The interaction between the renin-angiotensin system and peroxisome proliferator activated receptors: A hypothesis including the participation of mitochondria in aging

The objective of improving health is intimately associated with preventing and delaying age-related diseases. Nutritional and pharmacological approaches aimed at retarding aging are uncovering mechanisms, whose definitive roles in cell and tissue physiology need to be defined. In this article we hypothesize that peroxisome proliferator activated receptor (PPAR)-modulation is a pivotal process that underlies the association between mitochondria and the renin-angiotensin system (RAS) in aging. This hypothesis is based on several lines of evidence suggesting that: a) mitochondrial function and oxidant production are active participants in the aging process; b) PPARs, by regulating mitochondrial function and uncoupling proteins (UCP), seem to play a major role in the age-retarding effects of caloric restriction; c) RAS inhibition delays the deleterious effects of aging and also upregulates PPARs; and d) a number of physiological and molecular events that occur in experimental caloric restriction, and experimental and clinical RAS inhibition, involve changes in mitochondrial functions.Fil: de Cavanagh, E. M. V.. Universidad de Buenos Aires; ArgentinaFil: Piotrkowski, Barbara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Fraga, César Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentin

Poly(amino acid)-grafted polymacrolactones. Synthesis, self-assembling and ionic coupling properties

Polyglobalide (PGl) with number average polymerization degree of ~20 was prepared by enzymatic ROP and then polyfunctionalized at 60% with aminothioethylene groups. The PGl20-(NH2)12 copolymer was used as macroinitiator for the ROP of NCAs of BLG (¿-benzyl L-glutamate) and ZLL (eN-carbobenzoxy-l-lysine) protected amino acids to produce neutral polypeptide-grafted polyglobalides poly[Gl20-graft-(AA)z] with z¿=¿5 and 12, which upon deprotection, afforded anionic and cationic copolymers, respectively. Both protected and deprotected graft copolymers were characterized in full detail by NMR, and their thermal properties were evaluated by TGA and DSC. The structure of these copolymers in the solid-state was examined by FTIR and XRD using synchrotron radiation. All grafted polyglobalides were amorphous but the polypeptide side chains were arranged in either alpha-helix or beta-sheet conformation, and reliable indications on the occurrence of supramolecular structures were frequently found. The capacity of poly[Gl20-graft-(AA)z] copolymers to self-assemble in aqueous medium was evidenced by the preparation of well-shaped spheroidal nanoparticles with a diversity of sizes depending on copolymer composition and charge. Loading and release of doxorubicin (DOX) from nanoparticles made of negatively charged poly[Gl20-graft-(LGA)12] as well as DNA complexation with cationic poly[Gl20-graft-(LL)5] were explored to appraise the potential of these copolymers for building drug delivery systems.Peer ReviewedPostprint (author's final draft

Frontostriatal anatomical connections predict age- and difficulty-related differences in reinforcement learning

Contains fulltext : 167812.pdf (Publisher’s version ) (Closed access)Reinforcement learning (RL) is supported by a network of striatal and frontal cortical structures that are connected through white-matter fiber bundles. With age, the integrity of these white-matter connections declines. The role of structural frontostriatal connectivity in individual and age-related differences in RL is unclear, although local white-matter density and diffusivity have been linked to individual differences in RL. Here we show that frontostriatal tract counts in young human adults (aged 18-28), as assessed noninvasively with diffusion-weighted magnetic resonance imaging and probabilistic tractography, positively predicted individual differences in RL when learning was difficult (70% valid feedback). In older adults (aged 63-87), in contrast, learning under both easy (90% valid feedback) and difficult conditions was predicted by tract counts in the same frontostriatal network. Furthermore, network-level analyses showed a double dissociation between the task-relevant networks in young and older adults, suggesting that older adults relied on different frontostriatal networks than young adults to obtain the same task performance. These results highlight the importance of successful information integration across striatal and frontal regions during RL, especially with variable outcomes.12 p

A Recombinant Avian Infectious Bronchitis Virus Expressing a Heterologous Spike Gene Belonging to the 4/91 Serotype

We have shown previously that replacement of the spike (S) gene of the apathogenic IBV strain Beau-R with that from the pathogenic strain of the same serotype, M41, resulted in an apathogenic virus, BeauR-M41(S), that conferred protection against challenge with M41 [1]. We have constructed a recombinant IBV, BeauR-4/91(S), with the genetic backbone of Beau-R but expressing the spike protein of the pathogenic IBV strain 4/91(UK), which belongs to a different serogroup as Beaudette or M41. Similar to our previous findings with BeauR-M41(S), clinical signs observations showed that the S gene of the pathogenic 4/91 virus did not confer pathogenicity to the rIBV BeauR-4/91(S). Furthermore, protection studies showed there was homologous protection; BeauR-4/91(S) conferred protection against challenge with wild type 4/91 virus as shown by the absence of clinical signs, IBV RNA assessed by qRT-PCR and the fact that no virus was isolated from tracheas removed from birds primarily infected with BeauR-4/91(S) and challenged with IBV 4/91(UK). A degree of heterologous protection against M41 challenge was observed, albeit at a lower level

Solution structure of the inhibitory phosphorylation domain of myosin phosphatase targeting subunit 1.

Cell motility, such as smooth muscle contraction and cell migration, is controlled by the reversible phosphorylation of the regulatory light chain of myosin II and other cytoskeletal proteins. Mounting evidence suggests that in smooth muscle cells and other types of cells in vertebrates, myosin phosphatase (MP) plays an important role in controlling the phosphorylation of myosin II as well as other cytoskeletal proteins, including ezrin, moesin, and radixin.1 MP is a holoenzyme consisting of a catalytic subunit of a type-1 Ser/Thr phosphatase (PP1C) delta isoform, a myosin phosphatase targeting subunit 1 (MYPT1), and an accessory subunit M21. In this ternary complex, MYPT1 is responsible for regulating the phosphatase activity.1 A recent X-ray crystallographic study revealed an allosteric interaction between PP1C and the N-terminal ankyrin repeat domain of MYPT1 that confers the substrate specificity of the enzyme.2 MP activity is suppressed when Thr696 or Thr853 of MYPT1 is phosphorylated by various kinases, such as ROCK, ZIPK, ILK, and PAK.1,3 However, it is still unclear how the phosphorylation of MYPT1 inhibits MP activity. The amino acid sequence around Thr696 of MYPT1 is highly conserved among MYPT1 family members including MYPT2 and MBS85. Therefore, structural insights into the inhibitory domain of MYPT1 are expected to provide new clues to fully elucidate the mechanism that controls phosphatase activity via the phosphorylation of MYPT1 or other family members involved in kinase-phosphatase crosstalk in cytoskeletal regulation. Here, we prepared a bacterial recombinant fragment of MYPT1 corresponding to residues 658 to 714, including the phosphorylation site Thr696, and determined its three-dimensional structure through the use of computer-assisted distance geometry and a simulated annealing protocol combined with stable-isotope-aided multi-dimensional NMR techniques

A peptide mimic of the chemotaxis inhibitory protein of Staphylococcus aureus: towards the development of novel anti-inflammatory compounds

Complement factor C5a is one of the most powerful pro-inflammatory agents involved in recruitment of leukocytes, activation of phagocytes and other inflammatory responses. C5a triggers inflammatory responses by binding to its G-protein-coupled C5a-receptor (C5aR). Excessive or erroneous activation of the C5aR has been implicated in numerous inflammatory diseases. The C5aR is therefore a key target in the development of specific anti-inflammatory compounds. A very potent natural inhibitor of the C5aR is the 121-residue chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS). Although CHIPS effectively blocks C5aR activation by binding tightly to its extra-cellular N terminus, it is not suitable as a potential anti-inflammatory drug due to its immunogenic properties. As a first step in the development of an improved CHIPS mimic, we designed and synthesized a substantially shorter 50-residue adapted peptide, designated CHOPS. This peptide included all residues important for receptor binding as based on the recent structure of CHIPS in complex with the C5aR N terminus. Using isothermal titration calorimetry we demonstrate that CHOPS has micromolar affinity for a model peptide comprising residues 7–28 of the C5aR N terminus including two O-sulfated tyrosine residues at positions 11 and 14. CD and NMR spectroscopy showed that CHOPS is unstructured free in solution. Upon addition of the doubly sulfated model peptide, however, the NMR and CD spectra reveal the formation of structural elements in CHOPS reminiscent of native CHIPS

Infectious Bronchitis Virus induces acute interferon-gamma production through polyclonal stimulation of chicken leukocytes

AbstractInfectious Bronchitis Virus, a member of the Coronaviridae, is a respiratory pathogen in poultry. We found that in vitro stimulation with IBV resulted in ChIFN-γ production in splenocytes of both infected birds and uninfected birds. The non-specific stimulation did not occur when other avian viruses or other coronaviruses were used or when mammalian cells were stimulated with IBV. Inactivation of IBV reduced ChIFN-γ production, but ChIFN-γ remained elevated compared to unstimulated cells. An increase in ChIFN-γ mRNA was detected in splenocytes from IBV-infected and uninfected chickens as early as 1 h after stimulation with IBV. These results indicate that IBV acts as a polyclonal stimulus, inducing a rapid production of IFN-γ even without previous exposure to the virus

Design and implementation of a low-cost mechatronic shoe for biomechanical analysis of the human locomotion

In this paper the development of a low-cost and easy wearable mechatronic system for the measurement of ground reaction forces (GRF) for the biomechanical analysis of the human locomotion is presented. The system consists of an insole, a conditioning device for the signals produced by the sensors applied to the insole and a data acquisition system connected to a USB portable storage. The sensors applied to the insole can measure the reaction forces in the horizontal and vertical directions during locomotion. The prototype was validated by comparing the data from the sensors with the values obtained using a force platform

The U&I study: study protocol for a feasibility randomised controlled trial of a pre-cognitive behavioural therapy digital ‘informed choice’ intervention to improve attitudes towards uptake and implementation of CBT for psychosis

Background: At least 40% of people with psychosis have persistent distressing symptoms despite optimal medication treatment. Cognitive Behaviour Therapy for psychosis (CBTp) is the only NICE recommended individual therapy for psychosis, with effects on symptoms, distress and quality of life. Yet fewer than 20% of service-users receive it and 94% of trusts struggle to provide it. Of those offered it, 22-43% refuse or do not attend. We have developed a new pre-CBTp informed choice intervention to address knowledge and attitudes that influence uptake and implementation and now want to test it in a feasibility trial. Methods: The design is a 2-arm, feasibility RCT, with 1:1 randomisation, stratified by participant group and site. Participants are 40 psychosis patients and 40 clinicians, who are ambivalent towards uptake or implementation of CBTp. Sites are community and inpatient services in Sussex and London. The intervention is a pre-CBT digital psychoeducation intervention designed to address identified knowledge and attitudinal barriers to uptake and implementation of CBTp, incorporating behaviour change mechanisms, and supported by animated introductory, patient and clinician stories. The comparator is the NHS choices website for CBT. The primary aim is to assess clinical feasibility (recruitment, randomization, acceptability, use, delivery, outcome measurement, retention). A secondary aim is a preliminary evaluation of efficacy. Outcomes will be assessed at baseline, post-intervention, and one-month follow up (blind to treatment arm). The primary efficacy outcome is likelihood of offering/taking up CBTp. Secondary outcomes include knowledge and attitudes towards CBTp; illness perceptions; empowerment; psychological wellbeing (patients only); CBTp implementation (clinicians only). Use of the intervention and CBT behaviours during the follow-up period will be recorded, and captured in a feedback questionnaire. Use, acceptability and experience of outcome assessment will be explored in qualitative interviews with participants (n = 6 per group). The efficacy evaluation will report descriptive data, key model parameters and 95% Highest Probability Density intervals in a Bayesian growth model. Discussion: This is the first feasibility trial of a digital ‘informed choice’ decision aid for the implementation of CBTp. If the trial proves feasible and demonstrates preliminary evidence of efficacy, a large multi-site trial will be warranted