Design of novel urogenital pharmabiotic formulations containing lactobacilli,salivaricin CRL 1328 and non-microbial compounds with different functionalities

Context: The administration of pharmabiotics is a promising alternative to antimicrobial drugs for the treatment and/or prevention of female urogenital infections.

Objective: To design pharmabiotic formulations including bioactive ingredients of microbial origin combined with non-microbial substances and then to evaluate the stability of the combinations during freeze-drying and storage.

Materials and methods: Different formulations including Lactobacillus gasseri CRL 1263, Lactobacillus salivarius CRL 1328, salivaricin CRL 1328 (a bacteriocin) and non-microbial compounds (lactose, inulin and ascorbic acid) were assayed, and the ingredients were freeze-dried together or separately. The formulations were stored in gelatin capsules at 4?°C for 360?d.

Results: The viability of lactobacilli was affected to different extents depending on the strains and on the formulations assayed. L. salivarius and ascorbic acid were successfully combined only after the freeze-drying process. Salivaricin activity was not detected in formulations containing L. gasseri. However, when combined with ascorbic acid, lactose, inulin or L. salivarius, the bacteriocin maintained its activity for 360?d. The selected microorganisms proved to be compatible for their inclusion in multi-strain formulations together with lactose, inulin and ascorbic acid. Salivaricin could be included only in a L. salivarius CRL 1328 single-strain formulation together with non-microbial substances.

Conclusions: This study provides new insights into the design of urogenital pharmabiotics combining beneficial lactobacilli, salivaricin CRL 1328 and compounds with different functionalities.     

Unusual Two-Step Assembly of a Minimalistic Dipeptide-Based Functional Hypergelator

Self-assembled peptide hydrogels represent the realization of peptide nanotechnology into biomedical products. There is a continuous quest to identify the simplest building blocks and optimize their critical gelation concentration (CGC). Herein, a minimalistic, de novo dipeptide, Fmoc-Lys(Fmoc)-Asp, as an hydrogelator with the lowest CGC ever reported, almost fourfold lower as compared to that of a large hexadecapeptide previously described, is reported. The dipeptide self-assembles through an unusual and unprecedented two-step process as elucidated by solid-state NMR and molecular dynamics simulation. The hydrogel is cytocompatible and supports 2D/3D cell growth. Conductive composite gels composed of Fmoc-Lys(Fmoc)-Asp and a conductive polymer exhibit excellent DNA binding. Fmoc-Lys(Fmoc)-Asp exhibits the lowest CGC and highest mechanical properties when compared to a library of dipeptide analogues, thus validating the uniqueness of the molecular design which confers useful properties for various potential applications.     

Design guidelines for titania-silica-alumina ceramics with tuned anatase to rutile transformation

Titania-based ceramics with adjustable anatase-rutile fractions were obtained by milling of anatase, quartz and corundum precursors, uniaxial pressing and firing at 1100?°C. The influence of silica and alumina, combined with milling time and compaction pressure, was studied by design of experiments. The L9 orthogonal array with a three-level noise factor was employed. Firing of pure titania at 1100?°C yielded complete anatase to rutile transformation (ART), whereas stabilized samples show that an optimum amount of 9% silica and 33% alumina reduces phase transformation to only about 5?wt% rutile. An extended correlation matrix combined with analysis of variance (ANOVA) was applied to assess the combined effects of quartz, alumina, milling time and uniaxial compressing pressure on relative density, and anatase to rutile transformation. Results show absence of ART after milling, and controlled partial conversion of anatase to rutile after firing. Very good fitting was obtained by multivariate analysis on considering first and second order terms for dependence on silica contents and interactions between silica and each of the remaining factors, including milling time. This empirical dependence could be interpreted on a sound physicochemical basis, allowing the prediction of suitable compositions and processing conditions to obtain rutile-free samples by conventional ceramic processing, and to design ceramic samples with controlled fractions of anatase and rutile.     

A self‐scalable load injection service

Load testing of applications is an important and costly activity for software provider companies. Classical solutions are very difficult to set up statically, and their cost is prohibitive in terms of both human and hardware resources. Virtualized cloud computing platforms provide new opportunities for stressing an application's scalability, by providing a large range of flexible and less expensive (pay‐per‐use model) computation units. On the basis of these advantages, load testing solutions could be provided on demand in the cloud. This paper describes a Benchmark‐as‐a‐Service solution that automatically scales the load injection platform and facilitates its setup according to load profiles. Our approach is based on: (i) virtualization of the benchmarking platform to create self‐scaling injectors; (ii) online calibration to characterize the injector's capacity and impact on the benched application; and (iii) a provisioning solution to appropriately scale the load injection platform ahead of time. We also report experiments on a benchmark illustrating the benefits of this system in terms of cost and resource reductions. Copyright © 2013 John Wiley & Sons, Ltd.     

A Dual Inhibitor of DYRK1A and GSK3β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877

Loss of β-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β-cell mass are less developed. Promoting β-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β) was previously reported to induce primary human β-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring β-cell proliferation.     

Milk from cows fed a diet with a high forage:concentrate ratio improves inflammatory state,oxidative stress,and mitochondrial function in rats

Excessive energy intake may evoke complex biochemical processes characterized by inflammation, oxidative stress, and impairment of mitochondrial function that represent the main factors underlying noncommunicable diseases. Because cow milk is widely used for human nutrition and in food industry processing, the nutritional quality of milk is of special interest with respect to human health. In our study, we analyzed milk produced by dairy cows fed a diet characterized by a high forage:concentrate ratio (high forage milk, HFM). In view of the low n-6:n-3 ratio and high content of conjugated linoleic acid of HFM, we studied the effects of this milk on lipid metabolism, inflammation, mitochondrial function, and oxidative stress in a rat model. To this end, we supplemented for 4 wk the diet of male Wistar rats with HFM and with an isocaloric amount (82 kJ, 22 mL/d) of milk obtained from cows fed a diet with low forage:concentrate ratio, and analyzed the metabolic parameters of the animals. Our results indicate that HFM may positively affect lipid metabolism, leptin:adiponectin ratio, inflammation, mitochondrial function, and oxidative stress, providing the first evidence of the beneficial effects of HFM on rat metabolism.