoter binding proteins, such that an alteration in function of any one member of the defined subcircuit, occurring with a change in cell fate, defines a change in status for all other members of the subcircuit. Here we describe a GRN subcircuit that links a tumor immune function with cell cycle de-regulation. All members of this subcircuit have a predictable status change in response to rescue of the growth-controlled phenotype. Given the similarities between the molecular mechanisms underlying cell status changes in tumorigenesis and development, application of GRN paradigms to tumor progression is particularly apt and offers the hope of providing a more concise, reliable, and therapeutically useful series of predictions linking gene regulation and tumor progression.     

Liquid crystalline side chain polymers and their behaviour in the electric field

The electro-optical properties of liquid crystalline polymers with polar mesogenic units in the side chain were investigated. It could be shown, that in an electric field, they show all effects known from low molecular weight liquid crystals, e.g. the Freedericksz-transition, the DAP-effect, the formation of William's domain, and the dynamic scattering. The optical response times are slightly longer than for low molecular weight liquid crystals, but in some cases at higher temperatures as short as 200 ms. By comparison of different polymers and some corresponding liquid crystalline monomers, it is found that: (1) the difference between the measuring temperature and the glass transition temperature mainly determines the optical response times, (2) the fixation of mesogenic groups to a polymer main chain via spacers influences the threshold voltage. Low values are found for long spacers. These results allow a discussion of the influence of polymer fixation of the mesogenic groups on their liquid crystalline properties, pointing to a partial decoupling of the motions of main chains and side chains.