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  • The subventricular zone responds dynamically to mechanical brain injuries

    17 October 2018

    © 2006 Springer Science-Business Media, Inc. All rights reserved. Brain injury is a common yet relatively untreatable problem (Thurman, 1999). Of the 500,000 cases of traumatic brain injury annually in the United States, greater than 90,000 result in disability (Valadka, 2000). Mechanical injuries often occur to external regions of the brain: the cerebral cortex and other parts of the telencephalon. They can produce a wide variety of longterm and devastating symptoms and pathologies due to neuronal death. The underlying biological predicament in recovery from brain injury is that the adult central nervous system is generally incapable of replacing dead neurons. This concept has been challenged by the discovery of neurogenic adult stem cells in the subventricular zone (SVZ) (Alvarez-Buylla et al., 2000). It has been estimated that the SVZ replaces tens of thousands of olfactory bulb (OB) interneurons per day in rodents. Behavioral studies suggest that the constant turnover of OB neurons allows olfactory discrimination (Gheusi et al., 2000). Adult humans and other primates have also been shown to possess neurogenic SVZ cells with many of the features delineated in rodents (Eriksson et al., 1998; Bernier et al., 2000; Weickert et al., 2000; Kornack and Rakic, 2001; Pencea et al., 2001b). Granted, the sense of smell is not of vital importance for humans, unless one is a sommelier. Yet, since the SVZ is in close proximity to the cerebral cortex and other functionally important forebrain nuclei, hope has risen that the great neurogenic and migratory potential of adult stem cells may be co-opted for repair. This optimism is bolstered by the fact that adult SVZ cells are descendants of the proliferative neuroepithelia which, during development, give rise to the myriad neural cells in the telencephalon.

  • Elucidation of binding sites of dual antagonists in the human chemokine receptors CCR2 and CCR5.

    17 October 2018

    Design of dual antagonists for the chemokine receptors CCR2 and CCR5 will be greatly facilitated by knowledge of the structural differences of their binding sites. Thus, we computationally predicted the binding site of the dual CCR2/CCR5 antagonist N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzohepten-8-yl] carbonyl]amino]benzyl]tetrahydro-2H-pyran-4-aminium (TAK-779), and a CCR2-specific antagonist N-(carbamoylmethyl)-3-trifluoromethyl benzamido-parachlorobenzyl 3-aminopyrrolidine (Teijin compound 1) in an ensemble of predicted structures of human CCR2 and CCR5. Based on our predictions of the protein-ligand interactions, we examined the activity of the antagonists for cells expressing thirteen mutants of CCR2 and five mutants of CCR5. The results show that residues Trp98(2.60) and Thr292(7.40) contribute significantly to the efficacy of both TAK-779 and Teijin compound 1, whereas His121(3.33) and Ile263(6.55) contribute significantly only to the antagonistic effect of Teijin compound 1 at CCR2. Mutation of residues Trp86(2.60) and Tyr108(3.32) adversely affected the efficacy of TAK-779 in antagonizing CCR5-mediated chemotaxis. Y49A(1.39) and E291A(7.39) mutants of CCR2 showed a complete loss of CCL2 binding and chemotaxis, despite robust cell surface expression, suggesting that these residues are critical in maintaining the correct receptor architecture. Modeling studies support the hypothesis that the residues Tyr49(1.39), Trp98(2.60), Tyr120(3.32), and Glu291(7.39) of CCR2 form a tight network of aromatic cluster and polar contacts between transmembrane helices 1, 2, 3, and 7.

  • Identification of sequences common to more than one therapeutic target to treat complex diseases: simulating the high variance in sequence interactivity evolved to modulate robust phenotypes.

    17 October 2018

    BACKGROUND: Genome-wide association studies show that most human traits and diseases are caused by a combination of environmental and genetic causes, with each one of these having a relatively small effect. In contrast, most therapies based on macromolecules like antibodies, antisense oligonucleotides or peptides focus on a single gene product. On the other hand, complex organisms seem to have a plethora of functional molecules able to bind specifically to multiple genes or genes products based on their sequences but the mechanisms that lead organisms to recruit these multispecific regulators remain unclear. RESULTS: The mutational biases inferred from the genomic sequences of six organisms show an increase in the variance of sequence interactivity in complex organisms. The high variance in the interactivity of sequences presents an ideal evolutionary substrate to recruit sequence-specific regulators able to target multiple gene products. For example, here it is shown how the 3'UTR can fluctuate between sequences likely to be complementary to other sites in the genome in the search for advantageous interactions. A library of nucleotide- and peptide-based tools was built using a script to search for candidates (e.g. peptides, antigens to raise antibodies or antisense oligonucleotides) to target sequences shared by key pathways in human disorders, such as cancer and immune diseases. This resource will be accessible to the community at www.wikisequences.org . CONCLUSIONS: This study describes and encourages the adoption of the same multitarget strategy (e.g., miRNAs, Hsp90) that has evolved in organisms to modify complex traits to treat diseases with robust pathological phenotypes. The increase in the variance of sequence interactivity detected in the human and mouse genomes when compared with less complex organisms could have expedited the evolution of regulators able to interact to multiple gene products and modulate robust phenotypes. The identification of sequences common to more than one therapeutic target carried out in this study could facilitate the design of new multispecific methods able to modify simultaneously key pathways to treat complex diseases.

  • Oligonucleotide-Based Therapy for FTD/ALS Caused by the C9orf72 Repeat Expansion: A Perspective.

    17 October 2018

    Amyotrophic lateral sclerosis (ALS) is a progressive and lethal disease of motor neuron degeneration, leading to paralysis of voluntary muscles and death by respiratory failure within five years of onset. Frontotemporal dementia (FTD) is characterised by degeneration of frontal and temporal lobes, leading to changes in personality, behaviour, and language, culminating in death within 5-10 years. Both of these diseases form a clinical, pathological, and genetic continuum of diseases, and this link has become clearer recently with the discovery of a hexanucleotide repeat expansion in the C9orf72 gene that causes the FTD/ALS spectrum, that is, c9FTD/ALS. Two basic mechanisms have been proposed as being potentially responsible for c9FTD/ALS: loss-of-function of the protein encoded by this gene (associated with aberrant DNA methylation) and gain of function through the formation of RNA foci or protein aggregates. These diseases currently lack any cure or effective treatment. Antisense oligonucleotides (ASOs) are modified nucleic acids that are able to silence targeted mRNAs or perform splice modulation, and the fact that they have proved efficient in repeat expansion diseases including myotonic dystrophy type 1 makes them ideal candidates for c9FTD/ALS therapy. Here, we discuss potential mechanisms and challenges for developing oligonucleotide-based therapy for c9FTD/ALS.