University of Delaware researchers have identified a protein, hiding in plain sight, that acts like a bodyguard to help protect and stabilize another key protein, that when unstable, is involved in Crohn’s disease. The fundamental research points to a possible pathway for developing an effective therapy for the inflammatory bowel disease.
The research was conducted by Catherine Leimkuhler Grimes, assistant professor of chemistry and biochemistry at UD, and Vishnu Mohanan, doctoral student in biological sciences,
As the scientists point out, our immune system provides the first line of defence against invading pathogens, a task even more challenging in the human gut, where over a trillion commensal bacteria live — resident microorganisms that help convert food into protein, vitamins and minerals.
To distinguish “bad” versus “good” bacteria, our bodies rely on a complex network of receptors that can sense patterns that are unique to bacteria, such as small fragments of bacterial cell wall. The receptors recognize and bind to these fragments, triggering an immune response to take out the “bad guys” or control the growth of the “good guys.”
However, when one of these receptors breaks down, or mutates, an abnormal immune response can occur, causing the body to mount an immune response against the “good” bacteria. Chronic inflammatory disorders, such as Crohn’s disease, are hypothesized to arise as a result.
The UD team focused on a protein called NOD2 — nucleotide-binding oligomerisation domain containing protein 2. More than 58 mutations in the NOD2 gene have been linked with various diseases, and 80 percent of these mutations are connected specifically to Crohn’s disease, according to Grimes.
In experiments to unveil NOD2’s signalling mechanisms and where they break down, “we stumbled on this chaperone molecule,” says Mohanan, who was the lead author of the scientific article.
The chaperone molecule was HSP70, which stands for “heat shock protein 70.” It assists with the folding of proteins into their correct three-dimensional shapes, even when cells are under stress from elevated body temperatures, such as a fever.
Grimes said she was a little sceptical at first about pursuing studies with HSP70 because it is a commonly known protein, but she found Mohanan’s initial data intriguing.
“Vishnu found that if we increased the expression level of HSP70, the NOD2 Crohn’s mutants were able to respond to bacterial cell wall fragments. A hallmark of the NOD2 mutations is inability to respond to these fragments. Essentially, Vishnu found a fix for NOD2, and we wanted to determine how we were fixing it.”
In further experiments, Mohanan created a tagged-wild-type NOD2 cell line in which NOD2 levels nearly matched the levels found in nature (versus “super” levels that might stimulate an artificial response) and found that NOD2 became more stabilized and degraded more slowly when treated with HSP70. In fact, HSP70 increased the half-life of NOD2 by more than four hours.
“Basically, HSP70 keeps the protein around — it kind of watches over and protects NOD2, and keeps it from going in the cellular trash can,” Grimes explains.
The researchers tested three human cell lines in their study: kidney cells, colon cells and white blood cells. In the next phase of the study, patient tissue will be examined through a collaboration with Nemours/A.I. duPont Hospital for Children to determine if NOD2 levels can be controlled via HSP70 expression.
“We want to figure out why the mutation in NOD2 results in an increase in inflammation,” says Mohanan. “Right now, we have limited knowledge. Once the signalling mechanism is figured out, we will have the keystone.”
University of Delaware
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Scientists have identified a crucial molecular key to healthy embryo implantation and pregnancy in a study that may offer new clues about the medical challenges of infertility/subfertility, abnormal placentation, and placenta previa.
Multi-institutional teams conducted the study and was led by researchers at Cincinnati Children’s Hospital Medical Center.
The authors found that uterine expression of a gene called Wnt5a – a major signalling molecule in cell growth and movement in both embryo development and disease – is also critical to healthy embryo implantation in the uterus.
The scientists say that molecular signalling from Wnt5a – working in tandem with its co-receptors ROR1 and ROR2 in the uterus – causes uterine implantation chambers (crypts) in mice to form at regular intervals. The signalling also helps direct embryos to migrate in the proper direction as they settle into the womb. The authors show that disruption of appropriate uterine Wnt5a-ROR signalling leads to abnormal uterine luminal epithelial architecture, crypt formation, disorderly spacing of embryos and implantation. These adverse effects led to defective decidualisation, placentation, and ultimately compromised pregnancy outcome.
“Proper implantation is important to healthy pregnancy, and it is not clearly understood what prompts embryos to move and implant within a uterine crypt with regular spacing,” said Sudhansu K. Dey, PhD, senior investigator and director of Division of Reproductive Sciences, Cincinnati Children’s Hospital Medical Center. “If something goes wrong at this stage, there could be adverse effects throughout the course of pregnancy – whether it is subfertility, infertility, restricted growth, miscarriage or preterm birth.”
Although there are similarities and differences between mouse and human implantation, a role for Wnt5a-ROR signalling in embryo spacing could be clinically relevant, Dey said. This is because the embryo can sometimes implant close to or on the cervix (placenta previa), which can cause extensive bleeding and lead to increased mortality or morbidity for the mother and foetus. Aberrant embryo spacing may also contribute to complications in a multiple gestation pregnancy.
Cincinnati Children’s Hospital
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Dysfunction in dopamine signalling profoundly changes the activity level of about 2,000 genes in the brain’s prefrontal cortex and may be an underlying cause of certain complex neuropsychiatric disorders, such as schizophrenia, according to UC Irvine scientists.
This epigenetic alteration of gene activity in brain cells that receive this neurotransmitter showed for the first time that dopamine deficiencies can affect a variety of behavioural and physiological functions regulated in the prefrontal cortex.
The study was led by Emiliana Borrelli, a UCI professor of microbiology & molecular genetics.
“Our work presents new leads to understanding neuropsychiatric disorders,” Borrelli said. “Genes previously linked to schizophrenia seem to be dependent on the controlled release of dopamine at specific locations in the brain. Interestingly, this study shows that altered dopamine levels can modify gene activity through epigenetic mechanisms despite the absence of genetic mutations of the DNA.”
Dopamine is a neurotransmitter that acts within certain brain circuitries to help manage functions ranging from movement to emotion. Changes in the dopaminergic system are correlated with cognitive, motor, hormonal and emotional impairment. Excesses in dopamine signalling, for example, have been identified as a trigger for neuropsychiatric disorder symptoms.
Borrelli and her team wanted to understand what would happen if dopamine signalling was hindered. To do this, they used mice that lacked dopamine receptors in midbrain neurons, which radically affected regulated dopamine synthesis and release.
The researchers discovered that this receptor mutation profoundly altered gene expression in neurons receiving dopamine at distal sites in the brain, specifically in the prefrontal cortex. Borrelli said they observed a remarkable decrease in expression levels of some 2,000 genes in this area, coupled with a widespread increase in modifications of basic DNA proteins called histones – particularly those associated with reduced gene activity.
Borrelli further noted that the dopamine receptor-induced reprogramming led to psychotic-like behaviours in the mutant mice and that prolonged treatment with a dopamine activator restored regular signalling, pointing to one possible therapeutic approach.
University of California, Irvine
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The age at which girls reach sexual maturity is influenced by ‘imprinted’ genes, a small sub-set of genes whose activity differs depending on which parent passes on that gene, according to new research.
The findings come from an international study of more than 180,000 women involving scientists from 166 institutions worldwide, including the University of Cambridge. The researchers identified 123 genetic variations that were associated with the timing of when girls experienced their first menstrual cycle by analysing the DNA of 182,416 women of European descent from 57 studies. Six of these variants were found to be clustered within imprinted regions of the genome.
Lead author Dr John Perry at the Medical Research Council (MRC) Epidemiology Unit, University of Cambridge says: “Normally, our inherited physical characteristics reflect a roughly average combination of our parents’ genomes, but imprinted genes place unequal weight on the influence of either the mother’s or the father’s genes. Our findings imply that in a family, one parent may more profoundly affect puberty timing in their daughters than the other parent.”
The activity of imprinted genes differs depending on which parent the gene is inherited from – some genes are only active when inherited from the mother, others are only active when inherited from the father. Both types of imprinted genes were identified as determining puberty timing in girls, indicating a possible biological conflict between the parents over their child’s rate of development. Further evidence for the parental imbalance in inheritance patterns was obtained by analysing the association between these imprinted genes and timing of puberty in a study of over 35,000 women in Iceland, for whom detailed information on their family trees were available.
This is the first time that it has been shown that imprinted genes can control rate of development after birth.
Dr Perry says: “We knew that some imprinted genes control antenatal growth and development – but there is increasing interest in the possibility that imprinted genes may also control childhood maturation and later life outcomes, including disease risks.”
Senior author and paediatrician Dr Ken Ong at the MRC Epidemiology Unit says: “There is a remarkably wide diversity in puberty timing – some girls start at age 8 and others at 13. While lifestyle factors such as nutrition and physical activity do play a role, our findings reveal a wide and complex network of genetic factors. We are studying these factors to understand how early puberty in girls is linked to higher risks of developing diabetes, heart disease and breast cancer in later life – and to hopefully one day break this link.”
Dr Anna Murray, a co-author from the University of Exeter Medical School, adds: “We found that there are hundreds of genes involved in puberty timing, including 29 involved in the production and functioning of hormones, which has increased our knowledge of the biological processes that are involved, in both girls and boys.”
University of Cambridge
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Most of the genetic risk for autism comes from versions of genes that are common in the population rather than from rare variants or spontaneous glitches, researchers funded by the National Institutes of Health have found. Heritability also outweighed other risk factors in this largest study of its kind to date.
About 52 percent of the risk for autism was traced to common and rare inherited variation, with spontaneous mutations contributing a modest 2.6 percent of the total risk.
“Genetic variation likely accounts for roughly 60 percent of the liability for autism, with common variants comprising the bulk of its genetic architecture,” explained Joseph Buxbaum, Ph.D., of the Icahn School of Medicine at Mount Sinai (ISMMS), New York City. “Although each exerts just a tiny effect individually, these common variations in the genetic code add up to substantial impact, taken together.”
Buxbaum, and colleagues of the Population-Based Autism Genetics and Environment Study (PAGES) Consortium, report on their findings in a unique Swedish sample in the journal Nature Genetics, July 20, 2014.
“Thanks to the boost in statistical power that comes with ample sample size, autism geneticists can now detect common as well as rare genetic variation associated with risk,” said Thomas R. Insel, M.D., director of the NIH’s National Institute of Mental Health (NIMH). “Knowing the nature of the genetic risk will reveal clues to the molecular roots of the disorder. Common variation may be more important than we thought.”
Although autism is thought to be caused by an interplay of genetic and other factors, including environmental, consensus on their relative contributions and the outlines of its genetic architecture has remained elusive. Recently, evidence has been mounting that genomes of people with autism are prone to harbouring rare mutations, often spontaneous, that exert strong effects and can largely account for particular cases of disease.
More challenging is to gauge the collective impact on autism risk of numerous variations in the genetic code shared by most people, which are individually much subtler in effect. Limitations of sample size and composition made it difficult to detect these effects and to estimate the relative influence of such common, rare inherited, and rare spontaneous variation.
Differences in methods and statistical models also resulted in sometimes wildly discrepant estimates of autism’s heritability – ranging from 17 to 50 percent.
NIH
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A protein that controls when genes are switched on or off plays a key role in specific areas of the brain to regulate metabolism, UT Southwestern Medical Center researchers have found.
The research potentially could lead to new therapies to treat obesity and diabetes, since the transcription factor involved – spliced X-box binding protein 1 (Xbp1s) – appears to influence the body’s sensitivity to insulin and leptin signalling. Insulin and leptin are hormones central to the body’s regulation of food intake and sugar disposal, and obesity and diabetes are conditions under which the body develops resistance to their actions.
“This study identifies critical molecular mechanisms that link the brain and peripheral endocrine tissues and that ultimately contribute to the regulation of body weight and glucose metabolism,” said Dr. Kevin Williams, Assistant Professor of Internal Medicine and co-first author of the study with Dr. Tiemin Liu, a postdoctoral research fellow in Internal Medicine.
Researchers found that over-expression of the gene Xbp1s in mice that were fed a high-fat diet protected them against obesity and diabetes, according to the recent study. On average, these mice were 30 percent leaner than mice fed the same food.
The gene’s actions took place in pro-opiomelanocortin (Pomc) neurons in the hypothalamic region of the brain. Elevated Xbp1s levels in Pomc neurons mimicked a “fed” signal, resulting in improved body weight, decreased blood glucose levels, and improved insulin sensitivity in the liver.
“Manipulating this one gene in the brain affected metabolism in the liver. This result shows that the brain is controlling glucose production by the liver,” said Dr. Joel Elmquist, Director of the Division of Hypothalamic Research, Professor of Internal Medicine, Pharmacology, and Psychiatry, and holder of the Carl H. Westcott Distinguished Chair in Medical Research, and the Maclin Family Distinguished Professorship in Medical Science, in Honor of Dr. Roy A. Brinkley.
Dr. Elmquist was co-senior author of the study, along with Dr. Philipp Scherer, Director of the Touchstone Center for Diabetes Research, Professor of Internal Medicine and Cell Biology, and holder of the Gifford O. Touchstone, Jr. and Randolph G. Touchstone Distinguished Chair in Diabetes Research.
No drug form of Xbp1s currently exists that could be used to test whether the gene is a target for the treatment of diabetes or obesity, though researchers see such a drug as a potential outgrowth of their research. Dr. Williams said other transcription factors involved in the same metabolic pathway will be studied to see if they have similar effects.
“We have studied one transcription factor out of many that participate in a large, complex cellular process,” said Dr. Williams of Xbp1s and its role during times of cellular stress.
UT Southwestern Medical Center
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The routine use of a molecular testing panel developed at UPMC greatly increases the likelihood of performing the correct initial surgery for patients with thyroid nodules and cancer, report researchers from the University of Pittsburgh Cancer Institute (UPCI), partner with UPMC CancerCenter.
The test improved the chances of patients getting the correct initial surgery by 30 percent, according to the study.
“Before this test, about one in five potential thyroid cancer cases couldn’t be diagnosed without an operation to remove a portion of the thyroid,” said lead author Linwah Yip, M.D., assistant professor of surgery in Pitt’s School of Medicine and UPMC surgical oncologist. Previously, “if the portion removed during the first surgery came back positive for cancer, a second surgery was needed to remove the rest of the thyroid. The molecular testing panel now bypasses that initial surgery, allowing us to go right to fully removing the cancer with one initial surgery. This reduces risk and stress to the patient, as well as recovery time and costs.”
Cancer in the thyroid, which is located in the “Adam’s apple” area of the neck, is now the fifth most common cancer diagnosed in women. Thyroid cancer is one of the few cancers that continues to increase in incidence, although the five-year survival rate is 97 percent.
Previously, the most accurate form of testing for thyroid cancer was a fine-needle aspiration biopsy, where a doctor guides a thin needle to the thyroid and removes a small tissue sample for testing. However, in 20 percent of these biopsies, cancer cannot be ruled out. A lobectomy, which is a surgical operation to remove half of the thyroid, is then needed to diagnose or rule-out thyroid cancer. In the case of a postoperative cancer diagnosis, a second surgery is required to remove the rest of the thyroid.
Researchers have identified certain gene mutations that are indicative of an increased likelihood of thyroid cancer, and the molecular testing panel developed at UPMC can be run using the sample collected through the initial, minimally invasive biopsy, rather than a lobectomy. When the panel shows these mutations, a total thyroidectomy is advised.
Dr. Yip and her colleagues followed 671 UPMC patients with suspicious thyroid nodes who received biopsies. Approximately half the biopsy samples were run through the panel, and the other half were not. Patients whose tissue samples were not tested with the panel had a 2.5-fold higher statistically significant likelihood of having an initial lobectomy and then requiring a second operation.
“We’re currently refining the panel by adding tests for more genetic mutations, thereby making it even more accurate,” said co-author Yuri Nikiforov, M.D., Ph.D., professor in the Department of Pathology at Pitt and director of thyroid molecular diagnostics at the UPMC/UPCI Multidisciplinary Thyroid Center. “Thyroid cancer is usually very curable, and we are getting closer to quickly and efficiently identifying and treating all cases of thyroid cancer.”
UPMC
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A genetic screening test may help predict which patients with one of the most common childhood kidney diseases will respond to standard therapies. Using this test could help guide clinicians as they counsel and treat patients.
Sporadic nephrotic syndrome is one of the most common kidney diseases in children, and it can have a genetic cause.
Paola Romagnani, MD, PhD, Sabrina Giglio, MD, PhD (University of Florence and Meyer Children’s Hospital, in Florence, Italy), and their colleagues designed an innovative diagnostic approach that allows for a fast analysis of all genes involved in the disease. Using this method, the team analysed 46 different genes at the same time in 69 children with the disease, and they found that genetic mutations in the kidney’s filtration barrier were frequently linked with a lack of response to immunosuppressive treatments in patients. The genetic test was even more predictive than a kidney biopsy for identifying children who would not benefit from immunosuppressive therapies.
“Thus, this type of genetic analysis can improve the clinical approach to children with nephrotic syndrome by promoting better genetic counselling for the risk of recurrence of the disease in the family, and a better management of treatment and clinical follow up,” said Professor Romagnani.
The application of this new diagnostic approach also improved the speed of clinical diagnoses of the disease and reduced costs. “With a single test, we can help build a truly personalized therapy,” said Professor Giglio.
American Society of Nephrology
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It has been some time in the making, but the newly designed Greiner Bio-One website was finally launched at the beginning of July along with our newly designed webshop.
Product and order information for the business divisions Preanalytics (specimen collection), BioScience (products for the biotech industry), Diagnostics (DNA arrays) and OEM (customised developments for the Life Science industry) can be accessed at www.gbo.com.
The innovative design with cool Parallax Scrolling technology at various levels is not the only thing that is new. Alongside the range of improvements, there are also a number of technical innovations, making it even easier to find the information you are looking for.
Features include:
A download menu divided into product groups, with downloads of flyers, brochures, etc. available in a range of languages
FAQs for the various products are answered in the "Frequently Asked Questions" section
The E-learning system "GBO Compass" and social media channels can now also be accessed via links
The latest developments are shown in brief and with an eye-catching layout in Marketing Highlights
Related content such as print material is shown directly on the various product pages in a separate box.
Greiner Bio-One International AG Greiner Bio-One is specialized in the development, production and distribution of high quality laboratory products made from plastic. The company is a technological partner for hospitals, laboratories, universities, research institutes and the diagnostic, pharmaceutical and biotechnology industries. Greiner Bio-One consists of four business units: Preanalytics, BioScience, Diagnostics and OEM. Today the company generates a turnover of 373 Mio. Euro. Greiner Bio-One is a member of the Greiner Group based in Kremsmünster (Austria).
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A study led by Yale Cancer Center may provide clues to how some aggressive cancers turn off, or silence, genes critical to suppressing tumours. The findings suggest that this gene silencing process could be interrupted to increase the chances that aggressive tumours will respond to treatment.
As cancer develops, it often outstrips its blood supply and receives less oxygen than normal tissue. This low-oxygen environment, called hypoxia, is associated with aggressive tumours of all types that are more likely to progress despite chemotherapy and radiation therapy.
The study, which used colon cancer tissue, found that hypoxia also triggers the silencing of a critical tumour-suppressing gene called MLH1.
The team also identified an enzyme, LSD1 (lysine specific demethylase), associated with MLH1 that could be a target to reverse or block the silencing process. Since LSDI is an enzyme, it is possible to target it with small molecules to inhibit its activity.
“We’ve long known that hypoxic tumours are associated with worse prognoses, but the idea that hypoxic tumours could silence genes was an unexpected finding,” said senior author Dr. Peter M. Glazer, the Robert H. Hunter Professor and chair of therapeutic radiology, and professor of genetics at Yale School of Medicine. “Now that we know how big a role hypoxia plays, we have a new and clinically-relevant path to explore in terms of circumventing this process. The next step is to determine how hypoxia affects other tumor-suppressing genes.”
Yale School of Medicine
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Crohn’s disease research
, /in E-News /by 3wmediaUniversity of Delaware researchers have identified a protein, hiding in plain sight, that acts like a bodyguard to help protect and stabilize another key protein, that when unstable, is involved in Crohn’s disease. The fundamental research points to a possible pathway for developing an effective therapy for the inflammatory bowel disease.
The research was conducted by Catherine Leimkuhler Grimes, assistant professor of chemistry and biochemistry at UD, and Vishnu Mohanan, doctoral student in biological sciences,
As the scientists point out, our immune system provides the first line of defence against invading pathogens, a task even more challenging in the human gut, where over a trillion commensal bacteria live — resident microorganisms that help convert food into protein, vitamins and minerals.
To distinguish “bad” versus “good” bacteria, our bodies rely on a complex network of receptors that can sense patterns that are unique to bacteria, such as small fragments of bacterial cell wall. The receptors recognize and bind to these fragments, triggering an immune response to take out the “bad guys” or control the growth of the “good guys.”
However, when one of these receptors breaks down, or mutates, an abnormal immune response can occur, causing the body to mount an immune response against the “good” bacteria. Chronic inflammatory disorders, such as Crohn’s disease, are hypothesized to arise as a result.
The UD team focused on a protein called NOD2 — nucleotide-binding oligomerisation domain containing protein 2. More than 58 mutations in the NOD2 gene have been linked with various diseases, and 80 percent of these mutations are connected specifically to Crohn’s disease, according to Grimes.
In experiments to unveil NOD2’s signalling mechanisms and where they break down, “we stumbled on this chaperone molecule,” says Mohanan, who was the lead author of the scientific article.
The chaperone molecule was HSP70, which stands for “heat shock protein 70.” It assists with the folding of proteins into their correct three-dimensional shapes, even when cells are under stress from elevated body temperatures, such as a fever.
Grimes said she was a little sceptical at first about pursuing studies with HSP70 because it is a commonly known protein, but she found Mohanan’s initial data intriguing.
“Vishnu found that if we increased the expression level of HSP70, the NOD2 Crohn’s mutants were able to respond to bacterial cell wall fragments. A hallmark of the NOD2 mutations is inability to respond to these fragments. Essentially, Vishnu found a fix for NOD2, and we wanted to determine how we were fixing it.”
In further experiments, Mohanan created a tagged-wild-type NOD2 cell line in which NOD2 levels nearly matched the levels found in nature (versus “super” levels that might stimulate an artificial response) and found that NOD2 became more stabilized and degraded more slowly when treated with HSP70. In fact, HSP70 increased the half-life of NOD2 by more than four hours.
“Basically, HSP70 keeps the protein around — it kind of watches over and protects NOD2, and keeps it from going in the cellular trash can,” Grimes explains.
The researchers tested three human cell lines in their study: kidney cells, colon cells and white blood cells. In the next phase of the study, patient tissue will be examined through a collaboration with Nemours/A.I. duPont Hospital for Children to determine if NOD2 levels can be controlled via HSP70 expression.
“We want to figure out why the mutation in NOD2 results in an increase in inflammation,” says Mohanan. “Right now, we have limited knowledge. Once the signalling mechanism is figured out, we will have the keystone.” University of Delaware
Study identifies molecular key to healthy pregnancy
, /in E-News /by 3wmediaScientists have identified a crucial molecular key to healthy embryo implantation and pregnancy in a study that may offer new clues about the medical challenges of infertility/subfertility, abnormal placentation, and placenta previa.
Multi-institutional teams conducted the study and was led by researchers at Cincinnati Children’s Hospital Medical Center.
The authors found that uterine expression of a gene called Wnt5a – a major signalling molecule in cell growth and movement in both embryo development and disease – is also critical to healthy embryo implantation in the uterus.
The scientists say that molecular signalling from Wnt5a – working in tandem with its co-receptors ROR1 and ROR2 in the uterus – causes uterine implantation chambers (crypts) in mice to form at regular intervals. The signalling also helps direct embryos to migrate in the proper direction as they settle into the womb. The authors show that disruption of appropriate uterine Wnt5a-ROR signalling leads to abnormal uterine luminal epithelial architecture, crypt formation, disorderly spacing of embryos and implantation. These adverse effects led to defective decidualisation, placentation, and ultimately compromised pregnancy outcome.
“Proper implantation is important to healthy pregnancy, and it is not clearly understood what prompts embryos to move and implant within a uterine crypt with regular spacing,” said Sudhansu K. Dey, PhD, senior investigator and director of Division of Reproductive Sciences, Cincinnati Children’s Hospital Medical Center. “If something goes wrong at this stage, there could be adverse effects throughout the course of pregnancy – whether it is subfertility, infertility, restricted growth, miscarriage or preterm birth.”
Although there are similarities and differences between mouse and human implantation, a role for Wnt5a-ROR signalling in embryo spacing could be clinically relevant, Dey said. This is because the embryo can sometimes implant close to or on the cervix (placenta previa), which can cause extensive bleeding and lead to increased mortality or morbidity for the mother and foetus. Aberrant embryo spacing may also contribute to complications in a multiple gestation pregnancy. Cincinnati Children’s Hospital
Researchers find epigenetic tie to neuropsychiatric disorders
, /in E-News /by 3wmediaDysfunction in dopamine signalling profoundly changes the activity level of about 2,000 genes in the brain’s prefrontal cortex and may be an underlying cause of certain complex neuropsychiatric disorders, such as schizophrenia, according to UC Irvine scientists.
This epigenetic alteration of gene activity in brain cells that receive this neurotransmitter showed for the first time that dopamine deficiencies can affect a variety of behavioural and physiological functions regulated in the prefrontal cortex.
The study was led by Emiliana Borrelli, a UCI professor of microbiology & molecular genetics.
“Our work presents new leads to understanding neuropsychiatric disorders,” Borrelli said. “Genes previously linked to schizophrenia seem to be dependent on the controlled release of dopamine at specific locations in the brain. Interestingly, this study shows that altered dopamine levels can modify gene activity through epigenetic mechanisms despite the absence of genetic mutations of the DNA.”
Dopamine is a neurotransmitter that acts within certain brain circuitries to help manage functions ranging from movement to emotion. Changes in the dopaminergic system are correlated with cognitive, motor, hormonal and emotional impairment. Excesses in dopamine signalling, for example, have been identified as a trigger for neuropsychiatric disorder symptoms.
Borrelli and her team wanted to understand what would happen if dopamine signalling was hindered. To do this, they used mice that lacked dopamine receptors in midbrain neurons, which radically affected regulated dopamine synthesis and release.
The researchers discovered that this receptor mutation profoundly altered gene expression in neurons receiving dopamine at distal sites in the brain, specifically in the prefrontal cortex. Borrelli said they observed a remarkable decrease in expression levels of some 2,000 genes in this area, coupled with a widespread increase in modifications of basic DNA proteins called histones – particularly those associated with reduced gene activity.
Borrelli further noted that the dopamine receptor-induced reprogramming led to psychotic-like behaviours in the mutant mice and that prolonged treatment with a dopamine activator restored regular signalling, pointing to one possible therapeutic approach. University of California, Irvine
Age of puberty in girls influenced by which parent their genes are inherited from
, /in E-News /by 3wmediaThe age at which girls reach sexual maturity is influenced by ‘imprinted’ genes, a small sub-set of genes whose activity differs depending on which parent passes on that gene, according to new research.
The findings come from an international study of more than 180,000 women involving scientists from 166 institutions worldwide, including the University of Cambridge. The researchers identified 123 genetic variations that were associated with the timing of when girls experienced their first menstrual cycle by analysing the DNA of 182,416 women of European descent from 57 studies. Six of these variants were found to be clustered within imprinted regions of the genome.
Lead author Dr John Perry at the Medical Research Council (MRC) Epidemiology Unit, University of Cambridge says: “Normally, our inherited physical characteristics reflect a roughly average combination of our parents’ genomes, but imprinted genes place unequal weight on the influence of either the mother’s or the father’s genes. Our findings imply that in a family, one parent may more profoundly affect puberty timing in their daughters than the other parent.”
The activity of imprinted genes differs depending on which parent the gene is inherited from – some genes are only active when inherited from the mother, others are only active when inherited from the father. Both types of imprinted genes were identified as determining puberty timing in girls, indicating a possible biological conflict between the parents over their child’s rate of development. Further evidence for the parental imbalance in inheritance patterns was obtained by analysing the association between these imprinted genes and timing of puberty in a study of over 35,000 women in Iceland, for whom detailed information on their family trees were available.
This is the first time that it has been shown that imprinted genes can control rate of development after birth.
Dr Perry says: “We knew that some imprinted genes control antenatal growth and development – but there is increasing interest in the possibility that imprinted genes may also control childhood maturation and later life outcomes, including disease risks.”
Senior author and paediatrician Dr Ken Ong at the MRC Epidemiology Unit says: “There is a remarkably wide diversity in puberty timing – some girls start at age 8 and others at 13. While lifestyle factors such as nutrition and physical activity do play a role, our findings reveal a wide and complex network of genetic factors. We are studying these factors to understand how early puberty in girls is linked to higher risks of developing diabetes, heart disease and breast cancer in later life – and to hopefully one day break this link.”
Dr Anna Murray, a co-author from the University of Exeter Medical School, adds: “We found that there are hundreds of genes involved in puberty timing, including 29 involved in the production and functioning of hormones, which has increased our knowledge of the biological processes that are involved, in both girls and boys.” University of Cambridge
Common gene variants account for most genetic risk for autism
, /in E-News /by 3wmediaMost of the genetic risk for autism comes from versions of genes that are common in the population rather than from rare variants or spontaneous glitches, researchers funded by the National Institutes of Health have found. Heritability also outweighed other risk factors in this largest study of its kind to date.
About 52 percent of the risk for autism was traced to common and rare inherited variation, with spontaneous mutations contributing a modest 2.6 percent of the total risk.
“Genetic variation likely accounts for roughly 60 percent of the liability for autism, with common variants comprising the bulk of its genetic architecture,” explained Joseph Buxbaum, Ph.D., of the Icahn School of Medicine at Mount Sinai (ISMMS), New York City. “Although each exerts just a tiny effect individually, these common variations in the genetic code add up to substantial impact, taken together.”
Buxbaum, and colleagues of the Population-Based Autism Genetics and Environment Study (PAGES) Consortium, report on their findings in a unique Swedish sample in the journal Nature Genetics, July 20, 2014.
“Thanks to the boost in statistical power that comes with ample sample size, autism geneticists can now detect common as well as rare genetic variation associated with risk,” said Thomas R. Insel, M.D., director of the NIH’s National Institute of Mental Health (NIMH). “Knowing the nature of the genetic risk will reveal clues to the molecular roots of the disorder. Common variation may be more important than we thought.”
Although autism is thought to be caused by an interplay of genetic and other factors, including environmental, consensus on their relative contributions and the outlines of its genetic architecture has remained elusive. Recently, evidence has been mounting that genomes of people with autism are prone to harbouring rare mutations, often spontaneous, that exert strong effects and can largely account for particular cases of disease.
More challenging is to gauge the collective impact on autism risk of numerous variations in the genetic code shared by most people, which are individually much subtler in effect. Limitations of sample size and composition made it difficult to detect these effects and to estimate the relative influence of such common, rare inherited, and rare spontaneous variation.
Differences in methods and statistical models also resulted in sometimes wildly discrepant estimates of autism’s heritability – ranging from 17 to 50 percent. NIH
Manipulation of key protein’s action in the brain holds potential for development of drugs to fight obesity and diabetes
, /in E-News /by 3wmediaA protein that controls when genes are switched on or off plays a key role in specific areas of the brain to regulate metabolism, UT Southwestern Medical Center researchers have found.
The research potentially could lead to new therapies to treat obesity and diabetes, since the transcription factor involved – spliced X-box binding protein 1 (Xbp1s) – appears to influence the body’s sensitivity to insulin and leptin signalling. Insulin and leptin are hormones central to the body’s regulation of food intake and sugar disposal, and obesity and diabetes are conditions under which the body develops resistance to their actions.
“This study identifies critical molecular mechanisms that link the brain and peripheral endocrine tissues and that ultimately contribute to the regulation of body weight and glucose metabolism,” said Dr. Kevin Williams, Assistant Professor of Internal Medicine and co-first author of the study with Dr. Tiemin Liu, a postdoctoral research fellow in Internal Medicine.
Researchers found that over-expression of the gene Xbp1s in mice that were fed a high-fat diet protected them against obesity and diabetes, according to the recent study. On average, these mice were 30 percent leaner than mice fed the same food.
The gene’s actions took place in pro-opiomelanocortin (Pomc) neurons in the hypothalamic region of the brain. Elevated Xbp1s levels in Pomc neurons mimicked a “fed” signal, resulting in improved body weight, decreased blood glucose levels, and improved insulin sensitivity in the liver.
“Manipulating this one gene in the brain affected metabolism in the liver. This result shows that the brain is controlling glucose production by the liver,” said Dr. Joel Elmquist, Director of the Division of Hypothalamic Research, Professor of Internal Medicine, Pharmacology, and Psychiatry, and holder of the Carl H. Westcott Distinguished Chair in Medical Research, and the Maclin Family Distinguished Professorship in Medical Science, in Honor of Dr. Roy A. Brinkley.
Dr. Elmquist was co-senior author of the study, along with Dr. Philipp Scherer, Director of the Touchstone Center for Diabetes Research, Professor of Internal Medicine and Cell Biology, and holder of the Gifford O. Touchstone, Jr. and Randolph G. Touchstone Distinguished Chair in Diabetes Research.
No drug form of Xbp1s currently exists that could be used to test whether the gene is a target for the treatment of diabetes or obesity, though researchers see such a drug as a potential outgrowth of their research. Dr. Williams said other transcription factors involved in the same metabolic pathway will be studied to see if they have similar effects.
“We have studied one transcription factor out of many that participate in a large, complex cellular process,” said Dr. Williams of Xbp1s and its role during times of cellular stress. UT Southwestern Medical Center
Test increases odds of correct surgery for thyroid cancer patients
, /in E-News /by 3wmediaThe routine use of a molecular testing panel developed at UPMC greatly increases the likelihood of performing the correct initial surgery for patients with thyroid nodules and cancer, report researchers from the University of Pittsburgh Cancer Institute (UPCI), partner with UPMC CancerCenter.
The test improved the chances of patients getting the correct initial surgery by 30 percent, according to the study.
“Before this test, about one in five potential thyroid cancer cases couldn’t be diagnosed without an operation to remove a portion of the thyroid,” said lead author Linwah Yip, M.D., assistant professor of surgery in Pitt’s School of Medicine and UPMC surgical oncologist. Previously, “if the portion removed during the first surgery came back positive for cancer, a second surgery was needed to remove the rest of the thyroid. The molecular testing panel now bypasses that initial surgery, allowing us to go right to fully removing the cancer with one initial surgery. This reduces risk and stress to the patient, as well as recovery time and costs.”
Cancer in the thyroid, which is located in the “Adam’s apple” area of the neck, is now the fifth most common cancer diagnosed in women. Thyroid cancer is one of the few cancers that continues to increase in incidence, although the five-year survival rate is 97 percent.
Previously, the most accurate form of testing for thyroid cancer was a fine-needle aspiration biopsy, where a doctor guides a thin needle to the thyroid and removes a small tissue sample for testing. However, in 20 percent of these biopsies, cancer cannot be ruled out. A lobectomy, which is a surgical operation to remove half of the thyroid, is then needed to diagnose or rule-out thyroid cancer. In the case of a postoperative cancer diagnosis, a second surgery is required to remove the rest of the thyroid.
Researchers have identified certain gene mutations that are indicative of an increased likelihood of thyroid cancer, and the molecular testing panel developed at UPMC can be run using the sample collected through the initial, minimally invasive biopsy, rather than a lobectomy. When the panel shows these mutations, a total thyroidectomy is advised.
Dr. Yip and her colleagues followed 671 UPMC patients with suspicious thyroid nodes who received biopsies. Approximately half the biopsy samples were run through the panel, and the other half were not. Patients whose tissue samples were not tested with the panel had a 2.5-fold higher statistically significant likelihood of having an initial lobectomy and then requiring a second operation.
“We’re currently refining the panel by adding tests for more genetic mutations, thereby making it even more accurate,” said co-author Yuri Nikiforov, M.D., Ph.D., professor in the Department of Pathology at Pitt and director of thyroid molecular diagnostics at the UPMC/UPCI Multidisciplinary Thyroid Center. “Thyroid cancer is usually very curable, and we are getting closer to quickly and efficiently identifying and treating all cases of thyroid cancer.” UPMC
Genetic test helps predict which children with kidney disease will respond to standard therapy
, /in E-News /by 3wmediaA genetic screening test may help predict which patients with one of the most common childhood kidney diseases will respond to standard therapies. Using this test could help guide clinicians as they counsel and treat patients.
Sporadic nephrotic syndrome is one of the most common kidney diseases in children, and it can have a genetic cause.
Paola Romagnani, MD, PhD, Sabrina Giglio, MD, PhD (University of Florence and Meyer Children’s Hospital, in Florence, Italy), and their colleagues designed an innovative diagnostic approach that allows for a fast analysis of all genes involved in the disease. Using this method, the team analysed 46 different genes at the same time in 69 children with the disease, and they found that genetic mutations in the kidney’s filtration barrier were frequently linked with a lack of response to immunosuppressive treatments in patients. The genetic test was even more predictive than a kidney biopsy for identifying children who would not benefit from immunosuppressive therapies.
“Thus, this type of genetic analysis can improve the clinical approach to children with nephrotic syndrome by promoting better genetic counselling for the risk of recurrence of the disease in the family, and a better management of treatment and clinical follow up,” said Professor Romagnani.
The application of this new diagnostic approach also improved the speed of clinical diagnoses of the disease and reduced costs. “With a single test, we can help build a truly personalized therapy,” said Professor Giglio. American Society of Nephrology
Your Power for Health
, /in E-News /by 3wmediaIt has been some time in the making, but the newly designed Greiner Bio-One website was finally launched at the beginning of July along with our newly designed webshop.
Product and order information for the business divisions Preanalytics (specimen collection), BioScience (products for the biotech industry), Diagnostics (DNA arrays) and OEM (customised developments for the Life Science industry) can be accessed at www.gbo.com.
The innovative design with cool Parallax Scrolling technology at various levels is not the only thing that is new. Alongside the range of improvements, there are also a number of technical innovations, making it even easier to find the information you are looking for.
Features include:
can now also be accessed via links
Greiner Bio-One International AG
Greiner Bio-One is specialized in the development, production and distribution of high quality laboratory products made from plastic. The company is a technological partner for hospitals, laboratories, universities, research institutes and the diagnostic, pharmaceutical and biotechnology industries. Greiner Bio-One consists of four business units: Preanalytics, BioScience, Diagnostics and OEM. Today the company generates a turnover of 373 Mio. Euro. Greiner Bio-One is a member of the Greiner Group based in Kremsmünster (Austria).
Study finds some aggressive tumours silence genes that fight cancer
, /in E-News /by 3wmediaA study led by Yale Cancer Center may provide clues to how some aggressive cancers turn off, or silence, genes critical to suppressing tumours. The findings suggest that this gene silencing process could be interrupted to increase the chances that aggressive tumours will respond to treatment.
As cancer develops, it often outstrips its blood supply and receives less oxygen than normal tissue. This low-oxygen environment, called hypoxia, is associated with aggressive tumours of all types that are more likely to progress despite chemotherapy and radiation therapy.
The study, which used colon cancer tissue, found that hypoxia also triggers the silencing of a critical tumour-suppressing gene called MLH1.
The team also identified an enzyme, LSD1 (lysine specific demethylase), associated with MLH1 that could be a target to reverse or block the silencing process. Since LSDI is an enzyme, it is possible to target it with small molecules to inhibit its activity.
“We’ve long known that hypoxic tumours are associated with worse prognoses, but the idea that hypoxic tumours could silence genes was an unexpected finding,” said senior author Dr. Peter M. Glazer, the Robert H. Hunter Professor and chair of therapeutic radiology, and professor of genetics at Yale School of Medicine. “Now that we know how big a role hypoxia plays, we have a new and clinically-relevant path to explore in terms of circumventing this process. The next step is to determine how hypoxia affects other tumor-suppressing genes.” Yale School of Medicine