Scientists at Washington University School of Medicine in St. Louis have linked a mutation in a gene known as TDP-43 to an inherited form of amyotrophic lateral sclerosis (ALS), the neurodegenerative condition often called Lou Gehrig’s disease.

Researchers found the connection intriguing because studies by other groups have revealed abnormalities in the TDP-43 protein in both sporadic and inherited ALS, as well as in several other neurodegenerative disorders.

“The potential link to sporadic ALS is particularly interesting. If we can confirm TDP-43′s association with inherited ALS, mutating this gene may give us a way to model sporadic ALS in laboratory animals for the first time,” says senior author Nigel Cairns, Ph.D., research associate professor of neurology and pathology and immunology. “That could give us a potent tool for better understanding ALS and developing new treatments.”

The study appears February 20 in Annals of Neurology. It was conducted at the Hope Center for Neurological Disorders, a partnership between the University and Hope Happens, a St. Louis-based non-profit organization dedicated to raising funds for neurological research.

Approximately 30,000 U.S. citizens have ALS, a condition that kills motor neurons, the nerve cells that control muscles. This causes gradually increasing paralysis and typically leads to death over a course of several years. Approximately five to 10 percent of all ALS cases are inherited; the rest are sporadic.

Hope Happens was founded by Christopher Hobler, a St. Louisan who developed ALS and died from the disorder in 2005. Hobler’s grandfather and cousin had previously died from the disorder, and Hobler and his family founded Hope Happens to promote awareness of ALS and other neurodegenerative conditions and to raise money for research to develop new treatments and cures.

In 1993, scientists linked an inherited form of ALS to mutations in the gene for a protein called superoxide dismutase-1 (SOD1). Since then, many had thought altering the SOD1 gene’s function was the most promising way to model and understand sporadic ALS.

“That has all been turned upside down in the last two years, though,” says Cairns. “In that time, abnormal TDP-43 deposits have been identified in sporadic ALS cases and in some inherited forms of ALS that don’t involve a SOD1 mutation.”

TDP-43 is an influential regulator of messenger RNA splicing, the process that edits protein-building instructions from DNA to allow the proteins to be built properly. TDP-43 abnormalities in ALS patients have included altered folding and a chemical change known as phosphorylation, both of which can radically alter the protein’s function.

As a result, several research groups have been looking for a case where a mutation in the TDP-43 gene was linked to inherited disease. The new study is the first to tentatively establish such a link. Michael Gitcho, Ph.D., a postdoctoral research associate in Dr. Cairns’ lab, and colleagues found that every member of a family affected by an inherited form of ALS had a particular mutation in TDP-43. Next, they looked at 1,505 people not related to the family and unaffected by ALS. This second search found no examples of the same mutation.

Because the family they studied is small, scientists need further evidence to confirm that the mutation is causing ALS. Researchers are working to introduce the mutated human TDP-43 gene they identified in the family into a transgenic mouse model. They hope the mouse will generate a model for ALS-like pathology.

If this affirms the link, they will begin tracing the effects of the mutation on genes whose splicing is regulated by TDP-43, working to identify key links in the chain reaction that leads to motor neuron death. These links may become new targets for pharmaceutical treatments.

What they learn may also shed light on other neurodegenerative disorders. Co-author Alison M. Goate, D. Phil., the Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry, notes that abnormal TDP-43 has been found in patients with frontotemporal dementia, the second most common cause of early-onset dementia after Alzheimer’s disease.

“As our understanding of these diseases progresses, we’re starting to see common elements,” says Goate. “This protein may allow us to link together a number of important disease entities and pinpoint new targets for therapeutic intervention.”

Gitcho MA, Baloh RH, Chakraverty S, Mayo K, Norton JB, Levitch D, Hatanpaa KJ, White CL, Bigio EH, Caselli R, Baker M, Al-Lozi MT, Morris JC, Pestronk A, Rademakers R, Goate AM, Cairns NJ. TDP-43 A315T mutation in familial motor neuron disease. Annals of Neurology, online edition.

Funding from the National Institutes of Health for the Alzheimer’s Disease Research Center, Washington University School of Medicine, the Arizona Alzheimer’s Disease Research Consortium, the Hope Center for Neurological Disorders, the Buchanan Fund and the Barnes-Jewish Hospital Foundation supported this research.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s Hospitals. The School of Medicine is one of the leading medical research, teaching, and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s Hospitals, the School of Medicine is linked to BJC HealthCare.

Washington University in St. Louis
One Brookings Dr., Campus Box 1070
St. Louis, MO 63130
United States
wustl.edu Read the rest of this entry »

The striking tissue-specific expression patterns of microRNAs (miRNAs) suggest that they play a role in tissue development. These small RNA molecules
(~22 bases in length) are processed from long primary transcripts (pri-miRNA) and regulate gene expression at the posttranscriptional level.

There are
hundreds of different miRNAs, many of which are strongly conserved. Vertebrate embryonic development is most easily studied in zebrafish, but
genetically disrupting miRNA genes to see which miRNA does what is technically challenging. In this study, the researchers interfere with miRNA
function during the first few days of zebrafish embryonic development by introducing specific antisense morpholino oligonucleotides (morpholinos have
been used previously to interfere with the synthesis of the much larger mRNAs). They show that morpholinos targeting the miRNA precursor can block
processing of the pri-miRNA or directly inhibit the activity of the mature miRNA.

The researchers also used morpholinos to study the developmental
effects of miRNA knockdown. Although they did not observe gross phenotypic defects for many miRNAs, they found that zebrafish miR-375 is essential for
formation of the insulin-secreting pancreatic islet. Loss of miR-375 results in dispersed islet cells by 36 hours postfertilization, representing one
of the first vertebrate miRNA loss-of-function phenotypes.

Kloosterman WP, Lagendijk AK, Ketting RF, Moulton JD, Plasterk RHA (2007)
Targeted inhibition of miRNA maturation with morpholinos reveals a role for miR-375 in pancreatic islet development.
PLoS Biol 5(8): e203. doi:10.1371/journal.pbio.0050203.
Please click here.

About the Public Library of Science

The Public Library of Science (PLoS) is a non-profit organization of scientists and physicians committed to making the world’s scientific and medical
literature a freely available public resource.

Public Library of Science
185 Berry Street, Suite 3100
San Francisco, CA 94107
USA
Read the rest of this entry »

Scientists have made a major breakthrough in understanding the genetics of the insect parasite that is being targeted by researchers as a way of preventing the spread of malaria.

Wolbachia bacteria are parasites that infect as many as 80 per cent of the world’s insects and manipulate reproduction in their hosts in order to improve their own transmission.

In species including the fruit fly and mosquito, they do this by altering the sperm of infected males to prevent them from successfully reproducing with uninfected females.

Females infected with Wolbachia produce, on average, more offspring than uninfected females.

This is because they can successfully mate with any male in the population, whereas uninfected females are restricted to uninfected males. As Wolbachia is maternally transmitted, this has the effect of spreading the infection through the insect population.

Researchers around the world have secured millions in research funding to help develop malaria control strategies that use genetically modified Wolbachia that would spread through mosquito populations and carry genes that make their mosquito hosts unable to transmit the plasmodium parasite that cause malaria.

For the first time, in new research published in the journal Genetics, scientists from the University of Bath (UK) and the University of Chicago (USA) have identified two of the genes that Wolbachia manipulates when it infects the fruit fly Drosophila simulans.

“This is a major breakthrough in our understanding of the genetic basis of Wolbachia infection,” said Dr Ben Heath, from the Department of Biology & Biochemistry at the University of Bath.

“In recent years there has been great interest in using transgenic Wolbachia as a way of modifying natural populations of insects such as mosquitoes which transmit malaria.

“However this would always be difficult to achieve without a full understanding of the genetics of how Wolbachia interacts with its host insect.

“Our discovery of two of the fruit fly genes manipulated by Wolbachia sheds light on this process, and we should now be able to develop a clearer picture of exactly how Wolbachia manipulate the reproductive process in a variety of its hosts.

“Part of the problem in studying Wolbachia is that it lives inside the cells of its host insect and cannot effectively be studied on its own because it needs the cellular machinery and materials it gets from its host to survive.

“Another difficulty is that the changes it makes in the development of sperm are so subtle that they can be difficult to trace.”

In their research the scientists compared the genes that were being expressed – switched on – in infected and uninfected male fruit flies. By subtracting one from the other, they were left with the genes that were being expressed as a result of the Wolbachia infection.

One of the genes they identified, called zipper, is well known to scientists but has never been associated with Wolbachia infection before.

“Infected males have increased expression of their zipper gene compared to those that are uninfected,” said Dr Heath.

“We were then able to work with transgenic flies which express the zipper gene more when warmed up slightly for periods of one hour during their development.

“This doesn’t harm the flies and provides an opportunity to mimic the effect of Wolbachia in fruit flies that don’t carry the bacteria.

“The zipper gene identified by the scientists also interacts with a second gene called lgl which is responsible for polarity within the cell and this becomes important when a cell divides into two different cells, such as when stem cells develop into sperm.

“By affecting the balance between these genes, it appears Wolbachia can promote cytoplasmic incompatibility by modifying the sperm of infected males.

“This prevents the sperm from being compatible with any egg from a female not infected with Wolbachia and results in sterility.

“However when infected males mate with infected females, the Wolbachia in the egg finds a way of correcting the modification to sperm and allows fertilization and normal development to continue.”

The researchers are now looking at the mechanisms present in other insect species with different levels of cytoplasmic incompatibility

In other insects Wolbachia infection has diverse and often dramatic results which all cause an increase in Wolbachia transmission for the simple reason that these bacteria are only transmitted through the maternal line, from mother to daughter.

In two-spot ladybirds Wolbachia kill male offspring leaving the surviving sisters to eat the bodies of their dead brothers, in Woodlice, infected males are turned into females, and infected parasitic wasps give birth without reproducing.

These reproductive effects are what made Wolbachia so fascinating to biologists in the first place and now they may also provide new ways of tackling insect-bourne diseases such as malaria.

The research was funded by the Biotechnology and Biological Sciences Research Council (UK), the Royal Society (UK) and the National Science Foundation (USA).

Notes
The University of Bath is one of the UK’s leading universities, with an international reputation for quality research and teaching. In 19 subject areas the University of Bath is rated in the top ten in the country.

Contact: Andrew McLaughlin

University of Bath Read the rest of this entry »

Inborn differences may help explain why trauma gives some people bad memories and others the nightmare of post-traumatic stress. Scientists in Germany and the United States have reported evidence linking genes to anxious behavior. The findings appear in the August issue of Behavioral Neuroscience, published by the American Psychological Association.

By showing that people who carry a common variation of a gene that regulates the neurotransmitter dopamine have an exaggerated “startle” reflex when viewing unpleasant pictures, the researchers offer a biochemical explanation for why some people find it harder to regulate emotional arousal. Their sensitivity may, in combination with other hereditary and environmental factors, make them more prone to anxiety disorders.

Researchers including Martin Reuter, PhD, of the University of Bonn, Germany, recruited 96 women averaging 22 years old from the Giessen Gene Brain Behavior Project, which investigates biomolecular causes of individual differences in behavior.

The researchers first determined which participants carried which variations (alleles) of the COMT gene, which encodes an enzyme that breaks down dopamine, weakening its signal. (COMT stands for a catabolic enzyme named catechol-O-methyltransferase.) Scientists call its two alleles Val158 and Met158. Depending on ethnicity, more or less half the population carries one copy of each. The rest of the population is roughly divided between carrying two copies of Val158 and two copies of Met158.

Using a well-validated psychophysiological measure, the researchers next measured the intensity of each participant’s startle response by attaching electrodes to the eye muscles that, upon emotional arousal, contract and cause a blink. Participants then viewed pictures that were emotionally pleasant (such as animals or babies), neutral (such as a power outlet or hairdryer), or aversive (such as weapons or injured victims at a crime scene) — 12 pictures of each type for six seconds each. A loud, 35-millisecond white noise, called a startle probe, sounded at random while they watched. When participants blinked, showing the startle response, a bioamplifier took readings from the electrodes and sent the information to a computer for analysis.

People carrying two copies of the Met158 allele of the COMT gene showed a significantly stronger startle reflex in the unpleasant-picture condition than did carriers of either two copies of Val158 allele or one copy of each. The two-Met carriers also disclosed greater anxiety on a standard personality test.

This finding confirms that specific variations in the gene that regulates dopamine signaling may play a role in negative emotionality. The authors speculated that the Met158 allele may raise levels of circulating dopamine in the brain’s limbic system, a set of structures that support (among other things) memory, emotional arousal and attention. The researchers said that more dopamine in the prefrontal cortex could result in an “inflexible attentional focus” on unpleasant stimuli, meaning that Met158 carriers can’t tear themselves away from something that’s arousing — even if it’s bad.

The Met158 allele was created by a relatively recent mutation and only in the evolution of human beings. Other primate species such as chimpanzees carry only the Val/Val genotype. Co-author Christian Montag, Dipl. Psych., observes that for humans, wariness may have been adaptive. He points out, “It was an advantage to be more anxious in a dangerous environment.”

A single gene variation, says Montag, can explain only a small portion of variation in anxious behavior – otherwise, in theory, up to half the population could be anxious.

“This single gene variation is potentially only one of many factors influencing such a complex trait as anxiety,” he says. “Still, to identify the first candidates for genes associated with an anxiety-prone personality is a step in the right direction.”

Although a great deal more research is needed, Montag says that if this line of research bears fruit, one day “it might be possible to prescribe the right dose of the right drug, relative to genetic makeup, to treat anxiety disorders.”

“COMT Genetic Variation Affects Fear Processing: Psychophysiological Evidence,”
Christian Montag, Dipl. Psych., University of Bonn; Joshua W. Buckholtz, MS, Vanderbilt University; Peter Hartmann, PhD, University of Aarhus; Michael Merz, Dipl. Psych., Christian Burk, PhD, and Juergen Hennig, PhD, University of Giessen; and Martin Reuter, PhD, University of Bonn
Behavioral Neuroscience, Vol 122, No. 4.
Click here to view article online

The American Psychological Association (APA), in Washington, DC, is the largest scientific and professional organization representing psychology in the United States and is the world’s largest association of psychologists. APA’s membership includes more than 148,000 researchers, educators, clinicians, consultants and students. Through its divisions in 54 subfields of psychology and affiliations with 60 state, territorial and Canadian provincial associations, APA works to advance psychology as a science, as a profession and as a means of promoting human welfare.

American Psychological Association
Read the rest of this entry »

After 12 years of searching, UCLA scientists have tracked down the first known gene mutation responsible for a heartbreaking disorder that kills newborn babies. Published in the April 1 online edition of the American Journal of Human Genetics, their findings will allow for earlier testing of embryos at risk for the disease.

Many things go awry in short-rib polydactyly syndrome. The fetus develops extra fingers and toes and its skeleton doesn’t grow, resulting in stunted ribs that prevent the lungs from maturing in the womb. Unable to breathe on its own, the child dies shortly after birth.

Parents currently must wait until the second trimester of pregnancy for a diagnosis a long time to wait for potentially agonizing news about one’s unborn child.

“Now that we’ve identified the genetic basis of the disease, families will be able to obtain a prenatal diagnosis within about 12 weeks,” explained Dr. Deborah Krakow, associate professor of orthopedic surgery and human genetics at the David Geffen School of Medicine at UCLA. “Parents will also be able to screen embryos conceived in vitro to help select those free of the genetic mutation before uterine implantation.”

Roughly one in 300 people are carriers of short-rib polydactyly syndrome. Both parents must carry the mutated gene in order for their child to inherit the disease.

In the hope of finding a common genetic link to the disease, the UCLA team studied DNA samples from three families whose children died of short-rib polydactyly syndrome. Dr. Stan Nelson, UCLA professor of human genetics, and his laboratory employed powerful genomic technology to rapidly test hundreds of thousands of gene variations in each fetus.

“It took scientists 10 years to map the human genome,” Nelson said. “New technology enables us to search a child’s entire genome in two weeks without testing the parents or other family members. It’s a highly efficient way to quickly sample DNA and identify shared gene variations among people.”

In the UCLA study, the research team identified a DNA sequence shared by all three infants from a single family. Like a signpost, it directed the scientists to a chromosomal location they suspected of housing the disease-causing gene.

“Each of us inherits different chromosomes from our mothers and fathers,” explained Nelson. “If the child’s genome contains the same DNA from both parents, we know that the mother and father are related in some way. They share a piece of ancestral DNA — a common red flag for people known to have or carry a genetic disease.”

After narrowing her search to three identical regions on the genome, Krakow zeroed in on one as the likely culprit. Her hunch proved correct. Not only did she identify the mutation in the initial family that lost three children, but she confirmed its presence in two other families whose infants also died of the disease.

Krakow and Nelson’s next step will be to seek out other genes that contribute to short-rib polydactyly syndrome and uncover how these factors interact to cause the disorder.

“One of the reasons this disease is hard to crack is that it is caused by multiple genes, not just one,” said Krakow. “We are searching for other gene variants in other families affected by the syndrome.”

The DNA-scanning techniques developed by Nelson and his colleagues can be used to identify any hereditary disease-causing gene. The findings will enhance doctors’ abilities to determine individual genes’ specific roles and provide a more complete picture for healthy and abnormal human development.

Roughly 3 percent of all infants are born with birth defects. Some 5 percent of these children suffer from genetic defects affecting the skeleton. In this group, about 5 percent are short-rib polydactyly syndrome patients.

The National Institute of Child Health and Human Development funded the study.

Coauthors included Amy Merrill, Barry Merriman, Clare Farrington-Rock, Natalia Camacho, Eiman Sebald, Vicente Funari, Matthew Schibler, Marc Firestein, Zachary Cohen, Maryann Priore, Alicia Thompson, David Rimoin and Daniel Cohn, all affiliated with UCLA and Cedars-Sinai Medical Center.

University of California, Los Angeles (UCLA)
924 Westwood Blvd., Ste. 350
Los Angeles
CA 90095
United States
ucla.edu Read the rest of this entry »

NEUROBIOLOGY: Too hot to handle: how heat causes pain

Our body detects heat above 43 degrees Celsius as painful. The main detector of noxious heat is the protein TRPV1 on pain-sensing sensory nerve cells. Exactly how TRPV1 sensitivity to heat is regulated has not been clearly determined. However, Kenneth Hargreaves and colleagues, at the University of Texas Health Science Center at San Antonio, have now identified in rodents two molecules known as 9-HODE and 13-HODE, which are generated by the breakdown of the omega-6 fat linoleic acid, as activators of TRPV1 and inducers of the feeling of pain in response to heat. As products of linoleic acid breakdown, such as 9-HODE and 13-HODE, are produced by injured cells, the authors suggest that agents blocking either the production or action of these substances could lead to therapeutic interventions for pain disorders.

In an accompanying commentary, David Brown and Gayle Passmore, at University College London, United Kingdom, discuss how the concept of a “heat messenger” released from damaged tissue provides new food for thought for those developing approaches to pain therapy.

TITLE: Heat generates oxidized linoleic acid metabolites that activate TRPV1 and produce pain in rodents

ACCOMPANYING COMMENTARY TITLE: Some new insights into the molecular mechanisms of pain perception

DEVELOPMENT: Mechanisms underlying 2 genetically distinct forms of cleft palate linked

Cleft lip and cleft palate are frequent and debilitating congenital malformations. Mutations in the genes p63 and IRF6 have each been shown to cause cleft lip and cleft palate, but the molecular and cellular mechanisms underlying this have not been clearly determined. However, two independent teams of researchers – one led by Jill Dixon, at the University of Manchester, United Kingdom, and Hans van Bokhoven, at Radboud University Nijmegen Medical Centrum, The Netherlands, and the other led by Antonio Costanzo, at the University of Rome “Tor Vergata,” Italy – have now found that in mice p63 and IRF6 operate within a regulatory loop to coordinate key events in the normal development of the palate (the structure that separates the nasal cavity from the oral cavity, allowing simultaneous breathing and eating); disruption of this loop as a result of mutations in p63 and IRF6 causes cleft lip and cleft palate. Amel Gritli-Linde, at the University of Gothenburg, Sweden, highlights the importance of these studies in an accompanying commentary.

TITLE: Cooperation between the transcription factors p63 and IRF6 is essential to prevent cleft palate in mice

ACCOMPANYING ARTICLE TITLE: A regulatory feedback loop involving p63 and IRF6 links the pathogenesis of 2 genetically different human ectodermal dysplasias

ACCOMPANYING COMMENTARY TITLE: p63 and IRF6: brothers in arms against cleft palate

DEVELOPMENT: Understanding how a rare genetic mutation causes a severe brain disorder

Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE) is a rare genetic disorder that was identified in an Old Order Mennonite pediatric population. It is characterized by abnormal brain development, an abnormally large brain, cognitive disability, and severe, therapy-resistant epilepsy. PMSE is caused by mutations in the gene STRADA. A team of researchers, led by Peter Crino, at the University of Pennsylvania, Philadelphia, has now provided insight into how mutations in STRADA cause PMSE by analyzing a human PMSE brain and mice. Specifically, their data indicate that the lack of STRAD-alpha protein caused by the STRADA gene mutations results in the protein LKB1 being abnormally localized, and that this leads to activation of the mTOR signaling pathway, thereby promoting abnormal cell growth and brain development. The authors suggest that early treatment with the mTOR inhibitor rapamycin, which is used in the clinic to prevent rejection of organ transplants, and other mTOR inhibitors may prevent the devastating neurological features of PMSE.

In an accompanying commentary, Lucy Osborne, at the University of Toronto, Canada, discusses how the data generated by Crino and colleagues adds PMSE to a group of disorders caused by uncontrolled mTOR pathway activation and characterized by benign tumors and malformations of the brain.

TITLE: STRAD-alpha deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice

ACCOMPANYING COMMENTARY TITLE: Caveat mTOR: aberrant signaling disrupts corticogenesis

MYCOLOGY: Visualizing brain invasion by a fungus

Infection with the fungus Cryptococcus neoformans can cause meningitis (inflammation of the membranes surrounding the brain) and encephalitis (inflammation of the brain itself), conditions that are often lethal. To elicit these effects, the fungus must somehow leave the blood stream and enter the brain, but little is known about how it does this. A team of researchers, at the University of Calgary, Canada, has now used a form of microscopy known as intravital microscopy, which enables researchers to observe events in real-time in live animals, to visualize in mice the process of brain invasion by Cryptococcus neoformans.

A key observation of the team, led by Christopher Mody, was that Cryptococcus neoformans stops suddenly in mouse brain capillaries that are similar or smaller in diameter than it is. Only after stopping abruptly was the fungus seen to cross the wall of the blood vessel and enter the brain. Interestingly, the protein urease was required for Cryptococcus neoformans to invade the brain, and treatment with a urease inhibitor reduced brain infection. The authors therefore suggest that therapeutics that inhibit urease might help prevent meningitis and encephalitis caused by infection with Cryptococcus neoformans.

In an accompanying commentary, Arturo Casadevall, at Albert Einstein College of Medicine, New York, suggests that such inhibitors might not be applicable in the clinic, because most patients already have substantial brain infection when they first seek medical help. However, he highlights that the study opens up numerous new avenues of research that could be exploited in the clinic in the future.

TITLE: Real-time imaging of trapping and urease-dependent transmigration of Cryptococcus neoformans in mouse brain

ACCOMPANYING COMMENTARY TITLE: Cryptococci at the brain gate: break and enter or use a Trojan horse?

Source:
Karen Honey
Journal of Clinical Investigation Read the rest of this entry »

The ENCODE Project produced an enormous amount of data on transcriptionally active regions (TARs). Because TARs are difficult to wrangle with, Dr. Mark Gerstein and colleagues constructed the Database of Active Regions and Tools (DART; dart.gersteinlab), which is a Web resource for classifying, storing, manipulating, and visualizing TARs.

Using the DART classification system, the scientists categorized 6,988 unannotated TARs based on expression profiles, sequence composition, relatedness to similar sequences from other organisms, and genomic location. Of the new TARs identified, approximately 20% were produced from previously unidentified potential genes. In addition, many of the TARs associated with known genes were found to have the potential to form functional secondary structures.

Reference:

Rozowsky, J. et al. 2007. The DART classification of unannotated transcription within the ENCODE regions: associating transcription with known and novel loci. Genome Res. 17: 732-745. (doi:10.1101/gr.5696007)

About Genome Research

Genome Research (genome) is an international, monthly, peer-reviewed journal published by Cold Spring Harbor Laboratory Press. Launched in 1995, it is one of the five most highly cited primary research journals in genetics and genomics.

The following articles also appear in this issue:

– Weinstock, G.M. 2007. ENCODE: More genomic empowerment. Genome Res. 17: 667-668. (doi:10.1101/gr.6534207)
– Gerstein, M. et al. 2007. What is a gene, post-ENCODE: A history culminating in an updated definition. Genome Res. 17: 669-681. (doi:10.1101/gr.6339607)
– Gingeras, T.R. 2007. Origin of phenotypes: Genes and transcripts. Genome Res. 17: 682-690. (doi:10.1101/gr.6525007)
– Koch, C.M. et al. 2007. The landscape of histone modifications across 1% of the human genome in five human cell lines. Genome Res. 17: 691-707. (doi:10.1101/gr.5704207)
– Rada-Iglesias, A. et al. 2007. Butyrate mediates decrease of histone acetylation centered on transcription start sites and down-regulation of associated genes. Genome Res. 17: 708-719. (doi:10.1101/gr.5540007)
– King, D.C. et al. 2007. Finding cis-regulatory elements using comparative genomics: Some lessons from ENCODE data. Genome Res. 17: 775-786. (doi:10.1101/gr.5592107)
– Zhang, Z.D. et al. 2007. Statistical analysis of the genomic distribution and correlation of regulatory elements in the ENCODE regions. Genome Res. 17: 787-797. (doi:10.1101/gr.5573107)
– Xi, H. et al. 2007. Analysis of overrepresented motifs in human core promoters reveals dual regulatory roles of YY1. Genome Res. 17: 798-806. (doi:10.1101/gr.5754707)
– Jin, V.X. et al. 2007. Identification of an OCT4 and SRY regulatory module using integrated computational and experimental genomics approaches. Genome Res. 17: 807-817. (doi:10.1101/gr.6006107)
– Lin, J.M. et al. 2007. Transcription factor binding and modified histones in human bidirectional promoters. Genome Res. 17: 818-827. (doi:10.1101/gr.5623407)
– Ruan, Y. et al. 2007. Fusion transcripts and transcribed retrotransposed loci discovered through comprehensive transcriptome analysis using Paired-End diTags (PETs). Genome Res. 17: 828-838. (doi:10.1101/gr.6018607)
– Zheng, D. et al. 2007. Pseudogenes in the ENCODE regions: Consensus annotation, analysis of transcription, and evolution. Genome Res. 17: 839-851. (doi:10.1101/gr.5586307)
– Washietl, S. et al. 2007. Structured RNAs in the ENCODE selected regions of the human genome. Genome Res. 17: 852-864. (doi:10.1101/gr.5650707)
– Karnani, N. et al. 2007. Pan-S replication patterns and chromosomal domains defined by genome-tiling arrays of ENCODE genomic areas. Genome Res. 17: 865-876. (doi:10.1101/gr.5427007)
– Giresi, P.G. et al. 2007. FAIRE (Formaldehyde-Assisted Isolation of Regulatory Elements) isolates active regulatory elements from human chromatin. Genome Res. 17: 877-885. (doi:10.1101/gr.5533507)
– Emanuelsson, O. et al. 2007. Assessing the performance of different high-density tiling microarray strategies for mapping transcribed regions of the human genome. Genome Res. 17: 886-897. (doi:10.1101/gr.5014607)
– Euskirchen, G.M. et al. 2007. Mapping of transcription factor binding regions in mammalian cells by ChIP: Comparison of array- and sequencing-based technologies. Genome Res. 17: 898-909. (doi:10.1101/gr.5583007)
– Bhinge, A.A. et al. 2007. Mapping the chromosomal targets of STAT1 by Sequence Tag Analysis of Genomic Enrichment (STAGE). Genome Res. 17: 910-916. (doi:10.1101/gr.5574907)
– Dennis, J.H. et al. 2007. Independent and complementary methods for large-scale structural analysis of mammalian chromatin. Genome Res. 17: 928-939. (doi:10.1101/gr.5636607)
– Greenbaum, J.A. et al. 2007. Detection of DNA structural motifs in functional genomic elements. Genome Res. 17: 940-946. (doi:10.1101/gr.5602807)
– Greenbaum, J.A. et al. 2007. Construction of a genome-scale structural map at single-nucleotide resolution. Genome Res. 17: 947-953. (doi:10.1101/gr.6073107)
– Elnitski, L.L. et al. 2007. The ENCODEdb portal: Simplified access to ENCODE Consortium data. Genome Res. 17: 954-959. (doi:10.1101/gr.5582207)
– Blankenberg, D. et al. 2007. A framework for collaboratoive analysis of ENCODE data: Making large-scale analyses biologist-friendly. Genome Res. 17: 960-964. (doi:10.1101/gr.5578007)

About Cold Spring Harbor Laboratory Press

Cold Spring Harbor Laboratory Press is an internationally renowned publisher of books, journals, and electronic media located on Long Island, New York. It is a division of Cold Spring Harbor Laboratory, an innovator in life science research and the education of scientists, students, and the public. For more information, visit cshlpress.

Since the completion of the Human Genome Project in 2003, research efforts have been aimed at analyzing the functions of various sequences in the genome, using both experimental and computational strategies. The June issue of Genome Research (genome) is devoted to The ENCODE (ENCyclopedia Of DNA Elements) Project, whose goal is to characterize all functional elements in the human genome. Genome Research’s ENCODE issue includes 25 research papers, which report on the validation of the main results of the pilot project and are essential the community as they scale up to cataloguing functional elements in the whole genome. In addition, the issue also contains commentary and perspectives on how our views of the genome have changed as a result of the ENCODE investigations. The major findings span the areas of chromatin and replication, gene transcription and regulation, and evolutionary constraint, some of which are highlighted below. The entire issue will be freely available online on June 14 to coordinate with the ENCODE consortium publication in the journal Nature. Read the rest of this entry »

The Natural Sciences and Engineering Research Council of Canada (NSERC) is pleased to feature Canadian science and engineering research excellence during the American Association for the Advancement of Science (AAAS) Annual Meeting from February 12 to 16, 2009, in Chicago, Illinois.

The “Canadian way” of pursuing scientific research through partnerships and networks, within Canada and internationally, was highlighted at a Canadian Reception on February 12. This reception, sponsored by the Canadian Embassy in Washington, will bring together scientists, policymakers, educators and students, as well as senior representatives from the following Canadian organizations: Association of Universities and Colleges of Canada, Canada Foundation for Innovation, Canadian Institutes of Health Research, Foreign Affairs and International Trade Canada, Natural Sciences and Engineering Research Council of Canada, and Social Sciences and Humanities Research Council of Canada.

Seven Canadians will be inducted as AAAS Fellows at the Annual Fellows Forum on Saturday, February 14. AAAS Fellows are recognized for meritorious efforts to advance science or its applications. Canadians to be inducted are as follows:
Walter Craig, McMaster University: For research on partial differential equations, dispersive waves and Hamiltonian systems, which found surprising connections between fluid dynamics, solitons, singular cohomology and diophantine approximation;

D. Grant Allen, University of Toronto: For distinguished contributions to biotechnology, particularly the use of biological processes to treat air emissions and wastewater, and for service to the chemical engineering profession;

Brendan J. Frey, University of Toronto: For distinguished contributions to the field of information processing and machine learning, and to genomics research;

Laura-Ann Petitto, University of Toronto: For insightful contributions to our understanding of human language, including bilingualism and sign language, using behavioral and neuroscience techniques;

Mary Jane Phillips, University of Toronto: For distinguished service to the engineering profession, and for her role as a pioneering woman in the profession and as a mentor to female engineers;

Christopher Yip, University of Toronto: For distinguished contributions to biophysical science and bioengineering, particularly single molecule biophysics, and for contributions to bioengineering education; and

Wolff-Michael Roth, University of Victoria: For distinguished contributions to research in science education, particularly for development of theory and methods, and exemplary empirical research on learning and teaching science.

NSERC President, Dr. Suzanne Fortier, will be one of four presenters at the Internationalization of Science: Looking Ahead Symposium on February 15.

Throughout the AAAS Annual Meeting, guest speakers from across Canada will make presentations on a range of topics including climate change, agriculture, mathematics, animal behaviour, toxicology, aquaculture and genomics.

If you are in Chicago and want to know more about Canadian research in the natural sciences and engineering, visit NSERC’s booth at the tradeshow February 13 to 16. We will be located at booths 1119-1121, at the Hyatt Regency Chicago Riverside Centre.

NSERC is a federal agency whose vision is to help make Canada a country of discoverers and innovators for the benefit of all Canadians. The agency supports some 26,500 university students and post-doctoral fellows in their advanced studies. NSERC promotes discovery by funding more than 11,800 university professors every year and fosters innovation by encouraging more than 1,400 Canadian companies to participate and invest in university research projects.

Source: Shannon Cobb

Natural Sciences and Engineering Research Council Read the rest of this entry »

In an effort to sidestep the ethical dilemma involved in using human embryonic stem cells to treat diseases, scientists are developing non-controversial alternatives: In particular, they are looking for drug-like chemical compounds that can transform adult skin cells into the stem cells now obtained from human embryos. That’s the topic of a fascinating article in Chemical & Engineering News (C&EN), ACS’ weekly newsmagazine.

C&EN Associate Editor Sarah Everts notes that in 2006, researchers in Japan figured out a way to use genetic engineering to coax a skin cell to become a so-called “pluripotent” stem cell – a type of cell that can potentially morph or change into any cell of the human body. The scientists achieved the result by infecting the skin cell with a virus containing certain genes instructing the cell to change.

Now chemists are trying to reproduce this cellular alchemy with drug-like substances because gene therapies have faced trouble getting into the clinic. Scientists are looking for chemical ways to go backward in cell development – to reprogram mature cells into stem cells. Others are trying to identify substances that can morph one cell directly into other cell types – for example, from a skin cell directly into a nerve cell that might treat Parkinson’s disease – without the use of stem cells at all. The ultimate goal is to be able to reprogram any cell of the body into another by means of a simple molecular kit, the article notes. But as chemists start putting together toolkits with these drug-like molecules, they face many technical hurdles as well as challenges getting acceptance from the stem cell community.

This story is available at
pubs.acs/cen/science/88/8806sci1.html

Article: “Back to the future with stem cells”

Source:
Michael Bernstein

American Chemical Society Read the rest of this entry »

This fascinating and entertaining lecture raised physicians’ awareness of the role of assisted reproductive technology (ART) in the genetic management of endangered wildlife species. This lecture was based on experiences by Smithsonian scientists in applying techniques in reproductive sciences to the study and genetic management of rare species.

Dr. David Wildt spoke to the remarkable species differences simply among cats. He emphasized the fact that there is a general lack of specific and general knowledge of each species. There are differences relating to geographic dispersion, innate behavior and variability.

An important function of endangered animal management programs is to maintain the integrity of species. Those animals in captivity should be like those in wild, and there should be genetic diversity.

An example of poorly preserved genetic diversity is the Florida panther. This species has absolutely no genetic diversity. It is like an inbred strain of laboratory mice. They have sperm morphology defects, cryptorchidism, vaginal abnormalities and atrial septal defects.

Dr. Wildt spoke of the giant panda – a favorite of all. The female giant panda is in estrous once per year and for 24 hours. Thus there is not much opportunity for reproduction and this can be affected by sexual incompatibility, an issue that exists even in wild. Thus, ART is essential for the preservation of this species. In 1998, there were 104 giant pandas in captivity, and the population was not self- sustaining. This resulted in a concerted effort to study and understand the species. They were seen to be aggressive animals (rather than cute and cuddly animals). Their reproduction was affected by diet, i.e., the need for a bamboo diet to reproduce. Since employing ART, the population has reached 300 in captivity and is self-sustaining. There were many other examples of ART in management of wildlife species including the black-footed ferret, dolphins, and killer whales.

Dr. Wildt clearly demonstrated the importance of genetic management in the preservation and survival of endangered species.

Presented by David E. Wildt, PhD, at the 64th Annual Meeting of the American Society for Reproductive Medicine – November 8 – 12, 2008 – San Francisco, California

Reported by UroToday Contributing Editor Harris M. Nagler, MD

UroToday – the only urology website with original content global urology key opinion leaders actively engaged in clinical practice.

To access the latest urology news releases from UroToday, go to:
www.urotoday

Copyright © 2008 – UroToday Read the rest of this entry »