热门疾病
不限 癌症 糖尿病 心血管疾病 精神/神经疾病 自身免疫性疾病 炎症及感染性疾病 代谢性疾病 呼吸系统疾病 其他

论文局灶性TLR4激活介导受干扰的流动诱导的内皮炎症

Aims Disturbed blood flow at arterial branches and curvatures modulates endothelial function and predisposes the region to endothelial inflammation and subsequent development of atherosclerotic lesions. Activation of the endothelial Toll-like receptors (TLRs), in particular TLR4, contributes to vascular inflammation. Therefore, we investigate whether TLR4 can sense disturbed flow to mediate the subsequent endothelial inflammation. Methods and Results En face staining of endothelium revealed that TLR4 expression, activation, and its downstream inflammatory markers were elevated in mouse aortic arch compared to thoracic aorta, which were absent in Tlr4mut mice. Similar results were observed in the partial carotid ligation model where TLR4 signaling was activated in response to ligation-induced flow disturbance in mouse carotid arteries and such effect was attenuated in Tlr4mut mice. Disturbed flow in vitro increased TLR4 expression and activation in human endothelial cells and promoted monocyte-endothelial cell adhesion, which were inhibited in TLR4-knockdown endothelial cells. Among endogenous TLR4 ligands examined as candidate mediators of disturbed flow-induced TLR4 activation, fibronectin containing the extra domain A (FN-EDA) expressed by endothelial cells was increased by disturbed flow and revealed to directly interact and activate TLR4. Conclusions Our findings demonstrate the indispensable role of TLR4 in disturbed flow-induced endothelial inflammation and pinpoint FN-EDA as the endogenous TLR4 activator in this scenario. This novel mechanism of vascular inflammation under disturbed flow condition may serve as a critical initiating step in atherogenesis.展开>><<收起

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论文受磷蛋白p.Arg14del致心律失常性心肌病的不同分子特征

Phospholamban (PLN) p.Arg14del cardiomyopathy is characterized by a distinct arrhythmogenic biventricular phenotype that can be predominantly left ventricular, right ventricular, or both. Our aim was to further elucidate distinct features of this cardiomyopathy with respect to the distribution of desmosomal proteins observed by immunofluorescence (IF) in comparison to desmosomal arrhythmogenic cardiomyopathy and co-existent genetic variants. We studied eight explanted heart specimens from PLN p.Arg14del mutation carriers. Macro- and microscopic examination revealed biventricular presence of fibrofatty replacement and interstitial fibrosis. Five out of 8 (63%) patients met consensus criteria for both arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM). In four cases, targeted next-generation sequencing revealed one additional pathogenic variant and six variants of unknown significance. IF showed diminished junction plakoglobin signal intensity at the intercalated disks in 4 (67%) out of 6 cases fulfilling ARVC criteria but normal intensity in both cases fulfilling only DCM criteria. Notably, the four cases with diminished junction plakoglobin were also those where an additional gene variant was detected. IF for two proteins recently investigated in desmosomal arrhythmogenic cardiomyopathy (ACM), synapse-associated protein 97 and glycogen synthase kinase-3 beta, showed a distinct distributional pattern in comparison to desmosomal ACM. In 7 (88%) out of 8 cases we observed both a strong synapse-associated protein 97 signal at the sarcomeres and no glycogen synthase kinase-3 beta translocation to the intercalated discs. Phospholamban p.Arg14del cardiomyopathy is characterized by a distinct molecular signature compared to desmosomal ACM, specifically a different desmosomal protein distribution. This study substantiates the idea that additional genetic variants play a role in the phenotypical heterogeneity.展开>><<收起

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受基因变化影响的儿童肥胖风险

新闻受基因变化影响的儿童肥胖风险

A child's risk of obesity as they grow up can be influenced by modifications to their DNA prior to birth, a new University of Southampton study has shown. These changes, known as epigenetic modifications, control the activity of our genes without changing the actual DNA sequence. One of the main epigenetic modifications is DNA methylation, which plays a key role in the development of the embryo and the formation of different cell types, regulating when and where genes are switched on.  DNA methylation can be affected by a range of environmental factors such as parental health, diet and lifestyle. Researchers from the University of Southampton, as part of the EpiGen Global Consortium, analysed the levels of DNA methylation at the SLC6A4 gene which is an important mediator in serotonin levels in the body and has been implicated in mood and appetite regulation. The samples taken were umbilical cord tissue of babies born in the Southampton Women's Survey at birth and compared with the amount of fat tissue in the child at four and six years of age. They found that lower DNA methylation levels at the SLC6A4 gene at birth was associated with a higher fat mass at six to seven years of age. Each unit lower SLC6A4 methylation at birth was associated with a seven per cent higher child's fat mass at age six years. The Southampton team compared the results to the mother's health during pregnancy and found that higher weight gain during pregnancy and a lower number of previous births was associated with lower SLC6A4 DNA methylation. Co-lead author Karen Lillycrop, from the University of Southampton, said: "Our results add to the growing evidence that epigenetic changes detectable at birth are linked to a child's health as they grow up. Additionally, it also strengthens the body of evidence that shows a mother's health during pregnancy can affect the future health of her child. It could allow us to more accurately predict the future risk of obesity." The results, published in the International Journal of Obesity were replicated in other groups of children and adults, notably the Western Australian Pregnancy Cohort Study and the UK BIOCLAIMS cohort. This latest Southampton study is another example of how the health of parents before and during pregnancy can affect the health of their future baby. Emma Garratt, co-lead author, from the University of Southampton, said: "These results offer more evidence and more opportunity to allow us to develop strategies and interventions in early life that could reduce childhood obesity rates." Professor Keith Godfrey, a member of the research team and Director of the EpiGen Global Consortium, added: "The new findings strengthen the case that primary prevention of childhood obesity needs to begin before birth, and might 'reset' appetite levels in ways that protect infants and children from putting on excessive weight.  "Ongoing research is examining whether diet and lifestyle interventions before and during pregnancy might be able to tackle and even reverse the childhood obesity epidemic."详情>>

2019-02-21 00:00:00
与盲症相关的数百个基因可能会促使新疗法

新闻与盲症相关的数百个基因可能会促使新疗法

Inherited diseases of the eye account for at least 2 million cases of blindness worldwide. A few hundred genes that cause eye disease have been identified, but in many cases the cause is unknown because not all eye disease genes have been identified. As a result, genetic testing is only able to determine the mutation responsible for blindness in only 50 to 75 percent of blind children and young adults. As an eye doctor and researcher, I am frustrated at the lack of treatments for my patients with genetic forms of blindness such as retinitis pigmentosa, Stargardt disease and age-related macular degeneration. To address this problem, my lab launched a study of genes required for normal eye formation and function. We discovered 347 genes that, if mutated, cause blindness in laboratory mice. Of these, 261 had never been linked to vision loss before our study, which we published recently in the journal Communications Biology. Knockout mice help identify more blindness genes Researchers first identified eye disease genes in the late 1980s by studying families in the United States with inherited forms of retinitis pigmentosa, a disease of retinal cells called rod photoreceptors in children and young adults, which leads to eventual blindness. Since then, more and more families have been studied to add to the list of blinding mutations in people. To figure out which genes cause blindness, we took advantage of something called knockout technology. Researchers engineer a knockout mouse by deleting both copies of any single gene. This effectively deletes it from the mouse's genome. Abnormalities result, and they provide clues as to the function of the "knocked out" gene. The mouse genome is similar to that of humans and contains roughly 22,000-25,000 genes. So far, scientists around the world have knocked out about about 7,000 genes in mice, and the process of studying these mice is ongoing. The invention of knockout mouse technology in the 1990s led to the identification of eye disease genes by studying the eyes of mice with targeted deletions. The International Mouse Phenotyping Consortium (IMPC), which consists of more than a dozen mouse biology centers across North America, Europe and Asia, aims to create a knockout mouse for every gene in the mouse genome. The IMPC has created and carefully examined over 4,364 knockout mice. By analyzing the recorded data from the mouse eye exams at all IMPC centers across the globe, my colleagues and I found that 347 of these knockout mice, each one representing a single deleted gene, had eye abnormalities as determined by trained ophthalmic experts. The abnormalities sometimes involved the anterior structures of the eye, such as the eyelids, cornea and lens, and sometime posterior structures, such as the retina and optic nerve. Researchers have discovered genes controlling all parts of eye development are linked to heritable eye diseases. Credit: solar22/Shutterstock.com Testing mouse eye disease genes in humans Since the mouse and human genomes are similar, it's highly likely that these newly identified genes, if mutated, also cause human eye diseases. The next step is to study these newly implicated mouse genes in blind human patients. Specifically, we will analyze the genomes of patients whose prior genetic testingcould not link their condition to one of the previously known eye disease genes. The addition of hundreds of new eye disease genes in this IMPC study will help eye doctors like me around the world provide more precise genetic diagnoses to our patients. To validate these genes in humans, we plan to create a panel of these new 261 genes that can be scanned for mutations. Furthermore, the knockout mice themselves will serve as publicly available research models for the newly discovered eye disease genes. All of these knockout mice are available to all researchers and can be ordered from the IMPC repository for additional scientific studies and therapeutic discoveries. These mousemodels can be used to test new medications, gene therapies and stem cell approaches. Knockout mice teach us about the genetics The scientific discoveries of the IMPC are quickly advancing our understanding of the thousands of genes and molecules that underlie many human disease processes. In each organ system of the body, researchers are finding many genes that have never been linked with disease. The results of the IMPC project, including the eye disease genes, could advance the diagnostic capability, and identify new targets for novel therapies. I hope that eye doctors at major universities and eye centers will cross reference our list of 261 new eye disease genes from micewith the genetic sequence of their human patients in whom they found no mutation that causes disease. We hope our list of genes will guide our colleagues to the genetic culprit in many cases and provide both a specific diagnosis and a path forward toward eventual treatment for those families afflicted with inherited forms of blindness.详情>>

2019-02-21 00:00:00
全球首个针对视力丧失常见原因的基因治疗手术

新闻全球首个针对视力丧失常见原因的基因治疗手术

Researchers in Oxford have carried out the world's first gene therapy operation to tackle the root cause of age-related macular degeneration (AMD), the UK's most common cause of sight loss. The procedure was carried out at the John Radcliffe Hospital by Professor Robert MacLaren, Professor of Ophthalmology at the University of Oxford, with the support of the NIHR Oxford Biomedical Research Centre in a clinical trial sponsored by Gyroscope Therapeutics, a UK-based company developing genetically-defined therapies for the treatment of eye diseases. Professor MacLaren says: "AMD is the number one cause of untreatable blindness in the developed world. A genetic treatment administered early on to preserve the vision in patients who would otherwise lose their sight would be a tremendous breakthrough and certainly something I hope to see in the near future." Age-related macular degeneration (AMD) is the biggest cause of sight loss in the UK, affecting over 600,000 people. Dry AMD is a slow deterioration of the cells of the macula. It affects the central part of a patient's vision with gaps or 'smudges," making everyday activities like reading and recognising faces difficult. If successful, the treatment could have a beneficial impact of patients' quality of life and their ability to remain independent. The first person to undergo the procedure was Mrs Janet Osborne of Oxford. Like many people with AMD, she has the condition in both eyes, but it is more advanced in her left eye. As is typical with this condition, the central vision in her left eye has deteriorated and is very hazy, although her peripheral vision is better. The 80-year-old says that her restricted vision makes household tasks like preparing vegetables and sewing difficult, and she cannot read for very long. Often she finds it hard to recognise faces. She says her motivation for taking part in the trial was the possibility of helping others with AMD: "I wasn't thinking of me. I was thinking of other people. For me, I hope my sight doesn't get any worse. That would be fantastic. It means I wouldn't be such a nuisance to my family." The operation was part of the FOCUS trial, sponsored by Gyroscope Therapeutics, a UK biotech company developing gene therapy products for ocular diseases such as dry AMD, which was founded and built by Syncona. Some of the enabling viral vector development took place at the University of Oxford with NIHR funding. The operation involves detaching the retina and injecting a solution containing a virus underneath. The virus contains a modified DNA sequence, which infects cells, called the retinal pigment epithelium (RPE), and corrects a genetic defect that causes AMD. Ideally if successful, gene therapy would only need to be performed once, as the effects are thought to be long-lasting. A key factor in AMD is the complement system, a system of proteins in our immune system that fights bacteria. In macular degeneration, these proteins are over-active and start to attack the retinal cells, in a similar way to how they would attack bacteria. Professor MacLaren explains: "We're harnessing the power of the virus, a naturally occurring organism, to deliver the DNA into the patient's cells. When the virus opens up inside the retinal cell it releases the DNA of the gene we have cloned, and the cell starts making a protein that we think can modify the disease, correcting the imbalance of the inflammation caused by the complement system. "The idea of this gene therapy is to 'deactivate' the complement system, but at a very specific point at the back of the eye, so the patient would otherwise be unaffected by it, and we hope that in future it will slow down the progression of macular degeneration." Sir Peter Lachman, the scientist from the University of Cambridge who led the pioneering work on the complement system leading to the creation of Gyroscope Therapeutics, said: "We have a better understanding now on the relationship between the complement system and the AMD disease which lead us to the discovery that restoring the balance of a hyperactive complement system could be a potential therapeutic approach in dry AMD." The aim of the therapy is to halt the progress of the condition and preserve what vision patients have remaining. If successful, it is hoped that gene therapy can be used in the future on patients with early AMD and so halt the disease before their vision has started to deteriorate. Professor MacLaren ran the first gene therapy clinical trials from Oxford for rarer causes of blindness, Choroideremia and retinitis pigmentosa. Professor MacLaren said: "This is a rapidly evolving field. Given that we understand a lot more now about the manufacture of the treatment, and the effects of the virus when doing gene therapyat the back of the eye, as well as all the other gene therapyprogrammes being developed at the moment, I would hope that we'll see a treatment for people with dry AMD within the next few years."详情>>

2019-02-20 00:00:00
研究发现,在一些高危肾病患者中他汀类药物的使用率较低

新闻研究发现,在一些高危肾病患者中他汀类药物的使用率较低

Clinical trials have shown that cholesterol-lowering statin drugs can significantly reduce the risk of cardiovascular disease in kidney disease patients who are not on dialysis. But a new study has found that statins are used by only 21.8 percent of such patients who do not already have cardiovascular disease or diabetes or have not been diagnosed with high cholesterol. The study by researchers from Loyola Medicine, Loyola University Chicago and Hines VA Hospital was published in Clinical Kidney Journal. "Our findings suggest a need for education efforts to increase statin use in adults with non dialysis-dependent chronic kidney disease," reported first author Talar Markossian, Ph.D., MPH, corresponding author Holly Kramer, MD, MPH, and colleagues. More than 500 million people worldwide have chronic kidney disease and are not on dialysis. Most cases are due to diabetes and high blood pressure, which also are strong risk factors for heart attacks, strokes and other forms of cardiovascular disease. The risk of cardiovascular disease increases sharply as kidney disease becomes worse. In the new study, researchers examined records of 581,344 patients receiving care from Veterans Affairs facilities. Patients were aged 50 and older, with stages 3-5 kidney disease that did require dialysis. About three-fourths of patients who had kidney disease plus cardiovascular disease or diabetes used statins. But in the absence of cardiovascular disease, diabetes or high cholesterol, statin use was only 21.8 percent. This finding is concerning because about 90 percent of such patients have at least a 10 percent risk of developing cardiovascular disease in the next 10 years, and this risk could be reduced by taking statins. Statin use also is believed to be low in patients outside the VA.详情>>

2019-02-20 00:00:00

论文心脏病学2018:心衰

This article summarizes some of the research highlights on heart failure published in the previous year. Hopefully, it will show that Moliere’s perception of doctors is no longer quite as true as it once may have been. A key emerging theme in the science and medicine of heart failure is the need to identify and target specific causes of heart failure, defined by phenotype or genotype, which will respond to a particular intervention (Take home figure). QRS duration (a marker of cardiac dyssynchrony),1,2 mitral regurgitation,3,4 iron deficiency,5,6 and amyloidosis7 each identifies patients that will respond to a specific intervention. Just as for that other large cluster of malignant diseases called cancer, the ‘war’ on heart failure will be won one ‘battle’ at a time. The outcome of many large clinical trials is determined neither by universal failure nor universal success but rather the proportions of patients that obtained benefit or harm compared with those for whom the intervention had little effect. For instance, the success of trials of beta-blockers may be because they did not enrol too many patients that respond poorly to these agents, including those with atrial fibrillation, a pacemaker or with a left ventricular ejection fraction (LVEF) >50%.8,9 Had the trials been less selective they might have been neutral. Had they been more selective, the trials would have been smaller and shown an even larger benefit. Conversely, many interventions for heart failure with a preserved LVEF (≥50%; HFpEF) probably benefited some patients within this phenotype but not a large enough proportion to drive the overall result. We should take care that we do not reject effective treatments due to misunderstanding the results of trials that required a huge investment from patients, clinicians, academics, clinical research organizations, and funders. Of course, a phenotype only really matters to a patient and a clinician when it informs management. This last year has seen an explosion of data on a variety of ‘therapeutic phenotypes’ that matter.展开>><<收起

European Heart Journal. Published: 18 February 2019  0
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研究人员发现DNA变异显着影响体脂分布

新闻研究人员发现DNA变异显着影响体脂分布

A new breakthrough from the Genetic Investigation of Anthropometric Traits consortium, which includes many public health researchers from the University of North Carolina at Chapel Hill, identifies multiple genetic variants associated with how the body regulates and distributes body-fat tissue. The new findings broaden the understanding of how genes can predispose certain individuals to obesity. The GIANT Consortium is a major international collaboration of more than 275 scientists that seeks to identify genetic sites that affect human body size and shape, including height and measures of obesity. Kari E. North, professor of epidemiology at the University of North Carolina at Chapel Hill Gillings School of Global Public Health, is joint lead author of the new study, "Protein-Coding Variants Implicate Novel Genes Related to Lipid Homeostasis 1 Contributing to Body Fat Distribution," published February 18 in Nature Genetics. Other co-authors from the UNC Gillings School include assistant professor Kristin Young, assistant professor Misa Graff, and postdoctoral fellow Heather Highland, all in the UNC Gillings School's department of epidemiology. Identifying the genetic variants associated with obesity is central to developing targeted interventions that can reduce the risk of chronic illnesses, such as hypertension, type 2 diabetes, and heart disease, to which obesity contributes in significant ways. Genome-wide association studies previously identified 49 loci, or positions along a chromosome where the related genetic variants are located, that predispose individuals to a higher waist-to-hip ratio, which is a way to assess body-fat distribution. Lower values of WHR are associated with lower incidence of these diseases. In this study, with a specific focus on coding variation, the team found 24 coding loci—15 common and nine rare—along the chromosomes of individuals that predispose to higher WHR. Further analysis revealed pathways and gene sets that influenced not only metabolism but also the regulation of body fat tissue, bone growth and adiponectin, a hormone that controls glucose levels and breaks down fat. The team also performed functional studies across other organisms and identified two genes that were associated with a significant increase in triglyceride levels and body fat across species. "For the first time, we were able to examine, on a large scale, how low-frequency and rare variants influence body fat distribution," said Kari E. North. "These variants are rarer in the population, but the effects they have on individuals are much larger, possibly making them more clinically relevant." Another major finding from this study is the importance of lipid metabolism to body­fat distribution, which could lead to a better understanding of how obesity causes downstream diseases such as Type 2 diabetes and cardiovascular disease. "A better understanding of the genetic underpinnings of body fat distribution may lead to better treatments for obesity and the cascade of downstream diseases obesity also impacts, for example type 2 diabetes and heart disease" North said.详情>>

2019-02-19 00:00:00
单一CRISPR治疗为小鼠提供长期益处

新闻单一CRISPR治疗为小鼠提供长期益处

Researchers at Duke University have shown that a single systemic treatment using CRISPR genome editing technology can safely and stably correct a genetic disease—Duchenne muscular dystrophy (DMD)—for more than a year in mice, despite observed immune responses and alternative gene editing outcomes. The study appears online on February 18 in the journal Nature Medicine. In 2016, Charles Gersbach, the Rooney Family Associate Professor of Biomedical Engineering at Duke, published one of the first successful uses of CRISPR to treat an animal model of genetic disease with a strategy that has the potential to be translated to human therapy. Many additional examples have since been published, and several genome editing therapies targeting human diseases are currently in clinical trials, with more on the way. Gersbach's latest research focuses on a mouse model of DMD, which is caused by the body's inability to produce dystrophin, a long protein chain that binds the interior of a muscle fiber to its surrounding support structure. Dystrophin is encoded by a gene containing 79 protein-coding regions, called exons. If one or more exons are disrupted or deleted by an inherited mutation, the chain does not get built, causing muscle to slowly shred and deteriorate. Most patients are wheelchair-bound by age 10 and don't live beyond their 20s or early 30s. Gersbach has been working on potential genetic treatments for Duchenne since 2009. His lab was one of the first to begin focusing on CRISPR/Cas9, a modified version of a bacterial defense system that targets and slices apart the DNA of invading viruses. His approach uses CRISPR/Cas9 to snip out dystrophin exons around the genetic mutation, leaving the body's natural DNA repair system to stitch the remaining gene back together to create a shortened—but functional—version of the dystrophin gene. "As we continue to work to develop CRISPR-based genetic therapies, it is critical to test our assumptions and rigorously assess all aspects of this approach," Gersbach said. "A goal of our experiments was to test some ideas being discussed in the field, which will help us understand the potential of CRISPR to treat genetic diseases in general and Duchenne muscular dystrophy in particular. This includes monitoring the long-term durability of the response in the face of potential immune responses against the bacterial Cas9 protein." The first eight-week study demonstrated that functional dystrophin was restored and muscle strength increased. It did not, however, explore the long-term durability of the treatment. "It is widely believed that gene editing leads to permanent gene correction," Gersbach said. "However, it's important to explore theoretical possibilities that could undermine the effects of gene editing, such as losing treated cells or an immune response." The goal of the new study was to explore factors that could alter the long-term effects of CRISPR/Cas9-based gene editing. Christopher Nelson, the post-doctoral fellow in Gersbach's lab who led the work, administered a single dose of the CRISPR therapy intravenously to both adult and newborn mice carrying a defective dystrophin gene. Over the course of the following year, researchers measured how many muscle cells were successfully edited and what types of genetic alterations were made, as well as the generation of any immune response against the bacterial CRISPR protein, Cas9, which acts as the "scissors" that makes cuts to the genome. Other studies have reported that the mouse immune system can mount a response to Cas9, which could potentially interfere with the benefit of CRISPR therapies. Several groups have also reported that some people have preexisting immunity to Cas9 proteins, likely because of previous exposure to the bacterial host. "The good news is that even though we observed both antibody and T cell responses to Cas9, neither appeared to result in any toxicity in these mice," said Nelson. "The response also did not prevent the therapy's ability to successfully edit the dystrophin gene and produce long-term protein expression." The results also suggested approaches to address potential challenges, should they arise in the future. For example, the researchers observed that when two-day-old mice without fully developed immune systems were treated intravenously, no immune response was detected. The CRISPR genome editing remained stable and, in some cases, even strengthened over the course of a year. One could imagine delivering the therapy to infants as a method of circumventing or modulating an unwanted immune response. Gersbach and Nelson acknowledge, however, that the mouse immune system often functions quite differently from the human immune system. And newborn screening for DMD is not currently widely performed; most Duchenne diagnoses occur when children are three to five years old. To address this challenge, Gersbach said suppressing the immune system during treatment may be a viable approach. The researchers are also investigating potential strategies to restrict the expression or delivery of Cas9 to only the muscle cells for short durations, which may lessen immune detection. "We were pleased to observe that all the mice were doing well a year after treatment, but our results show that there needs to be more focus on the immune response as we move toward larger animal models," Nelson said. Nelson and Gersbach have previously investigated the potential of off-target editing by CRISPR/Cas9 to unintentionally modify other sites in the genome and reported minimal activity at likely off-target sites. Other recent studies, however, have reported that CRISPR can sometimes make genetic edits at the correct site but not in the intended manner. For example, some studies have shown that CRISPR can cut out genetic sections much larger than intended or that pieces of DNA can embed at the site of the cut. These types of edits had previously been unreported in genome editing studies because the methods being used only detected the intended edit. To comprehensively map all the edits occurring in the dystrophin gene, Nelson used a DNA sequencing approach that agnostically reports any type of edit. Surprisingly, there were many types of edits being made in addition to the intended removal of the targeted exon, including a high level of insertion of DNA sequences from the viral vector encoding the CRISPR/Cas9 system. Depending on the type of tissue and the dosage of CRISPR delivered, as many as half of the on-target edits resulted in these alternative sequence changes. Although this result was surprising, the unintended sequence changes do not appear to impact the safety or efficacy of this CRISPR/Cas9 gene editing approach for DMD. "None of these edits would necessarily be a cause for concern in this case because the dystrophin gene is already defective," said Nelson. "That being said, any unintended results could potentially take away from the efficiency of the gene editing you're trying to achieve, which supports the importance of designing ways to objectively identify and mitigate alternative edits in future studies." "Previous studies suggested that some of these other types of edits could happen," Gersbach said. "But this is one of the first comprehensive measurements of these events in an animal model using a therapeutically relevant approach. Moving forward, this phenomenon needs to be monitored carefully and better understood. Methods that avoid these alternative edits and increase the frequency of the intended edit will be important to maximizing the potential of genome editing to treat disease."详情>>

2019-02-19 00:00:00
新研究表明隐藏的基因可能是自闭症严重程度的基础

新闻新研究表明隐藏的基因可能是自闭症严重程度的基础

Scientists at the University of Colorado Anschutz Medical Campus have implicated a largely hidden part of the human genome in the severity of autism symptoms, a discovery that could lead to new insights into the disorder and eventually to clinical therapies for the condition. The researchers found the critical genes are part of the human genome that is so complex and difficult to study that it has been unexamined by conventional genome analysis methods. In this case, the region encodes most copies of the Olduvai (formerly DUF1220) protein domain, a highly duplicated (~300 copies in the human genome) and highly variable gene coding family that has been implicated in both human brain evolution and cognitive disease. The researchers, led by James Sikela, Ph.D., a professor in the Department of Biochemistry and Molecular Genetics at the CU School of Medicine, analyzed the genomes of individuals with autism and showed that, as the number of copies of Olduvai increased, the severity of autism symptoms became worse. While the Sikela lab has shown this same trend previously, the discovery has not been pursued by other researchers due to the complexity of the Olduvai family. "It took us several years to develop accurate methods for studying these sequences, so we fully understand why other groups have not joined in." Sikela said. "We hope that by showing that the link with autism severity holds up in three independent studies, we will prompt other autism researchers to examine this complex family." In order to provide more evidence that the association with autism severity is real, the Sikela lab used an independent population and developed a different, higher resolution measurement technique. This new method also allowed them to zero in on which members of the large Olduvai family may be driving the link with autism. Though autism is thought to have a significant genetic component, conventional genetic studies have come up short in efforts to explain this contribution, Sikela said. "The current study adds further support to the possibility that this lack of success may be because the key contributors to autism involve difficult-to-measure, highly duplicated and highly variable sequences, such as those encoding the Olduvai family, and, as a result, have never been directly measured in other studies of autism," Sikela said. The study was published today in the American Journal of Psychiatry.详情>>

2019-02-18 00:00:00