Week Ending FRIDAY July 10, 2009---------------------------News Archive / Return to News Alerts
In Rwanda, The Poorer You Are, The Fewer Sons You'll Have
Desperate to have a baby girl? It helps to be poor
That's the conclusion of a study in Rwanda, which shows that, when men marry multiple women, low-ranking wives are more likely to have daughters than sons. The findings indicate that the social ranking of human mothers can influence the sex of their offspring.
In 1973, evolutionary biologists Richard Trivers and Dan Willard predicted that in many species, social and environmental factors may influence whether a female has more sons or daughters.
For instance, in a polygynous species, where males mate with more than one female, males in good condition are at a reproductive advantage over less-fit males because they have more mating partners. According to the Trivers-Willard hypothesis, well-off females in these societies are better off having sons, because sons will have more chances to pass on their parents' genes.
However, if moms in polygynous unions don't have many resources to invest, they're better off producing daughters, because only affluent males have multiple wives; daughters will be mated with regardless of status.
Over the years, several studies have supported the Trivers-Willard hypothesis, including work in red deer, mice, and a variety of nonhuman primates. And in humans, studies of Hungarian Roma and mothers in rural Ethiopia have shown evidence of a Trivers-Willard pattern, but others looking into modern Venezuelan society and the Sudanese Bari ethnic group haven't returned the same results.
Thomas Pollet, an evolutionary psychologist at the University of Groningen in the Netherlands, thinks the confusion is partly a result of researchers struggling to determine what constitutes better or worse conditions for mothers. So Pollet and his colleagues looked at a novel maternal situation: the ranking of wives in polygynous Rwandan societies, within which the links between social standing, resource availability, and offspring are easy to tease out.
The team examined census data for 843,000 women in 12 regions in Rwanda and compared the sex ratio of offspring among three groups of women: those in monogamous unions, the first or second wives in polygynous unions, and third wives. The researchers found that, in addition to having fewer children in general, the third wives were 9% to 12% more likely than higher-ranking wives to have surviving infant daughters than sons. The monogamous, first and second wives had more sons than daughters.
Pollet and colleagues believe these results fit with the Trivers-Willard hypothesis. One possible explanation, the authors report today in Biology Letters, is that women in dominant positions, such as first or only wives, have higher levels of testosterone, making them more likely to have sons.
Lena Edlund, an economist at Columbia University who has previously studied how the Trivers-Willard hypothesis fits with social status, says Pollet's methods are sound and that wife rank seems to be a good measure of women's status. One possible mechanism not mentioned in the study, she says, is that lower-ranked wives might suffer nutritionally, which has been shown to influence a child's sex. Low glucose levels, she says, could lead to more daughters, for example.
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Newborn Brain Cells Lead the Way
Although the fact that we generate new brain cells throughout life is no longer disputed, their purpose has been the topic of much debate
Now, an international collaboration of researchers made a big leap forward in understanding what all these newborn neurons might actually do. Their study, published in the July 10, 2009, issue of the journal Science, illustrates how these young cells improve our ability to navigate our environment.
"We believe that new brain cells help us to distinguish between memories that are closely related in space," says senior author Fred H. Gage, Ph.D., a professor in the Laboratory for Genetics at the Salk Institute and the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases, who co-directed the study with Timothy J. Bussey, Ph.D., a senior lecturer in the Department of Experimental Psychology at the University of Cambridge, UK, and Roger A. Barker, PhD., honorary consultant in Neurology at Addenbrookes Hospital and Lecturer at the University of Cambridge.
When the first clues emerged that adult human brains continually sprout new neurons, one of the central tenets of neurosciencewe are born with all the brain cells we'll ever havewas about to be overturned. Although it is never easy to shift a paradigm, a decade later the question is no longer whether neurogenesis exists but rather what all these new cells are actually good for.
"Adding new neurons could be a very problematic process if they don't integrate properly into the existing neural circuitry," says Gage. "There must be a clear benefit to outweigh the potential risk."
The most active area of neurogenesis lies within the hippocampus, a small seahorse-shaped area located deep within the brain. It processes and distributes memory to appropriate storage sections in the brain after readying the information for efficient recall. "Every day, we have countless experiences that involve time, emotion, intent, olfaction and many other dimensions," says Gage. "All the information comes from the cortex and is channeled through the hippocampus. There, they are packaged together before they are passed back out to the cortex where they are stored."
Previous studies by a number of laboratories including Gage's had shown that new neurons somehow contribute to hippocampus-dependent learning and memory but the exact function remained unclear.
The dentate gyrus is the first relay station in the hippocampus for information coming from the cortex. While passing through, incoming signals are split up and distributed among 10 times as many cells. This process, called pattern separation, is thought to help the brain separate individual events that are part of incoming memories. "Since the dentate gyrus also happens to be the place where neurogenesis is occurring, we originally thought that adding new neurons could help with the pattern separation," says Gage.
This hypothesis allowed graduate student Claire Clelland, who divided her time between the La Jolla and the Cambridge labs, to design experiments that would specifically challenge this function of the dentate gyrus using different behavioral tasks and two distinct strategies to selectively shut down neurogenesis in the dentate gyrus.
In the first set of experiments, mice had to learn the location of a food reward that was presented relative to the location of an earlier reward within an eight-armed radial maze. "Mice without neurogenesis had no trouble finding the new location as long as it was far enough from the original location," says Clelland, "but couldn't differentiate between the two when they were close to each other."
A touch screen experiment confirmed the inability of neurogenesis-deficient mice to discriminate between locations in close proximity to each other but also revealed that these mice had no problem recalling spatial information in general. "Neurogenesis helps us to make finer distinctions and appears to play a very specific role in forming spatial memories," says Clelland. Adds Gage, "There is value in knowing something about the relationship between separate events and the closer they get the more important this information becomes."
But pattern separation might not be the only role that new neurons have in adult brain function: a computer model simulating the neuronal circuits in the dentate gyrus based on all available biological information suggested an additional function. "To our surprise, it turned out that newborn neurons actually form a link between individual elements of episodes occurring closely in time," says Gage.
Given this, he and his team are now planning experiments to see whether new neurons are also critical for coding temporal or contextual relationships.
Attractive Males Release Fewer Sperm!?
Attractive males release fewer sperm per mating to maximise their chances of producing offspring across a range of females, according to a new paper on the evolution of ejaculation strategies
The findings by researchers at UCL and the University of Oxford suggest that, paradoxically, matings with attractive males may be less fertile than those with unattractive ones.
In a paper to be published in the journal American Naturalist, the team mathematically modelled a range of male ejaculation strategies to look for the optimum “sperm load” per mating, and how this might vary depending on mating patterns. Previous studies have shown that in animals such as the domestic fowl, and fish such as the Arctic charr, males with privileged access to females produce ejaculates of lower fertilising quality than subordinate males.
Sam Tazzyman, from UCL CoMPLEX (Centre for Mathematics and Physics in the Life Sciences and Experimental Biology), said: “In some species, females mate with many different males. Each male’s sperm competes with that of other males in a process known as ‘sperm competition’. Since males have finite resources to allocate to breeding, they allocate them carefully to each mating to maximise their number of offspring. If a male puts a lot of resources into each mating he will get more offspring per mating, but at the expense of fewer matings. If, on the other hand, a male puts few resources into each mating he will secure less paternity per mating, but will be able to carry out more matings overall. Thus, there is a trade-off between number of matings and success per mating.”
“How a male negotiates this trade-off depends on how easy he finds it to attract females. The more attractive a male is, the more females will be willing to mate with him, reducing the value of each mating to him. This means it is optimal for him to contribute fewer sperm per mating. Although this reduces fertility per mating, it maximises the number of offspring he sires overall. Less attractive males secure fewer matings but value each of them more highly, and by allocating more sperm to each mating make the most of their meagre opportunities. This leads to the rather paradoxical prediction that matings with attractive males may be less fertile than those with unattractive males.”
“There are as yet few good examples of this process found in nature, as it has generally been assumed that more attractive or higher quality males will be more fertile. A possible case can be seen in chickens, which in the wild live in groups of varying numbers of males and females. Females mate with many males, so males are subject to sperm competition. However, the attractiveness of a male is determined in large part by his social standing. Males higher up the pecking order find it easier to secure matings with the females, but they transfer fewer sperm to females. In addition, the sperm of dominant birds is less motile and has lower fertilising efficiency than the sperm of subordinate birds. Scientists can artificially change the pecking order, and when this is done, the new dominant male's sperm quickly loses motility, while that of males reduced to subordinate status increases in motility.”
“Further work in this area should look at males that are similarly attractive, but have different levels of resources to allocate to sperm production, to see how this alters their sperm number and quality. The model should also be expanded to include the effects of short-term sperm depletion, which is known to affect ejaculate content when males re-mate quickly. We also would like to explore whether the lower fertility of attractive males causes females to start avoiding attractive males that mate too often, as these males reduce their fertility.”
“Finally, how this work applies to humans and other primates is not yet known. Human attractiveness is complicated and influenced by a number of factors including cultural preferences. Nonetheless, ejaculate size and sperm quality are likely to have been moulded by similar forces, like attractiveness and the number of sexual partners, that are important in other species.”
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Key to Maintaining Embryonic Stem Cells in Lab
In a new study that could transform embryonic stem cell (ES cell) research, scientists at UT Southwestern Medical Center have discovered why mouse ES cells can be easily grown in a laboratory while other mammalian ES cells are difficult, if not impossible, to maintain
If the findings in mice can be applied to other animals, scientists could have an entirely new palette of research tools to work with, said Dr. Steven McKnight, chairman of biochemistry at UT Southwestern and senior author of the study appearing in the July 9 issue of Science Express.
"This might change the way medical research is done. But it's still a big 'if,'" he said.
According to the research, the activation of a gene called TDH in mouse ES cells results in the cells entering a unique metabolic state that is similar to that of rapidly growing bacterial cells. The gene controls the production of the threonine dehydrogenase (TDH) enzyme in mouse ES cells. This enzyme breaks down an amino acid called threonine into two products. One of the two products goes on to control a cellular process called one carbon metabolism; the other provides ES cells with an essential metabolic fuel.
Both of the threonine breakdown products are necessary to keep the ES cells growing and dividing rapidly in a petri dish without differentiating into specific tissues.
The various substances currently used by scientists to keep mouse ES cells alive in the laboratory were found by trying many different combinations until something worked, Dr. McKnight said. But until now, it wasn't known that these culture conditions keyed into keeping the TDH gene actively expressed.
"Scientists added this and that until they got the right 'soup,' one that works in the mouse ES cells to somehow activate the TDH gene," he said, adding that exactly how that gene is regulated is still unknown.
Other mammalian species have a functional version of the TDH gene, suggesting the possibility that the process could also be activated in them.
"You would think that the 'mouse soup' would then work for all species, but it doesn't. Researchers have been trying for 20 years to get the right formula for maintaining ES cells from other species. With few exceptions, however, they still haven't gotten it right," Dr. McKnight said.
The research was funded by a National Institutes of Health Director's Pioneer Award, which Dr. McKnight received in 2004. The program encourages investigators to take on creative, unexplored avenues of research that carry a relatively high potential for failure but that also possess a greater chance for truly groundbreaking discoveries.
"By applying a highly innovative technique to manipulate the TDH gene, McKnight's work could be an important breakthrough with a profound impact on future research," said Dr. Raynard S. Kington, acting director of the NIH. "This research, which was partially funded by our Pioneer Award program, shows the value of supporting exceptionally creative approaches to major challenges in biomedical and behavioral research."
Embryonic stem cells are "blank slate" cells derived from embryos that go on to develop into any of the more than 200 types of cells in the adult body.
Because mouse ES cells are easily maintained in the lab, they can be manipulated genetically to produce adult mice in which various genes are either modified or eliminated. So-called "knockout mice" allow scientists to study the genetic aspects of many diseases and conditions, including cancer, Alzheimer's, Parkinson's and paralysis.
In the living mouse, and in other species, ES cells exist for only a short time. In that time, they need to grow rapidly in order to accumulate enough cells to begin the process of differentiating into all the body's cell types. Dr. McKnight hypothesizes that the TDH gene tightly controls this process in the animal, allowing the ES cells to grow, but then it shuts off when it's time to differentiate.
"If we can tweak conditions and determine how to keep the gene turned on in other animals, we might be able to grow and maintain ES cells for study in many species. It's still speculative at this point whether it will work, but if it does, then this may prove to represent a transformational discovery," Dr. McKnight said.
Interestingly, although humans carry a form of the TDH gene, it contains three inactivating mutations. As such, human ES cells do not produce the TDH enzyme.
"In the human embryo, something else is taking the place of this TDH-mediated form of rapid cell growth," Dr. McKnight said. "Human ES cells may exist in a unique metabolic state, but it would not appear to involve threonine breakdown."
Human ES cells grow slowly and are difficult to maintain in the laboratory, which is a huge impediment to this field of study, Dr. McKnight said.
"If scientists could repair the mutated human TDH gene and replace it into human ES cells, could they make those cells grow faster in culture? I don't know whether this will work or not it's highly speculative. But if so, it would be profound," he said.
THURSDAY July 9, 2009---------------------------News Archive / Return to News Alerts
Bisphenol A Retards Growth, Function of Reproductive Cells
Bisphenol A, a chemical widely used in plastics and known to cause reproductive problems in the offspring of pregnant mice exposed to it, also has been found to retard the growth of follicles of adult mice and hinder their production of steroid hormones, researchers report
Their study is the first to show that chronic exposure to low doses of BPA can impair the growth and function of adult reproductive cells. The researchers will describe their findings this month at the annual meeting of the Society for the Study of Reproduction.
A healthy, mature follicle, called an antral follicle, includes a single egg cell surrounded by layers of cells and fluid which support the egg and produce steroid hormones, said University of Illinois veterinary biosciences professor Jodi Flaws, who led the study with graduate student Jackye Peretz.
These are the only follicles that are capable of ovulating and so if they don't grow properly they're not going to ovulate and there could be fertility issues," Flaws said. "These follicles also make sex steroid hormones, and so if they don't grow properly you're not going to get proper amounts of these hormones." Such hormones are essential for reproduction, she said, "but they're also required for healthy bones, a healthy heart and a healthy mood."
BPA is widely used in plastics and is a common component of food containers and baby bottles.
The chemical structure of BPA is similar to that of estradiol, a key steroid hormone, and it can bind to estrogen receptors on the surface of some cells. It is not known whether BPA blocks, or mimics or enhances estrogen's activity on these cells, Flaws said.
Human studies have found BPA in many tissues and fluids, including urine, blood, breast milk, the amniotic fluid of pregnant women and the antral fluid of mature follicles. A national survey conducted by the federal Centers for Disease Control and Prevention in 2003-2004 found BPA in 93 percent of the 2,517 people (age 6 and up) who were tested.
BPA has a short half-life, Peretz said, and the chemical is quickly eliminated from the body. The fact that so many people tested positive "probably means that we're being constantly exposed to BPA," she said. The new study found that follicle growth was impaired after 48 hours of exposure to BPA, Peretz said. Reductions in three key steroid hormones progesterone, testosterone and estradiol were also seen after 120 hours of exposure to BPA.
The drop in steroid hormone production was quite dramatic. After 120 hours in a medium that included 10 micrograms per milliliter of BPA, mouse follicle cells produced about 85 percent less estradiol, 97 percent less progesterone and 95 percent less testosterone. Lower doses of BPA had a less dramatic but still considerable dampening effect on steroid hormone levels. And at 120 hours, follicle cells grown in the BPA medium were 25 percent smaller than normal, the researchers report.
A review of the health risks of BPA by the National Toxicology Program of the U.S. Department of Health and Human Services concluded in 2008 that while BPA has been shown to harm the reproductive health of laboratory animals in some studies, such adverse effects "are observed at levels of exposure that far exceed those encountered by humans."
However, the NTP reported that laboratory studies that showed effects in animals exposed to low doses of BPA led it to have "some concern for effects on the brain, behavior and prostate gland in fetuses, infants and children at current human exposures to bisphenol A."
The new study points to possible concerns in adults as well, Flaws said.
"I think there's a need for more studies where people look in adult humans to see if BPA is affecting follicle growth and steroid hormone levels," she said. If it is, that might help explain some infertility or menopausal symptoms, she said.
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A Link Between Obesity and Oral Bacterial Infection
A scientific team from The Forsyth Institute has discovered new links between certain oral bacteria and obesity
In a recent study, the researchers demonstrated that the salivary bacterial composition of overweight women differs from non-overweight women. This preliminary work may provide clues to interactions between oral bacteria and the pathology of obesity. This research may help investigators learn new avenues for fighting the obesity epidemic.
This work will be published in the Journal of Dental Research, and is available online today at http://jdr.sagepub.com/cgi/content/full/88/6/519."There has been a world-wide explosion of obesity, with many contributing factors," said Dr. J. Max Goodson, senior author of the study. "However, the inflammatory nature of the disease is also recognized. This led me to question potential unknown contributing causes of obesity. Could it be an epidemic involving an infectious agent?" "It is exciting to image the possibilities if oral bacteria are contributing to some types of obesity," added Goodson.
Summary of Study
In order to measure the salivary bacterial populations of overweight women, samples were collected from 313 women with a body mass index between 27 and 32 (classifying them as overweight). Using DNA analysis, the researchers measured the bacterial populations of this group and compared it with historical data from 232 individuals that were not overweight. Significant differences in seven of the 40 species studied occurred in the salivary bacteria of subjects in the overweight group. In addition, more than 98 percent of the overweight women could be identified by the presence of a single bacterial species, called Selenomanas noxia, at levels greater than 1.05 percent of the total salivary bacteria. These data suggest that the composition of salivary bacteria changes in overweight women. It seems likely that these bacterial species could serve as indicators of a developing overweight condition and possibly be related to the underlying causation.
Dr. Goodson noted that the reasons for a relationship between obesity and oral bacteria are likely complex. The observed relationship may be circumstantial as being related to diet or opportunistic due to metabolic changes. In the next phase of this research, Dr. Goodson plans to further examine this relationship by initially conducting a controlled cohort study to see if this initial observation can be reproduced. In addition, he hopes to conduct longitudinal studies in children to see if oral infection relates to weight gain. Ultimately, the development of strategies to eliminate specific oral bacteria would be required to provide definitive evidence that certain oral bacteria may be responsible for weight gain.
Fruits and Vegetables Reduce Risk of Upper Respiratory Infection in Pregnant Women
Boston University School of Medicine researchers (BUSM) have observed in a study of pregnant women that consumption of at least seven servings per day of fruits and vegetables moderately reduced the risk of developing an upper respiratory tract infection (URTI)
The BUSM study appears online in the journal Public Health Nutrition.
URTIs include the common cold and sinus infections, which can lead to lower respiratory problems, such as asthma or pneumonia. Even though the majority of URTIs are uncomplicated colds, identifying ways to prevent their occurrence is important because colds are the most common reason for school and work absences. Eating nutritious foods, especially fruits and vegetables, improves immunity but hadn't previously been associated with reducing the risk of URTIs in pregnant women.
BUSM researchers studied more than 1,000 pregnant women and found those who ate the most fruits and vegetables were 26 percent less likely to have URTI relative to those who ate the least amount. Neither fruit nor vegetable intake alone was found to be associated with the five-month risk of URTI. The patterns observed for total fruit and vegetable intake and either fruit or vegetable intake alone in relation to the three-month risk of URTI were consistent with those when assessing the five-month risk of URTI. Women in the highest quartile of fruit and vegetable intake had a stronger reduced three-month risk than the five-month risk of URTI. Moreover, there was a significant decreasing linear trend for the three-month risk of URTI with consumption of fruits and vegetables.
Pregnant women have been recommended to consume at least five servings of fruits and vegetables per day. This study showed that intake of higher levels, 6.71 servings per day, was associated with a moderate risk reduction for URTI.
"Pregnant women may require more fruits and vegetables than usual because of the extra demands on the body," said senior author Martha M. Werler, M.P.H., Sc.D., professor at Slone Epidemiology Center at Boston University.
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Stem Cells' 'Suspended' State Preserved by Key Step
Scientists have identified a gene that is essential for embryonic stem cells to maintain their all-purpose, pluripotent state
Exploiting the finding may lead to a greater understanding of how cells acquire their specialized states and provide a strategy to efficiently reprogram mature cells back into the pluripotent state, an elusive step in stem cell research but one crucial to a range of potential clinical treatments.
The research was led by University of California, San Francisco scientists. It is being reported Wednesday, July 8, 2009, in the advanced online edition of the journal Nature, and will be published in the journal's print edition at the end of July.
Embryonic stem cells are suspended in an "open" state, uniquely poised to become any one of many types of specialized cells, as genetic instructions dictate. Directing the specialization of embryonic stem cells to cells needed by patients is an area of enormous promise in stem cell research. Reversing the natural process -- converting specialized cells back into the all-purpose stem cell stage is another great promise of stem cell research.
Reprogramming specialized cells from Parkinson's patients, for example, would allow scientists to study the mechanisms that cause neurons in the brain to develop the disease. It also could lead to treatments by directing the restored stem cells to produce healthy neurons to introduce into patients.
The new research, conducted on mouse embryo cells, revealed that a gene known as Chd1 loosens the packaging that normally protects DNA in the cell nucleus. This step, known as chromatin remodeling, allows the cell's protein-making machinery to gain access to the DNA and transform progenitor cells into specialized cells and tissue, such as neurons, muscle and bone.
A number of genes are known to trigger chromatin remodeling, allowing small sections of DNA to become accessible in order to make specific proteins. Chd1 is the first gene found to regulate a "global" loosening of the DNA in embryonic stem cells, the scientists report. The global condition sets the stage for turning on many different genes to make a broad range of specialized cells.
"Embryonic stem cells are characterized by this open state, but, up to now, we didn't know the mechanisms that maintain this state, or even if it is necessary for the full stem cell potential," said Alexandre Gaspar-Maia, lead author of the paper.
"We found that Chd1 is critical for both, and for allowing an efficient reprogramming. Chd1 is important for allowing the normal differentiation process, and it is essential for playing the 'differentiation tape' backwards bringing differentiated cells back to pluripotency."
Gaspar-Maia is a graduate student (from the PhD Program in Experimental Biology and Biomedicine, at the University of Coimbra, Portugal) in the lab of senior author Miguel Ramalho-Santos, PhD, of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.
The scientists discovered the pivotal role of Chd1 by using the powerful technique of RNA interference, or RNAi, to screen this gene and 40 other candidate genes. (RNAi is a naturally occurring process in which small RNAs bind to other RNAs to increase or decrease their activity.) In this case, the scientists used the technique to silence Chd1. When they did so, embryonic stem cells could not make the full range of specialized cells.
In a laboratory test used to simulate normal cell specialization, the scientists detected no differentiation of cardiac muscle, and also no formation of a tissue known as primitive endoderm, which is essential for the embryo to survive and develop.
Chd1 also was shown by the research team to be necessary for the reprogramming of specialized cells back to the pluripotent stem cell state. The team plans to study chromatin remodeling in still more detail to clarify what other molecules work in concert with the Chd1 gene to direct the process. This would aid efforts to increase the efficiency and safety of reprogramming cells. This research may also shed light on how cells transition from one type to another, a process that happens normally during embryonic development and goes astray in cancer.
"We now know that Chd1 is essential, and, so far, appears unique in its global effect, but we expect that there are major players yet to be discovered," said senior author Ramalho-Santos, UCSF assistant professor of obstetrics, gynecology and reproductive sciences, and pathology.
"If we can understand how Chd1 works, that will also tell us more about how the cells regulate their precise specialization during development, and turn on their pluripotency program during reprogramming."
The scientists conclude that embryonic stem cells exist in a dynamic state, poised between the open condition that may assure the cell's full potential, and the more constrained state that allows only certain kinds of cells to progress. Chd1, they say, is central to maintaining the open, pluripotent stem cell state.
WEDNESDAY July 8, 2009---------------------------News Archive / Return to News Alerts
Battle of the Sexes Benefits Offspring, Says Research
Parents compensate for a lazy partner by working harder to bring up their offspring, but not enough to completely make up for the lack of parenting, says research by bird biologists at the University of Bath
In nature, it is quite rare for both parents to be involved in raising young, but it is very common in birds, some fish and primates including humans. Researchers therefore wanted to find out why, for some animals, parents stick together.
The study, published in the Journal of Evolutionary Biology, analysed more than 50 previous studies of birds to understand why and how they share their parental duties.
The research was led by Dr Freya Harrison and Professor Tamás Székely at the Biodiversity lab at the University of Bath, in collaboration with researchers from the University of Bristol and the University of Debrecen (Hungary).
Dr Harrison explained: “Caring for offspring is essential for their survival in many species, but it is also very costly in time and effort. Time spent bringing up your young means lost opportunities for remating and having more offspring, so parents face a trade-off between caring for current offspring and creating future offspring.
“This creates a conflict of interest between parents, since each parent would benefit by leaving their partner holding the baby whilst they go off and start a new brood elsewhere.
“This is exactly what happens in most animal species, so we wanted to understand how and why animals like birds and primates have evolved the tendency to share their parental duties.”
The researchers analysed data published over the last 30 years on parenting in birds to see if there was a common pattern in the behaviour of all the species studied.
Dr Harrison said: “In our study we found that if one parent starts slacking off or deserts, its mate works harder to bring up the brood, but not so hard as to completely compensate for their partner’s laziness.
“Some say that marriage is a state of antagonistic cooperation - in this case we found that the secret to a stable pairing was to only partially compensate for your lazy partner’s failings, to make sure that they stick around.”
Professor Innes Cuthill, Professor of Behavioural Ecology at the University of Bristol, added: “Of course, we are not claiming that fish and birds, or even humans, are necessarily making a consciously calculated decision.
“More likely there are innate rules for responding, perhaps modified through learning, that allow successful participation in joint activities without leaving room for being exploited.”
The researchers hope that this work could help scientists better understand how biparental care has evolved in humans.
The study was supported by the European Commission coordination action project: Integrating Cooperation Research Across Europe (INCORE).
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A Downside to Female Promiscuity
A new study has revealed a mating conundrum in the animal kingdom: Less fit male seed beetles father more offspring than their high quality competitors when they mate with the same female, says a paper published online today in Science. The findings contradict the widespread belief that females can benefit from taking multiple mates by allowing the best male to father the kids.
Researchers have generally assumed that males with the best genes sire more of offspring, passing on their good genes to a female's sons and daughters, but "in this case, it was exactly the opposite," said evolutionary ecologist Alexei Maklakov of Uppsala University in Sweden, who was not involved in the research.
"This is rather puzzling," evolutionary biologist Tom Tregenza of the University of Exeter in England, who was not involved in the research, said in an email. "If males that are better at sperm competition actually have lower fitness offspring, then females should avoid creating sperm competition by only mating with one male."
Female seed beetles, however, do indeed mate with multiple males, despite the high costs of mating -- male genitalia have frightening spikes that can leave some very nasty lacerations. "One of the common explanations [for female promiscuity] is that the female gets direct benefits" such as gifts of food upon copulation, or parental care, explained Trine Bilde, an evolutionary ecologist at University of Aarhus in Denmark and the lead author of the study. While we can't rule it out entirely, this doesn't seem to be the case in this species, she said, and "in mating systems where such benefits are absent, we have to look for other types of benefits."
Researchers previously thought indirect benefits could be gained in the form of a wide choice of sperm -- somehow, it was believed, females were able to choose which male's sperm fertilized a greater proportion of her eggs, and thus, select the best genes for her offspring. But Bilde's results suggest that's not the case: When female seed beetles were mated with two different males -- one known to produce more offspring than the other -- her eggs tend to be fertilized by the less fit partner, which resulted in up to 17% fewer offspring. Furthermore, the daughters of these crosses had fewer offspring as well.
If there's no fitness benefit, why do females subject themselves to the pain of mating more than once? Maybe it's not their choice, Bilde suggests. It could be that males "are under high selection to evolve traits that allow them to win in sperm competition, [which has] negative side effects on females." Indeed, females are usually resistant to the attempts of male suitors after they have mated once.
This type of conflict between male and female interests is known as sexual antagonism, and "seems to be relatively common" in the animal kingdom, Bilde said. Male Drosophila, for example, produce proteins in their ejaculate that are harmful to their mates. At the same time, "these proteins are also involved in attacking sperm from other males [and] helping males in gaining a high share of paternity," she said.
To really understand if female promiscuity in seed beetles is indeed a case of sexual antagonism, said Maklakov, will require looking at the fitness of the sons. "The current study demonstrates that successful males produce unsuccessful daughters, but it's also possible that these successful males produce successful sons," he said. "It is very likely that the sons of these males could also be relatively successful in sperm competition." The benefits of producing successful sons could "more or less cancel out" the costs of producing unsuccessful daughters, in which case mating with the "lower quality male" isn't so bad for the female after all.
Mammalian Egg Production Traced to Bone Marrow
Harvard researchers have found new evidence that female mammals can produce egg cells throughout life and have traced their production out of the ovary and into the bone marrow in findings that could both reshape science's understanding of female reproduction and provide new avenues for treatment of infertility
In a series of experiments on sterile female mice, researchers from Massachusetts General Hospital (MGH), a Harvard teaching hospital, were able to restore egg production by transplanting bone marrow from fertile mice. The researchers believe that egg stem cells in the donor bone marrow established themselves in the sterile mice and began producing egg cells, also called oocytes.
Stem cells are precursor cells that develop into specific kinds of tissues, replenishing blood, skin, and other kinds of cells in the body.
The results, which build upon a study published last year, further erode the long-held belief that female mammals are born with a lifetime supply of egg cells that they slowly use up until the supply is exhausted.
If further experiments bear out the study's results and the processes discovered in mice hold true for humans, the findings could have far-reaching ramifications for treatment of human infertility and solve the mystery surrounding reported cases of spontaneous restoration of fertility in sterile women who've undergone bone marrow transplants.
Fertility expert Kutluk Oktay, an associate professor at Cornell University's Weill Medical College, said the research was "revolutionary" and said the most shocking finding was that the bone marrow, not the ovary itself, was the site of egg cell replenishment.
"It's nearly impossible to digest for many scientists," Oktay said.
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Salamander Limbs Regrow Without Pluripotent Stem Cells
The cells responsible for the salamander's famed ability to regenerate amputated limbs aren't pluripotent, as scientists have thought, a study published online in Nature - July 2, 2009 - reports
That's good news for regenerative medicine: If the mechanism salamander cells use for regrowing body parts doesn't depend on pluripotent stem cells, it may be easier than researchers have assumed to mimic that organism's regenerative strategy in potential therapies.
"This is a very important finding for this field and also for regenerative medicine in general," said regeneration biologist Andras Simon of the Karolinska Institutet in Sweden, who was not involved in the research. "The data very strongly suggest that during regeneration cells don't really shift lineage. I think many people expected more flexibility than what this study shows."
Salamanders' regenerative abilities were thought to rely on the dedifferentiation of cells near the damaged limb to a pluripotent state -- a feat that mammalian cells are normally incapable of. Development and cell biologist Elly Tanaka of the Center for Regenerative Therapy at Dresden University of Technology in Germany and colleagues examined the lineage of these regenerative cells more closely. They created green fluorescent axolotls -- a Mexican salamander frequently used as a model system for limb regeneration -- by linking green fluorescent protein (GFP) to a promoter of cytoplamsic actin, a protein expressed in every cell of the body. By grafting cells from green axolotl embryos to normal animals before amputation, the researchers could track the GFP to examine the fate of specific cell types in a regenerating limb after amputation in juveniles.
Using these techniques, the researchers looked at four different tissue types: dermis, cartilage, muscle, and Schwann cells -- neural tissue that insulates the nerves of the limbs. With the exception of dermal cells, they found that the grafted green cells showed up only in those same tissue types in the regrown limb.
"What's surprising about this finding is that it shows clearly that those cells in the blastema" -- the ball of cells that forms at the site of the amputation to build the regenerated limb -- "are not homogenous," said developmental biologist Kenneth Poss of the Duke University Medical Center, who was not involved in the research. "They're retaining their memory of the tissues they came from, and they go on to form cells of that same type. That's not what most people thought was going on."
Interestingly, dermal cells contributed to cartilage, connective tissue, and tendons, in addition to the dermis. This may be a result of the common origin of dermal and cartilage cells in the embryo, Tanaka said. The formation of a blastema thus either activates a stem cell that is a common progenitor of cartilage and dermis, or causes dermal cells to be dedifferentiated into one of these progenitors.
"It is likely that [the cells] are dedifferentiating [and somehow] retain a memory of what they need to differentiate back into," explained Alejandro Sánchez Alvarado, a developmental biologist at the University of Utah School of Medicine and author of a review article accompanying the Tanaka study. "They probably do go back to an embryonic state," Tanaka agreed, "but it's not to a pluripotent state."
The results "really shift the focus" of regenerative research, Simon said. Instead of trying to generate multipotent or pluripotent cells, "one should try to understand how these cells get the appropriate signals to make a new limb in terms of organizing the different tissue types."
The cell lineage specificity of the blastema cells "is probably a closer situation to what we see in other vertebrates," agreed developmental biologist Randal Voss of University of Kentucky, who did not participate in the research. Applying an understanding of that mechanism to future therapies thus becomes "something that's more achievable in regenerative medicine."
However, the current study examined regeneration in juvenile axolotls, and to fully understand the implications for regenerative medicine involving adult tissue, it is important to extend the current findings to limb regeneration in adult axolotls, Sánchez Alvarado said.
Also, it's still unclear whether this same loyalty of tissue type applies to other appendages and other regenerating species, Tanaka said. Regenerating cells in the axolotl tail, for example, do seem to differentiate into multiple tissue types. This may be because the tail blastema contains cells from the spinal cord, which may be more plastic than other types of tissue, or it could be an artifact of the labeling technique those studies used. "So now we have to see if the previous result is really true or whether the previous technology was unreliable," Tanaka said.
TUESDAY July 7, 2009---------------------------News Archive / Return to News Alerts
Laboring Without the Hospital Labor Bed - It's a Good Thing
A University of Toronto pilot study that re-conceptualized the hospital labour room by removing the standard, clinical bed and adding relaxation-promoting equipment had a 28 per cent drop in infusions of artificial oxytocin, a powerful drug used to advance slow labours
The study, called PLACE (Pregnant and Labouring in an Ambient Clinical Environment) was published in the current edition of the journal Birth.
In addition, more than 65 percent of the labouring women in the ambient room, compared to 13 per cent in the standard labour room, reported they spent less than half their hospital labour in the standard labour bed.
Led by Dr. Ellen Hodnett, Bloomberg Faculty of Nursing professor and Heather M. Reisman Chair in Perinatal Nursing Research at the University of Toronto, PLACE included 62 women at two Toronto teaching hospitals.
Hodnett devised a set of simple, but radical modifications to the standard hospital labour room, with the intention of surrounding the women and their caregivers with specific types of auditory, visual and tactile stimuli.
"The removal of the standard hospital bed sent a message that this was not the only place a woman could labour," says Hodnett. A portable, double-sized mattress with several large, comfortable cushions was set up in the corner of the ambient room. Fluorescent lighting was dimmed, and DVDs of ocean beaches, waterfalls and other soothing vistas were projected onto a wall. A wide variety of music was also made available.
"The intent was to allow the women the ability to move about freely during their labour, to permit close contact with their support people, and to promote feelings of calm and confidence," says Hodnett.
Reaction to the ambient room was overwhelmingly positive, as respondents were pleased to have options for mobility and for helping to cope with their labour. They also indicated they received greater one-on-one attention and support from their nurses.
"This study raises questions about the assumptions underlying the design of the typical hospital labour room," says Hodnett. "The birth environment seems to affect the behaviour of everyone in it the laboring women as well as those who provide care for her.
Hodnett hopes to further this study with a larger, randomized controlled trial.
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Multiple Sclerosis: A New Theory for Why Repair of the Brain’s Wiring Fails
Scientists have uncovered new evidence suggesting that damage to nerve cells in people with multiple sclerosis (MS) accumulates because the body’s natural mechanism for repairing the nerve coating called myelin stalls out
The new research, published by Howard Hughes Medical Institute investigator David H. Rowitch and colleagues in the July 2009 issue of the journal Genes & Development, shows that repair of nerve fibers is hampered by biochemical signals that inhibit cellular repair workers in the brain, called oligodendrocytes.
The symptoms of MS, which range from tingling and numbness in the limbs to loss of vision and paralysis, develop when nerve cells lose their ability to transmit a signal. Axons, which are the fibrous cables radiating from nerve cells, transmit impulses to neighboring neurons. They are dependent on myelin, which protects nerve cells and helps transmit their electrical signals properly. In people with MS, immune cells attack and erode this protective layer of myelin. In the early stages of the disease, damage accumulates in the myelin sheath only, but it does not affect the nerve cells themselves. Later on, axons without myelin and the nerve cells themselves die.
Although damaged myelin can usually be repaired, in some people with MS the repair effort is inefficient, said Rowitch, who is at the University of California, San Francisco. This could be because oligodendrocytes themselves might not work properly, or they may be killed off by the disease. Rowitch explained that in chronically demyelinated areas of the central nervous system, oligodendrocyte precursor cells have been found, but they appear stalled in development and never become fully functional oligodendrocytes.
Rowitch and his team set out to see if they could determine what was slowing down myelin repair. With colleagues at UCSF and the University of Cambridge in England, Rowitch destroyed a small region of white matter in the spinal cords of healthy mice, then monitored the repair process, examining the tissue after five, 10, and 14 days.
To find out which genes were contributing to three key stages in the repair process the recruitment of oligodendrocyte precursors to the site of injury, the maturation of those cells into functional oligodendrocytes, and the formation of a new myelin sheath -- the researchers measured the activity of 1,040 genes. All of the genes they studied encode transcription factors, which regulate the activity of other genes. Their experiments showed that 50 transcription factors are working during key steps in myelin repair.
“They turned on and off at particular time points associated with recognized stages of the repair process, such as recruitment of repair cells back into the lesion, early differentiation [of the precursor cells into more specialized cells], and then myelin production,” said Rowitch.
The team focused, in particular, on one of the genes called Tcf4. In damaged areas where repair attempts were under way, expression of Tcf4 was strong, Rowitch said.
Tcf4 is involved in a cascade of biochemical events known as the Wnt (pronounced “wint”) pathway. While the pathway’s importance has been recognized in normal development of many tissues, including the brain, Rowitch said Wnt had never before been linked to myelin production or repair.
To glean further evidence about Wnt’s role, the researchers hyperactivated the Wnt pathway in the oligodendrocytes of mice, testing whether this helped or hurt myelin repair. Doing so caused a profound delay in repair, Rowitch said. Upon further analysis, the researchers concluded that the Wnt pathway activation was creating a roadblock that prolonged oligodendrocyte precursor development.
“These animals did eventually show repair,” Rowitch said, “but it was delayed by about 10 days compared to normal mice.” The researchers also tested human tissue for the presence of Tcf4, and found the protein in areas damaged by MS but not in healthy white matter. Further, the researchers examined available data from another study and found that many signaling molecules of the Wnt pathway are overactive in patients with MS.
Rowitch’s team is starting to examine some of the other genes it found to be active in the myelin repair process, and is developing new mouse models to help test potential therapies that might manipulate the Wnt pathway to improve myelin repair. Given the pathway’s role in so many different processes, however, Rowitch cautioned that targeting Wnt could cause unintended side effects.
The new work may also have implications in another disease Rowitch studiesperiventricular leukomalacia (PVL), a deficiency of white matter around the brain’s ventricles, which connect to the central canal of the spinal cord. PVL usually occurs in extremely premature infants with brain injury, who often go on to develop cerebral palsy.
Although scientists had previously believed PVL resulted when oligodendrocytes were killed off by stress or toxic injury, Rowitch and colleagues at Children’s Hospital in Boston recently found that, as in the MS study, oligodendrocyte precursors had been recruited to the site of white matter lesions and stood poised to repair the damage, but for some reason did not proceed.
Sex May Have Evolved As Part of a Defense Against Parasites
What's so great about sex?
From an evolutionary perspective, the answer is not as obvious as one might think. An article published in the July issue of the American Naturalist suggests that sex may have evolved in part as a defense against parasites.
Despite its central role in biology, sex is a bit of an evolutionary mystery. Reproducing without sexlike microbes, some plants and even a few reptileswould seem like a better way to go. Every individual in an asexual species has the ability to reproduce on its own. But in sexual species, two individuals have to combine in order to reproduce one offspring. That gives each generation of asexuals twice the reproductive capacity of sexuals. Why then is sex the dominant strategy when the do-it-yourself approach is so much more efficient?
One hypothesis is that parasites keep asexual organisms from getting too plentiful. When an asexual creature reproduces, it makes clonesexact genetic copies of itself. Since each clone has the same genes, each has the same genetic vulnerabilities to parasites. If a parasite emerges that can exploit those vulnerabilities, it can wipe out the whole population. On the other hand, sexual offspring are genetically unique, often with different parasite vulnerabilities. So a parasite that can destroy some can't necessarily destroy all. That, in theory, should help sexual populations maintain stability, while asexual populations face extinction at the hands of parasites.
The scenario works on mathematical models, but there have been few attempts to see if it holds in nature.
Enter Potamopyrgus antipodarum, a snail common in fresh water lakes in New Zealand. What makes these snails interesting is that there are sexual and asexual versions. They provide scientists with an opportunity to compare the two versions side-by-side in nature.
Jukka Jokela of the Swiss Federal Institute of Aquatic Science and Technology, Mark Dybdahl of the University of Washington and Curtis Lively of Indian University, Bloomington began observing several populations of these snails for ten years starting in 1994. They monitored the number of sexuals, the number asexuals, and the rates of parasite infection for both.
The team found that clones that were plentiful at the beginning of the study became more susceptible to parasites over time. As parasite infections increased, the once plentiful clones dwindled dramatically in number. Some clonal types disappeared entirely. Meanwhile, sexual snail populations remained much more stable over time. This, the authors say, is exactly the pattern predicted by the parasite hypothesis.
"The rise and fall of these female-only lineages was surprisingly fast and consistent with the prediction of the parasite hypothesis for sex," Jokela said. "These results suggest that sexual reproduction provides an evolutionary advantage in parasite rich environments."
So we may well have to thank parasitesin spite of their nasty reputationfor the joy of sex.
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Human Cardiac Master Stem Cells Identified
Harvard Stem Cell Institute researchers at Massachusetts General Hospital have identified the earliest master human heart stem cell from human embryonic stem cells - ISL1+ progenitors - that give rise to a family of cells that form the essential portions of the human heart
The discovery, by a group led by Kenneth Chien, director of both HSCI’s Cardiovascular Disease Program and the MGH Cardiovascular Research Center, is particularly important because the cells were found in regions of the heart known as hot spots for congenital heart disease.
These latest findings, published today in the journal Nature, build upon and expand earlier work by Chien’s team and others in mice.
What is truly groundbreaking about the study, and has enormous implications in terms of the future treatment of heart disease, Chien says, is that “the study provides a new way of understanding heart disease at it appears in children and in adults. Congenital heart disease is the most common birth defect in children worldwide, and the studies imply that congenital heart disease could be a stem cell disease.” A number of congenital cardiac diseases appear to begin in these cells, and genes that affect the cells are known to cause heart disease in children, he added.
By identifying and manipulating the pathways along which these cells grow and differentiate, Chien says, researchers might be able to influence congenital heart disease significantly, converting severe forms of the disease to those with a better prognosis.
In adult heart disease, the major cause of morbidity is heart failure, where the implantation of human heart progenitors such as these might prove more therapeutically valuable than already differentiated heart muscle cells. “When people think of cardiovascular regenerative medicine, they think of end stage heart failure and humans needing a transplant,” Chien says. “This study has importance for both this adult form of heart disease as well as those in children, where understanding how embryonic heart stem cells build the heart may ultimately impact therapy.”
“This is a wonderful and important study for several reasons,” said Doug Melton, co-director of HSCI and co-chair of Harvard’s interschool Department of Stem Cell and Regenerative Biology. “Finding a cell that can make all the parts of the heart, including the contracting muscle, the smooth muscle and the vessels, brings us much closer to the possibility of repairing human hearts with new cells. In addition, this human progenitor cell will likely become the standard starting point for all researchers to aiming to investigate human heart development and genetic diseases of the cardiovascular system,” Melton added.
Because these cardiac progenitor cells are extremely rare in the adult heart, the researchers don’t believe they play a role in the regeneration of the fully developed adult organ. However, researchers do believe these cells have a potential role in the fetal and immediate post-natal heart to prevent congenital heart disease.
Chien’s group was particularly focused on answering the question of how the human heart expands from its small fetal size to its adult-form dimensions. “The human heart at birth is more than a thousand times bigger than the adult mouse heart, yet the size of the initial embryos are close in size. Humans are just a heck of a lot bigger than mice, and every organ is bigger. How is that achieved?”
There are two possible answers to the question:
The first is that various independent cell lineages give rise to each of the heart structures. “The pacemaker, the valves, all these things arise, and then those cells replicate, and that replication accounts for the marked expansion,” Chien explains.
Or, the answer might be what Chien calls “a stem cell paradigm, in which a single form of progenitor cells replicate, and massively expand the pool of heart cell precursors, and then differentiate into the different structures. “The way that you could distinguish between those two possibilities,” he says, “is by looking for large numbers of those progenitors at a later stage of human cardiogenesis [in contrast with what you see in the mouse].”
To identify and track the fate of human embryonic-stem-cell-derived ISL1+ progenitors, Chien and his team genetically tagged a human embryonic stem cell line. The researchers were then astonished that when they looked at the developing tissue they observed a heart “loaded” with progenitor ISL1+ stem cells. The biggest concentration of them was observed at a location associated with congenital heart disease, particularly in the outflow track, the aorta.
The team observed not only a large number of progenitor ISL1+ stem cells, but also distinctive intermediate cell types that give rise to all of the components of the heart.
As Chien sees it, “a stem-cell-mediated process clearly exists for expansion of the human heart, particularly in regions that are affected by congenital heart disease,” which he and his colleagues believe implicates heart ILS1+ stem cell progenitors in undergrowth or mal-growth of heart structures.
Currently the team is studying three types of disease that affect children: Duchenne muscular dystrophy, specific chromosomal disorders such as DiGeorge and Down syndromes, and rare genetically based congenital heart diseases. In each of these case, Chien argues, mouse models are not enough: “They are not likely to fully recapitulate the human disease.”
For Chien and his colleagues, this study also underscores the importance of continuing to use human embryonic stem (ES) cells in research, and not just induced pluripotent stem cells (iPS), which are created in the lab by forcing gene expression. “Manipulating human ES cells genetically, by gene targeting, you can create human models of human disease directly in a simplified format, in human ES cells,” Chien says. “I think the iPS cells are going to be good for some diseases, but not all. I’m not sure they will be good for heart diseases.”
The heart cells that come out of iPS cells may not be as strong, he says. “If you get iPS cells from a patient with congenital heart disease, what do you use as a control? Another patient?” Chien adds, “The degree of variation in the iPS cell lines is significant. So how do you even compare this cell to itself? These are still early days for human heart iPS-derived cells.”
A renewable resource, ES cells may represent an alternative to adult cell-based therapy down the road, especially, says Chien, since the ability of most adult heart progenitor cells (as well as other non-heart adult cells such as bone marrow-, fat-, and endothelial-progenitor cells) to convert to authentic heart muscle over an extended period of time remains unclear.
MONDAY July 6, 2009---------------------------News Archive / Return to News Alerts
Supplement Could Reduce Risk of Gestational Diabetes in Pregnant Women
Women who enter pregnancy with a higher body weight face serious risks: higher rates of gestational diabetes, high blood pressure and the risk of a larger baby who could go on to have obesity, diabetes and heart disease in the future
But a nutritional supplement, already shown to benefit fetal brain and vasculature development, could reduce those risks in both mother and child.
That's why a nutrition researcher at the University of Cincinnati is launching a local, two-year clinical trial to study the effects of the supplement in pregnant women.
Principal investigator Debra Krummel, PhD, UC department of nutritional sciences, believes the nutrient, omega-3 fatty acid docosahexaenoic acid (DHA), can lower blood sugar levels and improve insulin sensitivity in pregnant women.
Krummel says DHA has proven benefits, but most women do not get an adequate amount of it in their diet.
“It’s already been shown to be safe and good for the brain, but we’re studying whether it might have another benefit, which is improving insulin resistance,” she says.
National health officials are recognizing the risks associated with obesity during pregnancy. This year, the Institute of Medicine and the National Research Council revised their gestational weight gain guidelines for the first time since 1990, lowering the recommended levels of weight gain for women entering pregnancy with a higher body weight.
But Krummel says those guidelines don’t help women right now.
“We have to find a way to help these women once they’re already pregnant, and that’s what this supplement is about,” she says. “If this supplement can improve insulin sensitivity and markers of inflammation in pregnant women, it’s a huge clinical benefit. It’s already good for the baby but if it can have this other benefit, it’s huge.”
For this trial, researchers are looking for 90 pregnant women 18-40 years old who are less than 26 weeks pregnant and in good health overall.
Trial participants are expected to visit the General Clinical Research Center at Cincinnati Children’s Hospital Medical Center three times during their pregnancy.
On their first visit, women will be randomly assigned to a control group or an omega-3 group. The control group will not receive omega-3. Then, and on subsequent visits, researchers will take a blood sample and discuss dietary habits with the participants. After birth, samples will be taken from placentas.
In addition to receiving prenatal vitamins and dietary analysis, participants will be compensated for their time.
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New Connection Between Cancer Cells and Stem Cells
A molecule called telomerase, best known for enabling unlimited cell division of stem cells and cancer cells, has a surprising additional role in the expression of genes in an important stem cell regulatory pathway, say researchers at the Stanford University School of Medicine
The unexpected finding may lead to new anticancer therapies and a greater understanding of how adult and embryonic stem cells divide and specialize.
“Telomerase is the factor that accounts for the unlimited division of cancer cells,” said Steven Artandi, MD, PhD, associate professor of hematology, “and we’re very excited about what this connection might mean in human disease.” Artandi is the senior author of the research, published in the July 2 issue of the journal Nature. He is also a member of Stanford’s Cancer Center.
In many ways, telomerase is the quintessential molecule of mystery hugely important and yet difficult to pin down. Telomerase was known to stabilize telomeres, special caps that protect the ends of chromosomes. It stitches short pieces of DNA on these chromosome ends in stem cells and some immune cells, conferring a capacity for unlimited cell division denied to most of the body’s other cells.
Its importance is highlighted by the fact that it is inappropriately activated in more than 90 percent of cancer cells, suggesting that drugs or treatments that block telomerase activity may be effective anticancer therapies. However, its vast size, many components and relative rarity it is not expressed in most of the body’s cells hinder attempts to learn more about it.
Artandi and his lab have spent many years identifying and studying the components of the telomerase complex. In this most recent study, they were following up on a previous finding suggesting that one part, a protein called TERT, was involved in more than just maintaining telomeres. They had discovered that overexpressing TERT in the skin of mice stimulated formerly resting adult stem cells to divide even in the absence of other telomerase components. “This was a pretty clear hint that TERT was involved in something more than just telomere maintenance,” he said.
Artandi and his colleagues recognized that the cells’ response to TERT mimicked that seen when another protein, beta-catenin, was overexpressed in mouse skin. Beta-catenin is a component of a vital signaling cascade known as the Wnt pathway, which is important in development, stem cell maintenance and stem cell activation. Stanford developmental biologist and professor Roeland Nusse, PhD, a collaborator on the current study, identified the first Wnt molecule in 1982.
In this study, Artandi and his colleagues purified the TERT protein from cultured human cells and found that it was associated with a chromatin-remodeling protein implicated in the Wnt pathway. They showed that overexpression of TERT in the presence of the remodeling protein enhanced the expression of Wnt-inducible genes. Finally, they found that TERT is required for mouse embryonic stem cells to respond appropriately to Wnt signals and that blocking TERT expression impairs the development of frog embryos.
“This is completely novel,” said Artandi, who went on to show that TERT physically occupies the upstream promoter regions of the genes. “No one had any idea that TERT was directly regulating the Wnt pathway.” He speculates that interfering with the protein’s Wnt-associated activity may be a faster way to inhibit cancer cells than blocking telomerase activity, which depends on the gradual shortening of telomeres with each cell division.
“The Wnt pathway and telomerase activity are two separate but coherent functions in stem cell self-renewal and cancer cell proliferation,” said Artandi. “Nature evolved a way to connect these two crucial functions by recruiting a component of telomerase directly into the Wnt pathway.” The researchers are now investigating what role TERT may play in normal and cancerous cells.
In addition to Artandi and Nusse, other Stanford collaborators on the current study include postdoctoral scholars Jae-Il Park, PhD, Jinkuk Choi, PhD, and Marina Shkreli, PhD; graduate students Andrew Venteicher, PhD, and Peggie Cheung; and research assistants Sohee Jun and Woody Chang. The research was funded by the National Cancer Institute and the California Breast Cancer Research Program.
Sugar Is a Poison, Says UCSF Obesity Expert
The rise of obesity is usually blamed on too much eating and not enough exercising, but Robert Lustig, MD, a Univeristy of California San Francisco (UCSF) Medical Center pediatric neuroendocrinologist, asks us to look beyond the obvious.
But behaviors that some might refer to as gluttony and sloth are merely consequences of the true cause of the epidemic, Lustig says. Food was just as abundant before obesity’s ascendance. The problem is the increase in sugar consumption. Sugar both drives fat storage and makes the brain think it is hungry, setting up a “vicious cycle,” according to Lustig.
More specifically, it is fructose that is harmful, according to Lustig. Fructose is a component of the two most popular sugars. One is table sugar sucrose. The other is high-fructose corn syrup. High-fructose corn syrup has become ubiquitous in soft drinks and many other processed foods.
Lustig presented his case against fructose in a recent UCSF Mini Medical School course on diet and nutrition, part of a series sponsored by the Osher Lifelong Learning Institute. Audience members may have been surprised to hear such unequivocally strong statements from a researcher. Lustig framed the obesity epidemic as a societal issue that pits the food-selling agenda of federal agencies and profit-seeking behavior of major corporations against public health needs.
Lustig quit working in the lab a decade ago. Now he spends more time with pediatric patients. He is on the front lines of the world’s weight woes, treating kids who already are obese, a condition that sets the stage for health problems that begin long before these children become adults.
Lustig still conducts clinical research. He evaluates dietary lifestyle, as well as pharmacologic interventions that might hold the pounds at bay. He tracks down associations between diet, lifestyle and health outcomes in an effort to identify biological mechanisms that will explain them.
Insulin and Leptin
Lustig’s own groundbreaking studies more than a decade ago stimulated the development of his controversial ideas about metabolism and biological feedback in weight control. One not-yet-popular idea is that, calorie for calorie, sugar causes more insulin resistance in the liver than other edibles. The pancreas then has to release more insulin to satisfy the liver’s needs. High insulin levels, in turn, interfere with the brain’s receipt of signals from a hormone called leptin, secreted by fat cells, Lustig believes.
In the 1990s, Lustig worked with children diagnosed with hypothalamic obesity, a disorder that can occur after brain tumor surgery. The children were making more insulin than was necessary for normal energy storage in fat cells. Lustig thought the kids were not receiving signals from leptin, which helps send a message that the appetite has been sated.
Lustig concluded that the children’s brains were fooled into thinking that they were starving. Lustig administered a drug called octreotide, known to block insulin release. Insulin levels fell; the children ate less, lost weight, spontaneously became more active and improved their quality of life.
Lustig tried the same treatment with obese adults, and found that a subset responded in the same way as the children with hypothalamic obesity.
Eating stimulates secretion of insulin and leptin. The conventional view holds that insulin, like leptin, feeds back in the brain to limit food intake, Lustig explains. But Lustig does not think that chronically elevated insulin levels feed back negatively to curb eating. Instead, chronically elevated insulin blocks leptin’s negative feedback signal, Lustig believes. “Most people think insulin does the same thing as leptin,” he says. “I think it does just the opposite.”
Lustig believes that fructose generates greater insulin resistance than other foodstuffs, and that fructose calories, therefore, fail to blunt appetite in the same way as other foods.
A Calorie Is Not Just a Calorie
Lustig also is at odds with mainstream scientific viewpoints when it comes to explaining how fructose is shunted through biochemical pathways and converted into fat and other molecules.
Unlike conventional calorie counters, Lustig does not believe all food calories have the same impact on fat storage and energy expenditure, regardless of whether they come from fat, protein or carbohydrate. Fructose, a type of carbohydrate, is not metabolized like other foodstuffs, and not even like glucose, the other major carbohydrate, Lustig says.
In addition, Lustig claims that fructose is just as bad as alcohol in causing fat storage in the liver and in causing fatty liver disease.
Lustig advances these controversial ideas primarily by citing already published studies, most of them by other researchers. But he also tries to enlist bench scientists in research collaborations in the hopes that additional studies will prove to others that these ideas are correct.
Sugar No Better Than Fat
Each sucrose molecule consists of one molecule of fructose joined to one molecule of glucose. In the gut, these two components are quickly split apart. High-fructose corn syrup is a less expensive mixture of glucose and fructose. There is no point in belaboring the difference, Lustig says. “High-fructose corn syrup and sucrose are exactly the same,” Lustig says. “They’re equally bad. They’re both poison in high doses.”
Over the past century, Americans have increased their fructose consumption from 15 grams per day to 75 grams per day or more, Lustig explains. The trend accelerated beginning about three decades ago, when cheap, easy-to-transport high-fructose corn syrup became widely available.
Much of processed food labeled “reduced fat” instead has sugar added to make it more palatable, Lustig says. But when it comes to harmful health effects, sugar is worse than fat, he claims. Consumption of either results in elevated levels of artery-clogging fats being made by the liver and deposited in the bloodstream. But fructose causes even further damage to the liver and to structural proteins of the body while fomenting excessive caloric consumption, Lustig says.
Four Simple Guidelines
Lustig prescribes four simple guidelines for parents coping with kids who are too heavy:
Get rid of every sugared liquid in the house. Kids should drink only water and milk.
Provide carbohydrates associated with fiber.
Wait 20 minutes before serving second portions.
Have kids buy their “screen time” minute-for-minute with physical activity.
Fructose is abundant in fruit. Fruit is fine, Lustig says, but we should think twice before drinking juice or feeding it to our kids. The fiber in whole fruit contributes to a sense of fullness. Lustig says it is rare to see a child eat more than one orange, but it is common for kids to consume much more sugar and calories as orange juice.
Eating fiber also results in less carbohydrate being absorbed in the gut, Lustig notes. In addition, he says, fiber consumption allows the brain to receive a satiety signal sooner than it would otherwise, so we stop eating sooner.
Exercise burns only a modest amount of calories, Lustig notes. But it does have other benefits. Exercise improves insulin sensitivity in skeletal muscle, lowering insulin levels in the bloodstream. Exercise reduces stress and, therefore, reduces stress-induced eating, according to Lustig. Lastly, exercise increases metabolic rate.
The directive to balance active play with computer, video and TV time is the most difficult one to comply with, Lustig says. But failure to limit sugar intake appears to be the most predictive of poor weight control in children, he adds.
“You are not what you eat; you are what you do with what you eat,” Lustig concludes. “And what you do with fructose is particularly dangerous.”