Masses of immune cells that form as a hallmark of tuberculosis (TB) have long been thought to be the body’s way of trying to protect itself by literally walling off the bacteria.  But a new study in the January 9th issue of the journal Cell, a Cell Press publication, offers evidence that the TB bacteria actually sends signals that encourage the growth of those organized granuloma structures, and for good reason: each granuloma serves as a kind of hub for the infectious bugs in the early stages of infection, allowing them to expand further and spread throughout the body.

” This fundamentally turns our understanding of granulomas all topsy turvy,” said Lalita Ramakrishnan of the University of Washington, Seattle.  “Scientists thought they were protective, but they are not—at least not in early infection.  The bacteria use them to reproduce and disseminate themselves.”

Not only do the bacteria expand themselves within the first granuloma to form, she added, but some of the immune cells in that initial mass leave to start new granulomas elsewhere.  Those new granulomas then also serve as breeding grounds for the bacteria.

The finding suggests a new avenue for TB therapy at an important time in the struggle against TB infection.  “We might think about ways to prevent granulomas that might be therapeutic,” Ramakrishnan said.  That might be done either by intercepting the bacterial signal that spurs granulomas’ formation or by manipulating the human immune system in some other way.

” Finding a new way to intervene in the infection is particularly relevant now because there is a horrible epidemic of drug-resistant TB,” she added.  “Many of the bugs are resistant to practically everything.”

At the outset of human pulmonary tuberculosis, the inhaled bacteria (Mycobacterium tuberculosis) is gobbled up by immune cells known as macrophages and transported into the lung.  There, infected macrophages recruit additional macrophages and other immune cells to form granulomas.  Under the classical view, those granulomas help protect against the bacteria, even if they don’t successfully contain the infection.  They were also thought to form only after the adaptive immune system shifts into gear.

But Ramakrishnan’s team began to find evidence calling that classical view into question by studying the disease in zebrafish embryos.  Because zebrafish embryos are transparent, they allowed the team to literally watch the infection take hold and spread in real time.

Their initial studies showed that, contrary to the classical view, granulomas form well before adaptive immunity comes into play, within days of infection.  Indeed, granulomas’ formation coincides with the bacteria’s expansion.  In addition, in embryonic fish infected with a less-virulent, mutant strain of bacteria, which lacked a secretion system known as ESX-1/RD1, granulomas didn’t form nearly as well.  Together, those findings suggested to Ramakrishnan’s team that granuloma formation actually works not as a protective maneuver on the part of the infected host, but rather as a bacterial tool for expanding infection.

To further investigate in the new study, the researchers observed and quantified the events in zebrafish embryos infected with normal TB bacteria and the mutant bacteria lacking the ESX-1/RD1 system.  They found that, once transported inside of cells by macrophages, the bacteria use the RD1 signal to call on new macrophages to come and move in to the growing granuloma.  As multiple macrophages arrive, they efficiently find and consume infected and dying macrophages to become infected themselves.  That process leads to a rapid, iterative expansion of infected macrophages and thereby bacterial numbers, they report.  The primary granuloma also seeds secondary granulomas as infected macrophages leave for other parts of the body.

” In summary,” the researchers wrote, “we propose that the pathway of granuloma formation and subsequent bacterial dissemination is based upon macrophage responses that are of themselves generally protective and that work reasonably well against less virulent (i.e., RD1-deficient) infection.  Rather than block these host responses, RD1-competent mycobacteria appear to accelerate them to turn the granuloma response into an effective tool for pathogenesis.  The initiation of the adaptive immune response then may halt bacterial expansion not by forming granulomas as suggested by the classical model but by altering the early granuloma into a form of stalemate between host and pathogen.”

The first people to arrive in America traveled as at least two separate groups to arrive in their new home at about the same time, according to new genetic evidence published online on January 8th in Current Biology, a Cell Press publication.

After the Last Glacial Maximum some 15,000 to 17,000 years ago, one group entered North America from Beringia following the ice-free Pacific coastline, while another traversed an open land corridor between two ice sheets to arrive directly into the region east of the Rocky Mountains.  (Beringia is the landmass that connected northeast Siberia to Alaska during the last ice age.)  Those first Americans later gave rise to almost all modern Native American groups of North, Central, and South America, with the important exceptions of the Na-Dene and the Eskimos-Aleuts of northern North America, the researchers said.

” Recent data based on archeological evidence and environmental records suggest that humans entered the Americas from Beringia as early as 15,000 years ago, and the dispersal occurred along the deglaciated Pacific coastline,” said Antonio Torroni of Università di Pavia, Italy.  “Our study now reveals a novel alternative scenario: Two almost concomitant paths of migration, both from Beringia about 15,000 to 17,000 years ago, led to the dispersal of Paleo-Indians—the first Americans.”

Such a dual origin for Paleo-Indians has major implications for all disciplines involved in Native American studies, he said.  For instance, it implies that there is no compelling reason to presume that a single language family was carried along with the first migrants.

When Columbus reached the Americas in 1492, Native American occupation stretched from the Bering Strait to Tierra del Fuego, Torroni explained.  Those native populations encompassed extraordinary linguistic and cultural diversity, which has fueled extensive debate among experts over their interrelationships and origins.

Recently, molecular genetics, together with archaeology and linguistics, has begun to provide some insights.  In the new study, Ugo Perego and Alessandro Achilli of Torroni’s team analyzed mitochondrial DNA from two rare haplogroups, meaning mitochondrial types that share a common maternal ancestor.  Mitochondria are cellular components with their own DNA that allow scientists to trace ancestry and migration because they are passed on directly from mother to child over generations.

Their results show that the haplogroup called D4h3 spread from Beringia into the Americas along the Pacific coastal route, rapidly reaching Tierra del Fuego.  The other haplogroup, X2a, spread at about the same time through the ice-free corridor between the Laurentide and Cordilleran Ice Sheets and remained restricted to North America.

” A dual origin for the first Americans is a striking novelty from the genetic point of view and makes plausible a scenario positing that within a rather short period of time, there may have been several entries into the Americas from a dynamically changing Beringian source,” the researchers concluded.

The combination of estrogen plus progestin, which women stopped taking in droves following the news that it may increase their risk of breast cancer, may decrease their risk of colorectal cancer, according to a report published in the January issue of Cancer Epidemiology, Biomarkers and Prevention, a journal of the American Association for Cancer Research.

“Compared to women who had never taken these hormones, the use of estrogen plus progestin was associated with a reduced risk of colorectal cancer,” said Jill R. Johnson, M.P.H., a doctoral student at the University of Minnesota School of Public Health.

The largest risk reduction, approximately 45 percent, was seen among women who had completed use of estrogen plus progestin five or more years previously.

Johnson and her colleagues extracted data from 56,733 postmenopausal women who participated in the Breast Cancer Detection Demonstration Project follow-up study.  Hormone therapy use and other risk factors were ascertained through telephone interviews and mailed questionnaires between 1979 and 1998.  During an average 15 years of follow-up, Johnson and colleagues identified 960 new cases of colorectal cancer in this population.

Any use of estrogen therapy was associated with a 17 percent reduced risk in colorectal cancer.  Among those who used estrogen, the largest reductions were seen among those who were current users (25 percent reduced risk) and users of ten or more years duration (26 percent reduced risk).

Researchers also found a 22 percent reduced risk among those who had ever used estrogen plus progestin in combination.  They further found a 36 percent reduction in risk among those who had used progestin sequentially or less than 15 days per month.  Past users of estrogen plus progestin, who had stopped at least five years ago, had a 45 percent risk reduction.

Although Johnson’s study was not designed to look at biological mechanisms for the protective effect of estrogen therapy, she did say that previous research has suggested that hormones may play a role in decreasing levels of insulin-like growth factors, thereby reducing risk.  “The biological mechanism will need to be explored in further studies,” said Johnson.

Childhood trauma is a potent risk factor for development of chronic fatigue syndrome (CFS), according to a study by researchers at Emory University School of Medicine and the Centers for Disease Control and Prevention (CDC).  The study is published in the Jan. 5, 2009 Archives of General Psychiatry.

Results of the study confirm that childhood trauma, particularly emotional maltreatment and sexual abuse, is associated with a six-fold increased risk for CFS.  The risk further increases with the presence of posttraumatic stress disorder symptoms.

The study also found that low levels of cortisol, a hallmark biological feature of CFS, are associated with childhood trauma.  Cortisol is frequently referred to as the “stress hormone” and is important to regulate the body’s response to stress.  A lack of cortisol’s effects may cause altered or prolonged stress responses.

“The study indicates that low cortisol levels may actually reflect a marker for the risk of developing CFS rather than being a sign of the syndrome itself,” said Christine M. Heim, PhD, lead author of the study and associate professor in the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine.

The population-based study analyzed data from 113 people with CFS, and a control group of 124 people without CFS, drawn from a sample of almost 20,000 Georgians.  The results confirm earlier findings from a 2006 study conducted in Wichita, Kan.

Study participants completed a self-reported questionnaire on five different types of childhood trauma including emotional, physical and sexual abuse, and emotional and physical neglect.  Researchers also collected saliva samples from participants to record levels of cortisol over one hour after awakening, typically an individual’s highest cortisol levels for the day.

“When looking at CFS cases with and without histories of childhood trauma, only those with childhood trauma had the classic low cortisol levels often seen in CFS cases,” explains Heim.

“It is important to emphasize that not all patients with CFS have been through childhood trauma,” she says.  “CFS may be part of a spectrum of disorders associated with childhood adversity, which includes depression and anxiety disorders.”

Certain experiences children have while the brain is developing and vulnerable can make a difference in the way the body reacts to stress later in life, and may have long-term health consequences.

“Trauma that occurs at different times in childhood may be linked to different long term changes.  It’s an area in which more work is needed,” says Heim.

A new study reveals that the metadherin gene (MTDH) plays a role in both cancer metastasis and resistance to chemotherapy.  The research, published by Cell Press in the January 6th issue of the journal Cancer Cell, identifies MTDH as a promising therapeutic target for high risk breast cancers.

“Most breast cancer patients resist currently available therapeutic regimens and succumb to recurrent tumors that spread to distant vital organs, such as lung, bone, liver and brain,” explains senior study author, Dr. Yibin Kang from the Department of Molecular Biology at Princeton University.  “Resistance to chemotherapy and metastasis remain major challenges to curative therapy.”

Previous research identified several clinically applicable genetic signatures associated with poor clinical outcomes of breast cancer.  However, the signatures differed between independent studies, making it difficult to identify overlapping, functionally relevant genes that might be useful for understanding, and eventually preventing, breast cancer metastasis and chemoresistance.

To further unravel the complex genetic events involved in breast cancer, Dr. Kang and colleagues developed a sophisticated computational algorithm designed to identify genomic changes in an extensive collection of breast tumor samples.  The researchers discovered abnormally high copy numbers of chromosomal region 8q22 in more than 30% of breast cancers examined.  Patients having this type of breast cancer often had a shorter survival time due to recurrent and metastatic cancers.

The researchers went on to find that among a handful of genes in the 8q22 region, MTDH was responsible for both increased metastasis and increased resistance to chemotherapeutics.  MTDH protein increased metastasis of breast cancers to distant organs by enhancing the binding of cancer cells to blood vessels in these organs.  In addition, MTDH protein promoted cell survival, allowing cancer cells to become more resistant to a wide variety of chemotherapeutic agents that are currently used to treat breast cancer.  Further, when the researchers genetically altered the cancer cells to reduce expression of MTDH, the tumor cells became less capable of metastasis and more likely to be eliminated by chemotherapeutic agents.

“These findings establish MTDH as an important therapeutic target for simultaneously enhancing chemotherapy efficacy and reducing metastasis risk,” concludes Dr. Kang.  “Molecular targeting of MTDH may not only prevent the seeding of breast cancer cells to the lung and other vital organs but also sensitize tumor cells to chemotherapy, thereby stopping the deadly spread of breast cancer.”

A new study reveals critical molecular mechanisms associated with the development and progression of human neuroblastoma, the most common cancer in young children.  The research, published by Cell Press in the January 6th issue of the journal Cancer Cell, may lead to development of future strategies for treatment of this aggressive and unpredictable cancer.

Neuroblastoma cells are derived from migratory neural crest cells that give rise to the peripheral sympathetic nervous system.  During normal development, neural crest cells stop dividing and differentiate.  However, neuroblastoma cells seem to have lost this capacity.  Previous work has shown that amplification of the MYCN gene, which disrupts control of cell division and differentiation, is a strong predictor of poor prognosis in neuroblastoma.

“We speculated that genes that are expressed in a MYCN-dependent manner might be required specifically for the growth of MYCN-amplified neuroblastomas and that MYCN-amplified neuroblastomas might depend not only on N-Myc itself, but also on upstream regulatory factors or downstream target genes,” explains senior study author, Dr. Martin Eilers, from the University of Wurzburg in Germany.

Dr. Eilers and colleagues performed a genetic screen of nearly 200 genes that are dependent on amplified MYCN in human neuroblastoma or are direct targets of Myc.  The researchers found that the oncogene AURKA is required for growth of MYCN-amplified neuroblastoma cells, but not cells lacking amplified MYCN.

AURKA encodes the kinase Aurora A which is dysregulated in multiple types of cancer cells.  Interestingly, Aurora A kinase activity was not required for N-Myc stabilization.  Instead, elevated Aurora A levels in MYCN-amplified neuroblastoma cells interfered with the PI3-kinase-dependent and mitosis-specific degradation of N-Myc.  This suggests that small molecule inhibitors of Aurora A kinase may not be effective at inhibiting the oncogenic functions of Aurora A.

“Our results show that stabilization of N-Myc is a critical oncogenic function of Aurora A in childhood neuroblastoma; the challenge will now be to find ways to interfere with this function in order to find new approaches for the therapy of these tumors,” says Dr. Eilers.  “The findings also suggest that the current views about why Aurora A is oncogenic may need to be re-evaluated.”

An international team led by University of Pittsburgh School of Medicine researchers has identified genetic markers associated with risk for ulcerative colitis.  The findings, which appear today as an advance online publication of the journal Nature Genetics, bring researchers closer to understanding the biological pathways involved in the disease and may lead to the development of new treatments that specifically target them.

Ulcerative colitis is a chronic, relapsing disorder that causes inflammation and ulceration in the inner lining of the rectum and large intestine.  The most common symptoms are diarrhea (oftentimes bloody) and abdominal pain.  Ulcerative colitis and Crohn’s disease, another chronic gastrointestinal inflammatory disorder, are the two major forms of inflammatory bowel disease (IBD).

“Ulcerative colitis and Crohn’s disease are chronic conditions that impact the day-to-day lives of patients,” said senior author of the study Richard H. Duerr, M.D., associate professor of medicine and human genetics at the University of Pittsburgh School of Medicine and Graduate School of Public Health.  “IBD is most often diagnosed in the teenage years or early adulthood.  While patients usually don’t die from IBD, affected individuals live with its debilitating symptoms during the most productive years of their lives.”

Because IBD tends to run in families, researchers have long thought that genetic factors play a role.  Technology developed in recent years has enabled systematic, genome-wide searches for gene markers associated with common human diseases, and the discovery of more than 30 genetic risk factors for Crohn’s disease has been one of the major success stories in this new era of research.  While some genetic factors associated with Crohn’s disease also predispose individuals to ulcerative colitis, markers specific for ulcerative colitis had yet to be found.  To do so, researchers performed a genome-wide association study of hundreds of thousands of genetic markers using DNA samples from 1,052 individuals with ulcerative colitis and pre-exisiting data from 2,571 controls, all of European ancestry and residing in North America.  Several genetic markers on chromosomes 1p36 and 12q15 showed highly significant associations with ulcerative colitis, and the association evidence was replicated in independent European ancestry samples from North America and southern Italy.  Nearby genes implicated as possibly playing a role in ulcerative colitis include the ring finger protein 186 (RNF186), OTU domain containing 3 (OTUD3), and phospholipase A2, group IIE (PLA2G2E) – genes on chromosome 1p36, and the interferon, gamma (IFNG), interleukin 26 (IL26), and interleukin 22 (IL22) genes on chromosome 12q15.  RNF186 and OTUD3 are members of gene families involved in protein turnover and diverse cellular processes.  PLA2G2E, IFNG, IL26 and IL22 are known to play a role in inflammation and the immune response.  The study also found highly suggestive associations between ulcerative colitis and genetic markers on chromosome 7q31 within or near the laminin, beta 1 (LAMB1) gene, which is a member of a gene family known to play a role in intestinal health and disease, and confirmed previously identified associations between ulcerative colitis and genetic variants in the interleukin 23 receptor (IL23R) gene on chromosome 1p31 and the major histocompatibility complex on chromosome 6p21.

“My laboratory is focused on studying the genetic basis for IBD,” said Dr. Duerr.  “Through genetic mapping, we and our collaborators are successfully identifying regions of the genome that contain IBD genes.  The next steps are to understand the functional significance of IBD-associated genetic variants, and then to develop new treatments that specifically target biological pathways implicated by the genetic discoveries.  The overall goal of this work is to improve the lives of the millions of patients worldwide that suffer from IBD.”

Researchers at the Salk Institute for Biological Studies have developed a versatile mouse model of glioblastoma—the most common and deadly brain cancer in humans—that closely resembles the development and progression of human brain tumors that arise naturally.

“Mouse models of human cancer have taught us a great deal about the basic principles of cancer biology,” says Inder Verma, Ph.D., a professor in the Laboratory of Genetics.  “By definition, however, they are just that: approximations that simulate a disease but never fully capture the molecular complexity underlying disease in humans.”

Trying to mimic randomly occurring mutations that lie at the heart of all tumors, the Salk researchers used modified viruses to shuttle cancer-causing oncogenes into a handful of cells in adult mice.  Their strategy, described in the Jan. 4, 2009 online issue of the journal Nature Medicine, could not only prove a very useful method to faithfully reproduce different types of tumors but also to elucidate the nature of elusive cancer stem cells.

The most frequently used mouse cancer model relies on xenografts: Human tumor tissue or cancer cell lines are transplanted in immuno-compromised mice, which quickly develop tumors.  “These tumors are very reproducible, but this approach ignores the fact that the immune system can make or break cancer,” says first author Tomotoshi Marumoto, Ph.D., a former postdoctoral researcher in the Verma lab and now an assistant professor at the Kobe Medical Center Hospital in Kobe, Japan.  Other animal models either express oncogenes in a tissue-specific manner or shut down the expression of tumor suppressor genes in the whole tissue.  “But we know that tumors generally develop from a single cell or a small number of cells of a specific cell type, which is one of the major determinants of the characteristics of tumor cells,” explains postdoctoral researcher and co-author Dinorah Friedmann-Morvinski.

To sidestep the shortcomings of currently used cancer models, the Salk team harnessed the power of lentiviral vectors to infect nondividing as well as dividing cells and ferry activated oncogenes into a small number of cells in adult, fully immunocompetent mice.  After initial experiments confirmed that the approach was working, Marumoto injected lentiviruses carrying two well-known oncogenes, H-Ras and Akt, into three separate brain regions of mice lacking one copy of the gene encoding the tumor suppressor p53: the hippocampus, which is involved in learning and memory; the subventricular zone, which lines the brain’s fluid-filled cavity; and the cortex, which governs abstract reasoning and symbolic thought in humans.

He specifically targeted astrocytes, star-shaped brain cells that are part of the brain’s support system.  They hold neurons in place, nourish them, digest cellular debris, and are suspected to be the origin of glioblastoma.  Within a few months, massive tumors that displayed all the histological characteristics of glioblastoma multiforme preferentially developed in the hippocampus and the subventricular zone.

The ability of adult stem cells to divide and generate both new stem cells (called self-renewal) as well as specialized cell types (called differentiation) is the key to maintaining healthy tissues.  The cancer-stem-cell hypothesis posits that cancers grow from stem cells in the same way healthy tissues do.  Known as tumor-initiating cells with stem like properties these cells have many characteristics in common with normal stem cells in that they are self-replicating and capable of giving rise to populations of differentiated cells.

To test whether the induced glioblastomas contained bona fide cancer stem cells, Marumoto isolated cultured individual tumor cells in the lab.  These cells behaved and looked just like neural stem cells.  They formed tiny spheres—often called tumor spheres—and expressed proteins typically found in immature neural progenitor cells.  When given the right chemical cues, these brain cancer stem cells matured into neurons and astrocytes.

“They displayed all the characteristics of cancer stem cells, and less than 100 and as few as 10 cells were enough to initiate a tumor when injected into immunodeficient mice,” says Friedmann-Morvinski.  Most xenograft models for brain tumors using tumor cell lines require at least 10,000 cells.

“These findings show that our cancer model will not only allow us to start understanding the biology of glioblastoma but will also allow us to answer many questions surrounding cancer stem cells,” says Verma.  Although the work described to date pertains to glioblastoma, Verma and his team are currently using this methodology to investigate lung, pancreatic, and pituitary cancers.

MIT engineers have developed a new, highly efficient way to pair up cells so they can be fused together into a hybrid cell.

The new technique should make it much easier for scientists to study what happens when two cells are combined.  For example, fusing an adult cell and an embryonic stem cell allows researchers to study the genetic reprogramming that occurs in such hybrids.

The researchers, led by a collaboration between Joel Voldman, associate professor of electrical engineering and computer science, and Rudolf Jaenisch, professor of biology and a member of the Whitehead Institute, report the new technique in the Jan. 4 online edition of Nature Methods.

The work was spearheaded by two postdoctoral associates, Alison Skelley, who worked in Voldman’s lab, and Oktay Kirak, who works with Jaenisch.  Skelley and Kirak are lead authors of the Nature Methods paper.  Heikyung Suh, a technical associate in the Whitehead Institute, is also an author of the paper.

The team’s simple but ingenious sorting method increases the rate of successful cell fusion from around 10 percent to about 50 percent, and allows thousands of cell pairings at once.

Though cell fusion techniques have been around for a long time, there are many technical limitations, said Voldman.

Getting the right cells to pair up before fusing them is one major obstacle.  If scientists are working with a mixture of two cell types, for example A and B, they end up with many AA and BB pairings, as well as the desired AB match.

Researchers had previously trapped cells in tiny cups as they flow across a chip.  Each cup can hold only two cells, but there is no way to control whether the cups capture an A and a B, two As or two Bs.

In contrast, the cell-trapping cups on Voldman and Jaenisch’s new sorting device are arranged strategically to capture and pair up cells of different types.

First, type A cells are flowed across the chip in one direction and caught in traps that are large enough to hold only one cell.  Once the cells are trapped, liquid is flowed across the chip in the opposite direction, pushing the cells out of the small cups and into larger cups across from the small ones.

Once one A cell is in each large cup, type B cells are flowed into the large cups.  Each cup can only hold two cells, so each ends up with one A and one B. After the cells are paired in the traps, they can be joined together by an electric pulse that fuses the cell membranes.

In addition to helping with studies of stem cell reprogramming, this technique could be used to study interactions between any types of cells.  “It’s a very general type of device,” said Voldman.

Aquaculture production of seafood will probably remain the most rapidly increasing food production system worldwide through 2025, according to an assessment published in the January 2009 issue of BioScience.  The assessment, by James S. Diana of the University of Michigan at Ann Arbor, notes that despite well-publicized concerns about some harmful effects of aquaculture, the technique may, when practiced well, be no more damaging to biodiversity than other food production systems.  Moreover, it may be the only way to supply growing demand for seafood as the human population increases.

Diana notes that total production from capture fisheries has remained approximately constant for the past 20 years and may decline.  Aquaculture, in contrast, has increased by 8.8 percent per year since 1985 and now accounts for about one-third of all aquatic harvest by weight.  Finfish, mollusks, and crustaceans dominate aquaculture production; seafood exports generate more money for developing countries than meat, coffee, tea, bananas, and rice combined.

Among the most potentially harmful effects of aquaculture, according to Diana, are the escape of farmed species that then become invasive, pollution of local waters by effluent, especially from freshwater systems, and land-use change associated with shrimp aquaculture in particular.  Increased demand for fish products for use in feed and transmission of disease from captive to wild stocks are also hazards.

Nonetheless, when carefully implemented, aquaculture can reduce pressure on overexploited wild stocks, enhance depleted stocks, and boost natural production of fishes as well as species diversity, according to Diana.  Some harmful effects have diminished as management techniques have improved, and aquaculture has the potential to provide much-needed employment in developing countries.  Diana points to the need for thorough life-cycle analyses to compare aquaculture with other food production systems.  Such analyses are, however, only now being undertaken, and more comprehensive information is needed to guide the growth of this technique in sustainable ways.

RE1-silencing transcription factor (REST) inhibits expression of neuronal genes in non-neural cells.  Huntingtin sequesters REST in the cytoplasm of neurons, precluding transcriptional repression and allowing neuronal specification.  Mutations in huntingtin disrupt its interactions with REST, enabling repression of neuronal genes and contributing to Huntington’s disease (HD).  Among the genes inhibited by REST are several miRNAs — small, noncoding RNAs that inhibit translation by binding to complementary sequences in regulatory regions of mRNA.  Packer et al.  Found that the levels of several miRNAs decreased as HD progressed.  Of these, miR-9 and miR-9* had upstream regulatory regions that enabled repression by REST.  Interestingly, regulatory regions of REST and its cofactor CoREST have complementary sequences targeted by miR-9 and miR-9*, and miR-9 reduced expression of REST, while miR-9* targeted CoREST.  These molecules apparently form a double negative feedback loop, which is likely important for precise regulation of cell fate commitment.

Each year, thousands of publications present functional magnetic resonance imaging (fMRI) data that suggest that a particular brain region is active during a particular cognitive task.  Casual readers of such papers might forget that this technique does not actually measure neural activity, but rather blood oxygenation level-dependent (BOLD) contrasts.  Synaptic transmission requires large energy expenditures, and increased energy metabolism has been hypothesized to act directly on blood vessels to increase blood flow and alter BOLD signals.  This week, however, Devor et al.  Report that this hypothesis is not always correct.  As expected, stimulating the forepaw of rats increased blood oxygenation, vessel diameter, glucose uptake, spiking, and synaptic release in the contralateral primary somatosensory cortex.  In the ipsilateral cortex, however, neural activity and glucose uptake increased, but blood oxygenation and blood flow did not.  These results indicate that blood flow is not directly tied to metabolism, and BOLD signals do not always reflect neural activity.

Amyloid-B  (AB)  Is generally considered a toxic agent in Alzheimer’s disease, but it is also released during synaptic transmission in healthy brains.  Whether AB  Has a positive function — or is simply an unwanted byproduct created when amyloid precursor protein is cleaved to produce more essential fragments — remains a matter of debate.  Evidence from transgenic mice suggests the former: knock-out of enzymes required for AB  Production impairs memory and long-term potentiation (LTP).  More evidence for a positive role of AB  Is presented by Puzzo et al.  They found that picomolar (near physiological) amounts of monomeric and oligomeric AB42 enhanced LTP in mouse hippocampal slices and strengthened reference and contextual fear memory in vivo.  In contrast, nanomolar concentrations reduced LTP.  The enhancement of LTP appeared to occur presynaptically, likely by increasing calcium accumulation, and it required activation of a7 nicotinic acetylcholine receptors.  Whether monomeric AB, oligomeric AB, or both was responsible for the enhancement is unknown.

An action potential’s threshold and shape are governed by the distribution and subunit composition of voltage-gated sodium and potassium channels in the axon.  To learn how differences in subunit expression might contribute to the exact site of action potential initiation, Lorincz and Nusser examined the distribution of four potassium and sodium channel subunits (Nav1.1, Nav1.6, Kv1.1, and Kv1.2) in the axon initial segment (AIS) of neurons in several regions of adult rat brain.  The expression pattern was surprisingly heterogeneous across cell types and brain regions.  For example, only inhibitory interneurons expressed Nav1.1, and in some neurons, it was expressed along the entire AIS, whereas in others it was restricted to the proximal AIS.  Likewise, expression of other subunits was uniform or graded depending on cell type.  In Purkinje cells — in which action potential generation occurs in the first node of Ranvier rather than the AIS — neither potassium channel subunit was expressed in the AIS.

Women who took beta carotene or vitamin C or E or a combination of the supplements had a similar risk of cancer as women who did not take the supplements, according to data from a randomized controlled trial in the December 30 online issue of the Journal of the National Cancer Institute.

Epidemiological studies have suggested that people whose diets are high in fruits and vegetables, and thus antioxidants, may have a lower risk of cancer.  Results from randomized trials that address the issue, however, have been inconsistent and have rarely supported that observation.

In the current study, Jennifer Lin, Ph.D., of the Brigham and Women’s Hospital and Harvard Medical School in Boston, and colleagues tested the impact of antioxidant supplements on cancer incidence in a randomized controlled trial.  A total of 7,627 women who were at high risk of cardiovascular disease were randomly assigned to take vitamin C, vitamin E, or beta-carotene.

With an average of 9.4 years of follow-up time, there was no statistically significant benefit from antioxidant use compared with placebo in terms of disease risk or mortality due to cancer.  Overall, 624 women developed cancer and 176 died from cancer during the follow-up time.  Compared with placebo, the relative risk of a new cancer diagnosis was 1.11 for women who took vitamin C, 0.93 for women who took vitamin E, and 1.00 for women who took beta carotene.  None of these relative risks was statistically significantly different from 1.

“Supplementation with vitamin C, vitamin E, or beta carotene offers no overall benefits in the primary prevention of total cancer incidence or cancer mortality,” the authors conclude.  “In our trial, neither duration of treatment nor combination of the three antioxidant supplements had effects on overall fatal or nonfatal cancer events.  Thus, our results are in agreement with a recent review of randomized trials indicating that total mortality was not affected by duration of supplementation and single or combined antioxidant regimens.”

In an accompanying editorial, Demetrius Albanes, M.D., of the National Cancer Institute, reviewed data from previous randomized controlled trials that examined supplement use and cancer incidence.  He noted that while the trial data reported by Lin are negative with respect to lowering cancer risk, there is valuable information uncovered that should not be overlooked.  There was a trend for a reduction in colon cancer with vitamin E supplementation, which has been observed in other studies.  Additionally, beta carotene use was associated with a modest excess of lung cancer, which is consistent with previous reports.

“Null trials or those with unexpected outcomes should not, however, be viewed as failures; they have and will con¬tinue to shed light on the causes of cancer and help us discover the means for its prevention,” the editorialist concludes.