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TEXT ALERGY 1:
How Household Dogs Protect Against Asthma and Infection
Dec. 16, 2013 Children's risk for developing allergies and asthma is reduced when
they are exposed in early infancy to a dog in the household, and now researchers have
discovered a reason why.
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Exposure of mice to dust from houses where canine pets are permitted both indoors and outdoors can reshape the community of
microbes that live in the mouse gut -- collectively known as the gastrointestinal microbiome -- and also diminish immune system
reactivity to common allergens, according to a new study by researchers led by Susan Lynch, PhD, associate professor with the
Division of Gastroenterology at UC San Francisco, and Nicholas Lukacs, PhD, professor with the Department of Pathology at the U
Michigan.
The scientists also identified a specific bacterial species within the gut that is critical to protecting the airways against both allergens
and viral respiratory infection.
The study, funded by the National Institute of Allergy and Infectious Diseases (NIAID), is published online this week in
theProceedings of the National Academy of Sciences (PNAS) and involves a multi-disciplinary group of researchers from UCSF,
the University of Michigan, Henry Ford Health System and Georgia Regents University.
The results were obtained in studies of mice challenged with allergens after earlier exposure to dust from homes with dogs, but the
results also are likely to explain the reduced allergy risk among children raised with dogs from birth, according to the study leaders.
In their study the scientists exposed mice to cockroach or protein allergens. They discovered that asthma-associated inflammatory
responses in the lungs were greatly reduced in mice previously exposed to dog-associated dust, in comparison to mice that were
exposed to dust from homes without pets or mice not exposed to any dust.
Among the bacterial species in the gut microbiome of these protected mice, the researchers homed in on one, Lactobacillus
johnsonii. When they fed it alone to mice, they found it could prevent airway inflammation due to allergens or even respiratory
syncytial virus (RSV) infection. Severe RSV infection in infancy is associated with elevated asthma risk.
The researchers showed in this experiment that protection of the lungs' airways was associated with reduced numbers and activity
of asthma-associated immune cells.
The level of protection with this single species was less than that obtained with the full complement of dust microbes from dog
owners' homes, indicating that other, environmentally sourced bacterial species probably are necessary for full airway protection,
Lynch said.
This result suggests that Lactobacillus johnsonii or other species of "good" bacteria might one day be used to reshape the gut
microbiome in ways that can prevent the development of asthma or allergies, or perhaps even to treat existing cases, she said.
Lynch's own work and research by several others in the field has led her to become convinced that "the composition and function of
the gut microbiome strongly influence immune reactions and present a novel avenue for development of therapeutics for both
allergic asthma and a range of other diseases."
The current study demonstrates that changes in the gut microbiome can have wide-reaching effects on immune function beyond
the gut, at sites elsewhere in the body, Lynch said.
The team had previously demonstrated that the presence of a dog that roams both inside and outside was associated with a
significantly more diverse house dust microbiome that was enriched for species found in the gastrointestinal tract of humans.
After teaming up with Lukacs, an expert on immune responses in lung disease, Lynch said, "We set out to investigate whether
being exposed to a distinct house dust microbiome associated with indoor/outdoor dogs mediated a protective effect through
manipulation of the gut microbiome and, by extension, the host immune response."
"The results of our study indicate that this is likely to be one mechanism through which the environment influences immune
responses in early life, and it is something we are currently examining using human samples in a large multi-institutional
collaborative study funded by the NIAID."
"Gut microbiome manipulation represents a promising new therapeutic strategy to protect individuals against both pulmonary
infection and allergic airway disease," Lynch said.
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TEXT ALERGY 2:
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Link Between Allergies, Increased Risk of Blood Cancers in Women

Nov. 22, 2013 A team of scientists looking into the interplay of the immune system
and cancer have found a link between a history of airborne allergies -- in particular to
plants, grass and trees -- with risk of blood cancers in women.
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Notably, the study did not find the same association in men, which suggests a possible gender-specific role in chronic stimulation of
the immune system that may lead to the development of hematologic cancers. The findings are published online ahead of the
December print issue of the American Journal of Hematology. "To the best of our knowledge, ours is the first study to suggest
important gender differences in the association between allergies and hematologic malignancies," wrote first author Mazyar
Shadman, M.D., M.P.H., a senior fellow in the Clinical Research Division at Fred Hutchinson Cancer Research Center.
According to Shadman, who led the research, the immune system's potential role in cancer causation is a focus of intense scientific
interest. "If your immune system is over-reactive, then you have problems; if it's under-reactive, you're going to have problems.
Increasing evidence indicates that dysregulation of the immune system, such as you find in allergic and autoimmune disorders, can
affect survival of cells in developing tumors." For the study, Shadman, principal investigator Emily White, Ph.D., of the Public Health
Sciences Division at Fred Hutch and their colleagues drew on a large, population-based sample of men and women from the
VITamins And Lifestyle (VITAL) cohort, which included people aged 50-76 years old from western Washington. The study
participants answered a 24-page questionnaire that focused on three major areas: health history and cancer risk factors,
medication and supplement use, and diet. Participants provided information on age, race/ethnicity, education, smoking, diet (fruit
and vegetable intake), and other lifestyle characteristics, self-rated health, medical history, and family history of leukemia or
lymphoma.
History of asthma and allergies was also taken, including allergies to plants, grasses or trees; mold or dust; cats, dogs or other
animals; insect bites or stings; foods; and medications.
Of the 79,300 VITAL participants who filled out the questionnaires, more than 66,000 individuals were selected after eliminating
those who had a prior history of malignancies other than non-melanoma skin cancers and missing information on baseline cancer
history. Participants were followed for a median of eight years until they withdrew from the study, moved away, had a cancer
diagnosis other than hematologic malignancy or non-melanoma skin cancer, or died. Incidence of hematologic malignancies and
other cancers was identified via the Surveillance, Epidemiology and End Results (SEER) cancer registry of western Washington.
Of the participants, 681 developed a hematologic malignancy during the follow-up period. These participants were more likely to be
male, to have two or more first-degree relatives with a family history of leukemia or lymphoma, to be less active and rank their
health status as low. A history of allergies to airborne antigens was associated with a higher risk of hematologic malignancies. The
most statistically significant association was seen with allergies to plants, grass and trees.
Further, the study looked at associations between the different subtypes of allergies and hematologic malignancies and found that
a history of allergies to plants, grass and trees was significantly associated with mature B-cell neoplasms, one of four major
categories of lymphoma. There was also an increased risk of plasma-cell neoplasms for participants who reported a history of
allergies to cats, dogs or other animals. Plasma-cell neoplasms are conditions, both cancerous and noncancerous, in which the
body makes too many plasma cells. When stratified by gender, the incidence of blood cancers in response to these allergens was
increased in women but not in men. The reason for this is as yet unknown.
"It is tempting to speculate that the additional effect of allergy may reach statistical significance in women because of their lower
baseline risk for the development of hematologic malignancies compared to men," the authors wrote. "However, hormonal effects
on the immune system and interactions with carcinogenesis may offer an alternative biological explanation that will require further
mechanical studies, in particular if our findings are replicated in an independent study cohort."
The data analysis took into account potential confounding factors such as sex, race/ethnicity, education, history of smoking,
consumption of vegetables and fruits, level of exercise, family history of leukemia/lymphoma and self-reported health status. Types
of allergy medication participants used were not controlled for. "It's tough to eliminate allergy treatment as a confounder, because
just about everyone with allergies is on some medication. But none of the allergy medications are known to cause cancer,"
Shadman said.
The authors cite the study's strengths as its large population size, the comprehensive baseline data regarding cancer risk and
medical conditions, its prospective design and its use of the SEER registry, an award-winning cancer registry program based at
Fred Hutch. Meanwhile the authors acknowledge the study's limitations, namely the reliance on self-reporting of allergies, the
limitation of soliciting answers about current allergies only, and particularly the limited number of hematologic cancers for each
subset of allergy types.
"Given the limited number of cases within each subtype of hematologic cancer, the risk estimates need to be interpreted with
caution and the possibility of chance finding due to multiple testing should be recognized," Shadman and colleagues wrote.
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TEXT ALERGY 3:
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Nothin' to Sneeze At: New Treatment for Common Allergies

Oct. 3, 2013 Researchers have successfully tested treatments for people with
allergies to grasses and to dust mites.
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There are two treatments, one for grass allergy, which is commonly known as hay fever, and the other for dust mite allergy. They
are expected to be helpful for the millions of people who, as a reaction to grass pollen or the tiny bugs that live in house dust, have
sneezing, itching eyes and a running nose that often significantly impacts their productivity at school or work.
The two studies were conducted by Adiga Life Sciences, a joint venture between McMaster University and Circassia, a U.K. based
biotechnology company, and was supported by St. Joseph's Healthcare Hamilton.
It is estimated that together, these allergens are responsible for more than 50% of allergic respiratory disease. Between 15 and 25
per cent of the population in North America and Europe is sensitive to pollen from different grass species. One in four people is
sensitized to house dust mites, more than any other common allergen, which includes millions of people in these regions.
The treatments are from a new class of therapy, known as 'synthetic peptide immuno-regulatory epitopes', or SPIREs.
The 280 patients in the phase two clinical trial for the grass allergy treatment recorded their allergy symptoms while exposed to
grass pollen in a controlled environment, both before treatment and at the end of the hay fever season. Study participants received
one of three treatment regimens over three months, completed prior to the beginning of the pollen season. Those who had the
optimal short course of therapy had significantly improved symptoms at the end of the season, compared to those who had a
placebo. This treatment, called Grass-SPIRE, was well tolerated.
During the clinical trial for the dust mite treatment, 172 patients who received four doses of the treatment over 12 weeks had
significantly improved allergy symptoms a year after the start of treatment, compared to patients who received a placebo. The
treatment, called HDM-SPIRE, was well tolerated.
"This result is an important validation of the approach we are taking to treat allergic diseases," said Mark Larch, who led the
design of the treatments. "Positive results, first with a cat allergy therapy and now with house dust mite and grass allergy
treatments, suggest that this approach may be used for many common allergies."
Larch is a professor of medicine of the Michael G. DeGroote School of Medicine at McMaster and member of the Firestone
Institute for Respiratory Health at St. Joseph's Healthcare Hamilton.
Hay fever is a seasonal response to many different grass pollens which are heaviest in the spring and fall.
Dust mites are close relatives of spiders and ticks and are too small to see without a microscope. They eat skin cells shed by
people, and they thrive in warm, humid environments. Upholstered furniture, bedding and carpeting provide an ideal environment
for dust mites.
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TEXT ANEMY 1:
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Link Between Red Cell Distribution Width Levels, Depression

Nov. 18, 2013 Researchers at the Intermountain Medical Center Heart Institute have
discovered a link between elevated red cell distribution width levels and depression in
patients being treated for heart disease. This new discovery can help physicians
provide earlier diagnosis and treatment for possible depression in heart patients.
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Red cell distribution width or RDW is a parameter that measures variation in red blood cell size or red blood cell volume. A high
RDW (over 14.5%) means that the red blood cells vary a lot in size. A normal RDW is 11.6 to 14.6%, but researchers from the
Intermountain Medical Center Heart Institute found that patients with a RDW level greater than or equal to 12.9% had an increased
risk for depression.
The new study found that the higher the RDW, the greater the risk for depression for patients. This is the first time this association
has been discovered.
Results of the study will be presented during the American Heart Association Scientific Sessions in Dallas, on Monday, November
18 at 9:30 am, ET.
"Elevated red blood distribution widths are associated with anemia, but it also appears to be associated with other poor outcomes,
like heart attacks, heart failure, death and now depression," said Heidi May, PhD, MSPH, the study's principal researcher at the
Intermountain Medical Center Heart Institute in Murray, Utah.
This study looked at 43,226 patients and evaluated them for an average of 5.3 years, identifying RDW levels of patients at time of
diagnosis and comparing them to a follow-up diagnosis of depression.
RDW is routinely tested as part of the complete blood count panel and is generally used in combination with other tests to
differentiate forms of anemia. The tests detect pulses that are produced by red blood cells. The stronger the pulses are, the greater
the red blood cells are in size. Likewise, the weaker the pulses are, the smaller the red blood cells are in size.
"Patients and physicians should be more aware that depression may be one of those poor outcomes and should be more diligent in
screening for depression among patients who have an elevated RDW," Dr. May said.
Previous studies have also shown RDW to be a powerful indicator of poor outcomes, particularly among cardiovascular patients.
However, depression has never been studied as a possible outcome for heart patients, according to Dr. May.
"With these findings, physicians should be more aware of this association and note that heart patients with an elevated RDW are at
a higher risk for depression," she said. "This should encourage physicians to be more diligent in screening for depression and
treating it accordingly."
"This study is important as it's the first to show an association between elevated RDW and depression in heart patients," said Dr.
May. "Our hope is that other studies can be done to look at this association in different populations, even a more general medical
population, to see if an association remains."
The findings of this study persisted despite adjustment for risk factors, medications, and indicators of other diseases. Additional
studies will be required to determine if the association is causal, wherein depression is a result of abnormal red cell size, anemia or
some other co-morbidity.
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TEXT ANEMY 2:
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Iron Supplementation Can Provide Cognitive, Physical Benefits to Anemic

Children
Oct. 15, 2013 Giving daily iron supplements to anemic primary-school-aged children
can have cognitive and physical benefits, according to a study published
in CMAJ (Canadian Medical Association Journal).
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Globally, approximately 25% of school-aged children are anemic, with iron deficiency the cause of about half of all cases. Iron
deficiency, which has been associated with impaired cognitive and physical development, is caused by a lack of dietary iron and, in
developing countries, by parasites such as hookworm and schistosomiasis. In developed countries, newcomers, native people and
some ethnic populations can be anemic. About 3% of primary-school-aged children in Canada are anemic. However, concerns that
iron supplementation may have negative health effects limit efforts to address iron deficiencies.
To understand the effects of iron supplementation, Australian researchers conducted an analysis of 32 studies including 7089
children mainly in low- and middle-income countries. Anemic children who received iron supplements had higher cognitive scores
than children in the control groups (9 studies with 2355 children). They also showed substantial improvement in IQ scores and
other cognitive tests. Children who received iron supplements were also slightly taller for their age and had improved weight-forage compared with children who did not.
"We found evidence of a benefit of iron supplementation on cognitive performance among primary-school-aged children, including
on IQ among children with anemia," writes Dr. Sant-Rayn Pasricha, The Royal Melbourne Hospital and the Faculty of Medicine,
Dentistry and Health Sciences, The University of Melbourne, with coauthors. "Iron may also improve growth. Daily iron
supplementation decreased the prevalence of anemia by about 50% and reduced the prevalence of iron deficiency by 79%."
There appeared to be no adverse effects, with no differences in the prevalence of malaria or gastrointestinal issues between the
groups that received iron and the control groups. In addition, some studies reported fewer respiratory tract infections.
The study is larger and broader than others, with a comprehensive analysis of benefits and safety of iron supplementation.
"Iron supplementation benefits global cognitive performance .Routine daily iron supplementation is likely to benefit cognitive
performance in primary school children in developing settings where anemia is prevalent and testing hemoglobin before iron
supplementation may not be feasible," the authors conclude.
In a related commentary, Dr. Katherine Gray-Donald, McGill University, Montral, writes that this meta-analysis "is important in that
it quantifies the robust effects of iron supplementation on cognitive performance among anemic children who are iron deficient. The
next challenge is to determine how to safely, economically and sustainably provide better iron nutrition to children in many poor
settings of the world. Clearly anemic children will benefit, but the risks of iron for all remain to be elucidated."
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TEXT TRATAMENT GENETIC 1:

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Ceratin Gene Mutations Make Breast Cancers Treatment-Resistant

Dec. 12, 2013 Women with breast cancer characterized by high levels of the protein
HER2 and hormone receptors gained much less benefit from presurgery treatment with
chemotherapy and HER2-targeted therapies if their cancer had one or more mutations
in the PIK3CA gene, according to results presented at the 2013 San Antonio Breast
Cancer Symposium, held Dec. 10-14.
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Treatment given to shrink or eliminate a tumor before surgery is called neoadjuvant therapy. In some women with breast cancer
treated with neoadjuvant therapy, no residual invasive cancer can be detected in breast tissue samples and lymph nodes removed
during surgery. Emerging data suggest that these women, who are said to have had a pathologic complete response, have a
greater chance of long-term survival compared with women who do not have a pathologic complete response.
"Mutations in the PIK3CA gene are among the most common genetic aberrations in breast cancer," said Sibylle Loibl, M.D.,
professor at the German Breast Group in Neu-Isenburg, Germany. "We found that very few women with HER2- and hormone
receptor-positive breast cancer with a PIK3CA mutation experienced a pathologic complete response after receiving neoadjuvant
therapy.
"We need to identify new treatment options for this group of patients and evaluate them in clinical trials," continued Loibl. "We also
need to integrate PIK3CA mutation analysis of breast tumors into routine practice so that we can ensure women receive the most
appropriate neoadjuvant therapy for their tumor type."
Loibl and colleagues investigated whether the presence of a PIK3CA mutation affected patients enrolled in the GeparSixto (G6)
clinical trial in experiencing a pathologic complete response after neoadjuvant therapy. There were 595 participants in the G6
clinical trial, and information on the presence or absence of PIK3CA gene mutations was available for 512,240 with HER2-postive
breast cancer and 272 with triple-negative breast cancer.
Participants in the G6 clinical trial received neoadjuvant chemotherapy (paclitaxel and nonpegylated-liposomal doxorubicin) and
were randomly assigned the chemotherapy carboplatin or no additional chemotherapy. Patients with HER2-positive disease also
received neoadjuvant trastuzumab and lapatinib, two HER2-targeted therapies, while patients with triple-negative disease also
received neoadjuvant bevacizumab.
Loibl and colleagues found that patients with HER2-postive breast cancer were more likely to have at least one PIK3CA mutation in
their tumor compared with women with triple-negative breast cancer. Overall, the pathologic complete response rate was lower
among women with at least one PIK3CA mutation in their tumor compared with women without a PIK3CA mutation, but the effect
was only significant among the group of women with HER2- and hormone receptor-positive breast cancer. Among these women,
patients with a PIK3CA mutation had a pathologic complete response rate of only 6.5 percent compared with 30.8 percent for those
without a PIK3CA mutation.
"To evaluate these findings in a group with only one HER2 treatment, we are currently analyzing data from another clinical trial, the
GeparQuinto clinical trial, which is a randomized, phase III clinical trial evaluating two different neoadjuvant therapy regimens with a
single anti-HER2 treatment [trastuzumab or lapatinib] for women with HER2-positive breast cancer," said Loibl. "We hope to
present these results together with those from the G6 clinical trial in San Antonio."
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Long-Lasting Gene Therapy Benefits Advanced Heart Failure Patients

Nov. 19, 2013 Researchers from the Cardiovascular Research Center at Icahn
School of Medicine at Mount Sinai reported the long-term benefits of a single dose of
their gene therapy AAV1/SERCA2a in advanced heart failure patients on Nov. 19 at the
American Heart Association Scientific Sessions 2013.
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The new long-term follow-up results from their initial Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In
Cardiac Disease (CUPID 1) clinical trial found a one-time, high-dose injection of the AAV1/SERCA2a gene therapy results in the
presence of the delivered SERCA2a gene up to 31 months in the cardiac tissue of heart failure patients.
In addition, study results show clinical event rates in gene therapy patients are significantly lower three years later compared to
those patients receiving placebo. Also, patients experienced no negative side effects following gene therapy delivery at three-year
follow-up.
"This study shows AAV1/SERCA2a gene therapy has long-lasting and beneficial effects for congestive heart failure patients
allowing us to block the downward spiral of patients with severe heart failure, " says principal investigator Roger J. Hajjar, MD,
Director of the Cardiovascular Research Center and the Arthur & Janet C. Ross Professor of Medicine at Icahn School of Medicine
at Mount Sinai, who developed the gene therapy approach.
The gene therapy uses a modified adeno-associated viral-vector derived from a parvovirus. The one-time gene therapy is injected
through the coronary arteries of heart failure patients using catheters. It works by introducing healthy SERCA2a genes into cells.
The delivery of the SERCA2a gene produces SERCA2a enzymes, which helps heart cells restore their proper use of calcium.
SERCA2a is an enzyme critical for proper pumping of calcium in calcium compartments within cells. SERCA2a dysfunction or
reduced expression occurs in patients with heart failure. When SERCA2a is down-regulated, calcium stays longer in the cells than
it should, and it induces pathways that lead to overgrowth of new and enlarged cells. This contributes to an enlarged heart in heart
failure patients.
Previously, CUPID 1 study results showed the gene therapy to be clinically safe and effective for over 12 months with improved
heart function status and left ventricular function, along with a significant decrease in recurrent cardiovascular events. CUPID 1 was
the first-in human clinical gene therapy randomized, double-blind study which enrolled 39 patients with advanced heart failure.
"AAV1/SERCA2a gene therapy has been proven to be a safe and effective therapeutic intervention for advanced heart failure,"
says Dr. Hajjar. "Our long-term results support the potential use of AAV1/SERCA2a gene therapy as a new important additional
tool for treating and managing advanced heart failure patients."
This study was presented as an Oral Session (Abstract 10667): Long Term Follow-up of Patients with Advanced Heart Failure
Following a Single Intracoronary Infusion of AAV1/SERCA2a. In addition, on Nov. 19 Dr. Hajjar also presented at the AHA
Scientific Sessions 2013 a Plenary talk entitled, "How the Postgenome Era Will Change the Practice of Cardiology" and discussed
his work on targeted gene therapy for human heart failure.
In his Plenary talk, Dr Hajjar presented his new findings just published in the journal Science Translational Medicine on Nov. 13 that
show delivery of small ubiquitin-related modifier 1 (SUMO-1), an important regulator of SERCA2a, in preclinical heart failure models
improves cardiac contractility and prevents left ventricular dilatation -- two major aspects of heart failure. According to Dr. Hajjar,
the transition of this SUMO-1 gene therapy from pigs to humans seems likely in the short-term. Also, Dr. Hajjar revealed that
development of novel cardiotropic vectors may render cardiovascular gene therapy easier and less-invasive in the near future.
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RNA Build-Up Linked to Dementia, Motor Neuron Disease

Oct. 30, 2013 A new toxic entity associated with genetically inherited forms of
dementia and motor neuron disease has been identified by scientists at the UCL
Institute of Neurology. The toxin is the result of a genetic mutation that leads to the
production of RNA molecules which could be responsible for the diseases. The findings
are published in the journalActa Neuropathologica.
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1
Frontotemporal dementia and motor neuron disease are related neurodegenerative diseases that affect approximately 15,000
people in the UK. Frontotemporal dementia causes profound personality and behaviour changes. Motor neuron disease leads to
muscle weakness and eventual paralysis.
The most common known cause for both frontotemporal dementia and motor neuron disease is an unusual genetic mutation in the
C9orf72 gene. The mutation involves a small string of DNA letters at the beginning of the gene, which expand massively to produce
thousands of copies.
The new research, funded by Alzheimer's Research UK and the Medical Research Council, has shown that this DNA expansion
acts in a peculiar way, leading to the generation of unexpected RNA molecules that could cause the disease.
When a gene is turned on, an RNA copy of the gene's DNA is generated. The gene's DNA code has directionality, so that it is
normally turned on in only one direction, termed the 'sense direction'. The new research shows that the DNA expansion is turned
on in both directions.
This leads to the normal sense RNA being produced, as well as RNA in the opposite direction, termed 'antisense RNA'. Both RNA
types accumulate into aggregates in the neurons of people with frontotemporal dementia.
Intriguingly, the research showed that people with more of these aggregates in their brains developed the disease earlier than
people with less RNA aggregates. This correlation suggests that the build-up may be important in causing frontotemporal dementia
and motor neuron disease, making the C9orf72 DNA expansion a potential target for therapy.
Dr Adrian Isaacs, lead researcher at the UCL Institute of Neurology, said: ""These findings identify new, potentially toxic molecules
in diseases caused by DNA expansions. The next steps will be to determine how they might kill neurons and how to stop them
building up."
Dr Simon Ridley, Head of Research at Alzheimer's Research UK, the UK's leading dementia research charity, said: "The discovery
of the C9ORF72 gene was a major step forward for research into frontotemporal dementia and motor neuron disease, and it's
positive to see researchers beginning to untangle how this gene may cause these diseases in some people. Alzheimer's Research
UK is delighted to have supported this promising study. By unravelling some of the biological mechanisms at play, this research
could take us further on the road to new treatments that are so desperately needed by the thousands of people with these
devastating diseases. For these results to reach their full potential it's vital that we continue to invest in research."
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TEXT NUTRITITION 1:
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Diet Quality Links Old, Young

Dec. 18, 2013 Understanding how dietary habits are connected through the
generations could have valuable benefits for community health, a new study shows.
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The Taiwanese study assessed the relationship between the quality of children's diets and that of their elders in a wide range of
representative communities, generating findings that have international relevance.
Led by Emeritus Professor Mark Wahlqvist from Monash University's Department of Epidemiology and Preventive Medicine and the
Monash Asia Institute, the research used national survey information on health and nutrition for more than 2400 students aged from
six to 13, and nearly 1800 elderly people.
"The groups of children who scored highest on dietary quality showed a correlation with high dietary scores among their respective
elders," Professor Wahlqvist said.
This was seen within the context of a range of factors that were shown to influence the quality of children's diets.
"Factors from level of household income and parental education to the amount of time children spend watching television were all
found to be significant determinants of dietary quality in children," Professor Wahlqvist said.
When the overall findings were adjusted for these aspects, the quality of elders' diets was still significantly associated with that of
young people's.
The researchers believe grandparents may be even more likely than parents to influence food habits.
"It is likely that the grandparent generation is transmitting what the cultural group has acquired over several generations, modulated
by their children and grandchildren," Professor Wahlqvist said.
The research also raised the possibility that the association works both ways, with children's familiarity with information technology,
for example, boosting their influence over their elders.
Given the links between diet and health issues such as obesity and longevity, the intergenerational associations are particularly
relevant, Professor Wahlqvist said.
"Our findings suggest that a decline in nutritional capacity in communities, represented by intergenerational transfer of food
patterns, may place community health at risk. At the same time, the observations suggest that intervening with healthy eating
measures in one generation may benefit other generations as well."
The study, which also involved the National Health Research Institutes, Taiwan, will be published later this month in theEcology of
Food and Nutrition journal.
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Study Links Sleep to Mood Disturbance, Poor Quality of Life in Obese

Dec. 4, 2013 A new study shows that poor sleep quality is strongly associated with
mood disturbance and lower quality of life among people with extreme obesity.
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Results show that 74.8 percent of participants were poor sleepers, and their mean self-reported sleep duration was only six hours
and 20 minutes. Fifty-two percent of study subjects were anxious, and 43 percent were depressed. After controlling for age, sex,
hypertension, diabetes, and obstructive sleep apnea, sleep quality and daytime sleepiness were significantly associated with mood
disturbance and quality of life impairment.
"There was a clear association between the sleep problems such as short sleep duration and the psychological disorders and with
quality of life," said Dr. G. Neil Thomas, lead supervisor, study methodology lead and reader in epidemiology at the Department of
Public Health, Epidemiology and Biostatistics at the University of Birmingham in the United Kingdom. "These associations
remained significant even after adjusting for a range of potential confounders."
The study involved 270 patients with a mean body mass index (BMI) of 47.0 kg/m2 who were consecutively enrolled in a regional
specialist weight management service. They had a mean age of 43 years. Sleep disturbance, daytime sleepiness, mood and
quality of life were assessed using standardized questionnaires.
The study results appear in the December issue of the journalSleep.
"This study emphasizes the need for physicians to conduct routine screenings for sleep problems among people with severe
obesity," said American Academy of Sleep Medicine President Dr. M. Safwan Badr. "Improving sleep quality and quantity will
provide a physical, mental and emotional boost for people who are making the difficult lifestyle changes involved in managing
obesity."
According to the authors, the potential role of sleep in the health and well-being of individuals with severe obesity is
underappreciated. Although the cross-sectional design of the study did not allow for an examination of causality, the results
suggest that the early detection of disturbed sleep could prevent the potential development and perpetuation of psychological
problems among people with extreme obesity.
"Despite the very high levels of problems in these patients, those involved with their care usually don't ask about sleep problems
and often pay little heed to the psychological issues underlying the obesity," said Thomas. "The focus is often on treating the
obesity and its consequences, such as diet and exercise interventions, rather than addressing its underlying cause, which may be
psychological in nature, such as an unhappy marriage or job stress."
According to the Centers for Disease Control and Prevention, 35.7 percent of U.S. adults are obese with a BMI of 30 or higher. The
CDC estimates that the annual medical cost of obesity in the U.S. was $147 billion in 2008 dollars.
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TEXT NERVOUS SYSTEM 1:

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Will Stem Cell Therapy Help Cure Spinal Cord Injury?

Dec. 17, 2013 A systematic survey of the scientific literature shows that stem cell
therapy can have a statistically significant impact on animal models of spinal cord
injury, and points the way for future studies.
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1
Spinal cord injuries are mostly caused by trauma, often incurred in road traffic or sporting incidents, often with devastating and
irreversible consequences, and unfortunately having a relatively high prevalence (250,000 patients in the USA; 80% of cases are
male). High-profile campaigners like the late actor Christopher Reeve, himself a victim of sports-related spinal cord injury, have
placed high hopes in stem cell transplantation. But how likely is it to work?
This question is addressed in a paper published 17th December in the open access journal PLOS Biology by Ana Antonic, David
Howells and colleagues from the Florey Institute and the University of Melbourne, Australia, and Malcolm MacLeod and colleagues
from the University of Edinburgh, UK.
Stem cell therapy aims to use special regenerative cells (stem cells) to repopulate areas of damage that result from spinal cord
injuries, with the hope of improving the ability to move ("motor outcomes") and to feel ("sensory outcomes") beyond the site of the
injury. Many studies have been performed that involve animal models of spinal cord injury (mostly rats and mice), but these are
limited in scale by financial, practical and ethical considerations. These limitations hamper each individual study's statistical power
to detect the true effects of the stem cell implantation.
This new study gets round this problem by conducting a "meta-analysis" -- a sophisticated and systematic cumulative statistical
reappraisal of many previous laboratory experiments. In this case the authors assessed 156 published studies that examined the
effects of stem cell treatment for experimental spinal injury in a total of about 6000 animals.
Overall, they found that stem cell treatment results in an average improvement of about 25% over the post-injury performance in
both sensory and motor outcomes, though the results can vary widely between animals. For sensory outcomes the degree of
improvement tended to increase with the number of cells introduced -- scientists are often reassured by this sort of "dose
response," as it suggests a real underlying biologically plausible effect.
The authors went on to use their analysis to explore the effects of bias (whether the experimenters knew which animals were
treated and which untreated), the way that the stem cells were cultured, the way that the spinal injury was generated, and the way
that outcomes were measured. In each case, important lessons were learned that should help inform and refine the design of future
animal studies. The meta-analysis also revealed some surprises that should provoke further investigation -- there was little
evidence of any beneficial sensory effects in female animals, for example, and it didn't seem to matter whether immunosuppressive
drugs were administered or not.
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The authors conclude: "Extensive recent preclinical literature suggests that stem cell-based therapies may offer promise; however
the impact of compromised internal validity and publication bias means that efficacy is likely to be somewhat lower than reported
here."
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Scientists Accelerate Aging in Stem Cells to Study Age-Related Diseases Like

Parkinson's
Dec. 5, 2013 Stem cells hold promise for understanding and treating
neurodegenerative diseases, but so far they have failed to accurately model disorders
that occur late in life. A study published by Cell Press December 5th in the journalCell
Stem Cell has revealed a new method for converting induced pluripotent stem cells
(iPSCs) into nerve cells that recapitulate features associated with aging as well as
Parkinson's disease. The simple approach, which involves exposing iPSC-derived cells
to a protein associated with premature aging called progerin, could enable scientists to
use stem cells to model a range of late-onset disorders, opening new avenues for
preventing and treating these devastating diseases.
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"With current techniques, we would typically have to grow pluripotent stem cell-derived cells for 60 or more years in order to model
a late-onset disease," says senior study author Lorenz Studer of the Sloan-Kettering Institute for Cancer Research. "Now, with
progerin-induced aging, we can accelerate this process down to a period of a few days or weeks. This should greatly simplify the
study of many late-onset diseases that are of such great burden to our aging society."
Modeling a specific patient's disease in a dish is possible with iPSC approaches, which involve taking skin cells from patients and
reprogramming them to embryonic-like stem cells capable of turning into other disease-relevant cell types like neurons or blood
cells. But iPSC-derived cells are immature and often take months to become functional, similar to the slow development of the
human embryo. As a result of this slow maturation process, iPSC-derived cells are too young to model diseases that emerge late in
life.
To overcome this hurdle, Studer and his team exposed iPSC-derived skin cells and neurons, originating from both young and old
donors, to progerin. After short-term exposure to this protein, these cells showed age-associated markers that are normally present
in old cells.
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The researchers then used iPSC technology to reprogram skin cells taken from patients with Parkinson's disease and converted
the stem cells into the type of neuron that is defective in these patients. After exposure to progerin, these neurons recapitulated
disease-related features, including neuronal degeneration and cell death as well as mitochondrial defects.
"We could observe novel disease-related phenotypes that could not be modeled in previous efforts of studying Parkinson's disease
in a dish," says first author Justine Miller of the Sloan-Kettering Institute for Cancer Research. "We hope that the strategy will
enable mechanistic studies that could explain why a disease is late-onset. We also think that it could enable a more relevant
screening platform to develop new drugs that treat late-onset diseases and prevent degeneration."
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New Clues to Memory Formation May Help Better Treat Dementia

Nov. 27, 2013 Do fruit flies hold the key to treating dementia? Researchers at the
University of Houston (UH) have taken a significant step forward in unraveling the
mechanisms of Pavlovian conditioning. Their work will help them understand how
memories form and, ultimately, provide better treatments to improve memory in all
ages.
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Gregg Roman, an associate professor of biology and biochemistry at UH, and Shixing Zhang, his postdoctoral associate, describe
their findings in a paper titled "Presynaptic Inhibition of Gamma Lobe Neurons Is Required for Olfactory Learning in Drosophila,"
appearing Nov. 27 in Current Biology, a scientific bimonthly journal published by Cell Press.
"Memory is essential to our daily function and is also central to our sense of self," Roman said. "To a large degree, we are the sum
of our experiences. When memories can no longer be retrieved or we have difficulty in forming new memories, the effects are
frequently tragic. In the future, our work will enable us to have a better understanding of how human memories form."
Roman and Zhang set about to unravel some of these mysteries by studying the brains of fruit flies (Drosophila). Within the fly
brain, Roman says, there are nerve cells that play a role in olfactory learning and memory. Olfactory learning, he says, is an
example of classical conditioning first described by Pavlov in his experiment with dogs. In their study, the flies were trained to
associate a weak electric shock with an odor. After training, the flies avoided that odor.
"We found that these particular nerve cells -- the gamma lobe neurons of the mushroom bodies in the insect brain -- are activated
by odors. Training the flies to associate an odor with an electric shock changed how these cells responded to odors by developing
a modification in gamma lobe neuron activity, known as a memory trace," he said. "Interestingly, we found that training caused the
gamma lobe neurons to be more weakly activated by odors that were not paired with an electric shock, while the odors paired with
electric shock maintained a strong activation of these neurons. Thus, the gamma lobe neurons responded more strongly to the
trained odor than to the untrained odor."
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The team also showed that a specific protein -- the heterotrimeric G(o) protein -- is naturally involved in inhibiting gamma lobe
neurons. Roman says removing the activity of this protein only within the gamma lobe neurons resulted in a loss of the memory
trace and, thus, poor learning. Therefore, inhibiting the release of neurotransmitters from these neurons through the actions of the
G(o) protein is key to forming the memory trace and associative memories.
The significance of using fruit flies is that while their brain structure is much simpler with far fewer neurons, the mushroom body is
analogous to the perirhinal cortex in humans, which serves the same function of sensory integration and learning. This simplicity
allows scientists to gain insights into how memories are acquired, stored and retrieved.
"Drosophila represents the Goldilocks principle of neural research, with sufficient behavioral complexity, while maintaining a huge
advantage in neural simplicity," Roman said. "The complex behaviors allow us to examine many behavioral processes like learning,
attention, aggression and addiction-like behaviors, while the simplicity allows us to dissect the crucial neural activities down to
single cells. Additionally, Drosophila has the most powerful genetic toolkit available for behavioral experimentation. In using these
tools, we are genetically identifying the molecules necessary to perform these behaviors and dissecting the logic of the neural
circuits that allow for changes in behavior to occur."
The pair says all their experience to date suggests the molecules and logic will translate to most animals, including humans,
leading to a more complete understanding of how memories form in humans, both at the level of molecules and through the activity
of neural circuits.
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Different Gene Expression in Male, Female Brains May Help Explain Brain
Disorder Differences
Nov. 22, 2013 UCL scientists have shown that there are widespread differences in
how genes, the basic building blocks of the human body, are expressed in men and
women's brains.
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2
Based on post-mortem adult human brain and spinal cord samples from over 100 individuals, scientists at the UCL Institute of
Neurology were able to study the expression of every gene in 12 brain regions. The results are published inNature
Communications.
They found that the way that the genes are expressed in the brains of men and women were different in all major brain regions and
these differences involved 2.5% of all the genes expressed in the brain.
Among the many results, the researchers specifically looked at the gene NRXN3, which has been implicated in autism. The gene is
transcribed into two major forms and the study results show that although one form is expressed similarly in both men and women,
the other is produced at lower levels in women in the area of the brain called the thalamus. This observation could be important in
understanding the higher incidence of autism in males.
Overall, the study suggests that there is a sex-bias in the way that genes are expressed and regulated, leading to different
functionality and differences in susceptibility to brain diseases observed by neurologists and psychiatrists.
Dr. Mina Ryten, UCL Institute of Neurology and senior author of the paper, said: "There is strong evidence to show that men and
women differ in terms of their susceptibility to neurological diseases, but up until now the basis of that difference has been unclear.
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"Our study provides the most complete information so far on how the sexes differ in terms of how their genes are expressed in the
brain. We have released our data so that others can assess how any gene they are interested in is expressed differently between
men and women."
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TEXT ALZHEIMER 1:
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Origin of Alzheimer's Gene Mutation Discovered

Dec. 4, 2013 The age and origin of the E280A gene mutation responsible for earlyonset Alzheimer's in a Colombian family with an unusually high incidence of the
disease has been traced to a single founder dating from the 16th century.
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2
Kenneth S. Kosik, Harriman Professor in Neuroscience at UC Santa Barbara and co-director of the campus's Neuroscience
Research Institute (NRI), conducted the study. The findings appear in the journal Alzheimer's & Dementia.
"Some mutations just increase your risk, but this mutation is not a risk," Kosik said. "This mutation is highly penetrant, which means
that if you carry the mutation, you will get early-onset Alzheimer's disease."
Kosik's team sequenced the genomes of more than 100 family members and applied identity-by-descent analysis to identify
regions of common ancestry. DNA is inherited from both the parents and recombined in chunks. From these pieces, scientists can
identify which parent -- and sometimes which grandparent or great-grandparent -- is the source of the DNA. As time goes by,
sections of DNA recombine into smaller and smaller segments, each representing a history of its ancestry.
Sequencing the genomes came about because the researchers knew that while most family members with the mutation develop
early-onset Alzheimer's at age 45, there were a small number of outliers. "A few people got it a decade later, a few got it a decade
earlier and we wondered if there was a gene that was protecting those who got the disease later," Kosik explained. "That protective
gene -- even though this mutation exists only in this Colombian family -- might be useful for all of us. That research is still ongoing."
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Out of the genome sequencing came the idea of determining where the gene mutation originated. In addition to DNA analysis, the
researchers conducted interviews with the older healthy individuals of each affected family and spoke to genealogists and
historians in Colombia's Antioquian region. Kosik's co-author Francisco Lopera examined local historical and genealogical books,
last wills and ecclesiastical records dating as far back as 1540.
When the scientists examined the DNA patterns around the gene mutation site, they found markers from the Iberian peninsula.
They estimated the age and geographic origin of E280A to be consistent with a single founder dating from the time of the Spanish
Conquistadors who began colonizing Colombia during the early 16th century.
"This doesn't have big medical implications, but it shows that genetics is a very powerful tool and can be used to reconstruct
history," Kosik said. "What we've done here might be called 'neuroarchaeology.' "
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TEXT ALZHEIMER 2:
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Brain Area Attacked by Alzheimer's Links Learning, Rewards

Dec. 18, 2013 One of the first areas of the brain to be attacked by Alzheimer's
disease is more active when the brain isn't working very hard, and quiets down during
the brain's peak performance.
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The question that Duke University graduate student Sarah Heilbronner wanted to resolve was whether this brain region, called the
posterior cingulate cortex, or PCC, actively dampens cognitive performance, say by allowing the mind to wander, or is instead
monitoring performance and trying to improve it when needed.
If the PCC were monitoring and improving performance, increased activity there would be the result of poor performance, not the
cause of it.
The PCC connects to both learning and reward systems, Heilbronner said, and is a part of the "default mode network." It lies along
a mid-line between the ears, where many structures related to rewards can be found. "It's kind of a nexus for multiple systems,"
said Heilbronner, who is currently a postdoctoral researcher in neuroanatomy at the University of Rochester.
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"As this area begins to deteriorate, people begin to show the early signs of cognitive decline -- problems learning and remembering
things, getting lost, trouble planning -- that ultimately manifest as outright dementia," said Michael Platt, director of the Duke
Institute for Brain Sciences, who supervised Heilbronner's 2012 dissertation. Their findings appear Dec. 18 in the journal Neuron.
Heilbronner's experiment to better understand the PCC's role in learning and remembering relied on two rhesus macaque monkeys
fitted with electrodes to read out the activity of individual neurons in their brains. Their task was akin to playing video games with
their eyes. The monkeys were shown a series of photographs each day marked with dots at the upper left and lower right corners.
To get a rewarding squirt of juice, they had to move their gaze to the correct target dot on a photo, and they learned by trial and
error which dot would yield the reward for each photo.
Each day, they were shown up to 12 photos from an assortment of Heilbronner's vacation snaps at Yellowstone National Park and
the Grand Canyon. Some of each day's images were familiar with a known reward target, and others were new. As the monkeys
responded with their gaze, the researchers watched the activity of dozens of neurons in each monkey's brain immediately following
correct and incorrect responses. They also altered the amount of juice dispensed in some cases, creating a sense of high-reward
and low-reward answers.
If the PCC actively dampened performance, the researchers would expect to see it active before a choice is made or the feedback
is received. Instead, they saw it working after the feedback, lasting sometimes until the next image was presented. Neurons in the
PCC responded strongly when the monkeys needed to learn something new, especially when they made errors or didn't earn
enough reward to keep motivated.
The researchers also ran the task after administering a drug, muscimol, that impaired the function of the PCC temporarily during
testing. With the center inactivated by the drug, the monkeys could recall earlier learning regardless of the size of the reward.
Learning a new item was still possible when the reward was large, but the monkeys couldn't learn anything new when rewards
were small. "Maybe it didn't seem worth it," Heilbronner said.
The dampening experiment also reinforced what the researchers had seen in the timing of the PCC's response. If this center's role
is to let the mind wander, performance should have improved when the muscimol was administered, but the opposite was true.
Heilbronner concludes that the PCC summons more resources for a challenging cognitive task. So rather than being the cause of
poor performance on a task, PCC actually steps in during a challenge to improve the situation.
"This study tells us that a healthy PCC is required for monitoring performance and keeping motivated during learning, particularly
when problems are challenging," Platt said.
Heilbronner is now interested in finding out whether the PCC is more important to learning than it is to recall, and how motivation
interacts with PCC abnormalities seen in Alzheimer's disease.
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TEXT VACCINES 1:
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Animal Vaccine Study Yields Insights That May Advance HIV Vaccine Research
Dec. 18, 2013 A vaccine study in monkeys designed to identify measurable signs
that the animals were protected from infection by SIV, the monkey version of HIV, as
well as the mechanism of such protection has yielded numerous insights that may
advance HIV vaccine research. Seven laboratories collaborated on the study led by
Mario Roederer, Ph.D., and John R. Mascola, M.D., at the Vaccine Research Center of
the National Institute of Allergy and Infectious Diseases (NIAID), part of the National
Institutes of Health.
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By examining both viral amino-acid sequences and the animals' immune responses, the scientists could determine the
mechanisms of protection from SIV infection. The study demonstrated that antibodies to the virus spikes that SIV uses to infect
cells are necessary and sufficient to prevent SIV infection. The study also identified clear measures of immune responses in
monkeys that predict protection from SIV infection.
Amid the genetically heterogeneous mix of SIV to which the vaccinated monkeys were exposed, vaccine-induced immune
responses tended to block infection by those viruses sensitive to neutralization by SIV antibodies, while neutralization-resistant
forms of SIV tended to cause infection. A two-amino-acid change to the spikes on SIV converted neutralization-sensitive SIV to
neutralization-resistant SIV, and vice versa. A similar change to the spikes on HIV had a related effect. Thus, SIV and HIV escape
the immune system in similar ways, the scientists discovered. They concluded that the reasons why future human HIV vaccine
trials fail or succeed will become clearer if scientists integrate information on the amino-acid sequence and neutralization sensitivity
or resistance of the infecting virus together with information about volunteers' immune responses to the vaccine.
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New Method for Stabilizing Hemoglobin Could Lead to Stable Vaccines, Artificial
Blood
Dec. 4, 2013 A UConn research team has found a way to stabilize hemoglobin, the
oxygen carrier protein in the blood, a discovery that could lead to the development of
stable vaccines and affordable artificial blood substitutes.
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The team's novel approach involves wrapping the polymer poly(acrylic acid) around hemoglobin, protecting it from the intense heat
used in sterilization and allowing it to maintain its biological function and structural integrity.
In addition to having potential applications in the stabilization of vaccines and development of inexpensive artificial blood, the
stabilizing polymer also allows vaccines and other biomedical products to be stored for longer periods without refrigeration. It could
also have applications in biomaterials, biosensors, and biofuels.
"Protein stability is a major issue in biotechnology," says Challa V. Kumar, UConn professor of chemistry and biochemistry and the
primary investigator on the project. "What we've done is taken this protein molecule and wrapped it up in a polymer chain in order
to stabilize it. In thermodynamics terms, we have restricted the entropy of the denatured state of the protein and stabilized it beyond
our expectations. The system also exhibits a high degree of reversibility. The protein can be denatured and renatured many, many
times. This is the very first example of its kind in the literature of all protein science. No one has ever been able to achieve this kind
of stability for proteins."
A popular example of denaturation can be found in the protein present in eggs. As the egg is cooked and the protein around the
yolk turns white, the protein in the egg is denatured and cannot return to its prior, natural state. Likewise, when proteins in a living
cell are exposed to heat they become denatured, which disrupts their activity and can lead to cell death. When protein is a critical
element in a vaccine and breaks down, the product becomes useless.
In searching for a viable material to serve as a protein stabilizer, Kumar's team found one that is readily available, inexpensive, and
can be modified chemically for further improvements.
The poly(acrylic acid) used in the study is the same material found in disposable diapers, and one of the most abundant synthetic
polymers on the planet. This particular polymer, says Kumar, is very hydrophilic, meaning it likes water. The polymer naturally
binds to hemoglobin, creating a tight seal that protects the protein molecule and allows it to retain its structural integrity even after
heating it to 120C for extended periods of time (steam sterilization).
Joining him on the project was Rajeswari Kasi, associate professor of chemistry, an expert in synthetic polymers and hybrid
materials. The research team also included graduate students: Vamsi Mudhivarthi, Kyle Cole, Inoka Deshapriya, Caterina Riccardi,
and Yuxiang Zhou, as well as undergraduate students Marc Novak and Westley Kipphut.
Kumar is proud of the fact that undergraduates participated in such a major research endeavor. "One of our missions at the
University is to train undergraduates in research," he says, "and we take that very seriously."
The team tested various protein-polymer compositions using transmission electron microscopy (TEM) and optical spectroscopy
techniques. The research was supported by multiple grants from the National Science Foundation, topping $3 million over the past
10 years.
In a paper published last year in the Journal of Materials Chemistry, Kumar and his team showed how hemoglobin wrapped in low
molecular weight poly(acrylic acid) formed nanoparticles that retained their natural state and structure, even after they were
subjected to the harsh conditions of steam sterilization. Under the same conditions, hemoglobin samples that were not wrapped in
the polymer lost the majority of their structure and function.
Kumar said these test results signaled the project's breakthrough moment.
As part of its research, the team chose to examine the feasibility of using hemoglobin as an artificial blood substitute. Hemoglobin,
when extracted from blood, breaks down and is toxic in its pure form. Since hemoglobin is the critical oxygen carrier protein in
blood, Kumar and his team are looking at ways of stabilizing hemoglobin in its natural form so that it retains its activity and stays
harmless when administered as a transfusion agent. This could lead to a new substitute for human blood, which is frequently in
short supply. Blood shortages are expected to get worse in coming years, as more and more people in the world are likely to need
blood transfusions, Kumar said.
The research has caught the attention of scientists at Merck, a global leader in prescription medicine, vaccines, and biologic
therapies.
"Being able to control the placement of proteins in polymer matrices of defined size brings exciting opportunities for producing
potent and heat-stable vaccine antigens," says Henryk Mach, a senior investigator with Merck's vaccine drug product development
division. "Prof. Kumar's work may well provide technologies for vaccine delivery in the developing world."
The abundance of the polymer, the flexibility of the process, and the simplicity of the approach enhances its potential for mass
production, Kumar says.
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TEXT VACCINES 3:
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New Tuberculosis Vaccine Developed

Oct. 1, 2013 A tuberculosis vaccine developed at McMaster University offers new
hopes for the global fight against tuberculosis.
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"We are the first to have developed such a vaccine for tuberculosis," said Dr. Fiona Smaill, professor and chair of the Department
of Pathology and Molecular Medicine of the Michael G. DeGroote School of Medicine at McMaster. She led the phase one clinical
study published today in the journal Science Translational Medicine.
The vaccine, based on a genetically modified cold virus, was developed in the lab of Zhou Xing, professor of pathology and
molecular medicine and the McMaster Immunology Research Centre, who co-led the phase one study. Both are also members of
the Michael G. DeGroote Institute for Infectious Disease Research.
"Tuberculosis is a serious public health threat," Smaill said. "One-third of world's population is infected with the organism that
causes tuberculosis, and it remains the top infectious killer of people only secondary to HIV; yet, the current vaccine used to
prevent it is ineffective."
The control of tuberculosis (TB) has met with further challenge from high incidence of multi-drug resistant tuberculosis, she added.
The new vaccine was developed to act as a booster to Bacille Calmette Guerin (BCG), currently the only TB vaccine available.
BCG was developed in the 1920s and has been used worldwide. The new "booster" would reactivate immune elements that over
time diminish following BCG vaccination.
Currently the BCG vaccine is part of the World Health Organization's immunization program in Asia, Africa, Eastern Europe and
South America, as well as Nunavut, the only Canadian jurisdiction where the BCG vaccine is routinely given because of the high
rate of tuberculosis in the territory. It is typically given in the first year of life.
The McMaster vaccine has been more than a decade in the making. McMaster researchers began the first human clinical trial in
2009 with 24 healthy human volunteers, including 12 who were previously BCG-immunized.
"The primary goal was to look at the safety of a single dose vaccine injection," said Xing, "as well as its potency to engage the
immune system."
By 2012 they established that the vaccine was safe and observed a robust immune response in most trial participants. More clinical
trials are needed to measure the vaccine's real potential, Xing added.
Smaill added: "As a doctor who looks after patients who have tuberculosis, including those who are HIV infected, I realize how
important it is going to be to control this infection with a good vaccine.
"We are probably one of a few groups in the world who are actually doing bench-to-human tuberculosis vaccine work, and we are
excited to be part of this and thrilled that it started at McMaster."
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New Insight in Quest for Single Vaccine Against Multiple Flus

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Oct. 21, 2013 A study led by St. Jude Children's Research Hospital scientists
highlights a new approach for developing a universal influenza vaccine that could
protect against multiple flu strains, including deadly pandemic strains. The research
appears today in the advance online edition of the scientific journalNature Immunology.
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Researchers used the immune suppressing drug rapamycin to shift the immune response following flu vaccination to favor
production of antibodies that broadly target flu viruses. The result was a more diverse antibody response to the vaccination that
expanded protection to include pandemic strains not targeted by the vaccine. Vaccination is the most effective strategy against flu,
particularly the pandemic strains that emerge periodically, but efforts to develop a single, universal vaccine against all flu strains
have been unsuccessful.
The findings highlight a novel way to generate antibodies that recognize and target proteins shared by most influenza A strains
rather than those unique to each strain. Antibodies are produced by B cells to recognize and defend against viruses. The same
strategy might aid efforts to design vaccines against other viruses, researchers said.
Current flu vaccines emphasize production of highly specific antibodies. They target and bind tightly to strain-specific regions of
hemagglutinin (HA) and neuraminidase (NA) proteins on the virus. That approach requires developing and administering a new flu
vaccine each year to keep up with changes in those unique and highly variable HA and NA proteins.
Investigators showed the new strategy protected mice -- vaccinated against the H3N2 influenza A flu strain, which causes mild
disease -- from succumbing to the more dangerous H5N1 and H7N9 strains weeks later. When researchers transferred antibodyrich serum from vaccinated to unvaccinated mice, the unvaccinated animals were also protected from later H5N1 infection, an
indication that the protection came from antibodies rather than from other immune system components.
"This study has changed our approach to developing a universal flu vaccine," said corresponding author Maureen McGargill, Ph.D.,
an assistant member of the St. Jude Department of Immunology. "Instead of trying to enhance a highly specific, targeted immune
response, our results show that a more diverse, less focused response provides a broader repertoire of antibodies that target
different flu strains."
Influenza -- particularly pandemic strains that emerge periodically as flu viruses mix and form novel strains -- remains a global
health threat. The influenza A H5N1 avian pandemic strain has a mortality rate of nearly 60 percent. The World Health Organization
estimates that each year flu and flu-related complications kill more than 250,000 individuals worldwide. Vaccination is the most
effective strategy to combat the infection. But existing vaccines protect against just the dominant seasonal flu strain and not
emerging flu strains.
This study also advanced understanding of the role a protein named mTOR plays in generating the highly specific antibodies.
Rapamycin works by inhibiting mTOR, which is involved in cell survival and proliferation. Researchers used the drug to track how
blocking mTOR affected the immune response of mice following H3N2 vaccination.
Inhibiting mTOR disrupted generation of the antibodies that target specific regions of the HA proteins that are unique to each flu
strain. Researchers showed that loss of mTOR delayed the formation of the immune structure called a germinal center. That is
where antibodies are reshaped through a process called class switching. The process hones their focus and primes them to target
flu viruses based on the unique, rather than shared, surface proteins.
The finding was surprising because previous research had highlighted a likely role for white blood cells known as CD8+ and CD4+
memory T cells for broadening the immune response against different flu strains. Unlike antibodies, the T cells recognize flu viruses
based on shared internal proteins. The T cells reduce flu-related complications by eliminating flu-infected cells and speeding the
virus' clearance from the body. In addition, rapamycin was known to increase the number of memory CD8+ T cells.
McGargill and her colleagues showed that memory CD8+ T cells were not required for enhanced protection in rapamycin-treated
mice following vaccination and that the CD4+ cells played an indirect role. "This led us to the B-cell response and evidence that the
cross-reactive antibodies provide crucial protection against different flu strains," said first author Rachael Keating, Ph.D., a St. Jude
scientist.
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TEXT VIRUS 1:
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Viruses Are as Simple as They Are 'Smart'

Nov. 25, 2013 Viruses are as simple as they are "smart": too elementary to be able
to reproduce by themselves, they exploit the reproductive "machinery" of cells, by
inserting pieces of their own DNA so that it is transcribed by the host cell. To do this,
they first have to inject their own genetic material into the cells they infect. An
international team of researchers, including Cristian Micheletti from SISSA (the
International School for Advanced Studies in Trieste), has studied how this occurs and
how long it takes for this process to be completed.
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Micheletti and colleagues constructed a computer model of viral DNA and then simulated the release of genetic material from the
viral capsid into the host cell nucleus. Far from being a fluid process, this ejection is subject to frictional forces that depend on the
conformation of the DNA strand. "Fluidity of the process depends on how and how tightly the viral DNA is entangled," explains
Micheletti. "The more topologically ordered is the double strand of the genome, the faster it is ejected from the virus. The situation
is somewhat similar to the behaviour of an anchor line that has been correctly coiled: when the anchor is thrown overboard, the line
uncoils neatly without stops or jerks due to tangles."
DNA has an intrinsic characteristic that makes its pattern of spontaneous arrangement very singular. Because it has two strands,
DNA has a tendency to form highly ordered coils, just like anchor lines or thread spools. This isn't the case with generic polymers,
which form complex and chaotic tangles. The simulations by Micheletti and colleagues compared the behaviour of a model strand
of DNA and a simple strand of generic polymer. "In 95% of cases the model DNA slid through the exit pore of the virus much faster
than the simple polymer, as a result of the greater spontaneous order of its conformation," comments Micheletti. "The simple
strands may be even ten times slower than the DNA strands. Another interesting thing is that, although much more slowly, the
simple strands in our observations always succeeded in leaving the virus completely. By contrast, in a small minority of cases, the
DNA remained totally blocked, and this too is related to its tendency to form a spool that may sometimes present such complex
torus knots -- i.e., doughnut-like -- to completely block ejection from the virus."
The process timescales observed by Micheletti and colleagues are perfectly consistent with empirical observations, "including all
cases of complete DNA stalling that have been reported, though not explained, in some experiments," concludes Micheletti. "Our
study, which estimated the time it takes viral DNA to leave the capsid in relation to its length and degree of packing could provide
the starting point for designing artificial viral vectors."
The study has just been published in the Proceedings of the National Academy of Sciences (PNAS).
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Scientists Discover Why Newborns Get Sick So Often

Oct. 31, 2013 If you think cold and flu season is tough, trying being an infant. A new
research finding published in the November 2013 issue of the Journal of Leukocyte
Biology sheds new light on why newborns appear to be so prone to getting sick with
viruses -- they are born without one of the key proteins needed to protect them. This
protein, called "toll-like receptor 3" or "TLR3," is involved in the recognition of different
viruses and mediates the immune response to them. Without this protein, newborn
immune cells are not equipped to recognize and react appropriately to certain viruses,
in particular, the herpes simplex virus known as HSV.
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"This study helps to understand the molecular basis for the immaturity of the immune system of newborns, which we believe will
contribute to development of therapeutic interventions to protect this vulnerable population group," said Lucija Slavica, a researcher
involved in the work from the Department of Rheumatology and Inflammation Research at the University of Gothenburg in
Gothenburg, Sweden.
To make this discovery, scientists compared cells from the cord blood of newborns with the same type of blood cells from adults.
The cells from newborns did not contain the protein TLR3, which was present in adult cells. These cells rid the body of viralinfected cells, ultimately eliminating viral infections. When researchers treated both cell groups with a synthetic component
mimicking a viral presence, the adult immune cells reacted by secreting substances involved in immune reaction against viruses
(interferon-gamma) and killed cells infected with virus, while cells from newborns could not do this or were impaired in performing
this function.
"This study adds to the growing body of research stemming from the Nobel-winning discovery in 2011 on how the immune system
recognizes microbes by shedding light on how these pathways develop over time after birth," said John Wherry, Ph.D., Deputy
Editor of the Journal of Leukocyte Biology. "This report is particularly important -- as any new parent can attest, infants are
particularly susceptible to infections and understanding which pathways are not yet functional could lead to novel therapies."
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TEXT VIRUS 3:
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What the Smallest Infectious Agents Reveal About Evolution

May 23, 2013 Radically different viruses share genes and are likely to share
ancestry, according to research published in BioMed Central's open access
journal Virology Journal this week. The comprehensive phylogenomic analysis
compares giant viruses that infect amoeba with tiny viruses known as virophages and
to several groups of transposable elements. The complex network of evolutionary
relationships the authors describe suggests that viruses evolved from non-viral mobile
genetic elements and vice versa, on more than one occasion.
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The recent discovery of virophages inside the giant viruses, which in turn infect amoeba, has led to speculation about their origin
and their relationship to other viruses and small transposable genetic elements. To try to answer this question a research team
including Eugene Koonin from the NIH and Didier Raoult from URMITE compared the genetic material from virophages, such as
the Mavirus, Sputnik, or OLV (which was isolated from an Antarctic organic lake), to eukaryotic self replicating transposable
elements known as Polintons or Mavericks.
Eugene Koonin explains: "Between the known virophages there are six conserved genes, arranged in a similar way. Five of these
have counterparts in the Polintons, but their sequence and arrangement are sufficiently different to discount suggestions that
Polintons evolved directly from a Maviruse-like ancestor. Rather our data suggests that Maviruses have evolved from a fusion
between a Politon/Maverick-like transposable element and an unknown virus."
Including information about other viruses and virus-like elements: adenoviruses that infect animals and are one of the causes of the
common cold; certain bacteriophages that infect bacteria; transpovirons which infect giant viruses; and a Tetrahymena
transposable element (Tlr1), the virus "evolutionary tree" appears as a network of swapped genes.
Didier Raoult, whose team discovered the transpovirons, says: "It appears that viruses have evolved from non-viral genetic
elements and vice versa on more than one occasion. Viral evolution is more complex than we thought."
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TEXTS OTHER MATTERS:

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High Cholesterol Fuels Growth, Spread of Breast Cancer

Nov. 28, 2013 A byproduct of cholesterol functions like the hormone estrogen to fuel
the growth and spread of the most common types of breast cancers, researchers at the
Duke Cancer Institute report.
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The researchers also found that anti-cholesterol drugs such as statins appear to diminish the effect of this estrogen-like molecule.
Published in the Nov. 29, 2013, edition of the journal Science, the findings are early, using mouse models and tumor cells. But the
research for the first time explains the link between high cholesterol and breast cancer, especially in post-menopausal women, and
suggests that dietary changes or therapies to reduce cholesterol may also offer a simple, accessible way to reduce breast cancer
risk.
"A lot of studies have shown a connection between obesity and breast cancer, and specifically that elevated cholesterol is
associated with breast cancer risk, but no mechanism has been identified," said senior author Donald McDonnell, Ph.D., chair of
the Department of Pharmacology and Cancer Biology at Duke. "What we have now found is a molecule -- not cholesterol itself, but
an abundant metabolite of cholesterol -- called 27HC that mimics the hormone estrogen and can independently drive the growth of
breast cancer."
The hormone estrogen feeds an estimated 75 percent of all breast cancers. In a key earlier finding from McDonnell's lab,
researchers determined that 27-hydroxycholesterol -- or 27HC -- behaved similarly to estrogen in animals.
For their current work, the researchers set out to determine whether this estrogen activity was sufficient on its own to promote
breast cancer growth and metastasis, and whether controlling it would have a converse effect.
Using mouse models that are highly predictive of what occurs in humans, McDonnell and colleagues demonstrated the direct
involvement of 27HC in breast tumor growth, as well as the aggressiveness of the cancer to spread to other organs. They also
noted that the activity of this cholesterol metabolite was inhibited when the animals were treated with antiestrogens or when
supplementation of 27HC was stopped.
The studies were substantiated using human breast cancer tissue. An additional finding in the human tissue showed a direct
correlation between the aggressiveness of the tumor and an abundance of the enzyme that makes the 27HC molecule. They also
noted that 27HC could be made in other places in the body and transported to the tumor.
"The worse the tumors, the more they have of the enzyme," said lead author Erik Nelson, Ph.D., a post-doctoral associate at Duke.
Nelson said gene expression studies revealed a potential association between 27HC exposure and the development of resistance
to the antiestrogen tamoxifen. Their data also highlights how increased 27HC may reduce the effectiveness of aromatase inhibitors,
which are among the most commonly used breast cancer therapeutics.
"This is a very significant finding," McDonnell said. "Human breast tumors, because they express this enzyme to make 27HC, are
making an estrogen-like molecule that can promote the growth of the tumor. In essence, the tumors have developed a mechanism
to use a different source of fuel."
McDonnell said the findings suggest there may be a simple way to reduce the risk of breast cancer by keeping cholesterol in check,
either with statins or a healthy diet. Additionally, for women who have breast cancer and high cholesterol, taking statins may delay
or prevent resistance to endocrine therapies such as tamoxifen or aromatase inhibitors.
The next steps for research include clinical studies to verify those potential outcomes, as well as studies to determine if 27HC plays
a role in other cancers, McDonnell said.
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Scientists Discover How Immune Cells Die During HIV Infection; Identify
Potential Drug to Block AIDS
Dec. 19, 2013 Research led by scientists at the Gladstone Institutes has identified
the precise chain of molecular events in the human body that drives the death of most
of the immune system's CD4 T cells as an HIV infection leads to AIDS. Further, they
have identified an existing anti-inflammatory drug that in laboratory tests blocks the
death of these cells -- and now are planning a Phase 2 clinical trial to determine if this
drug or a similar drug can prevent HIV-infected people from developing AIDS and
related conditions.
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Two separate journal articles, published simultaneously today in Nature andScience, detail the research from the laboratory of
Warner C. Greene, MD, PhD, who directs virology and immunology research at Gladstone, an independent biomedical-research
nonprofit. His lab's Science paper reveals how, during an HIV infection, a protein known as IFI16 senses fragments of HIV DNA in
abortively infected immune cells. This triggers the activation of the human enzyme caspase-1 and leads to pyroptosis, a fiery and
highly inflammatory form of cell death. As revealed in the Nature paper, this repetitive cycle of abortive infection, cell death,
inflammation and recruitment of additional CD4 T cells to the infection "hot zone" ultimately destroys the immune system and
causes AIDS. The Nature paper further describes laboratory tests in which an existing anti-inflammatory inhibits caspase-1, thereby
preventing pyroptosis and breaking the cycle of cell death and inflammation.
"Gladstone has made two important discoveries, first by showing how the body's own immune response to HIV causes CD4 T cell
death via a pathway triggering inflammation, and secondly by identifying the host DNA sensor that detects the viral DNA and
triggers this death response," said Robert F. Siliciano, MD, PhD, a professor of medicine at Johns Hopkins University, and a
Howard Hughes Medical Institute investigator. "This one-two punch of discoveries underscores the critical value of basic science -by uncovering the major cause of CD4 T cell depletion in AIDS, Dr. Greene's lab has been able to identify a potential new therapy
for blocking the disease's progression and improving on current antiretroviral medications."
The research comes at a critical time, as so-called AIDS fatigue leads many to think that HIV/AIDS is solved. In fact, HIV infected
an additional 2.3 million people last year, according to UNAIDS estimates, bringing the global total of HIV-positive people to 35.3
million. Antiretroviral medications (ARVs) can prevent HIV infections from causing AIDS, but they do not cure AIDS. Further, those
taking ARVs risk both a latent version of the virus, which can rebound if ARVs are discontinued, and the premature onset of
diseases that normally occur in aging populations. Plus, some 16 million people who carry the virus do not have access to ARVs,
according to World Health Organization estimates.
Seeking solutions for all these challenges, the new Gladstone discovery builds on earlier research from Dr. Greene's lab, published
in Cell in 2010. This study showed how HIV attempts, but fails, to productively infect most of the immune system's CD4 T cells. In
an attempt to protect the body from the spreading virus, these immune cells then commit "cellular suicide," leading to the collapse
of the immune system -- and AIDS.
After that research, the Gladstone scientists began to look for ways to prevent this process by studying exactly how the suicidal
response is initiated. Working in the laboratory with human spleen and tonsil tissue, as well as lymph-node tissue from HIV-infected
patients, the researchers found that these so-called abortive infections leave fragments of HIV's DNA in the immune cells. As
described in Nature, pyroptosis ensues as immune cells rupture and release inflammatory signals that attract still more cells to
repeat the death cycle.
"Our studies have investigated and identified the root cause of AIDS -- how CD4 T cells die," said Gladstone Staff Research
Investigator Gilad Doitsh, PhD, who is the Nature paper's lead author, along with Nicole Galloway and Xin Geng, PhD. "Despite
some 30 years of HIV research, this key HIV/AIDS process has remained pretty much a black box."
Once the scientists discovered this key process, as described in Nature, they began to investigate how the body senses the
fragments of HIV's DNA in the first place, before alerting the enzyme caspase-1 to launch an immune response in the CD4 T cells.
To identify the so-called DNA sensor, the scientists found a way to genetically manipulate CD4 T cells in spleen and tonsil tissue. In
doing so, they discovered that reducing the activity of a protein known as IFI16 inhibited pyroptosis, explained Zhiyuan Yang, PhD,
a Gladstone postdoctoral fellow who is one of the paper's two lead authors.
"This identified IFI16 as the DNA sensor, which then sends signals to caspase-1 and triggers pyroptosis," says Kathryn M. Monroe,
PhD, the Science paper's other lead author, who completed the research while a postdoctoral fellow at Gladstone. "We can't block
a process until we understand all of its steps -- so this discovery is critical to devising ways to inhibit the body's own destructive
response to HIV. We have high hopes for the upcoming clinical trial."
The Phase 2 trial -- which will test an existing anti-inflammatory's ability to block inflammation and pyroptosis in HIV-infected people
-- promises to validate a variety of expected advantages to this therapy. For example, by targeting the human body, or host, instead
of the virus, the drug is likely to avoid the rapid emergence of drug resistance that often plagues the use of ARVs. The anti-
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inflammatory may also provide a bridge therapy for the millions without access to ARVs, while also reducing persistent
inflammation in HIV-infected people already on ARVs. Many suspect this inflammation drives the early onset of aging-related
conditions such as dementia and cardiovascular disease. By reducing inflammation, the drug might also prevent expansion of a
reservoir of latent virus that hides in the body where it thwarts a cure for HIV/AIDS.
"This has been an absolutely fascinating voyage of discovery," said Dr. Greene, who is also a professor of medicine, microbiology
and immunology at the University of California, San Francisco, with which Gladstone is affiliated. "Every time we turned over an
'experimental rock' in the studies, a new surprise jumped out."
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Imaging Technology Could Unlock Mysteries of Childhood Disease

Dec. 30, 2013 By the time they're two, most children have had respiratory syncytial
virus (RSV) and suffered symptoms no worse than a bad cold. But for some children,
especially premature babies and those with underlying health conditions, RSV can lead
to pneumonia and bronchitis -- which can require hospitalization and have long-term
consequences.
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A new technique for studying the structure of the RSV virion and the activity of RSV in living cells could help researchers unlock the
secrets of the virus, including how it enters cells, how it replicates, how many genomes it inserts into its hosts -- and perhaps why
certain lung cells escape the infection relatively unscathed. That could provide scientists information they need to develop new
antiviral drugs and perhaps even a vaccine to prevent severe RSV infections.
"We want to develop tools that would allow us to get at how the virus really works," said Philip Santangelo, an associate professor
in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. "We really need to be able
to follow the infection in a single living cell without affecting how the virus infects its hosts, and this technology should allow us to do
that."
The research was supported by the National Institutes of Health's National Institute of General Medical Sciences and published
online ahead of print in the journal ACS Nano on December 30, 2013. While RSV will be the first target for the work, the
researchers believe the imaging technique they developed could be used to study other RNA viruses, including influenza and
Ebola.
"We've shown that we can tag the genome using our probes," explained Santangelo. "What we've learned from this is that the
genome does get incorporated into the virion, and that the virus particles created are infectious. We were able to characterize some
aspects of the virus particle itself at super-resolution, down to 20 nanometers, using direct stochastic optical reconstruction
microscopy (dSTORM) imaging."
RSV can be difficult to study. For one thing, the infectious particle can take different forms, ranging from 10-micron filaments to
ordinary spheres. The virus can insert more than one genome into the host cells and the RNA orientation and structure are
disordered, which makes it difficult to characterize.
The research team, which included scientists from Vanderbilt University and Emory University, used a probe technology that
quickly attaches to RNA within cells. The probe uses multiple fluorophores to indicate the presence of the viral RNA, allowing the
researchers to see where it goes in host cells -- and to watch as infectious particles leave the cells to spread the infection.
"Being able to see the genome and the progeny RNA that comes from the genome with the probes we use really give us much
more insight into the replication cycle," Santangelo said. "This gives us much more information about what the virus is really doing.
If we can visualize the entry, assembly and replication of the virus, that would allow us to decide what to go after to fight the virus."
The research depended on a new method for labelling RNA viruses using multiply-labeled tetravalent RNA imaging probes
(MTRIPS). The probes consist of a chimeric combination of DNA and RNA oligonucleotide labeled internally with fluorophores
tetravelently complexed to neutravidin. The chimeric combination was used to help the probes evade cellular defenses.
"There are lots of sensors in the cell that look for foreign RNA and foreign DNA, but to the cell, this probe doesn't look like
anything," Santangelo explained. "The cell doesn't see the nucleic acid as foreign."
Introduced into cells, the probes quickly diffuse through a cell infected with RSV and bind to the virus's RNA. Though binding
tightly, the probe doesn't affect the normal activities of the virus and allows researchers to follow the activity for days using standard
microscopy techniques. The MTRIPS can be used to complement other probe technology, such as GFP and gold nanoparticles.
Work done by graduate student Eric Alonas to concentrate the virus was essential to the project, Santangelo said. The
concentration had to be done without adversely affecting the infectivity of the virus, which would have impacted its ability to enter
host cells.
"It took quite a bit of work to get the right techniques to concentrate the RSV," he said. "Now we can make lots of infectious virus
that's labelled and can be stored so we can use it when we want to."
To study the infection's progress in individual cells, the researchers faced another challenge: living cells move around, and
following them complicates the research. To address that movement, the laboratory of Thomas Barker -- also in the Coulter
Department -- used micro-patterned fibronectin on glass to create 50-micron "islands" that contained the cells during the study.
Among the mysteries that the researchers would like to tackle is why certain lung cells are severely infected -- while others appear
to escape ill effects.
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"If you look at a field of cells, you see huge differences from cell to cell, and that is something that's not understood at all,"
Santangelo said. "If we can figure out why some cells are exploding with virus while others are not, perhaps we can figure out a
way to help the bad ones look more like the good ones."
In addition to those already mentioned, the research team included James Crowe, professor of pediatrics at Vanderbilt University;
Elizabeth Wright, assistant professor in the School of Medicine at Emory University; Daryll Vanover, Jeenah Jung, Chiara Zurla,
Jonathan Kirschman, Vincent Fiore, and Alison Douglas from the Wallace H. Coulter Department of Biomedical Engineering at
Georgia Tech and Emory University; Aaron Lifland and Manasa Gudheti from Vutara Inc. in Salt Lake City, and Hong Yi from the
Emory University School of Medicine.
One of the challenges of studying RSV is maintaining its activity in the laboratory setting -- a problem parents of young children
don't share.
"When you handle this virus in the lab, you have to always be careful about it losing infectivity," Santangelo noted. "But if you take a
room full of children who have not been infected and let one infected child into the room, 15 minutes later all of the children will be
infected."
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Scientists Explain Age-Related Obesity: Brown Fat Fails

Jan. 2, 2014 As most people resolve themselves to lose weight this New Year,
here's why it seems to get easier and easier to pack on unwanted pounds: New
research published in the January 2014 issue of The FASEB Journal, shows that as we
age, the thermogenic activity of brown fat is reduced. Brown fat is a "good" fat located
in the backs of our necks that helps burn "bad" white fat around our bellies.
Additionally, the researchers also discovered a possible metabolic on/off switch that
could reactivate brown fat.
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"Future studies on how PAF/PAFR signaling controls UCP1 levels through beta3-AR production in the BAT of animals and humans
may reveal new therapeutic targets to treat metabolic disorders associated with obesity," said Junko Sugatani, Ph.D., a researcher
involved in the work from the Department of Pharmaco-Biochemistry at the School of Pharmaceutical Sciences at the University of
Shizuoka in Shizuoka, Japan.
To make this discovery, scientists analyzed two groups of mice. The first group had the platelet-activating factor receptors (PAFR)
gene knocked out. The second group was normal. PAFR-deficient mice developed a more severe obese state characterized by
higher body and epididymal fat mass with age than that of wild-type littermates. Findings from the PAFR-KO genetic model reveal
that PAFR-deficiency causes brown adipose tissue (BAT) dysfunction, which converges to induce the development of obesity, due
to impaired thermogenic activity of BAT. This study could elucidate the molecular mechanism underlying the PAF/PAF receptormediated anti-obesity, leading to the development of new targets for the treatment of obesity and related disorders, such as
diabetes, high blood pressure, heart disease, cancer, infertility and ulcers.
"A common complaint is that older people have to work twice as hard with their diets and exercise to get half of the results of
younger people," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "Now we have a much better idea why this
is the case: Our brown fat stops working as we age. Unfortunately, until a way to turn it back on is developed, we'll have to be
prepared to eat more salads and lean proteins, while logging more miles on the treadmill than our younger counterparts."
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Adults, Especially Women, Have Calorie-Burning 'Brown Fat'

June 12, 2009 Keeping your baby fat turns out to be a good thing, as long as it is
"brown fat"the kind that burns calories, according to a study that found adults have
much more of this type of fat than previously thought. The results, which suggest a new
way to treat obesity, were presented at The Endocrine Society's 91st Annual Meeting in
Washington, D.C.
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Brown fat burns off calories and generates heat in babies and small mammals. Most of our body fat is white fat, which also
provides insulation but stores calories. It becomes "bad" fat when you have too much. The "good" fatbrown fatwas considered
essentially nonexistent in human adults.
"We now know that it is present and functional in adults," said the study's lead author, Aaron Cypess, MD, PhD, MMSc, of the
Joslin Diabetes Center in Boston. "Three ounces of brown fat can burn several hundred calories a day."
For the first time, the researchers were able to measure patches of brown adipose tissuebrown fatin people, thanks to a hightech imaging method that combines positron emission tomography and computed tomography, called PET/CT. By evaluating
biopsy tissue of what appeared to be brown fat on PET/CT scans in some patients who had neck surgery, the authors confirmed
that they were, indeed, looking at stores of brown fat. More than 1,970 study participants had PET/CT scans, from mid-skull to midthigh.
Brown fat (when it could be detected) was located in an area extending from the front of the neck to the chest. Of the subjects who
had detectable brown fat, about 6 percent had 3 ounces or more of the fat.
"We believe that this percentage greatly underestimates the number of adults in the population who have a large amount of brown
fat," said Cypess, whose results were published in the April 9 issue of the New England Journal of Medicine, along with those of
two other independent studies of brown fat in adults.
That is because one of the other studies found that PET/CT can detect much more brown fat if people are in a room cooled to
61F. Likewise, Cypess and his colleagues found that people who underwent PET/CT in the winter had more brown fat activity than
those scanned in the summer.
They also discovered that brown fat is most abundant in young women and least frequent in older, overweight men. In fact, women
were more than twice as likely as men to have substantial amounts of brown fat.
"One theory for this is that women may have less muscle mass overall, so they need more brown fat to generate heat and keep
warm," Cypess said.
Brown fat provides a new focus for developing treatments protecting against obesity and its complications, according to Cypess.
However, it may not be enough to lose weight to just have brown fat. The researcher said, "We may have to turn it on and make
sure it burns calories in a regulated, safe manner."
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Schizophrenia Linked to Abnormal Brain Waves: Neurological Hyperactivity

Produces Disordered Thinking
Oct. 16, 2013 Schizophrenia patients usually suffer from a breakdown of organized
thought, often accompanied by delusions or hallucinations. For the first time, MIT
neuroscientists have observed the neural activity that appears to produce this
disordered thinking.
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The researchers found that mice lacking the brain protein calcineurin have hyperactive brain-wave oscillations in the hippocampus
while resting, and are unable to mentally replay a route they have just run, as normal mice do.
Mutations in the gene for calcineurin have previously been found in some schizophrenia patients. Ten years ago, MIT researchers
led by Susumu Tonegawa, the Picower Professor of Biology and Neuroscience, created mice lacking the gene for calcineurin in the
forebrain; these mice displayed several behavioral symptoms of schizophrenia, including impaired short-term memory, attention
deficits, and abnormal social behavior.
In the new study, which appears in the Oct. 16 issue of the journal Neuron, Tonegawa and colleagues at the RIKEN-MIT Center for
Neural Circuit Genetics at MIT's Picower Institute for Learning and Memory recorded the electrical activity of individual neurons in
the hippocampus of these knockout mice as they ran along a track.
Previous studies have shown that in normal mice, "place cells" in the hippocampus, which are linked to specific locations along the
track, fire in sequence when the mice take breaks from running the course. This mental replay also occurs when the mice are
sleeping. These replays occur in association with very high frequency brain-wave oscillations known as ripple events.
In mice lacking calcineurin, the researchers found that brain activity was normal as the mice ran the course, but when they paused,
their ripple events were much stronger and more frequent. Furthermore, the firing of the place cells was abnormally augmented and
in no particular order, indicating that the mice were not replaying the route they had just run.
This pattern helps to explain some of the symptoms seen in schizophrenia, the researchers say.
"We think that in this mouse model, we may have some kind of indication that there's a disorganized thinking process going on,"
says Junghyup Suh, a research scientist at the Picower Institute and one of the paper's lead authors. "During ripple events in
normal mice we know there is a sequential replay event. This mutant mouse doesn't seem to have that kind of replay of a previous
experience."
The paper's other lead author is David Foster, a former MIT postdoc. Other authors are Heydar Davoudi and Matthew Wilson, the
Sherman Fairchild Professor of Neuroscience at MIT and a member of the Picower Institute.
The researchers speculate that in normal mice, the role of calcineurin is to suppress the connections between neurons, known as
synapses, in the hippocampus. In mice without calcineurin, a phenomenon known as long-term potentiation (LTP) becomes more
prevalent, making synapses stronger. Also, the opposite effect, known as long-term depression (LTD), is suppressed.
"It looks like this abnormally high LTP has an impact on activity of these cells specifically during resting periods, or post exploration
periods. That's a very interesting specificity," Tonegawa says. "We don't know why it's so specific."
The researchers believe the abnormal hyperactivity they found in the hippocampus may represent a disruption of the brain's
"default mode network" -- a communication network that connects the hippocampus, prefrontal cortex (where most thought and
planning occurs), and other parts of the cortex.
This network is more active when a person (or mouse) is resting between goal-oriented tasks. When the brain is focusing on a
specific goal or activity, the default mode network gets turned down. However, this network is hyperactive in schizophrenic patients
before and during tasks that require the brain to focus, and patients do not perform well in these tasks.
Further studies of these mice could help reveal more about the role of the default mode network in schizophrenia, Tonegawa says.
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Could Poor Sleep Contribute to Symptoms of Schizophrenia?

Nov. 14, 2012 Neuroscientists studying the link between poor sleep and
schizophrenia have found that irregular sleep patterns and desynchronised brain
activity during sleep could trigger some of the disease's symptoms. The findings,
published in the journal Neuron, suggest that these prolonged disturbances might be a
cause and not just a consequence of the disorder's debilitating effects.
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The possible link between poor sleep and schizophrenia prompted the research team, led by scientists from the University of
Bristol, the Lilly Centre for Cognitive Neuroscience and funded by the Medical Research Council (MRC), to explore the impact of
irregular sleep patterns on the brain by recording electrical brain activity in multiple brain regions during sleep.
For many people, sleep deprivation can affect mood, concentration and stress levels. In extreme cases, prolonged sleep
deprivation can induce hallucinations, memory loss and confusion all of which are also symptoms associated with schizophrenia.
Dr Ullrich Bartsch, one of the study's researchers, said: "Sleep disturbances are well-documented in the disease, though often
regarded as side effects and poorly understood in terms of their potential to actually trigger its symptoms."
Using a rat model of the disease, the team's recordings showed desynchronisation of the waves of activity which normally travel
from the front to the back of the brain during deep sleep. In particular the information flow between the hippocampus -- involved in
memory formation, and the frontal cortex -- involved in decision-making, appeared to be disrupted. The team's findings reported
distinct irregular sleep patterns very similar to those observed in schizophrenia patients.
Dr Matt Jones, the lead researcher from the University's School of Physiology and Pharmacology, added: "Decoupling of brain
regions involved in memory formation and decision-making during wakefulness are already implicated in schizophrenia, but
decoupling during sleep provides a new mechanistic explanation for the cognitive deficits observed in both the animal model and
patients: sleep disturbances might be a cause, not just a consequence of schizophrenia. In fact, abnormal sleep patterns may
trigger abnormal brain activity in a range of conditions."
Cognitive deficits -- reduced short term memory and attention span, are typically resistant to medication in patients. The findings
from this study provide new angles for neurocognitive therapy in schizophrenia and related psychiatric diseases.
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Children With Autism Benefit from Peer Solicitation

Dec. 12, 2013 Peer solicitation -- a child inviting another to play -- can improve
reciprocal social interaction among children with autism, according to a Vanderbilt
University study released today in theJournal of Child Psychology and Psychiatry.
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Researchers studied playground interactions between children with autism and typically developing peers and found the two
groups play similarly when engaged in independent play with kids they just met.
While the children with autism initiated and engaged in less play overall than typically developing children, the researchers found
that other children can facilitate and increase interactions by simple requests. These findings highlight the pivotal role that peers
have in social interaction, noting that it only takes a single child to prompt other children -- with or without autism -- to interact.
"Most children consider playgrounds a fun place to interact with other kids, but for children with autism, this may be a very
challenging and stressful environment," said lead author Blythe Corbett, Ph.D., associate professor of Psychiatry and Vanderbilt
Kennedy Center investigator. "One of the key places we learn about social rules growing up is during play, but if you don't
participate, chances are you're not going to learn the rules or be motivated to interact with other children."
Corbett and colleagues studied more than 30 peer interactions in children ages 8-12 on an actual playground by using state-of-theart technology including four remotely operated cameras and battery-operated microphones. Three children were on the
playground for the observations -- a typically developing child trained as a research assistant, called a "confederate;" another
typically developing child there for play only; and a child with autism.
The confederate was trained to invite the other two children to play and wore an ear microphone in order to receive directions from
the researchers, who observed from a nearby lab overlooking the playground.
The stress hormone cortisol was measured through saliva samples taken both at home and several times after the playground
interactions to compare the stress level of participants in a typical environment vs. playtime with peers. The children with autism
demonstrated elevated stress during social interactions, with higher cortisol levels observed in children who showed less motivation
to play with the other children.
"Although children with autism may experience increased stress in social interactions, it was encouraging to see that reciprocal
socialization can be facilitated by peer solicitation," Corbett said. "It all starts with a simple bid to play."
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Poor Sleep for Obese Adolescents

Apr. 11, 2010 Obese adolescents go to bed later and sleep less than their lighter
contemporaries. This is the finding of a study published in the April issue of Australian
and New Zealand Journal of Public Health.
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Professor Tim Olds and his colleagues at the University of South Australia explored the sleep patterns of 9-18 year old Australians
on different days of the week. The poor sleep among obese students was particularly evident on Sundays -- the night before school
resumed after a weekend off.
Other findings that may help parents understand their adolescent children included: * On average, girls slept more, because of
earlier bedtimes. * As adolescents grow older, they sleep less. * Underweight children went to bed significantly earlier than those of
normal weight.
Prof. Olds said the 'cause and effect' between sleep patterns and weight was unclear.
"The sleep patterns we found sit comfortably with the theory that short sleep duration predisposes towards obesity," he said.
"However, there may also be some third factor that contributes to both overweight and short sleep duration."
This third factor may be linked to the time adolescents spend in front of computer or TV screens or low physical activity. "Sleep
intervention studies examining the relationship between screen time, weight status and sleep would help to clarify these issues.
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New Device Aims To Give Sleep Apnea Sufferers Relief And Rest
Oct. 6, 2008 For some, a full nights rest can be anything but restful. Thats because
they have sleep apnea, which causes them to struggle for breath in bouts throughout
the night. Six percent of the population is affected by the conditionbut many dont
even know they have it.
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They dont make the connection between the fact that they snore loudly at night and they complain about being tired during the
day, says Samuel Krachman, D.O. , professor of medicine and director of the Sleep Disorders Center at Temple University School
of Medicine and Hospital. They think that theyre just tired, not getting enough sleep or just working too hard. But in reality, its
related to the sleep apnea.
Krachman is leading research on an experimental device to help patients who suffer from positional sleep apnea. Positional sleep
apnea refers to patients who have episodes where they stop breathing when theyre on their back, but when they are on their side,
the abnormal breathing resolves. Fifty percent of patients with mild sleep apnea (those who experience anywhere from five to 15
events an hour) and 20 percent of people with moderate sleep apnea (15 to 30 events an hour) have positional sleep apnea.
Krachman explains how wearing the device, called Zzoma, works to reduce those episodes.
Zzoma is a device which is worn around the chest area like a belt, with a device on the back, which is a firm, foam material
wrapped in canvas to keep them from moving on their backs. Over the last year, weve been studying its use in treating patients
with mild to moderate positional sleep apnea.
The device was created by former Temple Fellow Joseph G. Crocetti. He and Krachman have worked together to treat positional
sleep apnea. Their research has shown that the Zzoma device is less obtrusive and easier to use than the leading alternative, a
continuous positive airway pressure machine or CPAP, a mask that blows air on a persons face to keep the airway open.
Although CPAP is very effective, the best studies have shown its only used correctly 50 percent of the time, says Krachman.
That leaves many diagnosed with sleep apnea but not treated.
Untreated sleep apnea can lead to a host of other medical problems. Just having sleep apnea is an independent risk factor for
developing high blood pressure, coronary disease and heart failure. Thats why Krachman hopes the FDA approves Zzoma to treat
positional sleep apnea, to give sufferers an effective alternative to the burden of CPAP.
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Sex Matters for Microbes

Jan. 3, 2014 Caught in the act! Researchers from the University of Bristol have
observed mating for the first time in the microbes responsible for African sleeping
sickness. This tropical disease is caused by trypanosomes, single-celled parasites that
are found in the blood of those afflicted.
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The Bristol team were able to see what the trypanosomes were getting up to inside the tsetse flies that carry the disease by using
fluorescent markers [see image -- link below]. The microscopic beasts were seen twirling and gyrating together before joining up
into one hybrid cell. To tell which was which, individual trypanosomes were tagged with different colours, with the result that the
hybrid cells had both colours.
Professor Wendy Gibson, who led the research, commented: "It's not only bigger animals that have intricate courtship -- but you
need a powerful microscope to see this!"
Sex matters for microbes because it enables genes to be swapped between different strains, leading to new combinations of
genes. In the case of disease-causing microbes like the trypanosome, sex can potentially lead to a lot of harmful genes being
combined in one strain. These new results suggest that sex is not an optional or rare part of this microbe's life cycle, but probably
happens every time two different trypanosomes find themselves together in the same tsetse fly.
Trypanosomes belong to a strange group of protozoa that includes several other medically important parasites such
asLeishmania, Trichomonas and Giardia. In the past, all these microbes were thought to reproduce just by splitting in half, but now
results show that they also use sex to swap genes between strains. This research helps scientists understand how new strains of
disease-causing microbes arise and how characteristics such as drug resistance get spread between different strains.
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New Surgical Technique for Bell's Palsy Facial Paralysis

June 11, 2013 A Loyola University Medical Center surgeon is using electrical
stimulation as part of an advanced surgical technique to treat Bell's palsy. Bell's palsy is
a condition that causes paralysis on one side of a patient's face.
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During surgery, Dr. John Leonetti stimulates the patient's damaged facial nerve with an electric current, helping to jump-start the
nerve in an effort to restore improved facial movement more quickly.
Leonetti said some patients who have received electrical stimulation have seen muscle movement return to their face after one or
two months -- rather than the four-to-six months it typically takes for movement to return following surgery.
A virus triggered Bell's palsy in Audrey Rex, 15, of Lemont, Ill. Her right eye could not close and her smile was lopsided, making her
feel self-conscious. She had to drink from a straw, and eating was frustrating -- she would accidentally bite her bottom lip when it
got stuck on her teeth.
She was treated with steroids, but after six weeks, there were no improvements. So Audrey's mother did further research and made
an appointment with Leonett Leonetti recommended surgery with electrical stimulation, followed by physical therapy. Today,
Audrey's appearance has returned to normal, and she has regained nearly all of the facial muscle movements she had lost.
"I feel very blessed that we were referred to Dr. Leonetti," said Deborah Rex, Audrey's mother.
Bell's palsy is classified as an idiopathic disorder, meaning its cause is not definitely known. However, most physicians believe
Bell's palsy is caused by a viral-induced swelling of the facial nerve within its bony covering. Symptoms include paralysis on one
side of the face; inability to close one eye; drooling; dryness of the eye; impaired taste; and a complete inability to express emotion
on one side of the face.
Bell's palsy occurs when the nerve that controls muscles on one side of the face becomes swollen, inflamed or compressed. The
nerve runs through a narrow, bony canal called the Fallopian canal. Following a viral infection, the nerve swells inside the canal,
restricting the flow of blood and oxygen to nerve cells.
Most cases can be successfully treated with oral steroids, and 85 percent of patients experience good recovery within one month.
But if symptoms persist for longer than a month, the patient may need surgery, Leonetti said. If surgery is delayed for longer than
three months, the nerve damage from Bell's palsy can be permanent. Thus, the optimal window for surgery is between one and
three months after onset of symptoms.
The surgery is called microscopic decompression of the facial nerve. The surgeon removes the bony covering of the facial nerve,
then slits open the outer covering of the nerve. This gives the nerve room to swell. In addition to this standard procedure, Leonetti
uses an electric stimulator to send a current through the nerve. This jump starts the nerve to speed its recovery.
Decompression of the facial nerve is an established technique for treating Bell's palsy, and electric stimulation is an established
technique used in other surgeries involving the nerve. "We are combining two standard treatments to create an exceptional
treatment," Leonetti said.
Following surgery, Audrey worked with Loyola physical therapist Lisa Burkman, who used a mirror and biofeedback to teach
Audrey individualized exercises of her mouth, eye, forehead, cheek and chin. Leonetti said Audrey's case illustrates that the road
back from Bell's palsy is a multidisciplinary effort that involves the surgeon, physical therapist and patient.
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Leonetti is a Professor and Vice Chairman in the department of Otolaryngology, Head and Neck Surgery, and Co-Director of the
Loyola Center for Cranial Base Tumors at Loyola University Chicago Stritch School of Medicine. In addition to facial nerve
disorders, his special interests include parotid gland tumors, ear disorders and skull base tumors.
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Innovative Screening Strategy Swiftly Uncovers New Drug Candidates, New

Biology
Dec. 22, 2013 Scientists at The Scripps Research Institute (TSRI) have
demonstrated a drug-discovery strategy with a double payoff -- it enables the rapid
selection of chemical compounds that have a desired effect on cells and also highlights
how the compounds work.
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To illustrate the power of the innovative technique, the TSRI researchers used it to identify a compound that shows promise for
treating obesity-linked diabetes. At the same time, they were able to identify the fat-cell enzyme that the compound inhibits -- an
enzyme that has not yet been a focus of diabetes drug development.
"This integrated strategy we've developed has the potential to accelerate the discovery of important biological pathways and may
lead to faster development of new drugs for multiple diseases," said TSRI Associate Professor Enrique Saez.
Saez and his colleague Benjamin F. Cravatt, chair of TSRI's Department of Chemical Physiology, were the senior authors of the
new study, which is reported December 22, 2013, in an advance online issue of Nature Chemical Biology.
Facilitating Drug Discovery
The new strategy has great potential to streamline drug discovery, a process whose importance to human health can hardly be
overemphasized.
Typically, pharmaceutical scientists start the discovery process by "screening" large libraries of chemical compounds in search of
one or a few that might treat disease. The dominant strategy of recent decades has been to screen compounds for a specific
activity against a known target, for example, inhibiting the function of a certain enzyme thought to be critical for the disease in
question. A key advantage of this "target-based" screening is that it uses biochemical tests that can be done relatively simply in a
test-tube -- or rather, in a large array of tiny test tubes via automated, rapid screening systems that sort through hundreds of
thousands of different compounds.
Target-based screening has enabled scientists to discover many useful new drugs, but some wonder whether this basic discovery
strategy has already taken all the "low hanging fruit." In recent years, compounds selected with target-based in vitro tests have
seemed to be failing increasingly often when tested in the more realistic biological environments of cells and animals.
An older strategy, "phenotypic" screening, avoids much of this problem by testing compounds for their ability to produce a desired
effect directly on living cells. Unfortunately, such cell-based tests often leave open the question of how a useful compound works.
"If you don't know what its relevant molecular target is, then developing that compound into a drug -- optimizing its potency, its
selectivity, its half-life in the bloodstream and so on -- is going to be difficult," said Saez.
Identifying the molecular targets of compounds selected by phenotypic screens is typically burdensome and time-consuming. But in
their new study, Saez, Cravatt and their colleagues were able to speed up the process dramatically. Indeed, their combined
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phenotypic screening and target-identification approach enabled them to quickly discover, characterize and carry out preclinical
tests of a potential new drug for obesity-linked diabetes: a complex metabolic disorder that affects 347 million people worldwide.
A New Diabetes Drug Candidate, Plus Insights into the Disease
The strategy makes use of the increasing availability of special libraries of related compounds that act as inhibitors of entire
enzyme classes. In this case, the researchers used a set of compounds, recently synthesized by Cravatt's laboratory, that tend to
inhibit serine hydrolases -- a vast enzyme family whose members participate in most biological processes in mammals.
The scientists started with a phenotypic screen, testing their library of compounds for the ability to make young fat cells mature
faster and store more fat. Better fat storage means that less fat leaks from fat cells into the liver, muscles and pancreas -- a
process that frequently occurs with obesity, often interfering with insulin signaling enough to bring on diabetes.
The screen quickly yielded several compounds that had a strong effect in promoting fat-cell fat storage. The researchers then used
a method called "activity-based profiling" to identify the fat-cell serine hydrolases that the compounds inhibited most strongly. One
of the most potent compounds, WWL113, turned out to work principally by inhibiting Ces3, a serine hydrolase enzyme that
scientists have not studied in the context of obesity or diabetes.
The researchers quickly demonstrated WWL113's effectiveness in two different mouse models of obesity-linked diabetes -- one in
which the mice are genetically programmed to become obese and diabetic, and another in which normal mice are made obese and
diabetic with a high-fat diet. "The treated animals showed resistance to weight gain -- they were not putting on as much weight as
the controls," said Saez. "Their blood biochemistry also was getting normalized; their glucose, triglyceride and cholesterol levels
were coming down towards normal levels."
In these mouse tests, WWL113 -- without any optimization for use as a drug -- performed about as well as the FDA-approved
diabetes treatment rosiglitazone (Avandia). Notably, the new compound lacked one of the side effects that drugs in rosiglitazone's
class have in mice: the toxic accumulation of lipids in the liver. "Our compound clears lipids from the diabetic mouse liver, whereas
rosiglitazone has the opposite effect," said Saez.
To explore the relevance of these results to humans, the TSRI team worked with collaborating researchers in Australia to test fat
samples from obese humans and diabetics. The tests confirmed that the human version of Ces3 also is unusually active in such
patients. This suggests that an inhibitor may also work as a diabetes treatment in people.
Saez and his colleagues will next focus on using the new screening strategy to uncover more biological pathways that could yield
new mechanisms to develop potential therapies.
Contributors to the study, "Integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes," also included first
author Eduardo Dominguez, then a postdoctoral fellow in the Saez Laboratory; as well as TSRI's Andrea Galmozzi, Jae Won
Chang, Ku-Lung Hsu, Joanna Pawlak, Weiwei Li, Cristina Godio, Jason Thomas, David Partida, Sherry Niessen and Daniel K.
Nomura; and Australian researchers Paul E. O'Brien and Matthew J. Watt of Monash University, and Aaron P. Russell of Deakin
University.
The study was funded in part by the National Institutes for Health (DK081003, DK099810), the American Diabetes Association, The
McDonald's Center for Type 2 Diabetes and Obesity, the National Health and Medical Research Council of Australia, the Hewitt
Foundation for Medical Research and the Xunta de Galicia, Spain.
ANOTAES
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