Effects of oxidized low density lipoprotein, lipid mediators and statins on vascular cell interactions

The integrin heterodimer CD11b/CD18 (alpha M beta 2, Mac-1, CR3) expressed on monocytes or polymorphonuclear leukocytes (PMN) is a receptor for iC3b, fibrinogen, heparin, and for intercellular adhesion molecule (ICAM)-1 on endothelium, crucially contributing to vascular cell interactions in inflammation and atherosclerosis. In this report, we summarize our findings on the effects of lipid mediators and lipid-lowering drugs. Exposure of endothelial cells to oxidized low density lipoprotein (oxLDL) induces upregulation of ICAM-1 and increases adhesion of monocytic cells expressing Mac-1. Inhibition experiments show that monocytes use distinct ligands, i.e. ICAM-1 and heparan sulfate proteoglycans for adhesion to oxLDL-treated endothelium. An albumin-transferable oxLDL activity is inhibited by the antioxidant pyrrolidine dithiocarbamate (PDTC), while 8-epi-prostaglandin F2 alpha (8-epi-PGF2 alpha) or lysophosphatidylcholine had no effect, implicating yet unidentified radicals. Sequential adhesive! and signaling events lead to the firm adhesion of rolling PMN on activated and adherent platelets, which may occupy areas of endothelial denudation. Shear resistant arrest of PMN on thrombin-stimulated platelets in flow conditions requires distinct regions of Mac-1, involving its interactions with fibrinogen bound to platelet alpha llb beta 3, and with other platelet ligands. Both arrest and adhesion strengthening under flow are stimulated by platelet-activating factor and leukotriene B4, but not by the chemokine receptor CXCR2. We tested whether Mac-1-dependent monocyte adhesiveness is affected by inhibitors of hydroxy-methylglutaryl-Coenzyme A reductase (statins) which improve morbidity and survival of patients with coronary heart disease. As compared to controls, adhesion of isolated monocytes to endothelium ex vivo was increased in patients with hypercholesterolemia. Treatment with statins decreased total and low density lipoprotein (LDL) cholesterol plasma levels, surface expression of Mac-1, and resulted in a dramatic reduction of Mac,mediated monocyte adhesion to endothelium. The inhibition of monocyte adhesion was reversed by mevalonate but not LDL in vitro,indicating that isoprenoid precursors are crucial for adhesiveness of Mac-1. Such effects may crucially contribute to the clinical benefit of statins, independent of cholesterol-lowering, and may represent a paradigm for novel, anti-inflammatory mechanisms of action by this class of drugs

Linear magnetoresistance in commercial n-type silicon due to inhomogeneous doping

Free electron theory tells us that resistivity is independent of magnetic field. In fact, most observations match the semiclassical prediction of a magnetoresistance that is quadratic at low fields before saturating. However, a non-saturating linear magnetoresistance has been observed in exotic semiconductors such as silver chalcogenides, lightly-doped InSb, N-doped InAs, MnAs-GaAs composites, PrFeAsO, and epitaxial graphene. Here we report the observation of a large linear magnetoresistance in the ohmic regime in commonplace commercial n-type silicon wafer. It is well-described by a classical model of spatially fluctuating donor densities, and may be amplified by altering the aspect ratio of the sample to enhance current-jetting: increasing the width tenfold increased the magnetoresistance at 8 T from 445 % to 4707 % at 35 K. This physical picture may well offer insights into the large magnetoresistances recently observed in n-type and p-type Si in the non-ohmic regime.Comment: submitted to Nature Material

Iridium wire grid polarizer fabricated using atomic layer deposition

In this work, an effective multistep process toward fabrication of an iridium wire grid polarizer for UV applications involving a frequency doubling process based on ultrafast electron beam lithography and atomic layer deposition is presented. The choice of iridium as grating material is based on its good optical properties and a superior oxidation resistance. Furthermore, atomic layer deposition of iridium allows a precise adjustment of the structural parameters of the grating much better than other deposition techniques like sputtering for example. At the target wavelength of 250 nm, a transmission of about 45% and an extinction ratio of 87 are achieved

‘Warrant’ revisited: Integrating mathematics teachers’ pedagogical and epistemological considerations into Toulmin’s model for argumentation

In this paper, we propose an approach to analysing teacher arguments that takes into account field dependence—namely, in Toulmin’s sense, the dependence of warrants deployed in an argument on the field of activity to which the argument relates. Freeman, to circumvent issues that emerge when we attempt to determine the field(s) that an argument relates to, proposed a classification of warrants (a priori, empirical, institutional and evaluative). Our approach to analysing teacher arguments proposes an adaptation of Freeman’s classification that distinguishes between: epistemological and pedagogical a priori warrants, professional and personal empirical warrants, epistemological and curricular institutional warrants, and evaluative warrants. Our proposition emerged from analyses conducted in the course of a written response and interview study that engages secondary mathematics teachers with classroom scenarios from the mathematical areas of analysis and algebra. The scenarios are hypothetical, grounded on seminal learning and teaching issues, and likely to occur in actual practice. To illustrate our proposed approach to analysing teacher arguments here, we draw on the data we collected through the use of one such scenario, the Tangent Task. We demonstrate how teacher arguments, not analysed for their mathematical accuracy only, can be reconsidered, arguably more productively, in the light of other teacher considerations and priorities: pedagogical, curricular, professional and personal

Tumours and tumour-like lesions of the lower face at Korle Bu Teaching Hospital, Ghana – an eight year study

<p>Abstract</p> <p>Background</p> <p>The oro-facial region including the jawbones, the maxilla and mandible and related tissues can be the site of a multitude of neoplastic conditions. These tumours have a predilection for the entire facial region; however, odontogenic tumours tend to affect the mandible more than the maxilla, especially, in West African children. We report results from a retrospective study spanning eight years on the frequency, clinical presentation, sites and character of lower face tumours seen in the main referral hospital in Ghana.</p> <p>Patients and methods</p> <p>Records of consecutive patients of all age and sex seen by the first author's team at the Department of Oral and Maxillofacial Surgery, Korle-Bu Teaching Hospital with tumours affecting the lower part of the face from January 1996 to December 2003 were retrieved, coded and entered into a database. The data were then analyzed by age, sex, presenting signs and symptoms, site of lesion, and their histology.</p> <p>Results</p> <p>A total of 394 patients with oro-facial swellings were retrieved from the registry out of which 210 had lower face tumour and tumour-like lesions. The complete data set was obtained for 171 patients, comprising 99 (58%) males and 72 (42%) females. The most common clinical presenting features were mandibular facial swelling (63%), intra-oral swelling (55%), pain (41%) and ulceration (29%). The tumours were predominantly found in the right (43%), anterior (19%) and left (18%) aspects of the lower face. The remainder making up 20% were found in the floor of the mouth, tongue and lips. Seventy eight (45.6%) of the patients presented with lesions that were classified as malignant of which 54 (62%) were diagnosed as squamous cell carcinoma (SCC). Sixty-two (36.3%) had benign odontogenic tumours and thirty-one (18.1%) had non-odontogenic tumour-like lesions. Fifty-four (62%) of malignant tumours were squamous cell carcinoma; 58 (93.6%) of the benign odontogenic tumours were classified as ameloblastoma. The mean age at presentation of all lesions was 40.4 years with over 50% of benign lesions in patients aged between 11 and 30 years. Malignant tumours were more commonly detected in patients between 41 and 70 years (63%).</p> <p>Conclusion</p> <p>Tumours and tumour-like lesions of the lower face comprising the mandible, tongue and adjacent structures are a diverse group of neoplasm and are seen commonly in practice of Maxillofacial surgery. Both malignant and benign tumours are seen in the Ghanaian population. In the present study, SCC and ameloblastoma were the commonest malignant and benign odontogenic tumours seen respectively; the two representing more than 65% of all tumours.</p

In Situ Oxygen Dynamics in Coral-Algal Interactions

Background: Coral reefs degrade globally at an alarming rate, with benthic algae often replacing corals. However, the extent to which benthic algae contribute to coral mortality, and the potential mechanisms involved, remain disputed. Recent laboratory studies suggested that algae kill corals by inducing hypoxia on the coral surface, through stimulated microbial respiration. Methods/Findings: We examined the main premise of this hypothesis by measuring in situ oxygen microenvironments at the contact interface between the massive coral Porites spp. and turf algae, and between Porites spp. and crustose coralline algae (CCA). Oxygen levels at the interface were similar to healthy coral tissue and ranged between 300-400 μM during the day. At night, the interface was hypoxic (~70 μM) in coral-turf interactions and close to anoxic (~2 μM) in coral-CCA interactions, but these values were not significantly different from healthy tissue. The diffusive boundary layer (DBL) was about three times thicker at the interface than above healthy tissue, due to a depression in the local topography. A numerical model, developed to analyze the oxygen profiles above the irregular interface, revealed strongly reduced net photosynthesis and dark respiration rates at the coral-algal interface compared to unaffected tissue during the day and at night, respectively. Conclusions/Significance: Our results showed that hypoxia was not a consistent feature in the microenvironment of the coral-algal interface under in situ conditions. Therefore, hypoxia alone is unlikely to be the cause of coral mortality. Due to the modified topography, the interaction zone is distinguished by a thicker diffusive boundary layer, which limits the local metabolic activity and likely promotes accumulation of potentially harmful metabolic products (e.g., allelochemicals and protons). Our study highlights the importance of mass transfer phenomena and the need for direct in situ measurements of microenvironmental conditions in studies on coral stress. © 2012 Wangpraseurt et al

Schmallenberg virus pathogenesis, tropism and interaction with the innate immune system of the host

Schmallenberg virus (SBV) is an emerging orthobunyavirus of ruminants associated with outbreaks of congenital malformations in aborted and stillborn animals. Since its discovery in November 2011, SBV has spread very rapidly to many European countries. Here, we developed molecular and serological tools, and an experimental in vivo model as a platform to study SBV pathogenesis, tropism and virus-host cell interactions. Using a synthetic biology approach, we developed a reverse genetics system for the rapid rescue and genetic manipulation of SBV. We showed that SBV has a wide tropism in cell culture and “synthetic” SBV replicates in vitro as efficiently as wild type virus. We developed an experimental mouse model to study SBV infection and showed that this virus replicates abundantly in neurons where it causes cerebral malacia and vacuolation of the cerebral cortex. These virus-induced acute lesions are useful in understanding the progression from vacuolation to porencephaly and extensive tissue destruction, often observed in aborted lambs and calves in naturally occurring Schmallenberg cases. Indeed, we detected high levels of SBV antigens in the neurons of the gray matter of brain and spinal cord of naturally affected lambs and calves, suggesting that muscular hypoplasia observed in SBV-infected lambs is mostly secondary to central nervous system damage. Finally, we investigated the molecular determinants of SBV virulence. Interestingly, we found a biological SBV clone that after passage in cell culture displays increased virulence in mice. We also found that a SBV deletion mutant of the non-structural NSs protein (SBVΔNSs) is less virulent in mice than wild type SBV. Attenuation of SBV virulence depends on the inability of SBVΔNSs to block IFN synthesis in virus infected cells. In conclusion, this work provides a useful experimental framework to study the biology and pathogenesis of SBV

The programming of sequences of saccades

Saccadic eye movements move the high-resolution fovea to point at regions of interest. Saccades can only be generated serially (i.e., one at a time). However, what remains unclear is the extent to which saccades are programmed in parallel (i.e., a series of such moments can be planned together) and how far ahead such planning occurs. In the current experiment, we investigate this issue with a saccade contingent preview paradigm. Participants were asked to execute saccadic eye movements in response to seven small circles presented on a screen. The extent to which participants were given prior information about target locations was varied on a trial-by-trial basis: participants were aware of the location of the next target only, the next three, five, or all seven targets. The addition of new targets to the display was made during the saccade to the next target in the sequence. The overall time taken to complete the sequence was decreased as more targets were available up to all seven targets. This was a result of a reduction in the number of saccades being executed and a reduction in their saccade latencies. Surprisingly, these results suggest that, when faced with a demand to saccade to a large number of target locations, saccade preparation about all target locations is carried out in paralle

Tumor volume in subcutaneous mouse xenografts measured by microCT is more accurate and reproducible than determined by 18F-FDG-microPET or external caliper

<p>Abstract</p> <p>Background</p> <p>In animal studies tumor size is used to assess responses to anticancer therapy. Current standard for volumetric measurement of xenografted tumors is by external caliper, a method often affected by error. The aim of the present study was to evaluate if microCT gives more accurate and reproducible measures of tumor size in mice compared with caliper measurements. Furthermore, we evaluated the accuracy of tumor volume determined from ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET.</p> <p>Methods</p> <p>Subcutaneously implanted human breast adenocarcinoma cells in NMRI nude mice served as tumor model. Tumor volume (n = 20) was determined <it>in vivo </it>by external caliper, microCT and ¹⁸F-FDG-PET and subsequently reference volume was determined <it>ex vivo</it>. Intra-observer reproducibility of the microCT and caliper methods were determined by acquiring 10 repeated volume measurements. Volumes of a group of tumors (n = 10) were determined independently by two observers to assess inter-observer variation.</p> <p>Results</p> <p>Tumor volume measured by microCT, PET and caliper all correlated with reference volume. No significant bias of microCT measurements compared with the reference was found, whereas both PET and caliper had systematic bias compared to reference volume. Coefficients of variation for intra-observer variation were 7% and 14% for microCT and caliper measurements, respectively. Regression coefficients between observers were 0.97 for microCT and 0.91 for caliper measurements.</p> <p>Conclusion</p> <p>MicroCT was more accurate than both caliper and ¹⁸F-FDG-PET for <it>in vivo </it>volumetric measurements of subcutaneous tumors in mice.¹⁸F-FDG-PET was considered unsuitable for determination of tumor size. External caliper were inaccurate and encumbered with a significant and size dependent bias. MicroCT was also the most reproducible of the methods.</p