The evolution of adaptations for life on land have long puzzled biologists – are feathers descendents of dinosaur scales, how did arms and legs evolve from fins, and from what ancient fish organ did the lung evolve?
Biologists have known that the co-development of the cardiovascular and pulmonary systems is a recent evolutionary adaption to life outside of water, coupling the function of the heart with the gas exchange function of the lung. And, the lung is one of the most recent organs to have evolved in mammals and is arguably the most vital for terrestrial life.
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Wnt2+ CPPs (green cells) populate multiple cell lineages in the developing lung including airway and vascular smooth muscle. The smooth muscle of the branching airways and large blood vessels are stained in red.Credit: Edward E. Morrisey, Ph.D. |
The coordinated maturation of the cells of these two systems is illustrated during embryonic development, when the primitive lung progenitor cells protrude into the primitive cardiac progenitor cells as the two organs develop in parallel to form the cardiopulmonary circulation. However, little is known about the molecular cues guiding this simultaneous development, and how a common progenitor cell for both organs may influence the pathology of such related diseases as pulmonary hypertension.
In a new paper published this week online in Nature, a team from the Perelman School of Medicine, University of Pennsylvania, shows that the pulmonary vasculature, the blood vessels that connect the heart to the lung, develops even in the absence of the lung. Mice in which lung development is inhibited still have pulmonary blood vessels, which revealed to the researchers that cardiac progenitors, or stem cells, are essential for cardiopulmonary co-development.
The Penn team, led by Edward E. Morrisey, PhD, professor of Medicine and Cell and Developmental Biology and scientific director of the Penn Institute for Regenerative Medicine, identified a population of multi-potent CardioPulmonary mesoderm Progenitor cells they named CPPs. The CPPs can be distinguished from many other early embryonic cells by the expression of a well-studied signaling molecule Wnt2.
“We asked if these progenitor cells are capable of generating both heart and
lung derivatives,” says Morrisey. “Our data show that Wnt2-positive cells exist
prior to lung development and help coordinate lung and heart co-development by
generating cell types in both tissues.”
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Pancreatic cancer carries a dismal prognosis. According to the National Cancer Institute, the overall five-year relative survival for 2003-2009 was 6 percent.
Still, researchers and clinicians don’t have a non-invasive way to even detect early cells that portent later disease. ‘There’s no PSA test for pancreatic cancer,’ they say, and that’s one of the main reasons why pancreatic cancer is detected so late in its course.
They have been searching for a human-cell model of
early-disease progression. Now, Penn scientists have used stem-cell technology
to create a research cell line from a patient with advanced pancreatic ductal
adenocarcinoma (PDAC).
This first-of-its-kind human-cell model of pancreatic cancer progression was published this week in Cell Reports from the lab of Ken Zaret, PhD, professor of Cell and Developmental Biology.
“It is the first example using induced pluripotent stem [iPS] cells to model
cancer progression directly from a solid tumor, and the first human cell line
that can model pancreatic cancer progression from early to invasive stages,”
says Zaret, also the associate director of the Penn Institute for Regenerative
Medicine.
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Sperm doesn’t appear to forget anything. Stress felt by dad—whether as a preadolescent or adult—leaves a lasting impression on his sperm that gives sons and daughters a blunted reaction to stress, a response linked to several mental disorders. The findings, published in a new preclinical study in the Journal of Neuroscience by researchers at Penn, point to a never-before-seen epigenetic link to stress-related diseases such as anxiety and depression passed from father to child.
While environmental challenges, like diet, drug abuse, and chronic stress, felt by mothers during pregnancy have been shown to affect offspring neurodevelopment and increase the risk for certain diseases, dad’s influence on his children are less well understood. The effects of lifelong exposures to dad on children are even more out of reach.
Now, a team of researchers led by Tracy
L. Bale, PhD, have shown that stress on preadolescent and adult
male mice induced an epigenetic mark in their sperm that reprogrammed their
offspring’s hypothalamic-pituitary-adrenal (HPA) axis, a region of the brain
that governs responses to stress. Surprisingly, both male and female offspring
had abnormally low reactivity to stress.
This stress pathway dysregulation—when reactivity is either heightened or reduced—is a sign that an organism doesn’t have the ability to respond appropriately to a changing environment. And as a result, their stress response becomes irregular, which can lead to stress-related disorders.
“It didn’t matter if dads were going through puberty or in adulthood when
stressed before they mated. We’ve shown here for the first time that stress can
produce long-term changes to sperm that reprogram the offspring HPA stress axis
regulation,” said Bale. “These findings suggest one way in which paternal-stress
exposure may be linked to such neuropsychiatric diseases.”
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The kidney and liver cancer drug sorafenib holds metastatic thyroid cancer at bay for nearly twice as long as a placebo, according to results of a randomized phase III trial, which will be presented today by a researcher from the Abramson Cancer Center and the Perelman School of Medicine at Penn in a plenary session during the American Society of Clinical Oncology’s annual meeting (Abstract #4).
If approved for use in thyroid cancer patients by the Food and Drug Administration, sorafenib (Nexavar), a kinase inhibitor that mediates tumor cell division and growth of tumor blood vessels, would be the first effective agent for this patient population. Thyroid cancer is highly curable through surgery and radioactive iodine treatment, but about 10 percent of the 60,000 patients who are diagnosed with the disease each year fail to respond to standard therapies, with tumors eventually appearing in the lymph nodes, bones, lungs, and other sites. The only other drug for advanced thyroid cancer, doxorubicin, which was approved in 1974, is not used because it is highly toxic and is not effective.
“Until we began using sorafenib, we had no medical options
for these patients who suffered due to progression of their disease,” said Marcia S.
Brose, MD, PhD, an assistant professor of Otolaryngology and Head
and Neck Surgery and Hematology/Oncology, who led the study, which is known as
DECISION. “Now, we can give patients hope – a breakthrough medication that can
stop the progression of the disease for 5 months. This trial is the first step
in a promising series of clinical trials to identify new drugs that are shifting
the horizon for patients with advanced thyroid cancer.”
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The clock never seems to stop. Every day, it seems, we're
fighting it: rushing to get to work, getting errands done, catching whatever
sleep we can. There's never enough time to do what we need or want to do, and
just when we almost seem to get caught up on the weekends or our days off, the
clock keeps going and the merry-go-round starts all over again.
That's life for most people in our hectic 21st-century society. Undoubtedly, most of us have occasionally cursed creators of the merciless work schedules, keepers of the deadlines, masters of the timebound obligations by which our economy and society continuously operate. But as arbitrary as they may sometimes seem, clocks, calendars, and schedules aren't an invention of humans. Clocks – mechanisms to track and mark the passage of time – are an integral and indispensable part of life on Earth, from the simplest and most primitive one-celled organisms all the way to human beings.
The study of how biological clocks work to control and regulate almost every function of life is called chronobiology. It's a rich discipline encompassing a broad range of sciences, synthesizing their techniques and viewpoints in new and exciting ways. And almost without even trying to, the University of Pennsylvania has become one of the world's leading centers of chronobiology, with cutting-edge research that involves almost every one of Penn Medicine's science departments and several departments of its hospitals.
"Chronobiology is biological timing," says Amita
Sehgal, Ph.D., professor of neuroscience and a Howard Hughes
Medical Institute Investigator. "It basically refers to the process by which
organisms time physiology and behavior, so that everything takes place in a
rhythmic fashion." The persistent rhythms of life, the body clocks that control
when you wake, sleep, eat, digest food, and perform nearly every other function
of a living organism, are all the province of chronobiology.
Click here for the full article by Mark Wolverton.
Researchers at the Perelman School of Medicine have developed a new gene therapy to thwart a potential influenza pandemic. Specifically, investigators in the Gene Therapy Program, Department of Pathology and Laboratory Medicine, directed by James M. Wilson, MD, PhD, demonstrated that a single dose of an adeno-associated virus (AAV) expressing a broadly neutralizing flu antibody into the nasal passages of mice and ferrets gives them complete protection and substantial reductions in flu replication when exposed to lethal strains of H5N1 and H1N1 flu virus. These strains were isolated from samples associated from historic human pandemics – one from the infamous 1918 flu pandemic and another from 2009.
Wilson, Anna Tretiakova, PhD, Senior Research Scientist, Maria P. Limberis, PhD, Research Assistant Professor, all from the Penn Gene Therapy Program, and colleagues published their findings online this week in Science Translational Medicine ahead of print. In addition to the Penn scientists, the international effort included colleagues from the Public Health Agency of Canada, Winnipeg; the University of Manitoba, Winnipeg; and the University of Pittsburgh. Tretiakova is also the director of translational research, and Limberis is the director of animal models core, both with the Gene Therapy Program.
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An Institute of Medicine group, led by Med’s Brian Strom, finds no evidence of health benefits from reducing sodium intake to levels recommended in dietary guidelines.
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Labs around the world, and a core group at Penn, have been
studying recently described populations of immune cells called innate lymphoid
cells (ILCs). Some researchers liken them to foot soldiers that protect boundary
tissues such as the skin, the lining of the lung, and the lining of the gut from
microbial onslaught. They also have shown they play a role in inflammatory
disease, when the body’s immune system is too active.
In animal studies, group-2 innate lymphoid cells (ILC2s) confer immunity during a parasitic infection in mice and are also involved in allergic airway inflammation. A team of Penn researchers found that maturation of ILC2s requires T-cell factor 1 (TCF-1, the product of the Tcf7 gene) to move forward. TCF-1 is protein that binds to specific parts of DNA to control transcription of genetic information from DNA to messenger RNA.
Avinash Bhandoola, PhD, and Qi Yang, PhD, a postdoc in the Bhandoola lab, describe in Immunity that one mechanism used to build ILCs is the same as that in T cells. Both cell types use a protein pathway centered on Notch that the lab of coauthor Warren Pear, MD, PhD, has studied for the last two decades. Other contributing authors are from the laboratory of David Artis, PhD, that are experts in ILC function, and Angela Haczku, MD, PhD.
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Deep brain stimulation (DBS) in a precise region of the brain appears to reduce caloric intake and prompt weight loss in obese animal models, according to a new study led by researchers at Penn. The study, reported in the Journal of Neuroscience, reinforces the involvement of dopamine deficits in increasing obesity-related behaviors such as binge eating, and demonstrates that DBS can reverse this response via activation of the dopamine type-2 receptor.
"Based on this research, DBS may provide therapeutic relief to binge eating, a behavior commonly seen in obese humans, and frequently unresponsive to other approaches," said senior author Tracy L. Bale, PhD, associate professor of neuroscience in Penn’s School of Veterinary Medicine’s Department of Animal Biology and in the Perelman School of Medicine’s Department of Psychiatry. DBS is currently used to reduce tremors in Parkinson's disease and is under investigation as a therapy for major depression and obsessive-compulsive disorder.
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Penn’s signature event at the 3rd annual Philadelphia Science Festival next week is a sure sign of the times. “Big Ideas: Funding and Innovation” draws
on current themes and reminders of where the bright ideas really come from.
Fundamental research at such government agencies as the National Institutes of
Health and the National Science Foundation spur today’s most successful
businesses and healthcare innovations. Federal funds from taxpayer dollars drive
the development of nearly all of the top technologies that permeate our
lives.
On Tuesday, April 23, 2013 at 6:30pm at the historic Iron Gate
Theater, 3700 Chestnut Street, a group of Penn and Drexel innovators will share
their real-life examples of how federal funds have contributed to their Big
Ideas including BGS faculty members Garret
FitzGerald, MD, FRS, and Chris
Hunter, PhD.
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A dye-based imaging technique known as two-photon microscopy can produce pictures of active neural structures in much finer detail than functional magnetic resonance imaging, or fMRI, but it requires powerful and expensive lasers. Now, a research team at the University of Pennsylvania has developed a new kind of dye that could reduce the cost of the technique by several orders of magnitude.
The study was led by associate professor Sergei Vinogradov and postdoctoral researcher Tatiana Esipova, both of the Biochemistry and Biophysics graduate group, along with Christopher Murray, a professor in the departments of Chemistry in the School of Arts and Sciences and of Materials Science and Engineering in the School of Engineering and Applied Science.
It was published in the Proceedings
of the National Academies of Science.
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Two children with an aggressive form of childhood leukemia had a complete remission of their disease—showing no evidence of cancer cells in their bodies—after treatment with a novel cell therapy that reprogrammed their immune cells to rapidly multiply and destroy leukemia cells. A research team from The Children’s Hospital of Philadelphia (CHOP) and Penn published the case report of two pediatric patients Online First today in The New England Journal of Medicine. It will appear in the April 18 print issue.
One of the patients, 7-year-old Emily Whitehead, was featured in news stories in December 2012 after the experimental therapy led to her dramatic recovery after she relapsed following conventional treatment. Emily remains healthy and cancer-free, 11 months after receiving bioengineered T cells that zeroed in on a target found in this type of leukemia, called acute lymphoblastic leukemia. The other patient, a 10-year-old girl, who also had a complete response to the same treatment, suffered a relapse two months later when other leukemia cells appeared that did not harbor the specific cell receptor targeted by the therapy.
“This study describes how these cells have a potent anticancer effect in children,” said co-first author Stephan A. Grupp, M.D., Ph.D., of CHOP, where both patients were treated in this clinical trial. “However, we also learned that in some patients with ALL, we will need to further modify the treatment to target other molecules on the surface of leukemia cells.”
The current study builds on Grupp’s ongoing collaboration with Penn Medicine scientists who originally developed the modified T cells as a treatment for B-cell leukemias. The team is led by the current study’s senior author, Carl H. June, M.D., the Richard W. Vague Professor in Immunotherapy at Penn and director of Translational Research in Penn’s Abramson Cancer Center.
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MARCH 13, 2013 - Penn Researchers Show that Suppressing the Brain’s “Filter” Can Improve Performance in Creative Tasks
The brain’s prefrontal cortex is thought to be the seat of cognitive control, working as a kind of filter that keeps irrelevant thoughts, perceptions and memories from interfering with a task at hand.
Now, researchers at the University of Pennsylvania have shown that inhibiting this filter can boost performance for tasks in which unfiltered, creative thoughts present an advantage.
The research was conducted by Sharon Thompson-Schill, the Christopher H. Browne Distinguished Professor of Psychology and director of the Center for Cognitive Neuroscience, and Evangelia Chrysikou, a member of her lab who is now an assistant professor at the University of Kansas. They collaborated with Roy Hamilton and H. Branch Coslett of the Department of Neurology at Penn and Abhishek Datta and Marom Bikson of the Department of Biomedical Engineering at the City College of New York.
Their work was published in the journal Cognitive Neuroscience.
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It happens to everyone: You stay up late one night to
finish an assignment, and the next day, you’re exhausted. Humans aren’t unique
in that; all animals need sleep, and if they don’t get it, they must make it
up.
The biological term for that pay-the-piper behavior is “sleep homeostasis,” and now, thanks to a research team at Penn, one of the molecular players in this process has been identified – at least in nematode round worms.
David Raizen, MD, PhD, assistant professor of Neurology, and his colleagues report in Current Biology that even in Caenorhabditis elegans, a tiny nematode worm that feeds on bacteria, loss of sleep is “stressful.”
The researchers forced the animals to stay awake during a developmental stage when they normally sleep, called “lethargus.” These sleep-deprived worms, like college students after an all-nighter, exhibited signs of sleep homeostasis – they were harder to wake up compared to control worms.
While nematode worms do not sleep as vertebrates do, lethargus is a sleep-like state, says Raizen, characterized by episodic reversible immobility, elevated arousal thresholds, and homeostasis.
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Saying that the sense of taste is complicated is an understatement, that it is little understood, even more so. Exactly how cells transmit taste information to the brain for three out of the five primary taste types was pretty much a mystery, until now.
A team of investigators from nine institutions discovered how ATP – the body’s main fuel source – is released as the neurotransmitter from sweet, bitter, and umami, or savory, taste bud cells. The CALHM1 channel protein, which spans a taste bud cell’s outer membrane to allow ions and molecules in and out, releases ATP to make a neural taste connection. The other two taste types, sour and salt, use different mechanisms to send taste information to the brain.
Kevin Foskett, PhD, professor of Physiology at Penn, and colleagues from the Monell Chemical Senses Center, the Feinstein Institute for Medical Research, and others, describe in Nature how ATP release is key to this sensory information path. They found that the calcium homeostasis modulator 1 (CALHM1) protein, recently identified by the Foskett lab as a novel ion channel, is indispensable for taste via release of ATP.
“This is an example of a bona fide ATP ion channel with a clear physiological function,” says Foskett. “Now we can connect the molecular dots of sweet and other tastes to the brain.”
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Lung diseases such as asthma and chronic obstructive
pulmonary disease (COPD) are on the rise, according to the American Lung
Association and the National Institutes of Health.
These ailments are chronic, affect the small airways of the lung, and are thought to involve an injury-repair cycle that leads to the breakdown of normal airway structure and function. For now, drugs for COPD treat only the symptoms.
“A healthy lung has some capacity to regenerate itself like the liver,” notes Ed Morrisey, Ph.D., professor of Medicine and Cell and Developmental Biology and the scientific director of the Penn Institute for Regenerative Medicine at Penn. “In COPD, these reparative mechanisms fail.”
Morrisey is looking at how epigenetics controls lung repair and regeneration. Epigenetics involves chemical modifications to DNA and its supporting proteins that affect gene expression. Previous studies found that smokers with COPD had the most significant decrease in one of the enzymes controlling these modifications, called HDAC2.
Morrisey and colleagues published their findings in this week’s issue of Developmental Cell.
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The body’s immune system exists to identify and destroy foreign objects, whether they are bacteria, viruses, flecks of dirt or splinters. Unfortunately, nanoparticles designed to deliver drugs, and implanted devices like pacemakers or artificial joints, are just as foreign and subject to the same response.
Now, researchers at the University of Pennsylvania School of Engineering and Applied Science and Penn’s Institute for Translational Medicine and Therapeutics have figured out a way to provide a “passport” for such therapeutic devices, enabling them to get past the body’s security system.
The research was conducted by professor Dennis Discher, graduate students Pia Rodriguez, Takamasa Harada, David Christian and Richard K. Tsai and postdoctoral fellow Diego Pantano of the Molecular and Cell Biophysics Lab in Chemical and Biomolecular Engineering at Penn.
It was published in the journal Science.
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A recently described master regulator protein may
explain the development of aberrant cell growth in the pancreas spurred by
inflammation.
A team from Penn profiled gene expression of mouse pancreatic ductal and duct-like cells from different states - embryonic development, acute pancreatitis and K-ras mutation-driven carcinogenesis - to find the molecular regulation of these processes. Broadly speaking, two cellular compartments are important in a normal pancreas, endocrine cells, which produce hormones including insulin, and exocrine cells – acinar and ductal -- which make and secrete digestive enzymes.
A cover article from the lab of Anil Rustgi, MD, Chief, Division of Gastroenterology, published early online in Genes and Development, details the molecular changes of exocrine cells during inflammation, so-called acinar-ductal metaplasia (ADM), a prelude to pancreatic ductal adenocarcinoma.
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Double-strand breaks in DNA happen every time a cell divides and replicates. Depending on the type of cell, that can be pretty often. Many proteins are involved in everyday DNA repair, but if they are mutated, the repair system breaks down and cancer can occur. Cells have two complicated ways to repair these breaks, which can affect the stability of the entire genome.
Roger A. Greenberg, M.D., Ph.D., associate investigator, Abramson Family Cancer Research Institute and associate professor of Cancer Biology at the Perelman School of Medicine, University of Pennsylvania, together with postdoctoral researcher Jiangbo Tang Ph.D. and colleagues, found a key determinant in the balance between two proteins, BRCA1 and 53BP1, in the DNA repair machinery. Breast and ovarian cancer are associated with a breakdown in the repair systems involving these proteins. Their findings appear in the latest online issue of Nature Structural & Molecular Biology.
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It is perhaps impossible to overstate the importance of the
tumor suppressor gene p53. It is the single most frequently mutated gene in
human tumors. p53 keeps pre-cancerous cells in check by causing cells, among
other things, to become senescent – aging at the cellular level. Loss of p53
causes cells to ignore the cellular signals that would normally make mutant or
damaged cells die or stop growing.
In short, the p53 pathway is an obvious and attractive target for drug developers. But that strategy has so far proven difficult, as most p53 regulatory proteins operate via protein-protein interactions, which make for poor drug targets, as opposed to ones based on enzymes.
Now, a team of researchers from the Perelman School of Medicine at Penn has identified a class of p53 target genes and regulatory molecules that represent more promising therapeutic candidates. As Xiaolu Yang, PhD, professor of Cancer Biology and investigator in Penn’s Abramson Family Cancer Research Institute, and his team describe in an advance online Nature publication, p53 participates in a molecular feedback circuit with malic enzymes, thereby showing that p53 activity is also involved in regulating metabolism. (The Yang lab identified p53’s role in glucose metabolism in the past.)
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A team, led by senior author Morris J. Birnbaum, MD, PhD, the Willard and Rhoda Ware Professor of Medicine, with the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, found that the diabetes drug metformin works in a different way than previously understood. Their research in mice found that metformin suppresses the liver hormone glucagon’s ability to generate an important signaling molecule, pointing to new drug targets. The findings were published online this week in Nature.
For fifty years, one of the few classes of therapeutics effective in reducing the overactive glucose production associated with diabetes has been the biguanides, which includes metformin, the most frequently prescribed drug for type 2 diabetes. The inability of insulin to keep liver glucose output in check is a major factor in the high blood sugar of type 2 diabetes and other diseases of insulin resistance.
“Overall, metformin lowers blood glucose by decreasing liver production of glucose,” says Birnbaum. “But we didn’t really know how the drug accomplished that.”
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Calpain, a calcium-regulated enzyme, is essential to a host
of cellular processes, but can cause severe problems in its overactivated state.
It has been implicated as a factor in muscular dystrophy, AIDS, Alzheimer's
disease, multiple sclerosis, and cancer. As such, finding and exploiting calpain
inhibitors is an important area of research.
A team from the Perelman School of Medicine, in collaboration with the UCSF and Queen’s University, has developed a unique approach to calpain inhibition by mimicking a natural reaction with a synthesized molecule. The work was published in the latest issue of the Journal of the American Chemical Society.
"We have an interest in this protein because it’s important for Plasmodium development," explains Doron Greenbaum, PhD, assistant professor in of Pharmacology. "We initially found that calpain played a role in parasites being able to get out of their host cell, so we became interested in inhibitor development for human calpains."
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New research from the Perelman School of Medicine at Penn and Massachusetts General Hospital (MGH) reveals that sons of male rats exposed to cocaine are resistant to the rewarding effects of the drug, suggesting that cocaine-induced changes in physiology are passed down from father to son. The findings are published in the latest edition of Nature Neuroscience.
“We know that genetic factors contribute significantly to the risk of cocaine abuse, but the potential role of epigenetic influences, how certain genes related to addiction are expressed, is still relatively unknown,” said senior study author R. Christopher Pierce, PhD, associate professor of Neuroscience in Psychiatry at Penn. “This study is the first to show that the chemical effects of cocaine use can be passed down to future generations to cause a resistance to addictive behavior, indicating that paternal exposure to toxins can have profound effects on gene expression and behavior of their offspring.”
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Steven J. Fluharty, Ph.D. is a Professor of Pharmacology, Psychology and Neuroscience and the Senior Vice Provost for Research at the University of Pennsylvania. In this capacity Dr. Fluharty shapes policy and advances administrative initiatives for the University’s billion dollar research enterprise as well as plays a leadership role in strategic planning for research and administers the development of new research facilities. He also helps to oversee campus-wide research planning efforts, linkages between the University and industry, and the transfer of technologies from University laboratories to the public sector. In addition, he governs the research activities of Provostial Centers and Institutes, particularly those involving interdisciplinary collaboration.
Several fatal brain disorders, including Parkinson's disease, are connected by the misfolding of specific proteins into disordered clumps and stable, insoluble fibrils called amyloid. Amyloid fibrils are hard to break up due to their stable, ordered structure. For example, a-synuclein forms amyloid fibrils that accumulate in Lewy Bodies in Parkinson's disease. By contrast, protein clumps that accumulate in response to environmental stress, such as heat shock, possess a less stable, disordered architecture.
Hsp104, an enzyme from yeast, breaks up both amyloid fibrils and disordered clumps. In the most recent issue of Cell, James Shorter, PhD, assistant professor of Biochemistry and Biophysics, and colleagues show that Hsp104 switches mechanism to break up amyloid versus disordered clumps. For stable amyloid-type structures, Hsp104 needs all six of its subunits, which together make a hexamer, to pull the clumps apart. By contrast, for the more amorphous, non-amyloid clumps, Hsp104 required only one of its six subunits.
Unexpectedly, the bacterial version of the Hsp104 enzyme, called ClpB, behaves differently compared to Hsp104. Bacterial ClpB uses all six subunits to break up amorphous clumps and fails to break up amyloid fibrils. Bacteria just ignore these more stable structures, whereas yeast use Hsp104 to exploit amyloid fibrils for beneficial purposes.
“One surprise is that biochemists thought that Hsp104 and ClpB hexamers worked in the same way,” says first author and graduate student in the Shorter lab Morgan DeSantis. “This is not the case.”
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Understanding
how any disease progresses is one of the first and most important steps towards
finding treatments to stop it. This has been the case for such
brain-degenerating conditions as Alzheimer's disease. Now, after several years
of incremental study, researchers at the Perelman School of Medicine, University
of Pennsylvania have been able to piece together important steps in how
Parkinson’s disease (PD) spreads from cell to cell and leads to nerve cell
death.
In short, the Penn researchers found that, in healthy mice, a single injection of synthetic, misfolded α-Syn fibrils led to a cell-to-cell transmission of pathologic α-Syn proteins and the formation of Parkinson’s α-Syn clumps known as Lewy bodies in interconnected regions of the brain. Their findings appear in this week’s issue of Science. The team was led by senior author Virginia M.-Y Lee, PhD, director of the Center for Neurodegenerative Disease Research (CNDR) and professor of Pathology and Laboratory Medicine, and first author Kelvin C. Luk, PhD, research assistant professor in the CNDR.
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James
Eberwine, PhD, Elmer Holmes Bobst Professor of Pharmacology in the
Perelman School of Medicine, and Junhyong Kim,
PhD, Edmund J. and Louise W. Kahn Professor of Biology in the School of Arts and
Sciences, will be studying the role of how messenger RNA (mRNA) molecules vary
in their function in individual cells with a five-year, $10 million grant from
the National Institutes of Health (NIH). Their award is supported by the NIH
Common Fund and is part of three initiatives of the Single Cell Analysis Program
(SCAP). Eberwine and Kim are also Co-directors of the Penn Genomic Frontiers Institute.
The goal of the Penn grant is to characterize the variability in identity and abundances of RNA molecules that are transcribed from the genome of human neurons and heart cells. These are the so-called excitable cells, those that use bioelectricity for communication and everyday functions. Many human nervous system diseases derive from changes in electrical responsiveness of neurons and heart arrhythmias account for many heart-related deaths.
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The cancer-causing form of the gene Myc alters the metabolism of mitochondria, the cell’s powerhouse, making it dependent on the amino acid glutamine for survival. In fact, 40 percent of all “hard-to-treat” cancers have a mutation in the Myc gene. Accordingly, depriving cells of glutamine selectively induces programmed cell death in cells overexpressing mutant Myc.
Using Myc-active neuroblastoma cancer cells, a team led by Howard Hughes Medical Institute (HHMI) investigator M. Celeste Simon, Ph.D., scientific director for the Abramson Family Cancer Research Institute (AFCRI), identified the proteins PUMA, NOXA, and TRB3 as executors of the glutamine-starved cells. These three proteins represent a downstream target in the Myc pathway at which to aim drugs. Roughly 25 percent of all neuroblastoma cases are associated with Myc-active cells.
The findings appear in this week’s issue of Cancer Cell. Simon is also a professor of Cell and Developmental Biology at
the Perelman School of Medicine, University of Pennsylvania. The Penn team
collaborated with colleagues from The Children’s Hospital of Philadelphia (CHOP) John
Maris and Michael
Hogarty.
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When a virus such as influenza invades our bodies, interferon proteins are among the first immune molecules produced to fight off the attack. A study by scientists from the University of Pennsylvania School of Veterinary Medicine offers a new strategy for enhancing the effects of interferon in fighting off infection. The research suggests that, by targeting a particular molecule in the interferon signaling pathway, specially designed drugs may be able to boost the activity of a person’s own interferon, augmenting the immune system’s fight against viruses. It’s possible that the same drugs might also be effective against some types of cancer and certain autoimmune conditions.
Serge Fuchs, a professor of cell biology in Penn Vet’sDepartment of Animal Biology and director of the School’s Mari Lowe Comparative Oncology Center, was the senior author on the paper published in theProceedings of the National Academy of Sciences.
“The practical significance of our study is a demonstration of the ability to use emerging pharmaceuticals to reactivate an individual’s own interferon or to use a reduced dose to get the same effect,” Fuchs said.
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An international effort led by researchers at the Perelman School of Medicine at Penn has resulted in positive phase 3 clinical trial results for a new medicine to treat patients suffering from a rare and deadly cholesterol disorder. Penn researchers report in The Lancet that lomitapide, a first-in-class microsomal triglyceride transfer protein (MTP) inhibitor, substantially and stably reduced LDL cholesterol (the “bad” cholesterol) in patients with the orphan disease homozygous familial hypercholesterolemia (HoFH). Lomitapide works by inhibiting MTP, which is required for the production of VLDL — the precursor to LDL.
Senior study author Daniel J. Rader, MD, chief, Division of Translational Medicine and Human Genetics, has treated HoFH patients for more than two decades. In the early 1990s, Rader worked with colleagues to determine that mutations in MTP were the cause of a rare condition characterized by absent LDL in the blood, establishing MTP as a therapeutic target to reduce LDL. His colleagues then went on to discover the MTP inhibitor lomitapide at Bristol-Myers Squibb (BMS). Rader led a study at Penn in the late 1990s showing that lomitapide substantially reduced LDL in patients with moderately elevated LDL. However, because the agent caused some gastrointestinal side effects and increased liver fat, BMS decided to abandon further development of lomitapide for a much larger population of patients with elevated levels of cholesterol. Rader convinced BMS to donate the drug to Penn so that he could continue to develop it in patients with HoFH. Based on its mechanism and on a study in a rabbit model of the disease, Rader felt it would be effective against HoFH.
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A new study by researchers at the Perelman School of Medicine at the University of Pennsylvania demonstrates in an animal model that a commonly used inhaled anesthetic drug, isoflurane, works by directly causing sleep-promoting neurons in the brain to activate, thereby hijacking our natural sleep circuitry. The findings are the latest work by investigators in the Center for Anesthesia Research at Penn who are exploring how anesthetics interact within the central nervous system to cause a state of unconsciousness. Thenew research is published the latest edition of the journal Current Biology.
"Despite more than 160 years of continuous use in humans, we still do not understand how anesthetic drugs work to produce the state of general anesthesia," said study author Max B. Kelz, MD, PhD, assistant professor of Anesthesiology and Critical Care. "We show in this new work that a commonly used inhaled anesthetic drug directly causes sleep-promoting neurons to fire. We believe that this result is not simply a coincidence. Rather, our view is that many general anesthetics work to cause unconsciousness in part by commandeering the brain’s natural sleep circuitry, which initiates our nightly journey into unconsciousness."
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Scott Halpern of Medicine discusses a new end-of-life studies center that researches one of “health care's most contentious and painful areas.”
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Medicine's Virginia Lee and John Trojanowski discuss the need for drug discovery to combat the “natural disaster of our millennium,” neurodegenerative disease.
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Nearly 100 years after a British neurologist first mapped the blind spots caused by missile wounds to the brains of soldiers, Perelman School of Medicine researchers at the University of Pennsylvania have perfected his map using modern-day technology. Their results create a map of vision in the brain based upon an individual's brain structure, even for people who cannot see. Their result can, among other things, guide efforts to restore vision using a neural prosthesis that stimulates the surface of the brain. The study appears in the latest issue of Current Biology, a Cell Press journal.
"By measuring brain anatomy and applying an algorithm, we can now accurately predict how the visual world for an individual should be arranged on the surface of the brain," said senior author Geoffrey Aguirre, MD, PhD, assistant professor of Neurology. "We are already using this advance to study how vision loss changes the organization of the brain."
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We couldn’t live without our immune systems, always tuned to detect and eradicate invading pathogens and particles. But sometimes the immune response goes overboard, triggering autoimmune diseases like lupus, asthma or inflammatory bowel disease.
A
new study led by Christopher
Hunter, professor and chair in the Department of Pathobiology in
Penn’s School of Veterinary Medicine and Aisling O’Hara Hall, a
doctoral candidate in the Immunology
Graduate Group, has now identified a crucial signaling molecule involved in
counterbalancing the immune system attack.
“The immune response is like driving a car,” said Hunter. “You hit the accelerator and develop this response that’s required to protect you from a pathogen, but, unless you have a brake to guide the response, then you’ll just careen off the road and die because you can’t control the speed of the response.”
The study is published in the September issue of the journal Immunity.
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Researchers from the Perelman School of Medicine at Penn have been awarded a $3.7 million grant from the National Institutes of Health (NIH) to establish a new translational interdisciplinary research center to explore the role of sex and gender in behavioral health.
The new Center for the Study of Sex and Gender in Behavioral Health will be led by C. Neill Epperson, MD, associate professor of Psychiatry and founder and director of the Penn Center for Women's Behavioral Wellness, as principal investigator, along with Tracy L. Bale, PhD, Center co-director and associate professor of Psychiatry at the Perelman School of Medicine and director, Neuroscience Center at Penn's School Of Veterinary Medicine.
“It is well established that sex and gender are critical determinants of mental health and mental illness. But what isn’t clear is how hormonal developmental milestones such as puberty and early life traumatic events interact to impact neuropsychiatric health in women across the lifespan,” said Dr. Epperson. “Using behavioral and molecular models of stress and reproductive neuroendocrinology, psychophysiology, and neuroimaging, the new Center for the Study of Sex and Gender in Behavioral Health will investigate the unique mechanisms at play in women’s behavioral health.”
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How does one’s experience of an event get translated into a memory that can be accessed months, even years later? A team led by University of Pennsylvania scientists has come closer to answering that question, identifying key molecules that help convert short-term memories into long-term ones. Joshua Hawk (right), now a postdoctoral research fellow at Yale University, led the study, which was conducted as part of his Ph.D. work in the Neuroscience Graduate Group at Penn. He worked with Ted Abel (left), PhD, Penn’s Brush Family Professor of Biology.
“There are many drugs
available to treat some of the symptoms of diseases like schizophrenia,” Abel
said, “but they don’t treat the cognitive deficits that patients have, which can
include difficulties with memory. This study looks for more specific targets to
treat deficits in cognition.”
Published in the Journal of Clinical Investigation, the study focused on a group of proteins called nuclear receptors, which have been implicated in the regulation of a variety of biological functions, including memory formation.
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Researchers at the Perelman School of Medicine at the University of Pennsylvania report in a new study that thickening of the heart’s right ventricle is associated with an increased risk of heart failure and cardiovascular death in patients without clinical cardiovascular disease at baseline. The study is published online ahead of print in the journal Circulation.
“In most studies of the heart, researchers have focused on the more-easily-imaged left ventricle, the region of the heart affected by systemic high blood pressure and other common conditions,” said study author Steven Kawut, M.D., M.S., associate professor of Medicine and Epidemiology and director of the Pulmonary Vascular Disease Program at Penn. “But we know from the results of this study and previous work that focusing attention on the right ventricle (RV) is critical in our understanding of many conditions of the heart and lungs. This research revealed that approximately one in 10 heart failure events and cardiovascular deaths may be attributed to thickening of the RV in adults without clinical cardiovascular disease at baseline.”
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Yvonne
Paterson, PhD, professor of Microbiology (Cell & Molecular Biology and Immunology Graduate Groups), at the
Perelman School of Medicine, and professor and associate dean, at the School of
Nursing, has been awarded an almost $5 million renewal by the National Institute
for General Medical Sciences for the University of Pennsylvania Postdoctoral
Opportunities in Research and Training, or PENN-PORT, the postdoctoral-training
program she leads.
This program funds 15 postdoctoral fellows who teach in local colleges and universities that have a significant minority enrollment. The PENN-PORT program combines a traditional, three-year postdoctoral research training with a two-year mentored teaching experience at one of three partner minority-serving institutions: Lincoln University, Rutgers University-Camden, and Delaware County Community College.
The goals of the postdoctoral program are to enhance research-oriented teaching at the partner institutions; to promote research collaborations between faculty members at the three partner institutions and Penn; and to encourage minority students to enter graduate school and increase minority participation in biomedical research.
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Penn Medicine research presented on July 19th at the 2012 Alzheimer's Association International Conference (AAIC) shows that an anti-tau treatment called epithilone D (EpoD) was effective in preventing and intervening the progress of Alzheimer's disease in animal models, improving neuron function and cognition, as well as decreasing tau pathology.
"This drug effectively hits a tau target by correcting tau loss of function, thereby stabilizing microtubules and offsetting the loss of tau due to its formation into neurofibrillary tangles in animal models, which suggests that this could be an important option to mediate tau function in Alzheimer's and other tau-based neurodegenerative diseases," said John Trojanowski, MD, PhD, (Neuroscience Graduate Group). "In addition to drugs targeting amyloid, which may not work in advanced Alzheimer's disease, our hope is that this and other anti-tau drugs can be tested in people with Alzheimer's disease to determine whether stabilizing microtubules damaged by malfunctioning tau protein may improve clinical and pathological outcomes."
Bristol-Myers Squibb, who developed and owns the rights to the drug, has started enrolling patients into a phase I clinical trial in people with mild Alzheimer's disease.
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Researchers are hopeful that new advances in tissue engineering and regenerative medicine could one day make a replacement liver from a patient’s own cells, or animal muscle tissue that could be cut into steaks without ever being inside a cow. Bioengineers can already make 2D structures out of many kinds of tissue, but one of the major roadblocks to making the jump to 3D is keeping the cells within large structures from suffocating; organs have complicated 3D blood vessel networks that are still impossible to recreate in the laboratory.
Now, University of Pennsylvania researchers have developed an innovative solution to this perfusion problem: they’ve shown that 3D printed templates of filament networks can be used to rapidly create vasculature and improve the function of engineered living tissues.
The research was conducted by a team led by postdoctoral fellow Jordan S. Miller and Christopher S. Chen, the Skirkanich Professor of Innovation in the Department of Bioengineering at Penn (CAMB), along with Sangeeta N. Bhatia, Wilson Professor at MIT, and postdoctoral fellow Kelly R. Stevens in Bhatia’s laboratory.
Their work was published in the journal Nature Materials.
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Researchers have long been interested in discovering the ways that human brains represent thoughts through a complex interplay of electrical signals. Recent improvements in brain recording and statistical methods have given researchers unprecedented insight into the physical processes underlying thoughts.
A new study by University of Pennsylvania and Thomas Jefferson University scientists brings this work one step closer to actual mind reading by using brain recordings to infer the way people organize associations between words in their memories.
 |
The research was conducted by professor Michael J. Kahana, PhD (Neuroscience, left) and former graduate student Jeremy R. Manning, PhD (right), a 2011 graduate of the Neuroscience Graduate Group. They collaborated with other members of Kahana’s laboratory, as well as with research faculty at Thomas Jefferson University Hospital. |
Their study was published in The Journal of Neuroscience.
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Psoriasis is an independent risk for Type 2 Diabetes, according to a new study by researchers with the Perelman School of Medicine at the University of Pennsylvania, with the greatest risk seen in patients with severe psoriasis. Researchers estimate that an additional 115,500 people will develop diabetes each year due to the risk posed by psoriasis above and beyond conventional risk factors. The research is published in the latest issue of the Archives of Dermatology, a JAMA Network publication.
"These data suggest that patients with psoriasis are at increased risk for developing diabetes even if they don't have common risk factors such as obesity," said senior author Joel M. Gelfand, MD, MSCE (Epidemiology and Biostatistics group). "Patients with psoriasis should eat a healthy diet, get regular exercise, and see their physician for routine preventative health screenings such as checks of blood pressure, cholesterol, and blood sugar."
Psoriasis is a common inflammatory skin disease affecting over 7.5 million Americans and causes thick, inflamed, scaly patches of skin. The disease has previously been associated with increased risk of myocardial infarction, stroke, metabolic syndrome and cardiovascular mortality.
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The healthy human intestine is colonized with over 100 trillion
beneficial, or commensal, bacteria of many different species. In healthy people,
these bacteria are limited to the intestinal tissues and have a number of
helpful properties, including aiding in the digestion of food and promoting a
healthy immune system. However, several chronic human diseases, including
HIV/AIDS, inflammatory bowel disease, viral hepatitis, and obesity are
associated with the spread of these intestinal commensal bacteria to the blood
stream and other peripheral tissues, which can cause chronic inflammation.
David Artis, PhD, (Immunology, Cell & Molecular Biology), and Gregory F. Sonnenberg, PhD, a postdoctoral researcher in the Artis lab, have identified that immune cells, called innate lymphoid cells, are resident in the intestinal tissues of healthy humans, mice, and non-human primates, and are critical in limiting the location of commensal bacteria. If the innate lymphoid cells are depleted in mice, commensal bacteria move to peripheral tissues and promote inflammation.
"A fundamental question that has puzzled researchers for many years is how did the human body evolve to accommodate all these commensal bacteria and keep them in their correct locations?," asks Artis. "The indication from these studies is that the body may have many different pathways to limit the spread of commensal bacteria and these pathways may be tailored to specific types of bacteria."
The research was published in the current edition of Science.
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The Perelman School of Medicine at the University of Pennsylvania, in
collaboration with the University of Pennsylvania School of Nursing and School
of Dental Medicine, has been designated a national Center of Excellence in Pain
Education (CoEPEs) by the National Institutes of Health (NIH).
"Pain is one of the primary reasons that patients seek medical care," said John T. Farrar, MD, PhD (Epidemiology & Biostatistics group), co-principal investigator of the new center. "Learning how to properly diagnose the underlying cause and how to effectively treat both acute and chronic pain needs to be an important focus of medical education. The interprofessional collaboration between three Penn schools in this endeavor is pivotal to our mission to help redefine pain education in the U.S. health care system and improve the lives of all of our patients."
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By pairing an intimate knowledge of immune-system function with a deep understanding of statistical physics, a cross-disciplinary team at the University of Pennsylvania, led by senior authors Christopher Hunter, professor and chair of the Pathobiology Department in Penn’s School of Veterinary Medicine (Cell & Molecular Biology and Immunology Graduate Groups), and Andrea Liu, the Hepburn Professor of Physics in the Department of Physics and Astronomy, has arrived at a surprising finding: T cells use a movement strategy to track down parasites that is similar to strategies that predators such as monkeys, sharks and blue-fin tuna use to hunt their prey.
With this new insight into immune-cell movement patterns, scientists will be able to create more accurate models of immune-system function, which may, in turn, inform novel approaches to combat diseases from cancer to HIV/AIDS to arthritis.
The study, published in the journal Nature, was conducted in mice infected with the parasite Toxoplasma gondii.
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A new study published by researchers at the Perelman School of Medicine at the University of Pennsylvania, the Broad Institute, and Massachusetts General Hospital, challenges the conventional concept that raising a person's HDL levels (good cholesterol) will always help lower their risk of a heart attack. In the study, published in May 17 edition of The Lancet, the research team analyzed previously identified DNA sequence variations directly associated with elevated HDL levels in humans. After analyzing the genes of roughly 170,000 individuals, the team discovered that none of these established genetic variations actually reduced the risk of heart attack.
"The concept that genetic data can directly test the relationship between a biomarker like HDL to heart attack is an extremely potent one. Through our research, we have found that all roads that raise HDL do not always lead to the promise land of reduced risk of heart attack," said Benjamin F. Voight, PhD (PHRM), lead author of the new study. "These data have important implications for future development of therapies based on raising HDL levels."
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A team of University of Pennsylvania researchers has
recently been recognized by the National Science Foundation for the development
of computer models that will be instrumental in improving the design of
pharmaceuticals on an atomic scale.
Led by Ravi Radhakrishnan, PhD (BMB, GCB), the team also included Portonovo Ayyaswamy, PhD (Engineering) as well as David Eckmann, PhD, MD, and Vladimir Muzykantov, PhD (PHRM).
The team received a “Research Highlight” from the NSF’s Division of Chemical, Bioengineering, Environmental & Transport Systems, and the work for which they were honored was published in the Biophysical Journal.
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Nancy Bonini, PhD (NGG), Gideon Dreyfuss, PhD (CAMB, BMB), and Beatrice H. Hahn, MD (CAMB), of the University of Pennsylvania have been elected members of the National Academy of Sciences, considered one of the highest honors that can be accorded a U.S. scientist or engineer.
Cited for “their distinguished and continuing achievements in original
research,” the three scientists are part of the 2012 Academy class of 84 members
and 21 foreign associates.
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Garret FitzGerald, MD
(GCB), is among the 44 newly elected Fellows and eight newly elected Foreign
Members to the Royal Society.
"Science impacts on most aspects of modern life, improving our understanding of the world and playing an increasing role as we grapple with problems such as feeding a growing global population and keeping an aging population healthy. These scientists who have been elected to the Fellowship of the Royal Society are among the world's finest. They follow in the footsteps of luminaries such as Newton, Darwin and Einstein and I am delighted to welcome them into our ranks," noted Sir Paul Nurse, President of the Royal Society.
"I am deeply honored by this recognition of the efforts and accomplishments of those with whom I have been privileged to work," said FitzGerald.
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The 24-hour internal clock controls many aspects of human behavior and physiology, including sleep, blood pressure, and metabolism. Disruption in circadian rhythms leads to increased incidence of many diseases, including metabolic disease and cancer. Each cell of the body has its own internal timing mechanism, which is controlled by proteins that keep one another in check.
One of these proteins, called Rev-erb alpha, was thought to have a subordinate role because the clock runs fairly normally in its absence. New work, published in Genes and Development this month, from the lab of Mitchell Lazar, MD, PhD (CAMB, GCB, PRHM), found that a closely related protein called Rev-erb beta serves as a back-up for Rev-erb alpha. When both are not functioning, the cellular clock loses its time-keeping function.
The two Rev-erbs work together to control fat metabolism, and in their absence, the liver fills with fat. These findings establish the Rev-erbs as major regulators of both clock function and metabolism.
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When poet Walt Whitman wrote that we "contain multitudes," he was speaking metaphorically, but he was correct in the literal sense. Every human being carries over 100 trillion individual bacterial cells within the intestine -- ten times more cells than comprise the body itself.
Now, David Artis, PhD (IMUN, CAMB), along with postdoctoral fellow David Hill, PhD, and collaborators from The Children's Hospital of Philadelphia and institutions in Japan and Germany, have found that these commensal bacteria might play an important role in influencing and controlling allergic inflammation. The commensal relationship that develops between humans and internal bacteria is one in which both humans and bacteria derive benefits.
The study -- appearing this week in Nature Medicine -- suggests that therapeutic targeting of immune cell responses to resident gut bacteria may be beneficial in treating allergic diseases.
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Insulin resistance in the
brain precedes and contributes to cognitive decline above and beyond other known
causes of Alzheimer's disease, according to a new study by researchers from
Penn's Perelman School of Medicine. This is the first study to directly
demonstrate that insulin resistance occurs in the brains of people with
Alzheimer's disease. The study is now online in the Journal of Clinical
Investigation.
"Our research clearly shows that the brain's ability to respond to insulin, which is important for normal brain function, is going offline at some point...We believe that brain insulin resistance may be an important contributor to the cognitive decline associated with Alzheimer's disease," said senior author, Steven E. Arnold, MD (NGG).
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A growing body of evidence
underscores the importance of human gut bacteria in modulating human health,
metabolism, and disease. Yet bacteria are only part of the story. Viruses that
infect those bacteria also shape who we are. Frederic D.
Bushman, PhD (CAMB, GCB), led a study published this month in the
Proceedings of the National Academy of Sciences that sequenced the DNA of
viruses -- the virome -- present in the gut of healthy people.
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Dennis E. Discher,
PhD (CAMB, PHRM), has been elected to the National Academy of Engineering for
his accomplishments in "elucidation of the effects of mechanical forces on cell
physiology and stem cell development."
Election to the National Academy of Engineering is among the highest professional distinctions accorded to an engineer. Academy membership honors those who have made outstanding contributions to "engineering research, practice, or education, including, where appropriate, significant contributions to the engineering literature," and to the "pioneering of new and developing fields of technology, making major advancements in traditional fields of engineering, or developing/implementing innovative approaches to engineering education."
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The molecular pathway that carries time-of-day signals from the body's
internal clock to ultimately guide daily behavior is like a black box,
says Amita Sehgal, PhD (CAMB, NGG) the John Herr Musser
Professor of Neuroscience and Co-Director, Comprehensive Neuroscience Center, at
the Perelman School of Medicine, University of Pennsylvania.
Now, new research from the Sehgal lab is taking a peek inside, describing a molecular pathway and its inner parts that connect the well-known clock neurons to cells governing rhythms of rest and activity in fruit flies. Sehgal is also an investigator with the Howard Hughes Medical Institute.
The other co-author on the study is Wenyu Luo, PhD, a CAMB doctoral student who recently defended her dissertation. The findings, which will be featured on the cover of the February 17th issue of Cell, are published online this week.
"Most colleagues would say that we have some understanding of how the clock works and how it is synchronized with light,” says Sehgal. “But we are just beginning to get a glimpse of how the clock drives behavior in the rest of an organism's systems."
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Researchers from the Perelman School of Medicine at the University of Pennsylvania are in the midst of testing a personalized, dendritic cell vaccine in patients with recurrent ovarian, primary peritoneal or fallopian tube cancer – a group of patients who typically have few treatment options. Now, they have shown they can shorten the time to manufacture this type of anti-cancer vaccine, which reduces costs of manufacturing the treatment while still yielding powerful dendritic cells that may be beneficial for these and a variety of other tumor types. The data is published in the December issue of PLoS ONE.
“We are very excited about this development,” says senior author George Coukos, MD, PhD (CAMB, IGG), who directs the Ovarian Cancer Research Center in Penn’s Abramson Cancer Center. “Our work proves that these dendritic cells can be manufactured with a reasonable cost and retain their potency after being loaded with patients’ tumor extract. This is a very personalized approach to immunotherapy, which can be easily prepared for most patients with ovarian cancer undergoing surgery to remove their tumors.”
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James Eberwine, PhD, (NGG, GCB, PHRM), has received a Senior Scholar Award from the Ellison Medical Foundation. This supports basic biological research in aging, for $600,000 to be disbursed over the next four years. He is one of 20 investigators to receive this award.
“This grant will enable us to use cutting-edge technologies to assess the contribution of protein synthesis in modulating the aging cell phenotype,” says Eberwine. “One of the unique aspects of these studies is our ability to assess translation of multiple RNAs simultaneously in subregions of aging cells.”
The Ellison Senior Scholar program in Aging is designed to support established investigators to conduct research in the basic biological sciences relevant to age-related diseases and disabilities.
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On the quest for safe, reliable and accessible tools to accurately diagnose Alzheimer's disease, researchers from the Perelman School of Medicine at the University of Pennsylvania found a new way of diagnosing and tracking Alzheimer's disease, using an innovative magnetic resonance imaging (MRI) technique called Arterial spin labeling (ASL) to measure changes in brain function. The team determined that the ASL-MRI test is a promising alternative to the current standard, a specific PET scan that requires exposure to small amounts of a radioactive glucose analog and costs approximately four-times more than an ASL-MRI. Two studies now appear in Alzheimer's and Dementia: The Journal of the Alzheimer’s Association and Neurology.
In brain tissue, regional blood flow is tightly coupled to regional glucose consumption, which is the fuel the brain uses to function. Increases or decreases in brain function are accompanied by changes in both blood flow and glucose metabolism,” explained John A. Detre, MD, (NGG), senior author on the papers, who has worked on ASL-MRI for the past 20 years. “We designed ASL-MRI to allow cerebral blood flow to be imaged noninvasively and quantitatively using a routine MRI scanner.”
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Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a universally fatal neurodegenerative disease. Mutations in two related proteins, TDP-43 and FUS, cause some forms of ALS. Specifically, these two proteins are RNA-binding proteins that connect to RNA to regulate the translation of proteins and other cellular functions such as RNA splicing and editing. In a new study, researchers at the Perelman School of Medicine at the University of Pennsylvania discovered additional human genes with properties similar to TDP-43 and FUS that might also contribute to ALS.
There are over 200 human RNA-binding proteins, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathology. Using yeast as a model organism, the lab of cell biologist and senior author Aaron Gitler, PhD, (CAMB), surveyed 133 of these proteins. Their findings appear this week in the Proceedings of the National Academy of Sciences.
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By studying tumor biology at the molecular level, researchers are gaining a deeper understanding of drug resistance - and how to avoid it by designing pediatric cancer treatments tailored to specific mutations in a child’s DNA. In a fruitful collaboration, pediatric oncologists and biochemists are targeting neuroblastoma, an often-deadly childhood cancer of the peripheral nervous system.
"This has been a terrific collaboration," said study co-leader Mark A. Lemmon, Ph.D., (BMB, CAMB, PHRM). "We have been working for a long time to understand how growth factor receptors work as signaling 'machines.'"
The study appears in the Nov. 9 issue of Science Translational Medicine. For more information, please see the CHOP release.
The lining of the intestine regenerates itself every few days as compared to say red blood cells that turn over every four months. The various cell types that do this come from stem cells that reside deep in the inner recesses of the accordion-like folds of the intestines, called villi and crypts.
But exactly where the most important stem cell type is located -- and how to identify it -- has been something of a mystery. In fact, two types of intestinal stem cells have been proposed to exist but the relationship between them has been unclear.
Some researchers have been proponents of one type of stem cell or the other as the "true" intestinal stem cell. Recent work published this week in Science from the lab of Jonathan Epstein, MD, (CAMB) may reconcile this controversy. The findings suggest that these two types of stem cells are related.
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A research group at the Perelman School of Medicine of the University of Pennsylvania, led by John Lynch, MD, PhD, (CAMB) has received a National Cancer Institute grant to establish a Barrett's esophagus translational research network with Columbia University and the Mayo Clinic. Barrett's esophagus is an increasingly prevalent, pre-cancerous disorder that results primarily from reflux of acid and bile. It afflicts millions of Americans and is a precursor to esophageal adenocarcinoma, which has the fastest rate of increase of any cancer in the US.
"We are all very excited to be a part of this multicenter research network," says Lynch. "Our understanding of the pathogenesis of Barrett's esophagus and esophageal adenocarcinoma has lagged behind that of other cancers because we have not yet developed physiologically relevant laboratory models and an integrated research network, both of which are supported by this award."
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Obesity and insulin resistance are almost inevitably associated with increases in lipid accumulation in the liver, a serious disease that can deteriorate to hepatitis and liver failure. A real paradox in understanding insulin resistance is figuring out why insulin-resistant livers make more fat. Insulin resistance occurs when the body does a poor job of lowering blood sugars.
The signals to make lipid after a meal come from hormones - most notably insulin - and the direct effect of nutrients on the liver. In a recent issue of Cell Metabolism, Morris Birnbaum, MD, PhD (CAMB, BMB), describes the pathway that insulin uses to change the levels of gene expression that control lipid metabolism. Birnbaum is also associate director of the Institute of Diabetes, Obesity, and Metabolism at Penn.
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Research from the Perelman School of Medicine has found that small amounts of misshapened brain proteins can be taken up by healthy neurons and replicated within them to cause neurodegeneration. Virginia Man-Yee Lee, PhD (CAMB, PHRM, NGG, BMB), director of the Center for Neurodegenerative Disease Research and John H. Ware Professor in Alzheimer's Research, was senior author of the research, which shows a way that Parkinson’s disease (PD) can spread in the brain and provides a model for discovering therapeutics targeting PD neurodegeneration. This research was published in the neuroscience journal Neuron and funded by the National Institutes of Health for the Penn Udall Center, the Picower Foundation, the Jeff Keefer Foundation, the Parkinson Council, and the Stein-Bellet Family Foundation.
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Daniel J. Rader, MD (CAMB, PHRM) and Edward Morrisey, PhD (CAMB), along with researchers at the Medical College of Wisconsin, have received a five-year, $9 million grant for stem cell research from the National Institutes of Health’s National Human Genome Research and the National Heart Lung and Blood Institutes.
The funding will be used in a collaborative study between both institutions on the role of genetics in cardiovascular disease. Rader and Morrisey will take fat cells and change them into induced pluripotent stem cells, or iPS cells, which will be turned into liver cells to learn more about the causes of coronary artery disease and metabolic disorders.Click here for full release.