Functional Inactivation of Drosophila GCK Orthologs Causes Genomic Instability and Oxidative Stress in a Fly Model of MODY-2

Maturity-onset diabetes of the young (MODY) type 2 is caused by heterozygous inactivating mutations in the gene encoding glucokinase (GCK), a pivotal enzyme for glucose homeostasis. In the pancreas GCK regulates insulin secretion, while in the liver it promotes glucose utilization and storage. We showed that silencing the Drosophila GCK orthologs Hex-A and Hex-C results in a MODY-2-like hyperglycemia. Targeted knock-down revealed that Hex-A is expressed in insulin producing cells (IPCs) whereas Hex-C is specifically expressed in the fat body. We showed that Hex-A is essential for insulin secretion and it is required for Hex-C expression. Reduced levels of either Hex-A or Hex-C resulted in chromosome aberrations (CABs), together with an increased production of advanced glycation end-products (AGEs) and reactive oxygen species (ROS). This result suggests that CABs, in GCK depleted cells, are likely due to hyperglycemia, which produces oxidative stress through AGE metabolism. In agreement with this hypothesis, treating GCK-depleted larvae with the antioxidant vitamin B6 rescued CABs, whereas the treatment with a B6 inhibitor enhanced genomic instability. Although MODY-2 rarely produces complications, our data revealed the possibility that MODY-2 impacts genome integrity.     

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.     

Advances on methane steam reforming to produce hydrogen through membrane reactors technology: A review

Methane steam reforming is the most common industrial process used for almost the 50% of the world’s hydrogen production. Commonly, this reaction is performed in fixed bed reactors and several stages are needed for separating hydrogen with the desired purity. The membrane reactors represent a valid alternative to the fixed bed reactors, by combining the reforming reaction for producing hydrogen and its separation in only one stage. This article deals with the recent progress on methane steam reforming reaction, giving a short overview on catalysts utilization as well as on the fundamentals of membrane reactors, also summarizing the relevant advancements in this field.     

A Modular Composite Device of Poly(Ethylene Oxide)/Poly(Butylene Terephthalate) (PEOT/PBT) Nanofibers and Gelatin as a Dual Drug Delivery System for Local Therapy of Soft Tissue Tumors

In the clinical management of solid tumors, the possibility to successfully couple the regeneration of injured tissues with the elimination of residual tumor cells left after surgery could open doors to new therapeutic strategies. In this work, we present a composite hydrogel–electrospun nanofiber scaffold, showing a modular architecture for the delivery of two pharmaceutics with distinct release profiles, that is potentially suitable for local therapy and post-surgical treatment of solid soft tumors. The composite was obtained by coupling gelatin hydrogels to poly(ethylene oxide)/poly(butylene terephthalate) block copolymer nanofibers. Results of the scaffolds’ characterization, together with the analysis of gelatin and drug release kinetics, displayed the possibility to modulate the device architecture to control the release kinetics of the drugs, also providing evidence of their activity. In vitro analyses were also performed using a human epithelioid sarcoma cell line. Furthermore, publicly available expression datasets were interrogated. Confocal imaging showcased the nontoxicity of these devices in vitro. ELISA assays confirmed a modulation of IL-10 inflammation-related cytokine supporting the role of this device in tissue repair. In silico analysis confirmed the role of IL-10 in solid tumors including 262 patients affected by sarcoma as a negative prognostic marker for overall survival. In conclusion, the developed modular composite device may provide a key-enabling technology for the treatment of soft tissue sarcoma.