News 10 march 2009
Anesthesia Is Found To Induce
Hyperphosphorylation of Tau at Sites Related to Alzheimer’s Disease
Scientists from The New York State Office
of Mental Retardation and Developmental Disabilities’ (OMRDD) New York State
Institute for Basic Research in Developmental Disabilities (IBR) report today in the March
2009 issue of the Journal of Alzheimer’s Disease that anesthesia induces
phosphorylation of tau. Tau is a key neuronal protein involved in neurodegeneration in
Alzheimer’s disease (AD) and several other neurodegenerative disorders. Anesthesia
has previously been found to be associated with cognitive impairment and the risk for AD.
This study helps elucidate the molecular mechanisms underlying these associations. The
researchers found that in test animals, anesthesia for short periods (30 seconds to 5
minutes) induced tau phosphorylation at some selective phosphorylation sites to a small
but significant extent. Anesthesia for a longer time (1 hour) induced much more dramatic
phosphorylation at the same sites, possibly as a result of anesthesia-induced hypothermia.
The observation that anesthesia did not induce global hyperphosphorylation of brain
proteins, but instead specific hyperphosphorylation of tau protein at the AD-related
abnormal hyperphosphorylation sites suggests that tau hyperphosphorylation might be the
mechanism that links anesthesia and the risk of cognitive impairment and/or AD. AD is the
most common cause of dementia in adults and affects approximately 27 million individuals
worldwide and over four million in the United States alone. Most AD cases are sporadic and
are believed to be caused by multiple factors. Understanding the mechanism by which
anesthesia may increase the risk for cognitive impairment will help in the design of
strategies for preventing and treating dementia and AD. “This is a very important
finding related to Alzheimer’s disease,” said OMRDD Commissioner Diana Jones
Ritter. “I am pleased that these findings will lead to helping people live richer
lives through the research findings.”
Rearrangements of multifunctional
genes cause cancer in children and young people
A doctoral thesis presented at the
Sahlgrenska Academy, University of Gothenburg, Sweden, shows that three genes that lie
behind a number of malignant tumour diseases are normally involved in several fundamental
processes in the cell. This may be the reason that the tumours arise early in life and
principally affect children and young people. A family of genes known as the
"FET" genes has been investigated in the work presented in the thesis. This
family contains three genes that are found in modified forms in several malignant
soft-tissue tumours and several forms of leukaemia. The FET genes are found in these
tumours in the form of what are known as "fusion genes" in which parts of two
different genes have merged to form one gene. Fusion genes are translated into abnormal
fusion proteins, which can in certain cases transform normal cells to cancer cells. The
human body consists of many different types of specialised cell types such as nerve cells,
fat cells and intestinal cells. These are formed when stem cells multiply and mature
gradually along different developmental pathways. Cancer may arise if something goes wrong
in this process. The study has shown that the activities of the genes in the FET family
fall as the cells mature, and scientists therefore believe that these genes play a role
during the early stages of cell maturation, when the cells are not far from the stem cell
stage. The normal maturation pathway of a cell becomes blocked when fusion genes that
contain FET genes arise. The result is a cancer cell with properties similar to those of
stem cells, and such a cell can multiply in an uncontrolled manner.
Twin nanoparticle shown effective
at targeting, killing breast cancer cells
Breast cancer patients face many horrors,
including those that arise when fighting the cancer itself. Medications given during
chemotherapy can have wicked side effects, including vomiting, dizziness, anemia and hair
loss. These side effects occur because medications released into the body target healthy
cells as well as tumor cells. The trick becomes how to deliver cancer-fighting drugs
directly to the tumor cells. Brown University chemists think they have an answer: They
have created a twin nanoparticle that specifically targets the Her-2-positive tumor cell,
a type of malignant cell that affects up to 30 percent of breast cancer patients. The
combination nanoparticle binds to the Her-2 tumor cell and unloads the cancer-fighting
drug cisplatin directly into the infected cell. The result: Greater success at killing the
cancer while minimizing the anti-cancer drug's side effects."Like a missile, you
don't want the anti-cancer drugs to explode everywhere," explained Shouheng Sun, a
chemistry professor at Brown University and an author on the paper published online in The
Journal of the American Chemical Society. "You want it to target the tumor cells and
not the healthy ones." The researchers created the twin nanoparticle by binding one
gold (Au) nanoparticle with an iron-oxide (Fe3O4) nanoparticle. On one end, they attached
a synthetic protein antibody to the iron-oxide nanoparticle. On the other end, they
attached cisplatin to the gold nanoparticle. Visually, the whole contraption looks like an
elongated dumbbell, but it may be better to think of it as a vehicle, equipped with a very
good GPS system, that is ferrying a very important passenger.
Study of protein structures reveals
key events in evolutionary history
A new study of proteins, the molecular
machines that drive all life, also sheds light on the history of living organisms. The
study, in the journal Structure, reveals that after eons of gradual evolution, proteins
suddenly experienced a "big bang" of innovation. The active regions of many
proteins, called domains, combined with each other or split apart to produce a host of
structures that had never been seen before. This explosion of new forms coincided with the
rapidly increasing diversity of the three superkingdoms of life (bacteria; the microbes
known as archaea; and eucarya, the group that includes animals, plants, fungi and many
other organisms). ead author Gustavo Caetano-Anollés, a professor of bioinformatics in
the department of crop sciences at the University of Illinois and an affiliate of the
Institute for Genomic Biology, has spent years studying protein structures – he calls
them "architectures" – which he suggests offer a reliable record of
evolutionary events. All proteins contain domains that can be identified by their
structural and functional similarities to one another. These domains are the gears and
motors that allow the protein machinery to work. Every protein has one or more of them,
and very different proteins can contain the same, or similar, domains. By conducting a
census of all the domains that appear in different groups of organisms and comparing the
protein repertoires of hundreds of different groups, the researchers were able to
construct a timeline of protein evolution that relates directly to the history of life.
A simple balance test may predict
cognitive decline in Alzheimer's disease
A simple balance test may predict cognitive
decline in Alzheimer's Disease, according to a study published in the March 2009 issue of
the Journal of Alzheimer's Disease. This study was carried out in 16 university hospital
departments of neurology, geriatrics or psychiatry in ten cities with 686 outpatients
suffering from AD. This population is representative of the AD population seen by
clinicians in daily practice. Patients were evaluated by a geriatrician every six months
for up to two years, and their degree of cognitive impairment was measured using the Mini
Mental State Examination (MMSE). At the same time, a "one-leg balance" (OLB)
test was given, where a participant was asked to stand on one leg for as long as possible.
The OLB test was reported as abnormal when the participant was unable to stand on one leg
for 5 seconds or more. Participants with an abnormal OLB at baseline or/and during the
follow-up showed significantly more cognitive decline at 12, 18 and 24 months than the
participants with a OLB test normal at baseline and normal during the follow-up. The worst
condition (having an abnormal OLB at baseline and during the follow-up= no improvement)
was associated with a mean adjusted cognitive decline of 9.2 points. The best condition
(having a normal OLB at baseline and during the follow-up = no worsening) was associated
with a mean adjusted cognitive decline of 3.8 points.
Nurse practitioners don't realize
how much their prescribing is being influenced by drug marketing
Family nurse practitioners need to be more
aware of the commercial pressures they face as a result of their increased involvement in
prescribing, according to a survey published in the March issue of the UK-based Journal of
Advanced Nursing. "Our detailed study of 84 family nurse practitioners (FNPs) showed
low awareness of how marketing by pharmaceutical companies affects clinical decisions and
creates conflicts of interest" says Dr Nancy Crigger, from William Jewell College,
Missouri, USA. "However they were clear that some marketing activities, promotional
items and gifts were less ethical and acceptable than others. For example, gifts that
benefited patients and conferences were more acceptable than resort seminars and office
equipment." Dr Crigger, herself a qualified FNP, adds: "The influence of
marketing on physician prescribing has been widely researched and this indicates that the
more involved physicians are in marketing, the less likely they are to recognise when
their clinical judgement has been compromised. "Our study suggests that the same is
now happening to FNPs who have been given greater responsibility for prescribing some
types of medication."
Study shows microRNA-based
diagnostic identifies squamous lung cancer with 96 percent sensitivity
A new study shows for the first time that a
microRNA-based diagnostic test can objectively identify squamous lung cancer with 96%
sensitivity, according to Harvey Pass, M.D. of the NYU Cancer Institute at NYU Langone
Medical Center, one of the authors of the study published on-line ahead of print in the
Journal of Clinical Oncology. In a paper titled, "Diagnostic Assay Based on
has-miR-205 Expression Distinguishes Squamous From Non-Squamous Non-Small-Cell Lung
Carcinoma," researchers looked at 252 patients with lung cancer and sent their tumor
samples to a lab where a single microRNA biomarker identified squamous lung carcinomas
with 96% sensitivity and 90% specificity. This is important because studies have shown
that as many as 30% of squamous lung cancers are misclassified. If the type of lung cancer
is not identified correctly, patients may have side effects due to treatment and
medications. For example, squamous lung cancer carries increased risk of severe or fatal
bleeding for certain targeted biological therapies including Bevacizumab (Avastin) and
other drugs in development. Other approved therapies such as Pemetrexed (Alimta) are
indicated for non-squamous lung cancer only.The study, funded by Rosetta Genomics, was
conducted at the NYU Cancer Institute at NYU Langone Medical Center in collaboration with
researchers from Columbia University and Sheba Medical Center. "The results of this
study are very encouraging," says Harvey Pass, MD, professor of cardiothoracic
surgery and director, thoracic surgery and oncology at the NYU Cancer Institute at NYU
Langone Medical Center. "The study has demonstrated that a microRNA biomarker
successfully identifies squamous lung cancer with high reproducibility, sensitivity and
specificity. "The study certainly demonstrates the power of microRNAs in correctly
classifying lung cancer and hopefully can immediately translate into more accurate choices
of targeted therapies as well as cytotoxics for the disease."
Gene therapy shows early promise
for treating obesity
With obesity reaching epidemic levels,
researchers at the Ohio State University Medical Center are studying a potentially
long-term treatment that involves injecting a gene directly into one of the critical
feeding and weight control centers of the brain. "Obesity significantly increases the
risk for diabetes, cardiovascular disease, stroke and some cancers," says Dr. Matthew
During, senior author and professor in Ohio State Medical Center's department of molecular
virology, immunology and medical genetics. "Our findings represent a promising new
treatment for obesity that could ultimately provide a much safer and more effective
approach than some conventional therapies." Scientists have discovered that a
particular gene, BDNF, can result in improved insulin sensitivity, reduced fat mass and
weight loss when active in the hypothalamus. The findings are published online in the
journal Nature Medicine. According to first author Lei Cao, assistant professor in the
department of molecular virology, immunology and medical genetics, the study involved
injecting the BDNF gene in normal mice, diabetic mice and mice fed with a high fat diet,
to determine how the gene transfer would affect their weight. "The gene was active in
the overweight mice, but as they lost weight the gene expression was essentially 'dialed
down,' using a novel RNA interference approach, thus stopping the weight from continuing
to decrease and allowing a stable target weight to be reached," she says. During
indicated that with the initial results showing great promise, the next step is to obtain
the necessary FDA approvals to begin studying the therapy in humans at OSU Medical Center
and other centers around the country.
Live fast, die young? Maybe not
The theory that a higher metabolism means a
shorter lifespan may have reached the end of its own life, thanks to a study published in
the journal Physiological and Biochemical Zoology. The study, led by Lobke Vaanholt
(University of Groningen, The Netherlands), found that mice with increased metabolism live
just as long as those with slower metabolic rates. The theory that fast-living animals die
young, known as the rate-of-living theory, was first proposed in the 1920s. The premise is
simple: Aging is the inevitable byproduct of energy expenditure. The faster you expend
energy, the faster you age, and the sooner you die. It remained a prominent theory of
aging until recently, when comparisons across broad animal groups cast doubt on it. For
instance, birds have significantly higher metabolisms than mammals of similar size, yet
the birds live much longer. Vaanholt's study was designed to test the rate-of-living
theory among individuals of one species—in this case, mice. For their experiment,
Vaanholt and her team followed two groups of mice through their entire lives. One group's
environment was kept at 71 degrees Fahrenheit (22 degrees Celsius), and the other group's
at 50 degrees Fahrenheit (10 degrees Celsius). The colder group had to expend more energy
to maintain body temperature, and according to the rate-of-living theory, should therefore
die sooner than the warm group. But that's not what happened. "Despite a 48 percent
increase in overall daily energy expenditure and a 64 percent increase in mass-specific
energy expenditure throughout adult life, mice in the cold lived just as long on average
as mice in warm temperatures," the authors write. "These results strengthen
existing doubts about the rate-or-living theory." The finding is consistent with an
experiment Vaanholt conducted previously. That experiment manipulated metabolism in mice
through exercise rather than temperature. Mice that expended more energy over a lifetime
through exercise had the same lifespan as those that did not exercise. Both studies cast
significant doubt on a theory that just may have burned itself out.
The difference between eye cells
is…sumo?
Researchers at the Johns Hopkins University
School of Medicine and Washington University School of Medicine have identified a key to
eye development — a protein that regulates how the light-sensing nerve cells in the
retina form. While still far from the clinic, the latest results, published in the Jan. 29
issue of Neuron, could help scientists better understand how nerve cells develop.
"We've found a protein that seems to serve as a general switch for photoreceptor cell
development," says Seth Blackshaw, Ph.D., an assistant professor in the Solomon H.
Snyder Department of Neuroscience at Johns Hopkins. "This protein coordinates the
activity of multiple proteins, acting like a conductor of an orchestra, instructing some
factors to be more active and silencing others, and thus contributing to the development
of light-sensitive cells of the eye."
Blackshaw's laboratory is trying to understand the steps necessary for developing
light-sensitive eye cells to transition into one of two types: rod or cone cells. Any
breakdown in the development of either type of cell can lead to impaired eyesight and,
says Blackshaw, "the loss of cone cells in particular can lead to irreversible
blindness." Rod cells help us see in dim or dark light, and cone cells help us see
bright light and color. The research team was interested in how other genes that are
active in the developing retina can act to promote the development of rod cells while
suppressing the development of cone cells. So they took a closer look at the candidate
protein Pias3, short for protein inhibitor of activated Stat3. Pias3 was known to alter
gene control in cells outside of the eye. In these cells, Pias3 doesn't directly turn
genes on and off, but instead adds a chemical tag — through a process called
SUMOylation — to other proteins that do switch genes on and off. And, since Pias3
also is found in developing rod and cone and no other cells in the eye, the team
hypothesized that it might act to help these cells "decide" which type to
become.
Montana State team finds
Yellowstone alga that detoxifies arsenic
Arsenic may be tough, but scientists have
found a Yellowstone National Park alga that's tougher. The alga -- a simple one-celled
algae called Cyanidioschyzon -- thrives in extremely toxic conditions and chemically
modifies arsenic that occurs naturally around hot springs, said Tim McDermott, professor
in the Department of Land Resources and Environmental Sciences at Montana State
University. Cyanidioschyzon could someday help reclaim arsenic-laden mine waste and aid in
everything from space exploration to creating safer foods and herbicides, the scientists
said. The alga and how it detoxifies arsenic are described in a paper that's posted this
week (week of March 9) in the online edition of Proceedings of the National Academy of
Sciences, or PNAS. Lead authors are McDermott and Barry Rosen, of Florida International
University. Among the four co-authors is Corinne Lehr, who formerly worked with McDermott
as a postdoctoral scientist at MSU and is now a faculty member at California Polytechnic
State University. Arsenic is the most common toxic substance in the environment, ranking
first on the Superfund list of hazardous substances, the researchers wrote in their paper.
McDermott said arsenic is very common in the hot, acidic waters of Yellowstone and
presents real challenges for microorganisms living in these conditions. Indeed, there are
challenges for the researchers. McDermott said the acid in the soil and water are strong
enough that it sometimes eats holes through his jeans when he kneels to collect samples.
McDermott has worked in Yellowstone for more than a decade and travels year-round to the
Norris Geyser Basin to study the microbial mats that grow in acidic springs. Over the
years, he noticed thick algae mats that were so lush and green in December that they
looked like Astro-Turf, McDermott said. By June, they were practically gone. While
investigating the change, McDermott and his collaborators learned about the Cyanidiales
alga and its ability to reduce arsenic to a less dangerous form. "These algae are
such a dominant member of the microbiology community that they can't escape notice, but
for some reason they have not attracted much attention," McDermott said.
