Spitzer and Herschel Multiwavelength Characterization of the Dust Content of Evolved H II Regions

We have analyzed a uniform sample of 16 evolved H II regions located in a 2° × 2° Galactic field centered at (l,b) = (30°, 0°) and observed as part of the Herschel Hi-GAL survey. The evolutionary stage of these H II regions was established using ancillary radio-continuum data. By combining Hi-GAL PACS (70 μm, 160 μm) and SPIRE (250 μm, 350 μm, and 500 μm) measurements with MIPSGAL 24 μm data, we built spectral energy distributions of the sources and showed that a two-component gray-body model is a good representation of the data. In particular, wavelengths >70 μm appear to trace a cold dust component, for which we estimated an equilibrium temperature of the big grains (BGs) in the range 20-30 K, while for λ < 70 μm, the data indicate the presence of a warm dust component at temperatures of the order of 50-90 K. This analysis also revealed that dust is present in the interior of H II regions, although likely not in a large amount. In addition, the data seem to corroborate the hypothesis that the main mechanism responsible for the (partial) depletion of dust in H II regions is radiation-pressure-driven drift. In this framework, we speculated that the 24 μm emission that spatially correlates with ionized gas might be associated with either very small grain or BG replenishment, as recently proposed for the case of wind-blown bubbles. Finally, we found that evolved H II regions are characterized by distinctive far-IR and submillimeter colors, which can be used as diagnostics for their identification in unresolved Galactic and extragalactic regions

Elucidating the molecular mechanisms for lipoprotein processing and localisation of Factor H binding protein in Neisseria meningitidis

Neisseria meningitidis (Nm) is accountable for thousands of meningitis cases that lead to high mortality in children and young adults every year. Currently, as part of the efforts to combat this infectious disease caused by serogroup B strains, two vaccines have been licensed in recent years containing meningococcal lipoprotein Factor H binding protein (FHbp). Trumemba vaccine (Pfizer) has FHbp as its sole antigen and the Bexsero vaccine (GSK) has FHbp as one of four antigens in its vaccine formulation. The success of these vaccine formulations, in particular Trumemba, depends on sufficient surface display of FHbp in order to elicit protective serum antibody response. The expression level of FHbp varies between and within strains and the molecular mechanisms regulating this have been established. The aims of the work presented in this thesis were to elucidate the molecular mechanisms involved in the processing and surface localisation of FHbp, which is key for target recognition following immunisation with FHbp-based vaccines. Firstly, the generation of a transposon (Tn) library in strain MC58 enabled the discovery of the gene responsible for triacylation of FHbp in Nm. The impact of disruption of Lnt, which likely triacylates all other Nm lipoproteins was investigated and the data suggest the potential of Lnt as a novel drug target. Secondly, the identification of single nucleotide polymorphisms (SNPs) in the signal peptide (SP) of FHbp in strain L91543 led to the discovery of unprocessed FHbp on the cell surface and this finding was applicable to others Nm isolates. This has implications for current FHbp-based vaccines. In further detail in Chapter 3, the generation of a Tn library in strain MC58 is described. One mutant that lacked binding to the anti-FHbp monoclonal antibody (mAb) JAR4 was found to have been disrupted in the lnt gene. Experimental evidence was provided to support the predicted role of Lnt in acylating FHbp in Nm. In addition, data are shown that Lnt disruption affects FHbp expression at RNA and protein level suggesting a wider impact on the Nm cell than loss of ability to add the third fatty acid to FHbp. This chapter also presents data concerning the surface exposure of diacylated FHbp in the Lnt mutant which indicates a more flexible Lol machinery in the meningococcus than in E. coli, for which Lnt is essential. Due to the importance of lipoproteins for maintaining membrane integrity and likelihood of Lnt disruption affecting all Nm lipoproteins, it is speculated that the mutant would be significantly affected in membrane homeostasis. This is investigated in Chapter 4. RNAseq analysis of MC58Lnt reveals 183 genes to be DE, including genes encoding lipoproteins and genes related to RNA biology, and involved in adhesion and survival of the meningococcus. The biological impact of Lnt disruption is investigated in adhesion and invasion assays using of HCECs and HUVECs. While the mutant is shown to invade HCECs less, it invaded HUVECs more than when compared to the WT. HCECs and HUVECs also presented different pattern of expression of IL-6 and IL-8. HUVECs expressed more of these inflammatory proteins and this was suggested to be linked with higher invasion of MC58Lnt in this type of cells. Whereas survival and replication in THP-1 cells by the mutant was not affected, it displayed reduced ability to form biofilms on an abiotic surfaces and reduced virulence in the tested Galleria mellonella model. Importantly the disruption of Lnt leads to increased susceptibility of Nm to several antibiotics tested, supporting the potential of Lnt as a novel drug target. To further investigate molecular mechanisms that govern FHbp processing and surface localisation, the rest of the thesis is focused on the SP of FHbp. In Chapter 5, strain L91543 containing SP SNPs is taken for analysis. Site-directed mutagenesis (SDM) shows that these SNPs in the SP of FHbp are indeed responsible for processing and surface localisation. Specifically, a single SNP in the hydrophobic region of the SP, common to 88% of the UK isolates analysed (1742/1895), abolishes FHbp processing. This has important implications for Trumemba which consists of acylated FHbp. We show by FACS reduced display of FHbp in strains with SP SNPs and corresponding reduced susceptibility to killing by FHbp-specific antibodies in SBA assays

Self-assembled dextrin nanogel as protein carrier : controlled release and biological activity of IL-10

Interleukin-10 (IL-10) is an anti-inflammatory cytokine, which active form is a non-covalent homodimer. Given the potential of IL-10 for application in various medical conditions, it is essential to develop systems for its effective delivery. In previous work, it has been shown that a dextrin nanogel effectively incorporated and stabilized rIL10, enabling its release over time. In this work, the delivery system based on dextrin nanogels was further analyzed. The biocompatibility of the nanogel was comprehensively analyzed, through cytotoxicity (lactate dehydrogenase release, MTS, Live and Dead) and genotoxicity (comet) assays. The release profile of rIL-10 and its biological activity were evaluated in vivo, using C57BL/6 mice. Although able to maintain a stable concentration of IL-10 for at least 4 hours in mice serum, the amount of protein released was rather low. Despite this, the amount of rIL-10 released from the complex was biologically active inhibiting TNF-α production, in vivo, by LPSchallenged mice. In spite of the significant stabilization achieved using the nanogel, rIL-10 still denatures rather quickly. An additional effort is thus necessary to develop an effective delivery system for this cytokine, able to release active protein over longer periods of time. Nevertheless, the good biocompatibility, the protein stabilization effect and the ability to perform as a carrier with controlled release suggest that self-assembled dextrin nanogels may be useful protein delivery systems.Contract grant sponsor: Fundacao para a Ciencia e Tecnologia (FCT), PortugalContract grant number: SFRH/BD/27359/2006Contract grant sponsor: FCTContract grant number: PTDC/BIO/67160/2006; SUDOE-FEDERIMMUNONETSOE1/P1/E01

Brazilian Pediatric Reference Data For Quantitative Ultrasound Of Phalanges According To Gender, Age, Height And Weight

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Aims To establish normative data for phalangeal quantitative ultrasound (QUS) measures in Brazilian students. Methods The sample was composed of 6870 students (3688 females and 3182 males), aged 6 to 17 years. The bone status parameter, Amplitude Dependent Speed of Sound (AD-SoS) was assessed by QUS of the phalanges using DBM Sonic BP (IGEA, Carpi, Italy) equipment. Skin color was obtained by self-evaluation. The LMS method was used to derive smoothed percentiles reference charts for AD-SoS according to sex, age, height and weight and to generate the L, M, and S parameters. Results Girls showed higher AD-SoS values than boys in the age groups 7-16 (p<0.001). There were no differences on AD-SoS Z-scores according to skin color. In both sexes, the obese group showed lower values of AD-SoS Z-scores compared with subjects classified as thin or normal weight. Age (r(2) = 0.48) and height (r(2) = 0.35) were independent predictors of AD-SoS in females and males, respectively. Conclusion AD-SoS values in Brazilian children and adolescents were influenced by sex, age and weight status, but not by skin color. Our normative data could be used for monitoring AD-SoS in children or adolescents aged 6-17 years.106Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESP [2006/01978-0, 2011/23460-1, 2002/13021-1, 2012/16778-8

A case of paracoccidioidomycosis due to Paracoccidioides lutzii presenting sarcoid-like form

Paracoccidioidomycosis (PCM) is a fungal disease caused by Paracoccidioides spp., which can cause a systemic granulomatous infection with tegumentary and visceral involvement. Sarcoid-like skin lesions are uncommon and can be misdiagnosed due to similarities with other granulomatous diseases. We report a case of a women presenting with erythematous infiltrated plaques on her face that was treated for leprosy and rosacea with no response and was later diagnosed with PCM, presenting positive serology for Paracoccidioides lutzii.Univ Fed Espirito Santo, Med Sch, BR-29043900 Vitoria, Espirito Santo, BrazilUniv Fed Espirito Santo, Div Infect Dis, BR-29043900 Vitoria, Espirito Santo, BrazilUniv Fed Espirito Santo, Odontol Clin, BR-29043900 Vitoria, Espirito Santo, BrazilUniv Fed Espirito Santo, Dept Pathol, BR-29043900 Vitoria, Espirito Santo, BrazilUniv Fed Sao Paulo UNIFESP, Dept Microbiol Immunol & Parasitol, BR-04021001 Sao Paulo, BrazilUniv Fed Sao Paulo UNIFESP, Dept Microbiol Immunol & Parasitol, BR-04021001 Sao Paulo, BrazilWeb of Scienc

Charge-transfer metal-insulator transitions in the spin-one-half Falicov-Kimball model

The spin-one-half Falicov-Kimball model is solved exactly on an infinite-coordination-number Bethe lattice in the thermodynamic limit. This model is a paradigm for a charge-transfer metal-insulator transition where the occupancy of localized and delocalized electronic orbitals rapidly changes at the metal-insulator transition (rather than the character of the electronic states changing from insulating to metallic as in a Mott-Hubbard transition). The exact solution displays both continuous and discontinuous (first-order) transitions.Comment: 22 pages including 4 figures(eps), RevTe

Local Star formation triggered by SN shocks in magnetized diffuse neutral clouds

In this work, considering the impact of a SNR with a neutral magnetized cloud we derived analytically a set of conditions which are favorable for driving gravitational instability in the cloud and thus star formation. We have built diagrams of the SNR radius, versus the cloud density, that constrain a domain in the parameter space where star formation is allowed. The diagrams are also tested with fully 3-D MHD simulations involving a SNR and a self-gravitating cloud and we find that the numerical analysis is consistent with the results predicted by the diagrams. While the inclusion of a homogeneous magnetic field approximately perpendicular to the impact velocity of the SNR with an intensity ~1 $mu$G results only a small shrinking of the star formation triggering zone in the diagrams, a larger magnetic field (~10 $mu$G) causes a significant shrinking, as expected. Applications of the diagrams to a few regions of our own galaxy have revealed that star formation in those sites could have been triggered by shock waves from SNRs. Finally, we have evaluated the effective star formation efficiency for this sort of interaction and found that it is smaller than the observed values in our own Galaxy (sfe ~0.01-0.3). This result is consistent with previous work in the literature and also suggests that the mechanism presently investigated, though very powerful to drive structure formation, supersonic turbulence and eventually, local star formation, does not seem to be sufficient to drive global star formation in normal star forming galaxies, not even when the magnetic field in the neutral clouds is neglected. (abridged)Comment: 19 pages, 13 figures, accepted for pubblication in MNRA

Covalently binding atomically designed Au9 clusters to chemically modified graphene

Atomic resolution transmission electron microscopy was used to identify individual Au9 clusters on a sulfur functionalized graphene surface. The clusters were pre-formed in solution and covalently attached to the surface without any dispersion or aggregation. Comparison of the experimental images with simulations allowed the rotational motion of individual clusters to be discerned, without lateral displacement, demonstrating a robust covalent attachment of intact clusters to the graphene surface

Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs\u27 therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy