Definition of Naturally Processed Peptides Reveals Convergent Presentation of Autoantigenic Topoisomerase I Epitopes in Scleroderma.

ObjectiveAutoimmune responses to DNA topoisomerase I (topo I) are found in a subset of scleroderma patients who are at high risk for interstitial lung disease (ILD) and mortality. Anti-topo I antibodies (ATAs) are associated with specific HLA-DRB1 alleles, and the frequency of HLA-DR-restricted topo I-specific CD4+ T cells is associated with the presence, severity, and progression of ILD. Although this strongly implicates the presentation of topo I peptides by HLA-DR in scleroderma pathogenesis, the processing and presentation of topo I has not been studied.MethodsWe developed a natural antigen processing assay (NAPA) to identify putative CD4+ T cell epitopes of topo I presented by monocyte-derived dendritic cells (mo-DCs) from 6 ATA-positive patients with scleroderma. Mo-DCs were pulsed with topo I protein, HLA-DR-peptide complexes were isolated, and eluted peptides were analyzed by mass spectrometry. We then examined the ability of these naturally presented peptides to induce CD4+ T cell activation in 11 ATA-positive and 11 ATA-negative scleroderma patients.ResultsWe found that a common set of 10 topo I epitopes was presented by Mo-DCs from scleroderma patients with diverse HLA-DR variants. Sequence analysis revealed shared peptide-binding motifs within the HLA-DRβ chains of ATA-positive patients and a subset of topo I epitopes with distinct sets of anchor residues capable of binding to multiple different HLA-DR variants. The NAPA-derived epitopes elicited robust CD4+ T cell responses in 73% of ATA-positive patients (8 of 11), and the number of epitopes recognized correlated with ILD severity (P = 0.025).ConclusionThese findings mechanistically implicate the presentation of a convergent set of topo I epitopes in the development of scleroderma

Caracterização dos graus de fragilidades em estados geoecológicos da Unidade de Gerenciamento de Recursos Hídricos do Pontal do Paranapanema (SP, Brasil)

The Oeste Paulista, the second most degraded region in the State of São Paulo, has, in the Water Resources Management Unit - UGRHI 22 / Pontal do Paranapanema, the largest representation of the environmental damage that occurred in recent years in this portion of the state. The present paper aims to characterize the environmental units, potentialities and physical fragilities, throughout the integrated and systematic analysis of the natural components of the hydrographic basin that composes UGRHI 22. Therefore, the study in question brings as its theoretical and conceptual basis the Landscape Geoecology theory, which establishes that the relationships and interrelations between the components of the physical environment make possible to reflex and understand its dynamics. Thus, in order to achieve the objectives of this work, we initially conduct a survey of the regional natural components, such as Geology, Pedology, Geomorphology, and others, which resulted in the elaboration of thematic maps that enabled the identification of the characteristics of the elements of the landscape. We assigned weights from one to five for the landscape’s components, in which the lowest corresponds to a stabilized landscape - and the highest to a degraded landscape -, in order to identify the fragility according to its physical characteristics. Then, from the overlapping of the maps produced from these weights, their arithmetic averages were calculated. The results display a definition of the degrees attributed to each of the features and an arrangement of a synthesis map of the geoecological state, which contributes to the planning of UGHR-22’s anthropogenic activities.O Oeste Paulista, a segunda região mais degradada do Estado de São Paulo, tem na Unidade de Gerenciamento de Recursos Hídricos – UGRHI 22 / Pontal do Paranapanema a maior representação dos danos ao meio ambiente ocorridos nos últimos anos, nesta porção do estado. O presente trabalho tem por objetivo caracterizar as unidades ambientais, potencialidades e fragilidades físicas da bacia hidrográfica que compõe a UGRHI 22 por meio da análise integrada e sistêmica dos seus componentes naturais. Nesse sentido, o estudo em questão traz como embasamento teórico e conceitual a teoria da Geoecologia da Paisagem, a qual estabelece que as relações e inter-relações entre os componentes do meio físico possibilitam a reflexão e a compreensão de sua dinâmica. Assim, para a concretização dos objetivos do trabalho, inicialmente, realizou-se o levantamento dos componentes naturais da região, tais como a Geologia, Pedologia, Geomorfologia, dentre outros, o que resultou na elaboração de mapas temáticos que possibilitaram a identificação das características dos elementos da paisagem. Aos componentes atribuiu-se peso de um a cinco, no qual o mais baixo corresponde a uma paisagem estabilizada – e o mais alto a uma paisagem degradada –, tendo vista a identificação da fragilidade segundo suas características físicas Em seguida, a partir da sobreposição dos mapas produzidos a partir desses pesos, calcularam-se suas médias aritmé- ticas. Os resultados apresentam uma definição dos graus atribuídos a cada uma das feições e uma apresentação de um mapa síntese do estado geoecológico, que contribui para o planejamento das atividades antrópicas da UGHR – 22

Residual Lattice Strain and Phase Distribution in Ti 6Al 4V Produced by Electron Beam Melting

Residual stress strain and microstructure used in additively manufactured material are strongly dependent on process parameter combination. With the aim to better understand and correlate process parameters used in electron beam melting EBM of Ti 6Al 4V with resulting phase distributions and residual stress strains, extensive experimental work has been performed. A large number of polycrystalline Ti 6Al 4V specimens were produced with different optimized EBM process parameter combinations. These specimens were post sequentially studied by using high energy X ray and neutron diffraction. In addition, visible light microscopy, scanning electron microscopy SEM and electron backscattered diffraction EBSD studies were performed and linked to the other findings. Results show that the influence of scan speed and offset focus on resulting residual strain in a fully dense sample was not significant. In contrast to some previous literature, a uniform and Ti phase distribution was found in all investigated specimens. Furthermore, no strong strain variations along the build direction with respect to the deposition were found. The magnitude of strain in and phase show some variations both in the build plane and along the build direction, which seemed to correlate with the size of the primary grains. However, no relation was found between measured residual strains in and phase. Large primary grains and texture appear to have a strong effect on X ray based stress results with relatively small beam size, therefore it is suggested to use a large beam for representative bulk measurements and also to consider the prior grain size in experimental planning, as well as for mathematical modellin

Blaming Active Volcanoes or Active Volcanic Blame? Volcanic Crisis Communication and Blame Management in the Cameroon

This chapter examines the key role of blame management and avoidance in crisis communication with particular reference to developing countries and areas that frequently experience volcanic episodes and disasters. In these contexts, the chapter explores a key paradox prevalent within crisis communication and blame management concepts that has been rarely tested in empirical terms (see De Vries 2004; Brändström 2016a). In particular, the chapter examines, what it calls, the ‘paradox of frequency’ where frequency of disasters leads to twin dispositions for crisis framed as either: (i) policy failure (active about volcanic blame on others), where issues of blame for internal incompetency takes centre stage, and blame management becomes a focus of disaster managers, and/or: (ii) as event failure (in this case, the blaming of lack of external capacity on active volcanoes and thereby the blame avoidance of disaster managers). Put simply, the authors investigate whether perceptions of frequency itself is a major determinant shaping the existence, operation, and even perceived success of crisis communication in developing regions, and countries experiencing regular disaster episodes. The authors argue frequency is important in shaping the behaviour of disaster managers and rather ironically as part of crisis communication can shape expectations of community resilience and (non)-compliance. In order to explore the implications of the ‘paradox of frequency’ further, the chapter examines the case of the Cameroon, where volcanic activity and events have been regular, paying particular attention to the major disasters in 1986 (Lake Nyos Disaster - LND) and 1999 (Mount Cameroon volcanic eruption - MCE)

Role of cellular senescence and NOX4-mediated oxidative stress in systemic sclerosis pathogenesis.

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by progressive fibrosis of skin and numerous internal organs and a severe fibroproliferative vasculopathy resulting frequently in severe disability and high mortality. Although the etiology of SSc is unknown and the detailed mechanisms responsible for the fibrotic process have not been fully elucidated, one important observation from a large US population study was the demonstration of a late onset of SSc with a peak incidence between 45 and 54 years of age in African-American females and between 65 and 74 years of age in white females. Although it is not appropriate to consider SSc as a disease of aging, the possibility that senescence changes in the cellular elements involved in its pathogenesis may play a role has not been thoroughly examined. The process of cellular senescence is extremely complex, and the mechanisms, molecular events, and signaling pathways involved have not been fully elucidated; however, there is strong evidence to support the concept that oxidative stress caused by the excessive generation of reactive oxygen species may be one important mechanism involved. On the other hand, numerous studies have implicated oxidative stress in SSc pathogenesis, thus, suggesting a plausible mechanism in which excessive oxidative stress induces cellular senescence and that the molecular events associated with this complex process play an important role in the fibrotic and fibroproliferative vasculopathy characteristic of SSc. Here, recent studies examining the role of cellular senescence and of oxidative stress in SSc pathogenesis will be reviewed

Making a Step Forward Towards Urban Resilience. The Contribution of Digital Innovation

Starting from 'wicked problem' theory as the landmark for framing disaster events in terms of policy issue for city governments, this paper highlights the contribution provided by Big Data analytics and digital innovation in dealing with disaster risks. The research aims at answering the following question: what is the role that 'smart technologies' play in strengthening urban resilience to disaster risks

Histopathological cutaneous alterations in systemic sclerosis: a clinicopathological study

Introduction: The aims of the present study were to identify histopathological parameters which are linked to local clinical skin disease at two distinct anatomical sites in systemic sclerosis (SSc) patients with skin involvement (limited cutaneous systemic sclerosis (lcSSc) or diffuse cutaneous systemic sclerosis (dcSSc)) and to determine the sensitivity of SSc specific histological alterations, focusing on SSc patients without clinical skin involvement (limited SSc (lSSc)). Methods: Histopathological alterations were systematically scored in skin biopsies of 53 consecutive SSc patients (dorsal forearm and upper inner arm) and 18 controls (upper inner arm). Clinical skin involvement was evaluated using the modified Rodnan skin score. In patients with lcSSc or dcSSc, associations of histopathological parameters with local clinical skin involvement were determined by generalised estimation equation modelling. Results: The hyalinised collagen score, the myofibroblast score, the mean epidermal thickness, the mononuclear cellular infiltration and the frequency of focal exocytosis differed significantly between biopsies with and without local clinical skin involvement. Except for mononuclear cellular infiltration, all of the continuous parameters correlated with the local clinical skin score at the dorsal forearm. Parakeratosis, myofibroblasts and intima proliferation were present in a minority of the SSc biopsies, but not in controls. No differences were found between lSSc and controls. Conclusions: Several histopathological parameters are linked to local clinical skin disease. SSc-specific histological alterations have a low diagnostic sensitivity

Patient-reported outcome instruments for assessing Raynaud’s phenomenon in systemic sclerosis: A SCTC vascular working group report

The episodic nature of Raynaud’s phenomenon in systemic sclerosis has led to a reliance on patient-reported outcome instruments such as the Raynaud’s Condition Score diary. Little is known about the utilization in routine clinical practice and health professional attitudes toward existing patient-reported outcome instruments for assessing systemic sclerosis- Raynaud’s phenomenon. Members of the Scleroderma Clinical Trials Consortium Vascular Working Group (n = 28) were invited to participate in a survey gauging attitudes toward the Raynaud’s Condition Score diary and the perceived need for novel patient-reported outcome instruments for assessing patient-reported outcome. Nineteen Scleroderma Clinical Trials Consortium Vascular Working Group members (68% response rate) from academic units based in North America (n = 9), Europe (n = 8), South America (n = 1) and Australasia (n = 1) took part in the survey. There was broad consensus that Raynaud’s Condition Score diary returns could be influenced by factors including seasonal variation in weather, efforts made by patients to avoid or ameliorate attacks of Raynaud’s phenomenon, habituation to Raynaud’s phenomenon symptoms, evolution of Raynaud’s phenomenon symptom characteristics with progressive obliterative microangiopathy, patient-coping strategies, respondent burden and placebo effect. There was consensus that limitations of the Raynaud’s Condition Score diary might be a barrier to drug development (79% of respondents agree/strongly agree) and that a novel patient-reported outcome instrument for assessing systemic sclerosis-Raynaud’s phenomenon should be developed with the input of both clinicians and patients (84% agree/strongly agree). Perceived potential limitations of the Raynaud’s Condition Score diary have been identified along with concerns that such factors might impede drug development programs for systemic sclerosis-Raynaud’s phenomenon. There is support within the systemic sclerosis community for the development of a novel patient-reported outcome instrument for assessing systemic sclerosis-Raynaud’s phenomenon