The FKBP5 Gene Affects Alcohol Drinking in Knockout Mice and Is Implicated in Alcohol Drinking in Humans

FKBP5 encodes FK506-binding protein 5, a glucocorticoid receptor (GR)-binding protein implicated in various psychiatric disorders and alcohol withdrawal severity. The purpose of this study is to characterize alcohol preference and related phenotypes in Fkbp5 knockout (KO) mice and to examine the role of FKBP5 in human alcohol consumption. The following experiments were performed to characterize Fkpb5 KO mice. (1) Fkbp5 KO and wild-type (WT) EtOH consumption was tested using a two-bottle choice paradigm; (2) The EtOH elimination rate was measured after intraperitoneal (IP) injection of 2.0 g/kg EtOH; (3) Blood alcohol concentration (BAC) was measured after 3 h limited access of alcohol; (4) Brain region expression of Fkbp5 was identified using LacZ staining; (5) Baseline corticosterone (CORT) was assessed. Additionally, two SNPs, rs1360780 (C/T) and rs3800373 (T/G), were selected to study the association of FKBP5 with alcohol consumption in humans. Participants were college students (n = 1162) from 21–26 years of age with Chinese, Korean or Caucasian ethnicity. The results, compared to WT mice, for KO mice exhibited an increase in alcohol consumption that was not due to differences in taste sensitivity or alcohol metabolism. Higher BAC was found in KO mice after 3 h of EtOH access. Fkbp5 was highly expressed in brain regions involved in the regulation of the stress response, such as the hippocampus, amygdala, dorsal raphe and locus coeruleus. Both genotypes exhibited similar basal levels of plasma corticosterone (CORT). Finally, single nucleotide polymorphisms (SNPs) in FKBP5 were found to be associated with alcohol drinking in humans. These results suggest that the association between FKBP5 and alcohol consumption is conserved in both mice and humans.     

Feedback design in control reconfigurable systems

This paper is concerned with the design of reconfigurable control laws for fault-tolerant systems. From the control design point of view the issue of performance robustness during the system normal operation versus failure sensitivity at the time of a system component failure is addressed. To achieve a balanced design, a parametrized set of controllers satisfying a prescribed performance level is first constructed, and then the parameter is optimized under a detection criterion that sensitizes the measurements to some specific failures. An example involving aircraft surface impairment is given to explain the procedure for obtaining the optimized design.     

Der einfluß von faseroberflächen auf die matrixhärtung bei faserverbundwerkstoffen

The influence of extraction of reinforced fibres on surface properties and the curing reaction of epoxy resin matrix in composites were investigated. With increasing fibre surface polarity, as the result of the extraction, the resin wettability was improved and the reaction rate of curing of the epoxy resin matrix increased. The wettability and the reaction rate oppositely decreased with decreasing fibre surface polarity.     

Biological Implications of a Stroke Therapy Based in Neuroglobin Hyaluronate Nanoparticles. Neuroprotective Role and Molecular Bases

Exogenous neuroprotective protein neuroglobin (Ngb) cannot cross the blood–brain barrier. To overcome this difficulty, we synthesized hyaluronate nanoparticles (NPs), able to deliver Ngb into the brain in an animal model of stroke (MCAO). These NPs effectively reached neurons, and were microscopically identified after 24 h of reperfusion. Compared to MCAO non-treated animals, those treated with Ngb-NPs showed survival rates up to 50% higher, and better neurological scores. Tissue damage improved with the treatment, but no changes in the infarct volume or in the oxidative/nitrosative values were detected. A proteomics approach (p-value < 0.02; fold change = 0.05) in the infarcted areas showed a total of 219 proteins that significantly changed their expression after stroke and treatment with Ngb-NPs. Of special interest, are proteins such as FBXO7 and NTRK2, which were downexpressed in stroke, but overexpressed after treatment with Ngb-NPs; and ATX2L, which was overexpressed only under the effect of Ngb. Interestingly, the proteins affected by the treatment with Ngb were involved in mitochondrial function and cell death, endocytosis, protein metabolism, cytoskeletal remodeling, or synaptic function, and in regenerative processes, such as dendritogenesis, neuritogenesis, or sinaptogenesis. Consequently, our pharmaceutical preparation may open new therapeutic scopes for stroke and possibly for other neurodegenerative pathologies.     

Novel 1,3,5-Triazinyl Aminobenzenesulfonamides Incorporating Aminoalcohol,Aminochalcone and Aminostilbene Structural Motifs as Potent Anti-VRE Agents,and Carbonic Anhydrases I,II, VII,IX, and XII Inhibitors

A series of 1,3,5-triazinyl aminobenzenesulfonamides substituted by aminoalcohol, aminostilbene, and aminochalcone structural motifs was synthesized as potential human carbonic anhydrase (hCA) inhibitors. The compounds were evaluated on their inhibition of tumor-associated hCA IX and hCA XII, hCA VII isoenzyme present in the brain, and physiologically important hCA I and hCA II. While the test compounds had only a negligible effect on physiologically important isoenzymes, many of the studied compounds significantly affected the hCA IX isoenzyme. Several compounds showed activity against hCA XII; (E)-4-{2-[(4-[(2,3-dihydroxypropyl)amino]-6-[(4-styrylphenyl)amino]-1,3,5-triazin-2-yl)amino]ethyl}benzenesulfonamide (31) and (E)-4-{2-[(4-[(4-hydroxyphenyl)amino]-6-[(4-styrylphenyl)amino]-1,3,5-triazin-2-yl)amino]ethyl}benzenesulfonamide (32) were the most effective inhibitors with K_Is = 4.4 and 5.9 nM, respectively. In addition, the compounds were tested against vancomycin-resistant Enterococcus faecalis (VRE) isolates. (E)-4-[2-({4-[(4-cinnamoylphenyl)amino]-6-[(4-hydroxyphenyl)amino]-1,3,5-triazin-2-yl}amino)ethyl]benzenesulfonamide (21) (MIC = 26.33 µM) and derivative 32 (MIC range 13.80–55.20 µM) demonstrated the highest activity against all tested strains. The most active compounds were evaluated for their cytotoxicity against the Human Colorectal Tumor Cell Line (HCT116 p53 +/+). Only 4,4’-[(6-chloro-1,3,5-triazin-2,4-diyl)bis(iminomethylene)]dibenzenesulfonamide (7) and compound 32 demonstrated an IC₅₀ of ca. 6.5 μM; otherwise, the other selected derivatives did not show toxicity at concentrations up to 50 µM. The molecular modeling and docking of active compounds into various hCA isoenzymes, including bacterial carbonic anhydrase, specifically α-CA present in VRE, was performed to try to outline a possible mechanism of selective anti-VRE activity.     

Overexpression of microRNAs miR-25-3p,miR-185-5p and miR-132-3p in Late Onset Fetal Growth Restriction,Validation of Results and Study of the Biochemical Pathways Involved

In a prospective study, 48 fetuses were evaluated with Doppler ultrasound after 34 weeks and classified, according to the cerebroplacental ratio (CPR) and estimated fetal weight (EFW), into fetuses with normal growth and fetuses with late-onset fetal growth restriction (LO-FGR). Overexpression of miRNAs from neonatal cord blood belonging to LO-FGR fetuses, was validated by real-time PCR. In addition, functional characterization of overexpressed miRNAs was performed by analyzing overrepresented pathways, gene ontologies, and prioritization of synergistically working miRNAs. Three miRNAs: miR-25-3p, miR-185-5p and miR-132-3p, were significantly overexpressed in cord blood of LO-FGR fetuses. Pathway and gene ontology analysis revealed over-representation of certain molecular pathways associated with cardiac development and neuron death. In addition, prioritization of synergistically working miRNAs highlighted the importance of miR-185-5p and miR-25-3p in cholesterol efflux and starvation responses associated with LO-FGR phenotypes. Evaluation of miR-25-3p; miR-132-3p and miR-185-5p might serve as molecular biomarkers for the diagnosis and management of LO-FGR; improving the understanding of its influence on adult disease.     

Impact of Uremic Toxins on Endothelial Dysfunction in Chronic Kidney Disease: A Systematic Review

Patients with chronic kidney disease (CKD) are at a highly increased risk of cardiovascular complications, with increased vascular inflammation, accelerated atherogenesis and enhanced thrombotic risk. Considering the central role of the endothelium in protecting from atherogenesis and thrombosis, as well as its cardioprotective role in regulating vasorelaxation, this study aimed to systematically integrate literature on CKD-associated endothelial dysfunction, including the underlying molecular mechanisms, into a comprehensive overview. Therefore, we conducted a systematic review of literature describing uremic serum or uremic toxin-induced vascular dysfunction with a special focus on the endothelium. This revealed 39 studies analyzing the effects of uremic serum or the uremic toxins indoxyl sulfate, cyanate, modified LDL, the advanced glycation end products N-carboxymethyl-lysine and N-carboxyethyl-lysine, p-cresol and p-cresyl sulfate, phosphate, uric acid and asymmetric dimethylarginine. Most studies described an increase in inflammation, oxidative stress, leukocyte migration and adhesion, cell death and a thrombotic phenotype upon uremic conditions or uremic toxin treatment of endothelial cells. Cellular signaling pathways that were frequently activated included the ROS, MAPK/NF-κB, the Aryl-Hydrocarbon-Receptor and RAGE pathways. Overall, this review provides detailed insights into pathophysiological and molecular mechanisms underlying endothelial dysfunction in CKD. Targeting these pathways may provide new therapeutic strategies reducing increased the cardiovascular risk in CKD.     

Mitochondrial Processing Peptidases—Structure,Function and the Role in Human Diseases

Mitochondrial proteins are encoded by both nuclear and mitochondrial DNA. While some of the essential subunits of the oxidative phosphorylation (OXPHOS) complexes responsible for cellular ATP production are synthesized directly in the mitochondria, most mitochondrial proteins are first translated in the cytosol and then imported into the organelle using a sophisticated transport system. These proteins are directed mainly by targeting presequences at their N-termini. These presequences need to be cleaved to allow the proper folding and assembly of the pre-proteins into functional protein complexes. In the mitochondria, the presequences are removed by several processing peptidases, including the mitochondrial processing peptidase (MPP), the inner membrane processing peptidase (IMP), the inter-membrane processing peptidase (MIP), and the mitochondrial rhomboid protease (Pcp1/PARL). Their proper functioning is essential for mitochondrial homeostasis as the disruption of any of them is lethal in yeast and severely impacts the lifespan and survival in humans. In this review, we focus on characterizing the structure, function, and substrate specificities of mitochondrial processing peptidases, as well as the connection of their malfunctions to severe human diseases.     

Profiling of the Bacterial Microbiota along the Murine Alimentary Tract

Here, the spatial distribution of the bacterial flora along the murine alimentary tract was evaluated using high throughput sequencing in wild-type and Tff3-deficient (Tff3^KO) animals. Loss of Tff3 was linked to increased dextran sodium sulfate-induced colitis. This systematic study shows the results of 13 different regions from the esophagus to the rectum. The number of bacterial species (richness) increased from the esophagus to the rectum, from 50 to 200, respectively. Additionally, the bacterial community structure changed continuously; the highest changes were between the upper/middle and lower gastrointestinal compartments when comparing adjacent regions. Lactobacillus was the major colonizer in the upper/middle gastrointestinal tract, especially in the esophagus and stomach. From the caecum, a drastic diminution of Lactobacillus occurred, while members of Lachnospiraceae significantly increased. A significant change occurred in the bacterial community between the ascending and the transverse colon with Bacteroidetes being the major colonizers with relative constant abundance until the rectum. Interestingly, wild-type and Tff3^KO animals did not show significant differences in their bacterial communities, suggesting that Tff3 is not involved in alterations of intraluminal or adhesive microbiota but is obviously important for mucosal protection, e.g., of the sensitive stem cells in the colonic crypts probably by a mucus plume.     

The effect of environmental conditions on nutritional quality of cherry tomato fruits: evaluation of two experimental Mediterranean greenhouses

BACKGROUND: The aim of this study was to examine how different environmental factors (temperature, solar radiation, and vapour‐pressure deficit [VPD]) influenced nutritional quality and flavour of cherry tomato fruits (Solanum lycopersicum L. cv. Naomi) grown in two types of experimental Mediterranean greenhouses: parral (low technology) and multispan (high technology). RESULTS: Fruits were sampled three times during 3 years (2004, 2005 and 2006): at the beginning, middle and end of the fruit production period. Values for temperature, solar radiation, and VPD peaked in the third sampling in both greenhouses; values were higher in the parral‐type greenhouse, triggering abiotic stress. This stress reduced the accumulation of lycopene and essential elements, augmenting the phytonutrient content and the antioxidant capacity of tomatoes. During the third sampling, sugars were increased while organic acid content diminished, producing tomatoes with a sweeter‐milder flavour. The parral greenhouse produced tomatoes with higher phenolic compounds and ascorbic acid contents, together with a greater antioxidant capacity, without showing differences in flavour parameters. CONCLUSION: The higher phytonutrients content and antioxidant activity during the environmental stress, more pronounced in parral than multispan greenhouse, together with the sweeter‐milder flavour, conferred a notable nutritional benefit, which considerably improved the nutritional and organoleptic quality of these tomatoes. Copyright © 2010 Society of Chemical Industry