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Event of Interest
May 16 Operation Chastise: No. 617 Squadron RAF begins the famous dambusters Raid, bombing the Möhne and Eder dams in the Ruhr valley with bouncing bombs
- May 16 SS General Jürgen Stroop orders the burning of the Warsaw Ghetto, ending a month of Jewish resistance. 13,000 Jews have died, about half burnt alive or suffocated, German casualties less than 300
- May 17 The United States Army contracts with the University of Pennsylvania's Moore School to develop the ENIAC (Electronic Numerical Integrator And Computer).
- May 17 World War II: the Dambuster Raids by No. 617 Squadron RAF on German dams
Event of Interest
May 17 Millionaire Howard Hughes crashes into Lake Mead, while test flying his Sikorsky S-43, killing CAA inspector Ceco Cline and Richard Felt
- May 18 Allied bombers attack Pantelleria, an Italian island 100 km southwest of Sicily
- May 19 Berlin is declared "Judenrien" (free of Jews)
- May 19 Churchill pledges Britain's full support to US against Japan
- May 20 French, British and US victory parade in Tunis, Tunisia
- May 21 Fastest 9 inning AL baseball game (89 mins), White Sox beat Senators
- May 22 RAF scatters 1st copies of "The Flying Hollander"
- May 22 Stalin disbands Komintern
- May 23 -24] 826 Allied bombers attack Dortmund
Event of Interest
May 25 Agnes Moorehead appears in "Sorry, Wrong Number" on the radio program "Suspense", her most successful appearance
- May 26 Edwin Barclay of Liberia becomes first president of a black country to visit US
- May 26 Jews riot against Germany in Amsterdam
- May 26 Prime Minister Winston Churchill & General Marshall fly from US to North Africa
- May 27 French resistance under Jean Moulin meets secretly in Paris
- May 27 US forbids racial discrimination in war industry
- May 29 Meat and cheese rationed in US


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Peer reviewed
Direct link
Direct link
ERIC Number: EJ898976
Record Type: Journal
Publication Date: 2010-Nov
Pages: 22
Abstractor: As Provided
Reference Count: 56
The Judge Specificity of Evaluations of Youth Social Behavior: The Case of Peer Provocation
Dirks, Melanie A.; Treat, Teresa A.; Weersing, V. Robin
Social Development, v19 n4 p736-757 Nov 2010
Increasingly, theorists have suggested that social competence is an evaluative construct that will vary as a function of who is judging behavior. This study examined how two key groups in children's social environments--peers (N = 663, age range = 10.83-15.25 years) and teachers (N = 49)--rated the effectiveness of different behaviors generated by youth in response to physical, verbal, and relational provocation by peers. Results indicated that youth evaluated aggressive responses as more effective than teachers whereas teachers evaluated seeking an explanation as more effective than youth. Both groups judged responses combining assertive and aggressive elements to be more effective than "pure" aggression. Implications for measurement and intervention models of social competence are discussed.
Descriptors: Aggression, Social Behavior, Interpersonal Competence, Social Environment, Peer Relationship, Student Attitudes, Teacher Attitudes, Intervention, Measurement
Wiley-Blackwell. 350 Main Street, Malden, MA 02148. Tel: 800-835-6770; Tel: 781-388-8598; Fax: 781-388-8232; e-mail: email@example.com; Web site: http://www.wiley.com/WileyCDA/
Publication Type: Journal Articles; Reports - Evaluative
Education Level: N/A
Audience: N/A
Language: English
Sponsor: N/A
Authoring Institution: N/A


text:
South Africa's power utility, Eskom, appears to be lurching from one crisis to another.
The latest headache for the Eskom executives is the downgrading of the utility's bonds to junks status by rating agency Standard & Poor (S&P).
Eskom's long-term ratings were lowered to BB+ from BBB-, the lowest investment grade.
This (downgrading) is very bad news both for the sovereign and the utility
S&P slashed the utility's long-term ratings to non-investment grade and was accompanied by a negative forecast.
This means Eskom, which is already struggling to keep the lights on in one of Africa's largest economies, will continue to find it difficult to raise money on the international market.
"This (downgrading) is very bad news both for the sovereign and the utility," said Nic Boraine, a political analyst.
S&P said the negative outlook reflects 'our opinion that material execution risk remains associated with government's support plan'.
President Jacob Zuma in February promised that the government would inject millions of rand to the cash strapped utility.
The first installment of the cash injection is expected in the next 12 weeks.
However, analysts had predicted the negative rating, as Eskom has been struggling for the past year.
This week the utility was plunged into crisis after the shock announcement that several executives including the chief executive officer, Tsediso Matona had been suspended.
S&P said the suspensions led it to 'question' the corporate governance arrangements at Eskom.
Eskom chairman, Zola Tsotsi has launched an inquiry into the current status of the utility.
Three months have been set aside of the enquiry and S&P said it 'could lead to further deterioration in the company's credit quality'.
"The announcement by the board regarding the suspension of the CEO and three executives has led us to have less confidence in the company's corporate governance arrangements," S&P said.
But Boraine said the suspensions were necessary, an aspect S&P could have overlooked.
"The fundamental problem with how the agencies function is that they ask market participants what they think of one or other phenomenon that is affecting the market rather than examining the phenomenon itself," he said.
"Our call is that 'on balance' the suspensions are positive, giving government's 'war room' strategy elbow room to barge in and start doing some serious digging into the four features of the crisis at Eskom we have mentioned previously".
In a bid to deal with South Africa's crippling energy crisis, Deputy President, Cyril Ramaphosa this week appointed a high profile team led by senior business leaders into a new body known as the Energy Council.
Ramaphosa said the 'war room', which he leads, would advise government on how best to deal with the crisis.
South Africa has been experiencing electricity shortages since October 2014.
In the past few months, 34 percent of Eskom infrastructure has not been functioning.


text:
Complete these sentences by using the following words
Caption Cartoon Circulation Comic strip
Crossword Editorial Feature Gossip column
Headline Horoscope Obituary Preview
Review Supplement Tabloid
- The …………………………………………………… at the top of the page said "TALKS FAIL"
- The newspaper has increased its …………………………………………………… by 5000 copies a day.
- He was unhappy at some comments of his latest film in the ……………………………………………………
- I always turn to the …………………………………………………… first. I love reading about the private lives of famous people.
- I like the …………………………………………………… they've put below this picture.
- I prefer a …………………………………………………… newspaper because it's a more convenient size.
- They did a full-page special …………………………………………………… on poverty in inner city areas.
- She drew the political …………………………………………………… on the front page.
- I must read my …………………………………………………… to see if I'm going to have a good day.
- The critics went to a special …………………………………………………… of the musical, which opens next week.
- In his …………………………………………………… he said he did of a heart attack.
- The guide to the air show came as a free …………………………………………………… to the local newspaper.
- I only need one word to complete the ……………………………………………………
- If there's an exciting ……………………………………………………, people will keep buying the newspaper to see what happens next.
- There was a short but effective …………………………………………………… giving the newspaper's opinion of the defence policy.
1. Headline 2. Circulation 3. Review 4. Gossip column
5. caption 6. Tabloid 7. Feature 8. Cartoon
9. horoscope 10. Preview 11. Obituary 12. Supplement
13. crossword 14. Comic strip 15. editorial


text:
A repeat visit was just as enjoyable. Quiet location on a side street, modern low rise building with security-controlled lift access from the underground car park.
Really enjoyed Northcote's High Street. The nearby local Thai restaurant is a favourite as well as the choice of Vietnamese, Italian, Taiwanese and modern Australian fare - all within a short walk.
Westgarth Theatre has the latest movies screened during the day as well as at night. We managed to squeeze in and enjoyed "Murder on the Orient Express".
The warm Spring nights bring the spectacular view to light as daylight diminishes. Restful as well as ever changing! Difficult to pass up.
Just finished our weeks stay (again!) & hadn't yet explored all the High St restaurants & shops! It was too easy to linger in the warmth of this modern rooftop apartment & watch the CBD & surrounding skyline change as the rain rolled over & the sun peeked out. The floor to ceiling glass gives an amazing feeling. Even when I'm cooking the view is reflected in the kitchen splashback! Our friends & rellies who dropped by were gobsmacked as soon as the walked in the door!
An apartment for days, a week, a month or more. We enjoyed the morning views of an ever changing city skyline through expansive glass windows and the proximity to a plethora of restaurants on the ever developing, quintessential Melbourne, Northcote High Street. The just-off-High Street location is quiet, contemporary and with many close transport options to enjoy the city. The modern decor made this an apartment easy to stay in and enjoy.
Location, location, location. Exceeded expectations with the presentation of the apartment only exceeded by the view. Grab it when available, it won't be for long.
Very well set up apartment with everything you would need for a prolonged stay. Easy walk to the tram for the half an hour trip into the city. We were spoilt for choice for places to eat on the nearby shopping strip. The view from the apartment was ever-changing and amazing.


text:
Nuscope Recordings CD 1020 Gaga
Denman Maroney Quartet
Denman Maroney, Steinway B piano as Hyperpiano; Ned Rothenberg, alto saxophone, clarinet, bass clarinet; Reuben Radding, double bass, bass guitar; Michael Sarin, drums, percussion.
Fowler's blues (08:43)
Frogs (05:03)
Gaga (19.54)
Detach & retain (06:15)
Kilter (08.01)
Blip (03.15)
Social security (04.29)
Jug (06.19)
Recorded in Brooklyn, New York on May 26 and July 6, 2006 at Acoustic Recording.
Cover art (reproduced above)
Winter trees
by Chris Villars.
Go to
list of nuscope recordings
or to
Independent Record Labels page


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by Morgan Solomon
This month marks the 10-year anniversary of a horrible animal abuse case in Athens, GA. The Athens Area Humane Society had a huge hand in helping the felines in this case, making sure they found new homes for as many cats as possible.
On the evening of September 2, 2007, Athens-Clarke County (ACC) Animal Control entered a home after reports of animal abuse. A neighbor, who was a veterinarian, called animal control after finding a dead cat in the window of the house on Merlin Court. Animal control and police began rescuing cats the very next day. Throughout the rescue, more and more cats were discovered, totaling 51 cats found in the home.
According to Patrick Rives, ACC Animal Control Superintendent, it is one of the worst cases he has seen in his 21 years of working in animal control. When he arrived on the scene, most of the cats were malnourished and becoming feral. They had to use traps to catch some of the cats. The house was covered in waste and feces, making it unbearable to be in there for more than a few minutes at a time. The team of rescuers took turns entering the house.
By the time they finished, they had rescued 48 cats. These cats were kept at the Athens Area Humane Society (AAHS) shelter, which was located on Beaverdam Road at that time, as well as in foster homes. While the shelter did not have the space to house this many cats, they did their best to accommodate them. Of the 48 cats, four were quarantined for rabies after biting rescuers. The rest were dewormed and pronounced healthy by University of Georgia veterinarians.
After investigating the house, it was concluded that the owner left the tub faucet dripping so the cats could drink water. There were around 100 empty cans and bags of cat food and signs that the owner would sporadically return to feed the cats.
On September 14, 2007, the man responsible turned himself in. Wilford Bradford Sims was charged with 51 counts of animal cruelty. Ultimately, he was found guilty and sentenced to 20 days in jail. A neighbor had confronted Sims in May 2007 about how he neglected the cats, and after this, he rarely went to the house.
AAHS did not have the funds for vaccines or spaying and neutering each cat, but with help from the Athens community, they were able to raise $3,500. With this money they were able to provide care for every cat and hoped that this would also help them get adopted.
The week after the cats were found, only four had been adopted. The shelter feared that they would eventually have to put the rest down due to lack of space and resources. AAHS, the county's only contracted cat intake shelter at that time, had a policy where an animal must stay in their care for at least five days before being euthanized. Although the cats had been in their care for more than five days, they did not have any plans to euthanize them. In order to encourage adoption, the shelter waived the adoption fees. People could adopt the cats for $1 under a program called "Change their Luck for a Buck."
Things turned around, and by the middle of September, 33 of the cats had found homes. On October 9, 2007, the last cat found its home. AAHS did an amazing job. They did not give up even in the face of an overwhelming case and were able to find homes for these cats with limited resources.
Lindsay Porter was the only employee of AAHS working when the cats were first rescued. She was able to meet most of the cats and had an integral hand in the intake and initial care process, along with her husband and staff of the University of Georgia Small Animal Clinic who stayed until all cats were processed. She remembers the cats being very scared and the whole experience being frustrating and exhausting. Despite the frustration, Lindsay says it was a rewarding experience to help these cats who had suffered such terrible abuse. She even went the extra mile and adopted three of the cats.
Black Cat and Gray Cat were considered two of the most feral cats, so Lindsay brought them home to live in her barn. She later adopted BC (short for Boss Cat) after he was brought to the shelter as a stray and the owner did not want to reclaim him. At first BC spent most of his time under the bed, but soon he became her "ambassador cat" who welcomes any foster animal that stays in Lindsay's home.
Black Cat and Gray Cat spent eight years as barn cats before Black Cat passed away. Gray Cat then made the transition from feral to friendly when Lindsay decided to bring him inside. It took a while for him to warm up, but with the help and encouragement of BC, Gray Cat now lives a happy life indoors. Both cats are definitely mama's boys and have come to love each other in their own "bromance," according to Lindsay.
Thanks to AAHS and people like Lindsay who were willing to take in these cats as their own, this tragedy was transformed into a story of love and success for the animal community in Athens.
If you suspect someone of hoarding or other negligent behavior, please contact ACC Animal Control at 706-613-3540.
If you or someone you know adopted any of the cats from this hoarding case, we'd love to hear from you to share your stories, as the adoption records have been lost or misplaced since the case concluded. Please email us at firstname.lastname@example.com to get in touch.


text:
Francis Samonte*
University of the Philippines, Manila, Philippines
Received Date: April 04, 2017; Accepted Date: April 27, 2017; Published Date: May 05, 2017
Citation: Samonte F (2017) Neuroepigenetic Modification and Nutritional Status. J Transl Neurosci. 2:1.
Copyright: © 2017 Samonte F. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The study of epigenetic has brought about a deeper understanding of developmental programming through a complex network of modifications involving the DNA. While the DNA sequence remains conservative throughout, the mechanism of epigenetic modification involves changes through histone modification, DNA methylation, and chromatin remodelling. The overall dynamic effect of epigenetic modification allows the gene expression to be altered leading to a diverse phenotypical expression; a functional change in the genome without affecting the DNA. The emergence of nutritional neuroepigenetic serves to bring into focus the impact of nutrition as an environmental agent in regulating gene expression patterns leading to phenotypical expression with profound neurological and cognitive implication in later life. This link is supported by evidence from animal models suggesting that epigenetic marks, which are formed following DNA methylation or histone modification, can induce changes leading to developmental diseases or persist into adulthood. The difficulty in understanding the intrinsic biomolecular correlation between 1) epigenetic modification, 2) nutritional imbalance, and 3) cognitive impairment in an animal based model provides a compelling question regarding the developmental origins of cognitive related diseases. There have been few animal model studies involving the molecular basis of neuroepigenetic dysfunction in the relation to over nutrition or under nutrition. The main criteria in this review will focus on the few animal based studies in nutrition based epigenetic reprogramming and its role in neuroepigenetic dysregulation and cognitive impairment.
Cognition; Autism; Dementia; Malnutrition; Obesity; Neuroepigenetic; Memory
The field of epigenetics has brought a wide ranging understanding into somatically heritable states of gene expression [1] through changes in the genome without altering the DNA sequence. The phenomena of epigenetic changes are brought about through various mechanisms such as DNA methylation, histone modifications, chromatin remodelling and miRNA. During the developmental process of the fetus, maternal environmental exposures such as nutritional deficiency can lead to susceptible epigenomic dysregulation [2] with strong implications in the phenotypical expressivity or in the development of later life diseases. The impact of maternal nutritional deficiency has been implicated in poor nervous system development as a result of heritable changes in DNA methylation state during cell division [2-4]. While it is well known that folate deficiency during the early gestational period can result in spinal dysraphism, some epigenetic processes involving DNA methylation and histone methylation causes inheritance process (genomic imprinting). In Beckwith- Wiedemann Syndrome results from an epigenetic mutation wherein a preferential or exclusive domain from either the paternal or maternal allele is expressed [5].
The phenomenon of epigenetic imprinting through the DNA methylation has been well studied. DNA methylation is stable and common throughout the human genome. It occurs within the CpG dinucleotides, which exists in methylated and unmethylated form. The establishment of DNA methylation patterns occurs through a complex enzymatic action of DNA methyltransferases (DNMT). During this reaction the methyl group of S-adenosylmethionine is donated to the 5' position of cytosine, resulting in the formation of 5-methylcytosine [6,7]. The CpG dinucleotide methylation process provides the mechanism in transmitting DNA methylation patterns to subsequent generations, a form of epigenetic inheritance.
In order to achieve the inheritance pattern, the enzyme DNA methyltransferase 1 (DNMT1) acts to keep the methylation mark on the cytosine on the nascent strand during mitosis [6,8]. This is particularly important in epigenetic gene regulation since variations in this process have been associated with developmental abnormalities, particularly neurodegenerative disorders such as cerebellar ataxia, deafness and hereditary sensory neuropathy.
While DNA methylation provides a stable and well understood process, in contrast histone methylation is more complex and difficult. And while DNA methylation of CpG islands in the gene promoter region is associated with repression of gene transcription [6,7], in contrast histone methylation results in gene transcription that is typically either activated or repressed, depending on the type of methylation and position of the methyl group attached.
Histone proteins are part of the fundamental unit of a nucleosome. Work on histone modification is associated with transcriptional activation or deactivation. Histone modifications undergo a post-translational process involving methylation, phosphorylation, acetylation, ubiquitination, and sumoylation. During this stage, chromosome packaging and transcription activation or deactivation can take place, which can alter the chromatin structure. Epigenetic mark provides basis for quantitative detection of misguided transcriptional states and increased susceptibility to diseases [2,9,10].
Methylation is involved in nearly every aspect of life. S-Adenosyl Methionine (SAM) is a substrate in the methyl-transfer reaction that serves as the sole methyl donor for a variety of reactions in DNA, proteins, phosphilipids, and neurotransmitters. In histone methylation, Histone Methyltransferases (HMT) act on lysine or arginine residues of the H3 and H4 histones by transferring the methyl group from SAM, which also requires dietary folate as methyl donors. Histone methylation results in different effects on gene activity. For instance, the enrichment at H3K9me, H3K20me, or H4K27me will result in gene repression, whereas enrichment of histone methylation at H3K4me, H3K36me, or H3K79me [11-16] will result in active transcription. In adjusting the acetylation or methylation of histone modifying enzymes, dysregulation that occurs has been implicated in several types of cancer development.
Histone acetylation is generally more simplified. The acetylation of lysine residues in histone H3 and H4 involves the enzyme Histone Acetyltransferase (HAT), or deacetylation by Histone Deacetylases (HDACs). Histone acetylation can disrupt the chromatin structure by regulating the transcription activity. Actively transcribed regions of chromatin involve hyperacetylated histones, whereas transcriptionally silent regions involved hypoacetylated histones. This provides a more predictable correlation with activated transcribed genes, which is more often difficult to achieve in histone methylation [8,11,17]. Large number of studies provides evidence of the role of dietary Histone Deacetylase Inhibitor (HDAC) in cancer [18] and neuro-cognitive diseases [19-22].
The role of animal based studies is critically important in furthering our knowledge and understanding into the molecular basis of epigenetic modification and related environmental (nutrition) agents in disease causation. However, given the difficulty in designing protocols, knockout models, and techniques that are designed to look into nutritional epigenetics and developmental origins of cognitive impairment, it is not surprising that there a very few of these research studies undertaken. Furthermore, there are perils in using these animal models. For instance, rats expressing transgenes in the study of dementia that are similar to those used in transgenic mouse models, have been shown that few of them have actually develop the plaques notable in Alzheimer's dementia [23]. In addition, the problem of bias and randomization remains an inherent problem in the research community [24].
There are many studies in epigenetic programming looking at environmental (nutrition) influence and subsequent neuropsychological adverse outcome. However, there have been only a handful of animal studies looking at the causality and subsequent neural biology changes that occur following nutrition related epigenetic modifications. The scope of our journal search involved research articles in Scopus and ISI-indexed journals. The main selection criterion was based on animal based studies with these 2 key factors: 1) nutritional epigenetic modification, and 2) the resultant neuropsychological cognitive impairment.
Nutritional epigenetic modification: DNA methylation and histone acetylation
Even as we continue to gain insight and understanding in the mechanism of epigenetics the challenge in accurately predicting the outcome of a genome following DNA methylation or histone modification remains elusive. DNA methylation alone is involved in a wide array of tissue specific gene expression from differentiation, developmental programming, chromatin restructure and genomic imprinting resulting in phenotypic variance. Even though observations on the correlation between environment and epigenetic modification through DNA and histone methylation are well established, the specific, predictive function and outcome has yet to be elucidated. Environmental observation serves as a function of epigenetic modification that is necessary in the hierarchical understanding of how nutrition plays a critical role in a diverse range of biological processes involved in the regulation of gene expression. In turn these functional outcomes provide relevant understanding of disease programming and development.
Nutrition is a key environmental factor that has gained broad interest with its strong influence in epigenetic modification. The causal relationship between nutrition and DNA methylation has been clearly elucidated both in animal studies and clinical disease entities. The study of folic acid in DNA methylation process provides an invariable basis in nutritional epigenetic. It is a water soluble vitamin and a onecarbon source in the critical cellular pathway for DNA and protein methylation. The consumption of folic acid leads to its reduction into Tetrahydrofolate (THF), which in the presence of Vitamin B6 dependent enzyme serine hydroxymethyltransferase is ultimately reduced to 5- methyltetrahydrofolate (5-methyl THF). This reaction provides the supply of methyl groups for the remethylation of homocysteine to methionine as well as DNA methylation.
The association between diet and DNA methylation can lead to corresponding metabolic alterations with profound implications. Studies involving animal models [25-28] reveal changes in the gene expression activity and subsequent enzyme activity. These metabolic changes in turn can lead to increase susceptibility to chronic diseases such as diabetes, cardiovascular diseases, obesity and even cancer. The total burden of DNA hypermethylation and histone hypoacetylation is known to cause gene repression which can invariably lead to these diseases. For instance when DNA hypermethylation causes epigenetic control and suppression of adiponectin-a protein in humans that helps regulate glucose and fatty acid metabolism- there is a subsequent increase expression of DNA methyltransferase I (DNMT1) which acts to suppress the level of adiponectin activity. The result is a predictable exacerbation of obesity. Alternatively, when DNMT1 activity is suppressed, the level of adiponectin expression rises while decreasing obesity-induced glucose intolerance and insulin resistance [26]. This is particularly important as it suggests that the epigenetic modifications through DNA methylation can result in chromatin remodelling with adverse and deleterious effects on the metabolic outcome of individuals.
The epigenetic control of various metabolic processes is not limited to DNA methylation programs alone. Molecular mechanisms involving histone deacetylase inhibitor (HDAC) in mice [19,20,29] has led to further studies to determine possible therapeutic modalities. Histone Deacetylases (HDACs) has been implicated in insulin resistance and subsequent development of cognitive impairment in dementia. When mice were subjected to a high fat diet (8 weeks), the results revealed a reduction of H3 acetylation and BDNF (brain derived neurotrophic factor) along with decrease memory and learning deficits [29]. These findings represent findings that notable in Alzheimer's disease. In contrast mice that were fed with high fat diet and given HDAC inhibitor (Suberoylanilide Hydroxamic Acid (SAHA)) revealed increased levels of H3 acetylation and BDNF, suggesting a neuroprotective role and potential disease modifying agent.
Maternal nutrition and fetal programming
The honeybee model provides a unique example of the role of maternal diet in genomic imprinting that can affect the DNA methylation, resulting in a phenotypical different offspring. The caste determination in honeybees has been well studied in detail and represents an example of developmental programming in epigenetics. Even though female honeybee larvae possess identical gene sequences [30,31] they will develop either to become a worker or a queen bee, depending on the diet given to them. In this case, a female larvae fed with royal jelly will develop to become the queen bee, while other larvae fed with regular diet develops into worker bees. The difference in gene expression is primarily determined by DNA methylation. Studies have shown that silencing of the DNA methyltransferase 3 (DNMT3) induces the development of queen bees that are fed with royal jelly [31,32].
The precise role of epigenetic modification during fetal development is not yet fully understood. Strong evidence suggests that early life insult even during pregnancy can lead to fetal developmental programming by which epigenetic marks such as DNA methylation and histone modification could elicit lifelong effects on the health of the offspring. Observations made on the maternal nutritional state during pregnancy indicates that epigenetic changes in the fetus can in turn lead to susceptibility changes in the gene transcription process and later life diseases. Fetal overnutrition can have negative implications that can lead to neuro-metabolic syndrome of diabetes, obesity and adult onset dementia [25,27]. Recent epidemiological and animal studies have shown that patterns of obesity in later life is mediated by the early changes in gene expression starting from maternal nutrition to fetal programming leading to several transcription factor susceptibility changes.
The epigenetics of cognitive disorders and nutrition
Cognitive process implies the constructive ability to understand process information and create fund knowledge and store them through memory. The mechanism by which cognition takes place requires a series of refinement and cortical response by which the experience dependent neuroplasticity is altered and stored as memory. The regulation of synaptic plasticity and formation of memory is accomplished through epigenetic mechanisms of transcription regulation [33-35]. The role of DNA methylation on CpGs is an epigenetic activity that results in the silencing of transcription regulation through the catalytic activity of DNA Methyltransferases (DNMTs). Besides the CpG methylation, DNA methyltransferase is also involved in the active demethylation of 5mCpGs through deamination process. The active inhibition of methylation will result in demethylation and subsequent transcriptional activation. The overall result of DNA methylation and DNMTs is the consolidation of memory. This molecular storage and consolidation of memory relies on the hippocampal methylation and cortical hypermethylation for long term memory. Conversely, DNMT inhibition leads to demethylation and transcriptional activation of the memory suppressing genes [34-37]. These epigenetic events create a memory of cell identity while their genomic functions remain conservative, stable and maintain its function.
The construct relationship of cognitive neurosciences and nutrition is predicated upon the epigenetic regulation which serves to modify gene expression without changing the DNA sequence. As we continue to advance our knowledge in the epigenetic of nutrition, the global impact of cognitive disorders continue to rise. The effect of nutrition in cognitive development and degenerative conditions is mediated thru multiple gene expressivity and variability. Various studies looking into the role of nutrition and cognition reveals a cause and effect through methylation and histone modifications. The silencing of transcription factors while activating other factors suggest that nutrition plays a critical role in shaping the development of neuro-cognitive conditions through gene modification.
There is strong evidence from animal and human studies that support the level of understanding related to the development of cognitive impairment following epigenetic alterations and its effect in cell specific and age related gene expression. These results suggest that the key mechanism by which cognitive dysfunction occurs can be a long term effect of poor diet and nutrition which in turn mediate changes in the epigenome that can modify gene expression and enable the development of neurological diseases. This layer of regulation has important implications into the hypothesis of the "Developmental Origin of Health and Disease" (DOHaD). These epigenetic changes are, however, reversible which provides a critical concept in the role of nutrition in the prevention and treatment of diseases.
The effects of dietary factors in the brain have been well documented and elucidated in human and animal studies. The interaction between environmental factors such as nutrition, age, and physical activity is required for proper brain functioning. Alterations from this highly regulated interaction have been linked to cognitive decline such as dementia and Alzheimer's disease. One of the most widely investigated hypotheses has been the role of Vitamin B12 and folate can affect the methylation process by altering the one-carbon metabolism [3,7,38]. Altered cholesterol homeostasis in general has also been implicated in the development of late-onset Alzheimer's disease [39,40]. The elevated cholesterol level results in a pro-inflammatory environment in the brain which contributes to the development of cognitive impairment, but could also lead to enhanced amyloidogenesis by up-regulation of BACE-1 (the beta-secretase enzyme in Alzheimer's disease [39]. Studies on the role of polyunsaturated fatty acids in learning and behavioural impairment such as Attention Deficit Hyperactivity Disorder (ADHD) provide a potential treatment through nutritional supplement. Dietary supplementation of n-3 Polyunsaturated Fatty Acid (PUFA) on patients with Attention Deficit Hyperactivity Disorder (ADHD) [41,42] results in improvement of literacy and behaviour.
Neuroepigenetic dysregulation from overnutrition
Overnutrition is a metabolic condition that predisposes an individual to obesity, diabetes and nutritional deficiencies. Overnutrition can not only result in insulin resistance and hyperglycemia but its long term outcome can lead to epigenetic reprogramming. There have only been a few in vivo and in vitro studies by which the dynamic relationship between the contribution of DNA methylation and overnutrition (obesity) in relation to the development of cognitive related diseases has been shown. Part of the inherent difficulty in methylation studies and overnutrition comes from the diverse epigenetic expression across the spectrum of cognitive dysfunction. For instance the DNA methylation expression in the neuropathological substrates of Alzheimer's disease can vary significantly across the spectrum of disease. Even beyond the spectrum of the disease, methylation studies performed in blood reveals a complete different expression done in the brain [43]. This observation is supported by studies showing that the higher the methylation is around the gene, the lower the expression.
Childhood and adolescent overnutrition is causally related to obesity and juvenile onset diabetes. Early onset of obesity can lead to cognitive changes such as memory impairment and learning difficulties. Memory is a cognitive function that relies on the hippocampus part of the brain for storage and later retrieval. Damage to the hippocampus can lead to memory impairment and difficulty in establishing new memories. Recent studies suggest that the loss of memory in the state of obesity results from alterations in DNA methylation involving Sirtuin 1 (Sirt1) protein within the hippocampus. In vitro studies suggest that Sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Experimental animal models on obesity induced memory impairment [44] revealed that the effects of memory impairment from reduced hippocampal Sirt1 in knockout mice can be mitigated by dietary supplement of epigenetic based Sirt1 activating molecule (resveratrol). The result shows that the memory response mechanism improved following supplementation.
The epigenetic modification involved in obesity induced memory impairment is not restricted to DNA methylation alterations. Cognitive memory impairment can also result from alterations in Histone Deacetylase Activity (HDAC). Obesity induced cognitive impairment can result from impaired glucose tolerance and epigenetic changes in the DNA which controls energy metabolism. Mice fed with high fat diet resulted in changes in the mitochondrial activity in the neuronal cells, leading to energy deficit [45]. The addition of HDAC inhibitor trichostatin A proved to be beneficial in mediating an improved cognitive activity based on fMRI findings and isolated mitochondrial oxygen consumption. Nonetheless, the understanding of role of Histone Deacetylase (HDAC) in mitigating or reversing the effects of cognitive impairment induced by obesity remains incomplete. In a similar obesity induced mice model study, an increased expression of histone deacetylases 5 along with the reduced expression of brain-derived neurotrophic factor in the brain was observed following high-fat diet [46]. The findings of synaptic dysfunction in the hippocampus even after putting the mice on a regular diet suggest a more permanent and possibly irreversible epigenetic change in the brain that can persists following restoration of normal diet.
Obesity induced cognitive impairment is not limited to memory changes often linked to Alzheimer's disease, vascular dementia or learning disorders such ADHD. There are, however, exceptionally few studies linking obesity induced homeostatic dysregulation and cognitive impairment. Homeostatic regulation in the brain is a coordinated interaction involving the neurotransmitters, hormones, and peripheral metabolic organs. The homeostatic regulation impart by the brain is critical in the maintenance of energy and glucose metabolism. Dopamine is a neurotransmitter with a highly important role in regulating several metabolic processes. It serves a key role in the reward related brain regions, primarily involving prefrontal cortex, hypothalamus, Ventral Tegmental Area (VTA), and Nucleus Accumbens (NAc). Using a mouse model of diet induced obesity [47], alterations in the hypothalamic dopamine expression was observed, while decrease expression was noted in the prefrontal cortex, VTA and NAc circuitry. High-Fat Diet (HFD)-induced models of obesity have also been observed in the opioid system dysregulation [48]. Similar results of increase opioid expression in the hypothalamus while decrease expression in the other circuitry was also observed. Taken together, the results suggest that the epigenetic mechanism of DNA methylation linking the chronic intake of high fat diet led to altered dopamine or opioid related gene expression. Homeostasis was also altered with changes in either the dopamine or opioid expression in the reward related circuitry in the brain. These observations improves on further assumptions regarding the multiple, complex interaction between diet and the epigenetic modifications at various levels of involvement by which neuroepigenetic impairment can result in cognitive dysfunctions (Table 1).
|Cognitive Disorder
|Epigenetic Mechanism
|Neuro-Epigenetic Modification
|Obesity Weighs down Memory through a Mechanism Involving the Neuroepigenetic Dysregulation of Sirt1.
|Heyward et al. [44].
|Memory-impairing effect
|DNA methylation
|Effects of diet-induced obesity may potentially be mediated by neuroepigeneticalteration of Sirtuin 1 (Sirt1) via DNA methylationwithin the hippocampus.
|Epigenetic Modification in Metabolic Syndrome/Induced Brain Energy Impairment
|Varghese et al. [45]
|Dementia, Alzheimer's disease
|Histone deacetylase 5 (HDAC5)
|Diet induced metabolic syndrome (obesity) might induce epigenetic modification of DNA that controls energy metabolism, while modulation of HDAC activity may improve mitochondrial function in neurons.
|Childhood and adolescent obesity and long-term cognitive consequences during aging
|Wang et al. [46]
|Synaptic dysfunction
|Histone deacetylase 5 (HDAC5)
|Obesity and insulin resistance during childhood/adolescence induces irreversible epigenetic modifications leading to increased expression of histone deacetylases 5, accompanied by reduced expression of brain-derived neurotrophic factor (BDNF)
|Epigenetic dysregulation of the dopamine system in diet-induced obesity.
|Vucetic et al. [47]
|Dopamine homeostatic control of central reward circuitry
|DNA methylation
|High fat diet led to altered DNA methylation within the promoter regions of tyrosine hydroxylase (TH) and dopamine transporter (DAT), thereby affecting Ventral tegmental area (VTA), Nucleus accumbens (NAc), & Pre-frontal cortex (PFC).
|Chronic High-Fat Diet Drives Postnatal Epigenetic Regulation of μ-Opioid Receptor in the Brain.
|Vucetic et al. [48]
|μ-Opioid receptor (MOR) homeostatic control
|DNA methylation
|Increase DNA methylation led to increase binding of MeCP2 at the MOR promoter region (Ventral tegmental area (VTA), Nucleus accumbens (NAc), Prefrontal cortex (PFC), & hypothalamus). Subsequently increased H3K9 methylation and decreased H3 acetylation.
Table 1: Neuroepigenetic dysregulation from overnutrition.
Malnutrition and cognitive impairment
The effects of malnutrition on DNA methylation during the vulnerable stages of development in children affect the health and behavioural outcomes in later life. The role of either DNA or histone modification is central to the understanding of epigenetic inheritance, while the role of chromatin remodelling remains less clearly understood since not all epigenetic inheritance involves the chromatin modification. Histone modification enzymes include a variety of post-translational processes and often do not provide a straightforward outcome in relation to the environmental insult in malnutrition. The influence of diet to DNA methylation is direct which comes specifically from SAM donor feedstock. Methionine, choline, and folic acid in the diet provide a major source of methyl group during DNA methylation. Significant reduction in their supply has a direct effect on the DNA methylation and gene expression, resulting in the alteration of protein transcription.
While nutritional status of an individual from birth to adulthood is strongly correlated to intellectual and cognitive development, the Dutch famine at the end of World War II provides an example of how nutritional deprivation can impact the neurodevelopment and cognitive outcomes in adults following prenatal famine. The results of prenatal famine were associated to cognitive outcomes in the following condition:
1. Congenital anomalies of the central nervous system;
2. Schizophrenia;
3. Schizophrenia spectrum personality disorders.
The longitudinal studies from the great famines (Dutch, Chinese, Barbados) [49-51] provide an analysis into the extent of cognitive dysfunction with a wide range of phenotypical expression. The long term impact on behavioural and learning processing disorders as a result of profound malnutrition showed persisting effects into adulthood even independent from nutrition rehabilitation. Multiple regression analysis reveals problems related to focus, attention span, memory, and mood disorders were commonly observed in these studies. Research into the biomolecular effects of childhood nutritional deficiency in brain pathology suggests significant and potentially irreversible changes in the cortex, hippocampus, midbrain and brainstem [52-54]. These areas are crucial throughout the lifespan but even more significant during early cognitive development.
In the Barbados Nutrition Study [55], DNA methylation study was conducted on 168 individuals exposed to severe malnutrition revealed long lasting epigenetic changes in the prefrontal cortex that are associated with increase susceptibility to attention and cognitive disorders. The study identified 134 nutrition sensitive, differentially methylated genomic regions. Further identification of specific neuropsychiatric risk genes (including COMT, IFNG, MIR200B, SYNGAP1, and VIPR2) revealed the association of specific methyl-CpGs with attention and IQ. The lack of proper nutrition during maternal pregnancy can similarly lead to learning and behavioural disabilities (ADHD), autism spectrum disorder and even neuropsychiatric conditions [56]. The study suggests the role of maternal reprogramming of the hypothalamic-pituitary-adrenal axis which can then possibly lead to neuro-epigenetic modification and later cognitive susceptibility in the offspring (Table 2).
|Cognitive Disorder
|Epigenetic Mechanism Involved
|Neuro-Epigenetic Modification
|Impact of Maternal Stress in Pregnancy on Brain Function of the Offspring.
|Udagawa et al. [56]
|Increased risks schizophrenia, autism spectrum disorder (ASD), and attention-deficit hyperactivity disorder (ADHD)
|DNA methylation
|Maternal stress reprograms the hypothalamic-pituitary-adrenal (HPA) axis, which regulates the stress response in the offspring.
|S-adenosylmethionine reduces the progress of the Alzheimer-like features induced by B-vitamin deficiency in mice
|Fuso et al. [57]
|Alzheimer /Dementia
|DNA methylation
|Presenilin1 (PS1) & BACE (beta-secretase) regulated thru DNA methylation and that the reduction of folate and vitamin B12 in culture medium can cause a reduction of SAM levels
|Folic acid, neurodegenerative and neuropsychiatric disease
|Kronenberg et al. [55]
|Cerebral ischemia, Alzheimer's dementia and depression
|DNA methylation
|Low folate status and elevated homocysteine lead to induction of DNA damage, uracil misincorporation into DNA and altered patterns of DNA methylationand contribute to neurodegenerative and neuropsychiatric disease.
Table 2: Malnutrition and Cognitive Impairment.
The association of micronutrient deficiency in the development of neuro-epigenetic dysfunction has been elucidated in a few studies. For instance, the presentation of dementia in animal studies can be reduced by increasing the DNA methylation in conjunction with increased S-adenosylmethionine (SAM) expression [57].
The epigenetic modification that takes place in this process is highly regulated by the availability of folic acid and vitamin B micronutrients. A significant micronutrient dysregulation would, therefore, lead to neuroepigenetic changes and subsequent neuropsychiatric development.
Severe nutritional micronutrient deficiency (iodine, iron, zinc and vitamin B 12) can result in poor neuro-cognitive development. Iodine deficiency during the prenatal stage can result in devastating clinical outcomes resulting in congenital hypothyroid and related cognitive dysfunction. In many parts of the world, iron deficiency continues to be a significant cause of morbidity. Iron deficiency anemia can lead to reduced oxygen carrying capacity especially to the brain. Children are highly susceptible to learning and behavioural disorder due to low levels of focus and attention as the brain requires increased amount of oxygen from which the blood cannot sustain adequately. Various animal models involving the relationship between iron and zinc [58,59] deficiency reveals how the hippocampus-mediated spatial recognition learning is affected which ultimately leads to reduced memory and learning response. Observational studies link early life iron deficiency with the reduced expression of Brain-Derived Neurotrophic Factor (BDNF) [58], a gene critical for long-term memory and normal neuronal development in the hippocampus and prefrontal cortex in the brain which ultimately affects the cognitive function into adulthood. The influence of zinc deficiency in neuropsychiatric pathology is better understood than its role in neuronal plasticity. Animal studies [50,59] suggest that zinc is essential in cognitive development specifically involving sensory skills, thinking, memory, learning and attention. The exact mechanism in relation to epigenetic modification is not clear and evidence is limited. Neuronal zinc is widely distributed throughout the cortex, amygdala and hippocampus, which subserve mood regulation and cognitive functions. Studies reveal that zinc deficiency leads to increase histone acetylation and decrease in deacetylation, methylation and phosphorylation in post-translational modification of H3 [60]. These findings suggest that zinc deficiency can play a role in altering hippocampal DNA methylation in the development of neuropsychopathology.
In elucidating the interrelationship between nutrition and cognitive neuroscience through its epigenetic modification, our understanding of the developmental programming in later life diseases continue to unfold. The specific role of overnutrition or malnutrition in creating a chronic stress environment represents a state of unmitigated, repeated stress resulting in various neuroepigenetic reprogramming. This neuroepigenetic reprogramming represents a dysfunctional state by which a lack of recovery phase and loss of transcription regulation can lead to the development of cognitive impairment and other neuropsychological conditions. The burden of epigenetic misprogramming is affected by the degree of environmental (nutrition) insult, although the critical temporal process remains undefined.
Unfortunately the specific molecular basis and mechanism by which nutritional status (either overnutrition or malnutrition) can cause neuroepigenetic modification in relation to cognitive dysfunction is not yet fully understood. There are few human and animal molecular studies looking into the association and causal effects of diet and nutrition in mediating the programming leading to neuroepigenetic dysregulation. Majority of nutritional cognitive studies are based on clinical observations, although these generally lack the molecular basis and hierarchical mechanisms to further expand our understanding. While basic science research is needed to properly elucidate these mechanisms, the lack of animal models specifically focused on neuroepigenetic and cognitive related disorder are also few and requires further development to advance the breadth of our understanding.
The need to understand the interrelationship between the epigenetic of nutrition and cognitive dysfunction is critical in part due to the growing worldwide burden of metabolic disorders, malnutrition, dementia and psychiatric disorders. With the lack of understanding into the molecular mechanism of cognitive impairment, as it relates to nutritional epigenetic modification, the role of proper diet and nutrition will remain the cornerstone in improving the clinical outcome of cognitive related diseases. The need to improve our understanding in relation to nutritional epigenetics can be best achieved through increase animal based studies and its cognitive neurological outcomes. Animal based protocols should also be improved by creating new knockout models and techniques. Without these objectives in place, our knowledge based understanding will remain unperturbed and remote.
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