Design, synthesis, and biological evaluation of 2-aminobenzanilide derivatives as potent and selective HDAC inhibitors

Epigenetic regulation is an essential process for the normal functioning of genes. Therefore, targeting epigenetic dysregulation in cancer may be a valid therapeutic approach for the treatment of this severe disease. Histone deacetylases (HDACs) are enzymes involved in the regulation of epigenetic post-translational modifications; because they are overexpressed in many types of cancer, HDACs are valuable targets for the development of new anticancer agents. A large series of 2-aminobenzanilides linked at the 4'-position to α-amino acid amides, arenes, and heteroarenes through a methylene bridge were designed, synthesized, and tested as novel HDAC inhibitors. Several compounds showed IC(50) values in the two-digit nanomolar range in hrHDAC1 inhibition assays, lower than that of the reference compound MS-275. They also showed interesting selectivity profiles, as confirmed by western blot assays.     

Synthesis and Biological Evaluation of CTP Synthetase Inhibitors as Potential Agents for the Treatment of African Trypanosomiasis

Acivicin analogues with an increased affinity for CTP synthetase (CTPS) were designed as potential new trypanocidal agents. The inhibitory activity against CTPS can be improved by increasing molecular complexity, by inserting groups able to establish additional interactions with the binding pocket of the enzyme. This strategy has been pursued with the synthesis of α‐amino‐substituted analogues of Acivicin and N1‐substituted pyrazoline derivatives. In general, there is direct correlation between the enzymatic activity and the in vitro anti‐trypanosomal efficacy of the derivatives studied here. However, this cannot be taken as a general rule, as other important factors may play a role, notably the ability of uptake/diffusion of the molecules into the trypanosomes.     

Inhibition of verocytotoxigenic Escherichia coli by antimicrobial peptides caseicin A and B and the factors affecting their antimicrobial activities

The antimic robial activities of caseicin A and B antimicrobial peptides (AMPs) were assessed against a selection of verocytotoxigenic Escherichia coli (VTEC) strains (n = 11), other bacterial pathogenic and spoilage bacteria (n = 7), using a model broth system. The ability of the AMPs to retain their antimicrobial activities against a strain of E. coli O157:H7 380-94 under various test conditions (pH, temperature, water activity, sodium chloride concentrations, inoculum size and the presence of competitive microflora) was assessed and the minimum inhibitory concentrations (MIC) and number of surviving E. coli O157:H7 calculated. The mean number of VTEC surviving after exposure to 2 mg/ml caseicin A and B was reduced by 4.96 and 4.19 log₁₀ cfu/ml compared to the respective controls. The susceptibility of E. coli O157:H7 to the caseicin AMPs decreased as temperature, pH, water activity and inoculum size were reduced. The presence of sodium chloride (0.5-2.5%) did not affect the activity of caseicin A (p > 0.05), however it did inhibit the activity of caseicin B. The presence of a competitive microflora cocktail did not significantly (p > 0.05) affect the activities of the AMPs for the majority of the concentrations tested. Using a quantitative PCR assay, the levels of verotoxins (vt1 and vt2) expressed by E. coli O157:H7 following exposure to a sub-inhibitory concentration (0.5 mg/ml) of caseicin A showed that the verotoxin levels did not differ from the levels produced by the control cultures. The antimicrobial activity of caseicin A against E. coli O157:H7 was also tested in a model rumen system, however concentrations of ≥ 2 mg/ml did not significantly (p > 0.05) reduce E. coli O157:H7 numbers in the model system over a 24 h period. The application of caseicin AMPs in food and/or animal production may be valuable in combination with other antimicrobials although further research is required.     

Efficacy of trimming chilled beef during fabrication to control Escherichia coli O157:H7 surrogates on subsequent subprimals

Effectiveness of trimming external carcass surfaces from subprimals during fabrication to reduce Escherichia coli O157:H7 surrogates was evaluated. Carcass sides (n = 10 sides) were inoculated along the hide pattern opening before entering the blast chill cooler with a gelatin slurry containing a bacterial cocktail of three rifampicin-resistant, nonpathogenic E. coli biotype I strains. Following a 48 h chill, sides were fabricated to produce eight subprimals. Microbiological samples were taken from the original carcass fat surface area, initial lean surface area, trimmed fat surface area (where applicable), and trimmed lean surface area (where applicable). Newly exposed lean surfaces had lower (P < 0.05) counts of rifampicin-resistant E. coli than did the external fat surfaces. However, fat and lean surfaces that were not inoculated became contaminated during the fabrication process. Trimming external surfaces reduced levels of pathogens, but under normal fabrication processes, pathogens were still spread to newly exposed surfaces.     

Thermoelastic finite element model updating with application to monumental buildings

A reliable and predictive model of an existing structure entails the use of model updating techniques, which are usually performed on the basis of operational modal analysis campaigns. In this paper, a new model calibration strategy is proposed that adopts a multiphysics approach to exploit data collected by both static and dynamic monitoring systems. More specifically, mechanical and temperature data are assimilated into the model through a thermoelastic updating. The proposed scheme is validated with numerical simulations and applied on the Sanctuary of Vicoforte, a complex historical building that is subjected to both static and dynamic monitoring.     

Development of disease management recommendations for the durian and jackfruit industries in the Philippines using farmer participatory research

Promoting the adoption of improved technologies among smallholder farmers is a challenge faced by agricultural scientists and extension personnel around the world. In the southern Philippines, Phytophthora diseases severely affect the yields of durian and jackfruit. A limited understanding of these diseases among farmers and extension professionals compromises their effective management and significantly reduces yields. Recommended management interventions were rarely validated in field trials. A participatory research approach was used to collect information on current farming practices, identify industry constraints, and to develop and promote management strategies for smallholder durian and jackfruit growers. Farmers identified the development of effective disease management strategies as the highest priority so information on the biology, epidemiology and management of the suspected pathogen, Phytophthora, and other pests and diseases, was presented and discussed. Participants were then asked to propose and design research trials to diagnose the pathogen and to test simple management interventions on their crops. The trials were established and managed by participants and monitored by the group of growers, researchers and extension staff over 3 years. Responsibility for the on-farm trials encouraged participants to become directly involved in the research process, improving their skills in developing and critically assessing solutions for management of their orchards, and in decision-making processes. Results from the Participatory Action Research (PAR) trials were subjected to simple benefit-cost analyses and used to formulate a series of low-, medium- and high-input disease management packages. The low-input options included sanitation and manual pruning and weeding, and other activities requiring relatively low levels of time and financial investment. Medium- and high-input options required greater investment of time, resources and finances and included application of soil amendments, water management through construction of drainage channels and mounding, and the application of pesticides. The availability of a range of options facilitates the adoption of improved management by farmers from diverse backgrounds, resources and capacity.     

Scapania nemorea liverwort extracts: Investigation on volatile compounds, in vitro antimicrobial activity and control of Saccharomyces cerevisiae in fruit juice

This study was focused on chemical characterisation of liverwort Scapania nemorea extracts and their antimicrobial activity against pathogenic and food-spoiling yeasts and bacteria. The chemical composition of three different extracts of the liverwort S. nemorea was determined by solid phase microextraction gas chromatography-mass spectrometry (SPME GC–MS). The dominant compounds in extracts were sesquiterpenes β-bazzanene (11%, 17.9% and 14.6%), isobazzanene (10.2%, 15.8% and 11.7%) and aromadendrene (8.8%, 12.9% and 10.6%) in the methanol, ethanol and ethyl acetate extracts, respectively. Antimicrobial potential of S. nemorea extracts against food spoiling yeasts and bacteria was determined in vitro by microdilution method. The Minimum Inhibitory Concentration (MIC) varied from 0.5 to 3 mg/mL for bacteria, and from 0.2 to 1 mg/mL for yeasts. Moreover, the combined effects of dry methanol extract of S. nemorea and heat processing on the survival and growth of a spoilage yeast in an apple/orange-based beverage, have been assessed through a Central Composite Design. Changes in color and flavor of the beverages were considered acceptable also after one week of storage at 25 °C. The results provide evidence of antimicrobial potential of S. nemorea extracts and suggest its potential as natural antimicrobial agent for food preservation.     

A mechatronic platform for human touch studies

The development of a mechatronic tactile stimulation platform for touch studies is presented. The platform was developed for stimulation of the fingertip using textured surfaces, providing repeatable tangential sliding motion of stimuli with controlled indentation force. Particular requirements were addressed to make the platform suitable for neurophysiological studies in humans with particular reference to electrophysiological measurements, but allowing a variety of other studies too, such as psychophysical, tribological and artificial touch ones. The design of the mechatronic tactile stimulator is detailed, as well as the performance in tracking reference trajectories. Using microneurography, we recorded from human tactile afferents and validated the platform compatibility with the exacting demands of electrophysiological methods, comprising the absence of spurious vibrations and the lack of relevant electromagnetic interference.     

Comparison between Monte Carlo and experimental aluminum and silicon electron energy loss spectra

A Monte Carlo (MC) simulation is described and used to calculate the energy distribution spectra of backscattered electrons from Al and Si. For the simulations, elastic scattering cross sections are calculated by numerically solving the Dirac equation in a central field. Inelastic scattering cross sections are computed within the dielectric response theory developed by Ritchie, and by Tung et al. Extension from the optical case to non-zero momentum transfer is done according to Ritchie and Howie. To evaluate surface and bulk contributions to the spectra, the Monte Carlo model treats the surface excitations according to the Werner differential surface and volume excitation probability theory. The Monte Carlo calculations are compared with the experimental reflection electron energy loss (REEL) spectra acquired in our laboratory.     

Nutritional and health-related compounds in sprouts and seeds of soybean (<Emphasis Type="Italic">Glycine max</Emphasis>), wheat (<Emphasis Type="Italic">Triticum aestivum.L</Emphasis>) and alfalfa (<Emphasis Type="Italic">Medicago sativa</Emphasis>) treated by a new drying method

Nutritional and health-related compounds of alfalfa, wheat and soybean seeds dried by new drying process called the DIC process (controlled instantaneous pressure release) were evaluated, before and after sprouting. Vitamins (A, B₁, B₂, B₆, C and E), minerals (Fe, Mg, Ca, K, Mn, Na, Cu and Zn) and phytoestrogens (genistein and daidzein ) content were determined. Alfalfa, soybean and wheat seeds dried by DIC showed similar content of biological compounds to seeds dried by traditional processes. Sprouting DIC-seeds significantly increased the levels of vitamins, minerals and phytoestrogens, improving their nutrititional value and health quality compared to fresh products. The increase of 1250-fold and 10-fold of the initial vitamin A and vitamin C content, respectively, of alfalfa seeds due to sprouting is remarkable. Sprouts from DIC-seeds showed a significantly higher vitamin A content than sprouts obtained from seeds dried by other methods. Soybean sprouts obtained from DIC-seeds showed a significant increase in free phytoestrogens, quantified as genistein (70.34LJ.8 mg kg^-1 d.w.) and daidzein (109.17.3ᆥ.3 mg kg^-1 d.w.).