Zebrafish discovery may shed light on human kidney function

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Researchers say the discovery of how sodium ions pass through the gill of a zebrafish may be a clue to understanding a key function in the human kidney. The findings from a collaboration between Mayo Clinic and the Tokyo Institute of Technology appear in the online issue of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology.The researchers discovered a protein responsible for gas exchanges in the fish gill structure. Specifically they studied and characterized the Na+/H+ (sodium/hydrogen) exchanger named NHE3, responsible for controlling sodium and hydrogen ions across the gill. The researchers also directly demonstrated that NHE3 can function as a Na+/NH4+ (sodium/ammonium) exchanger.”This is significant because the fish tends to mimic the process in humans,” says Michael Romero, Ph.D., a Mayo Clinic physiologist who works in nephrology. “This is the true beauty of comparative physiology– a lot of the organs function by very similar processes, down to ionic transfer.”In this case the protein allows the sodium ions to be absorbed from the forming urine while at the same time discarding waste from normally functioning cells, thus keeping the body in balance and serving as an energy saving system. The researchers say the same NHE3 protein performs a similar function in the intestine, pancreas, liver, lungs and reproductive system.The gill is used in the fish as a transport system: sodium ions are nutrients and ammonium carries away waste. It’s a key process allowing zebrafish to extract sodium ions from fresh water. In humans, NHE3 is involved in the acid-waste control system in the kidney, but there hasn’t been a good analysis of that process in humans. Part of this acid-control process in the human kidney is “ammoniagenesis” which requires the initial part of the kidney tubule (proximal tubule) to export ammonia/ammonium. Physiologically, it has been assumed that NHE3 can perform a Na+/NH4+ exchange, but this has never been experimentally demonstrated.Ammoniagenesis and increased renal sodium bicarbonate absorption are partly under the control of the renin-angiotensin-aldosterone system (RAAS), which means that this work enhances understanding of human hypertension. …


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Discovery may help to explain mystery of "missing" genetic risk, susceptibility to common diseases

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A new study could help to answer an important riddle in our understanding of genetics: why research to look for the genetic causes of common diseases has failed to explain more than a fraction of the heritable risk of developing them.Susceptibility to common diseases is believed to arise through a combination of many common genetic variants that individually slightly increase the risk of disease, plus a smaller number of rare mutations that often carry far greater risk.However, even when their effects are added together, the genetic variants so far linked to common diseases account for only a relatively small proportion of the risk we know is conveyed by genetics through studies of family history.But the major new study, published in the journal PLOS Genetics, shows for the first time in cancer that some common genetic variants could actually be indicators of the presence of much more influential rare mutations that have yet to be found.Scientists at The Institute of Cancer Research, London, led an international consortium made up of more than 25 leading academic institutions on the study, which was funded by the European Union.The research, involving 20,440 men with prostate cancer and 21,469 without the disease, identified a cluster of four common genetic variants on chromosome 17 that appeared to give rise to a small increase in prostate cancer risk, using the standard statistical techniques for this type of study.But the study found an alternative explanation for the risk signal — a small proportion of the men with these common variants were in fact carriers of a rare mutation in the nearby HOXB13 gene, which is known to be linked to prostate cancer. Under this ‘synthetic association’, the number of people carrying a cancer risk variant was much lower than had been assumed, but those people who did inherit a variant had a much higher risk of prostate cancer than had been realised.The discovery shows that the prevailing genetic theory — that common cancers are predominantly caused by the combined action of many common genetic variants, each with only a very small effect — could potentially underestimate the impact of rare, as yet undiscovered mutations.The results are important because they show that there is a need for renewed effort by geneticists to find the causal variants, whether common or rare, behind the many common cancer-associated variants identified in recent years.Identifying any underlying rare mutations with a big effect on disease risk could improve the genetic screening and clinical management of individuals at greater risk of developing cancer, as well as other diseases.Study co-leader Dr Zsofia Kote-Jarai, Senior Staff Scientist at The Institute of Cancer Research (ICR), said: “As far as we are aware, this is the first known example of a ‘synthetic association’ in cancer genetics. It was exciting to find evidence for this theory, which predicts that common genetic variants that appear to increase risk of disease by only a modest amount may indeed sometimes be detected purely due to their correlation with a rarer variant which confers a greater risk.”Our study does not imply how widespread this phenomenon may be, but it holds some important lessons for geneticists in cancer, and other common diseases. It demonstrates the importance of identifying the causal genetic changes behind the many common variants that have already been shown to influence risk of disease.”Our study also demonstrates that standard methods to identify potential causal variants when fine-mapping genetic associations with disease may be inadequate to assess the contribution of rare variants. Large sequencing studies may be necessary to answer these questions unequivocally.”Study co-leader Professor Ros Eeles, Professor of Oncogenetics at The Institute of Cancer Research and Honorary Clinical Consultant at The Royal Marsden NHS Foundation Trust, said: “One important unanswered question in cancer genetics — and in genetics of common disease more generally — is why the genetic mutations we’ve discovered so far each seem to have such a small effect, when studies of families have shown that our genetic make-up has a very large influence on our risk of cancer.”Our study is an important step forward in our understanding of where we might find this ‘missing’ genetic risk in cancer. At least in part, it might lie in rarer mutations which current research tools have struggled to find, because individually each does not affect a large number of people.”


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Understanding (and Signing) the Mesothelioma Attorney-Client Agreement

Understanding (and Signing) the Mesothelioma Attorney-Client Agreement



In an earlier post we discussed how communication is vital to the attorney-client relationship. Once you’ve selected a qualified attorney who communicates clearly with you and makes you feel comfortable, it’s...

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Cortical convolutions controlled in sections: Non-coding DNA sequence affects brain"s characteristic folding, study shows

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Researchers have tied a particular gene to the development of cortical convolutions — the prominent but enigmatic folds covering the surface of the human brain. Their discovery should shed some light on these characteristic contours, which have been the subject of wild speculation for ages, and perhaps also provide a better understanding of how such brain ridges form, how they evolved from our pre-human ancestors and, ultimately, how they influence brain function.The exact role of cortical convolutions remains unknown, but theories have abounded. (Some, for example, have suggested that the folds act as the body’s cooling system and others have even proposed that Albert Einstein’s genius could have been traced to a single cortical fold on his brain.)Now, leveraging advances that permit a closer look at how these folds develop, research published in the 14 February issue of Science shows that a mutation affecting GPR56 causes cortical convolutions around the brain’s Sylvian fissure — a particularly deep indentation — to develop thinner and more convoluted than usual. The finding, which suggests that genes may assert control over the brain’s physical folding on a section-by-section basis, provides insight into the mysterious cortical development process.”There is already a list of genetic mutations that cause abnormal neocortical folding, which can be used for prenatal testing,” explained Byoung-il Bae from the Division of Genetics and Genomics at Boston Children’s Hospital and Harvard Medical School in Boston, Massachusetts, one of the lead authors of the Science report. “We intend to add this mutation to some of the panels.”Bae and colleagues from around the world investigated the genomes of five individuals with abnormalities on Broca’s area, or the language center of the brain. These study participants were from three different families — one Turkish and two Irish-American — and they suffered from refractory seizures as well as intellectual and language difficulties.The researchers found that all five patients harbored a mutation on a particular regulatory element that influences the GPR56 gene. Such regulatory DNA doesn’t code for any proteins itself but promotes the expression of genes elsewhere on the genome. Geneticists have long-suspected that such non-coding regions of the genome could play important roles in evolution. To observe the specific effects of the GPR56 “promoter” DNA sequence, Bae and his team used genetically modified mice.They discovered that low expression of GPR56 (gauged by low levels of mRNA) decreases the production of neuroprogenitor cells — those that will eventually give rise to neurons — around Broca’s area and the Sylvian fissure. By contrast, overexpression of the gene boosts the production of such progenitor cells in that region. …


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Prostate cancer advance could improve treatment options

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Findings published today in the British Journal of Cancer, and funded by the Association for International Cancer Research (AICR), show how a genetic mutation in untreated patients is linked to aggressive cancer later in life. It was previously thought that the mutation only occurred in response to therapy.The research highlights why relapses could occur in some men following hormone therapy. And it could help identify those patients that will develop fatal prostate cancer much earlier for life-extending therapy.Prostate cancer is the most common cancer in men in the UK, with more than 40,000 new cases diagnosed every year. Treatment options for patients diagnosed with early stage prostate cancer vary from “watchful waiting” to hormone-withdrawal therapy, radiotherapy or surgery.Additional tests for indicators of aggressive cancer are necessary to help categorise patients so that those with a low-risk of the disease spreading can avoid unnecessary treatment, and those diagnosed with a high-risk can be targeted for more aggressive first line therapy.Hormone-withdrawal therapy often results in a dramatic remission, however the disease invariably relapses with a resistant form of the cancer. A third of these are due to an increase in copy number of a particular gene called the ‘androgen receptor’. The gene is on the X-Chromosome and so there is normally only one copy of this gene present in men. Prostate cancer thrives on male hormones, and one way that they develop to grow better is to increase the number of copies of the androgen receptor gene. This also enables the cancer to resist therapy.Lead researchers Dr Jeremy Clark and Prof Colin Cooper from UEA’s school of Biological Sciences carried out the research at the Institute of Cancer Research, London, and at UEA.Dr Clark said: “By the age of 60, the majority of men will have signs of prostate cancer. However, only a small proportion of men will die of the disease. The question is — which of these cancers are dangerous and which are not? …


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New pathway for fear discovered deep within brain

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Fear is primal. In the wild, it serves as a protective mechanism, allowing animals to avoid predators or other perceived threats. For humans, fear is much more complex. A normal amount keeps us safe from danger. But in extreme cases, like post-traumatic stress disorder (PTSD), too much fear can prevent people from living healthy, productive lives. Researchers are actively working to understand how the brain translates fear into action. Today, scientists at Cold Spring Harbor Laboratory (CSHL) announce the discovery of a new neural circuit in the brain that directly links the site of fear memory with an area of the brainstem that controls behavior.How does the brain convert an emotion into a behavioral response? For years, researchers have known that fear memories are learned and stored in a small structure in the brain known as the amygdala. Any disturbing event activates neurons in the lateral and then central portions of the amygdala. The signals are then communicated internally, passing from one group of neurons to the next. …


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