|Bridging larger gaps in peripheral nerves using neural prosthetics and physical therapeutic agents|
Muhammad Sana Ullah Sahar, Matthew Barton, Geoffrey Douglas Tansley
Neural Regeneration Research 2019 14(7):1109-1115
Peripheral nerve injuries are relatively common and can be caused by a variety of traumatic events such as motor vehicle accidents. They can lead to long-term disability, pain, and financial burden, and contribute to poor quality of life. In this review, we systematically analyze the contemporary literature on peripheral nerve gap management using nerve prostheses in conjunction with physical therapeutic agents. The use of nerve prostheses to assist nerve regeneration across large gaps (> 30 mm) has revolutionized neural surgery. The materials used for nerve prostheses have been greatly refined, making them suitable for repairing large nerve gaps. However, research on peripheral nerve gap management using nerve prostheses reports inconsistent functional outcomes, especially when prostheses are integrated with physical therapeutic agents, and thus warrants careful investigation. This review explores the effectiveness of nerve prostheses for bridging large nerve gaps and then addresses their use in combination with physical therapeutic agents.
|Magnesium: Pathophysiological mechanisms and potential therapeutic roles in intracerebral hemorrhage|
Jason J Chang, Rocco Armonda, Nitin Goyal, Adam S Arthur
Neural Regeneration Research 2019 14(7):1116-1121
Intracerebral hemorrhage (ICH) remains the second-most common form of stroke with high morbidity and mortality. ICH can be divided into two pathophysiological stages: an acute primary phase, including hematoma volume expansion, and a subacute secondary phase consisting of blood-brain barrier disruption and perihematomal edema expansion. To date, all major trials for ICH have targeted the primary phase with therapies designed to reduce hematoma expansion through blood pressure control, surgical evacuation, and hemostasis. However, none of these trials has resulted in improved clinical outcomes. Magnesium is a ubiquitous element that also plays roles in vasodilation, hemostasis, and blood-brain barrier preservation. Animal models have highlighted potential therapeutic roles for magnesium in neurological diseases specifically targeting these pathophysiological mechanisms. Retrospective studies have also demonstrated inverse associations between admission magnesium levels and hematoma volume, hematoma expansion, and clinical outcome in patients with ICH. These associations, coupled with the multifactorial role of magnesium that targets both primary and secondary phases of ICH, suggest that magnesium may be a viable target of study in future ICH studies.
|Network-centric medicine for peripheral nerve injury: Treating the whole to boost endogenous mechanisms of neuroprotection and regeneration|
David Romeo-Guitart, Caty Casas
Neural Regeneration Research 2019 14(7):1122-1128
Peripheral nerve injuries caused by accidents may lead to paralysis, sensory disturbances, anaesthesia, and lack of autonomic functions. Functional recovery after disconnection of the motoneuronal soma from target tissue with proximal rupture of axons is determined by several factors: motoneuronal soma viability, proper axonal sprouting across inhibitory zones and elongation toward specific muscle, effective synapse contact rebuilding, and prevention of muscle atrophy. Therapies, such as adjuvant drugs with pleiotropic effects, that promote functional recovery after peripheral nerve injury are needed. Toward this aim, we designed a drug discovery workflow based on a network-centric molecular vision using unbiased proteomic data and neural artificial computational tools. Our focus is on boosting intrinsic capabilities of neurons for neuroprotection; this is in contrast to the common approach based on suppression of a pathobiological pathway known to be associated with disease condition. Using our workflow, we discovered neuroheal, a combination of two repurposed drugs that promotes motoneuronal soma neuroprotection, is anti-inflammatory, enhances axonal regeneration after axotomy, and reduces muscle atrophy. This drug discovery workflow has thus yielded a therapy that is close to its clinical application.
|Exogenous neural stem cell transplantation for cerebral ischemia|
Ling-Yi Liao, Benson Wui-Man Lau, Dalinda Isabel Sánchez-Vidaña, Qiang Gao
Neural Regeneration Research 2019 14(7):1129-1137
Cerebral ischemic injury is the main manifestation of stroke, and its incidence in stroke patients is 70–80%. Although ischemic stroke can be treated with tissue-type plasminogen activator, its time window of effectiveness is narrow. Therefore, the incidence of paralysis, hypoesthesia, aphasia, dysphagia, and cognitive impairment caused by cerebral ischemia is high. Nerve tissue regeneration can promote the recovery of the aforementioned dysfunction. Neural stem cells can participate in the reconstruction of the damaged nervous system and promote the recovery of nervous function during self-repair of damaged brain tissue. Neural stem cell transplantation for ischemic stroke has been a hot topic for more than 10 years. This review discusses the treatment of ischemic stroke with neural stem cells, as well as the mechanisms of their involvement in stroke treatment.
|Potential therapeutic molecular targets for blood-brain barrier disruption after subarachnoid hemorrhage|
Hideki Kanamaru, Hidenori Suzuki
Neural Regeneration Research 2019 14(7):1138-1143
Aneurysmal subarachnoid hemorrhage remains serious hemorrhagic stroke with high morbidities and mortalities. Aneurysm rupture causes arterial bleeding-induced mechanical brain tissue injuries and elevated intracranial pressure, followed by global cerebral ischemia. Post-subarachnoid hemorrhage ischemia, tissue injuries as well as extravasated blood components and the breakdown products activate microglia, astrocytes and Toll-like receptor 4, and disrupt blood-brain barrier associated with the induction of many inflammatory and other cascades. Once blood-brain barrier is disrupted, brain tissues are directly exposed to harmful blood contents and immune cells, which aggravate brain injuries furthermore. Blood-brain barrier disruption after subarachnoid hemorrhage may be developed by a variety of mechanisms including endothelial cell apoptosis and disruption of tight junction proteins. Many molecules and pathways have been reported to disrupt the blood-brain barrier after subarachnoid hemorrhage, but the exact mechanisms remain unclear. Multiple independent and/or interconnected signaling pathways may be involved in blood-brain barrier disruption after subarachnoid hemorrhage. This review provides recent understandings of the mechanisms and the potential therapeutic targets of blood-brain barrier disruption after subarachnoid hemorrhage.
|Choroid plexus tumor necrosis factor receptor 1: A new neuroinflammatory piece of the complex Alzheimer's disease puzzle|
Sophie Steeland, Roosmarijn E Vandenbroucke
Neural Regeneration Research 2019 14(7):1144-1147
Due to the aging of the population and despite the enormous scientific effort, Alzheimer’s disease remains one of the biggest medical and pharmaceutical challenges in current medicine. Novel insights highlight the importance of neuroinflammation as an undeniable player in the onset and progression of Alzheimer’s disease. Tumor necrosis factor is a master inflammatory cytokine that signals via tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2, but that also regulates several brain functions in health and disease. However, clinical trials investigating drugs that interfere with the tumor necrosis factor pathway in Alzheimer’s disease led to inconclusive results, partially because not only the pro-inflammatory tumor necrosis factor/tumor necrosis factor receptor 1, but also the beneficial tumor necrosis factor/tumor necrosis factor receptor 2 signaling was antagonized in these trials. We recently found that tumor necrosis factor is the main upregulated cytokine in the choroid plexus of Alzheimer’s disease patients, signaling via tumor necrosis factor receptor 1. In agreement with this, choroidal tumor necrosis factor/tumor necrosis factor receptor 1 signaling was also upregulated in different Alzheimer’s disease mouse models. Interestingly, both genetic and nanobody-based pharmacological blockage of tumor necrosis factor receptor 1 signaling was accompanied by favorable effects on Alzheimer’s disease-associated inflammation, choroidal morphology and cognitive functioning. Here, we briefly summarize the detrimental effects that can be mediated by tumor necrosis factor/tumor necrosis factor receptor 1 signaling in (early) Alzheimer’s disease, and the consequences this might have on the disease progression. As the main hypothesis in Alzheimer’s disease clinical trials is still based on the amyloid beta-cascade, the importance of Alzheimer’s disease-associated neuroinflammation urge the development of novel therapeutic strategies that might be effective in the early stages of Alzheimer’s disease and prevent the irreversible neurodegeneration and resulting memory decline.
|Transcriptional dysregulation in neurodegenerative diseases: Who tipped the balance of Yin Yang 1 in the brain?|
Zhefan Stephen Chen, Ho Yin Edwin Chan
Neural Regeneration Research 2019 14(7):1148-1151
Yin Yang 1 (YY1) is a multi-functional transcription factor that regulates gene expression in a range of cell types, including neurons. It controls neuronal differentiation, as well as neuronal specification and migration during the development of the mammalian nervous system. Besides, YY1 also mediates the transcription of genes that are required for neuronal survival. An impairment of the transcriptional function of YY1 causes neuronal death. This review summarizes recent research findings that unveil the dysfunction of YY1 in multiple neurodegenerative disorders. The expression of disease proteins perturbs the function of YY1 via distinct molecular mechanisms, including recruitment to protein aggregates, protein degradation and aberrant nuclear/cytoplasmic shuttling. Understanding the pathogenic roles of YY1 will further broaden our knowledge of the disease mechanisms in distinct neurodegenerative disorders.
|Effects of Ginkgo biloba extract EGb761 on neural differentiation of stem cells offer new hope for neurological disease treatment|
Chao Ren, Yong-Qiang Ji, Hong Liu, Zhe Wang, Jia-Hui Wang, Cai-Yi Zhang, Li-Na Guan, Pei-Yuan Yin
Neural Regeneration Research 2019 14(7):1152-1157
Stem cell transplantation has brought new hope for the treatment of neurological diseases. The key to stem cell therapy lies in inducing the specific differentiation of stem cells into nerve cells. Because the differentiation of stem cells in vitro and in vivo is affected by multiple factors, the final differentiation outcome is strongly associated with the microenvironment in which the stem cells are located. Accordingly, the optimal microenvironment for inducing stem cell differentiation is a hot topic. EGb761 is extracted from the leaves of the Ginkgo biloba tree. It is used worldwide and is becoming one of the focuses of stem cell research. Studies have shown that EGb761 can antagonize oxygen free radicals, stabilize cell membranes, promote neurogenesis and synaptogenesis, increase the level of brain-derived neurotrophic factors, and replicate the environment required during the differentiation of stem cells into nerve cells. This offers the possibility of using EGb761 to induce the differentiation of stem cells, facilitating stem cell transplantation. To provide a comprehensive reference for the future application of EGb761 in stem cell therapy, we reviewed studies investigating the influence of EGb761 on stem cells. These started with the composition and neuropharmacology of EGb761, and eventually led to the finding that EGb761 and some of its important components play important roles in the differentiation of stem cells and the protection of a beneficial microenvironment for stem cell transplantation.
|Amelioration of Alzheimer's disease pathology and cognitive deficits by immunomodulatory agents in animal models of Alzheimer's disease|
Bridget Martinez, Philip V Peplow
Neural Regeneration Research 2019 14(7):1158-1176
The most common age-related neurodegenerative disease is Alzheimer’s disease (AD) characterized by aggregated amyloid-β (Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles, together with loss of cholinergic neurons, synaptic alterations, and chronic inflammation within the brain. These lead to progressive impairment of cognitive function. There is evidence of innate immune activation in AD with microgliosis. Classically-activated microglia (M1 state) secrete inflammatory and neurotoxic mediators, and peripheral immune cells are recruited to inflammation sites in the brain. The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects. Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials. Treatment with immunomodulatory/anti-inflammatory agents early in the disease process, while not preventive, is able to inhibit the inflammatory consequences of both Aβ and tau aggregation. The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD. The majority of the animal studies reviewed had used transgenic models of early-onset AD. More effort needs to be given to creat models of late-onset AD. The effects of a combinational therapy involving two or more of the tested pharmaceutical agents, or one of these agents given in conjunction with one of the cell-based therapies, in an aged animal model of AD would warrant investigation.
|Precision medicine in pantothenate kinase-associated neurodegeneration|
Mónica Alvarez-Cordoba, Marina Villanueva-Paz, Irene Villalón-García, Suleva Povea-Cabello, Juan M Suárez-Rivero, Marta Talaverón-Rey, Javier Abril-Jaramillo, Ana Belén Vintimilla-Tosi, José A Sánchez-Alcázar
Neural Regeneration Research 2019 14(7):1177-1185
Neurodegeneration with brain iron accumulation is a broad term that describes a heterogeneous group of progressive and invalidating neurologic disorders in which iron deposits in certain brain areas, mainly the basal ganglia. The predominant clinical symptoms include spasticity, progressive dystonia, Parkinson’s disease-like symptoms, neuropsychiatric alterations, and retinal degeneration. Among the neurodegeneration with brain iron accumulation disorders, the most frequent subtype is pantothenate kinase-associated neurodegeneration (PKAN) caused by defects in the gene encoding the enzyme pantothenate kinase 2 (PANK2) which catalyzed the first reaction of the coenzyme A biosynthesis pathway. Currently there is no effective treatment to prevent the inexorable course of these disorders. The aim of this review is to open up a discussion on the utility of using cellular models derived from patients as a valuable tool for the development of precision medicine in PKAN. Recently, we have described that dermal fibroblasts obtained from PKAN patients can manifest the main pathological changes of the disease such as intracellular iron accumulation accompanied by large amounts of lipofuscin granules, mitochondrial dysfunction and a pronounced increase of markers of oxidative stress. In addition, PKAN fibroblasts showed a morphological senescence-like phenotype. Interestingly, pantothenate supplementation, the substrate of the PANK2 enzyme, corrected all pathophysiological alterations in responder PKAN fibroblasts with low/residual PANK2 enzyme expression. However, pantothenate treatment had no favourable effect on PKAN fibroblasts harbouring mutations associated with the expression of a truncated/incomplete protein. The correction of pathological alterations by pantothenate in individual mutations was also verified in induced neurons obtained by direct reprograming of PKAN fibroblasts. Our observations indicate that pantothenate supplementation can increase/stabilize the expression levels of PANK2 in specific mutations. Fibroblasts and induced neurons derived from patients can provide a useful tool for recognizing PKAN patients who can respond to pantothenate treatment. The presence of low but significant PANK2 expression which can be increased in particular mutations gives valuable information which can support the treatment with high dose of pantothenate. The evaluation of personalized treatments in vitro of fibroblasts and neuronal cells derived from PKAN patients with a wide range of pharmacological options currently available, and monitoring its effect on the pathophysiological changes, can help for a better therapeutic strategy. In addition, these cell models will be also useful for testing the efficacy of new therapeutic options developed in the future.
Δευτέρα, 25 Φεβρουαρίου 2019
Improving the end-use quality traits is one of the primary objectives in wheat breeding programs. In the current study, a population of 127 recombinant inbred lines (RILs) derived from a cross between Glenn (PI-639273) and Traverse (PI-642780) was developed and used to identify quantitative trait loci (QTL) for 16 end-use quality traits in wheat. The phenotyping of these 16 traits was performed in nine environments in North Dakota, USA. The genotyping for the RIL population was conducted using the wheat Illumina iSelect 90K SNP assay. A high-density genetic linkage map consisting of 7,963 SNP markers identified a total of 76 additive QTL (A-QTL) and 73 digenic epistatic QTL (DE-QTL) associated with these traits. Overall, 12 stable major A-QTL and three stable DE-QTL were identified for these traits, suggesting that both A-QTL and DE-QTL played an important role in controlling end-use quality traits in wheat. The most significant A-QTL (AQ.MMLPT.ndsu.1B) was detected on chromosome 1B for mixograph middle line peak time. The AQ.MMLPT.ndsu.1B A-QTL was located very close to the position of the Glu-B1 gene encoding for a subunit of high molecular weight glutenin and explained up to 24.43% of phenotypic variation for mixograph MID line peak time. A total of 23 co-localized QTL loci were detected, suggesting the possibility of the simultaneous improvement of the end-use quality traits through selection procedures in wheat breeding programs. Overall, the information provided in this study could be used in marker-assisted selection to increase selection efficiency and to improve the end-use quality in wheat.
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Characterizing the genetic variation underlying phenotypic traits is a central objective in biological research. This research has been hampered in the past by the limited genomic resources available for most non-model species. However, recent advances in sequencing technologies and related genotyping methods are rapidly changing this. Here we report the use of genome-wide SNP data from the ecologically and commercially important marine fish species Chrysophrys auratus (snapper) to 1) construct the first linkage map for this species, 2) scan for growth QTLs, and 3) search for putative candidate genes in the surrounding QTL regions. The newly constructed linkage map contained ~11K SNP markers and is one of the densest maps to date in the fish family Sparidae. Comparisons with genome scaffolds of the recently assembled snapper genome indicated that marker placement was mostly consistent between the scaffolds and linkage map (R = 0.7), but that at fine scales (< 5 cM) some precision limitations occurred. Of the 24 linkage groups, which likely reflect the 24 chromosomes of this species, three were found to contain QTLs with genome-wide significance for growth-related traits. A scan of 13 candidate growth genes located the growth hormone, myogenin, and parvalbumin genes within 5.3, 9.6, and 25.0 cM of these QTLs, respectively. The linkage map and QTLs found in this study will advance the investigation of genome structure and aquaculture breeding efforts in this and related species.
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The protein titin plays a key role in vertebrate muscle where it acts like a giant molecular spring. Despite its importance and conservation over vertebrate evolution, a lack of high quality annotations in non-model species makes comparative evolutionary studies of titin challenging. The PEVK region of titin-named for its high proportion of Pro-Glu-Val-Lys amino acids-is particularly difficult to annotate due to its abundance of alternatively spliced isoforms and short, highly repetitive exons. To understand PEVK evolution across mammals, we developed a bioinformatics tool, PEVK_Finder, to annotate PEVK exons from genomic sequences of titin and applied it to a diverse set of mammals. PEVK_Finder consistently outperforms standard annotation tools across a broad range of conditions and improves annotations of the PEVK region in non-model mammalian species. We find that the PEVK region can be divided into two subregions (PEVK-N, PEVK-C) with distinct patterns of evolutionary constraint and divergence. The bipartite nature of the PEVK region has implications for titin diversification. In the PEVK-N region, certain exons are conserved and may be essential, but natural selection also acts on particular codons. In the PEVK-C, exons are more homogenous and length variation of the PEVK region may provide the raw material for evolutionary adaptation in titin function. The PEVK-C region can be further divided into a highly repetitive region (PEVK-CA) and one that is more variable (PEVK-CB). Taken together, we find that the very complexity that makes titin a challenge for annotation tools may also promote evolutionary adaptation.
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Quantification of dentin hypersensitivity (DH) is challenging and requires standardized, graded stimulation by natural‐like stimuli.
The present study aimed at identifying DH subjects and longitudinally monitoring their pain thresholds by cold air quantitative sensory testing (QST).
Subject recruitment started with an online DH questionnaire. Respondents were screened by dental air stimulation. Sensitizing and habituating subjects were excluded. A recently developed stimulation device was employed for cold air QST. Single tooth DH was verified by applying an equi‐intense stimulus to a control tooth. Descriptive statistics were applied for subject characteristics. Mean values were calculated for the stimulation parameters temperature and air flow. Reliability of temperatures for detecting pain and for evoking moderate pain over multiple time points within a three weeks period were analyzed by two‐way random single and average measures intra‐class correlation coefficients.
353 persons completed the online DH questionnaire of which 117 were screened. 44 passed the screening, yet 15 were excluded for various reasons. 29 subjects were monitored by QST across three weeks. Results revealed a high intra‐individual stability of the temperature inducing moderate to strong pain intensity (MPI) (single measures ICC of TMPI 0.83, p < 0.001). Mean TMPI was ‐13.69 °C, yet it highly varied among the 29 subjects (SD±10.04 °C).
Using a novel approach, namely dental QST based on cold air stimuli, we present evidence for temporally stable DH perceptions over a three weeks period. The method fulfills international guideline requirements and is recommendable for obtaining valid results when testing various interventions for DH management.
This article is protected by copyright. All rights reserved.
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Management of Peutz-Jeghers Syndrome in Children and Adolescents: A Position Paper From the ESPGHAN Polyposis Working Group
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Recanalization of Chronic Extrahepatic Portal Vein Obstruction in Pediatric Patients Using a Minilaparotomy Approach
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Intracellular Localization of Microbial Transglutaminase and Its Influence on the Transport of Gliadin in Enterocytes
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Are All Breast-fed Infants Equal? Clustering Metabolomics Data to Identify Predictive Risk Clusters for Childhood Obesity
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Clinical Safety and Utility of Pediatric Balloon-assisted Enteroscopy: A Multicenter Prospective Study in Japan
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Can Pediatric Endoscopists Accurately Assess Their Clinical Competency? A Comparison Across Skill Levels
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Prevalence of Celiac Disease in a Long-term Study of a Spanish At-genetic-risk Cohort From the General Population
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Ultrasound-Guided Botulinum Toxin Injections in Cervical Dystonia Needs Prompt Muscle Selection, Appropriate Dosage, and Precise Guidance
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Acute Phase Predictors of 6-Month Functional Outcome in Italian Stroke Patients Eligible for In-Hospital Rehabilitation: Erratum
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Effects of Video Games–Based Task-Oriented Activity Training (Xbox 360 Kinect) on Activity Performance and Participation in Patients With Juvenile Idiopathic Arthritis: A Randomized Clinical Trial
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Amputee Locomotion: Joint Moment Adaptations to Running Speed Using Running-Specific Prostheses after Unilateral Transtibial Amputation
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V-Mart, a Virtual Reality Grocery Store: A Focus Group Study of a Promising Intervention for Mild Traumatic Brain Injury and Posttraumatic Stress Disorder
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Morphological Changes of the Median Nerve After Carpal Tunnel Release in a Median Nerve Lipofibromatous Hamartoma
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An Investigation of Pressure Profiles and Wearer Comfort During Walking With a Transtibial Hydrocast Socket
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Motor Control Training Compared With Transcutaneous Electrical Nerve Stimulation in Patients With Disc Herniation With Associated Radiculopathy: A Randomized Controlled Trial
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The Effectiveness of Group-Based Physiotherapy-Led Behavioral Psychological Interventions on Adults With Chronic Low Back Pain: A Systematic Review and Meta-Analysis
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Mechanical In-exsufflation-Expiratory Flows as Indication for Tracheostomy Tube Decannulation: Case Studies
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Hypothesis Testing in Superiority, Noninferiority, and Equivalence Clinical Trials: Implications in Physical Medicine and Rehabilitation
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Author’s Response to Letter to the Editor on “Ultrasound-Guided Botulinum Toxin Injections in Cervical Dystonia Needs Prompt Muscle Selection, Appropriate Dosage, and Precise Guidance”
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Palm Oil and Beta-Palmitate in Infant Formula - A Position Paper by the ESPGHAN Committee on Nutrition
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Free-Breathing MRI Assessment of Body Composition in Healthy and Overweight Children: An Observational Study
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Effect of Ketoprofen and ATB-352 on the Immature Human Intestine: Identification of Responders and Non-Responders
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Disruption of the PTHLH regulatory landscape results in features consistent with hyperparathyroid disease
Parathyroid hormone like hormone (PTHLH) signaling is essential for the proper formation of bone and its elevation or disruption has been directly implicated in several different skeletal dysplasias. We report a patient with a 2.802 Mb deletion upstream of the PTHLH coding sequence who presents with multiple fractures, metaphyseal changes, and overall features consistent with hyperparathyroid like disease. Analysis of the deleted region revealed the loss of putative regulatory regions adjacent to PTHLH and the possible gain of a limb enhancer. Furthermore, PTHLH expression appeared to be mis‐regulated in fibroblasts derived from the patient. Altogether, we find that the disruption of the regulatory landscape of PTHLH likely results in its inappropriate expression and this novel clinical presentation.
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Cytosine methylation of mitochondrial DNA at CpG sequences impacts transcription factor A DNA binding and transcription
Publication date: Available online 23 February 2019
Source: Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Vishantie Dostal, Mair E.A. Churchill
In eukaryotes, cytosine methylation of nuclear DNA at CpG sequences (5mCpG) regulates epigenetic inheritance through alterations in chromatin structure. However, mitochondria lack nucleosomal chromatin, therefore the molecular mechanisms by which 5mCpG influences mitochondria must be different and are as yet unknown. Mitochondrial Transcription Factor A (TFAM) is both the primary DNA-compacting protein in the mitochondrial DNA (mtDNA) nucleoid and a transcription-initiation factor. TFAM must encounter hundreds of CpGs in mtDNA, so the occurrence of 5mCpG has the potential to impact TFAM-DNA recognition. We used biophysical approaches to determine whether 5mCpG alters any TFAM-dependent activities. 5mCpG in the heavy strand promoter (HSP1) increased the binding affinity of TFAM and induced TFAM multimerization with increased cooperativity compared to nonmethylated DNA. However, 5mCpG had no apparent effect on TFAM-dependent DNA compaction. Additionally, 5mCpG had a clear and context-dependent effect on transcription initiating from the three mitochondrial promoters. Taken together, our findings demonstrate that 5mCpG in the mitochondrial promoter region does impact TFAM-dependent activities in vitro.
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Coming full circle in cancer
Coming full circle in cancer, Published online: 25 February 2019; doi:10.1038/s41576-019-0104-8Three new studies characterize circular RNAs in cancer, with potential functional roles and clinical implications as biomarkers.
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Publication date: Available online 23 February 2019
Source: Journal of Genetics and Genomics
Author(s): Feng Chen, Fengling lai, Majing Luo, Yu-San Han, Hanhua Cheng, Rongjia Zhou
Insertion and deletion (indel) mutations, which can trigger single nucleotide substitutions on the flanking regions of genes, may generate abundant materials for disease defense, reproduction, species survival and evolution. However, genetic and evolutionary mechanisms of indels remain elusive. We establish a comparative genome-transcriptome-alignment approach for a large-scale identification of indels in Monopterus population. Over 2000 indels in 1738 indel genes, including 1‒21 bp deletions and 1‒15 bp insertions, were detected. Each indel gene had ∼1.1 deletions/insertions, and 2‒4 alleles in population. Frequencies of deletions were prominently higher than those of insertions on both genome and population levels. Most of the indels led to in frame mutations with multiples of three and majorly occurred in non-domain regions, indicating functional constraint or tolerance of the indels. All indel genes showed higher expression levels than non-indel genes during sex reversal. Slide window analysis of global expression levels in gonads showed a significant positive correlation with indel density in the genome. Moreover, indel genes were evolutionarily conserved and evolved slowly compared to non-indel genes. Notably, population genetic structure of indels revealed divergent evolution of Monopterus population, as bottleneck effect of biogeographic isolation by Taiwan Strait.
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Publication date: Available online 23 February 2019
Source: Journal of Genetics and Genomics
Author(s): Tao Tao, Jie Sun, Yajing Peng, Pei Wang, Xin Chen, Wei Zhao, Yeqiong Li, Lisha Wei, Wei Wang, Yan-Yan Zheng, Ye Wang, Xuena Zhang, Min-Sheng Zhu
As a critical guanine nucleotide exchange factor (GEF) regulating neurite outgrowth, Trio coordinates multiple processes of cytoskeletal dynamics through activating Rac1, Cdc42 and RhoA small GTPases by two GEF domains, but the in vivo roles of these GEF domains and corresponding downstream effectors have not been determined yet. We established multiple lines of knockout mice and assessed the respective roles of Trio GEF domains and Rac1 in axon outgrowth. Knockout of total Trio in cerebellar granule neurons (CGNs) led to an impaired F-actin rearrangement of growth cone and hence a retarded neurite outgrowth. Such a retardation was reproduced by inhibition of GEF1 domain or knockdown of Cdc42 and restored apparently by introduction of active Cdc42. As Rac1 deficiency did not affect the neurite outgrowth of CGNs, we suggested that Trio GEF1-mediated Cdc42 activation was required for neurite outgrowth. We established a GEF2-knockout line with deletion of all Trio isoforms except a cerebella-specific Trio8, a short isoform of Trio without GEF2 domain, and used this line as a GEF2-deficient animal model. The GEF2-deficient CGNs had a normal neurite outgrowth but abolished Netrin-1-promoted growth, without affecting Netrin-1 induced Rac1 activation. We thus suggested that Trio GEF1-mediated Cdc42 activation rather than Rac1 activation drives the F-actin dynamics necessary for neurite outgrowth, while GEF2 functions in Netrin-1-promoted neurite elongation. Our results delineated the distinct roles of Trio GEF domains in neurite outgrowth, which is instructive to understand the pathogenesis of clinical Trio-related neurodevelopmental disorders.
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