The Kunitz-Like Modulatory Protein Haemangin Is Vital for Hard Tick Blood-Feeding Success

Ticks are serious haematophagus arthropod pests and are only second to mosquitoes as vectors of diseases of humans and animals. The salivary glands of the slower feeding hard ticks such as Haemaphysalis longicornis are a rich source of bioactive molecules and are critical to their biologic success, yet distinct molecules that help prolong parasitism on robust mammalian hosts and achieve blood-meals remain unidentified. Here, we report on the molecular and biochemical features and precise functions of a novel Kunitz inhibitor from H. longicornis salivary glands, termed Haemangin, in the modulation of angiogenesis and in persistent blood-feeding. Haemangin was shown to disrupt angiogenesis and wound healing via inhibition of vascular endothelial cell proliferation and induction of apoptosis. Further, this compound potently inactivated trypsin, chymotrypsin, and plasmin, indicating its antiproteolytic potential on angiogenic cascades. Analysis of Haemangin-specific gene expression kinetics at different blood-feeding stages of adult ticks revealed a dramatic up-regulation prior to complete feeding, which appears to be functionally linked to the acquisition of blood-meals. Notably, disruption of Haemangin-specific mRNA by a reverse genetic tool significantly diminished engorgement of adult H. longicornis, while the knock-down ticks failed to impair angiogenesis in vivo. To our knowledge, we have provided the first insights into transcriptional responses of human microvascular endothelial cells to Haemangin. DNA microarray data revealed that Haemangin altered the expression of 3,267 genes, including those of angiogenic significance, further substantiating the antiangiogenic function of Haemangin. We establish the vital roles of Haemangin in the hard tick blood-feeding process. Moreover, our results provide novel insights into the blood-feeding strategies that enable hard ticks to persistently feed and ensure full blood-meals through the modulation of angiogenesis and wound healing processes

Dynamical Mean-Field Theory

The dynamical mean-field theory (DMFT) is a widely applicable approximation scheme for the investigation of correlated quantum many-particle systems on a lattice, e.g., electrons in solids and cold atoms in optical lattices. In particular, the combination of the DMFT with conventional methods for the calculation of electronic band structures has led to a powerful numerical approach which allows one to explore the properties of correlated materials. In this introductory article we discuss the foundations of the DMFT, derive the underlying self-consistency equations, and present several applications which have provided important insights into the properties of correlated matter.Comment: Chapter in "Theoretical Methods for Strongly Correlated Systems", edited by A. Avella and F. Mancini, Springer (2011), 31 pages, 5 figure

Friction phenomena and their impact on the shear behaviour of granular material

In the discrete element simulation of granular materials, the modelling of contacts is crucial for the prediction of the macroscopic material behaviour. From the tribological point of view, friction at contacts needs to be modelled carefully, as it depends on several factors, e.g. contact normal load or temperature to name only two. In discrete element method (DEM) simulations the usage of Coulomb’s law of friction is state of the art in modelling particle–particle contacts. Usually in Coulomb’s law, for all contacts only one constant coefficient of friction is used, which needs to reflect all tribological effects. Thus, whenever one of the influence factors of friction varies over a wide range, it can be expected that the usage of only one constant coefficient of friction in Coulomb’s law is an oversimplification of reality. For certain materials, e.g. steel, it is known that a dependency of the coefficient of friction on the contact normal load exists. A more tribological tangential contact law is implemented in DEM, where the interparticle friction coefficient depends on the averaged normal stress in the contact. Simulations of direct shear tests are conducted, using steel spheres of different size distributions. The strong influence of interparticle friction on the bulk friction is shown via a variation of the constant interparticle friction coefficient. Simulations with constant and stress-dependent interparticle friction are compared. For the stress-dependent interparticle friction, a normal stress dependency of the bulk friction is seen. In the literature, measurements of different granular materials and small normal loads also show a stress dependency of the bulk friction coefficient. With increasing applied normal stress, the bulk friction coefficient reduces both in the experiments and in the simulations

Tobacco chewing and female oral cavity cancer risk in Karunagappally cohort, India

This study examined oral cancer in a cohort of 78 140 women aged 30–84 years in Karunagappally, Kerala, India, on whom baseline information was collected on lifestyle, including tobacco chewing, and sociodemographic factors during the period 1990–1997. By the end of 2005, 92 oral cancer cases were identified by the Karunagappally Cancer Registry. Poisson regression analysis of grouped data, taking into account age and income, showed that oral cancer incidence was strongly related to daily frequency of tobacco chewing (P<0.001) and was increased 9.2-fold among women chewing tobacco 10 times or more a day. The risk increased with the duration of tobacco chewing during the first 20 years of tobacco chewing. Age at starting tobacco chewing was not significantly related to oral cancer risk. This is the first cohort study of oral cancer in relation to tobacco chewing among women

To respond or not to respond - a personal perspective of intestinal tolerance

For many years, the intestine was one of the poor relations of the immunology world, being a realm inhabited mostly by specialists and those interested in unusual phenomena. However, this has changed dramatically in recent years with the realization of how important the microbiota is in shaping immune function throughout the body, and almost every major immunology institution now includes the intestine as an area of interest. One of the most important aspects of the intestinal immune system is how it discriminates carefully between harmless and harmful antigens, in particular, its ability to generate active tolerance to materials such as commensal bacteria and food proteins. This phenomenon has been recognized for more than 100 years, and it is essential for preventing inflammatory disease in the intestine, but its basis remains enigmatic. Here, I discuss the progress that has been made in understanding oral tolerance during my 40 years in the field and highlight the topics that will be the focus of future research

Clinicopathologic characteristics and prognostic factors of ovarian fibrosarcoma: the results of a multi-center retrospective study

<p>Abstract</p> <p>Background</p> <p>Ovarian fibrosarcomas are very rare tumors, and therefore, few case studies have evaluated the prognostic factors of this disease. To our knowledge, this study represents the largest study to evaluate the clinical and pathologic factors associated with ovarian fibrosarcoma patients.</p> <p>Methods</p> <p>Thirty-one cases of ovarian fibrosarcoma were retrospectively reviewed, which included medical records for eight patients, and 23 published case reports from 1995 through 2009. Patient treatment regimens included total hysterectomy with bilateral adnexectomy and an omentectomy (BAO) (n = 9), oophorectomy (OR) (n = 8), chemotherapy (CT) (n = 1), BAO followed by chemotherapy (BAO+CT) (n = 11), BAO followed by radiotherapy (BAO+RT) (n = 1), and oophorectomy followed by radiotherapy (OR + RT) (n = 1).</p> <p>Results</p> <p>The patients of this cohort were staged according to the guidelines of the Federation of Gynecology and Obstetrics (FIGO), with 15, 6, 9, and 1 stage I-IV cases identified, respectively. Mitotic count values were also evaluated from 10 high-power fields (HPFs), and 3 cases had an average mitotic count < 4, 18 cases were between 4 and 10, and 10 cases had an average mitotic count value ≥ 10. The Ki-67 (MIB-1) proliferation index values were grouped according to values that as follows: < 10% (n = 5), between 10% and 50% (n = 9), and ≥ 50% (n = 5). Positive expression of vimentin (100%, 22/22) and negative expression of CD117 (0%, 5/5) were also detected. Moreover, expression of smooth muscle actin (2/18), desmin (1/13), epithelial membrane antigen (0/11), S-100 (1/19), CD99 (0/6), CD34 (1/5), α-inhibin (7/15), estrogen receptor (1/6), and progesterone receptor (1/6) were reported for subsets of the cases examined. After a median follow-up period of 14 months (range, 2-120), the 2-year overall survival rates (OS) and disease-free survival (DFS) rates for all patients were 55.9% and 45.4%, respectively. Cox proportional hazard regression analysis of survival showed that FIGO stage (<it>P </it>= 0.007) and treatment (<it>P </it>= 0.008) were predictive of poor prognosis. Furthermore, patients with stage I tumors that received BAO+CT were associated with a better prognosis.</p> <p>Conclusions</p> <p>Mitotic activity, and cells positive for Ki-67 were identified as important factors in the diagnosis of ovarian fibrosarcoma. Furthermore, FIGO stage and treatment modalities have the potential to be prognostic factors of survival, with BAO followed by adjuvant chemotherapy associated with an improved treatment outcome.</p

Intestinal Epithelial-Derived TAK1 Signaling Is Essential for Cytoprotection against Chemical-Induced Colitis

We have previously reported that intestinal epithelium-specific TAK1 deleted mice exhibit severe inflammation and mortality at postnatal day 1 due to TNF-induced epithelial cell death. Although deletion of TNF receptor 1 (TNFR1) can largely rescue those neonatal phenotypes, mice harboring double deletion of TNF receptor 1 (TNFR1) and intestinal epithelium-specific deletion of TAK1 (TNFR1KO/TAK1(IE)KO) still occasionally show increased inflammation. This indicates that TAK1 is important for TNF-independent regulation of intestinal integrity.In this study, we investigated the TNF-independent role of TAK1 in the intestinal epithelium. Because the inflammatory conditions were sporadically developed in the double mutant TNFR1KO/TAK1(IE)KO mice, we hypothesize that epithelial TAK1 signaling is important for preventing stress-induced barrier dysfunction. To test this hypothesis, the TNFR1KO/TAK1(IE)KO mice were subjected to acute colitis by administration of dextran sulfate sodium (DSS). We found that loss of TAK1 significantly augments DSS-induced experimental colitis. DSS induced weight loss, intestinal damages and inflammatory markers in TNFR1KO/TAK1(IE)KO mice at higher levels compared to the TNFR1KO control mice. Apoptosis was strongly induced and epithelial cell proliferation was decreased in the TAK1-deficient intestinal epithelium upon DSS exposure. These suggest that epithelial-derived TAK1 signaling is important for cytoprotection and repair against injury. Finally, we showed that TAK1 is essential for interleukin 1- and bacterial components-induced expression of cytoprotective factors such as interleukin 6 and cycloxygenase 2.Homeostatic cytokines and microbes-induced intestinal epithelial TAK1 signaling regulates cytoprotective factors and cell proliferation, which is pivotal for protecting the intestinal epithelium against injury

A Cysteine Protease Is Critical for Babesia spp. Transmission in Haemaphysalis Ticks

Vector ticks possess a unique system that enables them to digest large amounts of host blood and to transmit various animal and human pathogens, suggesting the existence of evolutionally acquired proteolytic mechanisms. We report here the molecular and reverse genetic characterization of a multifunctional cysteine protease, longipain, from the babesial parasite vector tick Haemaphysalis longicornis. Longipain shares structural similarity with papain-family cysteine proteases obtained from invertebrates and vertebrates. Endogenous longipain was mainly expressed in the midgut epithelium and was specifically localized at lysosomal vacuoles and possibly released into the lumen. Its expression was up-regulated by host blood feeding. Enzymatic functional assays using in vitro and in vivo substrates revealed that longipain hydrolysis occurs over a broad range of pH and temperature. Haemoparasiticidal assays showed that longipain dose-dependently killed tick-borne Babesia parasites, and its babesiacidal effect occurred via specific adherence to the parasite membranes. Disruption of endogenous longipain by RNA interference revealed that longipain is involved in the digestion of the host blood meal. In addition, the knockdown ticks contained an increased number of parasites, suggesting that longipain exerts a killing effect against the midgut-stage Babesia parasites in ticks. Our results suggest that longipain is essential for tick survival, and may have a role in controlling the transmission of tick-transmittable Babesia parasites