1,000 posts! Not a bad way to start a Tuesday!
Our 1,000th post was about human head lice … coincidence?

1,000 posts! Not a bad way to start a Tuesday!

Our 1,000th post was about human head lice … coincidence?

Close Nit
With Labor Day looming and the beginning of school, many of the academically minded among us turn their thoughts and eyes to topics like classroom supplies, textbooks and the likelihood little Johnny is going to come home with head lice.
It’s hard to know how many people get head lice (Pediculus humanus capitis) each year. The Centers for Disease Control estimates 6 to 12 million infestations annually in the United States among children three to 11 years of age – the most common targets.
Getting head lice is not a matter of cleanliness. The wingless parasitic insect is spread primarily by direct contact with the hair of an infested person. The most common way is head-to-head contact. Some studies suggest girls get head lice more often than boys.
Less common modes of transmission are wearing infested clothing, such as hats or scarves, using infested combs, brushes or towels or lying on a bed, couch, pillow or carpet recently in contact with an infested person.
Head lice are not known to transmit disease, but secondary bacterial skin infections may occur from scratching the infestation site. Some folks argue that beyond their basic harmlessness, head lice might actually promote health by boosting a natural immune response to body lice (Pediculus humanus humanus), which pose a more serious health threat.
Head lice spend their entire lives on human scalps, clamped onto a strand of hair, feeding exclusively on human blood. There are other species of lice that infest other mammals and birds.
Treatment involves the use of pediculicides – medicines that kill lice and their eggs. Supplemental measures include thorough cleaning of all clothes and exposed materials and grooming with a special, fine-toothed comb to extract adults and eggs, called nits.
Above: A colorized scanning electron micrograph of a nit (green) affixed to a strand of human hair, courtesy of Kevin Mackenzie, one of the winners of this year’s Wellcome Image Awards.

Close Nit

With Labor Day looming and the beginning of school, many of the academically minded among us turn their thoughts and eyes to topics like classroom supplies, textbooks and the likelihood little Johnny is going to come home with head lice.

It’s hard to know how many people get head lice (Pediculus humanus capitis) each year. The Centers for Disease Control estimates 6 to 12 million infestations annually in the United States among children three to 11 years of age – the most common targets.

Getting head lice is not a matter of cleanliness. The wingless parasitic insect is spread primarily by direct contact with the hair of an infested person. The most common way is head-to-head contact. Some studies suggest girls get head lice more often than boys.

Less common modes of transmission are wearing infested clothing, such as hats or scarves, using infested combs, brushes or towels or lying on a bed, couch, pillow or carpet recently in contact with an infested person.

Head lice are not known to transmit disease, but secondary bacterial skin infections may occur from scratching the infestation site. Some folks argue that beyond their basic harmlessness, head lice might actually promote health by boosting a natural immune response to body lice (Pediculus humanus humanus), which pose a more serious health threat.

Head lice spend their entire lives on human scalps, clamped onto a strand of hair, feeding exclusively on human blood. There are other species of lice that infest other mammals and birds.

Treatment involves the use of pediculicides – medicines that kill lice and their eggs. Supplemental measures include thorough cleaning of all clothes and exposed materials and grooming with a special, fine-toothed comb to extract adults and eggs, called nits.

Above: A colorized scanning electron micrograph of a nit (green) affixed to a strand of human hair, courtesy of Kevin Mackenzie, one of the winners of this year’s Wellcome Image Awards.

Finding Keys to Glioblastoma Therapeutic Resistance
Researchers at the University of California, San Diego School of Medicine have found one of the keys to why certain glioblastomas – the primary form of a deadly brain cancer – are resistant to drug therapy. The answer lies not in the DNA sequence of the tumor, but in its epigenetic signature. These findings have been published online as a priority report in the journal Oncotarget.
“There is a growing interest to guide cancer therapy by sequencing the DNA of the cancer cell,” said Clark Chen, MD, PhD, vice-chairman of Research and Academic Development, UC San Diego Division of Neurosurgery and the principal investigator of the study. “Our study demonstrates that the sensitivity of glioblastoma to a drug is influenced not only by the content of its DNA sequences, but also by how the DNA sequences are organized and interpreted by the cell.”
The team of scientists, led by Chen, used a method called comparative gene signature analysis to study the genetic profiles of tumor specimens collected from approximately 900 glioblastoma patients. The method allows investigators to discriminate whether specific cellular processes are “turned on” or “turned off” in glioblastomas. “Our study showed that not all glioblastomas are the same. We were able to classify glioblastomas based on the type of cellular processes that the cancer cells used to drive tumor growth,” said Jie Li, PhD, senior postdoctoral researcher in the Center for Theoretical and Applied Neuro-Oncology at UC San Diego and co-first author of the paper.
One of these cellular processes involves Epidermal Growth Factor Receptor (EGFR). The study revealed that EGFR signaling is suppressed in a subset of glioblastomas. Importantly, this suppression is not the result of altered DNA sequences or mutations. Instead, EGFR is turned off as a result of how the DNA encoding the EGFR gene is organized in the cancer cell. This form of regulation is termed “epigenetic.” Because EGFR is turned off in these glioblastomas, they become insensitive to drugs designed to inhibit EGFR signaling.
“Our research suggests that the selection of appropriate therapies for our brain tumor patients will require a meaningful synthesis of genetic and epigenetic information derived from the cancer cell,” said co-first author Zachary J. Taich.

Finding Keys to Glioblastoma Therapeutic Resistance

Researchers at the University of California, San Diego School of Medicine have found one of the keys to why certain glioblastomas – the primary form of a deadly brain cancer – are resistant to drug therapy. The answer lies not in the DNA sequence of the tumor, but in its epigenetic signature. These findings have been published online as a priority report in the journal Oncotarget.

“There is a growing interest to guide cancer therapy by sequencing the DNA of the cancer cell,” said Clark Chen, MD, PhD, vice-chairman of Research and Academic Development, UC San Diego Division of Neurosurgery and the principal investigator of the study. “Our study demonstrates that the sensitivity of glioblastoma to a drug is influenced not only by the content of its DNA sequences, but also by how the DNA sequences are organized and interpreted by the cell.”

The team of scientists, led by Chen, used a method called comparative gene signature analysis to study the genetic profiles of tumor specimens collected from approximately 900 glioblastoma patients. The method allows investigators to discriminate whether specific cellular processes are “turned on” or “turned off” in glioblastomas. “Our study showed that not all glioblastomas are the same. We were able to classify glioblastomas based on the type of cellular processes that the cancer cells used to drive tumor growth,” said Jie Li, PhD, senior postdoctoral researcher in the Center for Theoretical and Applied Neuro-Oncology at UC San Diego and co-first author of the paper.

One of these cellular processes involves Epidermal Growth Factor Receptor (EGFR). The study revealed that EGFR signaling is suppressed in a subset of glioblastomas. Importantly, this suppression is not the result of altered DNA sequences or mutations. Instead, EGFR is turned off as a result of how the DNA encoding the EGFR gene is organized in the cancer cell. This form of regulation is termed “epigenetic.” Because EGFR is turned off in these glioblastomas, they become insensitive to drugs designed to inhibit EGFR signaling.

“Our research suggests that the selection of appropriate therapies for our brain tumor patients will require a meaningful synthesis of genetic and epigenetic information derived from the cancer cell,” said co-first author Zachary J. Taich.

Protein-DNA Interaction Network Yields Surprising Discovery In Regulation Of Gene Expression
Although homeodomain proteins, which control development and execution of the body’s genetic roadmap, were described 30 years ago, scientists still do not fully understand how these proteins affect gene expression.
In a paper published online in Nature, researchers at the University of California, San Diego School of Medicine reveal that homeodomain transcription factors require interaction with subnuclear structures in order to function properly.
The POU-homeodomain protein Pit1 plays an important role in animal and human life by regulating expression of hormone genes in the pituitary gland. But a common mutation in this protein causes it to lose interaction with two other proteins, Satb1 and β-catenin, and in turn disconnects it from what turns out to be a vital subnuclear structure: the matrin-3 network. This naturally occurring mutation leads to a combined pituitary hormone deficiency.
In collaboration with scientists at the Lawrence Berkeley National Laboratory, California, researchers in the M. Geoffrey Rosenfeld laboratory were able for the first time to establish the functional link between this subnuclear structure and gene activation.
“This information allows us to see in even more detail how genes are activated at the exact time and place in the body,” said Dorota Skowronska-Krawczyk, PhD, an UC San Diego School of Medicine assistant project scientist in the Department of Cellular and Molecular Medicine and first author of the paper. “This helps us understand the process of gene expression. Scientists may use this information to investigate the role of matrin-3 subnuclear network in cancer or other diseases and whether the knowledge of its function could be used to improve existing therapies or design new ones.”

Protein-DNA Interaction Network Yields Surprising Discovery In Regulation Of Gene Expression

Although homeodomain proteins, which control development and execution of the body’s genetic roadmap, were described 30 years ago, scientists still do not fully understand how these proteins affect gene expression.

In a paper published online in Nature, researchers at the University of California, San Diego School of Medicine reveal that homeodomain transcription factors require interaction with subnuclear structures in order to function properly.

The POU-homeodomain protein Pit1 plays an important role in animal and human life by regulating expression of hormone genes in the pituitary gland. But a common mutation in this protein causes it to lose interaction with two other proteins, Satb1 and β-catenin, and in turn disconnects it from what turns out to be a vital subnuclear structure: the matrin-3 network. This naturally occurring mutation leads to a combined pituitary hormone deficiency.

In collaboration with scientists at the Lawrence Berkeley National Laboratory, California, researchers in the M. Geoffrey Rosenfeld laboratory were able for the first time to establish the functional link between this subnuclear structure and gene activation.

“This information allows us to see in even more detail how genes are activated at the exact time and place in the body,” said Dorota Skowronska-Krawczyk, PhD, an UC San Diego School of Medicine assistant project scientist in the Department of Cellular and Molecular Medicine and first author of the paper. “This helps us understand the process of gene expression. Scientists may use this information to investigate the role of matrin-3 subnuclear network in cancer or other diseases and whether the knowledge of its function could be used to improve existing therapies or design new ones.”

Memorable pictures
The hippocampus is a major component of the brains of humans and other vertebrates, playing critical roles in the consolidation of information from short-term memory to long-term memory and in spatial navigation. Damage to the hippocampus, whether from oxygen starvation, diseases such as encephalitis or epilepsy or physical trauma can result in memory loss and disorientation, including anterograde amnesia – the inability to form or retain new memories.
The hippocampus is also among the first regions of the brain to be affected by Alzheimer’s disease.
The hippocampus is a many-layered splendor, as these false-color confocal micrographs of a rat hippocampus by Thomas Deerinck of the National Center for Microscopy and Imaging Research at UC San Diego brilliantly show, layer upon lovely layer of pyramidal neurons, support cells and neuronal fibers.

Memorable pictures

The hippocampus is a major component of the brains of humans and other vertebrates, playing critical roles in the consolidation of information from short-term memory to long-term memory and in spatial navigation. Damage to the hippocampus, whether from oxygen starvation, diseases such as encephalitis or epilepsy or physical trauma can result in memory loss and disorientation, including anterograde amnesia – the inability to form or retain new memories.

The hippocampus is also among the first regions of the brain to be affected by Alzheimer’s disease.

The hippocampus is a many-layered splendor, as these false-color confocal micrographs of a rat hippocampus by Thomas Deerinck of the National Center for Microscopy and Imaging Research at UC San Diego brilliantly show, layer upon lovely layer of pyramidal neurons, support cells and neuronal fibers.

Aspirin, Take TwoWhite blood cell research shows how causing and conquering inflammation are inextricably linked
Hugely popular non-steroidal anti-inflammation drugs like aspirin, naproxen (marketed as Aleve) and ibuprofen (Advil, Motrin) all work by inhibiting or killing an enzyme called cyclooxygenase – a key catalyst in production of hormone-like lipid compounds called prostaglandins that are linked to a variety of ailments, from headaches and arthritis to menstrual cramps and wound sepsis.
In a new paper, published this week in the online early edition of PNAS, researchers at the University of California, San Diego School of Medicine conclude that aspirin has a second effect: Not only does it kill cyclooxygenase, thus preventing production of the prostaglandins that cause inflammation and pain, it also prompts the enzyme to generate another compound that hastens the end of inflammation, returning the affected cells to homeostatic health.
“Aspirin causes the cyclooxygenase to make a small amount of a related product called 15-HETE,” said senior author Edward A. Dennis, PhD, Distinguished Professor of Pharmacology, Chemistry and Biochemistry. “During infection and inflammation, the 15-HETE can be converted by a second enzyme into lipoxin, which is known to help reverse inflammation and cause its resolution – a good thing.”
Specifically, Dennis and colleagues looked at the function of a type of white blood cells called macrophages, a major player in the body’s immune response to injury and infection. They found that macrophages contain the biochemical tools to not just initiate inflammation, a natural part of the immune response, but also to promote recovery from inflammation by releasing 15-HETE and converting it into lipoxin as the inflammation progresses.
Dennis said the findings may open new possibilities for anti-inflammatory therapies by developing new drugs based on analogues of lipoxin and other related molecules that promote resolution of inflammation. “If we can find ways to promote more resolution of inflammation, we can promote health,” he said.  
Image: Scanning electron micrograph of macrophage. Image courtesy of National Cancer Institute.

Aspirin, Take Two
White blood cell research shows how causing and conquering inflammation are inextricably linked

Hugely popular non-steroidal anti-inflammation drugs like aspirin, naproxen (marketed as Aleve) and ibuprofen (Advil, Motrin) all work by inhibiting or killing an enzyme called cyclooxygenase – a key catalyst in production of hormone-like lipid compounds called prostaglandins that are linked to a variety of ailments, from headaches and arthritis to menstrual cramps and wound sepsis.

In a new paper, published this week in the online early edition of PNAS, researchers at the University of California, San Diego School of Medicine conclude that aspirin has a second effect: Not only does it kill cyclooxygenase, thus preventing production of the prostaglandins that cause inflammation and pain, it also prompts the enzyme to generate another compound that hastens the end of inflammation, returning the affected cells to homeostatic health.

“Aspirin causes the cyclooxygenase to make a small amount of a related product called 15-HETE,” said senior author Edward A. Dennis, PhD, Distinguished Professor of Pharmacology, Chemistry and Biochemistry. “During infection and inflammation, the 15-HETE can be converted by a second enzyme into lipoxin, which is known to help reverse inflammation and cause its resolution – a good thing.”

Specifically, Dennis and colleagues looked at the function of a type of white blood cells called macrophages, a major player in the body’s immune response to injury and infection. They found that macrophages contain the biochemical tools to not just initiate inflammation, a natural part of the immune response, but also to promote recovery from inflammation by releasing 15-HETE and converting it into lipoxin as the inflammation progresses.

Dennis said the findings may open new possibilities for anti-inflammatory therapies by developing new drugs based on analogues of lipoxin and other related molecules that promote resolution of inflammation. “If we can find ways to promote more resolution of inflammation, we can promote health,” he said.  

Image: Scanning electron micrograph of macrophage. Image courtesy of National Cancer Institute.

Happiness in SchizophreniaResearch suggests mental illness doesn’t preclude enjoying life
Schizophrenia is among the most severe forms of mental illness, yet some people with the disease are as happy as those in good physical and mental health according to a study led by researchers at the University of California, San Diego School of Medicine.
The study is published online this week in the journal Schizophrenia Research.
“People tend to think that happiness in schizophrenia is an oxymoron,” said senior author Dilip V. Jeste, MD, Distinguished Professor of Psychiatry and Neurosciences.
“Without discounting the suffering this disease inflicts on people, our study shows that happiness is an attainable goal for at least some schizophrenia patients,” said Jeste, who is also the Estelle and Edgar Levi Chair in Aging and director of the Sam and Rose Stein Institute for Research on Aging at UC San Diego. “This means we can help make these individuals’ lives happier.”
In a survey of people with the disease, researchers found that 37 percent of patients reported being happy all or most of the time.
Of clinical significance in terms of helping people with mental illness, the patients’ happiness was unrelated to the severity or duration of their illness, to cognitive or physical function or to socioeconomic factors such as age and education, which among healthy adults have been linked to a greater sense of well-being.
Instead, the study shows that happiness among those with chronic forms of schizophrenia is associated with positive psychological and social attributes such as resilience, optimism and lower perceived stress.
The researchers believe that these positive psychosocial attributes could be taught through behavioral modification and mindfulness training techniques.
The study is based on a survey of 72 English-speaking outpatients with schizophrenia in the San Diego area. At the time of the survey, all but nine of the patients were on at least one anti-psychotic medication and 59 percent were residents in assisted-living facilities.
The comparison group for the study included 64 healthy men and women who were part of an ongoing study on successful aging. These participants were not currently using alcohol or illicit substances and did not have diagnoses of dementia or other neurological problems. Participants ranged in age from 23 to 70 years old; the mean age for both groups was 50 years.
The survey probed respondents’ happiness during the previous week, asking them to rate statements such as “I was happy” and “I enjoyed life” on a scale from “never or rarely” to “all or most of the time.”
Responses suggest that about 37 percent of schizophrenia patients were happy most or all of the time, compared with about 83 percent for those in the comparison group.
Approximately 15 percent of schizophrenia patients reported being never or rarely happy. By contrast, none of in the comparison group reported such a low level of happiness for the week prior.
People’s self-reported happiness was then examined in relation to other factors, such as age, gender, education, living situation, medication status, anxiety levels and other mental health metrics, as well as physical health, cognitive function, and a list of “psychosocial factors” that included perceived stress, attitude toward aging, spirituality, optimism, resilience and personal mastery.
“People with schizophrenia are clearly less happy than those in the general population at large, but this is not surprising,” said lead author Barton W. Palmer, PhD, professor in the UC San Diego Department of Psychiatry. “What is impressive is that almost 40 percent of these patients are reporting happiness and that their happiness is associated with positive psychosocial attributes that can be potentially enhanced.”
Image source: happyologist

Happiness in Schizophrenia
Research suggests mental illness doesn’t preclude enjoying life

Schizophrenia is among the most severe forms of mental illness, yet some people with the disease are as happy as those in good physical and mental health according to a study led by researchers at the University of California, San Diego School of Medicine.

The study is published online this week in the journal Schizophrenia Research.

“People tend to think that happiness in schizophrenia is an oxymoron,” said senior author Dilip V. Jeste, MD, Distinguished Professor of Psychiatry and Neurosciences.

“Without discounting the suffering this disease inflicts on people, our study shows that happiness is an attainable goal for at least some schizophrenia patients,” said Jeste, who is also the Estelle and Edgar Levi Chair in Aging and director of the Sam and Rose Stein Institute for Research on Aging at UC San Diego. “This means we can help make these individuals’ lives happier.”

In a survey of people with the disease, researchers found that 37 percent of patients reported being happy all or most of the time.

Of clinical significance in terms of helping people with mental illness, the patients’ happiness was unrelated to the severity or duration of their illness, to cognitive or physical function or to socioeconomic factors such as age and education, which among healthy adults have been linked to a greater sense of well-being.

Instead, the study shows that happiness among those with chronic forms of schizophrenia is associated with positive psychological and social attributes such as resilience, optimism and lower perceived stress.

The researchers believe that these positive psychosocial attributes could be taught through behavioral modification and mindfulness training techniques.

The study is based on a survey of 72 English-speaking outpatients with schizophrenia in the San Diego area. At the time of the survey, all but nine of the patients were on at least one anti-psychotic medication and 59 percent were residents in assisted-living facilities.

The comparison group for the study included 64 healthy men and women who were part of an ongoing study on successful aging. These participants were not currently using alcohol or illicit substances and did not have diagnoses of dementia or other neurological problems. Participants ranged in age from 23 to 70 years old; the mean age for both groups was 50 years.

The survey probed respondents’ happiness during the previous week, asking them to rate statements such as “I was happy” and “I enjoyed life” on a scale from “never or rarely” to “all or most of the time.”

Responses suggest that about 37 percent of schizophrenia patients were happy most or all of the time, compared with about 83 percent for those in the comparison group.

Approximately 15 percent of schizophrenia patients reported being never or rarely happy. By contrast, none of in the comparison group reported such a low level of happiness for the week prior.

People’s self-reported happiness was then examined in relation to other factors, such as age, gender, education, living situation, medication status, anxiety levels and other mental health metrics, as well as physical health, cognitive function, and a list of “psychosocial factors” that included perceived stress, attitude toward aging, spirituality, optimism, resilience and personal mastery.

“People with schizophrenia are clearly less happy than those in the general population at large, but this is not surprising,” said lead author Barton W. Palmer, PhD, professor in the UC San Diego Department of Psychiatry. “What is impressive is that almost 40 percent of these patients are reporting happiness and that their happiness is associated with positive psychosocial attributes that can be potentially enhanced.”

Image source: happyologist

New Mouse Model Points to Therapy for Liver Disease
Non-alcoholic fatty liver disease (NAFLD) is a common affliction, affecting almost 30 percent of Americans, with a significant number suffering from its most severe form, called non-alcoholic steatohepatitis or NASH, which can lead to cirrhosis and liver cancer. In recent years, NASH has become the leading cause of liver transplantation.
Development of effective new therapies for preventing or treating NASH has been stymied by limited small animal models for the disease. In a paper published online in Cancer Cell, scientists at the University of California, San Diego School of Medicine describe a novel mouse model that closely resembles human NASH and use it to demonstrate that interference with a key inflammatory protein inhibits both the development of NASH and its progression to liver cancer.
“These findings strongly call for clinical testing of relevant drugs in human NASH and its complications,” said senior author Michael Karin, PhD, Distinguished Professor of Pharmacology in UC San Diego’s Laboratory of Gene Regulation and Signal Transduction. “Our research has shown that, at least in this mouse model, chemical compounds that include already clinically approved drugs that inhibit protein aggregation can also be used to prevent NASH caused by a high fat diet.”
The increasing prevalence of NAFLD is linked to the nation’s on-going obesity epidemic. In the past decade, the rate of obesity has doubled in adults and tripled in children, in large part due to a common diet rich in simple carbohydrates and saturated fats. NASH is characterized by inflammation and fibrosis, which damage the liver and can lead to cirrhosis, hepatocellular carcinoma (HCC), the major form of liver cancer, and loss of function. Often, the only remedy is organ transplantation.
“Developing new strategies for NASH that successfully block progression to cirrhosis or HCC required the creation of appropriate small animal models that are amenable to genetic analysis and therapeutic intervention,” said first author Hayato Nakagawa, PhD, a member of Karin’s lab who headed the research effort and is currently an assistant professor at the University of Tokyo School of Medicine. 
The resulting new mouse model takes advantage of an existing mouse strain called MUP-uPA that develops liver damage similar to humans when fed a high-fat diet (in which 60 percent of calories are fat derived) similar to the so-called “American cafeteria diet.” The mice show clinical signs characteristic of NASH within 24 weeks and full-blown HCC after 40 weeks. “The pathological characteristics of these tumors are nearly identical to those of human HCC,” said Nakagawa.
Using the new mouse model, Nakagawa and colleagues showed that a protein called tumor necrosis factor (TNF), involved in the body’s inflammatory response, plays a critical role in both NASH pathogenesis and progression to fibrosis and HCC. By interfering with TNF synthesis or its binding to its receptor, using genetic tools or an anti-psoriasis and rheumatoid arthritis drug called Enbrel, the researchers inhibited both development of NASH and its progression to HCC in the mouse model.
“Given the dramatic and persistent increase in the incidence of obesity and its consequences in the United States and elsewhere, these studies have a high impact on a major public health problem. In addition to developing a more suitable model for the study of NASH, this new work suggests some immediate targets for prevention and therapeutic intervention,” said Karin, who is an American Cancer Society Research Professor and holds the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases.
Image source: http://1-in-10.org/nafld-a-silent-killer-associated-with-pcos

New Mouse Model Points to Therapy for Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is a common affliction, affecting almost 30 percent of Americans, with a significant number suffering from its most severe form, called non-alcoholic steatohepatitis or NASH, which can lead to cirrhosis and liver cancer. In recent years, NASH has become the leading cause of liver transplantation.

Development of effective new therapies for preventing or treating NASH has been stymied by limited small animal models for the disease. In a paper published online in Cancer Cell, scientists at the University of California, San Diego School of Medicine describe a novel mouse model that closely resembles human NASH and use it to demonstrate that interference with a key inflammatory protein inhibits both the development of NASH and its progression to liver cancer.

“These findings strongly call for clinical testing of relevant drugs in human NASH and its complications,” said senior author Michael Karin, PhD, Distinguished Professor of Pharmacology in UC San Diego’s Laboratory of Gene Regulation and Signal Transduction. “Our research has shown that, at least in this mouse model, chemical compounds that include already clinically approved drugs that inhibit protein aggregation can also be used to prevent NASH caused by a high fat diet.”

The increasing prevalence of NAFLD is linked to the nation’s on-going obesity epidemic. In the past decade, the rate of obesity has doubled in adults and tripled in children, in large part due to a common diet rich in simple carbohydrates and saturated fats. NASH is characterized by inflammation and fibrosis, which damage the liver and can lead to cirrhosis, hepatocellular carcinoma (HCC), the major form of liver cancer, and loss of function. Often, the only remedy is organ transplantation.

“Developing new strategies for NASH that successfully block progression to cirrhosis or HCC required the creation of appropriate small animal models that are amenable to genetic analysis and therapeutic intervention,” said first author Hayato Nakagawa, PhD, a member of Karin’s lab who headed the research effort and is currently an assistant professor at the University of Tokyo School of Medicine. 

The resulting new mouse model takes advantage of an existing mouse strain called MUP-uPA that develops liver damage similar to humans when fed a high-fat diet (in which 60 percent of calories are fat derived) similar to the so-called “American cafeteria diet.” The mice show clinical signs characteristic of NASH within 24 weeks and full-blown HCC after 40 weeks. “The pathological characteristics of these tumors are nearly identical to those of human HCC,” said Nakagawa.

Using the new mouse model, Nakagawa and colleagues showed that a protein called tumor necrosis factor (TNF), involved in the body’s inflammatory response, plays a critical role in both NASH pathogenesis and progression to fibrosis and HCC. By interfering with TNF synthesis or its binding to its receptor, using genetic tools or an anti-psoriasis and rheumatoid arthritis drug called Enbrel, the researchers inhibited both development of NASH and its progression to HCC in the mouse model.

“Given the dramatic and persistent increase in the incidence of obesity and its consequences in the United States and elsewhere, these studies have a high impact on a major public health problem. In addition to developing a more suitable model for the study of NASH, this new work suggests some immediate targets for prevention and therapeutic intervention,” said Karin, who is an American Cancer Society Research Professor and holds the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases.

Image source: http://1-in-10.org/nafld-a-silent-killer-associated-with-pcos

New Blood: Tracing the Beginnings of Hematopoietic Stem CellsResearchers uncover earliest clues yet to development of cells that produce all adult blood cells
Hematopoietic stem cells (HSCs) give rise to all other blood cell types, but their development and how their fate is determined has long remained a mystery. In a paper published online this week in Nature, researchers at the University of California, San Diego School of Medicine elaborate upon a crucial signaling pathway and the role of key proteins, which may help clear the way to generate HSCs from human pluripotent precursors, similar to advances with other kinds of tissue stem cells. 
Principal investigator David Traver, PhD, professor in the Department of Cellular and Molecular Medicine, and colleagues focused on the Notch signaling pathway, a system found in all animals and known to be critical to the generation of HSCs in vertebrates. “Notch signaling between emitting and receiving cells is key to establishing HSC fate during development,” said Traver. “What has not been known is where, when and how Notch signal transduction is mediated.”
Traver and colleagues discovered that the Notch signal is transduced into HSC precursor cells from signal emitting cells in the somite – embryologic tissues that eventually contribute to development of major body structures, such as skeleton, muscle and connective tissues – much earlier in the process than previously anticipated. 
More specifically, they found that JAM proteins, best known for helping maintain tight junctions between endothelial cells to prevent vascular leakage, were key mediators of Notch signaling. When the researchers caused loss of function in JAM proteins in a zebrafish model, Notch signaling and HSCs were also lost. When they enforced Notch signaling through other means, HSC development was rescued.
“To date, it has not been possible to generate HSCs de novo from human pluripotent precursors, like induced pluripotent stem cells,” said Traver. “This has been due in part to a lack of understanding of the complete set of factors that the embryo uses to make HSCs in vivo. It has also likely been due to not knowing in what order each required factor is needed.”
“Our studies demonstrate that Notch signaling is required much earlier than previously thought. In fact, it may be one of the earliest determinants of HSC fate. This finding strongly suggests that in vitro approaches to instruct HSC fate from induced pluripotent stem cells must focus on the Notch pathway at early time-points in the process. Our findings have also shown that JAM proteins serve as a sort of co-receptor for Notch signaling in that they are required to maintain close contact between signal-emitting and signal-receiving cells to permit strong activation of Notch in the precursors of HSCs.” 
The findings may have far-reaching implications for eventual development of hematopoietic stem cell-based therapies for diseases like leukemia and congenital blood disorders. Currently, it is not possible to create HSCs from differentiation of embryonic stem cells or induced pluripotent stem cells – pluripotent cells artificially derived from non-pluripotent cells, such as skin cells – that are being used in other therapeutic research efforts.

New Blood: Tracing the Beginnings of Hematopoietic Stem Cells
Researchers uncover earliest clues yet to development of cells that produce all adult blood cells

Hematopoietic stem cells (HSCs) give rise to all other blood cell types, but their development and how their fate is determined has long remained a mystery. In a paper published online this week in Nature, researchers at the University of California, San Diego School of Medicine elaborate upon a crucial signaling pathway and the role of key proteins, which may help clear the way to generate HSCs from human pluripotent precursors, similar to advances with other kinds of tissue stem cells. 

Principal investigator David Traver, PhD, professor in the Department of Cellular and Molecular Medicine, and colleagues focused on the Notch signaling pathway, a system found in all animals and known to be critical to the generation of HSCs in vertebrates. “Notch signaling between emitting and receiving cells is key to establishing HSC fate during development,” said Traver. “What has not been known is where, when and how Notch signal transduction is mediated.”

Traver and colleagues discovered that the Notch signal is transduced into HSC precursor cells from signal emitting cells in the somite – embryologic tissues that eventually contribute to development of major body structures, such as skeleton, muscle and connective tissues – much earlier in the process than previously anticipated. 

More specifically, they found that JAM proteins, best known for helping maintain tight junctions between endothelial cells to prevent vascular leakage, were key mediators of Notch signaling. When the researchers caused loss of function in JAM proteins in a zebrafish model, Notch signaling and HSCs were also lost. When they enforced Notch signaling through other means, HSC development was rescued.

“To date, it has not been possible to generate HSCs de novo from human pluripotent precursors, like induced pluripotent stem cells,” said Traver. “This has been due in part to a lack of understanding of the complete set of factors that the embryo uses to make HSCs in vivo. It has also likely been due to not knowing in what order each required factor is needed.”

“Our studies demonstrate that Notch signaling is required much earlier than previously thought. In fact, it may be one of the earliest determinants of HSC fate. This finding strongly suggests that in vitro approaches to instruct HSC fate from induced pluripotent stem cells must focus on the Notch pathway at early time-points in the process. Our findings have also shown that JAM proteins serve as a sort of co-receptor for Notch signaling in that they are required to maintain close contact between signal-emitting and signal-receiving cells to permit strong activation of Notch in the precursors of HSCs.” 

The findings may have far-reaching implications for eventual development of hematopoietic stem cell-based therapies for diseases like leukemia and congenital blood disorders. Currently, it is not possible to create HSCs from differentiation of embryonic stem cells or induced pluripotent stem cells – pluripotent cells artificially derived from non-pluripotent cells, such as skin cells – that are being used in other therapeutic research efforts.

About

News from UC San Diego Health Sciences
Media Contacts: 619-543-6163
HealthSciComm@ucsd.edu

Blogroll

  • azspot
  • comedycentral
  • fyeahmedlab
  • afro-dominicano
  • medicalstate
  • scientificillustration
  • huffingtonpost
  • scienceyoucanlove
  • inothernews
  • newyorker
  • washingtonpost
  • melon-collies
  • mindblowingscience
  • scientificthought
  • seltzerlizard
  • ucrhub
  • nursefocker
  • doublejack
  • sciencefriday
  • science-and-logic
  • oupacademic
  • neurosciencestuff
  • think-progress
  • fastcompany
  • explore-blog
  • thevancouversun
  • kqedscience
  • biocanvas
  • salon
  • libertasacademica
  • latimes
  • boston
  • npr
  • ucsdcancer
  • aspiringdoctors
  • pbstv
  • americanpublicmedia
  • sdzoo
  • ucsdzone
  • msnbc
  • medresearch
  • publicradiointernational
  • journalofajournalist
  • wnyc
  • scishow
  • wired
  • theonion
  • forum-network
  • theweekmagazine
  • photojojo
  • pozmagazine
  • nydailynews
  • newsweek
  • todaysdocument
  • amnhnyc
  • mothernaturenetwork
  • longform
  • wnycradiolab
  • nbcnightlynews
  • katiecouric
  • guardian
  • abcworldnews
  • pritheworld
  • tballardbrown
  • thisisfusion
  • rollingstone
  • therumpus
  • staff
  • breakingnews
  • science-junkie
  • ucsdspecialcollections
  • plannedparenthood
  • mashablehq
  • nysci
  • dodgemedlin
  • scipak
  • nprfreshair
  • sdzsafaripark
  • cranquis
  • prnewswire
  • usagov
  • pulitzercenter
  • buzzfeed
  • prochoiceamerica
  • skunkbear
  • princeton-medbloro
  • jtotheizzoe
  • cenwatchglass
  • washingtonexaminer
  • infographicjournal
  • unicef
  • instagram
  • soupsoup
  • 3rdofmay
  • medicalschool
  • thebrainscoop
  • wsudiscovery
  • ucresearch
  • newswatchtv
  • md-admissions
  • ucsdcrossculturalcenter
  • houseofmind
  • lakeconews
  • usatoday
  • onaissues
  • pubhealth
  • wayfaringmd
  • sciencenetlinks
  • forbes
  • thedailyshow
  • medindia
  • stemcellculture
  • brookhavenlab
  • currentsinbiology
  • cnbc
  • actgnetwork
  • timelightbox
  • madsweat
  • pbsthisdayinhistory
  • ziyadnazem
  • post-mitotic
  • scienceisbeauty
  • smithsonianmag
  • mediclopedia
  • lewisandquark
  • whitehouse
  • bbglasses
  • psychotherapy
  • thescienceblog
  • mathcat345
  • statedept
  • usnews
  • lookatthisstory
  • shortformblog
  • austinstatesman
  • csmonitor
  • sesamestreet
  • doctorswithoutborders
  • queerability
  • yahoonews
  • scienceandfood
  • columbusdispatch
  • newshour
  • scinerds
  • uconnhealthlib
  • hospitalreina
  • ucsciencetoday
  • articulomortis
  • nprglobalhealth
  • codeit
  • cancerninja
  • robertreich
  • laboratoryequipment
  • peacecorps
  • researchchla
  • minnpost
  • today
  • yaleuniversity
  • missmdisme
  • exploratorium
  • nprontheroad
  • sciencesoup
  • alscientist
  • healthcareinfoguide
  • ari-abroad
  • theskygazer
  • highcountrynews
  • natgeofound
  • timemagazine
  • artandsciencejournal
  • aarp
  • officialssay
  • nbcnews
  • thisissandiego
  • nypl
  • psydoctor8
  • artneuroscience
  • bbsrc
  • anaofta
  • tmagazine
  • shortyawards
  • molecularlifesciences
  • blamoscience
  • markcoatney
  • reuters
  • jayparkinsonmd
  • ottawahealth
  • blue-lights-and-tea
  • fuckyeahneuroscience
  • htdeverything
  • mediamed
  • phdr
  • topherchris
  • kateoplis
  • ohscience
  • artpoweratucsd
  • denverpost
  • motherjones
  • discoverynews
  • michiganengineering
  • oh4theloveofscience
  • nurse-on-duty
  • thenewrepublic
  • wgbhnews
  • theatlantic
  • colchrishadfield
  • fuckyeahcardiovascularsystem
  • fuckyeahnervoussystem
  • sciencenote
  • matthewkeys
  • robotmuesli
  • pneupnurse
  • medethicslady
  • themedicalchronicles
  • kpcc
  • ohyeahdevelopmentalbiology
  • ucsdcareerservicescenter
  • science
  • pacificstand
  • clearscience
  • bitesizedbiology
  • poptech
  • futureofscience
  • galindoyadira
  • genannetics
  • ucsd
  • ucsdmedialab
  • joshherigon
  • thescienceofreality
  • ladyjournos
  • sciencechicks
  • auditoryinsomniac
  • chronicleofhighered
  • vetstail
  • neurolove
  • ajebsary
  • neuroanatomyblog
  • goodideapublichealth
  • tedx
  • huffpostscience
  • thecoloradopursuit
  • brainmtters
  • bobedwardsradio
  • paraphyletic
  • sci-fact
  • nationalpost
  • carlzimmer
  • life
  • dailymedical
  • oceanportal
  • bklynmed
  • wellcomebrains
  • aljazeera
  • reportingonhealth
  • ucsfbioengineering
  • coolhealthinfographics
  • thedailywhat
  • villagevoice
  • nbclatino
  • guardiancomment
  • scientificbritain
  • adschu