News 31 aug 2009
Researchers Find Vulnerable Enzyme
in Pathogens
Researchers at Burnham Institute for Medical Research (Burnham), University of Texas
Southwestern Medical Center and University of Maryland have demonstrated that an enzyme
that is essential to many bacteria can be targeted to kill dangerous pathogens. In
addition, investigators discovered chemical compounds that can inhibit this enzyme and
suppress the growth of pathogenic bacteria. These findings are essential to develop new
broad-spectrum antibacterial agents to overcome multidrug resistance. T
Gene variation is 'major genetic
determinant of psoriasis'
A specific genetic region that has been increasingly identified as the strongest genetic
link to psoriasis has an even more significant role in the chronic skin disease than has
been suspected, University of Utah medical researchers show in a new study. In the Aug. 13
issue of PLoS Genetics, researchers in the U School of Medicine's Department of
Dermatology confirm that the presence of HLA-Cw*0602, a gene variation or allele on
chromosome 6 found to be associated with psoriasis by numerous investigators, is the
"major genetic determinant" of psoriasis, but that other nearby genetic
variations also play an independent role in contributing to the disease "The
HLA-Cw*0602 gene variation stands alone as a high risk for psoriasis," said Gerald G.
Krueger, M.D., professor of dermatology, Benning Presidential Endowed Chair holder, and a
co-author on the study. "A major question has been: are there other genetic
variations in this region that associate with psoriasis?" "The study reported in
PLoS Genetics identifies two other genetic variations on chromosome 6 that also have
significant association with psoriasis. People who have all three genetic variations are
nearly nine times more at risk for psoriasis.
Researchers report gene associated
with language, speech and reading disorders
A new candidate gene for Specific Language Impairment has been identified by a research
team directed by Mabel Rice at the University of Kansas, in collaboration with Shelley
Smith, University of Nebraska Medical Center, and Javier Gayán of Neocodex, Seville,
Spain. The finding, reported in the current issue of the Journal of Neurodevelopmental
Disorders, was discovered by examining genes previously identified as candidate genes for
reading impairments or speech sound disorders. The results point toward the likelihood of
multiple genes contributing to language impairment, some of which also contribute to
reading or speech impairment. A gene on Chromosome 6 – KIAA0319 – was associated
with variability in language abilities in a study of children with Specific Language
Impairment (SLI) and their family members, as well as with variability in speech and
reading abilities. Children with SLI who were selected for the study had no hearing loss,
general intellectual deficit or autism. Language ability involves vocabulary and grammar,
whereas speech involves the accuracy of sound production. Both language and speech ability
contribute to a child's ability to read. The finding that a candidate gene could influence
all three abilities suggests a common pathway that could contribute to overlapping
strengths or deficiencies across speech, language and reading. According to Rice, "We
don't understand the biological mechanisms yet but it's important that we have identified
the first gene that could be involved across these three different dimensions of
development."
Predicting cancer prognosis
Researchers led by Dr. Soheil Dadras at the Stanford University Medical Center have
developed a novel methodology to extract microRNAs from cancer tissues. The related report
by Ma et al, "Profiling and discovery of novel miRNAs from formalin-fixed
paraffin-embedded melanoma and nodal specimens," appears in the September 2009 issue
of the Journal of Molecular Diagnostics. Cancer tissues from patients are often stored by
a method that involves formalin fixation and paraffin embedding to retain morphological
definition for identification; however, this method frequently prevents further molecular
analysis of the tissue because of mRNA degradation. Even so, these tissues contain high
numbers of microRNAs (miRNAs), which are short enough (~22 nucleotides) to not be broken
down during the fixation process. In this study, Dr. Dadras and colleagues optimized a new
protocol for extracting miRNAs from formalin-fixed paraffin-embedded tissues. Using their
new procedure, they identified 17 new and 53 known miRNAs from normal skin, melanoma, and
sentinel lymph nodes. These miRNAs were well-preserved in a 10-year-old specimen. This new
protocol, therefore, will allow for the identification of novel miRNAs that may differ in
cancerous and healthy tissue, even from long-preserved tissue, leading to better
predictions of disease prognosis and treatment response.
U-Iowa improves delivery of
cancer-fighting molecules
Small interfering RNA (siRNA), a type of genetic material, can block potentially harmful
activity in cells, such as tumor cell growth. But delivering siRNA successfully to
specific cells without adversely affecting other cells has been challenging. University of
Iowa researchers have modified siRNA so that it can be injected into the bloodstream and
impact targeted cells while producing fewer side effects. The findings, which were based
on animal models of prostate cancer, also could make it easier to create large amounts of
targeted therapeutic siRNAs for treating cancer and other diseases. The study results
appeared online Aug. 23 in the journal Nature Biotechnology. "Our goal was to make
siRNA deliverable through the bloodstream and make it more specific to the genes that are
over expressed in cancer," said the study's senior author Paloma Giangrande, Ph.D.,
assistant professor of internal medicine and a member of Holden Comprehensive Cancer
Center. In previous research completed at Duke University, Giangrande's team showed that a
compound called an aptamer can be combined with siRNA to target certain genes. When the
combined molecule is directly injected into tumors in animal models, it triggers the
processes that stop tumor growth. However, directly injecting the combination into tumors
in humans is difficult. In the new study, the researchers trimmed the size of a prostate
cancer-specific aptamer and modified the siRNA to increase its activity. Upon injection
into the bloodstream, the combination triggered tumor regression without affecting normal
tissues.
An intelligent system avoids
forgetting things
A team of researchers from the University of Granada (UGR) has created a system with
Artificial Intelligence techniques which notifies elderly people or people with special
needs of the forgetting of certain everyday tasks. This system uses sensors distributed in
the environment in order to detect their actions and mobile devices which remind them, for
example, to take their keys before they leave home. An elderly lady is about to go to bed.
She goes into her room, sits down on the bed, takes off her slippers and turns off the
light. Suddenly, before getting into bed, a small alarm goes off and a mobile device
reminds her that she has not taken her tablets. This is how the new intelligent system
developed by researchers from the Department of Computer Science and Artificial
Intelligence of the UGR works. María Ros Izquierdo is from the Higher Technical School of
Computer Engineering of the UGR and the co-author of a study which is published this month
in the Expert Systems with Applications magazine. "It is a prototype which, in a
non-intrusive manner, facilitates the control of the activity of people with special needs
and increases their independence", she explained to SINC. The system recognizes the
everyday actions of the users by means of RFID (Radio Frequency Identification) labels.
These labels are discreetly placed on the objects that the individuals touch most often,
in such a way that, when they do so, a signal is sent to a computer or mobile device
situated in the house itself or at an assistance centre some distance away.
Skin-disease patients show brain
immunity to faces of disgust
People with psoriasis – an often distressing dermatological condition that causes
lesions and red scaly patches on the skin – are less likely to react to looks of
disgust by others than people without the condition, new research has found. University of
Manchester scientists used magnetic resonance imaging (MRI) scans to compare the brains of
26 men, half of whom had chronic psoriasis. The researchers looked at the insular cortex
– a part of the brain triggered by both feelings and observations of disgust –
to see how participants responded to images of disgusted faces. The study, published in
the Journal of Investigative Dermatology, found that the volunteers with psoriasis had a
much weaker response in their insular cortex than the healthy volunteers, suggesting they
have developed a coping mechanism to protect themselves from adverse emotional responses
to their condition by others. "Psoriasis has a significant negative impact on the
physical and psychological well-being of those affected but little is known about the
neurocognitive mechanisms of how patients cope with the adverse social stigma associated
with visible skin lesions," said Dr Elise Kleyn, the dermatologist who carried out
the research. "We had previously shown that psoriasis patients commonly believe that
they will be evaluated solely on the basis of their skin and so often avoid social
situations they think will be stressful or humiliating as a coping mechanism."For
this study we wanted to investigate whether the social impact of psoriasis is associated
with altered cognitive processing in response to facial expressions of disgust by
measuring brain activity in the insular cortex.
Beta-blockers and stroke -- new
insights into their use for older people
A University of Leicester-led study may have uncovered the reason why Beta-blockers are
less effective at preventing stroke in older people with high blood pressure, when
compared to other drugs for high blood pressure. The research, carried out by Bryan
Williams, Professor of Medicine at the University of Leicester, and his colleague Dr.
Peter Lacy, has been published in the prestigious Journal of the American College of
Cardiology and has been cited on the MDLinx.com site as currently the world's number one
leading finding in its field. Professor Williams' research shows that lowering heart rate
in older people, as Beta blockers do, can have a potentially detrimental effect on central
aortic pressures (pressures in the large arteries close to the heart).
Tunnels concentrate air pollution
by up to 1000 times
A toxic cocktail of ultrafine particles is lurking inside road tunnels in concentration
levels so high they have the potential to harm drivers and passengers, a new study has
found. The study, which has been published in Atmospheric Environment, measured ultrafine
particle concentration levels outside a vehicle travelling through the M5 East tunnel in
Sydney. Study co-author and director of Queensland University of Technology's
International Laboratory for Air Quality and Health, Professor Lidia Morawska, said road
tunnels were locations where maximum exposure to dangerous ultrafine particles in addition
to other pollutants occurred. "The human health effects of exposure to ultrafine
particles produced by fuel combustion are generally regarded as detrimental,"
Professor Morawska said. "Effects can range from minor respiratory problems in
healthy people, to acute myocardial infarction (heart attack) in people with existing
heart complaints. Professor Morawska said the study involved more than 300 trips through
the four kilometres of the M5 East tunnel, with journeys lasting up to 26 minutes,
depending on traffic congestion. "What this study aimed to do was identify the
concentration levels found in the tunnel. It generated a huge body of data on the
concentrations and the results show that, at times, the levels are up to 1000 times higher
than in urban ambient conditions," she said.
Collagen-deficient mice show signs
of osteoarthritis
Osteoarthritis (OA) and degenerative disc disease (DDD) are common, chronic
musculoskeletal disorders. Both diseases cause joint pain, loss of function, and decreased
quality of life for the more than 27 million OA and 59 million DDD suffers in the US.
According to a 2003 Medical Expenditure Panel Survey, arthritis such as OA costs the U.S.
economy nearly $128 billion per year in medical care and indirect expenses including lost
wages and productivity. Researchers at Duke University Medical Center, under a grant from
the National Institutes of Health (NIH), conducted a study of mice to determine the effect
of Type IX collagen (Col9a1) deficiency on functional ability. The authors found that mice
with the Col9a1 gene inactivated prematurely develop OA and DDD. Findings of this study
appear in the September issue of Arthritis & Rheumatism, a journal of the American
College of Rheumatology, published by Wiley-Blackwell. Duke University researchers led by
Kyle Allen, Ph.D. compared the behavioral abilities of Col9a1 deficient mice to wild-type
(WT) mice. Mice of advanced age (9-11 months) were selected because they represent an age
at which there is histological evidence of OA and DDD. Functional tests of reflexes,
posture, strength, coordination, balance, sensorimotor skills, and gait were conducted to
measure physical capabilities that could be impaired due to OA or DDD. Symptomatic pain
was assessed through mechanical and thermal withdrawal thresholds. "We observed a
pattern of behavioral changes in the collagen deficient mice that suggests a relationship
to OA- and DDD-like degeneration," stated Dr. Allen. The data shows that mice
deficient in Type IX collagen clearly displayed behavioral characteristics of pain and
functional loss. These mice had delayed righting reflex (ability to regain footing from a
back position), decreased sensorimotor skills, and altered gait compared with WT mice.
Collagen deficient mice also had elevated levels of knee and intervertebral disc
structural changes.
Chemotherapy resistance -
Checkpoint protein provides armor against cancer drugs
Cell cycle checkpoints act like molecular tripwires for damaged cells, forcing them to
pause and take stock. Leave the tripwire in place for too long, though, and cancer cells
will press on regardless, making them resistant to the lethal effects of certain types of
chemotherapy, according to researchers at the Salk Institute for Biological Studies. Their
findings, published in the Aug. 28 issue of Molecular Cell, help explain how the
checkpoint exit is delayed in some cancer cells, helping them to recover and resume
dividing after treatment with DNA-damaging cancer drugs. "A lot of progress has been
made in understanding the molecular details of checkpoint activation," says senior
author Tony Hunter, Ph.D., a professor in the Molecular and Cell Biology Laboratory,
"but checkpoint termination, which is essential for the resumption of cell cycle
progression, is less well understood." The Salk researchers say that a better
understanding of this crucial process may allow them to develop biological markers that
predict clinical resistance to chemotherapy and to design cancer drugs with fewer side
effects by exploiting the molecular mechanism underlying the checkpoint exit. "If we
could screen tumors for markers of chemo-resistance, we could then adjust the treatment
accordingly," hopes first author You-Wei Zhang, Ph.D., formerly a postdoctoral
researcher in Hunter's lab and now an assistant professor at Case Western Reserve
University in Cleveland, Ohio. In response to DNA damage and blocked replication—the
process that copies DNA—eukaryotes activate the DNA damage checkpoint pathway, which
stops the cell cycle, buying time to repair damage and recover from stalled or collapsed
replication forks. If not repaired, these errors can either kill a cell when it attempts
to divide or lead to genomic instability and eventually cancer.
'Fatostatin' is a turnoff for fat
genes
A small molecule earlier found to have both anti-fat and anti-cancer abilities works as a
literal turnoff for fat-making genes, according to a new report in the August 28th issue
of the journal Chemistry and Biology, a Cell Press journal. The chemical blocks a well
known master controller of fat synthesis, a transcription factor known as SREBP. That
action in mice that are genetically prone to obesity causes the animals to become leaner.
It also lowers the amount of fat in their livers, along with their blood sugar and
cholesterol levels. "We are frankly very excited about it," said Salih Wakil of
Baylor College of Medicine. "It goes to the origin of [fat synthesis] – all the
way back to gene expression." Unlike cholesterol-lowering statins in use today, which
block a single enzyme in the pathway, the chemical, which the researchers call fatostatin,
"hits fat from the very beginning," added Motonari Uesugi, who is now at Kyoto
University. In doing so, fatostatin influences many of the genes involved in fat
production and in various aspects of metabolic syndrome – a collection of risk
factors including obesity, high cholesterol and insulin resistance – in one go.
Studies in cell culture showed that fatostatin, previously known only as 125B11,
significantly lowers the activity of 63 genes, including 34 directly associated with fatty
acid or cholesterol synthesis. Many of those were known to be under the control of SREBP.
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