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The Worlds most Influential Business Thinkers 2015
Photo by Bloomberg News.
Harvard Business School professor Michael Porter is the most influential business thinker in the world, according to Thinkers50, a just-released ranking put out every other year by a consulting firm run by Stuart Crainer and Des Dearlove, British business consultants, authors and coaches. The list, which Crainer and Dearlove inaugurated in 2001, has been called the Oscars of management thinking. The 50 names were revealed this evening at a black tie event in London sponsored by companies like Japan's Fujitsu
Thinkers50 calls Porter, 68, "the father of modern business strategy." Regarded as an expert on competitiveness, he has consulted with dozens of corporations and a number of national governments including the U.K. "His Five Forces Framework was the definitive approach for decades and is still taught in every business school in the world," says the Thinkers50 awards announcement. Porter's theory posits that there are five forces that determine the competitive intensity and attractiveness of an industry. The forces include the threat of substitute products or services, the threat of established rivals and the threat of new entrants. He has also articulated, along with management consultant Mark Kramer, the concept of "shared value," which says companies can boost profits while addressing social problems. Porter was seventh on the list last year.
The second of three Harvard Business School professors on the list is widely revered best-selling author Clayton Christensen, 63, who topped the Thinkers50 ranking in 2011 and 2013. This year he's in second place. His 1997 book The Innovator's Dilemmais considered his classic work. It introduces the idea of disruptive innovation and explains why management practices that make companies industry leaders also make it tough for companies to develop the kinds of disruptive technologies that upstarts may use to take over markets. Christensen, who survived a heart attack, cancer and a stroke in the space of three years, also wrote How Will You Measure Your Life, about how people can create meaning in their personal lives.
W. Chan Kim and Renée Mauborgne, a pair of professors from INSEAD, take third place. INSEAD is a business school with campuses in Fontainebleau, France; Singapore and Abu Dhabi. Kim and Mauborne are both based in France. They wrote the blockbuster bestseller, Blue Ocean Strategy, which says organizations should focus on "blue ocean" spaces in the marketplace that are free of competitors. Says Thinkers50, their book "has been embraced by companies, not-for-profits and national governments around the world, including Malaysia, which has a national Blue Ocean Strategy."
To put together the ranking, Crainer and Dearlove first survey votes cast by the public on the Thinkers50 website. Some 20,000 people cast votes this year. Voters can suggest new names or voice support for people who have been on the list in the past. Then Crainer and Dearlove evaluate all the nominees with help from a team of advisers who include people from IE Business School in Madrid, where the two are adjunct professors. Mohi Ahmed, a senior director of innovation at Fujitsu, Harvard Business Review editor-in-chief Adi Ignatius, and author and consultant Deepa Prahalad, whose late father, C.K. Prahalad, topped the list in 2007 and 2009, are also advisors.
Crainer, Dearlove and their advisors use the following criteria to compile the ranking:
1. Relevance of ideas
2. Rigor of research
3. Presentation of ideas
4. Accessibility/dissemination of ideas
5. International outlook
6. Originality of ideas
7. Impact of ideas
8. Practicality of ideas
9. Business sense
10. Power to inspire
By Susan Adams.
http://www.forbes.com/sites/susanadams/2015/11/09/the-worlds-most-influential-business-thinkers-2015/
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Turkey says spy who helped British teens is Syrian national
Close friends Kadiza Sultana, 16, and 15-year-olds Shamima Begum and Amira Abase, crossed into Syria after boarding a flight from London to Istanbul on February 17 (File photo: AP)
By AFP Ankara Friday 13 March 2015
Three British girls who crossed into Syria to join Islamic State of Iraq and Syria (ISIS) militants were helped by a Syrian national working as an intelligence agent for one of the countries in the U.S.-led coalition against the militants, the Turkish foreign minister said Friday.
Turkish Foreign Minister Mevlut Cavusoglu unexpectedly announced Thursday that Turkey had arrested an intelligence agent who had helped the three teenage girls cross into Syria.
But amid frenetic speculation over which intelligence agency was involved, Cavusoglu gave no details over who the Syrian was working for.
"The person arrested by us is someone working for an intelligence agency in the coalition," he said in televised comments.
The person "is a Syrian citizen," he told reporters alongside his Macedonian counterpart without specifying further.
The Milliyet daily reported Friday that the individual was working for Canadian intelligence but this has already been denied by Ottawa.
A senior official in Ottawa told AFP Thursday the suspect "is not a Canadian citizen" and "was not employed by" its spy agency.
Close friends Kadiza Sultana, 16, and 15-year-olds Shamima Begum and Amira Abase, crossed into Syria after boarding a flight from London to Istanbul on February 17.
They took a bus from Istanbul to the southeastern Turkish city of Sanliurfa close to the Syrian border, from where they are believed to have crossed the frontier.
Cavusoglu had said the day earlier that the person arrested was not from the EU or the United States.
Along with the U.S. and EU states, Arabian Peninsula nations including Saudi Arabia and Qatar have been involved in the coalition against ISIS, as well as Australia and Canada.
British priest slammed for Muslim prayer service held in church
UNICEF urges talks with ISIS for aid access
14 million children suffering from Syria and Iraq wars: UNICEF
Indonesian women, children held in Turkey 'heading to join ISIS'
Lights out over Syria as war enters fifth year

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Home » Publications » Journals and Reports » Epigenetics—New Frontier for Alcohol Research
Alcohol Research: Current Reviews, Volume 35, Issue Number 1
Epigenetic Control of Gene Expression in the Alcoholic Brain
Igor Ponomarev, Ph.D.
Igor Ponomarev, Ph.D., is a research assistant professor at the Waggoner Center for Alcohol and Addiction Research and the College of Pharmacy, University of Texas at Austin, Austin, Texas.
Chronic alcohol exposure causes widespread changes in brain gene expression in humans and animal models. Many of these contribute to cellular adaptations that ultimately lead to behavioral tolerance and alcohol dependence. There is an emerging appreciation for the role of epigenetic processes in alcohol-induced changes in brain gene expression and behavior. For example, chronic alcohol exposure produces changes in DNA and histone methylation, histone acetylation, and microRNA expression that affect expression of multiple genes in various types of brain cells (i.e., neurons and glia) and contribute to brain pathology and brain plasticity associated with alcohol abuse and dependence. Drugs targeting the epigenetic "master regulators" are emerging as potential therapeutics for neurodegenerative disorders and drug addiction.
Key words: Alcohol consumption; alcoholism; chronic alcohol exposure; alcohol use, abuse and dependence; epigenetics; epigenetic therapeutics; gene expression; brain; brain cells; brain pathology; behavior; DNA methylation; histone; microRNA; transcription; pharmacotherapy; animal models; human studies
Whether a specific gene is transcribed or repressed is determined by the specific status (i.e., conformational state) of the complex of chromosomal DNA and proteins (i.e., the chromatin) and by the recruitment of specific proteins (i.e., transcription factors) to regulatory sites on the DNA (Copeland et al. 2010). Chromatin states can change as a result of enzyme-mediated covalent modifications of the DNA and structural chromatin proteins (i.e., histones) (Borrelli et al. 2008; Copeland et al. 2010). These changes in chromatin, which are often termed epigenetic marks, include such modifications as DNA methylation and histone methylation and acetylation. In addition, incorporation of histone variants, adenosine triphosphate (ATP)-dependent chromatin remodeling, and regulation of gene expression by noncoding RNAs also are considered epigenetic phenomena and play important roles in regulation of gene expression. It is becoming increasingly clear that epigenetic mechanisms play a key role in cellular differentiation and regulation of cell type– specific transcriptional programs, producing a remarkable heterogeneity of cellular transcriptomes1 that reflect the physiological properties and functional state of individual cells.
1 The first step of gene expression (i.e., transcription) involves the synthesis of intermediary molecules called messenger RNAs (mRNAs) that are copies of the gene(s) to be expressed and which serve as templates for the synthesis of the encoded protein(s) during the second step of gene expression (i.e., translation). A transcriptome is the entirety of all mRNAs found in a certain cell, organ, or organism.
The brain arguably is one of the most complex biological tissues and enables the organism to sense, remember, and respond to its environment. It constantly adapts to environmental stimuli through regulated changes in gene expression. Chronic alcohol exposure causes widespread changes in brain gene expression in humans and animal models (Mulligan et al. 2006; Ponomarev et al. 2012), and there is evidence that many of these changes mediate the processes of cellular adaptation leading to addiction (Mayfield et al. 2008). Until recently, the role of epigenetic processes in alcohol's effects on the central nervous system (CNS) has been largely understudied. However, in the past 5 years the number of studies that suggested a role for epigenetics in alcohol-related molecular and behavioral changes has grown considerably. This review summarizes evidence for the role of epigenetic modifications in alcohol's effects on brain gene expression and behavior.
DNA methylation generally is associated with transcriptional repression. It mainly occurs at sites where a cytosine and a guanosine nucleotide are located next to each other (i.e., CpG dinucleotides). If these CpG dinucleotides are located within regulatory sequences, such as promoter regions, their methylation can block the binding of transcription factors and/or establish a repressive chromatin state (Renthal and Nestler 2009b). One of the first indications that DNA methylation may play a role in alcoholism can be traced back to 1940s and 1950s, to the work of Dr. Roger J. Williams, a biochemistry professor at the University of Texas at Austin. He showed for the first time that dietary changes could affect beverage alcohol (i.e., ethanol) consumption in rodents. Specifically, diets deficient in B vitamins (e.g., folic acid and choline) increased consumption of solutions containing 10 percent ethanol in some rats, whereas vitamin-enriched diets decreased it (Williams et al. 1949). It now is well established that folates and several other B vitamins are critical for one-carbon metabolism and the synthesis of a compound called S-adenosyl-methionine (SAM), which serves as the primary methyl group donor in most transmethylation reactions, including DNA methylation (Hamid et al. 2009). Therefore, it is possible that dietary changes in this early study affected alcohol consumption via changes in DNA methylation and methylation-regulated gene expression.
Chronic alcohol consumption causes well-documented vitamin B and folate deficiencies that negatively affect the biochemical reactions in which a chemical unit containing one carbon atom (e.g., a methyl group) is transferred through several steps from a donor to another compound, such as DNA (i.e., one-carbon metabolism). These effects on one-carbon metabolism can result in excess levels of the SAM precursor homocysteine in the blood (i.e., homocysteinemia) and decreased SAM production (Blasco et al. 2005; Hamid et al. 2009). In addition, alcohol can affect DNA methylation through several other mechanisms, including the following:
The alcohol metabolite, acetaldehyde, may induce inhibition of an enzyme called DNA methyltransferase 1 (DNMT1) that mediates most DNA methylation reactions needed to maintain the cell's normal functioning (Garro et al. 1991).
Alcohol-induced DNA damage and the resulting repair reactions can lead to demethylation of 5-methylcytosine nucleotides (Chen et al. 2011).
Both of these mechanisms can cause reduced levels of methylation throughout the DNA (i.e., global DNA hypomethylation), a chromatin state associated with many pathological conditions, including cancer (Pogribny and Rusyn 2012). Alcohol-induced global DNA hypomethylation has been reported in several peripheral tissues of alcohol-related models and may play a role in alcoholic liver disease, fetal alcohol syndrome, and colon cancer (Choi et al. 1999; Garro et al. 1991; Hamid et al. 2009; Lu et al. 2000; Shukla et al. 2008). However, the effect of chronic alcohol on global DNA methylation seems to be tissue specific because one study reported enhanced DNA methylation (i.e., global DNA hypermethylation) in a certain type of blood cells (i.e., peripheral mononuclear cells) in alcoholic patients undergoing early alcohol withdrawal (Bonsch et al. 2004).
Two recent studies (Manzardo et al. 2012; Ponomarev et al. 2012) have examined alcohol's effects on global DNA methylation in the brain. Both studies measured DNA methylation in the frontal cortex of chronic alcoholics and matched control cases, but using two different methods. Ponomarev and colleagues (2012) studied genomic regions that included DNA sequences called long terminal repeat (LTR)- containing retrotransposons, also known as endogenous retroviruses (ERVs), most of which are nonfunctional remnants of ancient retroviral infections (Antony et al. 2004). The investigators showed that these repeats, which usually are heavily methylated, were less methylated in alcoholic brains, which was associated with their increased expression. Because ERVs constitute a significant part of the human genome, the study concluded that alcohol abuse causes global DNA hypomethylation in the brain, which is consistent with the majority of previous studies on alcohol-induced changes in DNA methylation. Manzardo and colleagues (2012) used immunological methods (i.e., immunoprecipitation) to isolate methylated DNA from alcoholics and control subjects and then applied this DNA to microarrays containing genomic promoter regions to identify promoters for which the methylation patterns differed between the two groups. The analyses found no differences between the groups in total methylation at the whole-genome level; however, about 20 percent of all promoters were differentially methylated between the groups, with less than half of these promoters showing greater methylation in alcoholics.
These complementary findings suggest that chronic alcohol causes a general decrease in the overall number of methylated cytosines but also could lead to the de novo methylation of previously unmethylated nucleotides at the promoters of some genes. Such a combination of these processes already has been widely reported in studies of cancer, showing, for example, that methyl-deficient diets induce development of liver tumors (i.e., hepatocarcinogenesis) associated with global DNA hypomethylation and promoter hypermethylation at specific genes (Ehrlich 2005; Pogribny and Rusyn 2012). Hypomethylated states associated with cancer and other pathological conditions often are accompanied by a downregulation of the gene encoding DNMT1 (Hervouet et al. 2010), which also has been observed in the brains of chronic alcoholics (Ponomarev et al. 2012). These striking similarities point to some common mechanisms of methyl deficiency across tissues.
Studies assessing epigenetic regulation of individual genes in the brain have shown that alcohol's effects on DNA methylation depend on a variety of factors, including the specific gene targets, developmental stage of exposure, and type of neuronal tissue affected. Much of this work has focused on the central effects of prenatal alcohol exposure and on gene regulation in cell cultures. Prenatal exposure of rats to alcohol resulted in DNA hypermethylation and a reduced expression of a protein called brain-derived neurotrophic factor (BDNF) in olfactory bulbs of rat pups, which was associated with loss of neurons in this brain region (Maier et al. 1999). Similar molecular results were obtained in a separate study where prenatal alcohol treatment of rats led to DNA hypermethylation and a decreased expression of a protein characteristically found in brain cells called astrocytes (i.e., glial fibrillary acidic protein [GFAP]) in the brains of the pups (Valles et al. 1997). In neural cell cultures, alcohol-induced downregulation of cell-cycle genes was paralleled by an increased DNMT activity and hypermethylation of the promoters of those genes (Hicks et al. 2010). Conversely, upregulation of the gene encoding a receptor subunit for the neurotransmitter glutamate (i.e., the NMDA NR2B receptor subunit) was associated with demethylation of CpG dinucleotides in the gene's promoter after chronic alcohol (Marutha Ravindran and Ticku 2004).
However, some reports suggest that the relationship between DNA methylation and the expression of neighboring genes may be even more complex than previously thought (Ehrlich 2005). For example, a recent study demonstrated an increased expression of a signaling molecule called prodynorphin (PDYN) that was associated with methylation of a CpG dinucleotide located in a DNA region behind the actual protein-coding region of the gene (i.e., in the 3′-untranslated region of the gene) in the brains of alcohol-dependent people (Taqi et al. 2011), although no causal link was established.
Specific DNA methylation patterns differ among tissues and cell types, and these differences contribute to establishing the cells' epigenetic landscape and transcriptional programs and defining cellular identity (Bernstein et al. 2007). Also, although alcohol's general effects on DNA methylation may be similar across various tissues, the specific genes affected by this regulation may differ depending on cell type. The epigenetic regulation of such proteins as GFAP, which is a marker of astrocytes, and the NR2B subunit, which generally is expressed in neurons, suggests that alcohol-induced epigenetic changes will affect molecular markers of individual cell types to a greater degree than other proteins. Many studies of alcohol's epigenetic modification of the chromatin have been conducted in blood cells obtained from alcoholics (Biermann et al. 2009; Bonsch et al. 2005; Hillemacher et al. 2009). Because of the concern regarding the tissue specificity of alcohol's epigenetic effects, however, the results of these important studies cannot be readily generalized to mechanisms in brain. Therefore, parallel measurements of the entirety of all alcohol-induced epigenetic changes (i.e., the epigenomic changes) in the blood and brain should be obtained and vigorously compared in animal models to detect common patterns, based on which generalization of results in humans can be made.
Histone proteins are the second major target of epigenetic changes. These proteins can be modified by a relatively large number of specific enzymes that mediate covalent attachment and removal of four classes of chemical groups: methyl, acetyl, phosphate, and ubiquitin (Bernstein et al. 2007; Borrelli et al. 2008). Studies of alcohol-induced modifications mainly have focused on two histone modifications: a trimethylation of histone 3 at the lysine 4 residue (H3K4me3), which is a promoter-enriched chromatin mark of actively transcribed genes, and acetylation of various residues of histones 3 and 4 (H3 and H4). Histone acetylation generally is associated with a more open, accessible structure of the chromatin and, consequently, increased transcription, whereas deacetylated histones can cause transcriptional repression (Bernstein et al. 2007).
Chronic alcohol abuse in humans can result in global and gene-specific increases in H3K4me3 in the brain cortex (Ponomarev et al. 2012) and in either increases or decreases of this modification in promoters of specific genes in the hippocampus (Zhou et al. 2011). The latter study used a combination of two techniques (i.e., chromatin immunoprecipitation followed by DNA sequencing [ChIP-Seq]) to detect individual genes with differences between alcoholics and control subjects in H3K4 promoter trimethylation and in parallel measured the levels of transcription of the same genes. Interestingly, differences in promoter methylation did not correlate with differences in gene expression, suggesting that H3K4me3 status alone is not a reliable predictor of genome-wide steady-state mRNA levels at a given time point. A possible explanation of these results is that the H3K4me3 mark in the promoter regions only indicates that the chromatin is in an open conformation that is accessible to regulatory or transcription factors but does not mean that transcription actually is initiated and the transcription machinery is present (Bernstein et al. 2007). A recent study (D'Addario et al. 2011) supports this hypothesis as well as previous findings showing mechanistically linked but temporally complex relationships between chromatin marks at gene promoters and mRNA abundance. The investigators explored the effects of ethanol and its metabolite acetaldehyde on various chromatin marks and the transcription of the PDYN gene in a human cell line derived from a tumor arising from nerve tissue cells (i.e., a neuroblastoma). The analyses suggested that the ethanol-induced increase in H3K4me3 that was observed after 72 hours of ethanol exposure did not result in initiation of PDYN transcription but kept the gene in a poised state for later reactivation. This is consistent with other findings regarding PDYN activation in human alcoholics (Taqi et al. 2011).
Most evidence to date on the role of central epigenetic processes in alcoholism has been collected from studies focusing on histone acetylation, often by modifying the activities of the enzymes that add acetyl groups (i.e., histone acetyl transferases [HATs]) or remove acetyl groups (i.e., histone deacetylases [HDACs]). Particularly, small molecules that inhibit HDAC function (HDACis) and thus result in increased histone acetylation have been investigated intensely in recent years. These molecules are attractive because they can enter the brain via the blood (i.e., cross the blood–brain barrier) and exert a broad range of effects in the CNS, including enhanced memory formation as well as anti-inflammatory and neuroprotective effects (Kazantsev and Thompson 2008; Sweatt 2009). Several studies using HDACis demonstrated effects of altered histone acetylation on different alcohol-related behaviors, including withdrawal-related anxiety (Pandey et al. 2008), locomotor sensitization (Sanchis-Segura et al. 2009), alcohol consumption (Wostenholme et al. 2011), conditioned place aversion (Pascual et al. 2012), and rapid tolerance (Sakharkar et al. 2012). For example, Pandey and colleagues (2008) showed that acute ethanol increased H3K9 and H4K8 acetylation in rats, whereas anxiety-like behaviors during withdrawal after chronic alcohol exposure were associated with decreases in these acetylation marks, decreased expression of several proteins (e.g., CREB-binding protein [CBP] and neuropeptide Y [NPY]), and increased HDAC activity. However, treatment with the HDACi, trichostatin A (TSA), to block HDAC activation prevented the deficits in gene expression and the development of withdrawal-related anxiety. Sanchis-Segura and colleagues (2009) demonstrated that treatment of mice with another HDACi (i.e., sodium butyrate) altered some alcohol-related behaviors (e.g., enhanced ethanol-induced locomotor sensitization) but had no effect on others (e.g., ethanol tolerance or withdrawal). Finally, daily injections of TSA in mice that had continuous access to both water and an alcohol solution increased the animals' alcohol consumption (Wolstenholme et al. 2011).
Similar to DNA methylation, alcohol's effects on histone acetylation are tissue, brain region–, and cell type–specific. For example, a single dose of ethanol2 into the stomach increased the levels of H3 acetylation in the liver, lungs, and testes but had no effects in other tissues, including whole brain, of rats (Kim and Shukla 2006). In the brain, ethanol- induced changes in H3/H4 acetylation were observed in the central and medial but not the basolateral nuclei of the amygdala (Pandey et al. 2008; Sakharkar et al. 2012); moreover, the increased histone acetylation appeared to be specific for neurons (Sakharkar et al. 2012).
2 The dose administered was 6 g/kg of a 32 percent ethanol solution.
Other factors that can affect alcohol-induced changes in histone acetylation include species, the organism's specific genetic makeup (i.e., genotype), age, the dose and route of ethanol administration, and duration of exposure. For example, ddY mice treated with chronic ethanol vapor showed increases of both global and gene-specific histone acetylation in the ventral midbrain during withdrawal that peaked around 10 hours post ethanol (Shibasaki et al. 2011). Also, intermittent alcohol exposure produced different effects on histone acetylation in adolescent and adult rats, with juvenile animals generally showing more changes (Pascual et al. 2009, 2012). Consistent with these studies was the finding that ethanol exposure during the early postnatal period in rats resulted in a marked reduction of CBP levels and histone acetylation in the developing cerebellum (Guo et al. 2011). In addition, possible interactions among various factors may result in different time courses for alcohol-induced changes, because histone acetylation measured 24 hours after the last of repeated alcohol injections was increased in some brain areas (e.g., frontal cortex and nucleus accumbens), decreased in others (e.g., striatum), and unchanged in still others (e.g., hippocampus) (Pascual et al. 2009).
Histone acetylation generally is associated with transcriptional activation, but similar to the H3K4me3 mark, the relationships between levels of histone acetylation and steady-state mRNA are complex, because activation of different genes is associated with acetylation of different residues of H3 and H4 at different time points (Renthal and Nestler 2009a). And although alcohol's effects on histone acetylation now are well established, the exact mechanisms underlying this influence on gene expression are not well understood. Alcohol-induced changes in histone acetylation are paralleled by regulation of several genes, including CBP, NPY (Pandey et al. 2008), FosB (Pascual et al. 2012), and NR2B (Qiang et al. 2011). One proposed mechanism involves the transcription factor CREB, to which CBP can bind (Moonat et al. 2010). CBP has intrinsic HAT activity and, when recruited by CREB, can promote transcriptional activation by acetylating histones. This mechanism has been shown to play a role in cocaine- induced regulation of FosB (Levine et al. 2005). A similar mechanism also was proposed to regulate H4 acetylation, transcription of the gene encoding the BK-type potassium channel, and tolerance to benzyl alcohol in the fruit fly, Drosophila (Wang et al. 2007).
Gene expression experiments have provided additional support for the role of histone acetylation in alcohol addiction. Several studies focusing on brain changes in human alcoholics have shown general downregulation of genes involved in histone acetylation and upregulation of genes promoting histone deacetylation. The latter group of genes includes those encoding proteins forming so-called transcription corepressor complexes (TCCs), which help suppress transcription by coupling HDAC activity with DNA methylation, thereby establishing a repressive chromatin state (McDonel et al. 2009). For example, transcripts of the genes encoding CREB and CBP were downregulated in alcoholics (Ponomarev et al. 2012). Conversely, transcripts of the gene MBD3, which encodes a key player in TCCs called methyl-CpG– binding protein, as well as many other TCC genes, such as SIN3A, SIN3B, MTA1, MTA2, RBBP4, GATAD2A, GATAD2B, and CHD4 were upregulated in alcoholics (Liu et al. 2006; Ponomarev et al. 2012; Zhou et al. 2011). Together, these observations validate previous findings that histone acetylation is decreased during alcohol withdrawal (Pandey et al. 2008) and suggest that TCCs are activated and play a role in the downregulation of some genes in the alcoholic brain.
MicroRNAs
MicroRNAs (miRNAs) comprise a specific class of noncoding RNAs that bind to complementary sequences on target mRNAs to repress translation and silence gene expression (Robison and Nestler 2011). Expression of miRNAs can alter the transcriptional potential of a gene in the absence of any change to the DNA sequence and therefore can be considered an epigenetic phenomenon. The most convincing evidence for the involvement of miRNAs in alcohol-related gene expression was presented by Pietrzykowski and colleagues (2008), who showed that alcohol upregulates expression of microRNA 9 (miR-9) in rat brain, which results in miR-9–dependent downregulation of BK channel variants with high sensitivity to alcohol. This mechanism is proposed to mediate the development of cellular tolerance and generally may contribute to neuronal adaptation to alcohol.
Additional evidence for the role of miRNAs in alcohol-induced regulation of gene expression and behavior comes from genomic studies measuring levels of multiple miRNAs after exposure to alcohol. Using neural cultures and a model of alcohol-induced teratogenesis, Sathyan and colleagues (2007) identified the first alcohol-sensitive miRNAs. Subsequent studies using miRNA microarrays detected multiple alcohol-regulated miRNAs in neural cultures (Yadav et al. 2011), fetal mouse brains (Wang et al. 2009), and brains of human alcoholics (Lewohl et al. 2011).
Summary and Future Directions
The findings reviewed in this article point to a central role of various epigenetic processes in controlling alcohol-induced changes in brain gene expression and behavior, which may play an important part in the development of alcohol addiction (see the figure). For example, chronic alcohol exposure can result in global DNA hypomethylation via several mechanisms, including vitamin B and folate deficiencies that can lead to an impairment of one-carbon metabolism and a decrease in SAM levels. However, these global effects of alcohol do not imply unidirectional changes across the whole genome, because many genes show the opposite epigenetic changes in their promoters.
Figure A hypothetical diagram for the role of epigenetic modifications in alcohol addiction. Yellow color indicates general increase, up-regulation, or activation, whereas blue color indicates general decrease, down-regulation, or degeneration. White background implies bidirectional changes. Potential interactions between different components of the diagram are discussed in the text.
Many of the observed chromatin modifications are mechanistically linked, resulting in a limited number of chromatin states (Jaenisch and Bird 2003). For example, trimethylation of H3K4 is mechanistically coupled with unmethylated DNA (Hashimoto et al. 2010), suggesting that the reduced DNA methylation observed in alcoholic brains can promote a general increase in the H3K4me3 levels. Histone actetylation patterns also are commonly altered by alcohol in a process that may be linked to DNA methylation. Thus, acute alcohol exposure promotes histone acetylation, whereas withdrawal from chronic alcohol often increases deacetylation of histones. Deacetylation via HDAC activity is coupled to DNA methylation through the actions of methyl-binding proteins and other TCC components. Chronic alcohol exposure leads to upregulation of TCC genes, which may serve to compensate for the reduced number of methylated CpGs. These cumulative changes in chromatin states can produce changes in global gene expression that may determine the functional states of different cell types and lead to activation of microglia, neuronal degeneration, and compensatory neuroadaptations in alcoholic brain. In summary, alcohol-induced epigenetically mediated changes in gene expression may underlie the brain pathology and adaptations in brain functioning (i.e., brain plasticity) associated with alcohol abuse and alcohol dependence and may contribute to alcohol relapse and craving.
To advance the current state of epigenetic research in alcoholism, future studies that look at both simplified models and entire regulatory systems (i.e., that use both reductionist and systems approaches) are needed. One focus of this research should be on understanding the exact mechanistic links between chronic alcohol exposure, epigenetic changes, and gene expression. Exploratory studies likely will first use discovery-driven approaches to investigate the mechanistic relationships between the epigenome and the transcriptome in animal models and formulate hypotheses at the single-gene, gene-network, and systems levels. Follow-up studies using both animal models and human postmortem material then can help test these hypotheses and validate functional predictions of the genome-wide experiments. Because of the complex temporal relationships between chromatin marks and transcriptional changes, time-course studies also will be required. The recently available epigenetic maps from the ENCODE (ENCyclopedia Of DNA Elements) Project (Dunham et al. 2012) should help accelerate these research efforts.
To address the causal relationships between epigenetic modifications and alcohol traits, it will be essential to use tools of both forward and reverse genetics. Forward-genetics approaches seek to determine the genetic basis of an observed trait (i.e., phenotype). Such approaches include mapping DNA regions that may contain disease- related genes (i.e., quantitative trait loci [QTLs]), using chromatin modifications as phenotypes. This can be achieved using genetic reference panels, such as recombinant inbred strains of mice and rats (Rosen et al. 2007). Many reference populations have been tested extensively for both expression of specific genes and alcohol-related behaviors and therefore can serve as powerful tools for integrating data across biological modalities and investigating mechanistic links between the genome and the entirety of all analyzed phenotypes (i.e., the phenome) through genetic mapping of the epigenome and the transcriptome. Conversely, reverse-genetics approaches study the phenotypes that arise as the result of alterations of particular genes. An example of a reverse-genetics approach is to assess alcohol-related behaviors in mice with genetic mutations of chromatin-binding proteins.
Another important research direction is to investigate the cellular specificity of alcohol-induced epigenetic changes. For example, future research should determine cell type–specific chromatin states that drive the unique molecular responses to alcohol in different neurons and glial cells and show how epigenetic modifications help establish functional states consistent with the pathophysiological changes observed in alcoholism. One example of this approach is the analysis of the role of epigenetically controlled ERVs in alcohol addiction (Ponomarev et al. 2012). Previous studies found that an ERV-encoded glycoprotein called syncytin can directly activate different types of glial cells (i.e., microglia and astrocytes) and induce neuroinflammation (Antony et al. 2004). Microglial activation, in turn, can result in neuronal degeneration (Crews et al. 2011), and syncytin- activated astrocytes can secrete compounds that are toxic to other glial cells (i.e., oligodendrocytes) and thus lead to myelin degeneration (Antony et al. 2004). Both of these effects are consistent with pathologies observed in alcoholics (Harper et al. 2003; Pfefferbaum et al. 2009; Zahr et al. 2011). Alcohol-induced neuroimmune responses have been suggested to be a critical factor in alcohol addiction (Crews et al. 2011), and Ponomarev and colleagues (2012) proposed a novel mechanism including the potential role for ERVs in neuroinflammation and brain pathophysiology of human alcoholism. Another approach to assessing the cell specificity of epigenetic processes is to compare alcohol-induced epigenetic changes across tissues and cell types. Human research often is limited to peripheral tissues (e.g., blood). To be able to draw parallels between peripheral and central mechanisms in humans, researchers first need to study the relationships between responses to alcohol in the brain and those in other tissues using animal models.
Other research efforts should focus on the potential exploitation of epigenetic mechanisms for alcoholism treatment. Epigenetic therapeutics, such as HDACis, offer unique advantages in treating diseases through chromatin-dependent changes in gene expression. These "master regulators" can affect expression of multiple genes. Therefore, in order to understand the effects of these agents on alcohol behaviors, it is important to study their mechanisms of action and identify the range of genes and molecular pathways affected. Large-scale genomic studies should focus on the global relationships between chromatin marks and gene expression in the context of chronic alcohol exposure and epigenetic therapeutics. Finally, multiple studies in humans and animal models have highlighted the importance of the genetic component in alcohol addiction (Crabbe 2008; Mayfield et al. 2008; Spanagel 2009). To better understand the interplay between genetic, epigenetic, and environmental factors in controlling gene expression in alcoholism, integrative approaches across studies are warranted. Many epigenetic therapeutics have been developed for other diseases, and understanding the functional relationships between epigenetic processes and the transcriptome in the alcoholic brain may lead to new molecular targets for medication development for human alcoholism.
This work was supported by a K-Award from the National Institute on Alcohol Abuse and Alcoholism (AA–017234). The author thanks Dr. Adron Harris for critical reading of the manuscript.
The author declares that he has no competing financial interests.
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text:
Beat The City Rush… Permanently
NewsState News
A planning expert has suggested what the Nationals have been saying for years: Encourage people to move to regional centres.
In an opinion piece written for Domain, University of Sydney academic Glen Searle says smaller cities need rapid growth to "pack a punch", but he suggests those efforts be focused on Adelaide and Canberra.
The NSW Nationals believe a process of decentralisation would make regional NSW a real solution to urban population pressures.
In his new book Weatherboard & Iron, Federal Member for New England Barnaby Joyce argues strongly in favour of developing regional cities.
Canberra, for example, was one such example of decentralisation, Mr Joyce writes. All those years ago, the public servants resisted the move out of Melbourne, but generations later the public servants resist moves out of Canberra.
A recent editorial from the left-leaning Canberra Times called out the Nationals' decentralisation policy, saying jobs should go to regions only when it makes sense to have them there. But that argument falls apart when you consider the Department of Agriculture and Water Resources is based in Canberra, a long way from fields of wheat and canola.
We need a real solution to the urban crush, if only for economic reasons. Sydney's WestConnex project has a price tag of almost $17 billion for a 33 kilometre motorway, and it's certainly needed as the city grinds away through congestion. By way of comparison, the Nationals-led Inland Rail project, which will stretch 1700 kilometres from Brisbane to Melbourne and through the centre of NSW, will cost only $10 billion. Inland Rail will transform regional NSW and costs little more than half of WestConnex, which will soon be clogged as more and more people move to Sydney.
The solution is clear: Invest significant funds into improving regional infrastructure – new roads, new schools, new hospitals – and then encourage job creation in the regions. Imagine if we spent $1 billion in Grafton, or Wagga, or Bathurst; what would that investment do to those cities?
In the United States, there are massive cities all across the country, not just on the coasts. They're built around rail and resources and they thrive. We have cities with similar attributes, they just need the investment required to make them a reality.
The NSW Nationals will continue to bang the drum for decentralisation, both from within the Government and out in the regions where we're from. We've seen a significant boost to regional spending since we came to Government in 2011, but we know there's always more to be done. The Nationals are from the regions and for the regions, and we'll never stop fighting for our people.
Categories: News, State News 10 Aug, 2018
Tags: barnaby joycecanberradecentralisationinland railnationals in governmentNSW Nationalswestconnex
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Nearly half of the employees surveyed by Randstand expect the job market to brighten in 2012, increasing their chances of finding new opportunities. The fact that many employees plan to seek greener pastures reveals a change in attitude over the last few years, says Peter Cappelli, director of the Wharton Center for Human Resources.
As the retention function encroaches ever closer to recruiting itself, recognition (does this seem like a lot of Rs to anyone?) has grown in importance. While typically something "handled" by HR, it's not always been given the (ahem) recognition it deserves or that it's currently enjoying, likely spurred by the aforementioned video, a economy that's slowly picking up, a still hot and competitive silicon valley scene plus a couple of recent acquisitions.
Where's the webinar on how to fire someone who won't recognize correctly? Or at all? That's a skill we need to implement more often. Recognition is a mission critical skill today. Get on it.
Study after study has shown that higher engagement levels generate higher profits, higher sales, higher customer loyalty and above average productivity. And the more celebratory "in the moment" moments for employees aligned with traditional performance management moments, the greater the recognition and improvement loops.
With all this focus on something that should be mainstream by now, it's no shocker that companies like Achievers, Rypple and Globoforce and even performance management crossover Sonar 6 are doing some of the most innovative marketing and branding in the market. Not to mention taking recognition beyond the plaques, checklists and "golden watch thinking".
In fact, both Rypple and SuccessFactors were acquired in late 2011 by industry giants Salesforce and SAP respectively. This is considerable evidence that the larger corporate world is finally taking note of the importance of employee recognition. In fact, some analysts speculate that, far from being standard "big company gobbles small company and extracts all potential value", these smaller more innovative companies may help their new "owners" see the value of employee motivation and autonomy. Both Rypple (2008) and SuccessFactors (2001) know whereof they speak, both founded in tough economic times, when the definition of "employment" was changing rapidly and budgets were being slashed.
Moving forward, recognition may finally have its day but platforms may not be enough. Solid training, enterprise wide focus and a true understanding of the new employment role will have to be factored (yuk, yuk) into the equation.


text:
US Supreme Court Center > Volume 552 > Gall v. United States 06-7949 (2007)
Gall v. United States - 06-7949 (2007)
Syllabus (pdf)
Opinion [ Justice Stevens ] (pdf)
Concurrence [ Justice Scalia ] (pdf)
Concurrence [ Justice Souter ] (pdf)
Dissent [ Justice Thomas ] (pdf)
Dissent [ Justice Alito ] (pdf)
GALL V. UNITED STATES
certiorari to the united states court of appeals for the eighth circuit
No. 06–7949. Argued October 2, 2007—Decided December 10, 2007
Petitioner Gall joined an ongoing enterprise distributing the controlled substance "ecstasy" while in college, but withdrew from the conspiracy after seven months, has sold no illegal drugs since, and has used no illegal drugs and worked steadily since graduation. Three and half years after withdrawing from the conspiracy, Gall pleaded guilty to his participation. A presentence report recommended a sentence of 30 to 37 months in prison, but the District Court sentenced Gall to 36 months' probation, finding that probation reflected the seriousness of his offense and that imprisonment was unnecessary because his voluntary withdrawal from the conspiracy and postoffense conduct showed that he would not return to criminal behavior and was not a danger to society. The Eighth Circuit reversed on the ground that a sentence outside the Federal Sentencing Guidelines range must be—and was not in this case—supported by extraordinary circumstances.
1. While the extent of the difference between a particular sentence and the recommended Guidelines range is relevant, courts of appeals must review all sentences—whether inside, just outside, or significantly outside the Guidelines range—under a deferential abuse-of-discretion standard. Pp. 7–14.
(a) Because the Guidelines are now advisory, appellate review of sentencing decisions is limited to determining whether they are "reasonable," United States v. Booker, 543 U. S. 220, and an abuse-of-discretion standard applies to appellate review of sentencing decisions. A district judge must consider the extent of any departure from the Guidelines and must explain the appropriateness of an unusually lenient or harsh sentence with sufficient justifications. An appellate court may take the degree of variance into account and consider the extent of a deviation from the Guidelines, but it may not require "extraordinary" circumstances or employ a rigid mathematical formula using a departure's percentage as the standard for determining the strength of the justification required for a specific sentence. Such approaches come too close to creating an impermissible unreasonableness presumption for sentences outside the Guidelines range. The mathematical approach also suffers from infirmities of application. And both approaches reflect a practice of applying a heightened standard of review to sentences outside the Guidelines range, which is inconsistent with the rule that the abuse-of-discretion standard applies to appellate review of all sentencing decisions—whether inside or outside that range. Pp. 7–10.
(b) A district court should begin by correctly calculating the applicable Guidelines range. The Guidelines are the starting point and initial benchmark but are not the only consideration. After permitting both parties to argue for a particular sentence, the judge should consider all of 18 U. S. C. §3353(a)'s factors to determine whether they support either party's proposal. He may not presume that the Guidelines range is reasonable but must make an individualized assessment based on the facts presented. If he decides on an outside-the-Guidelines sentence, he must consider the extent of the deviation and ensure that the justification is sufficiently compelling to support the degree of variation. He must adequately explain the chosen sentence to allow for meaningful appellate review and to promote the perception of fair sentencing. In reviewing the sentence, the appellate court must first ensure that the district court made no significant procedural errors and then consider the sentence's substantive reasonableness under an abuse-of-discretion standard, taking into account the totality of the circumstances, including the extent of a variance from the Guidelines range, but must give due deference to the district court's decision that the §3553(a) factors justify the variance. That the appellate court might have reasonably reached a different conclusion does not justify reversal. Pp. 11–14.
2. On abuse-of-discretion review, the Eighth Circuit failed to give due deference to the District Court's reasoned and reasonable sentencing decision. Since the District Court committed no procedural error, the only question for the Circuit was whether the sentence was reasonable, i.e., whether the District Judge abused his discretion in determining that the §3553(a) factors supported the sentence and justified a substantial deviation from the Guidelines range. The Circuit gave virtually no deference to the District Court's decision that the variance was justified. The Circuit clearly disagreed with the District Court's decision, but it was not for the Circuit to decide de novo whether the justification for a variance is sufficient or the sentence reasonable. Pp. 14–21.
446 F. 3d 884, reversed.
Stevens, J., delivered the opinion of the Court, in which Roberts, C. J., and Scalia, Kennedy, Souter, Ginsburg, and Breyer, JJ., joined. Scalia, J., and Souter, J., filed concurring opinions. Thomas, J., and Alito, J., filed dissenting opinions.
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There are lots of options when choosing what to wear for your headshot session. Below you will find some guidelines that I like to use, to help insure your image speaks to who you are rather than who your clothing designer is. This is your time to shine and we do that by keeping the focus on you.
Maybe your job doesn't require you to wear a suit and tie. There is no need to wear one then for your headshot session. Whether you bring a collared shirt or a t-shirt, make sure it fits you well. Avoid dingy whites and shirts with tired collars that don't stand at attention. A casual headshot should still look polished and professional. What you wear matters! Solid shirts work best. If you only wear patterns, bring some that are subdued to keep you as the focus not your shirt. Even little things, such as a colored stripe down the button seam is a distraction. Layering is a fun option also. A simple sweater or casual every day jacket are good options.
The business casual requires a well fitting button down under a form fitting jacket. For this look, solid is always the best option, but a subtle pattern is ok too as a lot of it is covered up by the jacket. If your jacket has a pattern, keep your shirt a solid. It's ultra important that your garments fit your frame. The collar should be against the back of your neck and not bulging at the sides and creating gaps between your neck and the shirt. The jacket should rest nicely on your shoulders rather than the seams dropping low over them. For me, the fit is more important than the color here. When choosing your jacket and shirt, ask yourself "what do I want my image to say about me and how do these garments reflect that message?
If your job requires a tie and jacket, bring a handful of both so we have some styling options at your headshot session. Ties should be current. If you've had that tie for over 5 years, you may need an update. Not only should your tie be on point, you need to tie your tie correctly. Can't quite get that dimple in your tie? I've got you covered in the video. (Click on the bottom right corner for full screen.) Shirt should fit correctly with collar touching your neck all around. Come with your shirts and jackets pressed and photo ready. If you choose a busy tie, choose a solid shirt and jacket. Patterned shirt equals a solid tie and jacket.
Planning ahead for your headshot session is ideal. Even if your headshot is on location, at your place of business, you can still have an amazing outcome if you dress for the photo. For the casual business style, choose a simple top with a scoop or crew neckline. A turtleneck is also a great choice, especially if you your jawline isn't as defined as you would like it to be. Sleeveless tops are also fine, if you are comfortable wearing them. I will work your arms so they look their thinnest in your image. Off the shoulder should be avoided unless you want that au naturale appearance. Go for solid colors and simple designs. Even a solid top that has lace cutouts can be a distraction.
If you have scheduled a studio session, you have an opportunity to bring a handful of wardrobe choices. If you choose to wear a jacket, it should fit your form to not add extra weight to your frame. Solids mix well with patterns as long as the patterns are subtle rather than extravagant. Collars should be crisp and not limp. They can be worn inside the jacket or outside and having them upright rather than flimsy makes a more polished impression. Dresses should be tailored and simple. Keep in mind the neckline and how a headshot is cropped when making your selections. Choose colors that flatter your eye color and underlying skin tones for best results.
The first step in your headshot session should start with good skin care. I am a Rodan + Fields Consultant, but I'm not here to promote products. I would be happy to talk to you about it during your session, if you are interested in hearing more or feel free to click on the link to take you to my site. It is the #1 skincare brand in the US and Canada and does have a 60 day money back guarantee, but enough about that. Let's talk about what suggestions I have for you before you head in for your session.
FACE: Finding the right photographer is the hardest part. The rest is icing on the cake. Speaking of icing, I don't recommend makeup for men for a headshot session. If you have oily skin, pick up a tube of Peter Thomas Roth Max Anti shine Matifying Gel, which is a miracle worker on oily skin. I have it here in studio for your use as well. Make sure you have moisturized skin and your lips are free from chapping. Bring lip balm with you the day of your shoot. For both men and women, avoid using moisturizer with SPF as it can cause flash back with the studio lights. Women, your makeup should be clean and fresh. No need to overdue it for your headshot session. Avoid strong, hard eyeliner lines, and brows that are heavily penciled in or squared off with liner or even stamps. Simply filling in bare areas is sufficient as well as cleaning up any stray hairs. Women, bring lip gloss, balm or color. When wearing color, it should compliment your skin tone, not take all the focus away from your other features. Make sure the color stays within the outline of your lips. Your foundation on your face needs to match your neck. Bring everything with you for touch ups as we go along.
Men, to help eliminate razor burn and irritation, use a new blade for shaving and moisten your face with hot water to prep the skin before using a quality shave cream. Don't forget to rinse with cool water and pat dry and apply a good moisturizer. Do you want photos with facial hair and without? Schedule enough time and you can shave at the studio in between looks.
HAIR: Hair should be clean and not recently cut. Hair needs a week or so to settle in to a haircut. I've had many cancellations due to haircuts that didn't go as planned or ended up shorter than intended. Please bring your brush, hairspray, bobby pins and even a ponytail holder. If you straighten or curl your hair, consider bringing those tools with you as well in case you need to make adjustments.
ACCESSORIES: If you wear glasses and have more than one pair, bring them all with you. Different glasses will sit on your face differently and lenses react to the light differently as well. Lenses with the anti glare coating is preferred, or bring frames without the lenses if you don't have the coating applied.
Jewelry should be kept to a minimum, if at all. Studs are fine as long as they don't go beyond the earlobe. Hoops can work as well, especially if you have a short, fun haircut. If you have gauges, consider bringing flesh toned plugs along. Necklaces are a no go, unless they are short and won't be cropped off in your headshot leaving the viewer wondering what is at the bottom of that chain. If you opt for a short necklace, say you wear it every day and can't take it off, keep it small and simple.


Dreams have been an integral component of human existence throughout our documented history.
In this world we create for ourselves, a dream allows us to do anything or go anywhere.
Lucid dreaming can be used for problem-solving purposes.
Even some of humanity's greatest stories have been inspired by dreams.
Authors from H.G. Wells to Stephen King to Mary Shelley have entertained millions because of what they remembered while dreaming.
To unlock this trait, it is necessary to know how to have vivid dreams. This is what can help you achieve this goal.
Some people say they don't dream at night.
Others say they dream every night and can recall vivid details from dreams they had years ago.
Why is there such a variation in dream memory within the human population?
There are some personal habits that can help to begin recalling dreams, such as starting a dream journal.
Having a consistent bedtime routine can be helpful as well.
The mechanics of dreaming, however, show us that for people who can sleep through multiple REM cycles without interruption, there is less of a chance for dream recall.
What does this information mean if you want to know how to have vivid dreams?
Remembering a dream, for those who are heavier sleepers, may require three specific elements.
Increasing the vividness of the dream so the brain is more likely to transfer it to a memory center for long-term storage and recall.
Improving the color, variety, and uniqueness of the dream to the point where it may cause an individual to immediately wake from it.
Changing sleep habits so that the last cycle of REM sleep occurs just before the morning alarm clock sounds.
People who remember their dreams also tend to respond strongly when someone calls their name when they are awake.
It is up to you to find a sleeping routine that works with your REM cycles so there is a better chance of remembering a dream upon waking.
You can then use a dream journal to immediately write down the dream after waking, which transitions the brain into moving the dream into memory.
For the other two elements, a product like Claridream Pro may be able to help you have vivid dreams on a regular basis.
This dietary supplement offers a combination of ingredients that work to elevate GABA levels while stopping the brain from breaking down a neurotransmitter called Acetylcholine.
It may not work for everyone, but it does offer a strong possibility for better, more colorful dreams.
How Does Claridream Pro Work to Improve Dream Vividness?
Claridream Pro takes advantage of the benefits that 5 key ingredients provide to improve the potential of dream recall.
In past civilizations, passionflower fruits were used as a sedative.
It creates feelings of fatigue because it promotes the release of GABA in the brain. As GABA levels increase, the central nervous system begins to calm down.
There is a noticeable reduction of anxiety when there is a measureable increase of GABA. For many, the results allow for insomnia to be conquered.
At the same time, increased GABA levels encourage the dreaming centers of the brain to be more active.
When you're falling asleep, the dream centers are waking up. That provides a better chance to have dreams which are vivid and complex.
Passionflower can also be used for asthma, ADHD, seizures, and high blood pressure.
This root has been used for medicinal purposes since the beginnings of the first documented human civilizations.
It comes from a plant that is native to Asia and Europe, but has spread to North America.
Hippocrates wrote about the uses of valerian root during his studies of medicine.
It can still be used to calm anxiety issues, treat insomnia, and help with menopause symptoms.
It will also inhibit the enzyme that is responsible for destroying GABA.
That is why it helps to promote vivid dreams and an increased chance of remembering them.
Chamomile tea is an old home remedy that is used to promote better sleep.
It is such a safe solution for promoting calm that this natural sedative is recommended for children who struggle with sleep.
How old is this remedy? Ancient Egyptians discovered that chamomile could help provide relief for fevers.
Chamomile works because it can relax the spasms of the intestinal tract while promoting a calmer mental state at the same time.
The active chemicals work on the brain in the same way that a mild sedative would work, but without the same threat of negative side effects.
For those who struggle to get to sleep, chamomile offers the chance to calm the central nervous system.
This promotes a sense of safety and well-being. When combined with the mild effects of sedation, a dream state can be achieved with consistency and the REM sleep cycles can be promoted.
Sometimes referred to as Wolf's Claw, Chinese Club Moss produces a component that is called Huperzine-A.
This ingredient works to inhibit the enzymes that would normally degrade acetylcholine in the brain.
Acetylcholine is partially responsible for the transfer of observed moments into memories that can be recalled.
After reading this, if you remember doing so tomorrow, it was because there was enough acetylcholine present to transfer your observations today into recalled memories tomorrow.
Because there is less breakdown of this neurotransmitter, the human brain can enhance the process of storing memories.
It promotes a greater cognition of the events that are happening at any given moment.
That includes moments of dreaming.
Huperzine-A is also called selagine, which can create some ingredient confusion, as there is a medication called selegiline, sold under the brand-name Eldepryl.
Huperzine-A is also sold under several different brand names, including Cerebra. That can sometimes be confused with prescription medications like Celexa, Celebrex, or Cerebyx.
This ingredient can also promote increased energy levels, focus, and alertness, which can improve the vividness of a dream during sleep.
Choline bitartate, though it is usually just called "choline," is a macronutrient that is similar to what the B Vitamins provide the body.
Humans produce their own choline in the liver. Many animal proteins contain choline as well.
This ingredient can be found in many foods. Muscle meats, animal liver, fish, and poultry eggs all have high levels of choline in them.
It can also be found in non-animal foods as well. Spinach, peas, legumes, nuts, and wheat germ all contain choline at some level.
If the ingredient sounds familiar, it is because choline is offered as a workout supplement.
When taken in higher doses, it can extend muscle energy reserves so people can work out longer and recover with greater speed.
Choline can also help to prevent neural tube defects during fetal development.
As a non-workout supplement, choline has been found to be useful in treating liver disease, certain memory-based health conditions like Alzheimer's disease, and it can help treat certain types of seizures.
Choline is also a precursor to the development of acetylcholine in the brain.
With more of it present, the neurotransmitter can be produced at greater levels. That promotes a prolonged and enhanced state of dreaming.
How Does Claridream Pro Encourage Vivid Dream States?
Claridream Pro takes advantage of a theory in neuroscience that is called Hebbian Theory.
Although it isn't always true in every circumstance, the basic foundation of this theory is that any neurons which fire together will eventually "wire" themselves together over time.
Let's say you have one neuron in your brain that fires when you're about to fall asleep.
This one tiny neuron tries to create a dream state for you, but it can't really get the job done because there are so many other neurons that are firing.
Your brain can't pick out that one neuron at all.
This will continue on until something changes.
You must learn something new to change the environment. You must also change the environment within the brain to encourage more neurons to fire.
As a person learns a new skill, additional neurons will fire with the first neuron, almost simultaneously.
At first, the number of neurons firing will remain small, but it does slowly build.
Over time, engrams form in the brain and the skill being learned becomes enhanced.
Claridream Pro helps to change the environment.
When you add new skills, such as changing your bedtime routine, creating a dream journal, or just discussing the dreams you remember with others, the possibility of engram building is increased.
For some, a product like Claridream Pro can have immediate results. For others, it may take some time to develop these engrams.
And there will always be some people who are such heavy sleepers that remembering a dream is next to impossible.
Will a Product Like Claridream Pro Work for Me?
Does Claridream Pro work? Yes.
Does Claridream Pro work for everyone? No.
Although medical science has rapidly advanced over the last century, there are still no absolute guarantees of success.
Physicians will even have you sign medical waivers that state you understand a medical condition may not be resolved or could return, even if a surgical procedure is successful.
For individuals who can safely take Claridream Pro, there is an excellent chance that it will improve the color, vividness, and even the lucidity of daily dream states.
There are certain population groups who should not take Claridream Pro or should seek medical advice before doing so.
Women who are pregnant or who are breast feeding should not take Claridream Pro.
Because the ingredients of Claridream Pro are designed to alter a mental state, it should not be taken by anyone who is already under a doctor's care for a mental health concern.
Some ingredients are strong enough on their own to use as a treatment for schizophrenia, so Claridream Pro may interact negatively with other prescriptions that are being taken.
Speak with a medical professional before taking Claridream Pro if you are taking an antibiotic, an antidepressant, or any other prescription medication.
It may be a safe inclusion to your current treatment plan, but that can only be determined by your doctor.
The primary active ingredient in Claridream Pro is huperzine-A.
This ingredient is known to slow a person's heart rate and could be problematic for those who already have a slow heart rate.
It may also cause unforeseen complications in individuals who have heart health concerns.
People who have a history of epilepsy or seizures should only take Claridream Pro under direct medical supervision.
There is a concern that it could cause seizures to return or make them worse.
Minor side effects include headache, constipation, and an increase in mucous or fluid secretions.
Stomach cramps are sometimes reported, as are muscle cramps.
However most people will not experience any of these side effects.
Anyone who is allergic to any of the ingredients of Claridream Pro should not take the product at any time.
An allergy may also develop after taking Claridream Pro successfully, which may start with a rash or be a serious allergic reaction.
To achieve a vivid dream state, it is necessary to reach a rapid eye movement (REM) sleep state.
If you remain in the stages of sleep that occur before you reach the REM stage, dreams are not going to occur.
Most people experience their first cycle of REM sleep about 90 minutes after first falling asleep.
For some, it can be as soon as 60 minutes after falling asleep.
Each REM cycle lasts longer than the previous one, which is why 7-9 hours of sleep is recommended for most individuals. That provides 3-4 full cycles of REM sleep.
Dreams are most often remembered when waking directly from the REM stage of sleep.
That's why timing your sleep cycles to wake up during your last stage of REM sleep, when combined with a product like Claridream Pro, can help you remember very vivid dreams.
You can also increase the chance of experiencing a vivid dream by incorporating these ideas into your daily routine.
Remove distractions from your sleeping environment. Let it be a place for real rest. Take out computers, items related to work, and even mirrors that rob you of your sleep focus.
Use aromatherapy to enhance your sleep environment. Mugwort and lavender are especially beneficial when attempting to achieve a vivid dream state.
Consider changing the color scheme of your bedroom to earth tones. Blue and green are also calming colors. Add any decorations to the room that help the space feel peaceful and comfortable.
Use affirmations right before going to sleep that promote dream retention. A simple phrase, such as, "I will remember my dreams tonight," can set the stage for an incredible dreaming experience.
Think about making a dream altar. People have a spiritual core that is given a high priority. By creating a dedicated space to your dreams, you're adding a subconscious level of importance to future dreams.
It is possible to achieve a vivid, colorful dream state naturally.
Many people can do it on their own without any assistance. Even lucid dreaming can be achieved in such a way.
For those who struggle with dream recall, however, there are solutions to be found. One of those solutions could be Claridream Pro.
Knowing how to have vivid dreams means creating a structure, in the mind and in your home, that will encourage dreams to be transferred to the brain's memory centers.
By following these ideas, you may be able to achieve your goal of having vivid, colorful dreams in the coming days.
If you think that Claridream Pro is something you would like to try out, then click here to learn more.


The Voyager is the flagship of the Offshore fleet, and she represents the utmost in refined elegance. Building a yacht that is this special requires intimate collaboration between an owner who knows what he wants, and a builder willing to execute those wishes flawlessly. Offshore welcomes this creative relationship because it ensures that each new Voyager becomes that owner's perfect yacht. Are you on board?


Death by pixels just got real.
It's 11pm and you're onto your 12th hour in front of a computer screen – Netflix binge included. This may sound like the typical work and play culture for most these days, but researchers are suggesting that it's also a ticket to your early funeral.
According to a new study published in the open access journal, BMC Medicine, the impact of extensive screen time on cardiovascular disease, cancer incidence and mortality may be increased in those who don't hit the gym when compared to those who do.
More specifically, the findings revealed that people who have lower levels of grip-strength, fitness and physical activity are the most at risk if they spend extensive hours basking under a screen.
The mortality rate of double just for binge watching your favourite show is probably the most unsettling factor for most, but there is a solution. Researchers from Glasgow University believe that by simply increasing your strength and fitness, couch potatoes can offset the life threatening health affects of screen gazing.
"Our study shows that the risks associated with sedentary behaviour are not the same for everyone; individuals with low physical activity experience the greatest adverse effects," says Dr Carlos Celis, the study's author.
Additionally, Dr. Celis believes that measuring grip strength is a very promising way to weed out those who are most at risk of the diseases.
Even though 391,089 participants from the UK had participated in this study, its researchers are aware that a straight cause and effect conclusion can't be drawn just yet. Factors such as self-reported screen time and hours spent on physical activity means that the result may be slightly inaccurate, if not indicative of future health concerns for workaholics.
Until then we'd highly recommend you take this as a precaution and work on preventing your muscle mass from deteriorating as you age.


Phd. (C), University of Barcelona, Spain. Degree in Psychology, University of Barcelona, Spain.
She has written the book "Widening the cake: three cases on the dynamics of negotiations." (Doubleday, 2004). She has written book chapters "Negative attitudes towards change", in: 50 Management Lessons: book commemorating the 50th anniversary of EADA. (Doubleday, 2007); "The organizational change as an opportunity for personal growth", in: Both are worth far: proposals on personal growth. (Doubleday, 2005).
She is Head of the Department of Human Resources EADA. She has been a consultant in Montaner & Asociados Consultancy, Azimut 360 and Adolescent Psychology Coordinator at Centre of Psychology INFAD; Program Director at EADA; Professor at ESADE, and FBG at the University of Barcelona.


text:
African Wildlife Conquers London
All photos and captions courtesy of Beverly Joubert. The wildlife of Great Britain has long since transitioned from giants like the red deer, brown bear, lion, and boar to the more quaintly sized denizens of Winnie-the-Pooh's Hundred Acre Wood and Mr. McGregor's garden. Starting today however, the big beasts are back. Now open at the...
All photos and captions courtesy of Beverly Joubert.
The wildlife of Great Britain has long since transitioned from giants like the red deer, brown bear, lion, and boar to the more quaintly sized denizens of Winnie-the-Pooh's Hundred Acre Wood and Mr. McGregor's garden.
Starting today however, the big beasts are back.
Now open at the National Geographic Store on Regents Street, "Visions of Africa" is a new exhibit of fine art photographs by NG Explorer-in-Residence Beverly Joubert, bringing the last of Earth's megafauna to the bustle of London. Epic vistas, heart-pounding action, and intimate details are all on display, in images collected over a ten-year period studying lions, leopards, and other wildlife in the Okavango Delta, Duba Plains, Mombo, and the Selinda Reserve.
Printed large on richly textured paper, the photographs appear like picture windows, giving the viewer a sense of presence unlike anything attainable in a magazine page or on a computer screen.
During the opening on Tuesday evening, Beverly and her filmmaker husband Dereck gave a talk while a silent auction of a print raised money for the Big Cats Initiative, dedicated to preserving these great predators in their natural habitats throughout the world.
Beverly and Dereck were also recently at National Geographic headquarters, where they gave their expert opinion on exactly what's going on in the "Baby vs. Lion" video making the rounds on YouTube. Watch their response below.
Cause an Uproar for Big Cats
Photos: "Relentless Enemies: Lions and Buffalo" by Beverly Joubert
Beavers Return to Scotland After 400 Years


text:
1Foundation
2Contents
4First Novel Award
6Sources
Books in Canada
Canadian literary magazine (1971–2008)
October 1971 cover
Olga Stein
The Canadian Review of Books Ltd. (Canada)
9/year
ISO 4 (alt) · Bluebook (alt1 · alt2)
NLM (alt) · MathSciNet (alt )
Books Can.
CODEN · JSTOR (alt) · LCCN (alt)
MIAR · NLM (alt) · Scopus
OCLC no.
Journal homepage
Books in Canada was a monthly magazine that reviewed Canadian literature, published in print form between 1971 and 2008. In its heyday it was the most influential literary magazine in Canada.
Foundation[edit]
One of the co-founders of Books in Canada in 1971 was the radio producer, book publisher and jazz music columnist Val Clery (1924–1996).[1] He decided the magazine was needed after writing a report for the Canadian Book Publishers' Council on promotion of books in Canada, and was the first editor of the magazine.[2] The journal received subsidies from the Canadian government.[3] It was published by Bedford House Publishing Corp.[2]
Contents[edit]
Books in Canada included reviews of Canadian poetry, literature and non-fiction books. Authors such as Margaret Atwood, Margaret Laurence, bpNichol and Michael Ondaatje contributed reviews.[4] It also included interviews with authors and profiles of authors, and other topics.[2] The author, journalist and second-hand bookstore owner Donald Herbert Bell (1936–2004) wrote a column called "Founde Bookes" that described his activity locating and selling books.[5]
Books in Canada was the most comprehensive book review journal in the 1980s and early 1990s, giving a broad overview of the Canadian literary scene that was valued by writers who wanted to keep in touch.[6] Books in Canada appeared nine times per year. It was sold in book stores and newsstands across the country, and by subscription. Circulation was about 12,000 per issue.[2] According to Stephen Henighan it was sometimes facile, and sometimes paid too much attention to activity in Toronto, but it published reviews by freelancers from across the country and covered almost all Canadian fiction and poetry publications. The magazine was readable, light and journalistic.[7]
Books in Canada was acquired by Adrian Stein in 1995.[8] The magazine was published through Stein's company named The Canadian Review of Books Ltd.[4] Olga Stein, wife of Adrian Stein, edited the journal.[3] The Steins converted Books in Canada to a new format. Henighan suggests that it became more selective about what it chose to review, ignoring important works in favor of obscure academic books and lengthy opinion columns. Circulation dropped sharply.[7] Early in 2000 the journal suspended publication.[8]
In 2001 Adrian Stein made a deal with Amazon.com, an online book retailer, which generated some controversy.[3] Stein sold Amazon the electronic rights to old reviews, while Amazon provided cash and advertising to the journal, which resumed publishing in July 2001.[8] With the new Amazon arrangement, print circulation increased dramatically to 100,000 copies per issue while subscriptions remained the same. Amazon offered every Canadian customer a complimentary copy of the publication in the mail.[citation needed]
In its last years Books in Canada was sometimes narrowly focused on Toronto, sometimes attempted to address the global market.[9] The Canada Council for the Arts, Ontario Arts Council and Canadian Heritage Magazine Fund reduced or dropped funding.[8] The magazine published an extensive defense of the Canadian newspaper publisher Conrad Black before his trial for fraud in the U.S.[3] The January/February 2008 issue had an article titled "The Knotted Knickers of Naomi Klein" with a caricature of the author.[10] The magazine continues to provide an online archive of its reviews.[11]
First Novel Award[edit]
Main article: Amazon.ca First Novel Award
Books in Canada established its prestigious "Books in Canada First Novel Award" in 1976. It was later sponsored by SmithBooks, a bookseller, and known as the "Smithbooks/Books in Canada First Novel Award".[12] When Smithbooks was acquired by Chapters in 1995 the award was renamed the "Chapters/Books in Canada First Novel Award". Later the award became the "Amazon.ca/Books in Canada First Novel Award". After Books in Canada closed it became the "Amazon.ca First Novel Award".[12]
^ Clery, Val, University of Toronto.
^ a b c d Woodcock 2009.
^ a b c d Ariss 2011.
^ a b Books in Canada, Collectors' Additions Canada.
^ Don Bell fonds, Concordia University.
^ Henighan 2002, p. 166-167.
^ a b Henighan 2002, p. 167.
^ a b c d Adams 2008.
^ Henighan 2002, p. 168.
^ Sexism on the cover of Books in Canada?, Rabble.
^ Canadian Literary Journals, Zines, and Periodicals.
^ a b Van Herk 2009.
Adams, James (2008-10-01). "This award night comes with a twist". The Globe and Mail. Retrieved 2014-08-11.
Ariss, Michelle (2011). "The rise and demise of a book-review magazine interpreting the cultural work of Books in Canada (1971-2008)". Retrieved 2014-08-11.
"Books in Canada". Collectors' Additions Canada. Archived from the original on 2014-08-12. Retrieved 2014-08-11.
"Canadian Literary Journals, Zines, and Periodicals". Canadian Literature Centre. University of Alberta. Retrieved 2014-08-11.
"Clery, Val". University of Toronto. Retrieved 2014-08-11.
"Don Bell fonds". Concordia University. Archived from the original on 2014-08-12. Retrieved 2014-08-11.
Henighan, Stephen (2002). When Words Deny the World: The Reshaping of Canadian Writing. The Porcupine's Quill. ISBN 978-0-88984-240-3. Retrieved 2014-08-11.
"Sexism on the cover of Books in Canada?". Rabble.ca. 22 March 2008. Retrieved 2014-10-18.
Van Herk, Aritha (2009-10-09). "Judging first fiction first". The Globe and Mail. Retrieved 2014-08-11.
Woodcock, George (2009-05-18). "Books in Canada". The Canadian Encyclopedia. Toronto: Historic Canada. Retrieved 2014-08-11.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Books_in_Canada&oldid=1069400316"
1971 establishments in Ontario
2008 disestablishments in Ontario
Defunct literary magazines published in Canada
Magazines established in 1971
Magazines disestablished in 2008
Magazines published in Toronto
Monthly magazines published in Canada
Nine times annually magazines
9 times per year journals (infobox)
This page was last edited on 2 February 2022, at 04:06 (UTC).


rock crushing plant was analyzed. The spectrogram, psychoacoustic parameters , and modulation indices were calculated from the calibrated, timedomain data. The different work phases of the recordings are shown in Table I. 3.1. Spectrogram. The spectrogram of the complete recording #83 below 200 Hz is in Figure 3.
FOR. MINERAL WORKS. (STONE CRUSHING PLANTS). BPM 11/1 (95). Environmental Protection Department. Air Policy Group. September 2008 to dust, not being any works described in any other specified process. 2. EMISSION 4.14 The surface of all surge piles and stockpiles of blasted rocks or aggregates shall be.
Oct 11, 2012 Being pulled into the crushing chamber when attempting to pull out contaminants (e.g. reinforcing bar). Struck by the loader bucket if the access platform is within the working radius of the loading machine (for 360 degree excavators). Falling if adequate guardrails and access arrangements are not provided.


When Jo contacted me with her idea to incorporate her daughter's drawing into their invitations I couldn't wait to get designing these truly personal and unique invites.
We went for a trifold design, with a detachable rsvp card in her wedding colours. I think Rosie could be competition in the future!