Researchers at Brigham and Women’s Hospital have found two new potential drug targets for treating arterial diseases such as atherosclerosis. By using proteomics to screen a vast number of molecules, the researchers identified PARP9 and PARP14 – two members of the PARP family of proteins – as regulators of macrophage activation, which has been linked to arterial disease by systems biology.
Though the mechanisms that activate macrophages, a type of digestive white blood cell that targets foreign cells, remain incompletely understood, previous research shows that macrophages play an important role in the development of atherosclerosis and its thrombotic complications. Masanori Aikawa, MD, PhD, director of the Center for Interdisciplinary Cardiovascular Sciences (CICS) at the Brigham, his research fellow Hiroshi Iwata, MD, PhD, and colleagues studied atherosclerosis on the protein-level to determine which molecules were most involved in the regulation of macrophages.
Once Aikawa and his colleagues narrowed down their search to these two proteins, they silenced each gene in cultured macrophages and found that tamping down PARP14 increased macrophage activation while tamping down PARP9 had the opposite effect.
Aikawa founded CICS and hopes that this hypothesis-generating method can be used to streamline the lengthy process of drug development. Aikawa and CICS are using a more systematic approach which hinges on network analysis; this analysis predicts which pathways are most likely to control their studied effect so that they can prioritize these pathways. Ideally, this process would take a fraction of the time in comparison to searching through each individual pathway unaware of their likelihood of affecting their studied effect.
Aikawa and his colleagues plan to augment these findings to develop targeted therapeutics for atherosclerosis and other diseases.
‘Macrophage activation plays a role in not only vascular disorders but also various inflammatory and autoimmune diseases,’ said Aikawa. ‘These results could provide important information about the mechanisms of these diseases and help to develop much needed new therapeutics.’
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:33:212021-01-08 11:09:53Activation of 2 genes linked to development of atherosclerosis
Children diagnosed with autism spectrum disorder (ASD) have greater numbers of harmful mutations in their mitochondrial DNA than family members, report Zhenglong Gu of Cornell University in Ithaca, New York, and colleagues, in a study.
Increasingly, studies point to malfunctions in mitochondria — the powerhouses of the cell — as a cause of autism spectrum disorder, but the biological basis for this relationship is unclear. To see if a genetic link exists between mitochondrial malfunction and ASD, the scientists analysed mitochondrial DNA sequences from 903 children with ASD, along with their unaffected siblings and mothers. They discovered a unique pattern of heteroplasmic mutations, where both mutant and normal mitochondrial DNA sequences exist in a single cell. Children with ASD had more than twice as many potentially harmful mutations compared to unaffected siblings, and 1.5 times as many mutations that would alter the resulting protein. The researchers went on to show that these mutations can be inherited from the mother, or the result of spontaneous mutation during development.
The scientists noted that the risk associated with these mutations is most pronounced in children with lower IQ and poor social behaviour compared to their unaffected siblings. Carrying harmful mutations in mitochondrial DNA is also associated with increased risk of neurological and developmental problems among children with ASD. Because mitochondria play a central role in metabolism, these findings may help explain the metabolic disorders commonly associated with ASD and other neurodevelopmental disorders. Evaluating mutations in the mitochondrial DNA of high-risk families could help improve the diagnosis and treatment of these diseases.
Zhenglong Gu says ‘The result of our study synergizes with recent work on ASD, calling attention to children diagnosed with ASD who have one or more developmental abnormalities or related co-morbid clinical conditions for further testing on mitochondrial DNA and mitochondrial function. Since many neurodevelopmental disorders and related childhood disorders show abnormalities that converge upon mitochondrial dysfunction, and may have mtDNA defects as a common harbinger, future research is needed to elucidate the mitochondrial mechanisms underpinning to these diseases. Ultimately, understanding the energetic aspects of neurodevelopmental disorders may lead to entirely new kinds of treatments, and preventative strategies that would target mitochondria.’
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:33:212021-01-08 11:09:53Autism spectrum disorder linked to mutations in some mitochondrial DNA
Two gene mutations that trigger a retinal disease that causes blindness in one in 5,000 males have been mapped, leading to the potential for new therapeutic treatments.
Researchers from The University of Manchester undertook a structural analysis of X-linked Retinoschisis (XLRS), a genetic disease leading to a type of macular degeneration in which the inner layers of the retina split causing severe loss of vision and gradual blindness. Currently, there is no effective treatment for XLRS, with research focused on understanding how the disease occurs in the retina.
XLRS is caused by mutations in the retinal protein retinoschisin. The protein plays a crucial role in the cellular organisation of the retina, assembling itself to form paired octameric (consisting of eight retinoschisin) rings. The rings each resemble an 8-bladed propeller. This new structural insight yielded important clues into how retinoschisin performs its crucial role in the retina and spurred efforts to investigate what happens to this structure when it is mutated in XLRS.
Using a cryo-electron microscope, the team examined the paired rings as well as the effects on the rings of two XLRS-causing mutations. The effects of these mutations, despite being reported to cause the disease, were unknown and may offer explanations on how the normal protein functions in the retina.
Clair Baldock, Professor of Biochemistry at The University of Manchester and lead author of the research team’s resulting paper, said the cryo-electron microscopy allowed them to identify the location of the mutations on the rings.
“We found that one disease-causing mutation sits in the interface between the octamer rings, causing retinoschisin to be less stable. The other mutation is on the propeller tip which we think is a novel interaction site for other binding proteins in the retina.”
As well as identifying the mutations and precisely mapping their locations, the research team held out the possibility that future work could lead to genetic interventions and treatments, which could limit or prevent the damage caused by XLRS.
“XLRS is a promising candidate for gene therapy, so our findings on these two different classes of mutations will be informative for future therapeutic strategies,” concluded Professor Baldock.
University of Manchesterwww.manchester.ac.uk/discover/news/genetic-mutations-that-lead-to-macular-degeneration-blindness-mapped-by-new-research/
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Some people adapt easily to shift work, but not everyone can handle constant disruptions to their daily rhythm. Finnish researchers have now found that a melatonin receptor gene influences tolerance to shift work. The new study is the first time the genetic factors underlying poor tolerance to shift work were systematically examined. Covering the entire genome, the study discovered that a common variation in the melatonin receptor 1A (MTNR1A) gene is linked to the job-related exhaustion experienced by shift workers.
Shift work often disrupts the circadian rhythm, which can lead to sleep disorders and daytime fatigue.
The study was led by Professor Tiina Paunio, and involved Finnish shift workers from many different lines of work. The differences in the job-related exhaustion reported by employees were contrasted with genetic differences in their entire genome.
The link to the melatonin receptor gene was discovered in a group of 176 shift workers included in the national Health 2000 survey. The connection was also found in a group of 577 shift workers covering rest of the shift workers from the Health 2000 survey as well as shift workers in care work and aviation.
The study also established that the risk variation of the melatonin receptor 1A (MTNR1A) gene is probably related to the methylation of DNA in the regulatory sequence of the MTNR1A gene as well as the weaker expression of the MTNR1A gene. The methylation of DNA is one of the epigenetic mechanisms regulating the functioning of the genome, influenced by not only by variations in DNA sequence, but also environmental factors such as fluctuations in the circadian rhythm.
As it results in a smaller number of melatonin receptors, the risk variant of the gene can cause weaker natural melatonin signalling, one of the regulatory mechanisms in stabilising the circadian rhythm.
The influence of the risk variant of the MTNR1A gene may explain the degree to which light exposure at night disrupts the circadian rhythm of shift workers. “The variant we have now discovered can only explain a small part of the variation between individuals, and it cannot be used as a basis to determine a person’s tolerance to shift work,” Paunio points out.
University of Helsinkiwww.helsinki.fi/en/news/genetic-cause-for-shift-work-fatigue-discovered
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The latest developments in prenatal technology conceived by scientists at the Wayne State University School of Medicine that make it possible to test for genetic disorders a little more than one month into pregnancy were revealed. In the article, the WSU researchers wrote that their non-invasive testing method – Trophoblast Retrieval and Isolation from the Cervix (TRIC) – offers the accuracy of more invasive tests, such as the needle-directed amniocentesis, and can also be utilized five to 10 weeks earlier than current testing modalities. TRIC was first publicized in 2014 in studies led by principal investigator and Professor of Obstetrics and Gynecology D. Randall Armant, Ph.D. The method isolates several hundred foetal cells that migrate from the placenta into the uterus using a retrieval technique akin to the common Pap smear, and can be done as early as five weeks into pregnancy. Armant’s co-principal investigator in the latest research is Associate Professor of Obstetrics and Gynecology Sascha Drewlo, Ph.D., who joined the team in 2014 to provide expertise in molecular biology and perinatal medicine.
A related paper published by the two “Altered Biomarkers in Trophoblast Cells Obtained Noninvasively Prior to Clinical Manifestation of Perinatal Disease,” describes the correlation between the levels of certain proteins in the foetal cells isolated by TRIC during the first trimester and the development of intrauterine growth restriction, which results in a small, undernourished foetus in the womb, or preeclampsia – hypertension and kidney disorder of the mother – in the last trimester.
“This finding suggests that it might one day be possible to test these protein levels to identify pregnancies at risk for complications. Such a test could help physicians to better manage the health of mother and baby, and would streamline research on new interventions to prevent or limit the effects of disease,” Armant said.
The paper demonstrates the researchers’ ability to isolate foetal DNA from the cells obtained by TRIC. Since the placenta is derived from the embryo and its DNA is the same as that of the foetus, the researchers can use cells obtained by TRIC for prenatal genetic testing. The paper was co-first authored by Chandni Jain, Ph.D., and Leena Kadam, working in the laboratories of Armant and Drewlo. “We sequenced the foetal DNA and compared it to that of the mothers, proving that they were different, but the foetal DNA always contained one copy of the mother’s DNA genes. We also had some DNA from the placenta and found that it was identical to the foetal DNA,” Armant said.
The sequencing was completed in 20 consecutive pregnancies collected at five to 19 weeks, with minimal maternal DNA contamination.
Wayne State Universityresearch.wayne.edu/news/studies-reveal-wsu-conceived-non-invasive-prenatal-genetic-test-is-accurate-five-weeks-into-pregnancy-21140
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Alzheimer’s disease is characterized by two types of cerebral lesion: amyloid plaques and neurofibrillary tangles. Amyloid beta peptide (Aβ), naturally present in the brain, builds up over the years as a result of genetic and environmental factors until it forms amyloid plaques. This build-up is toxic for nerve cells: it leads to a loss of neuronal structure and to what is known as ‘neurofibrillary’ tangles (abnormal aggregation of the tau protein), which in turn results in cell death.
In this study, the team led by Pierre Lafaye, Head of the Antibody Engineering Platform in the Citech at the Institut Pasteur, in collaboration with the Chemistry of Biomolecules and Integrative Neurobiology of Cholinergic Systems Units from the Institut Pasteur and the CNRS, developed two new types of antibody capable of detecting the extracellular and intracellular targets (respectively amyloid plaques and neurofibrillary tangles) that are characteristic of Alzheimer’s disease. To achieve this, they turned their attention to camelids, specifically llamas, since their small antibodies are easy to use. They used the variable region of the antibody, known as VHH or nanobodiesTM, to specifically recognize the markers of Alzheimer’s.
These antibodies have the rare ability to cross the blood-brain barrier, which generally protects the brain from microbial attacks but also prevents potential therapeutic molecules from reaching it.
This collaborative research project, jointly conducted by scientists from the Institut Pasteur, Inserm, the CNRS, the CEA, Pierre & Marie Curie and Paris Descartes Universities and the Roche Group, led to the development of anti-Aβ and anti-tau protein antibodies that specifically detect amyloid plaques and neurofibrillary tangles. These antibodies were subsequently tested in vitro on the brain tissue of Alzheimer’s patients.
The antibodies were then tested in vivo in two mouse models, each with one of the two characteristic lesions associated with Alzheimer’s disease. These antibodies, labelled with a green fluorochrome, were injected intravenously and crossed the blood-brain barrier, binding to the two targets the scientists were aiming to identify: amyloid plaques and neurofibrillary tangles. This made the signs of the disease visible in the brain using two-photon microscopy. The scientists involved in this collaborative project are currently working on the development of an MRI imaging technique to observe the lesions. In the long term this could be applied to humans.
‘Being able to diagnose Alzheimer’s at an early stage could enable us to test treatments before the emergence of symptoms, something we were previously unable to do,’ explained Pierre Lafaye. These VHH antibodies could be used in combination with therapeutic molecules so that the molecules can be delivered in a targeted way to the brain.
A frontline malaria treatment that combines fast-acting dihydroartemisinin with long-lasting piperaquine is quickly losing power in Cambodia due to the rapid spread of drug-resistant parasites. The presence of piperaquine-resistant malaria parasites in several Cambodian provinces was confirmed earlier this year by National Institutes of Health researchers and their colleagues. Now, by comparing the complete genomes of 297 parasites isolated from Cambodian malaria patients to a reference malaria parasite genome, the team has identified two genetic markers that are strongly associated with the parasites’ ability to resist piperaquine.
A simple test, performed after collecting blood from a finger pinprick, can show whether a malaria patient has parasites with the genetic markers. If so, dihydroartemisinin-piperaquine therapy is likely to fail, say the study authors, and an alternative drug combination (artesunate-mefloquine) should be used. Information about the distribution of these drug resistance markers is being used by officials in Cambodia and neighbouring countries to map the extent and spread of piperaquine resistance and to help guide region-wide malaria treatment approaches.
National Institute of Allergy and Infectious Diseases (NIAID) scientist Rick Fairhurst, M.D., Ph.D., and Roberto Amato, Ph.D., of the Wellcome Trust Sanger Institute (WTSI), Cambridge, UK, led the research team. The first marker they identified is a change of one subunit in a gene on the parasite’s chromosome 13. Parasites with this genetic change are much more likely to be resistant to piperaquine than parasites without it. The marker, while associated with drug resistance, likely does not play a functional role in enabling parasites to resist piperaquine, according to the researchers. In contrast, the second resistance marker identified by the investigators may have such a role. That marker is an increased number of copies of two genes (plasmepsin II and plasmepsin III) in those parasites that resist piperaquine. Malaria parasites use plasmepsins to help them digest human blood and, although the exact mechanism of action of piperaquine is not known, it is believed that the drug targets plasmepsins.
Parasites may react to piperaquine by increasing plasmepsin production, and any parasites with extra copies of the plasmepsin II and III genes may be better able to withstand piperaquine treatment. Of note, parasites with increased piperaquine resistance appear to have increased susceptibility to the malaria drug mefloquine. This observation hints at the possibility of devising malaria treatment regimens that combine three or more drugs to exploit opposing resistance-susceptibility attributes.
National Institute of Healthwww.niaid.nih.gov/news-events/two-genetic-markers-predict-malaria-treatment-failure-found
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A new bioinformatic framework developed by researchers at University of California San Diego School of Medicine has identified key proteins significantly altered at the gene-expression level in biopsied tissue from patients with diabetic kidney disease, a result that may reveal new therapeutic targets.
In a recently published paper, researchers, led by Kumar Sharma, MD, professor of medicine at UC San Diego School of Medicine, revealed that the protein MDM2 was consistently down-regulated and played a key role in diabetic kidney disease progression. The researchers used the new “MetBridge Generator” bioinformatics framework to identify the relevant enzymes and bridge proteins that link human metabolomics data to the pathophysiology of diabetic kidney disease at a molecular level.
“MetBridge Generator allows for efficient, focused analysis of urine metabolomics data from patients with diabetic kidney disease, providing researchers an opportunity to develop new hypotheses based on the possible cellular or physiological role of key proteins,” said Sharma, senior author and director of the Institute for Metabolomic Medicine and the Center for Renal Translational Medicine at UC San Diego School of Medicine. “The framework may also be used in the interpretation of other metabolomic signatures from a variety of diseases. For example, MDM2 is also involved in regulating tumour protein p53, which is a target for cancer treatments.”
In a previous study, the authors identified 13 metabolites that were found to be altered in patients with diabetic kidney disease. Combining this information and publicly available data on metabolic pathways, the researchers tested an hypothesis that some proteins act as bridges creating less well-defined pathways. The framework then created a map of metabolic and protein-protein interaction (PPI) networks. This allowed the team to look deeper into relevant bridges with the greatest number of interactions with enzymes that regulate the 13-metabolite signature of diabetic kidney disease.
The authors already identified protein-RNA interactions as possible sources for additional key pathways underlying disease progression that could be added to the MetBridge Generator network. This growth will continue to add to possible therapeutic targets for disease treatment.
University of California – San Diego
ucsdnews.ucsd.edu/pressrelease/new_bioinformatic_analysis_reveals_role_of_proteins_in_diabetic_kidney_dise
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Bacteria in your intestines may play an important role in determining if you will develop blinding wet Age-related Macular Degeneration (AMD).
Age-related Macular Degeneration (AMD) is the leading cause of irreversible blindness in the industrialized world, affecting over 10 million individuals in North America. A study lead by Dr. Przemyslaw (Mike) Sapieha, researcher at Hôpital Maisonneuve-Rosemont (CIUSSS de l’Est-de-l’Île-de-Montréal) and professor at the University of Montreal, uncovered that bacteria in your intestines may play an important role in determining if you will develop blinding wet AMD.
AMD is characterized by a heightened immune response, sizeable deposits of fat debris at the back of the eye called soft drusen (early AMD), destruction of nerve cells, and growth of new diseased blood vessels (wet AMD, late form). While only accounting for roughly 10% of cases of AMD, wet AMD is the primary form leading to blindness. Current treatments becomes less effective with time. It is therefore important to find new ways to prevent the onset of this debilitating disease.
While many studies on the genetics of AMD have identified several genes that predispose to AMD, no single gene can account for development of the disease. Epidemiological data suggests that in men, overall abdominal obesity is the second most important environmental risk factor, after smoking, for progression to late-stage blinding AMD. Until now, the mechanisms that underscore this observation remained ill defined. Elisabeth Andriessen, a PhD student in the lab of Professor Sapieha found that changes in the bacterial communities of your gut, such as those brought on by a diet rich in fat, can cause long-term low-grade inflammation in your whole body and eventually promote diseases such as wet AMD. Among the series of experiments conducted as part of this study, the group performed fecal transfers from mice receiving regular fat diets, compared to those receiving a high fat diet, and found a significant amelioration of wet AMD.
“Our study suggests that diets rich in fat alter the gut microbiome in a way that aggravates wet AMD, a vascular disease of the aging eye. Influencing the types of microbes that reside in your gut either through diet or by other means may thus affect the chances of developing AMD and progression of this blinding disease”, says Dr Sapieha. Professor Sapieha holds the Wolfe Professorship in Translational Vision Research and a Canada Research Chair in retinal cell biology.
University of Montreal
nouvelles.umontreal.ca/en/article/2016/11/15/microbes-in-your-gut-influence-major-eye-disease/
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Researchers have identified a new pathway and with it a protein, BRD4, necessary for breast cancer cells to spread.
The findings may provide a new target to suppress breast cancer metastasis.
Triple-negative breast cancer is considered the worst subgroup of breast cancer. It is highly aggressive and responds poorly to the current therapeutic tools resulting in a dismal prognosis for patients. Furthermore, the lack of identified targets has limited the development of new drug strategies.
Researchers from Boston University School of Medicine (BUSM) used breast cancer cell lines that present the clinical characteristics of an aggressive breast cancer subtype (clinically described as a triple-negative breast cancer). They then used an experimental design to model cancer cell metastasis. By suppressing the expression of the protein BRD4 in these cell lines, they observed that their dissemination capabilities were blocked, indicating that BRD4 drives breast cancer dissemination. In addition, they conducted a screening analysis of human breast tumours and found that tumours with a high expression of BRD4 were more likely to metastasize.
“The current treatment options for a triple-negative cancer are unacceptably limited. It is crucial to identify new therapeutic targets to tackle challenging cancer types, including triple negative breast cancer. BDR4 targeting represents an innovative strategy to ablate breast cancer metastasis,” explained lead investigator Guillaume Andrieu, PhD, a post-doctoral research associate at Boston University School of Medicine.
Although obesity per se is not thought of as a carcinogen, the abnormal, inflamed microenvironments found in obesity are critical for progression, invasion and metastasis of triple negative breast cancer. “Bromodomain and ExtraTerminal domain (BET) proteins, which include BRD2, BRD3 and BRD4, are known to regulate production of inflammatory mediators. Our study proposes that BRD4 couples inflammation to breast cancer dissemination. Thus, small molecules that block BET proteins possess anti-inflammatory properties that can be useful for therapy,” he added.
Although these findings primarily focus on breast cancer and metastasis, the researchers plan to expand their results to the treatment of prostate cancer, which they believe has similar pathways involved in its metastasis.
Boston University Medial Center
www.bu.edu/news/2016/11/15/researchers-identify-protein-required-for-breast-cancer-metastasis/
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Activation of 2 genes linked to development of atherosclerosis
, /in E-News /by 3wmediaResearchers at Brigham and Women’s Hospital have found two new potential drug targets for treating arterial diseases such as atherosclerosis. By using proteomics to screen a vast number of molecules, the researchers identified PARP9 and PARP14 – two members of the PARP family of proteins – as regulators of macrophage activation, which has been linked to arterial disease by systems biology.
Though the mechanisms that activate macrophages, a type of digestive white blood cell that targets foreign cells, remain incompletely understood, previous research shows that macrophages play an important role in the development of atherosclerosis and its thrombotic complications. Masanori Aikawa, MD, PhD, director of the Center for Interdisciplinary Cardiovascular Sciences (CICS) at the Brigham, his research fellow Hiroshi Iwata, MD, PhD, and colleagues studied atherosclerosis on the protein-level to determine which molecules were most involved in the regulation of macrophages.
Once Aikawa and his colleagues narrowed down their search to these two proteins, they silenced each gene in cultured macrophages and found that tamping down PARP14 increased macrophage activation while tamping down PARP9 had the opposite effect.
Aikawa founded CICS and hopes that this hypothesis-generating method can be used to streamline the lengthy process of drug development. Aikawa and CICS are using a more systematic approach which hinges on network analysis; this analysis predicts which pathways are most likely to control their studied effect so that they can prioritize these pathways. Ideally, this process would take a fraction of the time in comparison to searching through each individual pathway unaware of their likelihood of affecting their studied effect.
Aikawa and his colleagues plan to augment these findings to develop targeted therapeutics for atherosclerosis and other diseases.
‘Macrophage activation plays a role in not only vascular disorders but also various inflammatory and autoimmune diseases,’ said Aikawa. ‘These results could provide important information about the mechanisms of these diseases and help to develop much needed new therapeutics.’
EurekAlert www.eurekalert.org/pub_releases/2016-10/bawh-aot102516.php
Autism spectrum disorder linked to mutations in some mitochondrial DNA
, /in E-News /by 3wmediaChildren diagnosed with autism spectrum disorder (ASD) have greater numbers of harmful mutations in their mitochondrial DNA than family members, report Zhenglong Gu of Cornell University in Ithaca, New York, and colleagues, in a study.
Increasingly, studies point to malfunctions in mitochondria — the powerhouses of the cell — as a cause of autism spectrum disorder, but the biological basis for this relationship is unclear. To see if a genetic link exists between mitochondrial malfunction and ASD, the scientists analysed mitochondrial DNA sequences from 903 children with ASD, along with their unaffected siblings and mothers. They discovered a unique pattern of heteroplasmic mutations, where both mutant and normal mitochondrial DNA sequences exist in a single cell. Children with ASD had more than twice as many potentially harmful mutations compared to unaffected siblings, and 1.5 times as many mutations that would alter the resulting protein. The researchers went on to show that these mutations can be inherited from the mother, or the result of spontaneous mutation during development.
The scientists noted that the risk associated with these mutations is most pronounced in children with lower IQ and poor social behaviour compared to their unaffected siblings. Carrying harmful mutations in mitochondrial DNA is also associated with increased risk of neurological and developmental problems among children with ASD. Because mitochondria play a central role in metabolism, these findings may help explain the metabolic disorders commonly associated with ASD and other neurodevelopmental disorders. Evaluating mutations in the mitochondrial DNA of high-risk families could help improve the diagnosis and treatment of these diseases.
Zhenglong Gu says ‘The result of our study synergizes with recent work on ASD, calling attention to children diagnosed with ASD who have one or more developmental abnormalities or related co-morbid clinical conditions for further testing on mitochondrial DNA and mitochondrial function. Since many neurodevelopmental disorders and related childhood disorders show abnormalities that converge upon mitochondrial dysfunction, and may have mtDNA defects as a common harbinger, future research is needed to elucidate the mitochondrial mechanisms underpinning to these diseases. Ultimately, understanding the energetic aspects of neurodevelopmental disorders may lead to entirely new kinds of treatments, and preventative strategies that would target mitochondria.’
ScienceDaily www.sciencedaily.com/releases/2016/10/161028161729.htm
Genetic mutations that lead to macular degeneration blindness mapped
, /in E-News /by 3wmediaTwo gene mutations that trigger a retinal disease that causes blindness in one in 5,000 males have been mapped, leading to the potential for new therapeutic treatments.
Researchers from The University of Manchester undertook a structural analysis of X-linked Retinoschisis (XLRS), a genetic disease leading to a type of macular degeneration in which the inner layers of the retina split causing severe loss of vision and gradual blindness. Currently, there is no effective treatment for XLRS, with research focused on understanding how the disease occurs in the retina.
XLRS is caused by mutations in the retinal protein retinoschisin. The protein plays a crucial role in the cellular organisation of the retina, assembling itself to form paired octameric (consisting of eight retinoschisin) rings. The rings each resemble an 8-bladed propeller. This new structural insight yielded important clues into how retinoschisin performs its crucial role in the retina and spurred efforts to investigate what happens to this structure when it is mutated in XLRS.
Using a cryo-electron microscope, the team examined the paired rings as well as the effects on the rings of two XLRS-causing mutations. The effects of these mutations, despite being reported to cause the disease, were unknown and may offer explanations on how the normal protein functions in the retina.
Clair Baldock, Professor of Biochemistry at The University of Manchester and lead author of the research team’s resulting paper, said the cryo-electron microscopy allowed them to identify the location of the mutations on the rings.
“We found that one disease-causing mutation sits in the interface between the octamer rings, causing retinoschisin to be less stable. The other mutation is on the propeller tip which we think is a novel interaction site for other binding proteins in the retina.”
As well as identifying the mutations and precisely mapping their locations, the research team held out the possibility that future work could lead to genetic interventions and treatments, which could limit or prevent the damage caused by XLRS.
“XLRS is a promising candidate for gene therapy, so our findings on these two different classes of mutations will be informative for future therapeutic strategies,” concluded Professor Baldock.
University of Manchesterwww.manchester.ac.uk/discover/news/genetic-mutations-that-lead-to-macular-degeneration-blindness-mapped-by-new-research/
Genetic cause for shift work fatigue discovered
, /in E-News /by 3wmediaSome people adapt easily to shift work, but not everyone can handle constant disruptions to their daily rhythm. Finnish researchers have now found that a melatonin receptor gene influences tolerance to shift work.
The new study is the first time the genetic factors underlying poor tolerance to shift work were systematically examined. Covering the entire genome, the study discovered that a common variation in the melatonin receptor 1A (MTNR1A) gene is linked to the job-related exhaustion experienced by shift workers.
Shift work often disrupts the circadian rhythm, which can lead to sleep disorders and daytime fatigue.
The study was led by Professor Tiina Paunio, and involved Finnish shift workers from many different lines of work. The differences in the job-related exhaustion reported by employees were contrasted with genetic differences in their entire genome.
The link to the melatonin receptor gene was discovered in a group of 176 shift workers included in the national Health 2000 survey. The connection was also found in a group of 577 shift workers covering rest of the shift workers from the Health 2000 survey as well as shift workers in care work and aviation.
The study also established that the risk variation of the melatonin receptor 1A (MTNR1A) gene is probably related to the methylation of DNA in the regulatory sequence of the MTNR1A gene as well as the weaker expression of the MTNR1A gene. The methylation of DNA is one of the epigenetic mechanisms regulating the functioning of the genome, influenced by not only by variations in DNA sequence, but also environmental factors such as fluctuations in the circadian rhythm.
As it results in a smaller number of melatonin receptors, the risk variant of the gene can cause weaker natural melatonin signalling, one of the regulatory mechanisms in stabilising the circadian rhythm.
The influence of the risk variant of the MTNR1A gene may explain the degree to which light exposure at night disrupts the circadian rhythm of shift workers. “The variant we have now discovered can only explain a small part of the variation between individuals, and it cannot be used as a basis to determine a person’s tolerance to shift work,” Paunio points out.
University of Helsinkiwww.helsinki.fi/en/news/genetic-cause-for-shift-work-fatigue-discovered
Non-invasive prenatal genetic test is accurate five weeks into pregnancy
, /in E-News /by 3wmediaThe latest developments in prenatal technology conceived by scientists at the Wayne State University School of Medicine that make it possible to test for genetic disorders a little more than one month into pregnancy were revealed.
In the article, the WSU researchers wrote that their non-invasive testing method – Trophoblast Retrieval and Isolation from the Cervix (TRIC) – offers the accuracy of more invasive tests, such as the needle-directed amniocentesis, and can also be utilized five to 10 weeks earlier than current testing modalities.
TRIC was first publicized in 2014 in studies led by principal investigator and Professor of Obstetrics and Gynecology D. Randall Armant, Ph.D. The method isolates several hundred foetal cells that migrate from the placenta into the uterus using a retrieval technique akin to the common Pap smear, and can be done as early as five weeks into pregnancy.
Armant’s co-principal investigator in the latest research is Associate Professor of Obstetrics and Gynecology Sascha Drewlo, Ph.D., who joined the team in 2014 to provide expertise in molecular biology and perinatal medicine.
A related paper published by the two “Altered Biomarkers in Trophoblast Cells Obtained Noninvasively Prior to Clinical Manifestation of Perinatal Disease,” describes the correlation between the levels of certain proteins in the foetal cells isolated by TRIC during the first trimester and the development of intrauterine growth restriction, which results in a small, undernourished foetus in the womb, or preeclampsia – hypertension and kidney disorder of the mother – in the last trimester.
“This finding suggests that it might one day be possible to test these protein levels to identify pregnancies at risk for complications. Such a test could help physicians to better manage the health of mother and baby, and would streamline research on new interventions to prevent or limit the effects of disease,” Armant said.
The paper demonstrates the researchers’ ability to isolate foetal DNA from the cells obtained by TRIC. Since the placenta is derived from the embryo and its DNA is the same as that of the foetus, the researchers can use cells obtained by TRIC for prenatal genetic testing. The paper was co-first authored by Chandni Jain, Ph.D., and Leena Kadam, working in the laboratories of Armant and Drewlo.
“We sequenced the foetal DNA and compared it to that of the mothers, proving that they were different, but the foetal DNA always contained one copy of the mother’s DNA genes. We also had some DNA from the placenta and found that it was identical to the foetal DNA,” Armant said.
The sequencing was completed in 20 consecutive pregnancies collected at five to 19 weeks, with minimal maternal DNA contamination.
Wayne State Universityresearch.wayne.edu/news/studies-reveal-wsu-conceived-non-invasive-prenatal-genetic-test-is-accurate-five-weeks-into-pregnancy-21140
Diagnosis of Alzheimer’s disease: llama antibodies detect cerebral lesions
, /in E-News /by 3wmediaAlzheimer’s disease is characterized by two types of cerebral lesion: amyloid plaques and neurofibrillary tangles. Amyloid beta peptide (Aβ), naturally present in the brain, builds up over the years as a result of genetic and environmental factors until it forms amyloid plaques. This build-up is toxic for nerve cells: it leads to a loss of neuronal structure and to what is known as ‘neurofibrillary’ tangles (abnormal aggregation of the tau protein), which in turn results in cell death.
In this study, the team led by Pierre Lafaye, Head of the Antibody Engineering Platform in the Citech at the Institut Pasteur, in collaboration with the Chemistry of Biomolecules and Integrative Neurobiology of Cholinergic Systems Units from the Institut Pasteur and the CNRS, developed two new types of antibody capable of detecting the extracellular and intracellular targets (respectively amyloid plaques and neurofibrillary tangles) that are characteristic of Alzheimer’s disease. To achieve this, they turned their attention to camelids, specifically llamas, since their small antibodies are easy to use. They used the variable region of the antibody, known as VHH or nanobodiesTM, to specifically recognize the markers of Alzheimer’s.
These antibodies have the rare ability to cross the blood-brain barrier, which generally protects the brain from microbial attacks but also prevents potential therapeutic molecules from reaching it.
This collaborative research project, jointly conducted by scientists from the Institut Pasteur, Inserm, the CNRS, the CEA, Pierre & Marie Curie and Paris Descartes Universities and the Roche Group, led to the development of anti-Aβ and anti-tau protein antibodies that specifically detect amyloid plaques and neurofibrillary tangles. These antibodies were subsequently tested in vitro on the brain tissue of Alzheimer’s patients.
The antibodies were then tested in vivo in two mouse models, each with one of the two characteristic lesions associated with Alzheimer’s disease. These antibodies, labelled with a green fluorochrome, were injected intravenously and crossed the blood-brain barrier, binding to the two targets the scientists were aiming to identify: amyloid plaques and neurofibrillary tangles. This made the signs of the disease visible in the brain using two-photon microscopy. The scientists involved in this collaborative project are currently working on the development of an MRI imaging technique to observe the lesions. In the long term this could be applied to humans.
‘Being able to diagnose Alzheimer’s at an early stage could enable us to test treatments before the emergence of symptoms, something we were previously unable to do,’ explained Pierre Lafaye. These VHH antibodies could be used in combination with therapeutic molecules so that the molecules can be delivered in a targeted way to the brain.
Institut Pasteurwww.pasteur.fr/en/institut-pasteur/press/press-documents/diagnosis-alzheimer-s-disease-llama-antibodies-detect-cerebral-lesions
Two genetic markers that predict malaria treatment failure found
, /in E-News /by 3wmediaA frontline malaria treatment that combines fast-acting dihydroartemisinin with long-lasting piperaquine is quickly losing power in Cambodia due to the rapid spread of drug-resistant parasites. The presence of piperaquine-resistant malaria parasites in several Cambodian provinces was confirmed earlier this year by National Institutes of Health researchers and their colleagues. Now, by comparing the complete genomes of 297 parasites isolated from Cambodian malaria patients to a reference malaria parasite genome, the team has identified two genetic markers that are strongly associated with the parasites’ ability to resist piperaquine.
A simple test, performed after collecting blood from a finger pinprick, can show whether a malaria patient has parasites with the genetic markers. If so, dihydroartemisinin-piperaquine therapy is likely to fail, say the study authors, and an alternative drug combination (artesunate-mefloquine) should be used. Information about the distribution of these drug resistance markers is being used by officials in Cambodia and neighbouring countries to map the extent and spread of piperaquine resistance and to help guide region-wide malaria treatment approaches.
National Institute of Allergy and Infectious Diseases (NIAID) scientist Rick Fairhurst, M.D., Ph.D., and Roberto Amato, Ph.D., of the Wellcome Trust Sanger Institute (WTSI), Cambridge, UK, led the research team. The first marker they identified is a change of one subunit in a gene on the parasite’s chromosome 13. Parasites with this genetic change are much more likely to be resistant to piperaquine than parasites without it. The marker, while associated with drug resistance, likely does not play a functional role in enabling parasites to resist piperaquine, according to the researchers. In contrast, the second resistance marker identified by the investigators may have such a role. That marker is an increased number of copies of two genes (plasmepsin II and plasmepsin III) in those parasites that resist piperaquine. Malaria parasites use plasmepsins to help them digest human blood and, although the exact mechanism of action of piperaquine is not known, it is believed that the drug targets plasmepsins.
Parasites may react to piperaquine by increasing plasmepsin production, and any parasites with extra copies of the plasmepsin II and III genes may be better able to withstand piperaquine treatment. Of note, parasites with increased piperaquine resistance appear to have increased susceptibility to the malaria drug mefloquine. This observation hints at the possibility of devising malaria treatment regimens that combine three or more drugs to exploit opposing resistance-susceptibility attributes.
National Institute of Healthwww.niaid.nih.gov/news-events/two-genetic-markers-predict-malaria-treatment-failure-found
New bioinformatic analysis reveals role of proteins in diabetic kidney disease
, /in E-News /by 3wmediaA new bioinformatic framework developed by researchers at University of California San Diego School of Medicine has identified key proteins significantly altered at the gene-expression level in biopsied tissue from patients with diabetic kidney disease, a result that may reveal new therapeutic targets.
In a recently published paper, researchers, led by Kumar Sharma, MD, professor of medicine at UC San Diego School of Medicine, revealed that the protein MDM2 was consistently down-regulated and played a key role in diabetic kidney disease progression. The researchers used the new “MetBridge Generator” bioinformatics framework to identify the relevant enzymes and bridge proteins that link human metabolomics data to the pathophysiology of diabetic kidney disease at a molecular level.
“MetBridge Generator allows for efficient, focused analysis of urine metabolomics data from patients with diabetic kidney disease, providing researchers an opportunity to develop new hypotheses based on the possible cellular or physiological role of key proteins,” said Sharma, senior author and director of the Institute for Metabolomic Medicine and the Center for Renal Translational Medicine at UC San Diego School of Medicine. “The framework may also be used in the interpretation of other metabolomic signatures from a variety of diseases. For example, MDM2 is also involved in regulating tumour protein p53, which is a target for cancer treatments.”
In a previous study, the authors identified 13 metabolites that were found to be altered in patients with diabetic kidney disease. Combining this information and publicly available data on metabolic pathways, the researchers tested an hypothesis that some proteins act as bridges creating less well-defined pathways. The framework then created a map of metabolic and protein-protein interaction (PPI) networks. This allowed the team to look deeper into relevant bridges with the greatest number of interactions with enzymes that regulate the 13-metabolite signature of diabetic kidney disease.
The authors already identified protein-RNA interactions as possible sources for additional key pathways underlying disease progression that could be added to the MetBridge Generator network. This growth will continue to add to possible therapeutic targets for disease treatment.
University of California – San Diego ucsdnews.ucsd.edu/pressrelease/new_bioinformatic_analysis_reveals_role_of_proteins_in_diabetic_kidney_dise
Microbes in your gut influence major eye disease
, /in E-News /by 3wmediaBacteria in your intestines may play an important role in determining if you will develop blinding wet Age-related Macular Degeneration (AMD).
Age-related Macular Degeneration (AMD) is the leading cause of irreversible blindness in the industrialized world, affecting over 10 million individuals in North America. A study lead by Dr. Przemyslaw (Mike) Sapieha, researcher at Hôpital Maisonneuve-Rosemont (CIUSSS de l’Est-de-l’Île-de-Montréal) and professor at the University of Montreal, uncovered that bacteria in your intestines may play an important role in determining if you will develop blinding wet AMD.
AMD is characterized by a heightened immune response, sizeable deposits of fat debris at the back of the eye called soft drusen (early AMD), destruction of nerve cells, and growth of new diseased blood vessels (wet AMD, late form). While only accounting for roughly 10% of cases of AMD, wet AMD is the primary form leading to blindness. Current treatments becomes less effective with time. It is therefore important to find new ways to prevent the onset of this debilitating disease.
While many studies on the genetics of AMD have identified several genes that predispose to AMD, no single gene can account for development of the disease. Epidemiological data suggests that in men, overall abdominal obesity is the second most important environmental risk factor, after smoking, for progression to late-stage blinding AMD. Until now, the mechanisms that underscore this observation remained ill defined. Elisabeth Andriessen, a PhD student in the lab of Professor Sapieha found that changes in the bacterial communities of your gut, such as those brought on by a diet rich in fat, can cause long-term low-grade inflammation in your whole body and eventually promote diseases such as wet AMD. Among the series of experiments conducted as part of this study, the group performed fecal transfers from mice receiving regular fat diets, compared to those receiving a high fat diet, and found a significant amelioration of wet AMD.
“Our study suggests that diets rich in fat alter the gut microbiome in a way that aggravates wet AMD, a vascular disease of the aging eye. Influencing the types of microbes that reside in your gut either through diet or by other means may thus affect the chances of developing AMD and progression of this blinding disease”, says Dr Sapieha. Professor Sapieha holds the Wolfe Professorship in Translational Vision Research and a Canada Research Chair in retinal cell biology.
University of Montreal nouvelles.umontreal.ca/en/article/2016/11/15/microbes-in-your-gut-influence-major-eye-disease/
Protein required for breast cancer metastasis identified
, /in E-News /by 3wmediaResearchers have identified a new pathway and with it a protein, BRD4, necessary for breast cancer cells to spread.
The findings may provide a new target to suppress breast cancer metastasis.
Triple-negative breast cancer is considered the worst subgroup of breast cancer. It is highly aggressive and responds poorly to the current therapeutic tools resulting in a dismal prognosis for patients. Furthermore, the lack of identified targets has limited the development of new drug strategies.
Researchers from Boston University School of Medicine (BUSM) used breast cancer cell lines that present the clinical characteristics of an aggressive breast cancer subtype (clinically described as a triple-negative breast cancer). They then used an experimental design to model cancer cell metastasis. By suppressing the expression of the protein BRD4 in these cell lines, they observed that their dissemination capabilities were blocked, indicating that BRD4 drives breast cancer dissemination. In addition, they conducted a screening analysis of human breast tumours and found that tumours with a high expression of BRD4 were more likely to metastasize.
“The current treatment options for a triple-negative cancer are unacceptably limited. It is crucial to identify new therapeutic targets to tackle challenging cancer types, including triple negative breast cancer. BDR4 targeting represents an innovative strategy to ablate breast cancer metastasis,” explained lead investigator Guillaume Andrieu, PhD, a post-doctoral research associate at Boston University School of Medicine.
Although obesity per se is not thought of as a carcinogen, the abnormal, inflamed microenvironments found in obesity are critical for progression, invasion and metastasis of triple negative breast cancer. “Bromodomain and ExtraTerminal domain (BET) proteins, which include BRD2, BRD3 and BRD4, are known to regulate production of inflammatory mediators. Our study proposes that BRD4 couples inflammation to breast cancer dissemination. Thus, small molecules that block BET proteins possess anti-inflammatory properties that can be useful for therapy,” he added.
Although these findings primarily focus on breast cancer and metastasis, the researchers plan to expand their results to the treatment of prostate cancer, which they believe has similar pathways involved in its metastasis.
Boston University Medial Center www.bu.edu/news/2016/11/15/researchers-identify-protein-required-for-breast-cancer-metastasis/