Small Molecule Drugs for Treatment of Alzheimer’s Diseases Developed on the Basis of Mechanistic Understanding of the Serotonin Receptors 4 and 6

Alzheimer’s disease (AD) is the most common form of dementia affecting millions of people worldwide and currently, the only possible treatment is the use of symptomatic drugs. Therefore, there is a need for new and disease-modifying approaches. Among the numbers of biological targets which are today explored in order to prevent or limit the progression of AD, the modulation of serotonin receptors the subtype 4 and 6 receptors (5-HT4R and 5-HT6R) has received increasing attention and has become a promising target for improving cognition and limit the amyloid pathology through modulation of the neurotransmitter system. A large number of publications describing the development of ligands for these serotonin receptors have emerged, and their pharmaceutical potential is now quite evident. However, 5-HT4R and 5-HT6R functionality is much more complex than initially defined. This chapter describes recent advances in the understanding of this modulation as well as the medicinal chemistry efforts towards development of selective 5-HT4R or 5-HT6R ligands

Local biochemical and morphological differences in human Achilles tendinopathy: a case control study

<p>Abstract</p> <p>Background</p> <p>The incidence of Achilles tendinopathy is high and underlying etiology as well as biochemical and morphological pathology associated with the disease is largely unknown. The aim of the present study was to describe biochemical and morphological differences in chronic Achilles tendinopathy. The expressions of growth factors, inflammatory mediators and tendon morphology were determined in both chronically diseased and healthy tendon parts.</p> <p>Methods</p> <p>Thirty Achilles tendinopathy patients were randomized to an expression-study (<it>n </it>= 16) or a structural-study (<it>n </it>= 14). Biopsies from two areas in the Achilles tendon were taken and structural parameters: fibril density, fibril size, volume fraction of cells and the nucleus/cytoplasm ratio of cells were determined. Further gene expressions of various genes were analyzed.</p> <p>Results</p> <p>Significantly smaller collagen fibrils and a higher volume fraction of cells were observed in the tendinopathic region of the tendon. Markers for collagen and its synthesis collagen 1, collagen 3, fibronectin, tenascin-c, transforming growth factor-β fibromodulin, and markers of collagen breakdown matrix metalloproteinase-2, matrix metalloproteinase-9 and metallopeptidase inhibitor-2 were significantly increased in the tendinopathic region. No altered expressions of markers for fibrillogenesis, inflammation or wound healing were observed.</p> <p>Conclusion</p> <p>The present study indicates that an increased expression of factors stimulating the turnover of connective tissue is present in the diseased part of tendinopathic tendons, associated with an increased number of cells in the injured area as well as an increased number of smaller and thinner fibrils in the diseased tendon region. As no fibrillogenesis, inflammation or wound healing could be detected, the present data supports the notion that tendinopathy is an ongoing degenerative process.</p> <p>Trial registration</p> <p>Current Controlled Trials <a href="http://www.controlled-trials.com/ISRCTN20896880">ISRCTN20896880</a></p

A Mutational Analysis of the Endophilin-A N-BAR Domain Performed in Living Flies

BACKGROUND: Endophilin is a cytoplasmic protein with an important function in clathrin-dependent endocytosis at synapses and elsewhere. Endophilin has a BAR (Bin/Amphiphysin/Rvs-homology) domain, which is implicated in the sensing and induction of membrane curvature. Previous structure-function studies of the endophilin-A BAR domain have almost exclusively been made in reduced systems, either in vitro or ex vivo in cultured cells. To extend and complement this work, we have analyzed the role played by the structural features of the endophilin-A BAR domain in Drosophila in vivo. METHODOLOGY/PRINCIPAL FINDINGS: The study is based on genetic rescue of endophilin-A (endoA) null mutants with wild type or mutated endoA transgenes. We evaluated the viability of the rescuants, the locomotor behavior in adult flies and the neurotransmission at the larval neuromuscular junction. Whereas mutating the endophilin BAR domain clearly affected adult flies, larval endophilin function was surprisingly resistant to mutagenesis. Previous reports have stressed the importance of a central appendage on the convex BAR surface, which forms a hydrophobic ridge able to directly insert into the lipid bilayer. We found that the charge-negative substitution A66D, which targets the hydrophobic ridge and was reported to completely disrupt the ability of endophilin-BAR to tubulate liposomes in vitro, rescued viability and neurotransmission with the same efficiency as wild type endoA transgenes, even in adults. A similar discrepancy was found for the hydrophilic substitutions A63S/A66S and A63S/A66S/M70Q. The A66W mutation, which introduces a bulky hydrophobic side chain and induces massive vesiculation of liposomes in vitro, strongly impeded eye development, even in presence of the endogenous endoA gene. Substantial residual function was observed in larvae rescued with the EndoA(Arf) transgene, which encodes a form of endophilin-A that completely lacks the central appendage. Whereas a mutation (D151P) designed to increase the BAR curvature was functional, another mutation (P143A, DeltaLEN) designed to decrease the curvature was not. CONCLUSIONS/SIGNIFICANCE: Our results provide novel insight into the structure/function relationship of the endophilin-A BAR domain in vivo, especially with relation to synaptic function

Teleworking practice in small and medium-sized firms: Management style and worker autonomy

In an empirical study of teleworking practices amongst small and medium-sized enterprises (SMEs) in West London, organisational factors such as management attitudes, worker autonomy and employment flexibility were found to be more critical than technological provision in facilitating successful implementation. Consequently, we argue that telework in most SMEs appears as a marginal activity performed mainly by managers and specialist mobile workers

Democratic cultural policy : democratic forms and policy consequences

The forms that are adopted to give practical meaning to democracy are assessed to identify what their implications are for the production of public policies in general and cultural policies in particular. A comparison of direct, representative, democratic elitist and deliberative versions of democracy identifies clear differences between them in terms of policy form and democratic practice. Further elaboration of these differences and their consequences are identified as areas for further research

Immediate and Delayed Cochlear Neuropathy after Noise Exposure in Pubescent Mice

Moderate acoustic overexposure in adult rodents is known to cause acute loss of synapses on sensory inner hair cells (IHCs) and delayed degeneration of the auditory nerve, despite the completely reversible temporary threshold shift (TTS) and morphologically intact hair cells. Our objective was to determine whether a cochlear synaptopathy followed by neuropathy occurs after noise exposure in pubescence, and to define neuropathic versus non-neuropathic noise levels for pubescent mice. While exposing 6 week old CBA/CaJ mice to 8-16 kHz bandpass noise for 2 hrs, we defined 97 dB sound pressure level (SPL) as the threshold for this particular type of neuropathic exposure associated with TTS, and 94 dB SPL as the highest non-neuropathic noise level associated with TTS. Exposure to 100 dB SPL caused permanent threshold shift although exposure of 16 week old mice to the same noise is reported to cause only TTS. Amplitude of wave I of the auditory brainstem response, which reflects the summed activity of the cochlear nerve, was complemented by synaptic ribbon counts in IHCs using confocal microscopy, and by stereological counts of peripheral axons and cell bodies of the cochlear nerve from 24 hours to 16 months post exposure. Mice exposed to neuropathic noise demonstrated immediate cochlear synaptopathy by 24 hours post exposure, and delayed neurodegeneration characterized by axonal retraction at 8 months, and spiral ganglion cell loss at 8-16 months post exposure. Although the damage was initially limited to the cochlear base, it progressed to also involve the cochlear apex by 8 months post exposure. Our data demonstrate a fine line between neuropathic and non-neuropathic noise levels associated with TTS in the pubescent cochlea

Iron Oxide Nanoparticles as a Contrast Agent for Synchrotron Imaging of Sperm

Fast phase-contrast imaging offered by modern synchrotron facilities opens the possibility of imaging dynamic processes of biological material such as cells. Cells are mainly composed of carbon and hydrogen, which have low X-ray attenuation, making cell studies with X-ray tomography challenging. At specific low energies, cells provide contrast, but cryo-conditions are required to protect the sample from radiation damage. Thus, non-toxic labelling methods are needed to prepare living cells for X-ray tomography at higher energies. We propose using iron oxide nanoparticles due to their proven compatibility in other biomedical applications. We show how to synthesize and attach iron oxide nanoparticles and demonstrate that cell-penetrating peptides facilitate iron oxide nanoparticle uptake into sperm cells. We show results from the TOMCAT Nanoscope (Swiss Light Source), showing that iron oxide nanoparticles allow the heads and midpiece of fixed sperm samples to be reconstructed from X-ray projections taken at 10 keV.Comment: 21 pages, 6 figure

Age group, location or pedagogue: factors affecting parental choice of kindergartens in Hungary

Hungary has experienced significant political, economic, demographic and social changes since the end of Soviet domination in the 1990s. The gradual move towards liberal-democracy has been accompanied by growing emphasis on individualism, choice and diversity. Universal kindergarten provision for 5-6 year olds is a long established feature of the Hungarian education system, but little is known about parental choice (Török, 2004). A case study (Yin, 2004) of factors influencing parental choice and satisfaction was undertaken in one Hungarian town. This was based on a survey of 251 parents of children attending both mixed-age and same-age groups across 12 kindergartens. Parents suggested that the most important influences were geographical location and the individual pedagogue(s). Given that traditionally each pedagogue follows ‘their’ cohort from kindergarten entry to primary school, their influence appears heightened. Although generally satisfied with their chosen arrangement, parents from same-age groups expressed significantly more confidence and satisfaction, particularly in relation to cognitive development and preparation for school. Parents appear less convinced about the trend towards mixed-age groups and questions are raised about sufficiency of evidence of their benefits in a Hungarian context and the driving factors behind change

EXPERIENCES OF DRUG USERS IN IIA CLASS JAIL YOGYAKARTA

United Nations Office on Drugs and Crime (UNODC) estimated that about 149-272 million people or 3.3 % - 6.1 % of world population aged 15-64 years used drugs (even once) during their life time. This estimation will increase with time (BNN, 2011). The number of prisoners suffering HIV/AIDS in recent years were increasing as well if compared to its numbers in the year 2011 from 787 people to 1042 people. It was estimated that in the year 2015, the number of drug users in Indonesia would increase to 5.8 million people, since the number of drug users at the present time were reached 4 million people. For the time being, in Yogyakarta second A class drug jail , the number of drug users were 256 people; this number were constant; its mean that if there was prisoner got his / her freedom, another prisoner was incoming. Data from BNN in August 2013 years, 70% of 4 million drug users in Indonesia were workers (productive aged). Aim; To discovered population research experiences that cause them used drugs and depend on its. Research method: This was qualitative research with phenomenological approach. Data gathering technique were deep interview and FGD toward 30 respondents. Data were analyzed using reduction, data display, and conclusion drawing/verification. The majority of respondents mentioned that they used drugs because of they wanted to know and the influence of friends. Drugs, kinds of sabu, used to increase energy and ganja were used to obtain peacefulness. Drugs users wanted to use its forever; therefore, they wanted to stop because of punishment to be in jail not because of the drugs had negative effects to the body. The majority of respondents mentioned that to stop using drugs must be self motivated; on the contrary, the obstacle to stop using drugs because of missing sensation to use it. They named it suggest. Using drugs were conducted by research population because of environmental influence, to increase energy and to obtain peacefulness. Keywords : The experiences of drug use