Genetic Variants Demonstrate Humans Continue To Evolve Through Natural Selection

MedicalResearch.com Interview with:

Hakhamanesh Mostafavi, MS PhD student Department of Chemical Engineering Columbia University

Mostafavi Hakhamanesh

Hakhamanesh Mostafavi, MS
PhD student
Department of Biological Sciences
Columbia University 

MedicalResearch.com: What is the background for this study?

Response: We know very little about the genetic variants that underlie adaptation in humans. This is in part because we have mostly been limited to methods that search for footprints of ancient selection (that has acted for over thousands to millions of years) in the genomes of present-day humans; so by design are indirect and make strong assumptions about the nature of selection.

These days, thanks to advances in genomic technologies, genetic data for large numbers of people is being collected, mostly for biomedical purposes. Accompanied by information on survival and reproductive success of these individuals, such large datasets provide unprecedented opportunities for more direct ways to study adaptation in humans.

In this work, we introduced an approach to directly observe natural selection ongoing in humans. The approach consists in searching for mutations that change in frequency with the age of the individuals that carry them, and so are associated with survival. We applied it to around 210,000 individuals from two large US and UK datasets.

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Similar Signaling Pathways Trigger Anxiety In Variety of Species

MedicalResearch.com Interview with:

Yuanyuan Xie, PhD Postdoctoral Researcher Department of Neuroscience University of Pennsylvania Philadelphia, PA 19104

Dr.Yuanyuan Xie

Yuanyuan Xie, PhD
Postdoctoral Researcher
Department of Neuroscience
University of Pennsylvania
Philadelphia, PA 19104

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: I joined Dr. Richard Dorsky’s lab in mid 2013 after a lab switch toward the end of the fourth year in my PhD. By then, the Dorsky lab at the University of Utah had published zebrafish lef1 mutants with a hypothalamic neurogenesis phenotype. I was asked to perform an RNA-sequencing (RNA-seq) experiment to identify Lef1-dependent genes. In doing so, I also characterized the cellular phenotype in the hypothalamus of our zebrafish mutants in a greater detail.

The first transition of this project happened when I proposed in late 2013 to test whether Lef1’s function was conserved in the mouse hypothalamus. Dr. Dorsky liked that idea, but told me that I could only pursue that idea if there was a Lef1-flox mouse strain available, because he did not want me to delay my graduation after a lab switch by making a new mouse line. Fortunately, a quick google search located the right mouse line published from the group of Dr. Hai-Hui Xue, who was generous enough to share some mice with us. Because the Dorsky lab was a zebrafish lab by then, we collaborated with Dr. Edward Levine to maintain our mice under his animal protocol. I was initially trained by Dr. Levine and his lab specialist Anna Clark for general mouse colony management. After Dr. Levine moved to Vanderbilt University in early 2016, we began to maintain our mice under Dr. Camille Fung’s animal protocol. Dr. Dorsky also supported me in attending a 3-week Cold Spring Harbor Laboratory Course on Mouse Development, Stem Cells & Cancer in mid 2015, which made me much more confident in handling mouse work afterwards.

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How Much Does Mother’s BMI Influence Children’s Metabolic Health?

MedicalResearch.com Interview with:

Prof. Deborah A Lawlor MSc(Lond), MBChB, PhD(Bristol), MPH(Leeds), MRCGP, MFPHM Professor of Epidemiology MRC Integrative Epidemiology Unit at the University of Bristol NIHR Bristol Biomedical Research Centre Population Health Sciences, Bristol Medical School Oakfield House, Oakfield Grove, Bristol

Prof. Lawlor

Prof. Deborah A Lawlor
MSc(Lond), MBChB, PhD(Bristol), MPH(Leeds), MRCGP, MFPHM
Professor of Epidemiology
MRC Integrative Epidemiology Unit at the University of Bristol
NIHR Bristol Biomedical Research Centre
Population Health Sciences, Bristol Medical School
Oakfield House, Oakfield Grove, Bristol

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: As the obesity epidemic has occurred there has been increasing concern about pregnant women being more adipose (having higher levels of fat) during their pregnancy. One particular concern is that women who are on average fatter will have more extreme changes in pregnancy on their lipid, fatty acid, amino acid and glucose levels. In normal ‘healthy’ pregnancy these metabolites increase during pregnancy as part of the physiological response to pregnancy which ensures that the developing fetus has sufficient fuel (nutrients – fats, proteins, sugars) for healthy growth and development. Women who are more adipose tend to have a more extreme change in these fuels and as a consequence the developing fetus is ‘overfed’. There is a linear relationship between a pregnant woman’s body mass index and her infants birth weight, such that each increment greater adiposity (body mass index) of the mother there is on average and increment greater infant birth weight.

Recently, using a method that uses genetic variants (Mendelian randomization) we have shown that this association is likely to be causal (JAMA 2016). But whether there is a lasting effect on offspring health of being overfed in the uterus is unknown. There are concerns that there will be a lasting effect and that for daughters of more adipose women, this would mean that they go into their pregnancies on average fatter and with higher levels of the metabolites that could then overfeed their developing fetus. If this were the case it would mean the obesity epidemic could be accelerated across generations.

There are associations of mothers body mass index with later offspring body mass index, BUT this might not be anything to do with developmental overfeeding of the feeding in the uterus – it could simply reflect shared lifestyles that offspring adopt from their mother (and father) or shared genetic effects. In this study we tried to separate out whether there was evidence for a long-term offspring effect on their lipids, fatty acids, amino acids, glucose, and an inflammatory marker, of having a mother who was on average fatter during her pregnancy that was due to overfeeding in the uterus, as opposed to shared family lifestyle and genetics. We did this by comparing associations of mothers pre-pregnancy BMI with offspring outcomes to the same associations of fathers pre-pregnancy BMI with the same outcomes.

Our assumption here was that fathers BMI could not directly result in overfeeding of the fetus and so if the associations were similar this would suggest that they were largely driven by family factors.

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Evidence Does Not Support Gabapentinoids in Non-Specific Chronic Low Back Pain

MedicalResearch.com Interview with:

Harsha Shanthanna MBBS, MD, MSc Associate Professor, Anesthesiology Chronic Pain Physician St Joseph's Healthcare,McMaster University Hamilton, Canada Diplomate in National Board, Anesthesiology (India) Fellow in Interventional Pain Practice (WIP) European Diplomate in Regional Anesthesia and Pain (ESRA)

Dr. Shanthanna

Harsha Shanthanna MBBS, MD, MSc
Associate Professor, Anesthesiology
Chronic Pain Physician
St Joseph’s Healthcare,McMaster University
Hamilton, Canada
Diplomate in National Board, Anesthesiology (India)
Fellow in Interventional Pain Practice (WIP)
European Diplomate in Regional Anesthesia and Pain

MedicalResearch.com: What is the background for this study?

Response: Pregabalin (PG) and gabapentin (GB) are increasingly used for nonspecific Chronic Low Back Pain (CLBP) despite a lack of evidence. There have been concerns expressed over their increased prescribing for various non cancer pain indications in recent years. Their use requires slow titration to therapeutic doses and establishing maintenance on a long-term basis. With prolonged treatment, the potential gain over possible adverse effects and risks could become unclear.

We searched Cochrane, MEDLINE and EMBASE databases for randomized control trials reporting the use of gabapentinoids for chronic lower back pain treatment of 3 months or more in adult patients.

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Cadmium in Shellfish and Smoking Linked to Endometrial Cancer

MedicalResearch.com Interview with:

Jane McElroy, Ph.D. Associate professor Department of Family and Community Medicine MU School of Medicine

Dr. McElroy

Jane McElroy, Ph.D.
Associate professor
Department of Family and Community Medicine
MU School of Medicine

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: More than 31,000 new cases of endometrial cancer are expected to be diagnosed in 2017. Through a five-year observational study, we found that women with increased levels of cadmium had an increased risk of endometrial cancer. Cadmium is a metal commonly found in foods such as kidneys, liver and shellfish as well as tobacco It’s a finding we hope could lead to new treatments or interventions to prevent the fourth most common cancer in women.

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Blood Biomarkers Signal Multiple Organ Dysfunction Syndrome After Critical Injuries

MedicalResearch.com Interview with:

Dr. Joanna Shepherd Centre for Trauma Sciences Blizard Institute Queen Mary, University of London

Dr. Shepherd

Dr. Joanna Shepherd
Centre for Trauma Sciences
Blizard Institute
Queen Mary, University of London

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Recent advances in resuscitation and treatment of life-threatening critical injuries means that patients with previously unsurvivable injuries are now surviving to reach hospital.  However, many of these patients develop Multiple Organ Dysfunction Syndrome (MODS), which is a failure of several organs including the lung, heart, kidney, and liver.

We studied immune cell genes in the blood of critically injured patients within the first few minutes to hours after injury, a period called the ‘hyperacute window’. We found a small and specific response to critical injury during this window that then evolved into a widespread immune reaction by 24 hours.  The development of MODS was linked to changes in the hyperacute window, with central roles for innate immune cells (including natural killer cells and neutrophils) and biological pathways associated with cell death and survival.  By 24 hours after injury, there was widespread immune activation present in all critically injured patients, but the MODS signal had either reversed or disappeared.

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Menopause Facilitates Transmission of Cognitive Resources To Grandchildren

MedicalResearch.com Interview with:

“Grandmother” by Joe Shlabotnik is licensed under CC BY 2.0

“Grandmother” by Joe Shlabotnik

Carla Aimé PhD
Institute of Evolutionary Sciences of Montpellier
France

MedicalResearch.com: What is the background for this study? What are the main findings?

Response:  In all human populations, regardless of environmental and socioeconomic conditions, menopause occurs in women well before the end of their expected lifespan. Conversely, extensive post-reproductive life-span is rare in other species; except in some cetaceans. Evolutionary theory predicts that menopause and extensive post-reproductive lifespan should emerge and persist in populations only if it is advantageous for gene transmission. Identifying this advantage is a long-standing issue, and some hypotheses has already been suggested by other researchers. However, testing these hypotheses about the emergence of menopause is difficult, in particular because menopause exists today in all human populations. It is thus not possible to measure in real life the evolutionary advantage related to menopause by comparing gene transmission of women who stop reproduction and women who don’t stop reproduction. Here, we used computer simulations to overcome this difficulty by modeling the emergence of menopause in simulated human populations.

The main finding were the following :

– Physiological constraints are not required for menopause to emerge.

– The increasing cost of reproduction with age cannot explain menopause.

– Grandmothering is part of the process leading to menopause : stopping reproduction allow reallocating resources to existing children and grand-children, thus leading to increase gene transmission via increased fertility of children and survival of grand children

– Cognitive resources are also important. Indeed, cognitive abilities allow accumulation of skills and experience over the lifespan, thus providing an advantage for resource acquisition. These surplus resources can then be used to increase the number of offspring or be transmitted to existing offspring and grandoffspring. Stopping reproduction during aging allows allocating more resources to assist offspring and grandoffspring, thus increasing children’s fertility and grandchildren’s survival.

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How Does HPV Virus Lead To Skin Cancer?

MedicalResearch.com Interview with:
Prof. Dr. med. Sigrun Smola
Institute of Virology, Saarland University
Homburg/Saar, Germany

MedicalResearch.com: What is the background for this study?

Response: Non-melanoma skin cancer (NMSC), the most common cancer in humans, is caused by UV-irradiation. The potential co-factor role of cutaneous genus beta-human papillomaviruses (beta-HPV) in skin carcinogenesis, particularly in immunosuppressed patients, has become a major field of interest. However, the underlying mechanisms were unclear.

The skin has natural mechanisms providing protection against UV-induced damage. One important factor suppressing UV-induced skin carcinogenesis is the transcription factor C/EBPα belonging to the CCAAT/enhancer binding protein family. C/EBPα can induce cellular differentiation and is regarded as a tumor suppressor in various tissues. When C/EBPα expression is blocked in these tissues, tumorigenesis is enhanced.

Another important factor is the microRNA-203. It has been shown to control “stemness” in normal skin by suppressing a factor called p63. In many tumors miR-203 expression is shut off releasing this “brake”.

In our study we demonstrate that cutaneous beta-HPV interferes with both protective factors providing an explanation how cutaneous beta-HPV enhances the susceptibility to UV-induced carcinogenesis. Moreover, we provide evidence that these viruses regulate miR-203 via C/EBPα.

We have investigated this mechanism in Epidermodysplasia verruciformis (EV) patients that serve as a human model disease for studying the biology of genus beta-HPVs. They are highly susceptible to persistent genus beta-HPV infection, such as HPV8, and have an increased risk to develop non-melanoma skin cancer at sun-exposed sites.

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If High School Students Are Naturally Owls, Shouldn’t School Start Later?

MedicalResearch.com Interview with:
Dr. Dorothee Fischer
Department of Environmental Health
Harvard T.H. Chan School of Public Health, Boston, Massachusetts
Center for Injury Epidemiology, Liberty Mutual Research Institute for Safety
Hopkinton, Massachusetts,

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Chronotypes are a result of how the circadian clock embeds itself into the 24h light-dark cycle, producing earlier and later individuals (“larks and owls”) with regards to rhythms in physiology, cognition and behavior, including sleep.

It can be beneficial for health and safety to sync forced wake times (work, school) with individual chronotypes, thereby reducing the misalignment between sleep, circadian rhythms and external demands.

To better inform potential interventions such as tailored work schedules, more information is needed about the prevalence of different chronotypes and how chronotype differs by age and sex.

To the best of our knowledge, this is the first large-scale and nationally representative study of chronotypes in the US.
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Heroin Epidemic Costs US Over $50 Billion Per Year

MedicalResearch.com Interview with:

A. Simon Pickard, PhD

Dr. Pickard

A. Simon Pickard, PhD
Professor, Dept of Pharmacy Systems, Outcomes and Policy
University of Ilinois at Chicago
College of Pharmacy

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The heroin epidemic, which has left virtually no part of American society unscathed, can be viewed as an illness.  Unlike some illnesses, however, it was largely manufactured by stakeholders in the healthcare system, wittingly or unwittingly.

The main finding, that heroin addiction costs us just over $50 billion per year, is likely a conservative estimate.

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