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1.
Ann Noninvasive Electrocardiol ; 29(2): e13108, 2024 03.
Article in English | MEDLINE | ID: mdl-38450594

ABSTRACT

An 81-year-old male with a history of coronary artery disease, hypertension, paroxysmal atrial fibrillation and chronic kidney disease presents with asymptomatic bradycardia. Examination was notable for an early diastolic heart sound. 12-lead electrocardiogram revealed sinus bradycardia with a markedly prolonged PR interval and second-degree atrioventricular block, type I Mobitz. We review the differential diagnosis of early diastolic heart sounds and present a case of Wenckebach associated with a variable early diastolic sound on physical exam.


Subject(s)
Atrial Fibrillation , Atrioventricular Block , Heart Sounds , Aged, 80 and over , Humans , Male , Atrial Fibrillation/diagnosis , Atrioventricular Block/diagnosis , Bradycardia , Electrocardiography , Heart Atria
2.
Stat Appl Genet Mol Biol ; 19(2)2020 07 13.
Article in English | MEDLINE | ID: mdl-32649296

ABSTRACT

A major challenge in plant developmental biology is to understand how plant growth is coordinated by interacting hormones and genes. To meet this challenge, it is important to not only use experimental data, but also formulate a mathematical model. For the mathematical model to best describe the true biological system, it is necessary to understand the parameter space of the model, along with the links between the model, the parameter space and experimental observations. We develop sequential history matching methodology, using Bayesian emulation, to gain substantial insight into biological model parameter spaces. This is achieved by finding sets of acceptable parameters in accordance with successive sets of physical observations. These methods are then applied to a complex hormonal crosstalk model for Arabidopsis root growth. In this application, we demonstrate how an initial set of 22 observed trends reduce the volume of the set of acceptable inputs to a proportion of 6.1 × 10-7 of the original space. Additional sets of biologically relevant experimental data, each of size 5, reduce the size of this space by a further three and two orders of magnitude respectively. Hence, we provide insight into the constraints placed upon the model structure by, and the biological consequences of, measuring subsets of observations.


Subject(s)
Arabidopsis/growth & development , Plant Growth Regulators/physiology , Plant Roots/growth & development , Analysis of Variance , Arabidopsis/genetics , Arabidopsis/metabolism , Bayes Theorem , Computer Simulation , Gene Expression Regulation, Plant/genetics , Models, Biological , Plant Roots/genetics , Plant Roots/metabolism
3.
FASEB J ; 32(1): 195-207, 2018 01.
Article in English | MEDLINE | ID: mdl-28904018

ABSTRACT

Mitochondrial trafficking plays a central role in dorsal root ganglion (DRG) neuronal cell survival and neurotransmission by transporting mitochondria from the neuronal cell body throughout the bundles of DRG axons. In type 2 diabetes (T2DM), dyslipidemia and hyperglycemia damage DRG neurons and induce mitochondrial dysfunction; however, the impact of free fatty acids and glucose on mitochondrial trafficking in DRG neurons remains unknown. To evaluate the impact of free fatty acids compared to hyperglycemia on mitochondrial transport, primary adult mouse DRG neuron cultures were treated with physiologic concentrations of palmitate and glucose and assessed for alterations in mitochondrial trafficking, mitochondrial membrane potential, and mitochondrial bioenergetics. Palmitate treatment significantly reduced the number of motile mitochondria in DRG axons, but physiologic concentrations of glucose did not impair mitochondrial trafficking dynamics. Palmitate-treated DRG neurons also exhibited a reduction in mitochondrial velocity, and impaired mitochondrial trafficking correlated with mitochondrial depolarization in palmitate-treated DRG neurons. Finally, we found differential bioenergetic effects of palmitate and glucose on resting and energetically challenged mitochondria in DRG neurons. Together, these results suggest that palmitate induces DRG neuron mitochondrial depolarization, inhibiting axonal mitochondrial trafficking and altering mitochondrial bioenergetic capacity.-Rumora, A. E., Lentz, S. I., Hinder, L. M., Jackson, S. W., Valesano, A., Levinson, G. E., Feldman, E. L. Dyslipidemia impairs mitochondrial trafficking and function in sensory neurons.


Subject(s)
Dyslipidemias/metabolism , Mitochondria/metabolism , Sensory Receptor Cells/metabolism , Animals , Cells, Cultured , Diabetes Mellitus, Experimental/metabolism , Dyslipidemias/pathology , Energy Metabolism/drug effects , Ganglia, Spinal/drug effects , Ganglia, Spinal/metabolism , Ganglia, Spinal/pathology , Gene Dosage , Glucose/metabolism , Glucose/pharmacology , Humans , Hyperglycemia/metabolism , Membrane Potential, Mitochondrial/drug effects , Mice , Mice, Inbred C57BL , Mitochondria/drug effects , Mitochondria/genetics , Movement/drug effects , Palmitic Acid/metabolism , Palmitic Acid/pharmacology , Sensory Receptor Cells/drug effects , Sensory Receptor Cells/pathology
4.
J Chem Phys ; 150(15): 154301, 2019 Apr 21.
Article in English | MEDLINE | ID: mdl-31005103

ABSTRACT

Finding the possible stopping sites for muons inside a crystalline sample is a key problem of muon spectroscopy. In a previous study, we suggested a computational approach to this problem when dealing with muonium, the pseudoatom formed by a positive muon that has captured an electron, using density functional theory software in combination with a random structure searching approach that relies on a Poisson sphere distribution. In this work, we test this methodology further by applying it to muonium in three organic molecular crystal model systems: durene, bithiophene, and tetracyanoquinodimethane. Using the same sets of random structures, we compare the performance of density functional theory software CASTEP and the much faster lower level approximation of Density Functional Tight Binding provided by DFTB+ combined with the use of the 3ob-3-1 parameter set. We show the benefits and limitations of such an approach, and we propose the use of DFTB+ as a viable alternative to more cumbersome simulations for routine site-finding in organic materials. Finally, we introduce the Muon Spectroscopy Computational Project software suite, a library of Python tools meant to make these methods standardized and easy to use.

5.
J Neurosci ; 36(3): 762-72, 2016 Jan 20.
Article in English | MEDLINE | ID: mdl-26791207

ABSTRACT

The interneuronal propagation of aggregated tau is believed to play an important role in the pathogenesis of human tauopathies. It requires the uptake of seed-competent tau into cells, seeding of soluble tau in recipient neurons and release of seeded tau into the extracellular space to complete the cycle. At present, it is not known which tau species are seed-competent. Here, we have dissected the molecular characteristics of seed-competent tau species from the TgP301S tau mouse model using various biochemical techniques and assessed their seeding ability in cell and animal models. We found that sucrose gradient fractions from brain lysates seeded cellular tau aggregation only when large (>10 mer) aggregated, hyperphosphorylated (AT8- and AT100-positive) and nitrated tau was present. In contrast, there was no detectable seeding by fractions containing small, oligomeric (<6 mer) tau. Immunodepletion of the large aggregated AT8-positive tau strongly reduced seeding; moreover, fractions containing these species initiated the formation and spreading of filamentous tau pathology in vivo, whereas fractions containing tau monomers and small oligomeric assemblies did not. By electron microscopy, seed-competent sucrose gradient fractions contained aggregated tau species ranging from ring-like structures to small filaments. Together, these findings indicate that a range of filamentous tau aggregates are the major species that underlie the spreading of tau pathology in the P301S transgenic model. Significance statement: The spread of tau pathology from neuron to neuron is postulated to account for, or at least to contribute to, the overall propagation of tau pathology during the development of human tauopathies including Alzheimer's disease. It is therefore important to characterize the native tau species responsible for this process of seeding and pathology spreading. Here, we use several biochemical techniques to dissect the molecular characteristics of native tau protein conformers from TgP301S tau mice and show that seed-competent tau species comprise small fibrils capable of seeding tau pathology in cell and animal models. Characterization of seed-competent tau gives insight into disease mechanisms and therapeutic interventions.


Subject(s)
Amyloid/genetics , Brain , Neurofibrillary Tangles/genetics , Tauopathies/genetics , tau Proteins/genetics , Animals , Brain/pathology , Female , HEK293 Cells , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neurofibrillary Tangles/pathology , Tauopathies/pathology
6.
Dig Dis Sci ; 62(10): 2623-2630, 2017 10.
Article in English | MEDLINE | ID: mdl-28836046

ABSTRACT

Hereditary hemorrhagic telangiectasia (HHT), also called Osler-Weber-Rendu syndrome, is an autosomal dominant genetic disease that affects the vasculature of numerous organs. The prevalence of HHT is estimated to be between 1.5 and 2 persons per 10,000. While there is still much to learn about this condition, there is an increasing understanding its underlying pathophysiology, genetic basis, presentations, and management. Recognizing that the clinical manifestations of HHT can involve a number of organ systems will provide clinicians with a higher index of suspicion for the disease. This early diagnosis and genotyping can greatly reduce mortality for a patient with HHT through appropriate screening for complications. This review will focus on the gastrointestinal manifestations of HHT and how these can dictate treatment and prognosis.


Subject(s)
Gastrointestinal Diseases/diagnosis , Telangiectasia, Hereditary Hemorrhagic/diagnosis , Animals , Biopsy , Endoscopy, Gastrointestinal , Gastrointestinal Diseases/epidemiology , Gastrointestinal Diseases/genetics , Gastrointestinal Diseases/therapy , Genetic Predisposition to Disease , Humans , Molecular Diagnostic Techniques , Phenotype , Physical Examination , Predictive Value of Tests , Prevalence , Prognosis , Risk Factors , Telangiectasia, Hereditary Hemorrhagic/epidemiology , Telangiectasia, Hereditary Hemorrhagic/genetics , Telangiectasia, Hereditary Hemorrhagic/therapy , Tomography, X-Ray Computed
7.
J Biol Chem ; 290(2): 1049-65, 2015 Jan 09.
Article in English | MEDLINE | ID: mdl-25406315

ABSTRACT

Intracellular Tau inclusions are a pathological hallmark of several neurodegenerative diseases, collectively known as the tauopathies. They include Alzheimer disease, tangle-only dementia, Pick disease, argyrophilic grain disease, chronic traumatic encephalopathy, progressive supranuclear palsy, and corticobasal degeneration. Tau pathology appears to spread through intercellular propagation, requiring the formation of assembled "prion-like" species. Several cell and animal models have been described that recapitulate aspects of this phenomenon. However, the molecular characteristics of seed-competent Tau remain unclear. Here, we have used a cell model to understand the relationships between Tau structure/phosphorylation and seeding by aggregated Tau species from the brains of mice transgenic for human mutant P301S Tau and full-length aggregated recombinant P301S Tau. Deletion of motifs (275)VQIINK(280) and (306)VQIVYK(311) abolished the seeding activity of recombinant full-length Tau, suggesting that its aggregation was necessary for seeding. We describe conformational differences between native and synthetic Tau aggregates that may account for the higher seeding activity of native assembled Tau. When added to aggregated Tau seeds from the brains of mice transgenic for P301S Tau, soluble recombinant Tau aggregated and acquired the molecular properties of aggregated Tau from transgenic mouse brain. We show that seeding is conferred by aggregated Tau that enters cells through macropinocytosis and seeds the assembly of endogenous Tau into filaments.


Subject(s)
Protein Aggregates , Protein Aggregation, Pathological/metabolism , Tauopathies/metabolism , tau Proteins/chemistry , Animals , Brain/metabolism , Brain/pathology , Cytoskeleton/metabolism , Cytoskeleton/pathology , Disease Models, Animal , HEK293 Cells , Humans , Mice , Mice, Transgenic , Phosphorylation , Protein Conformation , Tauopathies/pathology , tau Proteins/biosynthesis , tau Proteins/metabolism
8.
Hum Mol Genet ; 23(17): 4651-62, 2014 Sep 01.
Article in English | MEDLINE | ID: mdl-24760771

ABSTRACT

Duchenne muscular dystrophy (DMD) is a common and relentlessly progressive muscle disease. Some interventions have been identified that modestly slow progression and prolong survival, but more meaningful therapies are lacking. The goal of this study is to identify new therapeutic pathways for DMD using a zebrafish model of the disease. To accomplish this, we performed a non-biased drug screen in sapje, a zebrafish line with a recessive nonsense mutation in dystrophin. We identified 6 positive hits (out of 640 total drugs tested) by their ability to prevent abnormal birefringence in sapje. Follow-up analyses demonstrated that fluoxetine, a selective serotonin reuptake inhibitor (SSRI), provided the most substantial benefit. Morpholino-based experimentation confirmed that modulation of the serotonin pathway alone can prevent the dystrophic phenotype, and transcriptomic analysis revealed changes in calcium homeostasis as a potential mechanism. In all, we demonstrate that monoamine agonists can prevent disease in a vertebrate model of DMD. Given the safe and widespread use of SSRIs in clinical practice, our study identifies an attractive target pathway for therapy development.


Subject(s)
Fluoxetine/therapeutic use , Muscular Dystrophy, Animal/drug therapy , Muscular Dystrophy, Duchenne/drug therapy , Zebrafish/physiology , Animals , Base Sequence , Birefringence , Calcium/metabolism , Disease Models, Animal , Drug Evaluation, Preclinical , Dystrophin/metabolism , Embryo, Nonmammalian/drug effects , Embryo, Nonmammalian/metabolism , Evans Blue/metabolism , Fluoxetine/pharmacology , Gene Expression Profiling , Gene Knockdown Techniques , Homeostasis/drug effects , Molecular Sequence Data , Morpholinos/pharmacology , Muscular Dystrophy, Animal/genetics , Muscular Dystrophy, Animal/pathology , Muscular Dystrophy, Duchenne/genetics , Muscular Dystrophy, Duchenne/pathology , Oligonucleotide Array Sequence Analysis , Phenotype , Serotonin Plasma Membrane Transport Proteins/metabolism , Stress, Mechanical , Survival Analysis , Zebrafish/embryology , Zebrafish/genetics
9.
Regul Toxicol Pharmacol ; 80: 348-57, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27155597

ABSTRACT

Central Nervous System (CNS)-related safety concerns are major contributors to delays and failure during the development of new candidate drugs (CDs). CNS-related safety data on 141 small molecule CDs from five pharmaceutical companies were analyzed to identify the concordance between rodent multi-parameter neurofunctional assessments (Functional Observational Battery: FOB, or Irwin test: IT) and the five most common adverse events (AEs) in Phase I clinical trials, namely headache, nausea, dizziness, fatigue/somnolence and pain. In the context of this analysis, the FOB/IT did not predict the occurrence of these particular AEs in man. For AEs such as headache, nausea, dizziness and pain the results are perhaps unsurprising, as the FOB/IT were not originally designed to predict these AEs. More unexpected was that the FOB/IT are not adequate for predicting 'somnolence/fatigue' nonclinically. In drug development, these five most prevalent AEs are rarely responsible for delaying or stopping further progression of CDs. More serious AEs that might stop CD development occurred at too low an incidence rate in our clinical dataset to enable translational analysis.


Subject(s)
Behavior, Animal/drug effects , Central Nervous System Diseases/chemically induced , Central Nervous System/drug effects , Clinical Trials, Phase I as Topic , Drug-Related Side Effects and Adverse Reactions/etiology , Toxicity Tests/methods , Animals , Central Nervous System/physiopathology , Central Nervous System Diseases/physiopathology , Dose-Response Relationship, Drug , Drug-Related Side Effects and Adverse Reactions/physiopathology , Humans , Mice , Rats , Reproducibility of Results , Risk Assessment , Species Specificity
10.
Acta Neuropathol ; 127(5): 667-83, 2014 May.
Article in English | MEDLINE | ID: mdl-24531916

ABSTRACT

Intracellular inclusions composed of hyperphosphorylated filamentous tau are a hallmark of Alzheimer's disease, progressive supranuclear palsy, Pick's disease and other sporadic neurodegenerative tauopathies. Recent in vitro and in vivo studies have shown that tau aggregates do not only seed further tau aggregation within neurons, but can also spread to neighbouring cells and functionally connected brain regions. This process is referred to as 'tau propagation' and may explain the stereotypic progression of tau pathology in the brains of Alzheimer's disease patients. Here, we describe a novel in vivo model of tau propagation using human P301S tau transgenic mice infused unilaterally with brain extract containing tau aggregates. Infusion-related neurofibrillary tangle pathology was first observed 2 weeks post-infusion and increased in a stereotypic, time-dependent manner. Contralateral and anterior/posterior spread of tau pathology was also evident in nuclei with strong synaptic connections (efferent and afferent) to the site of infusion, indicating that spread was dependent on synaptic connectivity rather than spatial proximity. This notion was further supported by infusion-related tau pathology in white matter tracts that interconnect these regions. The rapid and robust propagation of tau pathology in this model will be valuable for both basic research and the drug discovery process.


Subject(s)
Brain/pathology , Neurofibrillary Tangles/pathology , Tauopathies/pathology , tau Proteins/metabolism , Animals , Brain/metabolism , Disease Models, Animal , Disease Progression , Female , Hippocampus/metabolism , Hippocampus/pathology , Humans , Immunohistochemistry , Mice, Inbred C57BL , Mice, Transgenic , Neural Pathways/metabolism , Neural Pathways/pathology , Neurofibrillary Tangles/metabolism , Random Allocation , Synapses/metabolism , Synapses/pathology , Tauopathies/metabolism , Time Factors , White Matter/metabolism , White Matter/pathology , tau Proteins/genetics
11.
Mol Ther Nucleic Acids ; 35(1): 102117, 2024 Mar 12.
Article in English | MEDLINE | ID: mdl-38304729

ABSTRACT

Identifying therapeutic oligonucleotides that are cross-reactive to experimental animal species can dramatically accelerate the process of preclinical development and clinical translation. Here, we identify fully chemically-modified small interfering RNAs (siRNAs) that are cross-reactive to Janus kinase 1 (JAK1) in humans and a large variety of other species. We validated the identified siRNAs in silencing JAK1 in cell lines and skin tissues of multiple species. JAK1 is one of the four members of the JAK family of tyrosine kinases that mediate the signaling transduction of many inflammatory cytokine pathways. Dysregulation of these pathways is often involved in the pathogenesis of various immune disorders, and modulation of JAK family enzymes is an effective strategy in the clinic. Thus, this work may open up unprecedented opportunities for evaluating the modulation of JAK1 in many animal models of human inflammatory skin diseases. Further chemical engineering of the optimized JAK1 siRNAs may expand the utility of these compounds for treating immune disorders in additional tissues.

12.
Big Data ; 12(2): 155-172, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37289808

ABSTRACT

Diabetic foot ulcer (DFU) is a problem worldwide, and prevention is crucial. The image segmentation analysis of DFU identification plays a significant role. This will produce different segmentation of the same idea, incomplete, imprecise, and other problems. To address these issues, a method of image segmentation analysis of DFU through internet of things with the technique of virtual sensing for semantically similar objects, the analysis of four levels of range segmentation (region-based, edge-based, image-based, and computer-aided design-based range segmentation) for deeper segmentation of images is implemented. In this study, the multimodal is compressed with the object co-segmentation for semantical segmentation. The result is predicting the better validity and reliability assessment. The experimental results demonstrate that the proposed model can efficiently perform segmentation analysis, with a lower error rate, than the existing methodologies. The findings on the multiple-image dataset show that DFU obtains an average segmentation score of 90.85% and 89.03% correspondingly in two types of labeled ratios before DFU with virtual sensing and after DFU without virtual sensing (i.e., 25% and 30%), which is an increase of 10.91% and 12.22% over the previous best results. In live DFU studies, our proposed system improved by 59.1% compared with existing deep segmentation-based techniques and its average image smart segmentation improvements over its contemporaries are 15.06%, 23.94%, and 45.41%, respectively. Proposed range-based segmentation achieves interobserver reliability by 73.9% on the positive test namely likelihood ratio test set with only a 0.25 million parameters at the pace of labeled data.


Subject(s)
Diabetes Mellitus , Diabetic Foot , Internet of Things , Humans , Diabetic Foot/diagnostic imaging , Reproducibility of Results , Internet
13.
Clin Child Psychol Psychiatry ; 28(4): 1495-1508, 2023 Oct.
Article in English | MEDLINE | ID: mdl-36876474

ABSTRACT

Mental health difficulties in the preschool years require early intervention, but preschool children are underserved in mental healthcare. One explanation might be that parents do not seek services because their problem recognition, or labeling, ability is lacking. While previous research demonstrates that labeling is positively associated with help-seeking, interventions aimed at improving help-seeking by improving labeling are not always successful. Parental perceptions of severity, impairment, and stress also predict help-seeking, but have not been examined alongside labeling. Thus, it is unclear how much they add to the parental help-seeking process. The present study simultaneously examined labeling and parental perceptions of severity, impairment, and stress on help-seeking. Participants (82 adult mothers of children ages 3-5 years) read vignettes describing preschool-aged children with symptoms of depression, anxiety, and ADHD, and answered a series of questions to assess their labeling and likelihood of help-seeking for each of the problems presented. Help-seeking was found to be positively associated with labeling (r = .73; r = .60), severity (r = .66), impairment (r = .31), and stress (r = .25). Furthermore, severity, impairment, and stress predicted endorsements of help-seeking above and beyond what was predicted by labeling alone (R2 change = .12; χ2 (3) = 20.03, p < .01). These results underscore the importance of parental perceptions of children's behavior to the help-seeking process.


Subject(s)
Help-Seeking Behavior , Adult , Female , Humans , Child, Preschool , Mothers/psychology , Parents/psychology , Mental Health , Anxiety Disorders , Patient Acceptance of Health Care/psychology
14.
bioRxiv ; 2023 Jul 05.
Article in English | MEDLINE | ID: mdl-37461560

ABSTRACT

Nonalcoholic steatohepatitis (NASH) is a malady of multiple cell types associated with hepatocyte triglyceride (TG) accumulation, macrophage inflammation, and stellate cell-induced fibrosis, with no approved therapeutics yet available. Here, we report that stellate cell fatty acid synthase (FASN) in de novo lipogenesis drives the autophagic flux that is required for stellate cell activation and fibrotic collagen production. Further, we employ a dual targeting approach to NASH that selectively depletes collagen through selective stellate cell knockout of FASN (using AAV9-LRAT Cre in FASNfl/fl mice), while lowering hepatocyte triglyceride by depleting DGAT2 with a GalNac-conjugated, fully chemically modified siRNA. DGAT2 silencing in hepatocytes alone or in combination with stellate cell FASNKO reduced liver TG accumulation in a choline-deficient NASH mouse model, while FASNKO in hepatocytes alone (using AAV8-TBG Cre in FASNfl/fl mice) did not. Neither hepatocyte DGAT2 silencing alone nor FASNKO in stellate cells alone decreased fibrosis (total collagen), while loss of both DGAT2 plus FASN caused a highly significant attenuation of NASH. These data establish proof of concept that dual targeting of DGAT2 plus FASN alleviates NASH progression in mice far greater than targeting either gene product alone.

15.
Cureus ; 14(1): e21166, 2022 Jan.
Article in English | MEDLINE | ID: mdl-35165616

ABSTRACT

A comprehensive understanding of the anatomical variations of the internal jugular vein (IJV) is essential to prevent inadvertent injuries during neck procedures, particularly neck dissection. In addition, its relationship with the spinal accessory nerve in the upper part of the neck is relatively variable. IJV fenestration refers to bifurcation of the vein with reunion proximal to the subclavian vein, whereas IJV duplication refers to continued branching till joining the subclavian vein separately. We report a case of a fenestrated IJV identified intraoperatively with the spinal accessory nerve passing laterally to both divisions.

16.
J Neuroinflammation ; 8: 76, 2011 Jul 05.
Article in English | MEDLINE | ID: mdl-21729281

ABSTRACT

INTRODUCTION: Microglial activation in multiple sclerosis has been postulated to contribute to long-term neurodegeneration during disease. Fingolimod has been shown to impact on the relapsing remitting phase of disease by modulating autoreactive T-cell egress from lymph organs. In addition, it is brain penetrant and has been shown to exert multiple effects on nervous system cells. METHODS: In this study, the impact of fingolimod and other sphingosine-1-phosphate receptor active molecules following lysophosphotidyl choline-induced demyelination was examined in the rat telencephalon reaggregate, spheroid cell culture system. The lack of immune system components allowed elucidation of the direct effects of fingolimod on CNS cell types in an organotypic situation. RESULTS: Following demyelination, fingolimod significantly augmented expression of myelin basic protein in the remyelination phase. This increase was not associated with changes in neurofilament levels, indicating de novo myelin protein expression not associated with axonal branching. Myelin wrapping was confirmed morphologically using confocal and electron microscopy. Increased remyelination was associated with down-regulation of microglial ferritin, tumor necrosis factor alpha and interleukin 1 during demyelination when fingolimod was present. In addition, nitric oxide metabolites and apoptotic effectors caspase 3 and caspase 7 were reduced during demyelination in the presence of fingolimod. The sphingosine-1-phosphate receptor 1 and 5 agonist BAF312 also increased myelin basic protein levels, whereas the sphingosine-1-phosphate receptor 1 agonist AUY954 failed to replicate this effect on remyelination. CONCLUSIONS: The results presented indicate that modulation of S1P receptors can ameliorate pathological effectors associated with microglial activation leading to a subsequent increase in protein and morphological markers of remyelination. In addition, sphingosine-1-phosphate receptor 5 is implicated in promoting remyelination in vitro. This knowledge may be of benefit for treatment of chronic microglial inflammation in multiple sclerosis.


Subject(s)
Biomarkers/metabolism , Immunosuppressive Agents/pharmacology , Microglia/drug effects , Microglia/physiology , Myelin Sheath/metabolism , Propylene Glycols/pharmacology , Sphingosine/analogs & derivatives , Animals , Cell Culture Techniques , Cells, Cultured , Demyelinating Diseases/chemically induced , Demyelinating Diseases/pathology , Female , Fingolimod Hydrochloride , Humans , Immunosuppressive Agents/therapeutic use , Lysophosphatidylcholines/pharmacology , Microglia/cytology , Multiple Sclerosis, Relapsing-Remitting/immunology , Multiple Sclerosis, Relapsing-Remitting/pathology , Myelin Basic Protein/metabolism , Nerve Degeneration/drug therapy , Nerve Degeneration/pathology , Pregnancy , Propylene Glycols/therapeutic use , Rats , Rats, Sprague-Dawley , Receptors, Lysosphingolipid/metabolism , Spheroids, Cellular/cytology , Spheroids, Cellular/drug effects , Spheroids, Cellular/physiology , Sphingosine/pharmacology , Sphingosine/therapeutic use
17.
Mult Scler ; 17(8): 939-48, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21459808

ABSTRACT

BACKGROUND: There has been poor translation for the use of immunosuppressive agents from experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), into the treatment of MS. This may be due to the fact that most EAE studies examine prophylactic, pre-treatment regimes that prove to be therapeutically-ineffective in long-established, often progressive, MS. FTY720 (fingolimod/Gilenya) is a sphingosine-1-phosphate receptor modulator. This is a new oral agent that markedly reduces the number of relapses in people with MS, compared with currently licensed injectable agents such as the beta interferons. FTY720 has activity against lymphocytes but may also influence oligodendroglia and could therefore have the potential to influence progressive MS, by promoting remyelination. METHODS: The effect of FTY720 was assessed in relapsing-progressive EAE in mice. RESULTS: Early intervention during relapsing EAE could completely inhibit subsequent relapses, inhibited the accumulation of neurodegeneration, and facilitated motor recovery. However, when examined in secondary progressive EAE, that develops after the accumulation of deficit from relapsing disease, long-term treatment with FTY720 failed to slow deterioration when initiated late (4 months) into the disease course. CONCLUSIONS: This study indicates that early intervention with immunosuppressive agents may inhibit the generation of the neurodegenerative microenvironment, which is no longer responsive to potent immunosuppression. However, if treatment is initiated too late, progressive, neurological-disease continues unabated. This suggests that immunosuppression is insufficient to control secondary progression in animals, as has been found so far to be the case in MS, and may warrant early intervention with FTY720 for optimal treatment benefit.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/drug therapy , Immunosuppressive Agents/therapeutic use , Nerve Degeneration/drug therapy , Propylene Glycols/therapeutic use , Sphingosine/analogs & derivatives , Animals , Disease Progression , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Fingolimod Hydrochloride , Male , Mice , Recovery of Function/drug effects , Sphingosine/therapeutic use
18.
Work ; 68(3): 913-922, 2021.
Article in English | MEDLINE | ID: mdl-33612533

ABSTRACT

BACKGROUND: For campus workplace secure text mining, robotic assistance with feature optimization is essential. The space model of the vector is usually used to represent texts. Besides, there are still two drawbacks to this basic approach: the curse and lack of semantic knowledge. OBJECTIVES: This paper proposes a new Meta-Heuristic Feature Optimization (MHFO) method for data security in the campus workplace with robotic assistance. Firstly, the terms of the space vector model have been mapped to the concepts of data protection ontology, which statistically calculate conceptual frequency weights by term various weights. Furthermore, according to the designs of data protection ontology, the weight of theoretical identification is allocated. The dimensionality of functional areas is reduced significantly by combining standard frequency weights and weights based on data protection ontology. In addition, semantic knowledge is integrated into this process. RESULTS: The results show that the development of the characteristics of this process significantly improves campus workplace secure text mining. CONCLUSION: The experimental results show that the development of the features of the concept hierarchy structure process significantly enhances data security of campus workplace text mining with robotic assistance.


Subject(s)
Heuristics , Robotic Surgical Procedures , Computer Security , Data Mining , Humans , Semantics , Workplace
19.
Br Med Bull ; 95: 79-104, 2010.
Article in English | MEDLINE | ID: mdl-20603280

ABSTRACT

Multiple sclerosis (MS) is the commonest disabling neurological condition to afflict young adults and therefore has a high social burden. Over several decades, there has been a considerable progress in the understanding of the disease pathogenesis as well as in the clinical management of MS patients. The emphasis in managing MS patients has shifted to multidisciplinary teams working in specialist groups. A review of the literature was conducted using MedLine to identify recent advances in MS. The current consensus is that MS is an autoimmune disease triggered by environmental agents acting in genetically susceptible people. Based on that concept, new methods of immune intervention procedures have been introduced into clinical practice. Licensed first-line disease-modifying therapies reduce the MS attack or relapse rate by a third and delaying short-term disease progression. More effective therapies have emerged; however, these are associated with increased risks. New clinical and pathological insights are making us question the aetiology and pathogenesis of MS. The recognition of pathological heterogeneity has raised the question of whether MS is a single disease entity or a syndrome. Recent evidence suggests that the pathological subtype may predict therapeutic response to specific therapies. A new novel auto-antibody has defined a subset of neuromyelitis optica or Devic's disease as being distinct from MS. This is an attractive concept that is not widely accepted. The observation that MS progresses despite immunosuppressive therapy suggests that MS may be a neurodegenerative disease with overlapping immune activation possibly in response to the release of central nervous system auto-antigens. The development of neuroprotective therapies for MS is required to prevent the devastating effects of long-term disability as a result of progressive disease.


Subject(s)
Autoimmune Diseases/immunology , Genetic Predisposition to Disease , Immunosuppressive Agents/therapeutic use , Multiple Sclerosis/immunology , Adult , Autoimmune Diseases/drug therapy , Autoimmune Diseases/genetics , Disease Progression , Female , Humans , Male , Multiple Sclerosis/drug therapy , Multiple Sclerosis/genetics , Severity of Illness Index , Sex Factors
20.
J Anim Sci ; 98(3)2020 Mar 01.
Article in English | MEDLINE | ID: mdl-32052008

ABSTRACT

The use of portable X-ray fluorescence (PXRF) spectrometry to detect external markers on processed or unprocessed cattle and sheep fecal specimens to estimate apparent total tract digestibility (ATTD) was evaluated. Exp. 1: ruminally cannulated Angus-crossbred steers (n = 7; BW = 520 ± 30 kg) were individually fed ad libitum for 21 d in a completely randomized design (CRD). Markers (Cr2O3 and TiO2) were placed inside the rumen twice daily (7.5 g of each marker). Fecal samples were collected twice daily from day 14 to 21. Exp. 2: crossbred wethers (n = 8; BW = 68 ± 3 kg) were individually fed ad libitum for 21 d in a CRD. During this period, 2 g of Cr2O3 and TiO2 were top-dressed onto the feed twice daily. Sheep were housed in metabolism crates for 5 d for total fecal collection. Concentration of markers was determined on diets, refusals, and fecal specimens (fresh, dry-only, and dried/ground) using atomic absorption to detect Cr and spectrophotometry for Ti. Concentration of both markers was also determined via the PXRF spectrometer. Delta between ATTD estimated by wet chemistry and PXRF was not different from zero (P ≥ 0.14) when using cattle fresh fecal specimens for both markers, whereas ATTD estimated by PXRF with dry-only and dried/ground fecal specimens were 3.6 and 1.1 percent units lower (P ≤ 0.04), respectively, than ATTD estimated by wet chemistry for Cr and Ti, respectively. Regardless of the fecal sample preparation method on cattle specimens, Ti concentration was similar (P = 0.39) among methodologies, while Cr was underestimated (P < 0.01) by 13% when PXRF was used in dry-only or dried/ground samples. The ATTD of sheep was underestimated (P < 0.01) by 2.4 percent units compared with control when Cr was measured by PXRF in dry-only samples. The Cr concentration in dry-only fecal specimens of sheep tended (P = 0.09) to be lower compared with wet chemistry analysis. Fresh and dry/ground sheep fecal samples assessed for Cr, and dry-only assessed for Ti were not (P ≥ 0.49) affected by detection method. The Cr fecal recovery tended (P = 0.10) to be the lowest for dry-only, the greatest for wet chemistry, intermediate for fresh and dry/ground sheep-fecal specimens; while not affected (P = 0.40) for Ti. The PXRF is an accurate technology to detect Cr and Ti in fresh cattle fecal samples to estimate ATTD. For fresh and dry/ground, the technology was effective for determining the concentration of Cr, or dry-only fecal specimens when detecting Ti in sheep specimens.


Subject(s)
Cattle/anatomy & histology , Digestion/physiology , Gastrointestinal Tract/diagnostic imaging , Gastrointestinal Tract/physiology , Sheep/anatomy & histology , Spectrometry, X-Ray Emission/veterinary , Animal Feed/analysis , Animals , Diet/veterinary , Feces/chemistry , Gastrointestinal Motility , Male , Rumen/metabolism
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