Complementary Effects of Carbamylated and Citrullinated LL37 in Autoimmunity and Inflammation in Systemic Lupus Erythematosus

LL37 acts as T-cell/B-cell autoantigen in Systemic lupus erythematosus (SLE) and psoriatic disease. Moreover, when bound to “self” nucleic acids, LL37 acts as “danger signal,” leading to type I interferon (IFN-I)/pro-inflammatory factors production. T-cell epitopes derived from citrullinated-LL37 act as better antigens than unmodified LL37 epitopes in SLE, at least in selected HLA-backgrounds, included the SLE-associated HLA-DRB1*1501/HLA-DRB5*0101 backgrounds. Remarkably, while “fully-citrullinated” LL37 acts as better T-cell-stimulator, it loses DNA-binding ability and the associated “adjuvant-like” properties. Since LL37 undergoes a further irreversible post-translational modification, carbamylation and antibodies to carbamylated self-proteins other than LL37 are present in SLE, here we addressed the involvement of carbamylated-LL37 in autoimmunity and inflammation in SLE. We detected carbamylated-LL37 in SLE-affected tissues. Most importantly, carbamylated-LL37-specific antibodies and CD4 T-cells circulate in SLE and both correlate with disease activity. In contrast to “fully citrullinated-LL37,” “fully carbamylated-LL37” maintains both innate and adaptive immune-cells’ stimulatory abilities: in complex with DNA, carbamylated-LL37 stimulates plasmacytoid dendritic cell IFN-α production and B-cell maturation into plasma cells. Thus, we report a further example of how different post-translational modifications of a self-antigen exert complementary effects that sustain autoimmunity and inflammation, respectively. These data also show that T/B-cell responses to carbamylated-LL37 represent novel SLE disease biomarkers.     

Mutual Prodrugs of 5-Fluorouracil: From a Classic Chemotherapeutic Agent to Novel Potential Anticancer Drugs

The development of potent antitumor agents with a low toxicological profile against healthy cells is still one of the greatest challenges facing medicinal chemistry. In this context, the “mutual prodrug” approach has emerged as a potential tool to overcome undesirable physicochemical features and mitigate the side effects of approved drugs. Among broad-spectrum chemotherapeutics available for clinical use today, 5-fluorouracil (5-FU) is one of the most representative, also included in the World Health Organization model list of essential medicines. Unfortunately, severe side effects and drug resistance phenomena are still the primary limits and drawbacks in its clinical use. This review describes the progress made over the last ten years in developing 5-FU-based mutual prodrugs to improve the therapeutic profile and achieve targeted delivery to cancer tissues.     

A universal design resource for rich Internet applications based on design patterns

Rich Internet applications have removed most of the constraints of Web 1.0 while giving users more responsiveness and advanced browsing and interaction experiences. These new horizons, however, raise many challenges for people with disabilities or using limited hardware and software technologies, whose risk to be excluded from the benefits deriving from advanced web applications. To address this problem, WCAG 2.0 guidelines have been released as the newest World Wide Web Consortium recommendation for accessible web content, and WAI-ARIA is a candidate recommendation which provides reference specifications for accessible rich Internet applications. However, both specifications contain a huge amount of information that often discourages most web designers from dealing with accessibility issues. Moreover, guidelines are suitable and usually adopted to judge a design solution a posteriori, but they do not suggest how to face a design problem constructively. This paper proposes a design pattern language for accessibility. The language can be regarded as a universal design resource for helping web designers create accessible rich Internet applications compliant with the most recent standards. Knowledge representation through design patterns reflects the problem-solving approach usually followed by software and web designers, while pattern organization in a structured language aims to guide web designers throughout the design process. The language has been implemented as an accessible rich Internet application itself, thus allowing designers with disabilities to participate in web design. In order to evaluate the design pattern language, a three-step process was carried out including: (1) a heuristic analysis with a group of human–computer interaction experts, (2) a survey study with a group of web designers, and (3) a validation on the field with two designers who have been requested to apply the language in real design cases.     

Aspects of nucleosomal positional flexibility and fluidity

Nucleosomes have been considered until recently to be stable and uniquely localized particles. We focus here on two properties of nucleosomes that are emerging as central attributes of their functions: mobility and multiplicity of localization. The biological relevance of these phenomena is based on the fact that chromatin functions depend on the relative stability of nucleosomes, on their covalent or conformational modifications, their dynamics, their localization, and the density of their distribution. In order to understand these complex behaviors both the structure of the nucleosome core particles and the informational rules governing their interaction with defined DNA sequences are here taken into consideration. The fact that nucleosomes solve the problem of how to locate a specific interaction site on a potentially infinite combination of sequences, with interactions recurring to a controlled level of informational ambiguity and stochasticity, is discussed. Nucleosomes have been shown to slide along DNA. This novel facet of their behavior and its implications in chromatin remodeling are reviewed.     

An analysis of XQuery benchmarks

This paper presents a survey and an analysis of the XQuery benchmark publicly available in 2006—XMach-1, XMark, X007, the Michigan benchmark, and XBench—from different perspectives. We address three simple questions about these benchmarks: How are they used? What do they measure? What can one learn from using them? One focus of our analysis is to determine whether the benchmarks can be used for micro-benchmarking. Our conclusions are based on an usage analysis, on an in-depth analysis of the benchmark queries, and on experiments run on four XQuery engines: Galax, SaxonB, Qizx/Open, and MonetDB/XQuery.     

Characterization of microdevices for ferrous chloride separation for biosensing applications

Ferrous chloride has a variety of applications such as a reducing flocculation agent in waste-water treatment, especially for wastes containing chromate, in the laboratory synthesis of iron complexes and it is employed as a reducing agent in many organic syntheses. The device used for experiment was fabricated on the silicon wafer as support for two electrodes in a SU8 polymer microchannel with an inlet, for the injection of aqueous solution of ferrous chloride, and two outlets, for the two by-products of separated solutions. The various parameters of the device were measured by White Light Interferometer (WLI) and Scanning Electron Microscopy (SEM). The magnetic field created by applying different types of potential between two electrodes determined ferrous chloride to separate in ferrous oxide and chlorine (in gaseous form). If a protein is added in this solution we have the possibility to immobilize the protein on the iron particles and on the channel area. The electrical results were collected using a semiconductor system analyzer Keithley and were examined subsequently. The Fe complexes deposited on the electrodes were characterized by XRD analyses.     

How did you first get into computing?

The route to a computing career is often circuitous. As part of the ongoing research on the history of women in computing, we conducted oral history interviews with pioneers in the field, during which we asked about their first encounters with computers. Although individual experiences varied, a common thread in these stories is that women's opportunities were constrained by gender stereotypes, outright discrimination, and the demands of marriage and family. At the same time, computing was a relatively welcoming field for women, and it offered them a rare chance to put their technical abilities to work. Women's first experiences with computers often led to a challenging, enjoyable, and financially rewarding career.     

Effect of the chemical structure of aromatic polyimides on their thermal aging,relaxation behavior and mechanical properties

This article examines the effects of structural changes and thermal aging treatments on the relaxation processes and mechanical properties of three polyimides differing for their molecular structure i.e. PMDA-ODA, 6FDA-ODA, and 6FDA-6FpDA. These polyimides were obtained by thermal imidization of their polyamic acid precursors, which were synthesized from the respective dianhydrides [pyromellitic anhydride (PMDA), hexahydrofluoroisopropylidene diphthalic anhydride (6FDA)], and diamines [4,4′-diaminodiphenyl ether (ODA), 4,4′-(hexafluoroisopropylidene) dianiline (6FpDA)]. After the curing process, the polyimides were thermally aged at a fixed temperature for various times Dynamic mechanical measurements performed in a multi-frequency mode, were used to determine the glass-rubber and sub-glass transitions, as well as the activation energy of the β transition. It was found that the T _g decreased in the order PMDA-ODA > 6FDA-6FpDA > 6FDA-ODA as a result of an increased chain rigidity and molecular packing induced by charge transfer interactions during the thermal imidization process. The β sub-glass transition showed two relaxation processes identified as β′ and β′′. The β′ process was attributed to the local motion of the diamine constituents while the β′′ process was caused by the local motion of the dianhydride moiety. The cooperativity of these molecular motions was also assessed via the Starkweather method. The thermal aging enhanced the state of aggregation of polyimide chains and thus the T _g and the sub-glass transition properties. This effect was particularly marked for the PMDA-ODA polyimide. Also the mechanical properties were significantly affected by chemical structure and aging treatments. For non-aged samples the more influenced parameter was the elongation at break, which decreased in the order PMDA-ODA > 6FDA-ODA > 6FDA-6FpDA. The aging enhanced the elastic modulus and the tensile strength and reduced the elongation at break.     

A smartphone-based fall detection system

Falls are a major cause of injuries and hospital admissions among elderly people. Thus, the caregiving process and the quality of life of older adults can be improved by adopting systems for the automatic detection of falls. This paper presents a smartphone-based fall detection system that monitors the movements of patients, recognizes a fall, and automatically sends a request for help to the caregivers. To reduce the problem of false alarms, the system includes novel techniques for the recognition of those activities of daily living that could be erroneously mis-detected as falls (such as sitting on a sofa or lying on a bed). To limit the intrusiveness of the system, a small external sensing unit can also be used for the acquisition of movement data.