Interplay between Humoral and CLA+ T Cell Response against Candida albicans in Psoriasis

Candida albicans (CA) infections have been associated with psoriasis onset or disease flares. However, the integrated immune response against this fungus is still poorly characterized in psoriasis. We studied specific immunoglobulins in plasma and the CA response in cocultures of circulating memory CD45RA⁻ cutaneous lymphocyte antigen (CLA)^+/− T cell with autologous epidermal cells from plaque and guttate psoriasis patients (cohort 1, n = 52), and also healthy individuals (n = 17). A complete proteomic profile was also evaluated in plaque psoriasis patients (cohort 2, n = 114) regarding their anti-CA IgA levels. Increased anti-CA IgA and IgG levels are present in the plasma from plaque but not guttate psoriasis compared to healthy controls. CA cellular response is confined to CLA⁺ T cells and is primarily Th17. The levels of anti-CA IgA are directly associated with CLA⁺ Th17 response in plaque psoriasis. Proteomic analysis revealed distinct profiles in psoriasis patients with high anti-CA IgA. C-C motif chemokine ligand 18, chitinase-3-like protein 1 and azurocidin were significantly elevated in the plasma from plaque psoriasis patients with high anti-CA levels and severe disease. Our results indicate a mechanism by which Candida albicans exposure can trigger a clinically relevant IL-17 response in psoriasis. Assessing anti-CA IgA levels may be useful in order to evaluate chronic psoriasis patients.     

Amyloidogenic Properties of Peptides Derived from the VHL Tumor Suppressor Protein

The von Hippel-Lindau tumor suppressor protein (pVHL) is involved in maintaining cellular oxygen homeostasis through the regulated degradation of HIF-α. The intrinsically disordered nature of pVHL makes it prone to aggregation that impairs its function, and this is further aggravated in mutant versions of the protein, thus promoting tumor development. By using in silico analysis, we predicted six peptide fragments from pVHL to be amyloidogenic. This was verified for two of the peptides by biophysical approaches, which demonstrated self-assembly and formation of β-sheet-rich aggregates, which, under transmission electron microscopy, atomic force microscopy, and X-ray diffraction, displayed typical fibrillar amyloid characteristics. These motifs may serve as proxies for exploring the nature of pVHL aggregation.     

BRAF Gene and Melanoma: Back to the Future

As widely acknowledged, 40–50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E). The identification of the RAS–RAF–MEK–ERK (MAP kinase) signalling pathway and its targeting has represented a valuable milestone for the advanced and, more recently, for the completely resected stage III and IV melanoma therapy management. However, despite progress in BRAF-mutant melanoma treatment, the two different approaches approved so far for metastatic disease, immunotherapy and BRAF+MEK inhibitors, allow a 5-year survival of no more than 60%, and most patients relapse during treatment due to acquired mechanisms of resistance. Deep insight into BRAF gene biology is fundamental to describe the acquired resistance mechanisms (primary and secondary) and to understand the molecular pathways that are now being investigated in preclinical and clinical studies with the aim of improving outcomes in BRAF-mutant patients.     

Dual‐Action Cancer Therapy with Targeted Porous Silicon Nanovectors

There is a pressing need to develop more effective therapeutics to fight cancer. An idyllic chemotherapeutic is expected to overcome drug resistance of tumors and minimize harmful side effects to healthy tissues. Antibody‐functionalized porous silicon nanoparticles loaded with a combination of chemotherapy drug and gold nanoclusters (AuNCs) are developed. These nanocarriers are observed to selectively deliver both payloads, the chemotherapy drug and AuNCs, to human B cells. The accumulation of AuNCs to target cells and subsequent exposure to an external electromagnetic field in the microwave region render them more susceptible to the codelivered drug. This approach represents a targeted two‐stage delivery nanocarrier that benefits from a dual therapeutic action that results in enhanced cytotoxicity.     

Methods development for epidemiologic investigations of the health effects of prolonged ozone exposure. Part II. An approach to retrospective estimation of lifetime ozone exposure using a questionnaire and ambient monitoring data (California sites)

An extensive body of data supports a relation between acute exposures to ambient ozone and the occurrence of various acute respiratory symptoms and changes in measures of lung function. In contrast, relatively few data are available on the human health effects that result from long-term exposure to ambient ozone, Current efforts to study long-term ozone-related health effects are limited by the methods available for ascertaining lifetime exposures to ozone. The present feasibility study was undertaken as part of the Health Effects Institute's Environmental Epidemiology Planning Project (Health Effects Institute 1994) to (1) determine whether, in the context of an epidemiologic study, reliable estimates can be obtained for lifetime exposures to ozone by combining estimates from lifetime residential histories, typical activity patterns during life, and residence-specific ambient ozone monitoring data; (2) identify the minimum data required to produce reliable estimates of lifetime exposure; and (3) analyze the relations between various estimates of lifetime ozone exposure and measures of lung function. A convenience sample of 175 first-year students at the University of California, Berkeley, who lived all of their lives in selected areas of California (the Los Angeles Basin or the San Francisco Bay Area), were studied on two occasions (test and retest or test sessions 1 and 2), five to seven days apart. Residential and lifestyle data were obtained from a questionnaire: residence-based ambient ozone exposure values were assigned by interpolation of ambient ozone monitoring data to residential locations. Estimated lifetime exposure was based on average ozone levels between 10 a.m. and 6 p.m. and hours of exposure to ozone concentrations greater than 60 parts per billion (ppb). "Effective" lifetime exposure to ozone was based on a weighted average of estimated time spent in different ambient ozone environments as determined by different combinations of activity data. Pulmonary function was evaluated with flows and volumes from maximum expiratory flow-volume curves and slope of phase III of the single-breath nitrogen washout (SBNW) curves. Although the test-retest reliability of the residential history was acceptably high only for first and second residences, most of the unreliability for other residences came from residences occupied for relatively short durations. Therefore, the test-retest reliability of estimated lifetime exposure to ozone was high, with intraclass correlations greater than 0.90 for all approaches evaluated. Multiple, linear regression analyses showed a consistently negative relation between estimates of lifetime exposure to ozone and flows that reflect the physiology of pulmonary small airways. No relation was observed between lifetime ozone exposure and forced expiratory volume or the slope of phase III, and the relation between lifetime exposure and forced expiratory volume in one second was inconsistent. The results of the flow measures were unaffected by the method used to estimate lifetime exposure and gave effect estimates that were nearly identical. The data from this study indicate that useful and reproducible estimates of lifetime ozone exposure can be obtained in epidemiologic studies by using a residential history. However, the total burden of ozone to which the subjects were exposed cannot be determined accurately from such data. Nonetheless, the estimates so obtained appear to be associated with alterations in pulmonary function that are consistent with the predicted site of maximum effect of ozone in the human lung.     

Software Development Cultures and Cooperation Problems: A Field Study of the Early Stages of Development of Software for a Scientific Community

In earlier work, I identified a particular class of end-user developers, who include scientists and whom I term ‘professional end-user developers’, as being of especial interest. Here, I extend this work by articulating a culture of professional end-user development, and illustrating by means of a field-study how the influence of this culture causes cooperation problems in an inter-disciplinary team developing a software system for a scientific community. My analysis of the field study data is informed by some recent literature on multi-national work cultures. Whilst acknowledging that viewing a scientific development through a lens of software development culture does not give a full picture, I argue that it nonetheless provides deep insights.     

On Bounded Leg Shortest Paths Problems

Let V be a set of points in a d-dimensional l _p -metric space. Let s,t∈V and let L be a real number. An L-bounded leg path from s to t is an ordered set of points which connects s to t such that the leg between any two consecutive points in the set has length of at most L. The minimal path among all these paths is the L-bounded leg shortest path from s to t. In the s–t Bounded Leg Shortest Path (stBLSP) problem we are given two points s and t and a real number L, and are required to compute an L-bounded leg shortest path from s to t. In the All-Pairs Bounded Leg Shortest Path (apBLSP) problem we are required to build a data structure that, given any two query points from V and a real number L, outputs the length of the L-bounded leg shortest path (a distance query) or the path itself (a path query). In this paper we obtain the following results:     

Computing three-dimensional two-phase flows with a mass-conserving level set method

A method is described to compute three- dimensional two-phase flow, allowing large density ratios and coalescence and break-up of bubbles. The level set method is used to describe interfaces, and the volume-of-fluid method is used to ensure mass conservation. Efficiency in computing the interface dynamics is achieved by using a functional relation between the level set and volume-of-fluid functions. Difficulties and remedies in re-initialization of the level set function and inaccurate compution of surface tension are discussed. Test cases for validation are described, and demanding two-bubble computations to show the generality and the versatility of the method are presented.