Atlas details gene activity of prenatal brain

   (NIH) - 4/12/2014 - A comprehensive three-dimensional atlas of the developing human brain that incorporates gene activity along with anatomical reference atlases and neuroimaging data has released its first major report online in Nature. This National Institutes of Health (NIH)-funded resource, available to the public, enables researchers to answer questions related to the early roots of brain-based disorders such as autism and schizophrenia.
   This big science endeavor, which highlights the transcriptome — when and where genes are turned on in the brain — and anatomy of the human brain during mid-term pregnancy, was undertaken at the Allen Institute for Brain Science in Seattle. It is the first installment of a consortium project funded by the National Institute of Mental Health (NIMH), part of the NIH, called the BrainSpan Atlas of the Developing Human Brain, which aims to profile gene activity throughout the course of brain development.
   “Many neuropsychiatric diseases are likely the result of abnormal brain development during prenatal life,” said lead author Ed Lein, Ph.D., of the Allen Institute. “An anatomically precise molecular atlas of the brain during this time period is a first step to understanding how the human brain develops normally and what can go wrong.”
   Although animal studies have provided invaluable insights in the basic mechanisms of brain function, there are limitations that make studies based on human tissues, which are very difficult to obtain, incredibly important. One key area is the neocortex, the outermost brain region involved in higher functions such as action and thought. The neocortex is smooth in rodents; in humans and non-human primates, it is much more complexly organized, elaborately folded into grooves and wrinkles called sulci and gyri.
   Further differences in developmental compartments of this area exist between humans and non-human primates. The aim of this highly detailed atlas was to analyze all genes at this level of granularity, allowing meaningful analysis of the molecular underpinnings of human cortical development. Many psychiatric disorders show altered gene activity in the cortex, possibly highlighting changes that occurred during development of this region.
   Lein and other researchers studied four donated, intact, high-quality human prenatal brains from preterm stillbirths — two from 15–16 weeks and two from 21 weeks post-conception – as a framework for their atlas. Contributing labs provided data from a variety of genomic and imaging techniques.
   The BrainSpan Atlas aims to inspire new hypotheses regarding human brain development, and has already led to some surprising findings. For example, the study authors found significant differences between mouse and human brains in the subplate zone, a developmentally transient structure critical for proper cortical development. On the other hand, the researchers expected to find a unique molecular signature for the outer portion of the subventricular zone, an area which is not found in mice and which contains a hugely expanded pool of neuronal stem cells that give rise to our greatly expanded neocortex. Surprisingly, despite its much larger size, no significant differences were found between this zone and the inner portion of this layer that is conserved from mouse to human.
   “The BrainSpan Atlas becomes very powerful when one can understand where and when a particular gene is used — for instance, is it active in precursor cells or in the neurons derived from them?” Lein said, who gave the example that autism candidate genes are expressed very early in in the cortex. Knowledge of the time and location of these genes may lead to future treatment targets and early interventions for this brain disorder, he added.
   The BrainSpan Atlas already is making inroads in research surrounding human brain development and disease.
   “Although the many genes associated with autism and schizophrenia don’t show a clear relationship to each other in the adult brain, the BrainSpan Atlas reveals how these diverse genes are connected in the developing brain,” said NIMH Director Thomas R. Insel, M.D. “Findings of what goes on early in the prenatal brain can lead to the development of biomarkers for diagnosing brain disorders and for matching patients to treatment options most likely to be successful.
   “This atlas is a clear example of the progress that can be made when the public and private sectors work together,” Insel said. “On this first anniversary of the BRAIN Initiative, we are encouraged to see the impact the BrainSpan Atlas is already making on brain research.”
   The resource is freely available for viewing, searching, and data mining for gene activity patterns as part of the BrainSpan Atlas of the Developing Human Brain Developing Human Brain , and can also be found via the Allen Brain Atlas data portal Allen Brain Atlas data portal .
   Source: National Institutes of Health

Drug Sentencing Guidelines May Be Reduced

   WASHINGTON – 4/12/2014 - The U.S. Sentencing Commission voted on April 11 to reduce sentencing guidelines for certain people convicted of nonviolent drug offenses. The amendment would reduce the average sentence for drug traffickers by 11 months, by lowering the drug sentencing guidelines two levels. Attorney General Eric Holder endorsed the change during testimony before the commission last month.
   "Our country is slowly but steadily reversing the damage done by the failed, racially biased war on drugs," ACLU Senior Legislative Counse Jesselyn McCurdy said. "The actions taken by the Sentencing Commission . . . are another positive move toward reducing unnecessarily long sentences that have led to bloated, overcrowded prisons. Our criminal justice system is smarter, fairer, and more humane than it was a year ago, and we need to make sure momentum continues in the right direction."
   The amendment, along with several others that were passed, will go to Congress for its approval on May 1. Congress has six months to introduce and pass legislation to stop the proposed changes before they become law on November 1.
   Source: American Civil Liberties Union

Study: Obesity Primes the Colon for Cancer

   (NIH) - 4/5/2014 - Obesity, rather than diet, causes changes in the colon that may lead to colorectal cancer, according to a study in mice by the National Institutes of Health. The finding bolsters the recommendation that calorie control and frequent exercise are not only key to a healthy lifestyle, but a strategy to lower the risk for colon cancer, the second leading cause of cancer-related death in the United States.
   Paul Wade, Ph.D., and Thomas Eling, Ph.D., scientists at the National Institute of Environmental Health Sciences (NIEHS), part of NIH, led a collaborative team that made the discovery. The study appeared online April 1 in the journal Cell Metabolism.
   A large body of scientific literature says people who are obese are predisposed to a number of cancers, particularly colorectal cancer, Eling said. To better understand the processes behind this link, he and his colleagues fed two groups of mice a diet in which 60 percent of the calories came from lard. The first group of mice contained a human version of a gene called NAG-1, which has been shown to protect against colon cancer in other rodent studies. The second group lacked the NAG-1 gene.
   The NAG-1 mice did not gain weight after eating the high-fat diet, while mice that lacked the NAG-1 gene grew plump.
  The researchers noticed another striking difference between the two groups of animals.
   “The obese mice exhibited molecular signals in their gut that led to the progression of cancer, but the NAG-1 mice didn’t have those same indicators,” Eling said.
   The researchers looked for molecular clues, by isolating cells from the colons of the mice and analyzing a group of proteins called histones. Histones package and organize DNA in a cell’s nucleus, and sometimes undergo a process known as acetylation, in which chemical tags bind to their surface. The pattern of acetylation varies depending on the chemical processes taking place in the cell.
   Wade explained that the acetylation patterns for the obese mice and the thin NAG-1 mice were drastically different. Patterns from the obese mice resembled those from mice with colorectal cancer. The additional weight they carried also seemed to activate more genes that are associated with colorectal cancer progression, suggesting the obese mice are predisposed to colon cancer.
   “Any preexisting colon lesions in these animals are more likely to evolve rapidly into malignant tumors,” Wade said. “The same thing may happen in humans.”
   Wade and Eling want to find out exactly how obesity prompts the body to develop colorectal cancer. Wade said that the likely candidates for triggering tumor growth in the colon are fat cells, but there are many more possibilities. Finding these cellular switches may give rise to production of medications to keep people from getting colorectal cancer.
   “Once we identify the signaling pathways and understand how the signal is transduced, we may be able to design ways to treat colorectal cancer in obese patients,” Wade said.
  Source: National Institutes of Health