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The dispute over the paternity of western paper is a longstanding problem. In Italy, a country that has a long tradition of papermaking, many cities compete for the leadership in the production of this material; on the other hand, several studies attribute to Fabriano (13th century), a little center in Marche region, the birth of modern paper and its diffusion throughout Europe. During the 14thcentury, the nearby town of Camerino imposed itself on the paper market, triggering a historic rivalry with the manufacture of Fabriano. As scientific studies on these different productions are missing, a comparative, multidisciplinary investigation has been carried out to characterize a set of thirteenth-fifteenth century handmade papers from Camerino-Fabriano area. Several analytical techniques–some non-invasive such as Fourier-transform infrared spectroscopy (FTIR) and portable magnetic resonance (unilateral NMR), joined to micro-destructive ones such as scanning electron microscopy (SEM), 13C CPMAS NMR spectroscopy, thermo-gravimetric analysis (TGA), sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and reverse-phase liquid chromatography (RP-HPLC)–have been employed in order to study the morphology of the paper documents, to identify the substances used in production process and to define their preservation state. Moreover principal component analysis (PCA) has been applied to the spectroscopic data, allowing the clustering of Fabriano documents with respect to Camerino ones and dividing the samples in two sets. This work improves and confirms knowledges on paper production in Marche region, and the experimental data collected highlight similarities and differences between Camerino and Fabriano manufactures.

The roles of mesophilic lactobacilli in cheese manufacturing and ripening have been widely studied, but their impacts, especially as additives in preserving liquids, on the high-moisture mozzarella cheese quality parameters remained underexplored. The current study studied and compared the effects of four preserving liquid formulations - brine solution (sodium chloride, as control), a salt mixture solution, and two lactobacilli solutions (Lactiplantibacillus plantarum IMC 509 in brine solution) or SYNBIO® (a 1:1 ratio of Lacticaseibacillus rhamnosus IMC 501 and Lacticaseibacillus paracasei IMC 502) - on the microbial, chemical (volatile fatty acids), physicochemical (moisture, weight, pH, colour), texture (adhesiveness, hardness, cohesiveness, gumminess, springiness, chewiness) and sensorial qualities of mozzarella stored for 30 days at 4 °C. The quality of the governing solution, including microbial content, lactobacilli viability, pH, turbidity, and smell, was also monitored. For the first 10 days of storage, all samples demonstrated similar physicochemical variations: the firmness and chewiness of the mozzarella lessened, the pH values of the liquid decreased, but cheese microbial growth increased, as did the levels of free fatty acids, the mozzarella pH values and skin whiteness. At day 20, mozzarella stored in mesophilic lactobacilli liquid, especially SYNBIO®, had a spongy structure, tasted more bitter and sour, and had lower pH values than mozzarella in the simple brine solution. Moreover, the cheese sample and liquid of SYNBIO® also presented higher coliform and Pseudomonas spp. counts than that detected in the control, the SYNBIO® liquid, especially in the later period of storage, exhibited a yogurt smell and increased turbidity. By contrast, Mozzarella packed into salt mixture liquid exhibited somewhat more adhesiveness and gumminess, a saltier taste and slightly higher microbial counts than the control sample. The mozzarella samples differed slightly in colour and texture as well. The overall quality changes suggested that the use of the studied mesophilic lactobacilli as governing liquid additives may not be appropriate for high-moisture mozzarella cheese preservation.

In this work, the profile of the volatile compounds has been determined for the first time in fresh donkey milk and in donkey milk subjected to accelerated shelf-life test, freeze-drying and spray-drying processes. The effects of freeze-drying and spray-drying processes in donkey milk have been analyzed also on three representative whey proteins, β-lactoglobulin, α-lactalbumin and lysozyme, by determining the total amount, the enzymatic activity and the thermal stability. Considering the volatile compounds in fresh donkey milk, 2-heptanone, 1,3-bis (1,1-dimethylethyl)-benzene, nonanal, d -limonene, octanoic acid, and 1-octanol were detected. The accelerated shelf-life test revealed a constant increase of octanoic acid, 2-heptanone, and nonanal compared to fresh donkey milk (P

The effects of slaughter age (8 vs 12 months) were investigated on meat and carcass quality obtained from Martina Franca donkey foals. Sixteen male foals were used, eight were slaughtered at 8 months of age with a mean (±s.e.) final body weight of 101±18kg and the remaining 8 foals slaughtered at 12 months of age with a mean final body weight of 122±13kg. Carcass weight and dressing percentage were higher (P

Basal-like breast cancer (BLBC) remains a great challenge because of its clinically aggressive nature and lack of effective targeted therapy. We analyzed the potential anti-neoplastic effects of sanguinarine, a natural benzophenanthridine alkaloid, against BLBC cells. Sanguinarine treatment resulted in a reduction of cell migration, in a dose-dependent inhibition of cell viability and in the induction of cell death by apoptosis in both human (MDA-MB-231 cells) and mouse (A17 cells) in vitro models of BLBC. In vivo experiments demonstrated that oral administration of sanguinarine reduced the development and growth of A17 transplantable tumors in FVB syngeneic mice. Western blotting analysis revealed that suppression of BLBC growth by sanguinarine was correlated with a concurrent upregulation of p27 and downregulation of cyclin D1 and with the inhibition of STAT3 activation. In addition, we identified sanguinarine as a potent inhibitor of dihydrofolate reductase (DHFR), able to impair enzyme activity even in methotrexate resistant MDA-MB-231 cells. These results provide evidence that sanguinarine is a promising anticancer drug for the treatment of BLBC.

Human cytidine deaminase is an enzyme of the pyrimidine salvage pathways that metabolizes several cytosine nucleoside analogs used as prodrugs in chemotherapy. We carried out a characterization of the cytidine deaminase 79A>C and 208G>A Single Nucleotide Polymorphisms, in order to highlight their functional role and provide data that could help fine-tune the chemotherapic use of cytosine nucleosides in patients carrying the above mentioned SNPs. The 79A>C SNP results in a K27Q change in a protein region not involved in the catalytic event. The 208G>A SNP produces an alanine to threonine substitution (A70T) within the conserved catalytic domain. Q27 variant is endowed with a greater catalytic efficiency toward the natural substrates and the antileukemic agent cytarabine (Ara-C), when compared to K27 variant. Molecular modeling, protein stability experiments and site-directed mutagenesis suggest that K27 variant may have an increased stability with respect to Q27 due to an ionic interaction between a lysine residue at position 27 and a glutamate residue at position 24. The T70 variant has a lower catalytic efficiency toward the analyzed substrates when compared to the A70 variant, suggesting that patients carrying the 208G>A SNP may have a greater exposure to cytosine based pro drugs, with possible toxicity consequences.

CD38 (EC 3.2.2.6, NAD(+)-glycohydrolase) is a multifunctional enzyme catalyzing the synthesis and hydrolysis of cyclic ADP-ribose from NAD(+) to ADP-ribose. The loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications. Notably, it has been linked to HIV infection, leukemias, myelomas, solid tumors, Type II Diabetes mellitus, bone metabolism, as well as Autism Spectrum Disorder. Taking into account the crucial role played by CD38 in many diseases and in clinical practice, here we assessed the distribution of CD38 NADase activity in a healthy population (104 sex-matched unrelated individuals, 12-98 years) and determined its main predictors among genetic and physiological factors (age and sex). The mean value of CD38 NADase activity was 0.051±0.023 mU/mg (0.010-0.099 mU/mg), following a normal distribution in the study population (Kolmogorov-Smirnov test P=0.200). The TNF-α -308G>A (rs1800629) resulted the main predictor (β=0.364, P=0.00008), followed by Age (β=0.280, P=0.002) and the CD38 184C>G (rs6449182) (β=0.193, P=0.033). Our study contributes to understanding CD38 enzyme physiological functions, by reporting, for the first time, its activity distribution in healthy individuals and demonstrating a significant positive correlation with age. Moreover, the possible use of TNF-α -308G>A (rs1800629) and the CD38 184C>G (rs6449182) SNPs as predictive genetic markers of CD38 activity, clearly point toward possible pharmacogenomic applications and to a more refined use of CD38 in clinical settings.

This paper deals with the rheological and thermal characterisation of the self-assembling behaviour of different Poloxamer 407 systems (15-30%, w/v), both alone or after the addition of various amounts of hydroxypropyl beta-cyclodextrin (5-20%, w/v). The knowledge of the interactions existing between the two kinds of molecules could allow the development of systems for parenteral administration containing also proteins or peptides drugs. A rheology (temperature sweep and frequency sweep test) study has been performed to characterise the thermogelation process while thermal analysis (nanoDSC) allowed the determination of both micellization and sol/gelation transition processes. These two techniques were also utilised to outline the variation in the critical micelle temperature (cmT) or in the sol/gel temperature (sgT,) of the systems containing also hydroxypropyl beta-cyclodextrin (HP beta-CD). Both the rheology and thermal analysis showed the presence of interesting interactions between the HP beta-CD and the Poloxamer 407, which cause a shift of both cmT and sgT. The presence of HP beta-CD modified also Poloxamer samples elastic characters and microrheological structure as demonstrated by the G'-G'' mechanical spectra. Rheological and thermal results outlined how these new systems could open the possibility to join the thermogelling behaviour offered by Poloxamer 407 with the well-known stabilization and protection ability of HP beta-CD, which could make possible the formulation of systems for the parenteral delivery of peptides and proteins.

The structure–function relationships occurring on the bovine thymus 20S proteasome, which exhibits the features of an immunoproteasome, have been studied. The investigation has been performed, essentially, using a fluorimetric approach, taking advantage either of the sensitivity of the complex to sodium dodecil sulfate and chaotropic agents (urea and guanidine hydrochloride) or of the presence, on the molecule, of a high number of tryptophan residues. The results obtained indicate that the perturbation or the oxidation of these residues affect the catalytic events taking place on the thymus proteasome and that the functional effects determined by SDS and chaotropic agents most likely occur through a series of progressive structural modifications leading to an inactive molecule. The presence of structural intermediates in the proteasome inactivation process suggests that thymus proteasome is a molecule characterized, at the same time, by structural flexibility (modulation of active sites) and structural stability (maintaining of the quaternary structure) in agreement with its crucial role in the cell life cycle.

School of Biosciences and Biotechnology, University of Camerino, via Gentile III da Varano, 62032 Camerino, MC, Italy School of Pharmacy, University of Camerino, via circonvallazione 93/95, 62024 Matelica, MC, Italy School of Veterinary Medical Sciences, University of Camerino, via circonvallazione 93/95, 62024 Matelica, MC, Italy Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, Santiago de Compostela 15782, Spain Department of Chemistry, American University, Washington, DC 20016, USA

School of Veterinary Medical Sciences University of Camerino, via Gentile III da Varano, 62032 Camerino, MC, Italy School of Biosciences and Biotechnologies, via Gentile III da Varano, 62032 Camerino, MC, Italy Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, 20892 Bethesda, MD, United States School of Pharmacy, University of Camerino, via Gentile III da Varano, 62032 Camerino, MC, Italy