Innate Recognition of Fungal Cell Walls

The emergence of fungal infections as major causes of morbidity and mortality in immunosuppressed individuals has prompted studies into how the host recognizes fungal pathogens. Fungi are eukaryotes and as such share many similarities with mammalian cells. The most striking difference, though, is the presence of a cell wall that serves to protect the fungus from environmental stresses, particularly osmotic changes [1]. This task is made challenging because the fungus must remodel itself to allow for cell growth and division, including the conversion to different morphotypes, such as occurs during germination of spherical spores into filamentous hyphae. The cell wall also connects the fungus with its environment by triggering intracellular signaling pathways and mediating adhesion to other cells and extracellular matrices. Here, important facts and concepts critical for understanding innate sensing of the fungal cell wall by mammalian pathogens are reviewed

Proteomic Analysis of Pathways Involved in Estrogen-Induced Growth and Apoptosis of Breast Cancer Cells

Estrogen is a known growth promoter for estrogen receptor (ER)-positive breast cancer cells. Paradoxically, in breast cancer cells that have been chronically deprived of estrogen stimulation, re-introduction of the hormone can induce apoptosis.Here, we sought to identify signaling networks that are triggered by estradiol (E2) in isogenic MCF-7 breast cancer cells that undergo apoptosis (MCF-7:5C) versus cells that proliferate upon exposure to E2 (MCF-7). The nuclear receptor co-activator AIB1 (Amplified in Breast Cancer-1) is known to be rate-limiting for E2-induced cell survival responses in MCF-7 cells and was found here to also be required for the induction of apoptosis by E2 in the MCF-7:5C cells. Proteins that interact with AIB1 as well as complexes that contain tyrosine phosphorylated proteins were isolated by immunoprecipitation and identified by mass spectrometry (MS) at baseline and after a brief exposure to E2 for two hours. Bioinformatic network analyses of the identified protein interactions were then used to analyze E2 signaling pathways that trigger apoptosis versus survival. Comparison of MS data with a computationally-predicted AIB1 interaction network showed that 26 proteins identified in this study are within this network, and are involved in signal transduction, transcription, cell cycle regulation and protein degradation.G-protein-coupled receptors, PI3 kinase, Wnt and Notch signaling pathways were most strongly associated with E2-induced proliferation or apoptosis and are integrated here into a global AIB1 signaling network that controls qualitatively distinct responses to estrogen

Tyrosine Sulfation of Native Mouse Psgl-1 Is Required for Optimal Leukocyte Rolling on P-Selectin In Vivo

We recently demonstrated that tyrosine sulfation is an important contributor to monocyte recruitment and retention in a mouse model of atherosclerosis. P-selectin glycoprotein ligand-1 (Psgl-1) is tyrosine-sulfated in mouse monocyte/macrophages and its interaction with P-selectin is important in monocyte recruitment in atherosclerosis. However, whether tyrosine sulfation is required for the P-selectin binding function of mouse Psgl-1 is unknown. Here we test the function of native Psgl-1 expressed in leukocytes lacking endogenous tyrosylprotein sulfotransferase (TPST) activity.Psgl-1 function was assessed by examining P-selectin dependent leukocyte rolling in post-capillary venules of C57BL6 mice transplanted with hematopoietic progenitors from wild type (WT → B6) or Tpst1;Tpst2 double knockout mice (Tpst DKO → B6) which lack TPST activity. We observed that rolling flux fractions were lower and leukocyte rolling velocities were higher in Tpst DKO → B6 venules compared to WT → B6 venules. Similar results were observed on immobilized P-selectin in vitro. Finally, Tpst DKO leukocytes bound less P-selectin than wild type leukocytes despite equivalent surface expression of Psgl-1.These findings provide direct and convincing evidence that tyrosine sulfation is required for optimal function of mouse Psgl-1 in vivo and suggests that tyrosine sulfation of Psgl-1 contributes to the development of atherosclerosis

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

Search for high-mass resonances decaying to dilepton final states in pp collisions at s√=7 TeV with the ATLAS detector

The ATLAS detector at the Large Hadron Collider is used to search for high-mass resonances decaying to an electron-positron pair or a muon-antimuon pair. The search is sensitive to heavy neutral Z′ gauge bosons, Randall-Sundrum gravitons, Z * bosons, techni-mesons, Kaluza-Klein Z/γ bosons, and bosons predicted by Torsion models. Results are presented based on an analysis of pp collisions at a center-of-mass energy of 7 TeV corresponding to an integrated luminosity of 4.9 fb−1 in the e + e − channel and 5.0 fb−1 in the μ + μ −channel. A Z ′ boson with Standard Model-like couplings is excluded at 95 % confidence level for masses below 2.22 TeV. A Randall-Sundrum graviton with coupling k/MPl=0.1 is excluded at 95 % confidence level for masses below 2.16 TeV. Limits on the other models are also presented, including Technicolor and Minimal Z′ Models

The physiological responses of cacao to the environment and the implications for climate change resilience. A review

Cacao (Theobroma cacao L.) is a tropical perennial crop which is of great economic importance to the confectionary industry and to the economies of many countries of the humid tropics where it is grown. Some recent studies have suggested climate change could severely impact cacao production in West Africa. It is essential to incorporate our understanding of the physiology and genetic variation within cacao germplasm when discussing the implications of climate change on cacao productivity and developing strategies for climate resilience in cacao production. Here we review the current research on the physiological responses of cacao to various climate factors. Our main findings are 1) water limitation causes significant yield reduction in cacao but genotypic variation in sensitivity is evident, 2) in the field cacao experiences higher temperatures than is often reported in the literature, 3) the complexity of the cacao/ shade tree interaction can lead to contradictory results, 4) elevated CO2 may alleviate some negative effects of climate change 5) implementation of mitigation strategies can help reduce environmental stress, 6) significant gaps in the research need addressing to accelerate the development of climate resilience. Harnessing the significant genetic variation apparent within cacao germplasm is essential to develop modern varieties capable of high yields in non-optimal conditions. Mitigation strategies will also be essential but to use shading to best effect shade tree selection is crucial to avoid resource competition. Cacao is often described as being sensitive to climate change but genetic variation, adaptive responses, appropriate mitigation strategies and interactive climate effects should all be considered when predicting the future of cacao production. Incorporating these physiological responses to various environmental conditions and developing a deeper understanding of the processes underlying these responses will help to accelerate the development of a more resource use efficient tree ensuring sustainable production into the future

Virologic Failure of Protease Inhibitor-Based Second-Line Antiretroviral Therapy without Resistance in a Large HIV Treatment Program in South Africa

Background: We investigated the prevalence of wild-type virus (no major drug resistance) and drug resistance mutations at second-line antiretroviral treatment (ART) failure in a large HIV treatment program in South Africa. Methodology/ Principal Findings HIV-infected patients $\geq$15 years of age who had failed protease inhibitor (PI)-based second-line ART (2 consecutive HIV RNA tests >1000 copies/ml on lopinavir/ritonavir, didanosine, and zidovudine) were identified retrospectively. Patients with virologic failure were continued on second-line ART. Genotypic testing for drug resistance was performed on frozen plasma samples obtained closest to and after the date of laboratory confirmed second-line ART failure. Of 322 HIV-infected patients on second-line ART, 43 were adults with confirmed virologic failure, and 33 had available plasma for viral sequencing. HIV-1 RNA subtype C predominated (n = 32, 97%). Mean duration on ART (SD) prior to initiation of second-line ART was 23 (17) months, and time from second-line ART initiation to failure was 10 (9) months. Plasma samples were obtained 7(9) months from confirmed failure. At second-line failure, 22 patients (67%) had wild-type virus. There was no major resistance to PIs found. Eleven of 33 patients had a second plasma sample taken 8 (5.5) months after the first. Median HIV-1 RNA and the genotypic resistance profile were unchanged. Conclusions/ Significance: Most patients who failed second-line ART had wild-type virus. We did not observe evolution of resistance despite continuation of PI-based ART after failure. Interventions that successfully improve adherence could allow patients to continue to benefit from second-line ART therapy even after initial failure

GP88 (PC-Cell Derived Growth Factor, progranulin) stimulates proliferation and confers letrozole resistance to aromatase overexpressing breast cancer cells

<p>Abstract</p> <p>Background</p> <p>Aromatase inhibitors (AI) that inhibit breast cancer cell growth by blocking estrogen synthesis have become the treatment of choice for post-menopausal women with estrogen receptor positive (ER⁺) breast cancer. However, some patients display de novo or acquired resistance to AI. Interactions between estrogen and growth factor signaling pathways have been identified in estrogen-responsive cells as one possible reason for acquisition of resistance. Our laboratory has characterized an autocrine growth factor overexpressed in invasive ductal carcinoma named PC-Cell Derived Growth Factor (GP88), also known as progranulin. In the present study, we investigated the role GP88 on the acquisition of resistance to letrozole in ER⁺breast cancer cells</p> <p>Methods</p> <p>We used two aromatase overexpressing human breast cancer cell lines MCF-7-CA cells and AC1 cells and their letrozole resistant counterparts as study models. Effect of stimulating or inhibiting GP88 expression on proliferation, anchorage-independent growth, survival and letrozole responsiveness was examined.</p> <p>Results</p> <p>GP88 induced cell proliferation and conferred letrozole resistance in a time- and dose-dependent fashion. Conversely, naturally letrozole resistant breast cancer cells displayed a 10-fold increase in GP88 expression when compared to letrozole sensitive cells. GP88 overexpression, or exogenous addition blocked the inhibitory effect of letrozole on proliferation, and stimulated survival and soft agar colony formation. In letrozole resistant cells, silencing GP88 by siRNA inhibited cell proliferation and restored their sensitivity to letrozole.</p> <p>Conclusion</p> <p>Our findings provide information on the role of an alternate growth and survival factor on the acquisition of aromatase inhibitor resistance in ER⁺breast cancer.</p

Sleep quality, the neglected outcome variable in clinical studies focusing on locomotor system; a construct validation study

Background: In addition to general health and pain, sleep is highly relevant to judging the well-being of an individual. Of these three important outcome variables, however, sleep is neglected in most outcome studies. Sleep is a very important resource for recovery from daily stresses and strains, and any alteration of sleep will likely affect mental and physical health, especially during disease. Sleep assessment therefore should be standard in all population-based or clinical studies focusing on the locomotor system. Yet current sleep assessment tools are either too long or too specific for general use. Methods: Based on a literature review and subsequent patient-based rating of items, an expert panel designed a four-item questionnaire about sleep. Construct validation of the questionnaire in a random sample of the German-speaking Swiss population was performed in 2003. Reliability, correlation, and tests for internal consistency and validity were analyzed. Results: Overall, 16,634 (70%) out of 23,763 eligible individuals participated in the study. Test-retest reliability coefficients ranged from 0.72 to 0.87, and a Cronbach’s alpha of 0.83 indicates good internal consistency. Results show a moderate to good correlation between sleep disturbances and health perception, and between sleep disturbances and overall pain. Conclusions: The Sleep Standard Evaluation Questionnaire (SEQ-Sleep) is a reliable and short tool with confirmed construct validity for sleep assessment in population-based observational studies. It is easy to administer and therefore suitable for postal surveys of the general population. Criterion validity remains to be determined