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News Article | May 15, 2017
Site: www.prnewswire.com

"The development of a child inside the mother affects that child its entire life, and low birth weight has lifelong health implications for a child," says Mark Steinhoff, MD, corresponding author on the study and director of the Global Health Center at Cincinnati Children's Hospital Medical Center. "The overall positive effect of performing these vaccinations – which is not expensive – is quite significant." Funded by the Bill and Melinda Gates Foundation (grant 50274), the research team focused its study on the subtropical terai plains of southern Nepal in south Asia. This underdeveloped, agrarian region is known for a subsistence lifestyle, high rates of malnutrition and limited access to healthcare, and is representative of many tropical regions where 40 percent of the world's births occur. Researchers traveled to villages in southern Nepal during normal routine health visits by Nepalese members of the team. Participating households were then followed up and surveilled on a weekly basis during home visits. Collaborating on the study were researchers from the Nepal Nutrition Intervention Project and the Tribhuvan University Institute of Medicine, both based in the Nepalese capital of Kathmandu. In households where women between the ages of 15 and 40 were pregnant, volunteer participants were administered either influenza vaccine or placebo as part of a randomized, placebo-controlled Phase 4 clinical trial.  The trial was registered with ClinicalTrials.gov and the protocol was reviewed and approved by the institutional review boards of participating institutions. From April 2011 through September 2013, 3,693 mothers were recruited and randomized into two different annual research groups (or cohorts). In the first cohort of 2,090, 1,040 mothers were given placebo, and 1,049 were administered seasonally recommended trivalent inactivated vaccine (which contains three inactivated flu viruses). In the second cohort of 1,603 mothers, 805 were given placebo and 798 received vaccine. There were a total of 3,646 live births in both groups. The researchers assessed three primary outcomes: the incidence of laboratory confirmed infant influenza from 0-180 days post birth; the incidence of low birth weight; and the incidence of influenza-like illness in mothers 0-180 days following delivery. In cohort 1, compared to the placebo group influenza-like illness was reduced by 9 percent in pre- and post-partum mothers who received vaccine. In cohort 2, flu-like illness was reduced by 36 percent. This placed the average flu reduction rate for both groups of vaccinated mothers at 19 percent. For infants, lab-confirmed flu infections in cohort 1 decreased 16 percent in babies with vaccinated mothers. In cohort 2 they decreased by 60 percent – putting the average rate of reduction for both cohorts at 30 percent. As for birth weight, flu immunizations in pregnant mothers reduced the rate of low birth weight (less than 2,500 grams/5.5 pounds) by 15 percent in cohort 1 and by 15 percent in cohort 2 (average 15 percent for both groups). There were 111 infant deaths during the study – 50 in the placebo group and 51 in the vaccine group; and seven maternal deaths – five in the placebo group and two in the vaccine group. Researchers are following up their current study by gathering additional data to support the expansion of year-round flu vaccination to other regions where it is needed. Steinhoff said this is especially important for developing countries like Nepal and where influenza has a more significant impact on birth weights than in developed nations. An estimated 40 percent of the world's population lives in subtropical/tropical zones, although flu vaccine is not widely used in these areas, according to the authors. The benefits of vaccinating pregnant women is well documented in developed countries. Its use has not been prevalent in underdeveloped subtropical/tropical regions, where many local officials have believed until recently that influenza virus does not even exist. Study authors note that the timing, circulation and type of flu virus are highly variable in subtropical and tropical regions. During the current study in Nepal, the circulation of flu increased during the South Asian Southwest monsoon season in July-October. Active symptomatic flu virus was present among study participants for 24 (or 66 percent) of the study months, with two more strains of virus circulating during 18 of these months. Researchers also pointed out that most of positive effect from flu vaccination was observed in the second study group of mothers and infants. This second group received two different formulations of flu vaccine with a broader range of antigens to account for virus variability in the region. This high variability of influenza virus in the study region (and other subtropical/tropical climates) will require improved vaccines with broader antigenic coverage, the authors report. Other collaborating institutions include: the Johns Hopkins Bloomberg School of Public Health; the University of Washington, School of Medicine; the Milken Institute of Public Health at George Washington University. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/year-round-flu-vaccinations-promote-healthier-infants-in-subtropics-300457594.html


News Article | May 22, 2017
Site: www.prnewswire.com

"We found that when T cells activate and go through extraordinarily rapid cell division during initial immune responses, it leads to an unusual level of genomic stress in the cells," explains Michael B. Jordan, MD, lead author and physician/scientist in the divisions of Bone Marrow Transplantation and Immune Deficiency and Immunobiology. "Because T cells are always in a race with different viruses and bacteria, they have learned how to adapt and divide rapidly to respond, but this stress on their DNA means they also are living right on the edge of death," Jordan says. "In our experiments we selectively interrupted DNA damage repair in rapidly expanding T cells, and we threw them off balance and into a chasm of death." PPCA is a newly minted acronym for "p53 potentiation with checkpoint abrogation." The therapeutic approach was developed by Jordan and his colleagues, including Jonathan Katz, PhD, and David Hildeman, PhD, (Division of Immunobiology). It was conceived during experiments on mouse and donated human immune cells called lymphocytes, which include the aggressively effective germ killers, T cells and B cells. Researchers hypothesized that along with the highly adaptable and proliferative abilities of T cells came an abundance of genomic stress. They observed as T cells used DNA damage response pathways to survive while adapting and gearing up to attack lymphocytic choriomeningitis virus (LCMV) as it tried to infect cells and animal models. A gene and its protein called p53 (also called the "guardian of the genome") helps initiate DNA damage repair – the primary reason researchers decided to target it in T cells. They also leveraged a concept developed for the treatment of cancer called cell cycle checkpoint inhibition or abrogation – in which cells are forced to lose normal control over the mitotic cell division cycle. In selective instances of rapid T cell expansion in mouse models of HLH and experimental autoimmune encephalomyelitis (experimental mouse MS), the researchers used a small molecule called Nutlin to alter the activities of p53. They also inhibited cell cycle checkpoint proteins known as CHK1/2 or WEE1.  This prevented the T cells from pausing and repairing their DNA damage, which prompted them to die off. In mouse models of HLH – mainly a childhood disease where the immune system overheats, attacks healthy tissues, damages organs and causes early death – PPCA reduced disease in the animals and allowed them to survive long-term. The researchers also tested PPCA treatment in mice with experimental autoimmune encephalomyelitis (EAE) used to model multiple sclerosis. In MS, autoimmune-driven inflammation damages a protective insulating sheath on nerves called myelin. This causes disruptions in the central nervous system that disrupt signals between the brain and extremities, which can lead to paralysis and other symptoms. In EAE mouse models of MS, PPCA treatment killed off aggressively expanding T cells, tempered autoimmune processes and either reversed or prevented paralysis in the animals, authors report in their study. Jordan and his research colleagues – including first author Jonathan P. McNally (a recently graduated PhD student in the Immunology graduate program) – caution that their experimental results are early. Years of additional research are needed before knowing whether the current findings will eventually apply to clinical treatment in humans. The authors now plan to test PPCA in laboratory models of other autoimmune disorders to see how widely applicable it might be. Jordan is listed as an inventor of PPCA in a U.S. patent filing through the Center for Technology Commercialization at Cincinnati Children's. Funding support for the research came in part from the National Institutes of Health (RO1DK081175, RO1AI109810, RO1AI057753 and a Research Innovation Grant from Cincinnati Children's. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/experimental-therapy-for-immune-diseases-hits-achilles-heel-of-activated-t-cells-300461369.html


News Article | May 22, 2017
Site: www.eurekalert.org

CINCINNATI - Immune diseases like multiple sclerosis and hemophagocytic lymphohistiocytosis unleash destructive waves of inflammation on the body, causing death or a lifetime of illness and physical impairment. With safe and effective treatments in short supply, scientists report in PNAS Early Edition (Proceeding of the National Academy of Sciences) discovery of an experimental treatment that targets an Achilles heel of activated immune cells - killing them off and stopping autoimmune damage. Researchers at Cincinnati Children's Hospital Medical Center report in a study published the week of May 22 that a treatment modality they call PPCA takes advantage of DNA damage in rapidly expanding T cells, which they show was therapeutically beneficial in mouse models of hemophagocytic lymphohistiocytosis (HLH) and multiple sclerosis (MS). And for the most part it appears to be so without harming other immune system components needed to protect the body from infection. "We found that when T cells activate and go through extraordinarily rapid cell division during initial immune responses, it leads to an unusual level of genomic stress in the cells," explains Michael B. Jordan, MD, lead author and physician/scientist in the divisions of Bone Marrow Transplantation and Immune Deficiency and Immunobiology. "Because T cells are always in a race with different viruses and bacteria, they have learned how to adapt and divide rapidly to respond, but this stress on their DNA means they also are living right on the edge of death," Jordan says. "In our experiments we selectively interrupted DNA damage repair in rapidly expanding T cells, and we threw them off balance and into a chasm of death." PPCA is a newly minted acronym for "p53 potentiation with checkpoint abrogation." The therapeutic approach was developed by Jordan and his colleagues, including Jonathan Katz, PhD, and David Hildeman, PhD, (Division of Immunobiology). It was conceived during experiments on mouse and donated human immune cells called lymphocytes, which include the aggressively effective germ killers, T cells and B cells. Researchers hypothesized that along with the highly adaptable and proliferative abilities of T cells came an abundance of genomic stress. They observed as T cells used DNA damage response pathways to survive while adapting and gearing up to attack lymphocytic choriomeningitis virus (LCMV) as it tried to infect cells and animal models. A gene and its protein called p53 (also called the "guardian of the genome") helps initiate DNA damage repair - the primary reason researchers decided to target it in T cells. They also leveraged a concept developed for the treatment of cancer called cell cycle checkpoint inhibition or abrogation - in which cells are forced to lose normal control over the mitotic cell division cycle. In selective instances of rapid T cell expansion in mouse models of HLH and experimental autoimmune encephalomyelitis (experimental mouse MS), the researchers used a small molecule called Nutlin to alter the activities of p53. They also inhibited cell cycle checkpoint proteins known as CHK1/2 or WEE1. This prevented the T cells from pausing and repairing their DNA damage, which prompted them to die off. In mouse models of HLH - mainly a childhood disease where the immune system overheats, attacks healthy tissues, damages organs and causes early death - PPCA reduced disease in the animals and allowed them to survive long-term. The researchers also tested PPCA treatment in mice with experimental autoimmune encephalomyelitis (EAE) used to model multiple sclerosis. In MS, autoimmune-driven inflammation damages a protective insulating sheath on nerves called myelin. This causes disruptions in the central nervous system that disrupt signals between the brain and extremities, which can lead to paralysis and other symptoms. In EAE mouse models of MS, PPCA treatment killed off aggressively expanding T cells, tempered autoimmune processes and either reversed or prevented paralysis in the animals, authors report in their study. Jordan and his research colleagues - including first author Jonathan P. McNally (a recently graduated PhD student in the Immunology graduate program) - caution that their experimental results are early. Years of additional research are needed before knowing whether the current findings will eventually apply to clinical treatment in humans. The authors now plan to test PPCA in laboratory models of other autoimmune disorders to see how widely applicable it might be. Jordan is listed as an inventor of PPCA in a U.S. patent filing through the Center for Technology Commercialization at Cincinnati Children's. Funding support for the research came in part from the National Institutes of Health (RO1DK081175, RO1AI109810, RO1AI057753 and a Research Innovation Grant from Cincinnati Children's.


News Article | June 22, 2017
Site: www.eurekalert.org

CINCINNATI - Scientists used human pluripotent stem cells to generate human embryonic colons in a laboratory that function much like natural human tissues when transplanted into mice, according to research published June 22 in Cell Stem Cell. The study is believed to be the first time human colon organoids have been successfully tissue engineered in this manner, according to researchers at Cincinnati Children's Hospital Medical Center who led the project. The technology allows diseases of the colon to be studied in unprecedented detail in a human modeling system. It also comes with the potential to one day generate human gastrointestinal (GI) tract tissues for transplant into patients, according to James Wells, PhD, senior study investigator and director of the Cincinnati Children's Pluripotent Stem Cell Center. "Diseases affecting this region of the GI tract are quite prevalent and include ailments like colitis, colon cancer, Irritable Bowel Syndrome, Hirschsprung's disease and polyposis syndromes," Wells said. "We've been limited in how we can study these diseases, including the fact that animal models like mice don't precisely recreate human disease processes in the gastrointestinal tract. This system allows us to very effectively model human diseases and human development." In a series of studies published since 2009, researchers in Wells' laboratory used human pluripotent stem cells (hPSCs) to grow embryonic-stage small intestines with a functioning nervous system, and the antrum and fundus regions of the human stomach. The researchers - including Jorge Munera, PhD, first author and postdoctoral fellow in the Wells laboratory - note in their current paper the colon has been more difficult to generate than other parts of the GI tract. Part of the challenge to identifying the correct genetic and molecular programming to coax hPSCs in to colonic organoids has been a lack of data about embryonic development of the organ, according to the authors. They addressed this by conducting a series of molecular and genetic screens of developing hindgut tissues in animal models. The hindgut is the portion of the developing gut that gives rise to the entire large intestine - which includes the cecum, colon and rectum. They also mined public databases (GNCPro, TiGER, Human Protein Atlas) to identify molecular markers of the hindgut in the adult colon. To develop a model for generating the human colon, scientists first identified SATB2 (special AT-rich sequence-binding protein 2) as a definitive molecular marker for hindgut in frogs, mice and in humans. SATB2 is a DNA-binding protein that facilitates structural organization of chromosomes in the nucleus of cells. The protein sequence of SATB2 is remarkably similar between frogs, mice and humans. This led the authors to the hypothesis that molecular signals regulating SATB2 in frogs and mice could be used to make human colon organoids that express the protein. The authors also noticed that signaling from the growth factor BMP (bone morphogenetic protein) was highly active in the SATB2-expressing region of the gut tube. The researchers learned during their analysis of frog, mouse and human stem-cell derived intestine that signaling by BMP is needed to establish SATB2 in the developing hindgut. With SABT2 as a marker, the researchers show BMP signaling is required for development of tissues specific to the posterior gut region of frogs and mice where the colon develops. When BMP protein was added for three days in human pluripotent stem cell-derived gut tube cultures, it induced a posterior HOX code. HOX includes a critical set of genes that help control the embryo's development plan from head to toe. Researchers report the posterior HOX helps control the formation of SATB2-expressing human colon organoids. To see how human GI tissues perform in a living organism - and to test their future therapeutic potential - the research team included collaborators from the Division of Surgery, led by Michael Helmrath, MD, a pediatric surgeon and director of the Surgical Research program. The tissue-engineered colonic organoids were transplanted into the kidney capsules of immunocompromised mice for six to 10 weeks. During observation and analysis of the now in vivo organoids, study authors looked for signs of posterior region enteroendocrine cells, which make hormones found in naturally developed human colon. Researchers report that following transplant, the human colonic organoids assumed the form, different structures and molecular and cell properties of the human colon. Munera, study first author, pointed to a number of new ways that human colon organoids could be used study disease. "By exposing human colonic organoids to inflammatory triggers, we can now learn how the cell lining of the colon and the supporting cells beneath cooperate to respond to inflammation," Munera said. "This could be very relevant for patients with Crohn's disease or ulcerative colitis. And because the microbiome, the organisms that live in our guts, are most concentrated in the colon, the organoids potentially could be used to model the human microbiome in health and disease." Like other parts of the GI tract grown by the researchers, the human colon organoids also create a potential new platform for testing new drugs before the start of clinical trials. Most oral drugs are absorbed by the body through the gut. Funding support for the research came in part from National Institutes of Health grants: R01DK092456, U19 AI116491, U18EB021780, R01DK102551, U01DK103117, NIDDK070858 and a postdoctoral fellowship from the Crohn's and Colitis Foundation of America. A multimedia slideshow about the research can be found under private view on YouTube at this link, subject to the same media embargo as stated above.


News Article | June 14, 2017
Site: www.prnewswire.com

The scientists report online in Nature on June 14 that their bioengineered human liver tissues still need additional rounds of molecular fine tuning before they can be tested in clinical trials. The research was led by Takanori Takebe, MD, a physician/investigator at Cincinnati Children's Hospital Medical Center (Division of Gastroenterology, Hepatology & Nutrition) in the United States, and Barbara Treutlein, PhD, Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. The only current treatment for end-stage liver disease is a liver transplant, and the number of livers available from deceased donors is limited. Because of this, a major goal in regenerative medicine is to attain self-organizing human tissues – in which cells experience a series of coordinated molecular events precisely timed and spaced to form functioning three dimensional liver buds, the authors write. Nailing down the precise details and context of developmental molecular-cellular crosstalk in the endoderm of an embryo – where livers form – is critical to this technology's therapeutic potential. "The ability to bioengineer transplantable livers and liver tissues would be a great benefit to people suffering from liver diseases who need innovative treatments to save their lives," said Takebe at Cincinnati Children's. "Our data give us a new, detailed understanding of the intercellular communication between developing liver cells, and shows we can produce human liver buds that come remarkably close to recapitulating fetal cells from natural human development." In the current study, the authors used single-cell RNA sequencing (RNA-Seq) to monitor how individual cells change when they are combined in a three-dimensional (3D) microenvironment. This is where vascular cells, connective tissue cells and hepatic cells engage in a complex communication. The main advantage of using single-cell RNA-Seq technology is it provides a blueprint of gene activity in each and every cell type. The researchers zeroed in on developing a complete blueprint of active transcription factors (genes that tell other genes what to do) and the signaling molecules and receptors in each of the different cells before and after they come together to form liver tissue. Authors report they observed a dramatic change in the genetic-molecular conversations and how the cells behave when they all develop together in a 3D microenvironment. Single-cell RNA-Seq analysis also helped researchers benchmark the engineered 3D liver tissues generated from stem cells against naturally occurring human fetal and adult liver cells. Researchers observed that the lab-grown liver buds have molecular and genetic signature profiles that very closely resemble those found in naturally developing human liver cells. In particular they highlight molecular crosstalk between a signaling protein that cells produce to stimulate formation of blood vessels (VEGF) and a protein and receptor that communicates with VEGF to help trigger formation of a blood supply to the developing liver (KDR). The current study shows the communication between VEGF and KDR is critical to instructing the development and maturation of liver tissues. Researchers indicate they observed this crosstalk during development of mouse liver cells, natural human liver cells and in their bioengineered livers. "Our data reveals, in exquisite resolution, that the conversation between cells of different types changes the cells in a way that likely mimics what is going on during human development," said Treutlein at Max Planck. "There is still a lot left to learn about how to best generate a functioning human liver tissue in a dish, nevertheless, this a big step in that direction." The authors noticed the gene expression landscape in the generated liver buds – such as precisely where and when genes express themselves – did not completely match natural human liver cells. The remaining gaps between natural and bioengineered tissues may come from different developmental cues caused by the unique microenvironment of cells developing in a petri dish versus that of cells developing in a person or animal. The new cellular and molecular data uncovered in the current study will be "exploited in the future to further improve liver bud organoids" and "precisely recapitulate differentiation of all cell types" in fetal human development, the authors write. Co-first authors on the study are J. Gray Camp, PhD, Max Planck Institute for Evolutionary Anthropology, and Keisuke Sekine, PhD, at Yokohama City University. Funding support for the research came from: the Max Planck Society; PRESTO Japan Science and Technology Agency; the Ministry of Education Culture and Sports of Japan (#15H04922 and #15KK0314); and the AMED Research Center Network for Realization of Regenerative Medicine (Japan Agency for Medical Research and Development). Takebe also is a New York Stem Cell Foundation - Robertson Investigator and receives grant support from the organization. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/bioengineered-human-livers-mimic-natural-development-300473989.html


News Article | June 14, 2017
Site: www.eurekalert.org

CINCINNATI - An international team of researchers bioengineering human liver tissues uncovered previously unknown networks of genetic-molecular crosstalk that control the organ's developmental processes - greatly advancing efforts to generate healthy and usable human liver tissue from human pluripotent stem cells. The scientists report online in Nature on June 14 that their bioengineered human liver tissues still need additional rounds of molecular fine tuning before they can be tested in clinical trials. The research was led by Takanori Takebe, MD, a physician/investigator at Cincinnati Children's Hospital Medical Center (Division of Gastroenterology, Hepatology & Nutrition) in the United States, and Barbara Treutlein, PhD, Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. The only current treatment for end-stage liver disease is a liver transplant, and the number of livers available from deceased donors is limited. Because of this, a major goal in regenerative medicine is to attain self-organizing human tissues - in which cells experience a series of coordinated molecular events precisely timed and spaced to form functioning three dimensional liver buds, the authors write. Nailing down the precise details and context of developmental molecular-cellular crosstalk in the endoderm of an embryo - where livers form - is critical to this technology's therapeutic potential. "The ability to bioengineer transplantable livers and liver tissues would be a great benefit to people suffering from liver diseases who need innovative treatments to save their lives," said Takebe at Cincinnati Children's. "Our data give us a new, detailed understanding of the intercellular communication between developing liver cells, and shows we can produce human liver buds that come remarkably close to recapitulating fetal cells from natural human development." In the current study, the authors used single-cell RNA sequencing (RNA-Seq) to monitor how individual cells change when they are combined in a three-dimensional (3D) microenvironment. This is where vascular cells, connective tissue cells and hepatic cells engage in a complex communication. The main advantage of using single-cell RNA-Seq technology is it provides a blueprint of gene activity in each and every cell type. The researchers zeroed in on developing a complete blueprint of active transcription factors (genes that tell other genes what to do) and the signaling molecules and receptors in each of the different cells before and after they come together to form liver tissue. Authors report they observed a dramatic change in the genetic-molecular conversations and how the cells behave when they all develop together in a 3D microenvironment. Single-cell RNA-Seq analysis also helped researchers benchmark the engineered 3D liver tissues generated from stem cells against naturally occurring human fetal and adult liver cells. Researchers observed that the lab-grown liver buds have molecular and genetic signature profiles that very closely resemble those found in naturally developing human liver cells. In particular they highlight molecular crosstalk between a signaling protein that cells produce to stimulate formation of blood vessels (VEGF) and a protein and receptor that communicates with VEGF to help trigger formation of a blood supply to the developing liver (KDR). The current study shows the communication between VEGF and KDR is critical to instructing the development and maturation of liver tissues. Researchers indicate they observed this crosstalk during development of mouse liver cells, natural human liver cells and in their bioengineered livers. "Our data reveals, in exquisite resolution, that the conversation between cells of different types changes the cells in a way that likely mimics what is going on during human development," said Treutlein at Max Planck. "There is still a lot left to learn about how to best generate a functioning human liver tissue in a dish, nevertheless, this a big step in that direction." The authors noticed the gene expression landscape in the generated liver buds - such as precisely where and when genes express themselves - did not completely match natural human liver cells. The remaining gaps between natural and bioengineered tissues may come from different developmental cues caused by the unique microenvironment of cells developing in a petri dish versus that of cells developing in a person or animal. The new cellular and molecular data uncovered in the current study will be "exploited in the future to further improve liver bud organoids" and "precisely recapitulate differentiation of all cell types" in fetal human development, the authors write. Co-first authors on the study are J. Gray Camp, PhD, Max Planck Institute for Evolutionary Anthropology, and Keisuke Sekine, PhD, at Yokohama City University. Funding support for the research came from: the Max Planck Society; PRESTO Japan Science and Technology Agency; the Ministry of Education Culture and Sports of Japan (#15H04922 and #15KK0314); and the AMED Research Center Network for Realization of Regenerative Medicine (Japan Agency for Medical Research and Development). Takebe also is a New York Stem Cell Foundation - Robertson Investigator and receives grant support from the organization.


News Article | May 31, 2017
Site: www.prnewswire.com

Functional magnetic resonance imaging (fMRI) found significantly greater brain activation in 4-year-old children who were more highly engaged during story listening, suggesting a novel improvement mechanism of engagement and understanding. The study reinforces the value of "dialogic reading," where the child is encouraged to actively participate. "The takeaway for parents in this study is that they should engage more when reading with their child, ask questions, have them turn the page, and interact with each other," said John Hutton, MD, a pediatrician at Cincinnati Children's and lead author of the study. "In turn, this could fuel brain activation--or "turbocharge" the development of literacy skills, particularly comprehension, in preschool aged children." The study involved functional MRI scans of 22 girls, age 4, to explore the relationship between engagement and verbal interactivity during a mother-child reading observation and neural activation and connectivity during a story listening task. Children exhibiting greater interest in the narrative showed increased activation in right-sided cerebellar areas of the brain, thought to support cognitive skill acquisition and refinement via connection to language, association and executive function areas. "Our findings underscore the importance of interventions explicitly addressing both parent and child reading engagement, including awareness and reduction of distractions such as cellphones, which were the most common preventable barrier that we observed," said Hutton. Hutton says long-term studies are needed beginning in infancy to better understand mother-child factors contributing to healthy brain development and literacy skills, as this current study does not establish causation. Dr. Hutton is a clinical researcher in the Division of General and Community Pediatrics and the Reading and Literacy Discovery Center at Cincinnati Children's. Support for this study was provided by a grant (1R01HD066115-01A1) from the Eunice Kennedy Shriver National Institute for Child Health and Human Development. Support for neuroimaging, reading observations and related analyses were provided via a Ruth L Kirschstein National Research Service Award and an Academic Pediatric Association Young Investigator Award for Primary Care Strategies for the Promotion of Early Literacy and School Readiness Supported by Reach Out and Read. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/storytime-a-turbocharger-for-a-childs-brain-300466388.html


News Article | June 1, 2017
Site: www.eurekalert.org

CINCINNATI - A detour on the road to regenerative medicine for people with muscular disorders is figuring out how to coax muscle stem cells to fuse together and form functioning skeletal muscle tissues. A study published June 1 by Nature Communications reports scientists identify a new gene essential to this process, shedding new light on possible new therapeutic strategies. Led by researchers at the Cincinnati Children's Hospital Medical Center Heart Institute, the study demonstrates the gene Gm7325 and its protein - which the scientists named "myomerger" - prompt muscle stem cells to fuse and develop skeletal muscles the body needs to move and survive. They also show that myomerger works with another gene, Tmem8c, and its associated protein "myomaker" to fuse cells that normally would not. In laboratory tests on embryonic mice engineered to not express myomerger in skeletal muscle, the animals did not develop enough muscle fiber to live. "These findings stimulate new avenues for cell therapy approaches for regenerative medicine," said Douglas Millay, PhD, study senior investigator and a scientist in the Division of Molecular Cardiovascular Biology at Cincinnati Children's. "This includes the potential for cells expressing myomaker and myomerger to be loaded with therapeutic material and then fused to diseased tissue. An example would be muscular dystrophy, which is a devastating genetic muscle disease. The fusion technology possibly could be harnessed to provide muscle cells with a normal copy of the missing gene." One of the molecular mysteries hindering development of regenerative therapy for muscles is uncovering the precise genetic and molecular processes that cause skeletal muscle stem cells (called myoblasts) to fuse and form the striated muscle fibers that allow movement. Millay and his colleagues are identifying, deconstructing and analyzing these processes to search for new therapeutic clues. Genetic degenerative disorders of the muscle number in the dozens, but are rare in the overall population, according to the National Institutes of Health. The major categories of these devastating wasting diseases include: muscular dystrophy, congenital myopathy and metabolic myopathy. Muscular dystrophies are a group of more than 30 genetic diseases characterized by progressive weakness and degeneration of the skeletal muscles that control movement. The most common form is Duchenne MD. A previous study authored by Millay in 2014 identified myomaker and its gene through bioinformatic analysis. Myomaker is also required for myoblast stem cells to fuse. However, it was clear from that work that myomaker did not work alone and needed a partner to drive the fusion process. The current study indicates that myomerger is the missing link for fusion, and that both genes are absolutely required for fusion to occur, according to the researchers. To find additional genes that regulate fusion, Millay's team screened for those activated by expression of a protein called MyoD, which is the primary initiator of the all the genes that make muscle. The team focused on the top 100 genes induced by MyoD (including GM7325/myomerger) and designed a screen to test the factors that could function within and across cell membranes. They also looked for genes not previously studied for having a role in fusing muscle stem cells. These analyses eventually pointed to a previously uncharacterized gene listed in the database - Gm7325. Researchers then tested cell cultures and mouse models by using a gene editing process called CRISPR-Cas9 to demonstrate how the presence or absence of myomaker and myomerger - both individually and in unison - affect cell fusion and muscle formation. These tests indicate that myomerger-deficient muscle cells called myocytes differentiate and form the contractile unit of muscle (sarcomeres), but they do not join together to form fully functioning muscle tissue. The researchers are building on their current findings, which they say establishes a system for reconstituting cell fusion in mammalian cells, a feat not yet achieved by biomedical science. For example, beyond the cell fusion effects of myomaker and myomerger, it isn't known how myomaker or myomerger induce cell membrane fusion. Knowing these details would be crucial to developing potential therapeutic strategies in the future, according to Millay. This study identifies myomerger as a fundmentally required protein for muscle development using cell culture and laboratory mouse models. The authors emphasize that extensive additional research will be required to determine if these results can be translated to a clinical setting. Multiple authors with the Cincinnati Children's Heart Institute contributed to this study, including the listed first author Malgorzata Quinn, PhD. A complete list is included in the study abstract. Funding support came from the Cincinnati Children's Hospital Research Foundation, the National Institutes of Health (R01AR068286), and the Pew Charitable Trusts.


News Article | July 24, 2017
Site: www.eurekalert.org

CINCINNATI - With obesity related illnesses a global pandemic, researchers propose in the Journal of Clinical Investigation using a blood thinner to target molecular drivers of chronic metabolic inflammation in people eating high-fat diets to limit weight gain and disease. In a study published online July 24, a multi-institutional scientific team led by Cincinnati Children's Hospital Medical Center uncover a previously unknown molecular link in the body that drives obesity and inflammation. Obesity and metabolic inflammation are linked to cardiovascular disease, type 2 diabetes, fatty liver disease and several cancers. Researchers tested genetically manipulated mice on a high-fat diet and donated human tissues from obese people who had fatty liver disease. They found that an insoluble glycoprotein called fibrinogen binds with a receptor of leukocyte white blood cells called αMβ2-integrin, which fuels diet-induced obesity and disease. Obesity promotes activation of the clotting system that leads to the conversion of fibrinogen into insoluble fibrin strands. This causes an over-accumulation of leukocytes- which mature into macrophage immune cells - along with excessive inflammation and tissue damage and dysfunction, according to the authors. "Our findings provide a novel mechanistic link between elevated pro-coagulant function and fibrin-driven inflammation in adipose fat-storing tissue and the liver. These exacerbate obesity and its associated diseases," said Matthew Flick, PhD, lead study investigator and scientist in the Division of Experimental Hematology and Cancer Biology at Cincinnati Children's. "We also provide the proof-of-concept that targeting thrombin or fibrin may limit pathologies in obese patients." Flick and his colleagues used an FDA-approved blood thinner called dabigatran to treat mice fed a high-fat diet to block an enzyme called thrombin. Thrombin's job is to promote blood coagulation. In obesity, however, the enzyme can cause hyper-coagulation, inflammation, and the production of tissue-damaging insoluble fibrin strands. Treatment with the drug protected mice from the onset of obesity related disease, the researchers reported. To test their hypotheses about what drives metabolic inflammation and obesity, the researchers bred genetically manipulated Fibγ390-396 mice that carry a mutant form of fibrinogen. The mutant fibrinogen is unable to bind with the leukocyte receptor αMβ2-integrin. Although the animals were fed a high-fat diet, the tests revealed that Fibγ390-396 mice were significantly protected from diet-induced weight gain and elevated fat in adipose tissues. These mice also had markedly diminished systemic, adipose and liver inflammation. Researchers also noted these mice had significantly reduced macrophage white blood cell counts in white adipose tissue and almost complete protection from development of fatty liver disease and defective blood sugar metabolism. To simulate what happens to severely overweight people who eat a high-fat diet, the researchers also tested genetically altered homozygous thrombomodulin (Glu404Pro) mice. These mice have genetically-induced elevated thrombin and pro-coagulant function. On a high-fat diet, the genetically altered mice gained more weight and developed an exacerbated form of fatty liver disease. Normal wild-type mice fed a high-fat diet did not develop the same degree of disease symptoms. When researchers treated normal mice with established obesity with the direct thrombin inhibitor dabigatran, the animals' progression of high-fat-diet-induced obesity was stopped. Treatment also suppressed development of obesity related disease, according to the authors. Flick and his colleagues said there are several additional research steps needed before direct thrombin inhibition can be tested in overweight patients who may be at high risk of obesity related disease. This includes working with the Pediatric Obesity Tissue Repository at Cincinnati Children's, which contains donated biopsy samples from patients. The researchers will be looking for the amount of fibrin content in visceral adipose tissues to see if there is a correlation with diseases like non-alcoholic fatty liver disease (NASH), type 2 diabetes, hypertension and other obesity linked diseases. If researchers find this to be true, high fibrin content in white adipose tissue may serve as a biomarker for obese patients to identify those who are at high risk for progressing to NASH or severe type 2 diabetes, Flick said. The research team also is working with the German pharmaceutical company that developed the direct thrombin inhibitor dabigatran (Boehringer Ingelheim Pharmaceuticals Inc.) to determine whether patients who have taken the drug have reduced obesity and associated disease. The company provided the drug and participated in the study. "Depending on what we find in our future work, and combined with the data we present in the current paper, this could serve as strong rationale to put obese patients on the drug to suppress the development of metabolic syndrome and associated diseases," Flick said. Funding support for the research came from the National Institutes of Health (HL112603, ES017537), and the Digestive Disease Research Core Center at Cincinnati Children's (PHS Grant P30 DK078392). Funding also came from Boehringer Ingelheim through a research grant to study co-author James P. Luyendyk, PhD, (Department of Pathobiology and Diagnostic Investigation, Institute for Integrative Toxicology, Michigan State University). Additionally, two study co-authors are employees of Boehringer Ingelheim and declare financial conflicts of interest. All other authors declare no financial conflicts of interests.


News Article | July 17, 2017
Site: www.eurekalert.org

CINCINNATI -- A tool intended to detect signs of autism in high-risk infants can be used to help identify and treat patients with tuberous sclerosis complex (TSC), a genetic disorder, who most need early intervention. Moreover, they can identify these patients earlier than ever before. A new study, published online in Pediatric Neurology, evaluated children with TSC, which causes malformations and tumors in the brain and other vital organs and has a high prevalence of autism spectrum disorders (ASD). "Single gene syndromes with a high prevalence of neurodevelopmental disorders, such as TSC, provide unique opportunities to investigate the underlying biology and identify potential treatments for ASD," says Jamie Capal, MD, a neurodevelopmental and autism specialist in the Division of Neurology at Cincinnati Children's Hospital Medical Center and lead author of the study. "These disorders provide populations in which ASD symptoms can be identified and measured before the formal diagnosis of ASD is made." Capal led the study of 79 children up to 24 months old. These children with TSC are part of a larger group of children enrolled in the TSC Autism Center of Excellence Research Network (TACERN). This is a multicenter study to identify biomarkers of ASD. The researchers administered the Autism Observation Scale for Infants (AOSI) at 12 months of age followed by the Autism Diagnostic Observation Schedule-2 (ADOS-2), a diagnostic tool, at 24 months. The AOSI was designed primarily as a research tool to identify early signs of autism in high-risk infants who have an older sibling with autism. The scale includes seven activities that allow researchers to observe behaviors such as visual tracking and response to facial emotion. "The ASD group had a mean AOSI total score at 12 months significantly higher than the non-ASD group, demonstrating that it is a useful clinical tool in determining which infants with TSC are at increased risk of developing ASD." says Capal. The research was supported by grants from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (U01-NS082320, P20-NS080199), the Tuberous Sclerosis Alliance, the Developmental Synaptopathies Consortium (U54NS092090). The study used clinical research facilities and resources supported by the NCATS of the National Institutes of Health Grant (UL1-TR000077, UL1-TR000124). A full list of disclosures of conflicts of interest is available upon request.

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