Novel Bifunctional Compounds Targeting Nicotine and Dopamine Receptor Subtypes: Synthesis and Pharmacological Investigation

Future therapies for diseases associated with altered dopaminergic signaling, including Parkinson\u2019s disease, schizophrenia and drug addiction or drug dependence, may be substantially built on the existence of intramembrane receptor-receptor interactions within receptor mosaics where it is believed that the D2 receptor may operate as the \u201chub receptor\u201d [1]. In particular, it has been proposed that striatal dopaminergic neurotransmission could be under the control of receptor heteromers containing D2 autoreceptors and non-alpha7 nicotinic acetylcholine heteroreceptors [2]. In an attempt to investigate the biochemical and functional interactions between dopaminergic autoreceptors and nAChRs containing the beta2 subunit, we designed and prepared a group of potential bifunctional derivatives incorporating a D2/D3 agonist moiety and a nicotinic alpha4beta2 antagonist fragment, linked by polymethylene spacers of different length. The new compounds have been biologically characterized for their affinity/specificity/functional profile at the target nACh and D2 receptor subtypes. The synthesis of the designed derivatives and the results of their pharmacological investigation will be presented and discussed. [1] K.Fuxe, D.Marcellino, A.Rivera, Z.Diaz-Cabiale, M.Filip, B.Gago, D.C.S.Roberts, U.Langel, S.Genedani, L.Ferraro, A.de la Calle, J.Narvaez, S.Tanganelli, A.Woods, L.F.Agnati, Brain Res.Rev., 58, 2008, 415-452. [2] D.Quarta, F.Ciruela, K.Patkar, J.Borycz, M.Solinas, C.Lluis, R.Franco, R.A.Wise, S.R.Goldberg, B.T.Hope, A.Woods, S.Ferr\ue9, Neuropsychopharmacol., 32, 2007, 35-42

Folates in Trypanosoma brucei: achievements and opportunities

Trypanosoma brucei is the agent of human African trypanosomiasis (HAT), a neglected disease that threatens the lives of 65 million people in sub-Saharan Africa every year. Unfortunately, available therapies are unsatisfactory, due primarily to safety issues and development of drug resistance. Over the last decades significant effort has been made in the discovery of new potential anti-HAT agents, with help from the World Health Organization (WHO) and private\u2013public partnerships such as the Drugs for Neglected Diseases Initiative (DNDi). Whereas antifolates have been a valuable source of drugs against bacterial infections and malaria, compounds effective against T. brucei have not yet been identified. Considering the relatively simple folate metabolic pathway in T. brucei, along with results obtained in this research field so far, we believe that further investigations might lead to effective chemotherapeutic agents. Herein we present a selection of the more promising results obtained so far in this field, underlining the opportunities that could lead to successful therapeutic approaches in the future

Synthesis of novel epibatidine-related derivatives through 1,3-dipolar cycloaddition of pyridinenitrile oxides

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Clustering protein environments for function prediction: finding PROSITE motifs in 3D

Background: Structural genomics initiatives are producing increasing numbers of three-dimensional (3D) structures for which there is little functional information. Structure-based annotation of molecular function is therefore becoming critical. We previously presented FEATURE, a method for describing microenvironments around functional sites in proteins. However, FEATURE uses supervised machine learning and so is limited to building models for sites of known importance and location. We hypothesized that there are a large number of sites in proteins that are associated with function that have not yet been recognized. Toward that end, we have developed a method for clustering protein microenvironments in order to evaluate the potential for discovering novel sites that have not been previously identified. Results: We have prototyped a computational method for rapid clustering of millions of microenvironments in order to discover residues whose surrounding environments are similar and which may therefore share a functional or structural role. We clustered nearly 2,000,000 environments from 9,600 protein chains and defined 4,550 clusters. As a preliminary validation, we asked whether known 3D environments associated with PROSITE motifs were "rediscovered". We found examples of clusters highly enriched for residues that share PROSITE sequence motifs. Conclusion: Our results demonstrate that we can cluster protein environments successfully using a simplified representation and K-means clustering algorithm. The rediscovery of known 3D motifs allows us to calibrate the size and intercluster distances that characterize useful clusters. This information will then allow us to find new clusters with similar characteristics that represent novel structural or functional sites

A distributed interleaving scheme for efficient access to WideIO DRAM memory

Achieving the main memory (DRAM) required bandwidth at acceptable power levels for current and future applications is a major challenge for System-on-Chip designers for mobile platforms. Three dimensional (3D) integration and 3D stacked DRAM memories promise to provide a significant boost in bandwidth at low power levels by exploiting multiple channels and wide data interfaces. In this paper, we address the problem of efficiently exploiting the multiple channels provided by standard (JEDEC’s WIDEIO) 3D-stacked memories, to extract maximal effective bandwidth and minimize latency for main memory access. We propose a new distributed interleaved access method that leverages the on-chip interconnect to simplify the design and implementation of the DRAM controller, without impacting performance compared to traditional centralized implementations. We perform experiments on realistic workload for a mobile communication and multimedia platform and show that our proposed distributed interleaving memory access method improves the overall throughput while minimally impacting the performance of latency sensitive communication flows

Power Corrections to Perturbative QCD and OPE in Gluon Green Functions

We show that QCD Green functions in Landau Gauge exhibit sizable $O(1/\mu^2)$ corrections to the expected perturbative behavior at energies as high as 10 GeV. We argue that these are due to a $$-condensate which does not vanish in Landau gauge.Comment: 3 pages 1 figure lattice2001 (gaugetheories

Design and Optimization of a Lactate Amperometric Biosensor based on Lactate Oxidase and Multi Walled-Carbon Nanotubes

Lactate concentration in physiological fluids is an indicator of the energy production under anaerobic conditions of the whole organism [1]. Normal value for lactate level in blood ranges from 0.5 – 2.5 mM. Blood lactate values exceeding 7-8 mM are sometimes associated with a fatal outcome. The lactate level in blood is elevated under number of conditions. It is a major indicator of ischemic conditions, e.g. under the category of tissue hypoxia, the individual causes include shock (hypovolemic, cardiogenic or endotoxic), respiratory failure (asphyxia) and severe congestive heart failure. Gauging blood lactate is also relevant for the results of exercise and athletic performance [2]. Several approaches were made to develop a number of improved methods for lactic acid determination, such ad optic techniques (HPLC, mass spectroscopy, ion exchange chromatography, etc.) and electrochemical techniques (potentiometric and voltammetric detections, FET-based sensors, etc.) [1]. The present study is focused on development of technologies for lactate detection based on amperometric measures employing lactate oxidase (LOD). The project’s aim is double: the development of biosensors which can be integrated in Petri dishes for monitoring cell cultures, on one hand, and which can be integrated in point-of-care devices for human monitoring in personalized therapies, on the other hand. In both the cases, analysis of more than one substrate at the same time will be considered. Nanotechnology may be used in the optimization of electrodes with carbon nanotubes (CNT). Previous studies showed that CNTs can highly improve the electrocatalytic activity in electrochemical devices for monitoring metabolites [3]

Phaseolus vulgaris L. Extract: Alpha-amylase inhibition against metabolic syndrome in mice

To examine the effects of the alpha-amylase inhibitor isoform 1 called phaseolamin, a standardized extract from white kidney beans (Phaseolus vulgaris L) was tested against the hallmarks of metabolic syndrome. The efficacy of a per os repeated treatment with P. vulgaris extract (500 mg/kg) was compared with metformin (100 mg/kg) and atorvastatin (10 mg/kg) in a model of metabolic syndrome evoked by prolonged high fat diet (HFD; week 1 to week 19) in C57BL/6 mice. Bean extract and compounds administration started after metabolic syndrome establishment (week 11). P. vulgaris extract reduced the body weight overtime, as well as effectively lowered glycaemia, triglycerides, and cholesterol. On week 19, bean extract normalized the HFD-evoked tolerance to glucose and insulin. According to the phytochemical characterization, it inhibited the alpha-amylase activity. Animals treated with the extract were rescued from motor impairments and nociceptive threshold alterations induced by HFD. Specific organs analysis revealed that P. vulgaris extract decreased hepatic steatosis and lipid peroxidation in liver. It protected the heart from HFD oxidative alterations increasing the expression of the detoxifying enzymes catalase and glutathione reductase, and normalizing NADH dehydrogenase level. The histological analysis of aorta showed a protection about the development of fatty streaks in the muscular layers. In conclusion, a prolonged treatment with the standardized extract of P. vulgaris significantly reduced several pathological features related to a metabolic syndrome-like condition; a multifactorial approach that candidates this vegetal product as a possible therapeutic option against metabolic syndrome

Artefacts and <A2> power corrections : revisiting the MOM Z_psi and Z_V

We extract the power corrections due to the A^2 condensate in the overlap quark propagator (vector part of the inverse propagator Z_psi). The results are consistent with the previous gluon analysis. The role of artefacts is extensively discussed.Comment: 33 pages, 5 figure

GHz QKD at telecom wavelengths using up-conversion detectors

We have developed a hybrid single photon detection scheme for telecom wavelengths based on nonlinear sum-frequency generation and silicon single-photon avalanche diodes (SPADs). The SPAD devices employed have been designed to have very narrow temporal response, i.e. low jitter, which we can exploit for increasing the allowable bit rate for quantum key distribution. The wavelength conversion is obtained using periodically poled Lithium niobate waveguides (W/Gs). The inherently high efficiency of these W/Gs allows us to use a continuous wave laser to seed the nonlinear conversion so as to have a continuous detection scheme. We also present a 1.27GHz qubit repetition rate, one-way phase encoding, quantum key distribution experiment operating at telecom wavelengths that takes advantage of this detection scheme. The proof of principle experiment shows a system capable of MHz raw count rates with a QBER less than 2% and estimated secure key rates greater than 100 kbit/s over 25 km.Comment: 12 pages, 7 figure