BMS Derivatives C7-Linked to β-Cyclodextrin and Hyperbranched Polyglycerol Retain Activity against R5-HIV-1NLAD8 Isolates and Can Be Deemed Potential Microbicides

Amides from indole-3-glyoxylic acid and 4-benzoyl-2-methylpiperazine, which are related to entry inhibitors developed by Bristol-Myers Squibb (BMS), have been synthesized with aliphatic chains located at the C7 position of the indole ring. These spacers contain an azido group suitable for the well-known Cu(I)-catalyzed (3+2)-cycloaddition or an activated triple bond for the nucleophilic addition of thiols under physiological conditions. Reaction with polyols (β-cyclodextrin and hyperbranched polyglycerol) decorated with complementary click partners has afforded polyol-BMS-like conjugates that are not cytotoxic (TZM.bl cells) and retain the activity against R5-HIV-1_NLAD8 isolates. Thus, potential vaginal microbicides based on entry inhibitors, which can be called of 4^th generation, are reported here for the first time.     

Ivabradine Induces Cardiac Protection against Myocardial Infarction by Preventing Cyclophilin-A Secretion in Pigs under Coronary Ischemia/Reperfusion

In response to cardiac ischemia/reperfusion, proteolysis mediated by extracellular matrix metalloproteinase inducer (EMMPRIN) and its secreted ligand cyclophilin-A (CyPA) significantly contributes to cardiac injury and necrosis. Here, we aimed to investigate if, in addition to the effect on the funny current (I(f)), Ivabradine may also play a role against cardiac necrosis by reducing EMMPRIN/CyPA-mediated cardiac inflammation. In a porcine model of cardiac ischemia/reperfusion (IR), we found that administration of 0.3 mg/kg Ivabradine significantly improved cardiac function and reduced cardiac necrosis by day 7 after IR, detecting a significant increase in cardiac CyPA in the necrotic compared to the risk areas, which was inversely correlated with the levels of circulating CyPA detected in plasma samples from the same subjects. In testing whether Ivabradine may regulate the levels of CyPA, no changes in tissue CyPA were found in healthy pigs treated with 0.3 mg/kg Ivabradine, but interestingly, when analyzing the complex EMMPRIN/CyPA, rather high glycosylated EMMPRIN, which is required for EMMPRIN-mediated matrix metalloproteinase (MMP) activation and increased CyPA bonding to low-glycosylated forms of EMMPRIN were detected by day 7 after IR in pigs treated with Ivabradine. To study the mechanism by which Ivabradine may prevent secretion of CyPA, we first found that Ivabradine was time-dependent in inhibiting co-localization of CyPA with the granule exocytosis marker vesicle-associated membrane protein 1 (VAMP1). However, Ivabradine had no effect on mRNA expression nor in the proteasome and lysosome degradation of CyPA. In conclusion, our results point toward CyPA, its ligand EMMPRIN, and the complex CyPA/EMMPRIN as important targets of Ivabradine in cardiac protection against IR.     

Optimal design of water pipeline networks for the development of shale gas resources

One of the major concerns in shale gas production is water management. Millions of gallons of water are injected to fracture each well and a significant amount returns to the surface as flowback. Operators are increasingly reusing flowback to reduce freshwater consumption and impaired water disposal. Because of this, networks of water pipelines in U.S. shales are growing fast. This work is aimed at addressing the optimal planning of shale gas operations in multiple wellpads together with the design of water distribution networks (WDN). We propose a multiperiod mixed-integer linear programming model to solve the challenging stay-or-mobilize trade-off. The proposed model permits to schedule operations at a detailed level, accounting for the WDN required to maximize the reuse of impaired water. We present illustrative examples involving up to 20 pads, 4 frac-crews, and 100 wells developed over 1 year, showing that the design of the WDN can be effectively optimized.     

Microencapsulated Bifidobacterium bifidum and Lactobacillus gasseri in Combination with Quercetin Inhibit Colorectal Cancer Development in ApcMin/+ Mice

Recent studies have suggested that flavonoids such as quercetin and probiotics such as Bifidobacterium bifidum (Bf) and Lactobacillus gasseri (Lg) could play a relevant role in inhibiting colon cancer cell growth. Our study investigated the role of dietary supplementation with microencapsulated probiotics (Bf and Lg) along with quercetin in the development of mouse colorectal cancer (CRC). Methods: Adenomatous polyposis coli/multiple intestinal neoplasia (Apc^Min/+) mice were fed a standard diet or the same diet supplemented with microencapsulated probiotics (Bf and Lg strains, 10⁷ CFU/100 g food) or both probiotics strains plus microencapsulated quercetin (15 mg/100 g food) for 73 days. Changes in body and organ weights, energy metabolism, intestinal microbiota, and colon tissue were determined. The expression of genes related to the Wnt pathway was also analyzed in colon samples. Results: Dietary supplementation with microencapsulated probiotics or microencapsulated probiotics plus quercetin reduced body weight loss and intestinal bleeding in Apc^Min/+ mice. An improvement in energy expenditure was observed after 8 weeks but not after 10 weeks of treatment. A supplemented diet with microencapsulated Bf and Lg reduced the number of aberrant crypt foci (ACF) and adenomas by 45% and 60%, respectively, whereas the supplementation with Bf, Lg and quercetin decreased the number of ACF and adenomas by 57% and 80%, respectively. Microencapsulated Bf and Lg in combination with quercetin could exert inhibition of the canonical Wnt/β-catenin signaling pathway in the colon of Apc^Min/+ mice Conclusions: The administration of microencapsulated Bf and Lg, individually or in combination with quercetin, inhibits the CRC development in Apc^Min/+ mice.     

Insoluble Vascular Amyloid Deposits Trigger Disruption of the Neurovascular Unit in Alzheimer’s Disease Brains

Alzheimer’s disease (AD) is a neurodegenerative disease, characterized histopathologically by intra-neuronal tau-related lesions and by the accumulation of amyloid β-peptide (Aβ) in the brain parenchyma and around cerebral blood vessels. According to the vascular hypothesis of AD, an alteration in the neurovascular unit (NVU) could lead to Aβ vascular accumulation and promote neuronal dysfunction, accelerating neurodegeneration and dementia. To date, the effects of insoluble vascular Aβ deposits on the NVU and the blood–brain barrier (BBB) are unknown. In this study, we analyze different Aβ species and their association with the cells that make up the NVU. We evaluated post-mortem AD brain tissue. Multiple immunofluorescence assays were performed against different species of Aβ and the main elements that constitute the NVU. Our results showed that there are insoluble vascular deposits of both full-length and truncated Aβ species. Besides, insoluble aggregates are associated with a decrease in the phenotype of the cellular components that constitute the NVU and with BBB disruption. This approach could help identify new therapeutic targets against key molecules and receptors in the NVU that can prevent the accumulation of vascular fibrillar Aβ in AD.     

What do patent examiner inserted citations indicate for a region with low absorptive capacity?

Most studies of patents citations focus on national or international contexts, especially contexts of high absorptive capacity, and employ examiner citations. We argue that results can vary if we take the region as the context of analysis, especially if it is a region with low absorptive capacity, and if we study applicant citations and examiner-inserted citations separately. Using a sample from the Valencian Community (Spain), we conclude that (i) the use of examiner-inserted citations as a proxy for applicant citations, (ii) the interpretation of non-patent references as indicators of science-industry links, and (iii) the traditional results for geographical localization are not generalizable to all regions with low absorptive capacity.     

The effect of traditional wind vents called zarceras on the hygrothermal behaviour of underground wine cellars in Spain

This paper studies the hygrothermal behaviour of traditional underground wine cellars in one of the most important wine growing areas of Spain, the Ribera del Duero, paying special attention to the effects of traditional wind vents called zarceras. The purpose is to highlight energy-saving practices that aid the design and renovation of similar constructions. This was carried out by monitoring the temperature and relative humidity inside two wine cellars of similar properties throughout 2007, one with a zarcera and the other without. The results of the analysis show that the existence of the wind vent does not increase the ventilation from May to August. On the other hand, from September to March, the zarcera favours ventilation, affecting both temperature and relative humidity. The interior temperature is more greatly affected by the exterior temperature, giving rise to greater variations, although this difference is of little importance for maturing wine (annual variation 2.5 °C more than the cellar without a zarcera). The interior relative humidity is reduced, reducing the risk of condensation and problems of mould (the cellar without a zarcera reached excessively high values, 97% as an annual average, compared to 91% in the cellar with a zarcera). Thus the existence of zarceras in underground cellars improves the overall hygrothermal behaviour, providing suitable conditions for maturing wine without air conditioning systems, an advisable element in the building of new underground wine cellars.     

Comparison of the volatile profiles of Arzúa-Ulloa and Tetilla cheeses manufactured from raw and pasteurized milk

Levels of volatile compounds in Arzúa-Ulloa and Tetilla cheeses manufactured from raw and pasteurized milk were investigated. Analysis of volatile compounds in six raw milk (RM) starter-free cheeses (15–45 days old) and six pasteurized milk (PM) cheeses made with deliberately added starters (15–45 days old) manufactured in different dairies, was performed on an automatic dynamic headspace apparatus coupled to a GC/MS. The volatile fraction of RM cheeses displayed 46 volatile compounds (34 for PM cheeses) including fatty acids, esters, aldehydes, alcohols, ketones, hydrocarbons and sulphur compounds. Fatty acids and several esters were only detected in RM cheeses. Moreover, the highest contents of methylketones, secondary alcohols and branched-chain aldehydes and alcohols were also observed in RM cheeses. All results confirm more intense lipolysis in RM cheeses than in PM cheeses. In addition, branched-chain aldehydes and alcohols were significantly more abundant in RM than in PM cheeses, which indicates that catabolism of branched-chain amino acids was significantly higher in RM cheeses. This study has provided useful information which will allow the selection of starter and non-starter bacteria more suitable for manufacturing Arzúa-Ulloa and Tetilla pasteurized milk cheeses with organoleptic characteristics similar to those of traditional raw milk cheeses.     

Raman analysis of surimi gelation by addition of wheat dietary fibre

Raman analysis has been carried out to study the effects of Vitacel^® wheat dietary fibre (WDF) during gelation of surimi. The main results reveal the following: (a) Vitacel^® comprises natural cellulose I as major component; (b) hydration of WDF leads to νCH frequency upshifting and decreasing intensity. On the basis of these spectral features it is suggested that water transfer from protein to WDF can occur in surimi gels. WDF hydration can be interpreted in the sense that this fibre either takes water that is delivered from the gel protein upon heat-mediated formation of β-sheets and hydrophobic contacts and/or or acts as an active dehydrating agent. An increase of solvent-exposed hydrophobic side chains is observed in the sol phase, upon the addition of WDF, which may cause breaking of intermolecular protein hydrophobic contacts; a subsequent change upon WDF-containing gel formation is the reduction in the νCH intensity, which may be indicative of increasing hydrophobic WDF-protein contacts. Interestingly, these results constitute molecular data, to be considered when designing restructured fish products with these fibre ingredients.