Endogenous ADP-ribosylation of the G Protein β Subunit Prevents the Inhibition of Type 1 Adenylyl Cyclase

Mono-ADP-ribosylation is a post-translational modification of cellular proteins that has been implicated in the regulation of signal transduction, muscle cell differentiation, protein trafficking, and secretion. In several cell systems we have observed that the major substrate of endogenous mono-ADP-ribosylation is a 36-kDa protein. This ADP-ribosylated protein was both recognized in Western blotting experiments and selectively immunoprecipitated by a G protein beta subunit-specific polyclonal antibody, indicating that this protein is the G protein beta subunit. The ADP-ribosylation of the beta subunit was due to a plasma membrane-associated enzyme, was sensitive to treatment with hydroxylamine, and was inhibited by meta-iodobenzylguanidine, indicating that the involved enzyme is an arginine-specific mono-ADP-ribosyltransferase. By mutational analysis, the target arginine was located in position 129. The ADP-ribosylated beta subunit was also deribosylated by a cytosolic hydrolase. This ADP-ribosylation/deribosylation cycle might be an in vivo modulator of the interaction of betagamma with specific effectors. Indeed, we found that the ADP-ribosylated betagamma subunit is unable to inhibit calmodulin-stimulated type 1 adenylyl cyclase in cell membranes and that the endogenous ADP-ribosylation of the beta subunit occurs in intact Chinese hamster ovary cells, where the NAD(+) pool was labeled with [(3)H]adenine. These results show that the ADP-ribosylation of the betagamma subunit could represent a novel cellular mechanism in the regulation of G protein-mediated signal transduction

Infections in Thalassemia and Hemoglobinopathies: Focus on Therapy-Related Complications

The clinical approach to thalassemia and hemoglobinopathies, specifically Sickle Cell Disease (SCD), based on transfusions, iron chelation and bone marrow transplantation has ameliorated their prognosis. Nevertheless, infections still may cause serious complications in these patients. The susceptibility to infections in thalassemia and SCD arises both from a large spectrum of immunological abnormalities and from exposure to specific infectious agents. Four fundamental issues will be focused upon as central causes of immune dysfunction: the diseases themselves; iron overload, transfusion therapy and the role of the spleen. Thalassemia and SCD differ in their pathogenesis and clinical course. It will be outlined how these differences affect immune dysfunction, the risk of infections and the types of most frequent infections in each disease. Moreover, since transfusions are a fundamental tool for treating these patients, their safety is paramount in reducing the risks of infections. In recent years, careful surveillance worldwide and improvements in laboratory tests reduced greatly transfusion transmitted infections, but the problem is not completely resolved. Finally, selected topics will be discussed regarding Parvovirus B19 and transfusion transmitted infections as well as the prevention of infectious risk postsplenectomy or in presence of functional asplenia

Pyridostigmine in pediatric Intestinal pseudo-obstruction. case report of a 2-year old girl and literature review

Pediatric chronic intestinal pseudo-obstruction is a rare disorder characterized by a severe impairment of gastrointestinal motility leading to intestinal obstruction symptoms in the absence of mechanical causes. The diagnosis is usually clinical and diagnostic work is usually aimed to rule out mechanical obstruction and to identify any underlying diseases. Treatment is challenging and requires a multidisciplinary effort. In this manuscript we describe the youngest child successfully treated with the orally administrable, longacting, reversible anti-cholinesterase drug, pyridostigmine. Like other drugs belonging to cholinesterase inhibitors, pyridostigmine enhances gut motility by increasing acetylcholine availability in the enteric nervous system and neuro-muscular junctions. Based on the direct evidence from the reported case, we reviewed the current literature on the use of pyridostigmine in severe pediatric dysmotility focusing on intestinal pseudo-obstruction. The overall data emerged from the few published studies suggest that pyridostigmine is an effective and usually well tolerated therapeutic options for patients with intestinal pseudo-obstruction. More specifically, the main results obtained by pyridostigmine included marked reduction of abdominal distension, reduced need of parenteral nutrition, and improvement of oral feeding. The present case and review on pyridostigmine pave the way for eagerly awaited future randomized controlled studies testing the efficacy of cholinesterase inhibitors in pediatric severe gut dysmotility

Giant follicular cysts extended in pterygo-maxillary fossa, antro-naso-ethmoidal and orbital space associated to exophtalmos and diplopia in young patients

Abstract Follicular cysts develop from the enamel epithelium of an un-erupted tooth. Two cases of extremely large and extended follicular cysts related to the upper impacted third molars in young patients and treatments are described. Case 1 Female, aged 16 with swelling of the right cheek and oral vestibule, right exophthalmos and diplopia. Spiral Computed Tomography (CT) showed a massive lesion occupying the maxillary sinus with extension into the pterygo-maxillary space, due to the destruction of the posterior antral bone wall. Above the lesion was compressing the orbital floor. Transantral surgical excision was performed approaching to the pterygo-maxillary space and orbital structure also using the operating microscope. 5-years follow-up shows good restoring of the involved structures without relapse. Case 2 - Female, aged 22, with swelling of the left cheek and oral vestibule, left nasal obstruction, orbital pain and diplopia. Spiral CT-MR integrated study allowed a very accurate analysis: the lesion occupied the entire maxillary sinus, the pterygo-maxillary space, the left nasal cavity, ethmoidal structures with posterior orbital compression. Transantral surgical excision was performed approaching to the pterygo-maxillary space; nasal-ethmoidal and orbital structures were approached by endoscopic technique. Follow-up shows good clinical, anatomical and functional conditions. Histological examination confirmed in both cases the diagnosis of follicular cyst. Giant follicular cysts require an accurate preoperative study due to the delicate structures that may be involved. In the reported cases, the operating microscope and endoscopic surgical procedures were needed in the delicate surgical steps to perform the detachment in deep areas

Novena alla S. Madre Teresa di Giesu ... divisa in nove mercoledi

Copia digital : Junta de Castilla y León. Consejería de Cultura y Turismo, 2014Sign.: A-D8, E4

Vita della serafica vergine S. Madre Teresa de Giesu : compendio descritta e novena alla medesima Santa

Copia digital. Valladolid : Junta de Castilla y León. Consejería de Cultura y Turismo, 2013Sign.: a4, A-Z8, 2A8.Front. calc

The role of organic and inorganic indoor pollutants in museum environments in the degradation of dammar varnish

This paper investigates the effects of inorganic (NO2 and O3) and volatile organic acid (acetic acid) pollutants on the degradation of dammar varnish in museum environments. Model paint varnish samples based on dammar resin were investigated by Gas Chromatography Mass Spectrometry (GC-MS), Dynamic Mechanical Analysis (DMA) and Atomic Force Microscopy (AFM). Dammar is a natural triterpenoid resin, commonly used as a paint varnish. Samples were subjected to accelerated ageing by different levels of pollutants (NO2 and O3 and acetic acid) over a range of relative humidities (RH) and then analysed. The results revealed that as the dose of the pollutant was increased, so did the degree of oxidation and cross-linking of the resin. Most interestingly, it was shown for the first time that exposure to acetic acid vapour resulted in the production of an oxidised and cross-linked resin, comparable to the resin obtained under exposure to NO2 and O3. These conclusions were supported by the analyses of model varnishes exposed for about two years in selected museum environments, where the levels of pollutants had been previously measured. Exposures were performed both within and outside the selected microclimate frames for paintings. Results showed that varnishes placed within the microclimate frames were not always better preserved than those exposed outside the frames. For some sites, the results highlighted the protective effects of the frames from outdoor generated pollutants, such as NO2 and O3. For other sites, the results showed that the microclimate frames acted as traps for the volatile organic acids emitted by the wooden components of the mc-frames, which damaged the varnish

Combining Real Time Classifiers for Fast and Reliable Electronic Nose Response Analysis for Aerospace NDTs

AbstractFast response and reliability are a prerogative in non- destructive tests s p e c i f i c a l l y in aerospace industry for safety and efficiency reasons. Currently, composite panels bonding, in green aircraft concept, is lacking a validated NDT technique for the bond quality. E-noses equipped with PARC algorithms appear a promising choice to acquire speedily a complete pattern response maximizing reliability. In this paper, combining real time classifiers, we show how to obtain a rapid first- hand response with the possibility of increasing accuracy awaiting for the end of the e-nose measurement cycle. A reject option is casted on the base of classifier self-perceived reliability to nullify false negatives while keeping the false positive rate at minimum

A MALDI-TOF MS approach for mammalian, human, and formula milks’ profiling

Human milk composition is dynamic, and substitute formulae are intended to mimic its protein content. The purpose of this study was to investigate the potentiality of matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS), followed by multivariate data analyses as a tool to analyze the peptide profiles of mammalian, human, and formula milks. Breast milk samples from women at different lactation stages (2 (n = 5), 30 (n = 6), 60 (n = 5), and 90 (n = 4) days postpartum), and milk from donkeys (n = 4), cows (n = 4), buffaloes (n = 7), goats (n = 4), ewes (n = 5), and camels (n = 2) were collected. Different brands (n = 4) of infant formulae were also analyzed. Protein content (<30 kDa) was analyzed by MS, and data were exported for statistical elaborations. The mass spectra for each milk closely clustered together, whereas different milk samples resulted in well-separated mass spectra. Human samples formed a cluster in which colostrum constituted a well-defined subcluster. None of the milk formulae correlated with animal or human milk, although they were specifically characterized and correlated well with each other. These findings propose MALDI-TOF MS milk profiling as an analytical tool to discriminate, in a blinded way, different milk types. As each formula has a distinct specificity, shifting a baby from one to another formula implies a specific proteomic exposure. These profiles may assist in milk proteomics for easiness of use and minimization of costs, suggesting that the MALDI-TOF MS pipelines may be useful for not only milk adulteration assessments but also for the characterization of banked milk specimens in pediatric clinical settings

Antitumoral efficacy of the protease inhibitor gabexate mesilate in colon cancer cells harbouring KRAS, BRAF and PIK3CA mutations

The employment of anti-epidermal growth factor receptor (EGFR) antibodies represents a backbone of the therapeutic options for the treatment of metastatic colorectal cancer (mCRC). However, this therapy is poorly effective or ineffective in unselected patients. Mutations in KRAS, BRAF and PIK3CA genes have recently emerged as the best predictive factors of low/absent response to EGFR-targeted therapy. Due to the need for efficacious treatment options for mCRC patients bearing these mutations, in this short report we examined the antitumoral activity of the protease inhibitor gabexate mesilate, alone and in combination with the anti-EGFR monoclonal antibody cetuximab, in a panel of human CRC cell lines harbouring a different expression pattern of wild-type/mutated KRAS, BRAF and PIK3CA genes. Results obtained showed that gabexate mesilate significantly inhibited the growth, invasive potential and tumour-induced angiogenesis in all the CRC cells employed in this study (including those ones harbouring dual KRAS/PIK3CA or BRAF/PIK3CA mutation), while cetuximab affected these parameters only in CRC cells with KRAS, BRAF and PIK3CA wild-type. Notably, the antitumoral efficacy of gabexate mesilate and cetuximab in combination was found to be not superior than that observed with gabexate mesilate as single agent. Overall, these preliminary findings suggest that gabexate mesilate could represent a promising therapeutic option for mCRC patients, particularly for those harbouring KRAS, BRAF and PIK3CA mutations, either as monotherapy or in addition to standard chemotherapy regimens. Further studies to better elucidate gabexate mesilate mechanism of action in CRC cells are therefore warranted