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DNA Founder Closes in on Genetic Culprit for Undescribed Syndrome

DNA Founder Closes in on Genetic Culprit for Undescribed Syndrome | Amazing Science | Scoop.it

Hugh Rienhoff says that his nine-year-old daughter, Bea, is “a fire cracker”, “a tomboy” and “a very sassy, impudent girl”. But in a forthcoming research paper, he uses rather different terms, describing her hypertelorism (wide spacing between the eyes) and bifid uvula (a cleft in the tissue that hangs from the back of the palate). Both are probably features of a genetic syndrome that Rienhoff has obsessed over since soon after Bea’s birth in 2003. Unable to put on much muscle mass, Bea wears braces on her skinny legs to steady her on her curled feet. She is otherwise healthy, but Rienhoff has long worried that his daughter’s condition might come with serious heart problems.

 

Rienhoff, a biotech entrepreneur in San Carlos, California, who had trained as a clinical geneticist in the 1980s, went from doctor to doctor looking for a diagnosis. He bought lab equipment so that he could study his daughter’s DNA himself — and in the process, he became a symbol for the do-it-yourself biology movement, and a trailblazer in using DNA technologies to diagnose a rare disease (see Nature 449,773–776; 2007).

 

“Talk about personal genomics,” says Gary Schroth, a research and development director at the genome-sequencing company Illumina in San Diego, California, who has helped Rienhoff in his search for clues. “It doesn’t get any more personal than trying to figure out what’s wrong with your own kid.”

 

Now nearly a decade into his quest, Rienhoff has arrived at an answer. Through the partial-genome sequencing of his entire family, he and a group of collaborators have found a mutation in the gene that encodes transforming growth factor-β3 (TGF-β3). Genes in the TGF-β pathway control embryogenesis, cell differentiation and cell death, and mutations in several related genes have been associated with Marfan syndrome and Loeys–Dietz syndrome, both of which have symptomatic overlap with Bea’s condition. The mutation, which has not been connected to any disease before, seems to be responsible for Bea’s clinical features, according to a paper to be published in the American Journal of Medical Genetics.

 

Hal Dietz, a clinician at Johns Hopkins University School of Medicine in Baltimore, Maryland, where Rienhoff trained as a geneticist, isn’t surprised that the genetic culprit is in this pathway. “The overwhelming early hypothesis was that this was related,” says Dietz, who co-discovered Loeys–Dietz syndrome in 2005.

 

Rienhoff had long been tapping experts such as Dietz for assistance. In 2005, an examination at Johns Hopkins revealed Bea’s bifid uvula. This feature, combined with others, suggested Loeys–Dietz syndrome, which is caused by mutations in TGF-β receptors. But physicians found none of the known mutations after sequencing these genes individually. This was a relief: Loeys–Dietz is associated with devastating cardiovascular complications and an average life span of 26 years.

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A human antiviral enzyme (APOBEC3B) causes DNA mutations that lead to several forms of cancer

A human antiviral enzyme (APOBEC3B) causes DNA mutations that lead to several forms of cancer | Amazing Science | Scoop.it

Researchers have discovered that a human antiviral enzyme 

called APOBEC3B, is responsible for more than half of breast cancer cases. The previous study was published in Nature in February, 2013.

 

APOBEC3B is part of a family of antiviral proteins that Harris has studied for more than a decade. His effort to understand how these proteins work has led to these surprising discoveries that APOBEC3B is a broadly important cancer mutagen.

 

"We are very excited about this discovery because it indicates that a single enzyme is one of the largest known contributors to cancer mutation, possibly even eclipsing sources such as UV rays from the sun and chemicals from smoking," says Reuben Harris, a professor of biochemistry, molecular biology and biophysics based in the College of Biological Sciences. Harris, who led the study, is also a member of the Masonic Cancer Center, University of Minnesota.

 

For the current study, Harris, along with colleagues Michael Burns and Alpay Temiz, analyzed tumor samples from 19 different types of cancer for the presence of APOBEC3B and 10 related proteins. Results showed that APOBEC3B alone was significantly elevated in six types (bladder, cervix, two forms of lung cancer, head & neck, and breast). Levels of the enzyme, which is present in low levels in most healthy tissues, were elevated in several other types of cancer as well.

 

A second key finding was that the mutational signature of APOBEC3B is a close match to the actual mutation pattern in these cancers. "Much like we each have unique written signatures, these enzymes each leave a unique mark," Harris says.

 

Findings from both studies are counterintuitive because the enzyme, which is produced by the immune system, is supposed to protect cells from HIV and other viruses, not harm our own genomic DNA.

 

While it's well known that sunlight and chemical carcinogens can mutate DNA, and that mutations are essential for cancer to develop, Harris is the first to discover that this human enzyme is a major cause mutation in cancer. He believes that APOBEC3B is a biological "double-edged sword" that protects some cells from viruses such as HIV and produces mutations that give rise to cancer in others.

 

Harris hopes to find a way to block APOBEC3B from mutating DNA, just as sunscreen blocks mutations that lead to melanoma. Many cancer mutations have been identified, but discovering a common source of mutation such as APOBEC3B is expected to help researchers to move "upstream" and look for a way to stop carcinogenesis closer to its source, he says, "like damming a river before it wreaks havoc on downstream areas." It's also possible that a simple test for APOBEC3B could be used to detect cancer earlier.

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Cancer-Linked Fam190a Gene Found to Regulate Cell Division and Chromosomal Stability

Cancer-Linked Fam190a Gene Found to Regulate Cell Division and Chromosomal Stability | Amazing Science | Scoop.it

Johns Hopkins cancer scientists have discovered that a little-described gene known as FAM190A plays a subtle but critical role in regulating the normal cell division process known as mitosis, and the scientists’ research suggests that mutations in the gene may contribute to commonly found chromosomal instability in cancer.

 

In laboratory studies of cells, investigators found that knocking down expression of FAM190A disrupts mitosis. In three pancreatic cancer-cell lines and a standard human-cell line engineered to be deficient in FAM190A, researchers observed that cells often had difficulty separating at the end of mitosis, creating cells with two or more nuclei. The American Journal of Pathology published a description of the work online May 17, which comes nearly a century after German scientist Theodor Boveri linked abnormal mitosis to cancer. Until now, there had been no common gene alteration identified as the culprit for cancer-linked mitosis.

 

“These cells try to divide, and it looks like they succeed, except they wind up with a strand that connects them,” explains Scott Kern, M.D., professor of oncology and pathology at Johns Hopkins University School of Medicine and its Kimmel Cancer Center. “The next time they try to divide, all the nuclei come together, and they try to make four cells instead of two. Subsequently, they try to make eight cells, and so on.” Movies of the process taken by Kern’s laboratory are available on the journal Web site.

 

Kern’s group previously reported that deletions in the FAM190A gene could be found in nearly 40 percent of human cancers. That report, published in 2011 in the journal Oncotarget, and the current one are believed to be the only published papers focused solely on FAM190A, which is frequently altered in human cancers but whose function has been unknown. Alterations in FAM190A messages may be the third most common in human cancers after those for the more well-known genes p53 and p16, Kern says.

 

“We don’t think that a species can exist without FAM190, but we don’t think severe defects in FAM190A readily survive among cancers,” Kern says. “The mutations seen here are very special – they don’t take out the whole gene but instead remove an internal portion and leave what we call the reading frame. We think we’re finding a more subtle defect in human cancers, in which mitosis defects can occur episodically, and we propose it may happen in about 40 percent of human cancers.”

 

Abnormalities in FAM190A may cause chromosomal imbalances seen so commonly in cancers, Kern says. Multipolar mitosis is one of the most common functional defects reported in human cancers, and more than 90 percent of human cancers have abnormal numbers of chromosomes.

Kern says he plans to study FAM190A further by creating lab models of the subtle defects akin to what actually is tolerated by human cancer cells.

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World's Largest Blood and Urine Freezer at Biobank is Aiming to Create Trove of Genetic Data

World's Largest Blood and Urine Freezer at Biobank is Aiming to Create Trove of Genetic Data | Amazing Science | Scoop.it
The goal is to put the vast collection of data on genetic variations and health into databases open to researchers and doctors all over the world.

 

More than 70 medical, research and advocacy organizations active in 41 countries and including the National Institutes of Health announced Wednesday that they had agreed to create an organized way to share genetic and clinical information. Their aim is to put the vast and growing trove of data on genetic variations and health into databases — with the consent of the study subjects — that would be open to researchers and doctors all over the world, not just to those who created them.

Millions more people are expected to get their genes decoded in coming years, and the fear is that this avalanche of genetic and clinical data about people and how they respond to treatments will be hopelessly fragmented and impede the advance of medical science. This ambitious effort hopes to standardize the data and make them widely available.


“We are strong supporters of this global alliance,” said Dr. Francis Collins, director of the National Institutes of Health. “There is lots of momentum now, and we really do want to move quickly.”

 

In just the past few years, the price of determining the sequence of genetic letters that make up human DNA has dropped a millionfold, said Dr. David Altshuler, deputy director and chief academic officer at the Broad Institute of Harvard and M.I.T. As a result, instead of having access to just a few human genomes — the complete genetic material of a person, including genes and regions that control genes — researchers can now study tens of thousands of them, along with clinical data on peoples’ health and how they fared on various treatments.

 

In the next few years, Dr. Altshuler said, researchers expect that millions of people will have their genomes sequenced.

 

“The question is whether and how we make it possible to learn from these data as they grow, in a manner that respects the autonomy and privacy choices of each participant,” he said. No one wants to put DNA sequences and clinical data on the Internet without the permission of patients, he said, so it also is important to allow people to decide if they want their data — with no names or obvious identifiers attached — to be available to researchers.

 

Medical researchers say the best way forward is to have shared databases. Do patients with a particular genetic aberration tend to do well with a particular therapy? Do patients with another mutation have greater odds of developing cancer?

 

Dr. Collins said that cancers are so genetically complex that, most of the time, a mutation seen in a cancer patient will be uncommon. To figure out its significance, data from hundreds of thousands of patients — the world’s collected data — on that mutation are needed.


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Genetics of white tigers pinpointed - due to a single gene, SLC45A2

Genetics of white tigers pinpointed - due to a single gene, SLC45A2 | Amazing Science | Scoop.it

Chinese scientists trace the rare white coloration in Bengal tigers to a single change in a gene that affects a host of animals, including humans.

 

White tigers are a rare variant of the customary orange Bengal sub-species. Today, they are found exclusively in captive programmes where the limited numbers are interbred to maintain the distinctive fur color.

 

Shu-Jin Luo of Peking University and colleagues investigated the genetics of a family of tigers living in Chimelong Safari Park in Panyu, Guangzhou Province. This ambush of tigers included both white and orange individuals.

 

The study zeroed in on the pigment gene called SLC45A2, which has long been associated with the light colouration seen in some human populations, and in a range of other animals including horses, chickens, and fish.

 

The team identified a small alteration in the white-tiger version of SLC45A2 that appears to inhibit the production of red and yellow pigments. This change has no effect on the generation of black pigment - explaining why the whites still have their characteristic dark stripes.

 

A number of the white tigers found in zoos have health issues, such as eyesight problems and some deformities.

 

However, Luo and colleagues say these deficiencies are a consequence of inbreeding by humans and that the white coats are in no way indicative of a more general weakness in the Bengal variant.

 

Establishing this fact means that re-introducing them to the wild under a carefully managed conservation programme might be worth considering.

"The last known free-ranging white tiger was shot in 1958, before which sporadic sightings were made in India," the researchers write.

 

"Reasons for the extinction of wild white tigers were likely the same as those accounting for the dramatic decline in wild tigers in general: uncontrolled trophy hunting, habitat loss, and habitat fragmentation.

 

"However, the fact that many white tigers captured or shot in the wild were mature adults suggests that a white tiger in the wild is able to survive without its fitness being substantially compromised."

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Kate Richmond's curator insight, June 10, 2013 10:34 AM

This article could be an excellent content-reading activity for students while also bringing up issues of ethics in genetics and single-gene vs. polygenic traits.

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Non-coding Repeats Cause Peptide Clumps

Non-coding Repeats Cause Peptide Clumps | Amazing Science | Scoop.it
Protein aggregates in the brains of some people with dementia or motor neuron disease have a surprising origin.

 

A repetitive DNA sequence that was not believed to encode proteins is, in fact, the source of insoluble peptide chains that aggregate in the brain cells of patients displaying certain types of neurodegeneration, according to a recent study. These aggregates occur in a wide range of neurodegenerative disorders, so determining their identity is an important first step towards understanding how they might contribute to various pathologies.

 

FTLD-ALS spectrum disorders are a range of related neurodegenerative disorders from frontotemporal lobar degeneration (FTLD) right through to amyotrophic lateral sclerosis (ALS). Most cases are of unknown origin, but an expanded repeat region in a non-coding part of a gene called C9orf72 “is the most prevalent cause we know of for both FTLD and ALS,” Miller said. Almost all patients with FTLD-ALS have characteristic protein aggregates, or inclusions, in their brain cells, but patients with the C9orf72 mutation have an additional, more prominent type of inclusion.

 

When the mutation was first discovered, two principle hypotheses arose as to how it might cause disease, said Dieter Edbauer, a professor of translational neurobiochemistry at the Ludwig Maximilians Universität in Munich, Germany, who led the study. One idea is that the RNA transcript containing the repeats might sequester important RNA-binding proteins in aggregates, preventing their proper function. The other hypothesis posits that the repeats might inhibit correct transcription or RNA splicing of C9orf72. The possibility that the repeats might be translated into peptides was a bit of a shot in the dark, Edbauer admitted. “I thought, a lot of big labs will look into [the two main hypotheses], and I don’t have a real chance to compete with them,” he joked.

 

Although the repeats are in a non-coding region of the C9orf72 gene and thus should not be translated at all, there were precedents for such illegitimate translation and, moreover, the possibility was “so attractive,” said Edbauer. He realized that if translation did occur, the proteins “would be extremely hydrophobic, so it would really make sense that they would aggregate in patients.”

 

The repeating DNA sequence is 6 nucleotides long, and researchers estimate that several hundred copies of the sequence exist in FTLD-ALS patients carrying the C9orf72 mutation, with healthy people carrying fewer than 25. If translated, the sequence would encode chains of two-amino-acid, or dipeptide, repeats. And, depending on where in the sequence translation is initiated, those dipeptides could be glycine-alanine, glycine-proline, or glycine-arginine.

 

Edbauer created antibodies to detect all three possible dipeptide chains, and found that all three were present in protein aggregates in the postmortem brains of C9orf72 mutation-carrying patients. The peptide chains were not present in patients without the mutation, however.

 

Identifying the nature of the inclusions was an important issue to resolve, said Ian Mackenzie, a professor of pathology and laboratory medicine at the University of British Columbia in Vancouver, Canada, who was not involved in the study. But “even if the finding is correct, is it at all relevant from a pathogenic point of view?” he asked. Indeed, it is still possible that the other hypotheses about the C9orf72 mutation are correct and that the aggregates are a by-product.

 

The mutation could even cause disease by a combination of mechanisms, Mackenzie said. “The next set of experiments [should] be to see whether clearing these peptides or blocking them will protect cells,” Miller added.

Edbauer thinks it is likely the inclusions will turn out to be toxic. “We don’t know in what way they are toxic, but it is unlikely that they are doing anything good,” he said. “Normal people don’t have these proteins at all.”

 

The absence of the peptides in healthy people also “makes them an attractive target for therapy,” said Edbauer. “One could imagine it might be easier to find a specific strategy to block their synthesis, their toxicity, or their aggregation . . . without causing side effects.”

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Deleting the Perilipin 2 (Plin2) gene in mice prevents them from becoming obese even on a high fat diet

Deleting the Perilipin 2 (Plin2) gene in mice prevents them from becoming obese even on a high fat diet | Amazing Science | Scoop.it

“When fed a diet that induces obesity these mice don’t get fat. It may be possible to duplicate this in humans using existing technology that targets this specific gene,” Prof. McManaman said. The team created a strain of mice without the Plin2 gene which produces a protein that regulates fat storage and metabolism. They immediately found that the mice were resistant to obesity. Usually, mice fed a high fat diet will eat voraciously, yet these showed an unusual restraint. Not only did they eat less, they were more active.

 

Their fat cells were also 20 percent smaller than typical mice and did not show the kind of inflammation usually associated with obesity, the study said. Obesity-associated fatty liver disease, common in obese humans and rodents, was absent in the mice without the Plin2 gene.

 

“The mice were healthier,” Prof. McManaman said. “They had lower triglyceride levels, they were more insulin-sensitive, they had no incidents of fatty liver disease and there was less inflammation in the fat cells.”

“The absence of the gene may cause fat to be metabolized faster.” “Now we want to know why this works physiologically,” the scientist said. “We want to better understand how this affects food consumption.”

 

According to the study, understanding how Plin2 is involved in the control of energy balance will provide new insights into the mechanisms by which nutrition overload is detected, and how individuals adapt to, or fail to adapt to, dietary challenges. The consequences for people are highly significant since they also possess the Plin2 gene. “It could mean that we have finally discovered a way to disrupt obesity in humans,” Prof. McManaman said. “That would be a major breakthrough.”

 
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Study Finds Genetic Risk Factors Shared by 5 Psychiatric Disorders

Study Finds Genetic Risk Factors Shared by 5 Psychiatric Disorders | Amazing Science | Scoop.it

The psychiatric illnesses seem very different — schizophrenia, bipolar disorder, autism, major depression and attention deficit hyperactivity disorder. Yet they share several genetic glitches that can nudge the brain along a path to mental illness, researchers report. Which disease, if any, develops is thought to depend on other genetic or environmental factors.

 

Their study analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33 332 cases and 27 888 controls of European ancestory. To characterise allelic effects on each disorder, they applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. The research team examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. They undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders and used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples.Findings: SNPs at four loci surpassed the cutoff for genome-wide significance (p<5×10−8) in the primary analysis, Regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers.The new study does not mean that the genetics of psychiatric disorders are simple. Researchers say there seem to be hundreds of genes involved and the gene variations discovered in the new study confer only a small risk of psychiatric disease.

 

Steven McCarroll, director of genetics for the Stanley Center for Psychiatric Research at the Broad Institute of Harvard and M.I.T., said it was significant that the researchers had found common genetic factors that pointed to a specific signaling system. “It is very important that these were not just random hits on the dartboard of the genome,” said Dr. McCarroll, who was not involved in the new study.

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2013 Genomics: The Era Beyond the Sequencing of the Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.

2013 Genomics: The Era Beyond the Sequencing of the Human Genome: Francis Collins, Craig Venter, Eric Lander, et al. | Amazing Science | Scoop.it

Curator: Dr. Aviva Lev-Ari


One decade following the completion of the  Sequencing of the Human Genome – the field of Genomics, the discipline that has emerged as a result of project completion has FOUR sections: Comparative Genomics, Genome Sequencing and Annotation, Functional Genomics, and Translational Genomics.

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How Blue Eyed Parents Can Have Brown Eyed Children - Understanding Genetics

How Blue Eyed Parents Can Have Brown Eyed Children - Understanding Genetics | Amazing Science | Scoop.it

Eye color is much more complicated than is usually taught in high school (or presented in The Tech’s eye color calculator).  There we learn that two genes influence eye color. One gene comes in two versions, brown (B) and blue (b).  The other gene comes in green (G) and blue (b).  All eye color and inheritance was thought to be explained by this simple model.  Except of course for the fact that it is obviously incomplete.

 

The model cannot, for example, explain how blue eyed parents can have a brown eyed child.  Yet this can and does happen (although it isn’t common).   

New research shows that the first gene is actually two separate genes, OCA2 and HERC2.  In other words, there are two ways to end up with blue eyes.  

Normally this wouldn’t be enough to explain how blue eyed parents can have a brown eyed child.  Because of how eye color works (see below), if one gene can cause brown eyes, it would dominate over another that causes blue.  In fact, that is what happens with green eyes in the older model.  The brown gene dominates over the green one resulting in brown eyes.

 

The key is that if someone makes a lot of pigment in the front part of their eye, they have brown eyes.  And if they make none there, they have blue.

Part of the pigment making process involves OCA2 and HERC2.  A working HERC2 is needed to turn on OCA2 and OCA2 helps to actually get the pigment made.  They need each other to make pigment.

 

So someone with only broken HERC2 genes will have blue eyes no matter what OCA2 says.  This is because the working OCA2 can't be turned on so no pigment gets made.

 

And the opposite is true as well.  Someone with broken OCA2 genes will have blue eyes no matter what the HERC2 genes are.  Turning on a broken pigment making gene still gives you no pigment.  You need a working HERC2 and a working OCA2 to have brown eyes.

 

Because the two genes depend on each other, it is possible for someone to actually be a carrier of a dominant trait like brown eyes.  And if two blue eyed parents are carriers, then they can have a brown eyed child.

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Two Mutations drive malignant melanoma in 71 percent of all cases

Two Mutations drive malignant melanoma in 71 percent of all cases | Amazing Science | Scoop.it

Two mutations that collectively occur in 71 percent of malignant melanoma tumors have been discovered in what scientists call the “dark matter” of the cancer genome, where cancer-related mutations haven’t been previously found.

 

Harvard Medical School (HMS) researchers at the Dana-Farber Cancer Institute and researchers at the Broad Institute said the highly “recurrent” mutations — occurring in the tumors of many people — may be the most common mutations in melanoma cells found to date.

 

The researchers said these cancer-associated mutations are the first to be discovered in the vast regions of DNA in cancer cells that do not contain genetic instructions for making proteins. The mutations are located in non-protein-coding DNA that regulates the activity of genes.

 

This non-coding DNA, much of which was previously dismissed as “junk,” accounts for 99 percent of a cell’s genome. A large number of oncogenic mutations in cancer have been identified in the past several decades, but all have been found within the actual genetic blueprints for proteins.

 

“This new finding represents an initial foray into the ‘dark matter’ of the cancer genome,” said Levi Garraway, HMS associate professor of medicine and the article’s senior author.

 

A human melanoma cell line growing in tissue culture is pictured. The study of cancer cell lines such as this one allows scientists to investigate cancer cell biological processes and ways to modify them in order to design and test new treatments.

 

“In addition, this represents the discovery of two of the most prevalent melanoma gene mutations. Considered as a whole, these two TERT promoter mutations are even more common than BRAF mutations in melanoma. Altogether, this discovery could cause us to think more creatively about the possible benefits of targeting TERT in cancer treatment or prevention,” Garraway said.

 

The mutations affect a promoter region — a stretch of DNA code that regulates the expression of a gene — adjacent to the TERT gene. TERT contains the recipe for making telomerase reverse transcriptase, an enzyme that can make cells virtually immortal, and is often found overexpressed in cancer cells. A promoter region of DNA controls the rate of a gene’s transcription — the copying of its DNA recipe into a message used by the cell to manufacture a protein.

 

“We think these mutations in the promoter region are potentially one way the TERT gene can be activated,” said Franklin Huang, an HMS clinical fellow in medicine and co-first author of the report along with Harvard M.D.-Ph.D. student Eran Hodis.

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Inhibiting NLK in cancers with mutated PTEN could turn the cancer's strength against it

Inhibiting NLK in cancers with mutated PTEN could turn the cancer's strength against it | Amazing Science | Scoop.it

A mutation that allows cells to grow out of control could also provide a new way to target and destroy cancer cells. This potential Achilles’ heel comes from a mutation in a gene called PTEN, which is found in a wide range of cancers.

 

PTEN is one of many tumor suppressor genes that we have to prevent our cells from growing out of control. If the PTEN gene stops working because of a mutation, it can cause tumours to develop – indeed many tumors have a mutated form of PTEN. However when a door closes, a window opens: the PTEN mutation helps the tumor to grow, but it could also mark it out as a target.

 

Researchers from the Institute of Cancer Research, London, found that switching off another gene known as NLK (Nemo-like kinase) killed tumor cells that had the PTEN mutation. This makes NLK a good target for drug developers to create a new cancer treatment.


Initially, the researchers took samples of tumor cells with and without the mutation, and switched off genes for important proteins that are used for regulating lots of processes in the cell. To do this they used small interfering RNA (or siRNA) which interfere with the processes of specific genes. These siRNAs block the chain of events that allow a gene to produce a protein, effectively switching it off. By switching off 779 genes individually, they could look for ones where cells with the PTEN mutation died and cells without the mutation survived.

 

This is how the researchers discovered the powerful effect of switching off the NLK gene. They are not certain how this works but it appears to protect a protein called FOXO1 that can act as a backup tumor suppressor and cause the cancer cell to die. When PTEN is mutated, the FOXO1 protein becomes vulnerable to a process called phosphorylation, which means it is ejected from the cell nucleus and destroyed. NLK is one of the proteins that phosphorylates FOXO1 and so by switching off the NLK gene, FOXO1 is able to do its job.


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Rare disease in Amish children sheds light on common neurological disorders

Rare disease in Amish children sheds light on common neurological disorders | Amazing Science | Scoop.it
So often the rare informs the common. Penn researchers investigating a regulatory protein involved in a rare genetic disease have shown that it may be related to epileptic and autistic symptoms in other more common neurological disorders.

 

A team of researchers from the University of Pennsylvania School of Medicine, led by Peter B. Crino, MD, PhD, associate professor of Neurology and director of the Penn Epilepsy Center, demonstrate how mutations in the STRAD-alpha gene can cause a disease called PMSE (polyhydramnios, megalencephaly, and symptomatic epilepsy) syndrome, found in a handful of Amish children. PMSE is characterized by an abnormally large brain, cognitive disability, and severe, treatment-resistant epilepsy. Specifically, in an animal model, they found that the lack of the STRAD-alpha protein due to genetic mutations causes activation of the signaling pathway involving another protein called mTOR. In humans, this in turn may promote abnormal cell growth and cognitive problems in the developing brains of children. STRAD-alpha and mTOR proteins are part of a complex molecular network implicated in other, more common neurological disorders, many of which have autism-like symptoms as a component. "The identification of a new gene that regulates mTOR provides fascinating insights into how mTOR pathway dysfunction may be associated with neurological disorders," says Crino. "Each new mTOR regulatory protein that is identified provides a new possible therapeutic target for drug development and treatment."

 

The mTOR pathway normally controls cell growth, but in PMSE uncontrolled mTOR signaling leads to increases in brain size and areas in which the cerebral cortex is malformed. To prove this, the researchers knocked down the activity of the STRAD-alpha protein in a mouse model and caused malformations of the developing brain. The structure of these malformations was similar to what is seen in human PMSE and TSC and supports the conclusion that normal brain development in part depends on normal STRAD-alpha function. Localized brain malformations are among the most common causes of epilepsy and neurological disability in children.

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Overweight? Blame Your Genes -- Gene discovered that controls how fast calories are burned

Overweight? Blame Your Genes -- Gene discovered that controls how fast calories are burned | Amazing Science | Scoop.it
Researchers have found a genetic mutation that may help explain why some people can eat the same amount as others but gain more weight.

 

Scientists have long thought explanations for why some people get fat might lie in their genes. They knew body weight was strongly inherited. Years ago, for example, they found that twins reared apart tended to have similar weights and adoptees tended to have weights like their biological parents, not the ones who reared them. As researchers developed tools to look for the actual genes, they found evidence that many — maybe even hundreds — of genes may be involved, stoking appetites, making people voraciously hungry.


In a recent study, Dr. Majzoub and his colleagues describe figuring out how the gene they deleted, known as MRAP2, acts in the brain to control weight. They discovered that it is a helper gene. It normally acts in the brain to signal another gene already known to be involved in controlling appetite. So they developed a hypothesis. If the helper gene was deleted, the brakes should come off the gene that controls appetite. Animals should eat voraciously.


The first thing they noticed was that the mice got fat, ending up weighing twice as much as their normal siblings, with most of that extra weight due to fat accumulation.

 

“During the mouse equivalent of childhood and adolescence they were becoming rapidly obese,” Dr. Majzoub said.

 

The surprise came when the researchers figured out why. When the mice were young, they had normal appetites. The researchers measured what they and their normal siblings ate and determined they were eating the same amount of food. Yet the mice with the deleted gene still gained weight. The only way the obesity-prone mice could be kept slim was to be fed 10 to 15 percent less than their siblings.


But as adults, the mice with the missing gene developed monstrous appetites. Given a chance, they ate much more than their siblings, exacerbating the effects of their tendency to turn food into fat.

 

That led the researchers to ask if the same genetic phenomenon could be making people obese. They contacted Dr. Sadaf Farooqui of the University of Cambridge, whose group has been mapping the genes of massively obese children, and studied the data on 500 of the children, searching for mutations that disabled the same gene they had deleted in mice.

 

One child clearly had a gene-disabling mutation and three others had mutations that the investigators suspect might render the gene nonfunctional. None of the normal-weight children who served as controls had a mutation in the helper gene.

 

“From a basic science point of view, this is really interesting and exciting,” said David Allison, an obesity researcher at the University of Alabama in Birmingham who was not involved in the study. Any discovery that helps fill in the details of how the brain controls eating and weight gain is important, he added.

 

Jeffrey Friedman, an obesity researcher at Rockefeller University, who also was not involved in the study, said, “It is another piece in a very important puzzle.”

 

Dr. Majzoub and his colleagues are now trying to determine whether additional mutations in the gene they discovered — ones that hinder its function but do not completely disable it — might explain why some people gain weight.

 

“All we can do is hope,” Dr. Majzoub said.


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Multifunctional Genes: Taste Receptor Gene Inactivation Causes Male Sterility

Multifunctional Genes: Taste Receptor Gene Inactivation Causes Male Sterility | Amazing Science | Scoop.it
Two proteins called TAS1R3 and GNAT3, which have been previously known to be involved in oral taste detection, also play a crucial role in sperm development.

 

While breeding mice for taste-related studies, Dr Bedrich Mosinger from Monell Chemical Senses Center and his colleagues discovered that they were unable to produce offspring that were simultaneously missing two taste-signaling proteins – TAS1R3 and GNAT3.

 

TAS1R3 is a component of both the sweet and umami (amino acid) taste receptors. GNAT3 is a molecule needed to convert the oral taste receptor signal into a nerve cell response.

 

The researchers determined that fertility was affected only in males. Both taste proteins had previously been found in testes and sperm, but until now, their function there was unknown.

 

This study “highlights a connection between the taste system and male reproduction. It is one more demonstration that components of the taste system also play important roles in other organ systems,” Dr Mosinger explained.

 In order to explore the reproductive function of TAS1R3 and GNAT3, the team engineered mice that were missing genes for the mouse versions of the two proteins but expressed the human form of the TAS1R3 receptor – these mice were fertile. 

 

However, when the human TAS1R3 was blocked in the engineered mice by adding the drug clofibrate to their diet, thus leaving the mice without any functional TAS1R3 or GNAT3 proteins, the males became sterile due to malformed and fewer sperm.

 

The sterility was quickly reversed after clofibrate was removed from the diet.

Clofibrate belongs to a class of drugs called fibrates that frequently are prescribed to treat lipid disorders such as high blood cholesterol or triglycerides. Previous studies had revealed that it is a potent inhibitor of the human, but not mouse, TAS1R3 receptor.

 

“Noting the common use of fibrates in modern medicine and also the widespread use in modern agriculture of the structurally-related phenoxy-herbicides, which also block the human TAS1R3 receptor,” Dr Mosinger said, “these compounds could be negatively affecting human fertility, an increasing problem worldwide.”

 

“If our pharmacological findings are indeed related to the global increase in the incidence of male infertility, we now have knowledge to help us devise treatments to reduce or reverse the effects of fibrates and phenoxy-compounds on sperm production and quality. This knowledge could further be used to design a male non-hormonal contraceptive,” Dr Mosinger concluded.

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Epigenetics raises the possibility that a smoker can cause grandchildren to get asthma via genetics

Epigenetics raises the possibility that a smoker can cause grandchildren to get asthma via genetics | Amazing Science | Scoop.it

The adverse health effects of smoking can be passed down through multiple generations, according to new experiments conducted at the Los Angeles Biomedical Research Institute. In one experiment, pregnant rats were given nicotine injections that produced asthma in their offspring. What surprised researchers is that third-generation rats (the grandchildren of the smoker rats) also developed asthma. "Nicotine is not only affecting lung cells, [say researchers], but also affecting sex cells in ways that cause the lungs which ultimately develop from those cells to express their genes in the same abnormal ways."


Some biologists are highly skeptical of the recent findings because they appear to run contrary to Darwin's theory of evolution. The suggestion that learned traits, such as a smoking addiction, can be passed down genetically to future generations was initially a theory put forth by the French naturalist Jean-Baptiste Lamarck that rivaled Darwin's evolution. Today, genetic inheritances of learned traits are known as epigenetic changes, a term that refers to the regulation of gene expression by the chemical modification of DNA, or of the histone proteins in which DNA is usually wrapped. 

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Genetic Scientists Eliminate Schizophrenia Symptoms in Mice by Targeting Neuregulin-1 (NRG1)

Genetic Scientists Eliminate Schizophrenia Symptoms in Mice by Targeting Neuregulin-1 (NRG1) | Amazing Science | Scoop.it

Geneticists writing in the journal Neuron reversed schizophrenia-like symptoms in adult mice by restoring normal expression to the gene Neuregulin-1 (NRG1).

 

Targeting expression of NRG1, which makes a protein important for brain development, may hold promise for treating at least some patients with the brain disorder. Like patients with schizophrenia, adult mice biogenetically-engineered to have higher NRG1 levels showed reduced activity of the brain messenger chemicals glutamate and γ-aminobutyric acid (GABA). The mice also showed behaviors related to aspects of the human illness.

“They genetically engineered mice so they could turn up levels of NRG1 to mimic high levels found in some patients then return levels to normal,” explained senior author Dr Lin Mei from the Medical College of Georgia at Georgia Regents University.

 

“They found that when elevated, mice were hyperactive, couldn’t remember what they had just learned and couldn’t ignore distracting background or white noise. When they returned NRG1levels to normal in adult mice, the schizophrenia-like symptoms went away.”

 

While schizophrenia is generally considered a developmental disease that surfaces in early adulthood, the team found that even when they kept NRG1 levels normal until adulthood, mice still exhibited schizophrenia-like symptoms once higher levels were expressed. Without intervention, they developed symptoms at about the same age humans do.

 

“This shows that high levels of NRG1 are a cause of schizophrenia, at least in mice, because when you turn them down, the behavior deficit disappears,” Dr Mei said. “Our data certainly suggests that we can treat this cause by bringing down excessive levels of NRG1 or blocking its pathologic effects.”

 

“Schizophrenia is a spectrum disorder with multiple causes – most of which are unknown – that tends to run in families, and high NRG1 levels have been found in only a minority of patients. To reduce NRG1 levels in those individuals likely would require development of small molecules that could, for example, block the gene’s signaling pathways,” Dr Mei said.

 

“Current therapies treat symptoms and generally focus on reducing the activity of two neurotransmitters since the bottom line is excessive communication between neurons.”

 

The good news is it’s relatively easy to measure NRG1 since blood levels appear to correlate well with brain levels. To genetically alter the mice, the scientists put a copy of the NRG1 gene into mouse DNA then, to make sure they could control the levels, they put in front of the DNA a binding protein for doxycycline, a stable analogue for the antibiotic tetracycline, which is infamous for staining the teeth of fetuses and babies. The mice are born expressing high levels of NRG1 and giving the antibiotic restores normal levels.

 

“If you don’t feed the mice tetracycline, the NRG1 levels are always high. Endogenous levels of the gene are not affected. High-levels of NRG1 appear to activate the kinase LIMK1, impairing release of the neurotransmitter glutamate and normal behavior. The LIMK1 connection identifies another target for intervention,” Dr Mei concluded.

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Researchers Identify 4 New Genetic Risk Factors For Testicular Cancer

Researchers Identify 4 New Genetic Risk Factors For Testicular Cancer | Amazing Science | Scoop.it

Tapping into three genome-wide association studies (GWAS), the researchers, including Peter A. Kanetsky, PhD, MPH, an associate professor in the department of Biostatistics and Epidemiology, analyzed 931 affected individuals and 1,975 controls and confirmed the results in an additional 3,211 men with cancer and 7,591 controls. The meta-analysis revealed that testicular germ cell tumor (TGCT) risk was significantly associated with markers at four loci—4q22, 7q22, 16q22.3, and 17q22, none of which have been identified in other cancers. Additionally, these loci pose a higher risk than the vast majority of other loci identified for some common cancers, such as breast and prostate.

 

This brings the number of genomic regions associated with testicular cancer up to 17—including eight new ones reported in another study in this issue of Nature Genetics.

 

Testicular cancer is relatively rare; however, incidence rates have doubled in the past 40 years. It is also highly heritable. If a man has a father or son with testicular cancer, he has a four-to six-fold higher risk of developing it compared to a man with no family history. That increases to an eight-to 10-fold higher risk if the man has a brother with testicular cancer.

Given this, researchers continue to investigate genetic variants and their association with cancer.

 

In 2009, Dr. Nathanson and colleagues uncovered variation around two genes—KITLG and SPRY4—found to be associated with an increased risk of testicular cancer. The two variants were the first striking genetic risk factors found for this disease at the time. Since then, several more variants have been discovered, but only through single GWAS studies.

 

"This analysis is the first to bring several groups of data together to identify loci associated with disease," said Dr. Nathanson, "and represent the power of combining multiple GWAS to better identify genetic risk factors that failed to reach genome-wide significance in single studies."

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New evidence that red wine component resveratrol activates SIRT1 pathway and prolongs life

New evidence that red wine component resveratrol activates SIRT1 pathway and prolongs life | Amazing Science | Scoop.it

A new study demonstrates what researchers consider conclusive evidence that the red wine compound resveratrol directly activates a protein that promotes health and longevity in animal models. What’s more, the researchers have uncovered the molecular mechanism for this interaction, and show that a class of more potent drugs currently in clinical trials act in a similar fashion. Pharmaceutical compounds similar to resveratrol may potentially treat and prevent diseases related to aging in people, the authors contend.

 

For the last decade, the science of aging has increasingly focused onsirtuins, a group of genes that are believed to protect many organisms, including mammals, against diseases of aging. Mounting evidence has demonstrated that resveratrol, a compound found in the skin of grapes as well as in peanuts and berries, increases the activity of a specific sirtuin, SIRT1, that protects the body from diseases by revving up the mitochondria, a kind of cellular battery that slowly runs down as we age. By recharging the batteries, SIRT1 can have profound effects on health.

 

Mice on resveratrol have twice the endurance and are relatively immune from effects of obesity and aging. In experiments with yeast, nematodes, bees, flies and mice, lifespan has been extended.

 

“In the history of pharmaceuticals, there has never been a drug that binds to a protein to make it run faster in the way that resveratrol activates SIRT1,” said David Sinclair, Harvard Medical School professor of genetics. “Almost all drugs either slow or block them.”

 

In 2006, Sinclair’s group published a study showing that resveratrol could extend the lifespan of mice, and the company Sirtris Pharmaceuticals, which was started by HMS researchers, was founded to make drugs more potent than resveratrol. Sinclair is a co-founder of Sirtris, a GlaxoSmithKline company, and remains a scientific advisor. Sirtris currently has a number of sirtuin-activating compounds in clinical trials.

 

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Tony Barnes's curator insight, March 9, 2013 12:00 PM

I remember  in the 1970s there was talk of tocopherols having something this kind of health effect.  My chemistry's now rusty. Maybe resveratrol is a tocoperol. Anyway, it's very interesting.

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Million-page story of modern genetics launched by the Wellcome Library

Million-page story of modern genetics launched by the Wellcome Library | Amazing Science | Scoop.it

The papers of the pioneers of modern genetics - including Francis Crick, James D Watson, Maurice Wilkins and Rosalind Franklin - have been collected together for the first time and made freely available in a £3.9 million digitisation project from the Wellcome Library.


Codebreakers: Makers of modern genetics, which launches today atwellcomelibrary.org/codebreakers, contains more than one million pages of first-hand notes, letters, sketches, lectures, photographs and essays from the circle of brilliant minds responsible for uncovering the structure of DNA. The site lays bare the personal and professional thoughts, rivalries, blind alleys and breakthroughs of the scientists whose ideas transformed our understanding of the matter of life.

 

Drawing on five partner archives in the USA, London, Cambridge and Glasgow and the Wellcome Library's own holdings, Codebreakers offers an unparalleled and comprehensive primary resource for researchers and curious minds across the world and is launched ahead of the 60th anniversary of Crick and Watson's seminal 'Nature' paper revealing the structure of DNA. It holds the stories behind the discovery, which has shaped our genetic age, from diagnosis to drug development and from forensics to food production, and which lies at the heart of today's biomedical research.

 

The vast collections contain iconic documents - such as Crick's preliminary sketches of the double helix and Franklin's X-ray diffraction 'photo 51' - and everyday exchanges. The biological revolutions of the 1950s and 1960s, together with their legacies in the fields of medical genetics and genomics, are recorded in the scientists' own words and placed in the context of earlier research into the links between heredity and health, including the archives of the Eugenics Society, one of the most influential scientific organisations of the early 20th century.

 

Codebreakers sits within an entirely redesigned Wellcome Library website, and a new media player allows the close reading, downloading and embedding of digitised files. The content is free to all, and users can log in using Library membership, Facebook or Twitter accounts. A timeline and essays on key individuals and research groups offer navigational aids through the records.

 

Codebreakers is a collaborative project, uniting collections from five internationally important centres. Working with Cold Spring Harbor Laboratory, Churchill Archives Centre Cambridge, the University of Glasgow, King's College London and UCL, the digitised papers of James D Watson, Rosalind Franklin, Sydney Brenner, Lionel Penrose, J B S Haldane, Guido Pontecorvo, James Harrison Renwick, Malcolm Ferguson-Smith and Maurice Wilkins have been made available. They join material from the Wellcome Library's own holdings, including the papers of Francis Crick, Fred Sanger, Arthur Ernest Mourant, Peter Medawar, Hans Grüneberg, Honor Fell and Gerard Wyatt.

 

Users exploring the site will find treasures of beauty - such as Honor Fell's minutely observed cell drawings - and import, including richly annotated holographs of key papers and lectures unlocking the secrets of DNA. The archives are full of candid correspondence, keen professional insight and moving personal items, such as Peter Medawar's self-portraits, which were drawn after suffering a stroke.

 

Simon Chaplin, Head of the Wellcome Library says: "Codebreakers reveals the extraordinarily convoluted networks of influence, insight and inspiration that lie behind crucial moments of scientific discovery. It is a project made possible by a creative partnership with five outstanding libraries and archives, sharing a goal of free and open access. Together, our collections offer an extraordinarily rich research resource documenting one of the most significant periods of scientific innovation in human history."

 

The Wellcome Library's Codebreakers project is the first phase of a major digitisation programme that will create integrated online content, featuring digitised books, archives, films, photographs and audio covering every aspect of the history of medicine and biomedical science. A further half million pages will be added to Codebreakers over the next six months, and £5.8 million has been set aside for the next phase of the Library's digitisation plans, which focus on material relating to neurology and mental health. The Library itself is also expanding as part of a £17.5-million development of Wellcome Collection due for completion in summer 2014.


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Ngozi Odochi (Godwell) Nwokocha's curator insight, May 7, 2013 8:37 AM

A brilliant resource. I used them as a valuable resource when I did attend Middlesex University, London.

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JAG1 (Jagged-1 Ligand) stimulates stem cells to differentiate into bone-producing cells

JAG1 (Jagged-1 Ligand) stimulates stem cells to differentiate into bone-producing cells | Amazing Science | Scoop.it

JAG1, the gene for the Jagged-1 ligand (Jag1) in the Notch signaling pathway, is variably mutated in Alagille Syndrome (ALGS). ALGS patients have skeletal defects, and additionally JAG1 has been shown to be associated with low bone mass through genome wide association studies. Plating human osteoblast precursors (mesenchymal stem cells -- hMSC) on Jag1 is sufficient to induce osteoblast differentiation; however, exposure of mouse MSC (mMSC) to Jag1 actually inhibits osteoblastogenesis. Overexpression of the notch-2 intracellular domain (NICD) is sufficient to mimic the effect of Jag1 on hMSC osteoblastogenesis, while blocking Notch signaling with a gamma-secretase inhibitor or with dominant negative mastermind inhibits Jag1 induced hMSC osteoblastogenesis. In pursuit of interacting signaling pathways, we discovered that treatment with a PKCδ inhibitor abrogates Jag1 induced hMSC osteoblastogenesis. Jag1 results in rapid PKCδ nuclear translocation and kinase activation. Furthermore, Jag1 stimulates the physical interaction of PKCδ with NICD. Collectively, these results suggest that Jag1 induces hMSC osteoblast differentiation through canonical Notch signaling and requires concomitant PKCδ signaling. This research also demonstrates potential deficiencies in using mouse models to study ALGS bone abnormalities.

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One in 70 million chance: Texas woman has 2 sets of identical twins

One in 70 million chance: Texas woman has 2 sets of identical twins | Amazing Science | Scoop.it

A Texas woman got a quadruple Valentine's Day gift this year, giving birth to four babies -- two sets of identical twins. The twins were not the result of fertility treatments, the hospital said. Each pair of twins shared a placenta, the hospital said. Identical twins result when a fertilized egg splits into two embryos. Twins occur in about 2% of all pregnancies. Of those, 30% are identical twins. The odds of having two sets of twins at once is about 1 in 70 million, said Dr. Alan Penzias, associate professor of obstetrics, gynecology and reproductive biology at Harvard Medical School.

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24 new genes linked to nearsighted vision

24 new genes linked to nearsighted vision | Amazing Science | Scoop.it

Nearsightedness—also known as myopia—is a major cause of blindness and visual impairment worldwide, affecting 30 percent of Western populations and up to 80 percent of Asian people. At present, there is no cure.

 

During visual development in childhood and adolescence the eye grows in length, but in people with myopia the eye grows too long. Light entering the eye is then focused in front of the retina rather than on it, resulting in a blurred image.

 

The refractive error can be corrected with glasses, contact lenses, or surgery. But the eye remains longer and the retina is thinner, and could lead to retinal detachment, glaucoma, or macular degeneration, especially with higher degrees of myopia. Myopia is highly heritable, although up to now, little was known about the genetic background.

 

To find the genes responsible, researchers from Europe, Asia, Australia, and the United States analyzed genetic and refractive error data of over 45,000 people from 32 different studies, and found 24 new genes for this trait, and confirmed two previously reported genes.

 

Interestingly, the genes did not show significant differences between the European and Asian groups, despite the higher prevalence among Asian people. The new genes include those which function in brain and eye tissue signaling, the structure of the eye, and eye development. The genes lead to a high risk of myopia and carriers of the high-risk genes had a tenfold increased risk.

 

It was already known that environmental factors, such as reading, lack of outdoor exposure, and a higher level of education can increase the risk of myopia. The condition is more common in people living in urban areas.

An unfavorable combination of genetic predisposition and environmental factors appears to be particularly risky for development of myopia. How these environmental factors affect the newly identified genes and cause myopia remains intriguing, and will be further investigated.

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TXChildrenInNature's curator insight, July 21, 2013 2:34 PM

Children who spend too much time indoors, with fixed lighting, and too much screen time can actually be damaging thier eyes.  

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UCI team target p53 for treating wide spectrum of cancers

UCI team target p53 for treating wide spectrum of cancers | Amazing Science | Scoop.it

UC Irvine biologists, chemists and computer scientists have identified an elusive pocket on the surface of the p53 protein that can be targeted by cancer-fighting drugs. The finding heralds a new treatment approach, as mutant forms of this protein are implicated in nearly 40 percent of diagnosed cases of cancer, which kills more than half a million Americans each year.

 

In an open-source study published online this week in Nature Communications, the UC Irvine researchers describe how they employed a computational method to capture the various shapes of the p53 protein. In its regular form, p53 helps repair damaged DNA in cells or triggers cell death if the damage is too great; it has been called the “guardian of the genome.”

Mutant p53, however, does not function properly, allowing the cancer cells it normally would target to slip through control mechanisms and proliferate. For this reason, the protein is a key target of research on cancer therapeutics.

Within cells, p53 proteins undulate constantly, much like a seaweed bed in the ocean, making binding sites for potential drug compounds difficult to locate. But through a computational method called molecular dynamics, the UC Irvine team created a computer simulation of these physical movements and identified an elusive binding pocket that’s open only 5 percent of the time.

 

After using a computer to screen a library of 2,298 small molecules, the researchers selected the 45 most promising to undergo biological assays. Among these 45 compounds, they found one, called stictic acid, that fits into the protein pocket and triggers tumor-suppressing abilities in mutant p53s.

While stictic acid cannot be developed into a viable drug, noted study co-leader Peter Kaiser, professor of biological chemistry, the work suggests that a comprehensive screening of small molecules with similar traits may uncover a usable compound that binds to this specific p53 pocket.

 

“The discovery and pharmaceutical development of such a compound could have a profound impact on cancer treatments,” Kaiser said. “Instead of focusing on a specific form of the disease, oncologists could treat a wide spectrum of cancers, including those of the lung and breast.” He added that there is currently one group of experimental drugs – called Nutlins – that stop p53 degradation, but they don’t target protein mutations as would a drug binding to the newly discovered pocket.

 

The results are the culmination of years of labor by researchers with UC Irvine’s Institute for Genomics & Bioinformatics and the Chao Family Comprehensive Cancer Center.

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Engineered immune cells strongly resist HIV infection

Engineered immune cells strongly resist HIV infection | Amazing Science | Scoop.it

One of the big challenges in treating AIDS is that the virus is notorious for mutating, so patients must be treated with a cocktail of drugs — known as highly active antiretroviral therapy or HAART — which hit it at various stages of the replication process. The researchers were able to get around that problem with a new, multi-pronged genetic attack that blocks HIV on several fronts. Essentially, they hope to mimic HAART through genetic manipulation.

The technique hinges on the fact that the virus typically enters T cells by latching onto one of two surface proteins known as CCR5 and CXCR4.

 

Some of the latest drugs now used in treatment work by interfering with these receptors’ activity. A small number of people carry a mutation in CCR5 that makes them naturally resistant to HIV. One AIDS patient with leukemia, now famously known as the Berlin patient, was cured of HIV when he received a bone marrow transplant from a donor who had the resistant CCR5 gene.

 

Scientists at Sangamo BioSciences in Richmond, Calif., have developed a technique using a protein that recognizes and binds to the CCR5 receptor gene, genetically modifying it to mimic the naturally resistant version. The technique uses a zinc finger nuclease, a protein that can break up pieces of DNA, to effectively inactivate the receptor gene. The company is now testing its CCR5-resistant genes in phase-1 and -2 trials with AIDS patients at the University of Pennsylvania.

 

The Stanford scientists used a similar approach but with an added twist. They used the same nuclease to zero in on an undamaged section of the CCR5 receptor’s DNA. They created a break in the sequence and, in a feat of genetic editing, pasted in three genes known to confer resistance to HIV, Porteus said. This technique of placing several useful genes at a particular site is known as “stacking.”

 

Incorporating the three resistant genes helped shield the cells from HIV entry via both the CCR5 and CXCR4 receptors. The disabling of the CCR5 gene by the nuclease, as well as the addition of the anti-HIV genes, created multiple layers of protection.

 

Blocking HIV infection through both the CCR5 and CXCR4 receptors is important, Porteus said, as it hasn’t been achieved before by genome editing. To test the T cells’ protective abilities, the scientists created versions in which they inserted one, two and all three of the genes and then exposed the T cells to HIV.

 

Though the T cells with the single- and double-gene modifications were somewhat protected against an onslaught of HIV, the triplets were by far the most resistant to infection. These triplet cells had more than 1,200-fold protection against HIV carrying the CCR5 receptor and more than 1,700-fold protection against those with the CXCR4 receptor, the researchers reported. The T cells that hadn’t been altered succumbed to infection with 25 days.

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