Intramuscular Immunisation with Chlamydial Proteins Induces Chlamydia trachomatis Specific Ocular Antibodies.

BACKGROUND: Ocular infection with Chlamydia trachomatis can cause trachoma, which is the leading cause of blindness due to infection worldwide. Despite the large-scale implementation of trachoma control programmes in the majority of countries where trachoma is endemic, there remains a need for a vaccine. Since C. trachomatis infects the conjunctival epithelium and stimulates an immune response in the associated lymphoid tissue, vaccine regimens that enhance local antibody responses could be advantageous. In experimental infections of non-human primates (NHPs), antibody specificity to C. trachomatis antigens was found to change over the course of ocular infection. The appearance of major outer membrane protein (MOMP) specific antibodies correlated with a reduction in ocular chlamydial burden, while subsequent generation of antibodies specific for PmpD and Pgp3 correlated with C. trachomatis eradication. METHODS: We used a range of heterologous prime-boost vaccinations with DNA, Adenovirus, modified vaccinia Ankara (MVA) and protein vaccines based on the major outer membrane protein (MOMP) as an antigen, and investigated the effect of vaccine route, antigen and regimen on the induction of anti-chlamydial antibodies detectable in the ocular lavage fluid of mice. RESULTS: Three intramuscular vaccinations with recombinant protein adjuvanted with MF59 induced significantly greater levels of anti-MOMP ocular antibodies than the other regimens tested. Intranasal delivery of vaccines induced less IgG antibody in the eye than intramuscular delivery. The inclusion of the antigens PmpD and Pgp3, singly or in combination, induced ocular antigen-specific IgG antibodies, although the anti-PmpD antibody response was consistently lower and attenuated by combination with other antigens. CONCLUSIONS: If translatable to NHPs and/or humans, this investigation of the murine C. trachomatis specific ocular antibody response following vaccination provides a potential mouse model for the rapid and high throughput evaluation of future trachoma vaccines

A versatile all-optical parity-time signal processing device using a Bragg grating induced using positive and negative Kerr-nonlinearity

The properties of gratings with Kerr nonlinearity and PT symmetry are investigated in this paper. The impact of the gain and loss saturation on the response of the grating is analysed for different input intensities and gain/loss parameters. Potential applications of these gratings as switches, logic gates and amplifiers are also shown

Why are we not flooded by involuntary thoughts about the past and future? Testing the cognitive inhibition dependency hypothesis

© The Author(s) 2018In everyday life, involuntary thoughts about future plans and events occur as often as involuntary thoughts about the past. However, compared to involuntary autobiographical memories (IAMs), such episodic involuntary future thoughts (IFTs) have become a focus of study only recently. The aim of the present investigation was to examine why we are not constantly flooded by IFTs and IAMs given that they are often triggered by incidental cues while performing undemanding activities. One possibility is that activated thoughts are suppressed by the inhibitory control mechanism, and therefore depleting inhibitory control should enhance the frequency of both IFTs and IAMs. We report an experiment with a between-subjects design, in which participants in the depleted inhibition condition performed a 60-min high-conflict Stroop task before completing a laboratory vigilance task measuring the frequency of IFTs and IAMs. Participants in the intact inhibition condition performed a version of the Stroop task that did not deplete inhibitory control. To control for physical and mental fatigue resulting from performing the 60-min Stroop tasks in experimental conditions, participants in the control condition completed only the vigilance task. Contrary to predictions, the number of IFTs and IAMs reported during the vigilance task, using the probe-caught method, did not differ across conditions. However, manipulation checks showed that participants’ inhibitory resources were reduced in the depleted inhibition condition, and participants were more tired in the experimental than in the control conditions. These initial findings suggest that neither inhibitory control nor physical and mental fatigue affect the frequency of IFTs and IAMs.Peer reviewedFinal Published versio

Histone Demethylase JMJD2B Functions as a Co-Factor of Estrogen Receptor in Breast Cancer Proliferation and Mammary Gland Development

Estrogen is a key regulator of normal function of female reproductive system and plays a pivotal role in the development and progression of breast cancer. Here, we demonstrate that JMJD2B (also known as KDM4B) constitutes a key component of the estrogen signaling pathway. JMJD2B is expressed in a high proportion of human breast tumors, and that expression levels significantly correlate with estrogen receptor (ER) positivity. In addition, 17-beta-estradiol (E2) induces JMJD2B expression in an ERα dependent manner. JMJD2B interacts with ERα and components of the SWI/SNF-B chromatin remodeling complex. JMJD2B is recruited to ERα target sites, demethylates H3K9me3 and facilitates transcription of ER responsive genes including MYB, MYC and CCND1. As a consequence, knockdown of JMJD2B severely impairs estrogen-induced cell proliferation and the tumor formation capacity of breast cancer cells. Furthermore, Jmjd2b-deletion in mammary epithelial cells exhibits delayed mammary gland development in female mice. Taken together, these findings suggest an essential role for JMJD2B in the estrogen signaling, and identify JMJD2B as a potential therapeutic target in breast cancer

Partial Inhibition of Estrogen-Induced Mammary Carcinogenesis in Rats by Tamoxifen: Balance between Oxidant Stress and Estrogen Responsiveness

Epidemiological and experimental evidences strongly support the role of estrogens in breast tumor development. Both estrogen receptor (ER)-dependent and ER-independent mechanisms are implicated in estrogen-induced breast carcinogenesis. Tamoxifen, a selective estrogen receptor modulator is widely used as chemoprotectant in human breast cancer. It binds to ERs and interferes with normal binding of estrogen to ERs. In the present study, we examined the effect of long-term tamoxifen treatment in the prevention of estrogen-induced breast cancer. Female ACI rats were treated with 17β-estradiol (E2), tamoxifen or with a combination of E2 and tamoxifen for eight months. Tissue levels of oxidative stress markers 8-iso-Prostane F2α (8-isoPGF2α), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase, and oxidative DNA damage marker 8-hydroxydeoxyguanosine (8-OHdG) were quantified in the mammary tissues of all the treatment groups and compared with age-matched controls. Levels of tamoxifen metabolizing enzymes cytochrome P450s as well as estrogen responsive genes were also quantified. At necropsy, breast tumors were detected in 44% of rats co-treated with tamoxifen+E2. No tumors were detected in the sham or tamoxifen only treatment groups whereas in the E2 only treatment group, the tumor incidence was 82%. Co-treatment with tamoxifen decreased GPx and catalase levels; did not completely inhibit E2-mediated oxidative DNA damage and estrogen-responsive genes monoamine oxygenase B1 (MaoB1) and cell death inducing DFF45 like effector C (Cidec) but differentially affected the levels of tamoxifen metabolizing enzymes. In summary, our studies suggest that although tamoxifen treatment inhibits estrogen-induced breast tumor development and increases the latency of tumor development, it does not completely abrogate breast tumor development in a rat model of estrogen-induced breast cancer. The inability of tamoxifen to completely inhibit E2-induced breast carcinogenesis may be because of increased estrogen-mediated oxidant burden

1-methylnicotinamide and its structural analog 1,4-dimethylpyridine for the prevention of cancer metastasis

Background: 1-methylnicotinamide (1-MNA), an endogenous metabolite of nicotinamide, has recently gained interest due to its anti-inflammatory and anti-thrombotic activities linked to the COX-2/PGI2 pathway. Given the previously reported anti-metastatic activity of prostacyclin (PGI2), we aimed to assess the effects of 1-MNA and its structurally related analog, 1,4-dimethylpyridine (1,4-DMP), in the prevention of cancer metastasis. Methods: All the studies on the anti-tumor and anti-metastatic activity of 1-MNA and 1,4-DMP were conducted using the model of murine mammary gland cancer (4T1) transplanted either orthotopically or intravenously into female BALB/c mouse. Additionally, the effect of the investigated molecules on cancer cell-induced angiogenesis was estimated using the matrigel plug assay utilizing 4T1 cells as a source of pro-angiogenic factors. Results: Neither 1-MNA nor 1,4-DMP, when given in a monotherapy of metastatic cancer, influenced the growth of 4T1 primary tumors transplanted orthotopically; however, both compounds tended to inhibit 4T1 metastases formation in lungs of mice that were orthotopically or intravenously inoculated with 4T1 or 4T1-luc2-tdTomato cells, respectively. Additionally, while 1-MNA enhanced tumor vasculature formation and markedly increased PGI2 generation, 1,4-DMP did not have such an effect. The anti-metastatic activity of 1-MNA and 1,4-DMP was further confirmed when both agents were applied with a cytostatic drug in a combined treatment of 4T1 murine mammary gland cancer what resulted in up to 80 % diminution of lung metastases formation. Conclusions: The results of the studies presented below indicate that 1-MNA and its structural analog 1,4-DMP prevent metastasis and might be beneficially implemented into the treatment of metastatic breast cancer to ensure a comprehensive strategy of metastasis control

The Cholesterol Metabolite 25-Hydroxycholesterol Activates Estrogen Receptor α-Mediated Signaling in Cancer Cells and in Cardiomyocytes

The hydroxylated derivatives of cholesterol, such as the oxysterols, play important roles in lipid metabolism. In particular, 25-hydroxycholesterol (25 HC) has been implicated in a variety of metabolic events including cholesterol homeostasis and atherosclerosis. 25 HC is detectable in human plasma after ingestion of a meal rich in oxysterols and following a dietary cholesterol challenge. In addition, the levels of oxysterols, including 25 HC, have been found to be elevated in hypercholesterolemic serum.Here, we demonstrate that the estrogen receptor (ER) α mediates gene expression changes and growth responses induced by 25 HC in breast and ovarian cancer cells. Moreover, 25 HC exhibits the ERα-dependent ability like 17 β-estradiol (E2) to inhibit the up-regulation of HIF-1α and connective tissue growth factor by hypoxic conditions in cardiomyocytes and rat heart preparations and to prevent the hypoxia-induced apoptosis.The estrogen action exerted by 25 HC may be considered as an additional factor involved in the progression of breast and ovarian tumors. Moreover, the estrogen-like activity of 25 HC elicited in the cardiovascular system may play a role against hypoxic environments

Historical impact to drive research in peptic ulcer disease

The story of gastric acid secretion began with early ideas on gastric secretion (Spallanzani and de Réaumur, 17th century) and with first descriptions of food digestion (Dupuytren and Bichat, Beaumont, early 18th century), followed by proof that gastric juice contained acid (Prout, early 18th century). The research continued with first descriptions of gastric glands as the source of gastric acid and its changes upon digestive stimulus (Purkinje and Golgi, mid and late 19th century). The theory of 'nervism' - the neuro-reflex stimulation of gastric secretion by vagal nerve (Pavlov, early 20th century) was contrasted by a histamine-mediated concept of gastric secretion (Popielski and Code, mid 20th century). Thus, gastric acid and pepsin (Schwann, early 19th century) were found to be essential for food digestion and studies also pointed to histamine, being the most potent final common chemostimulator of oxyntic cells. The discoveries in etiopathogenesis of mucosal injury were marked by the famous dictum: 'No acid, no ulcer' ('Ohne saueren Magensaft kein peptisches Geschwür', Schwarz, 1910) that later induced the term of 'mucosal defense' and the notion that the breaking of 'gastric mucosal barrier' represents the initial step in the process of mucosal injury (Davenport, Code and Scholer, mid 20th century). The prostaglandins were shown to influence all major components of gastric mucosal barrier, described with the term 'cytoprotection' (Vane, Robert and Jacobson, 1970s). Beginning in the latter half of 19th century, the studies on gastric bacteriology that followed enabled the discovery of association between Campylobacter (Helicobacter) pylori and peptic ulcers (Warren and Marshall, 1980s) that led to worldwide major interventions in treating peptic ulcer disease. The surgical approach to peptic ulcer had been outlined by resection procedures (Billroth, Pean, Moynihan, late 19 century) and vagotomy, with or without drainage procedures (Jaboulay, Latarjet, Dragstedt, mid 20th century). Antacids, protective agents, anticholinergics, and later gastrin antagonists and prostaglandins were used for decades in the treatment of peptic ulcer, with differing effects. The advent of the concept of H(2)-receptor antagonists (Black, 1970s) and the discovery of acid (proton) pumps in parietal cells (Ganser, Forte and Sachs, late 1970s) paved the way for potent (H(2) antagonists) and profound acid inhibition (proton pump inhibitors) that revolutionized the treatment of acid-related disorders, including peptic ulcer disease. Worldwide, peptic ulcer and its complications remain the cause of significant morbidity, especially in older age groups, representing a major burden for ambulatory and hospital healthcare resources

Interactions among residues CD3, E7, E10, and E11 in myoglobins: attempts to simulate the ligand-binding properties of Aplysia myoglobin.

Site-directed mutations have been introduced singly and in combination at residues lysine/arginine(45) (CD3), histidine(64) (E7), threonine(67) (E10), and valine(68) (E11) in pig and sperm whale myoglobins. The mutations probe the roles of these key distal pocket residues and represent attempts to mimic the heme environment of Aplysia limacina myoglobin which achieves moderately high O-2 affinity in the absence of a distal histidine, In the mollusc myoglobin, arginine-E10 is believed to swing into the heme pocket and provide a hydrogen bond to the bound O-2, The association and dissociation rate constants for oxygen and carbon monoxide binding to H64V, T67A, T67V, T67E, T67R, V68I, V68T, H64V-T67R, H64V-V68T, H64V-V68I, and H64V-T67R-V68I pig myoglobin mutants and T67R, H64V-T67R, and R45D-H64V-T67R mutants of sperm whale myoglobin have been measured using stopped-flow rapid mixing and flash photolysis techniques. Replacement of histidine-E7 with valine in either pig or sperm whale myoglobin drastically lowers O-2 affinity while increasing CO affinity. Two second-site mutations, T67R and V68T, increase O-2 affinity in the H64V mutant, even though when introduced singly these mutations have no effect or lower KO2, respectively, However, the oxygen affinities of the H64V-T67R mutants are 5-10-fold lower than that of A. limacina myoglobin, The crystal structure of the pig H64V-T67R double mutant reveals that the valine-E7 side chain is similar to 1 Angstrom closer to the heme plane than in the mollusc protein which may restrict access of the arginine-E10 side chain into the heme pocket. The O-2 affinity of the H64V-T67R double mutant is not altered by the R45D replacement but is reduced 10-fold by the V68I mutation, The interactive effects of the T67R, V68I, and V68T mutations with the H64V substitution are discussed in terms of O-2, CO, and N-3(-) binding and the crystal structures of the H64V-T67R, H64V-V68I, and H64V-V68T double-mutant proteins. In many instances, the effects of second-site mutations in the valine(64) background are the opposite of those observed for the corresponding single mutations in the wild type background, These results can be understood in terms of the changes in the rate-determining steps for ligand association and dissociation and the loss of distal pecker water molecules which follow replacement of histidine(63) by valine