Gene genie

[Jo Bowyer]

HOW THE BRAIN ADAPTS TO STRESS

http://neurosciencenews.com/stress-d...genetics-4025/

Stress is a major burden in many people’s lives affecting their health and wellbeing. New research led by the University of Bristol has found that genes in the brain that play a crucial role in behavioural adaptation to stressful challenges are controlled by epigenetic mechanisms.

Adaptation to stress is known to require changes in the expression of so-called immediate-early genes in the brain, particularly in the hippocampus, a brain region that plays a crucial role in learning and memory.

Until now, however, the underlying molecular mechanisms controlling the expression of these genes has been unclear. The BBSRC-funded research conducted at the University of Bristol, in collaboration with King’s College London and the University of Exeter, has revealed that stressful events result in epigenetic modifications within immediate-early genes in hippocampus neurons.

The epigenetic modification studied is DNA methylation, which acts to suppress expression of genes. The findings, published in the international journal Proceedings of National Academy of Sciences (PNAS), showed that stress results in DNA de-methylation in immediate-early genes thereby freeing the suppressed expression of these genes in the hippocampus and facilitating manifestation of adaptive behavioural responses.

The researchers found that the gene and behavioural responses to stress depended on the concentration of the compound SAM (s-adenosyl methionine). SAM is a so-called methyl donor, which is required by the enzyme that methylates DNA. When SAM levels were elevated, a subsequent stressful event did not result in DNA de-methylation but elicited enhanced DNA methylation of immediate early genes, which suppressed their expression and led to impaired behavioural adaptation.

Hans Reul, Professor of Neuroscience of Bristol’s School of Clinical Sciences, said: “We discovered in our studies a link between SAM, a compound produced by the liver, and stress-related responses in the brain, which is important to pursue in future research.

I doubt that Professor Reul is an "ectodermalist".

[Jo Bowyer]

Familial Risk of Chronic Musculoskeletal Pain and the Importance of Physical Activity and Body Mass Index: Prospective Data from the HUNT Study, Norway

Abstract

The main objectives of the current study was i) to prospectively examine if chronic musculoskeletal pain in parents is associated with risk of chronic musculoskeletal pain in their adult offspring, and ii) to assess if these parent-offspring associations are modified by offspring body mass index and leisure time physical activity. We used data on 4,742 adult offspring linked with their parents who participated in the population-based HUNT Study in Norway in 1995–97 and in 2006–08. Family relations were established through the national Family Registry. A Poisson regression model was used to estimate relative risk (RR) with 95% confidence interval (CI). In total, 1,674 offspring (35.3%) developed chronic musculoskeletal pain during the follow-up period of approximately 11 years. Both maternal (RR: 1.26, 95% CI: 1.03, 1.55) and paternal chronic musculoskeletal pain (RR: 1.29, 95% CI: 1.06, 1.57) was associated with increased risk of offspring chronic musculoskeletal pain. Compared to offspring of parents without chronic musculoskeletal pain, the adverse effect of parental pain was somewhat stronger among offspring who reported a low (RR: 1.82, 95% CI: 1.32, 2.52) versus high (RR: 1.32, 95% CI: 0.95, 1.84) level of leisure time physical activity. Offspring of parents with chronic musculoskeletal pain and who were classified as obese had more than twofold increased risk (RR: 2.33, 95% CI: 1.68, 3.24) of chronic musculoskeletal pain compared to normal weight offspring of parents without pain. In conclusion, parental chronic musculoskeletal pain is positively associated with risk of chronic musculoskeletal pain in their adult offspring. Maintenance of normal body weight may reduce the risk of chronic musculoskeletal pain in offspring of pain-afflicted parents.

PLOS ONE

[Jo Bowyer]

Have a close-up look at DNA; you'll see it wiggles in the oddest way.

https://www.sciencedaily.com/release...0420111237.htm

Put more scientifically, a piece of DNA's movements are often counterintuitive to those of objects in our everyday grasp. Take a rod of rubber, for example. Bend it until its ends meet, and you can count on the elastic tension to snap it back straight when you let go, said biological physicist Harold Kim.

"That doesn't always work that way with a piece of DNA. When you bend it into a loop, the elastic energy more often than not wants to bend the chain further in instead of pushing it back out," said Kim, an associate professor at the Georgia Institute of Technology.

At the School of Physics, Kim is fine-tuning the observation of how biopolymers behave, in particular DNA at short lengths. He published his latest results on "Force distribution in a semiflexible loop" in the journal Physical Review E on April 18, 2016. The research is funded by National Institutes of Health. Georgia Tech's James T. Waters coauthored the research paper.

In complex simulations, Kim studied the motions of DNA chains at lengths where they still have springy qualities, in order to understand their mechanochemical properties, or how they work as microscopic objects. In particular, he has illuminated the forces acting upon DNA bound up in short loops.

That's a common and important shape that keeps DNA from expressing when it shouldn't and then possibly messing up cell functioning.

Kim's most significant counter-intuitive find could improve understanding of how DNA snaps free from the proteins that bind them into those loops. He has observed that looped DNA, though on average very gentle in its motions, is beset by moments of unusually high force.

"It would be a little like a chaotic spring drawn up to a loop making pretty even jumbly movements then suddenly whipping out violently," Kim said.

The range of observed forces on DNA loops breaks the bounds of what thermodynamics predicts. Even though the mean of the force distribution does indeed equal the thermodynamic force, the distribution of forces pushes past the anticipated norm, falling broadly outside a Gaussian distribution on both ends.

That's a key determination.

It could help scientists in various disciplines predict the lifespans of many DNA loops and understand the frequency and likelihood of their undoing.

The forces contributing to those momentary jerks and snaps work on the whole contrary to one another. While that elastic energy works on DNA pieces in its ways, the forces of entropy push hard in their own ways.

Reflective of the universe overall, in Kim's observations of springy DNA loops, entropy, here too, wins. Entropic forces slightly outdo the elastic forces.

And they, too, defy intuition.

To understand how, let's take a look back at that rubber bar. When a short DNA chain is not looped but only bent, it acts more like the rubber bar. The elastic force dominates and mostly wants to push it back straight, while entropy mostly wants to keep it curvy.

Then, as the DNA chain lengthens a bit and loops: That relation starkly turns on its head.

The elastic force then pulls inward with vehemence, and the entropic force then pushes the chain outward with even more vigor.

The length of a DNA loop appears to contribute strongly to how likely these intermittent extreme forces are to destabilize its bond with the protein holding it shut.

That, incidentally, plays right into many scientists' current discussions on other biopolymers.

"There's a lot of speculation right now that the kinds of force-peaks we observed actually regulate the length of some biopolymers, so, in an interesting way, our observations and methods may help colleagues explore this idea more closely," Kim said.

Kim's group augmented thermodynamic calculations with a novel simulation method, "phase-space sampling." It not only establishes the position of molecular components in space but also their momentum at a given time.

This took into account the constant bombardment by water molecules, i.e. the "heat bath."

This way, Kim was better able to access the fluctuating forces on looped DNA chains -- and see more closely how they really wriggle.

[Jo Bowyer]

Link Between Cognitive Decline Genes and Healthy Aging

http://neurosciencenews.com/cognitio...s-health-4098/

An eight-year-long accrual and analysis of the whole genome sequences of healthy elderly people, or “Wellderly,” has revealed a higher-than-normal presence of genetic variants offering protection from cognitive decline, researchers from the Scripps Translational Science Institute (STSI) reported today in the journal Cell.

[Jo Bowyer]

Genetic Factors Are Not the Major Causes of Chronic Diseases

Abstract

The risk of acquiring a chronic disease is influenced by a person’s genetics (G) and exposures received during life (the ‘exposome’, E) plus their interactions (G×E). Yet, investigators use genome-wide association studies (GWAS) to characterize G while relying on self-reported information to classify E. If E and G×E dominate disease risks, this imbalance obscures important causal factors. To estimate proportions of disease risk attributable to G (plus shared exposures), published data from Western European monozygotic (MZ) twins were used to estimate population attributable fractions (PAFs) for 28 chronic diseases. Genetic PAFs ranged from 3.4% for leukemia to 48.6% for asthma with a median value of 18.5%. Cancers had the lowest PAFs (median = 8.26%) while neurological (median = 26.1%) and lung (median = 33.6%) diseases had the highest PAFs. These PAFs were then linked with Western European mortality statistics to estimate deaths attributable to G for heart disease and nine cancer types. Of 1.53 million Western European deaths in 2000, 0.25 million (16.4%) could be attributed to genetics plus shared exposures. Given the modest influences of G-related factors on the risks of chronic diseases in MZ twins, the disparity in coverage of G and E in etiological research is problematic. To discover causes of disease, GWAS should be complemented with exposome-wide association studies (EWAS) that profile chemicals in biospecimens from incident disease cases and matched controls.

PLOS ONE

[Jo Bowyer]

Researchers uncover 'local heroes' of immune system

https://www.sciencedaily.com/release...0422115324.htm

The genes Hobit and Blimp1 have been identified, and researchers have found that these genes control a universal molecular program responsible for placing immune cells at the 'front lines' of the body to fight infection and cancer.

[Jo Bowyer]

GENETIC MODERATORS OF THE IMPACT OF PHYSICAL ACTIVITY ON DEPRESSIVE SYMPTOMS

http://www.jfrailtyaging.com/all-iss...ml?article=328

J Frailty Aging 2016;5(1):6-14

Background: Converging evidence suggests that physical activity is an effective intervention for both clinical depression and sub-threshold depressive symptoms; however, findings are not always consistent. These mixed results might reflect heterogeneity in response to physical activity, with some subgroups of individuals responding positively, but not others. Objectives: 1) To examine the impact of genetic variation and sex on changes in depressive symptoms in older adults after a physical activity (PA) intervention, and 2) to determine if PA differentially improves particular symptom dimensions of depression. Design: Randomized controlled trial. Setting: Four field centers (Cooper Institute, Stanford University, University of Pittsburgh, and Wake Forest University). Participants: 396 community-dwelling adults aged 70–89 years who participated in the Lifestyle Interventions and Independence for Elders Pilot Study (LIFE-P). Intervention: 12-month PA intervention compared to an education control. Measurements: Polymorphisms in the serotonin transporter (5-HTT), brain-derived neurotrophic factor (BDNF), and apolipoprotein E (APOE) genes; 12-month change in the Center for Epidemiologic Studies Depression Scale total score, as well as scores on the depressed affect, somatic symptoms, and lack of positive affect subscales. Results: Men randomized to the PA arm showed the greatest decreases in somatic symptoms, with a preferential benefit in male carriers of the BDNF Met allele. Symptoms of lack of positive affect decreased more in men compared to women, particularly in those possessing the 5-HTT L allele, but the effect did not differ by intervention arm. APOE status did not affect change in depressive symptoms. Conclusions: Results of this study suggest that the impact of PA on depressive symptoms varies by genotype and sex, and that PA may mitigate somatic symptoms of depression more than other symptoms. The results suggest that a targeted approach to recommending PA therapy for treatment of depression is viable.

[Jo Bowyer]

How cancer cells escape from tumors, spread

https://www.sciencedaily.com/release...0428152136.htm

The paper, published in Biophysical Journal, reveals how the abnormal proteinfiber scaffolding of tumors and the agility of the cancer cells themselves come together in a perfect storm to enable the escape. The quantitative method the researchers developed to understand the cells' sliding ability could also lead to a new way to screen for effective cancer drugs and help diag*nose the stage of a cancer early on.

"We are looking at the interaction between cancer cells' migrating and this sliding phenomenon, and how that's influenced by the proteinfiber environments of tumors," says Astha*giri. "In this paper we show that cancer cells migrating on these protein fibers have a unique ability that enhances their invasion capacity: When they bump into other cells -- which the microen*vi*ron*ment is packed with -- they slide around them. Normal cells halt and reverse direction."

[Jo Bowyer]

Potential Transmission of Non-Genetic Behavioral Traits From Mom to Child

http://neurosciencenews.com/behavior...ychology-4248/

Because it would be unethical to perform controlled experiments on interactions between women and their developing or newborn children, the mechanisms by which these behavioral symptoms are passed on have been difficult to determine. So Dr. Toth and colleagues turned to mice, where they could separate the genetic effects of maternal influence on new generations from those that occur in the womb and after birth. Their strategy was to transfer offspring at various stages of development, for example, when the embryo was 1-day old or immediately after birth, to a surrogate mother.

The group began with female mice missing one copy of a serotonin receptor, one of a family of proteins found on the surface of nerve cells that transmit the message carried by the neurochemical serotonin to the cell’s interior. Reduced activity of serotonin or its receptors is associated with anxiety, depression and stress disorders in humans and similar behavioral traits in mice.

Although some of the grandchildren displayed immune system aberrations and behavioral symptoms, embryo-transfer experiments demonstrated that the transmission was not direct from the grandmother. Instead, the whole process appeared to start anew, passing from the affected mother to her child.

Interestingly, another set of embryo-transfer experiments showed that a different behavioral trait in the mutant mice, a heightened response to stress, was directly transmitted to the grandchildren through non-genetic changes in the fetuses’ developing oocytes.

“Our study helps explain why individuals, even within the same family, can display various combinations of anxiety, depression, bipolar disease and schizophrenia symptoms,” Dr. Toth said. “We found that, at least in mice, each symptom can be passed on by a distinct mechanism.”

The group then asked how an indicator of stress or infection makes its mark on an offspring’s brain and persists to adulthood once it has been transferred from the mother. They turned to epigenetics, the study of how a series of chemical modifications to DNA, called methylation, can change how a gene is expressed but not the nature of its informational content. In the affected offspring, the scientists found these modifications on genes that are involved in nerve signaling and linked to behavioral traits.

[Jo Bowyer]

Genes Linked to the Effect of Stress and Mood on Longevity Identified

http://neurosciencenews.com/mood-lon...genetics-4285/

The visible impacts of depression and stress that can be seen in a person’s face, and contribute to shorter lives, can also be found in alterations in genetic activity, according to newly published research.

In a series of studies involving both C. elegans worms and human cohorts, researchers from the Indiana University School of Medicine and the Scripps Research Institute have identified a series of genes that may modulate the effects of good or bad mood and response to stress on lifespan. In particular, the research pointed to a gene known as ANK3 as playing a key role in affecting longevity. The research was published May 24, 2016 in the journal Molecular Psychiatry.

“We were looking for genes that might be at the interface between mood, stress and longevity”, said Alexander B. Niculescu III, M.D., Ph.D., professor of psychiatry and medical neuroscience at the IU School of Medicine. “We have found a series of genes involved in mood disorders and stress disorders which also seem to be involved in longevity.

“Our subsequent analyses of these genes found that they change in expression with age, and that people subject to significant stress and/or mood disorders, such as people who completed suicide, had a shift in expression levels of these genes that would be associated with premature aging and reduced longevity” said Dr. Niculescu, who is also attending psychiatrist and research and development investigator at the Indianapolis Veterans Affairs Medical Center.

Study Reverses Thinking on Genetic Link to Depression and Stress
http://neurosciencenews.com/genetics...n-stress-6341/

Scientists re-examine data exploring connection between serotonin gene, depression and stress.

New research findings often garner great attention. But when other scientists follow up and fail to replicate the findings? Not so much.

In fact, a recent study published in PLOS One indicates that only about half of scientific discoveries will be replicated and stand the test of time. So perhaps it shouldn’t come as a surprise that new research led by Washington University School of Medicine in St. Louis shows that an influential 2003 study about the interaction of genes, environment and depression may have missed the mark.

Since its publication in Science, that original paper has been cited by other researchers more than 4,000 times, and some 100 other studies have been published about links between a serotonin-related gene, stressful life events and depression risk. It indicated that people with a particular variant of the serotonin transporter gene were not as well-equipped to deal with stressful life events and, when encountering significant stress, were more likely to develop depression.

Such conclusions were widely accepted, mainly because antidepressant drugs called selective serotonin reuptake inhibitors (SSRIs) help relieve depression for a significant percentage of clinically depressed individuals, so many researchers thought it logical that differences in a gene affecting serotonin might be linked to depression risk.

But in this new study, the Washington University researchers looked again at data from the many studies that delved into the issue since the original publication in 2003, analyzing information from more than 40,000 people, and found that the previously reported connection between the serotonin gene, depression and stress wasn’t evident. The new results are published April 4 in the journal Molecular Psychiatry.

Update 04/04/2017

[Jo Bowyer]

Moving beyond race-based drugs

https://www.sciencedaily.com/release...0526190237.htm

Prescribing certain medications on the basis of a patient's race has long come under fire from those uneasy with using race as a surrogate for biology when treating disease.

One barrier to understanding the complex interplay between genes, environment and lifestyle is the lack of participant diversity in biomedical research and clinical trials. Addressing the problem will require recruiting more participants from minority groups to better reflect the diversity of the U.S. population.

We will also need cost controls for drugs found to be effective only in a few, the authors say.

Lastly, moving beyond race-based drug prescriptions will depend on the ability to equip health care providers with the resources and training they will need to collect and make sense of more types of data.

"Precision medicine is premised on the idea of improving health outcomes by generating and using many sources of personal data to more accurately group and treat patients," the authors say. "If the major challenges can be overcome, precision medicine could lead the way in reducing and ultimately eliminating the use of crude racial and ethnic census categories in drug prescribing."

My fierce Nigerian midwife as well as telling me how to bring up children so they become PhD students in their early twenties and spending forty minutes stitching me up thereby saving me a trip to Gynae outpatients, had my pink baby tested for sickle cell disease. As it happens we do have a Jamaican bloodline in the family dating from the 19th century.

She knew about genetics and she also knew that many of us don't know that we are of mixed race. My genes will be sequenced due to the requirements of a trial I'm in, and it won't be long before this is done as a matter of course for everyone.

N=1 is on the horizon.

Hurrah!




Born of pain, filled with power – a teenage girl’s art that confronts in order to heal

https://aeon.co/videos/born-of-pain-...-order-to-heal

The 17-year-old US artist Panteha Abareshi struggles with sickle cell disease, a chronic pain condition that prevents her from exerting herself physically, and frequently involves severe anxiety and depression. Her emotionally raw and graphically vibrant art confronts the role of pain and vulnerability in her life, depicting unflinching and unapologetic ‘physical manifestations’ of her inner struggles that she ‘can’t quite verbalise’. Through her work, she aims to both increase the visibility of women of colour dealing with mental illness, and to fight against the notion that pain is something that can simply be thought away.

Update 26/05/2017

[Jo Bowyer]

Effects of maternal smoking continue long after birth

https://www.sciencedaily.com/release...0530115534.htm

Early exposure to nicotine can trigger widespread genetic changes that affect formation of connections between brain cells long after birth, a new Yale-led study has found. The finding helps explains why maternal smoking has been linked to behavioral changes such as attention deficit and hyperactivity disorder, addiction and conduct disorder.

Nicotine does this by affecting a master regulator of DNA packaging, which in turn influences activity of genes crucial to the formation and stabilization of synapses between brain cells, according to the study published online May 30 in the journal Nature Neuroscience.

"When this regulator is induced in mice, they pay attention to a stimulus they should ignore,'' said Marina Picciotto, the Charles B.G. Murphy Professor of Psychiatry, professor in the Child Study Center and the Departments of Neuroscience and Pharmacology, and senior author of the paper.

An inability to focus is the hallmark of attention deficit hyperactivity disorder and other behavioral disorders, which have been linked to maternal smoking and exposure to second-hand smoke. However, scientists did not understand how early environmental exposure to smoking could create behavioral problems years later.

[Jo Bowyer]

Genetic code of red blood cells discovered

https://www.sciencedaily.com/release...0602132638.htm

Every individual has a unique genetic code, which is a complete instruction manual describing exactly how all the cells in the body are formed. This instruction manual is stored in the form of a specific DNA sequence in the cell nucleus. All human cells -- brain, muscle, fat, bone and skin cells -- have the exact same code. The thing that distinguishes the cells is which chapter of the manual the cells are able to read. The research group in Lund wanted to find out how the cells open the chapter that contains instructions on how to produce red blood cells. The skin cells on which the study was based had access to the instruction manual, but how were the researchers able to get them to open the chapter describing red blood cells?

With the help of a retrovirus, they introduced different combinations of over 60 genes into the skin cells' genome, until one day they had successfully converted the skin cells into red blood cells. The study is published in the scientific journal Cell Reports.

"This is the first time anyone has ever succeeded in transforming skin cells into red blood cells, which is incredibly exciting," says Sandra Capellera, doctoral student and lead author of the study.

The study shows that out of 20,000 genes, only four are necessary to reprogram skin cells to start producing red blood cells. Also, all four are necessary in order for it to work.

"It's a bit like a treasure chest where you have to turn four separate keys simultaneously in order for the chest to open," explains Sandra.

I have never been comfortable with the ecto/meso meme partly because it gets used by some to label themselves as "less wrong" meh!!!! and partly because it leave us blood n' guts fans out on a limb.

Besides which, the bottom line is gene expression.

[YT]CGQo6zpVzt8[/YT]

[Jo Bowyer]

Study Finds 36 Genes Associated With Pain and Nerve Sensitivity

http://neurosciencenews.com/smoke-alarm-gene-pain-4554/



Pain: From genes and proteins to cells in the living organism

http://onlinelibrary.wiley.com/doi/1...jnr.24046/full

“Of pain you could wish only one thing: that it should stop. Nothing in the world was so bad as physical pain. In the face of pain there are no heroes.…” Brain Tomasik, a character in George Orwell's novel Nineteen Eighty-Four, thus describes pain as an abhorrent sensation from which people seek urgent relief. Ironically, pain is a crucial warning mechanism that alerts and protects an organism against injury or harm. Our understanding of pain, its root causes and its physical and emotional impact, has given rise to an appreciation for the enormity of the chronic pain problem. To reflect the evolution of our understanding, pain is now defined by the International Association for the Study of Pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” In this Special Issue on pain, we provide an overview of some of the important findings to date, highlight existing challenges, and discuss how future studies can tackle these challenges by applying new knowledge and experimental techniques.

Update 24/04/2017

[Jo Bowyer]

Admixture into and within sub-Saharan Africa

https://elifesciences.org/content/5/e15266

Similarity between two individuals in the combination of genetic markers along their chromosomes indicates shared ancestry and can be used to identify historical connections between different population groups due to admixture. We use a genome-wide, haplotype-based, analysis to characterise the structure of genetic diversity and gene-flow in a collection of 48 sub-Saharan African groups. We show that coastal populations experienced an influx of Eurasian haplotypes over the last 7000 years, and that Eastern and Southern Niger-Congo speaking groups share ancestry with Central West Africans as a result of recent population expansions. In fact, most sub-Saharan populations share ancestry with groups from outside of their current geographic region as a result of gene-flow within the last 4000 years. Our in-depth analysis provides insight into haplotype sharing across different ethno-linguistic groups and the recent movement of alleles into new environments, both of which are relevant to studies of genetic epidemiology.