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Adelman K.,National Health Research Institute
Nature reviews. Genetics | Year: 2012

Recent years have witnessed a sea change in our understanding of transcription regulation: whereas traditional models focused solely on the events that brought RNA polymerase II (Pol II) to a gene promoter to initiate RNA synthesis, emerging evidence points to the pausing of Pol II during early elongation as a widespread regulatory mechanism in higher eukaryotes. Current data indicate that pausing is particularly enriched at genes in signal-responsive pathways. Here the evidence for pausing of Pol II from recent high-throughput studies will be discussed, as well as the potential interconnected functions of promoter-proximally paused Pol II.


Gain or loss of chromosomes resulting in aneuploidy can be important factors in cancer and adaptive evolution. Although chromosome gain is a frequent event in eukaryotes, there is limited information on its genetic control. Here we measured the rates of chromosome gain in wild-type yeast and sister chromatid cohesion (SCC) compromised strains. SCC tethers the newly replicated chromatids until anaphase via the cohesin complex. Chromosome gain was measured by selecting and characterizing copper-resistant colonies that emerged due to increased copies of the metallothionein gene CUP1. Although all defective SCC diploid strains exhibited increased rates of chromosome gain, there were 15-fold differences between them. Of all mutants examined, a hypomorphic mutation at the cohesin complex caused the highest rate of chromosome gain while disruption of WPL1, an important regulator of SCC and chromosome condensation, resulted in the smallest increase in chromosome gain. In addition to defects in SCC, yeast cell type contributed significantly to chromosome gain, with the greatest rates observed for homozygous mating-type diploids, followed by heterozygous mating type, and smallest in haploids. In fact, wpl1-deficient haploids did not show any difference in chromosome gain rates compared to wild-type haploids. Genomic analysis of copper-resistant colonies revealed that the "driver" chromosome for which selection was applied could be amplified to over five copies per diploid cell. In addition, an increase in the expected driver chromosome was often accompanied by a gain of a small number of other chromosomes. We suggest that while chromosome gain due to SCC malfunction can have negative effects through gene imbalance, it could also facilitate opportunities for adaptive changes. In multicellular organisms, both factors could lead to somatic diseases including cancer.


Yakel J.L.,National Health Research Institute
Pflugers Archiv European Journal of Physiology | Year: 2013

The neurotransmitter acetylcholine (ACh) can regulate neuronal excitability throughout the nervous system by acting on both the cys-loop ligand-gated nicotinic ACh receptor channels (nAChRs) and the G protein-coupled muscarinic ACh receptors (mAChRs). The hippocampus is an important area in the brain for learning and memory, where both nAChRs and mAChRs are expressed. The primary cholinergic input to the hippocampus arises from the medial septum and diagonal band of Broca, the activation of which can activate both nAChRs and mAChRs in the hippocampus and regulate synaptic communication and induce oscillations that are thought to be important for cognitive function. Dysfunction in the hippocampal cholinergic system has been linked with cognitive deficits and a variety of neurological disorders and diseases, including Alzheimer's disease and schizophrenia. My lab has focused on the role of the nAChRs in regulating hippocampal function, from understanding the expression and functional properties of the various subtypes of nAChRs, and what role these receptors may be playing in regulating synaptic plasticity. Here, I will briefly review this work, and where we are going in our attempts to further understand the role of these receptors in learning and memory, as well as in disease and neuroprotection. © 2013 Springer-Verlag Berlin Heidelberg (outside the USA).


Harry G.J.,National Health Research Institute
Pharmacology and Therapeutics | Year: 2013

Microglia are critical nervous system-specific cells influencing brain development, maintenance of the neural environment, response to injury, and repair. They contribute to neuronal proliferation and differentiation, pruning of dying neurons, synaptic remodeling and clearance of debris and aberrant proteins. Colonization of the brain occurs during gestation with an expansion following birth with localization stimulated by programmed neuronal death, synaptic pruning, and axonal degeneration. Changes in microglia phenotype relate to cellular processes including specific neurotransmitter, pattern recognition, or immune-related receptor activation. Upon activation, microglia cells have the capacity to release a number of substances, e.g., cytokines, chemokines, nitric oxide, and reactive oxygen species, which could be detrimental or beneficial to the surrounding cells. With aging, microglia shift their morphology and may display diminished capacity for normal functions related to migration, clearance, and the ability to shift from a pro-inflammatory to an anti-inflammatory state to regulate injury and repair. This shift in microglia potentially contributes to increased susceptibility and neurodegeneration as a function of age. In the current review, information is provided on the colonization of the brain by microglia, the expression of various pattern recognition receptors to regulate migration and phagocytosis, and the shift in related functions that occur in normal aging.


Merikangas K.R.,National Health Research Institute
Headache | Year: 2013

Background During the past decade, the introduction of the second edition of the International Classification of Headache Disorders (ICHD-II) and the initiation of active campaigns to increase awareness of the high magnitude, burden, and impact of migraine have stimulated numerous studies of population-based data on the prevalence, correlates, and impact of migraine. Objective This paper provides an update of the literature on the worldwide epidemiology of migraine from studies that included the ICHD-II criteria. The aims of this paper are: (1) to review evidence regarding the magnitude of migraine; (2) to summarize information on the correlates and impact of migraine; and (3) to discuss the contributions, challenges, and future directions in the epidemiology of migraine. Evidence on the magnitude of migraine is divided into the following types of data: (1) prevalence rates of ICHD-II-defined migraine and tension-type headache from international population-based studies of adults; (2) the magnitude of migraine in U.S. studies; (3) ICHD-II-based international prevalence rates of ICHD-II-defined migraine in children; and (4) incidence rates of migraine from prospective longitudinal studies. Methods A comprehensive review of the literature on the prevalence of migraine subtypes and tension-type headache defined by ICHD-II criteria during the past decade was conducted and aggregate weighted rates across studies were derived. Results Across the 19 studies of adults that employed the ICHD-II criteria, the aggregate weighted estimates of the 12-month prevalence of definite migraine are 11.5%, and probable migraine of 7%, yielding a total of 18.5%. The cross-study weighted aggregate rate of migraine with aura is 4.4%, chronic migraine is 0.5%, and of tension-type headache is 13%. There has been even greater growth in international prevalence data on migraine in children, with a total of 21 studies of children that have employed the ICDH-II criteria. The aggregate weighted rate of definite migraine in children is 10.1% and migraine with aura is 1.6%. The well-established demographic correlates of migraine including the equal sex ratio in childhood, with increasing prevalence of migraine in females across adolescence to mid-adulthood were confirmed in these studies. Despite increasing effort to increase awareness of migraine, approximately 50% of those with frequent and/or severe migraine do not receive professional treatment. Conclusions This review demonstrates that the descriptive epidemiology of migraine has reached its maturity. The prevalence rates and sociodemographic correlates have been stable across 50 years. These developments justify a shift in efforts to the application of the designs and methods of analytic epidemiology. Retrospective case-control studies followed by prospective cohort studies that test specific associations are likely to enhance our understanding of the predictors of incidence and progression of migraine, subtypes of migraine with differential patterns of onset and course, and specific environmental exposures that may have either causal or provocative influences on migraine etiology. © 2013 American Headache Society.

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