Chiral hplc-cd studies of the antituberculosis drug (+)-ethambutol

Long standing errors in major pharmacopoeiae (BP,USP, and Eu.Ph.) concerning the absolute stereochemistry of the widely used antituberculosis drug (+)-ethambutol have been clarified by unambiguous synthesis and chiral HPLC. on a Pirkle, covalent D -phenylglycine column of perbenzoyl derivatives of each stereomer; the enantiomeric (?)-(R,R) and (+)-(S,S)-ethambutols together with the optically inactive (meso)-(R,S)-ethambutol. This paper describes how circular dichroism (CD) alone and combined with HPLC is used to demonstrate this chiral separation and also to confirm the absolute stereochemistry of each stereomer of ethambutol and its synthetic precursor 2-aminobutan-1-ol from studies of ?exciton coupling.”? The strengths and weaknesses of these chiral techniques are discussed.     

Alzheimer’s Disease and Epilepsy: A Perspective on the Opportunities for Overlapping Therapeutic Innovation

Early-onset Alzheimer’s disease (AD) is associated with variants in amyloid precursor protein (APP) and presenilin (PSEN) 1 and 2. It is increasingly recognized that patients with AD experience undiagnosed focal seizures. These AD patients with reported seizures may have worsened disease trajectory. Seizures in epilepsy can also lead to cognitive deficits, neuroinflammation, and neurodegeneration. Epilepsy is roughly three times more common in individuals aged 65 and older. Due to the numerous available antiseizure drugs (ASDs), treatment of seizures has been proposed to reduce the burden of AD. More work is needed to establish the functional impact of seizures in AD to determine whether ASDs could be a rational therapeutic strategy. The efficacy of ASDs in aged animals is not routinely studied, despite the fact that the elderly represents the fastest growing demographic with epilepsy. This leaves a particular gap in understanding the discrete pathophysiological overlap between hyperexcitability and aging, and AD more specifically. Most of our preclinical knowledge of hyperexcitability in AD has come from mouse models that overexpress APP. While these studies have been invaluable, other drivers underlie AD, e.g. PSEN2. A diversity of animal models should be more frequently integrated into the study of hyperexcitability in AD, which could be particularly beneficial to identify novel therapies. Specifically, AD-associated risk genes, in particular PSENs, altogether represent underexplored contributors to hyperexcitability. This review assesses the available studies of ASDs administration in clinical AD populations and preclinical studies with AD-associated models and offers a perspective on the opportunities for further therapeutic innovation.

     

Production inEscherichia coli of activeSorghum phosphoenolpyruvate carboxylase which can be phosphorylated

Phosphoenolpyruvate carboxylase (PEPC)-deficient mutants ofEscherichia coli have been complemented with a plasmid bearing a full-length cDNA encoding the C4-type form ofSorghum leaf PEPC. Transformed cells grew on minimal medium. Two clones were selected which produce a functional and full-sized enzyme protein as determined by activity assays, immunochemical behavior and SDS-PAGE. In addition, regulatory phosphorylation of immunopurified recombinant PEPC was observed when the enzyme was incubated with a partially purified plant PEPC kinase. These results establish thatE. coli cells produce a genuine, phosphate-free, higher-plant PEPC. Application of immunoadsorbtion chromatography to bacterial extracts makes it possible to prepare highly pure protein available for biochemical studies.     

Quantitative pinch stimulator for exploring evoked nociceptive responses: A pilot study

Background  

A mechanical noxious stimulator is useful for studies of pain, both for clinic and basic research. We propose to use a pinch stimulator that can not only generate a quantitative, reproducible noxious pinch but also simultaneously provide a synchronous external trigger signal, which is essential for acquisition of evoked potentials.     

Morphogenetic Processes: Application to Cambial Growth Dynamics

Both the physiological and the pathological morphogenetic processes that we can meet in embryogenesis, neogenesis and degenerative dysgenesis present common features: they are ruled by three different kinds of mechanisms, one related to cell migration, the second to cell differentiation and the third to cell proliferation. We deal here with an application to the cambial growth which essentially involves the third type of mechanism. Woody plants produce secondary tissue (secondary xylem and phloem) from a meristematic tissue called vascular cambium, responsible for the radial growth of a tree. This paper focuses on the formation of secondary xylem, considered in two dimensions in a cross-section framework. A new discrete modelling approach is used, based on the cellular scale, in order to attain a more accurate understanding of how the elementary microscopic behaviour of each cell takes part in the macroscopic morphogenesis. The mathematical model essentially uses an occurrence method simulating the main features of radial growth with simple geometric rules, such as Thom's division rule (Thom,1972)to account for the cell proliferation. The study applies to concrete instances in which the changes made in the geometrical cellular patterns of the vascular cambium clearly affect the shape of the tree, as in Pinus radiata (D. Don.).     

Placenta proteome analysis from Down syndrome pregnancies for biomarker discovery

Down syndrome is one of the most frequent chromosomal disorders, with a prevalence of approximately 1/500 to 1/800, depending on the maternal age distribution of the pregnant population. However, few reliable protein biomarkers have been used in the diagnosis of this disease. Recent progress in quantitative proteomics has offered opportunities to discover biomarkers for tracking the progression and for understanding the molecular mechanisms of Down syndrome. In the present study, placental samples were analyzed by fluorescence two-dimensional differential gel electrophoresis (2D-DIGE) and differentially expressed proteins were identified by matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). In total, 101 proteins have been firmly identified representing 80 unique gene products. These proteins mainly function in cytoskeleton structure and regulation (such as vimentin and Profilin-1). Additionally, our quantitative proteomics approach has identified numerous previously reported Down syndrome markers, such as myelin protein. Here we present several Down syndrome biomarkers including galectin-1, ataxin-3 and sprouty-related EVH1 domain-containing protein 2 (SPRED2), which have not been reported elsewhere and may be associated with the progression and development of the disease. In summary, we report a comprehensive placenta-based proteomics approach for the identification of potential biomarkers for Down syndrome, in which serum amyloid P-component (APCS) and ataxin-3 have been shown to be up-regulated in the maternal peripheral plasma of Down syndrome cases. The potential of utilizing these markers for the prognosis and screening of Down syndrome warrants further investigation.