ABSTRACT
Notch2 and B cell antigen receptor (BCR) signaling determine whether transitional B cells become marginal zone B (MZB) or follicular B (FoB) cells in the spleen, but it is unknown how these pathways are related. We generated Taok3-/- mice, lacking the serine/threonine kinase Taok3, and found cell-intrinsic defects in the development of MZB but not FoB cells. Type 1 transitional (T1) B cells required Taok3 to rapidly respond to ligation by the Notch ligand Delta-like 1. BCR ligation by endogenous or exogenous ligands induced the surface expression of the metalloproteinase ADAM10 on T1 B cells in a Taok3-dependent manner. T1 B cells expressing surface ADAM10 were committed to becoming MZB cells in vivo, whereas T1 B cells lacking expression of ADAM10 were not. Thus, during positive selection in the spleen, BCR signaling causes immature T1 B cells to become receptive to Notch ligands via Taok3-mediated surface expression of ADAM10.
Subject(s)
ADAM10 Protein/metabolism , Adaptive Immunity , Amyloid Precursor Protein Secretases/metabolism , B-Lymphocytes/physiology , Cell Differentiation , Cell Lineage , Germinal Center/immunology , Membrane Proteins/metabolism , Protein Serine-Threonine Kinases/metabolism , ADAM10 Protein/genetics , Amyloid Precursor Protein Secretases/genetics , Animals , Cells, Cultured , Clonal Selection, Antigen-Mediated , Gene Expression Regulation , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Protein Serine-Threonine Kinases/genetics , Receptor, Notch2/metabolism , Receptors, Antigen, B-Cell/metabolism , Signal TransductionABSTRACT
The role of the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress in homeostasis of the immune system is incompletely understood. Here we found that dendritic cells (DCs) constitutively activated the UPR sensor IRE-1α and its target, the transcription factor XBP-1, in the absence of ER stress. Loss of XBP-1 in CD11c+ cells led to defects in phenotype, ER homeostasis and antigen presentation by CD8α+ conventional DCs, yet the closely related CD11b+ DCs were unaffected. Whereas the dysregulated ER in XBP-1-deficient DCs resulted from loss of XBP-1 transcriptional activity, the phenotypic and functional defects resulted from regulated IRE-1α-dependent degradation (RIDD) of mRNAs, including those encoding CD18 integrins and components of the major histocompatibility complex (MHC) class I machinery. Thus, a precisely regulated feedback circuit involving IRE-1α and XBP-1 controls the homeostasis of CD8α+ conventional DCs.
Subject(s)
Cross-Priming/immunology , DNA-Binding Proteins/immunology , Dendritic Cells/immunology , Endoribonucleases/immunology , Protein Serine-Threonine Kinases/immunology , Protein Unfolding , Transcription Factors/immunology , Unfolded Protein Response/immunology , Animals , Antigen Presentation/immunology , CD8 Antigens/immunology , CD8 Antigens/metabolism , DNA-Binding Proteins/metabolism , Dendritic Cells/metabolism , Endoplasmic Reticulum/immunology , Endoribonucleases/metabolism , Feedback, Physiological/physiology , Homeostasis/immunology , Immunoblotting , Immunohistochemistry , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Electron , Oligonucleotide Array Sequence Analysis , Protein Serine-Threonine Kinases/metabolism , Regulatory Factor X Transcription Factors , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factors/metabolism , X-Box Binding Protein 1ABSTRACT
Antigen-presenting conventional dendritic cells (cDCs) are broadly divided into type 1 and type 2 subsets that further adapt their phenotype and function to perform specialized tasks in the immune system. The precise signals controlling tissue-specific adaptation and differentiation of cDCs are currently poorly understood. We found that mice deficient in the Ste20 kinase Thousand and One Kinase 3 (TAOK3) lacked terminally differentiated ESAM+ CD4+ cDC2s in the spleen and failed to prime CD4+ T cells in response to allogeneic red-blood-cell transfusion. These NOTCH2- and ADAM10-dependent cDC2s were absent selectively in the spleen, but not in the intestine of Taok3-/- and CD11c-cre Taok3fl/fl mice. The loss of splenic ESAM+ cDC2s was cell-intrinsic and could be rescued by conditional overexpression of the constitutively active NOTCH intracellular domain in CD11c-expressing cells. Therefore, TAOK3 controls the terminal differentiation of NOTCH2-dependent splenic cDC2s.
Subject(s)
Cell Differentiation , Dendritic Cells/cytology , Dendritic Cells/enzymology , Protein Kinases/metabolism , Receptor, Notch2/metabolism , Spleen/cytology , Animals , Antigens, CD/metabolism , CD4-Positive T-Lymphocytes/immunology , Gene Expression Regulation , Intestine, Small/metabolism , Mice, Inbred C57BL , Phenotype , Protein Domains , Protein Kinases/deficiency , Receptor, Notch2/chemistry , Signal TransductionABSTRACT
Precise detection of brain regions harboring heightened electrical activity plays a central role in the understanding and treatment of diseases such as epilepsy. Superparamagnetic iron oxide nanoparticles (SPIONs) react to magnetic fields by aggregating and represent interesting candidates as new sensors for neuronal magnetic activity. We hypothesized that SPIONs in aqueous solution close to active brain tissue would aggregate proportionally to neuronal activity. We tested this hypothesis using an in vitro model of rat brain slice with different levels of activity. Aggregation was assessed with dynamic light scattering (DLS) and magnetic resonance imaging (MRI). We found that increasing brain slice activity was associated with higher levels of aggregation as measured by DLS and MRI, suggesting that the magnetic fields from neuronal tissue could induce aggregation in nearby SPIONs in solution. MRI signal change induced by SPIONs aggregation could serve as a powerful new tool for detection of brain electrical activity.
Subject(s)
Magnetite Nanoparticles , Animals , Brain , Magnetic Iron Oxide Nanoparticles , Magnetic Resonance Imaging/methods , Neurons , RatsABSTRACT
Current anabolic drugs to treat osteoporosis and other disorders of low bone mass all have important limitations in terms of toxicity, contraindications, or poor efficacy in certain contexts. Addressing these limitations will require a better understanding of the molecular pathways, such as the mitogen activated protein kinase (MAPK) pathways, that govern osteoblast differentiation and, thereby, skeletal mineralization. Whereas MAP3Ks functioning in the extracellular signal-regulated kinases (ERK) and p38 pathways have been identified in osteoblasts, MAP3Ks mediating proximal activation of the c-Jun N-terminal kinase (JNK) pathway have yet to be identified. Here, we demonstrate that thousand-and-one kinase 3 (TAOK3, MAP3K18) functions as an upstream activator of the JNK pathway in osteoblasts both in vitro and in vivo. Taok3-deficient osteoblasts displayed defective JNK pathway activation and a marked decrease in osteoblast differentiation markers and defective mineralization, which was also confirmed using TAOK3 deficient osteoblasts derived from human MSCs. Additionally, reduced expression of Taok3 in a murine model resulted in osteopenia that phenocopies aspects of the Jnk1-associated skeletal phenotype such as occipital hypomineralization. Thus, in vitro and in vivo evidence supports TAOK3 as a proximal activator of the JNK pathway in osteoblasts that plays a critical role in skeletal mineralization.
Subject(s)
Calcification, Physiologic/physiology , Cell Differentiation , Osteoblasts/cytology , Protein Serine-Threonine Kinases/genetics , Animals , Cells, Cultured , Femur/cytology , Femur/diagnostic imaging , Gene Expression , MAP Kinase Kinase Kinases/metabolism , MAP Kinase Signaling System/physiology , Mice, Inbred C57BL , Mice, Mutant Strains , Mitogen-Activated Protein Kinase 8/genetics , Mitogen-Activated Protein Kinase 8/metabolism , Osteoblasts/physiology , Phenotype , Protein Serine-Threonine Kinases/metabolism , X-Ray MicrotomographyABSTRACT
Although deposition of uric acid (UA) crystals is known as the cause of gout, it is unclear whether UA plays a role in other inflammatory diseases. We here have shown that UA is released in the airways of allergen-challenged asthmatic patients and mice, where it was necessary for mounting T helper 2 (Th2) cell immunity, airway eosinophilia, and bronchial hyperreactivity to inhaled harmless proteins and clinically relevant house dust mite allergen. Conversely, administration of UA crystals together with protein antigen was sufficient to promote Th2 cell immunity and features of asthma. The adjuvant effects of UA did not require the inflammasome (Nlrp3, Pycard) or the interleukin-1 (Myd88, IL-1r) axis. UA crystals promoted Th2 cell immunity by activating dendritic cells through spleen tyrosine kinase and PI3-kinase δ signaling. These findings provide further molecular insight into Th2 cell development and identify UA as an essential initiator and amplifier of allergic inflammation.
Subject(s)
Antigens/immunology , Asthma/immunology , Inhalation Exposure , Pyroglyphidae/immunology , Th2 Cells/drug effects , Th2 Cells/immunology , Uric Acid/therapeutic use , Adaptive Immunity , Animals , Asthma/drug therapy , Carrier Proteins/immunology , Dendritic Cells/immunology , Humans , Inflammasomes/immunology , Mice , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein , Phosphatidylinositol 3-Kinases/metabolismABSTRACT
BACKGROUND: Pharmacogenomic studies have shown that ADCY9 genotype determines the effects of the CETP (cholesteryl ester transfer protein) inhibitor dalcetrapib on cardiovascular events and atherosclerosis imaging. The underlying mechanisms responsible for the interactions between ADCY9 and CETP activity have not yet been determined. METHODS: Adcy9-inactivated ( Adcy9Gt/Gt) and wild-type (WT) mice, that were or not transgenic for the CETP gene (CETPtg Adcy9Gt/Gt and CETPtg Adcy9WT), were submitted to an atherogenic protocol (injection of an AAV8 [adeno-associated virus serotype 8] expressing a PCSK9 [proprotein convertase subtilisin/kexin type 9] gain-of-function variant and 0.75% cholesterol diet for 16 weeks). Atherosclerosis, vasorelaxation, telemetry, and adipose tissue magnetic resonance imaging were evaluated. RESULTS: Adcy9Gt/Gt mice had a 65% reduction in aortic atherosclerosis compared to WT ( P<0.01). CD68 (cluster of differentiation 68)-positive macrophage accumulation and proliferation in plaques were reduced in Adcy9Gt/Gt mice compared to WT animals ( P<0.05 for both). Femoral artery endothelial-dependent vasorelaxation was improved in Adcy9Gt/Gt mice (versus WT, P<0.01). Selective pharmacological blockade showed that the nitric oxide, cyclooxygenase, and endothelial-dependent hyperpolarization pathways were all responsible for the improvement of vasodilatation in Adcy9Gt/Gt ( P<0.01 for all). Aortic endothelium from Adcy9Gt/Gt mice allowed significantly less adhesion of splenocytes compared to WT ( P<0.05). Adcy9Gt/Gt mice gained more weight than WT with the atherogenic diet; this was associated with an increase in whole body adipose tissue volume ( P<0.01 for both). Feed efficiency was increased in Adcy9Gt/Gt compared to WT mice ( P<0.01), which was accompanied by prolonged cardiac RR interval ( P<0.05) and improved nocturnal heart rate variability ( P=0.0572). Adcy9 inactivation-induced effects on atherosclerosis, endothelial function, weight gain, adipose tissue volume, and feed efficiency were lost in CETPtg Adcy9Gt/Gt mice ( P>0.05 versus CETPtg Adcy9WT). CONCLUSIONS: Adcy9 inactivation protects against atherosclerosis, but only in the absence of CETP activity. This atheroprotection may be explained by decreased macrophage accumulation and proliferation in the arterial wall, and improved endothelial function and autonomic tone.
Subject(s)
Adenylyl Cyclases/deficiency , Aorta/enzymology , Aortic Diseases/prevention & control , Atherosclerosis/prevention & control , Cholesterol Ester Transfer Proteins/deficiency , Plaque, Atherosclerotic , Adenylyl Cyclases/genetics , Adiposity , Animals , Aorta/pathology , Aorta/physiopathology , Aortic Diseases/enzymology , Aortic Diseases/genetics , Aortic Diseases/pathology , Atherosclerosis/enzymology , Atherosclerosis/genetics , Atherosclerosis/pathology , Autonomic Nervous System/physiopathology , Biological Factors/metabolism , Cell Proliferation , Cholesterol Ester Transfer Proteins/genetics , Diet, High-Fat , Disease Models, Animal , Endothelial Cells/enzymology , Endothelial Cells/pathology , Lipids/blood , Lipolysis , Macrophages/enzymology , Macrophages/pathology , Male , Mice, Inbred C57BL , Mice, Knockout , Nitric Oxide/metabolism , Proprotein Convertase 9/genetics , Prostaglandin-Endoperoxide Synthases/metabolism , Signal Transduction , Vasodilation , Weight GainABSTRACT
MK5 is a protein serine/threonine kinase activated by p38, ERK3, and ERK4 MAPKs. MK5 mRNA and immunoreactivity are detected in mouse cardiac fibroblasts, and MK5 haplodeficiency attenuates the increase in collagen 1-α1 mRNA evoked by pressure overload. The present study examined the effect of MK5 haplodeficiency on reparative fibrosis following myocardial infarction (MI). Twelve-week-old MK5+/- and wild-type littermate (MK5+/+) mice underwent ligation of the left anterior descending coronary artery (LADL). Surviving mice were euthanized 8 or 21 days post-MI. Survival rates did not differ significantly between MK5+/+ and MK5+/- mice, with rupture of the LV wall being the primary cause of death. Echocardiographic imaging revealed similar increases in LV end-diastolic diameter, myocardial performance index, and wall motion score index in LADL-MK5+/+ and LADL-MK5+/- mice. Area at risk did not differ between LADL-MK5+/+ and LADL-MK5+/- hearts. In contrast, infarct size, scar area, and scar collagen content were reduced in LADL-MK5+/- hearts. Immunohistochemical analysis of mice experiencing heart rupture revealed increased MMP-9 immunoreactivity in the infarct border zone of LADL-MK5+/- hearts compared with LADL-MK5+/+. Although inflammatory cell infiltration was similar in LADL-MK5+/+ and LADL-MK5+/- hearts, angiogenesis was more pronounced in the infarct border zone of LADL-MK5+/- mice. Characterization of ventricular fibroblasts revealed reduced motility and proliferation in fibroblasts isolated from MK5-/- mice compared with those from both wild-type and haplodeficient mice. siRNA-mediated knockdown of MK5 in fibroblasts from wild-type mice also impaired motility. Hence, reduced MK5 expression alters fibroblast function and scar morphology but not mortality post-MI. NEW & NOTEWORTHY MK5/PRAK is a protein serine/threonine kinase activated by p38 MAPK and/or atypical MAPKs ERK3/4. MK5 haplodeficiency reduced infarct size, scar area, and scar collagen content post-myocardial infarction. Motility and proliferation were reduced in cultured MK5-null cardiac myofibroblasts.
Subject(s)
Cicatrix/enzymology , Collagen/metabolism , Haploinsufficiency , Intracellular Signaling Peptides and Proteins/deficiency , Myocardial Infarction/enzymology , Myocardium/enzymology , Myofibroblasts/enzymology , Protein Serine-Threonine Kinases/deficiency , Wound Healing , Animals , Cell Movement , Cell Proliferation , Cells, Cultured , Cicatrix/pathology , Cicatrix/physiopathology , Disease Models, Animal , Intracellular Signaling Peptides and Proteins/genetics , Male , Matrix Metalloproteinase 9/metabolism , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Myocardial Infarction/genetics , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Myocardium/pathology , Myofibroblasts/pathology , Protein Serine-Threonine Kinases/genetics , Signal Transduction , Ventricular Function, Left , Ventricular RemodelingABSTRACT
Perinatal infection and inflammatory episodes in preterm infants are associated with diffuse white matter injury (WMI) and adverse neurological outcomes. Inflammation-induced WMI was previously shown to be linked with later hippocampal atrophy as well as learning and memory impairments in preterm infants. Early evaluation of injury load and therapeutic response with non-invasive tools such as multimodal magnetic resonance imaging (MRI) would greatly improve the search of new therapeutic approaches in preterm infants. Our aim was to evaluate the potential of multimodal MRI to detect the response of interleukin-1 receptor antagonist (IL-1Ra) treatment, known for its neuroprotective properties, during the acute phase of injury on a model of neonatal WMI. Rat pups at postnatal day 3 (P3) received intracerebral injection of lipopolysaccharide with systemic IL-1Ra therapy. 24â¯h later (P4), rats were imaged with multimodal MRI to assess microstructure by diffusion tensor imaging (DTI) and neurochemical profile of the hippocampus with 1H-magnetic resonance spectroscopy. Astrocyte and microglial activation, apoptosis and the mRNA expression of pro-inflammatory and necroptotic markers were assessed. During the acute phase of injury, neonatal LPS exposure altered the concentration of hippocampus metabolites related to neuronal integrity, neurotransmission and membrane integrity and induced diffusivity restriction. Just 24â¯h after initiation of therapy, early indication of IL-1Ra neuroprotective effect could be detected in vivo by non-invasive spectroscopy and DTI, and confirmed with immunohistochemical evaluation and mRNA expression of inflammatory markers and cell death. In conclusion, multimodal MRI, particularly DTI, can detect not only injury but also the acute therapeutic effect of IL-1Ra suggesting that MRI could be a useful non-invasive tool to follow, at early time points, the therapeutic response in preterm infants.
Subject(s)
Multimodal Imaging/methods , White Matter/diagnostic imaging , White Matter/physiopathology , Animals , Animals, Newborn , Brain/drug effects , Brain Injuries/complications , Brain Injuries/diagnostic imaging , Diffusion Magnetic Resonance Imaging/methods , Diffusion Tensor Imaging/methods , Female , Hippocampus/drug effects , Inflammation/complications , Lipopolysaccharides/administration & dosage , Lipopolysaccharides/pharmacology , Magnetic Resonance Imaging/methods , Magnetic Resonance Spectroscopy/methods , Male , Neuroprotective Agents/pharmacology , Pregnancy , Rats , Rats, Sprague-Dawley , Receptors, Interleukin-1/antagonists & inhibitors , Receptors, Interleukin-1/metabolismABSTRACT
Continuous brain imaging techniques can be beneficial for the monitoring of neurological pathologies (such as epilepsy or stroke) and neuroimaging protocols involving movement. Among existing ones, functional near-infrared spectroscopy (fNIRS) and electroencephalography (EEG) have the advantage of being noninvasive, nonobstructive, inexpensive, yield portable solutions, and offer complementary monitoring of electrical and local hemodynamic activities. This article presents a novel system with 128 fNIRS channels and 32 EEG channels with the potential to cover a larger fraction of the adult superficial cortex than earlier works, is integrated with 32 EEG channels, is light and battery-powered to improve portability, and can transmit data wirelessly to an interface for real-time display of electrical and hemodynamic activities. A novel fNIRS-EEG stretchable cap, two analog channels for auxiliary data (e.g., electrocardiogram), eight digital triggers for event-related protocols and an internal accelerometer for movement artifacts removal contribute to improve data acquisition quality. The system can run continuously for 24 h. Following instrumentation validation and reliability on a solid phantom, performance was evaluated on (1) 12 healthy participants during either a visual (checkerboard) task at rest or while pedalling on a stationary bicycle or a cognitive (language) task and (2) 4 patients admitted either to the epilepsy (n = 3) or stroke (n = 1) units. Data analysis confirmed expected hemodynamic variations during validation recordings and useful clinical information during in-hospital testing. To the best of our knowledge, this is the first demonstration of a wearable wireless multichannel fNIRS-EEG monitoring system in patients with neurological conditions. Hum Brain Mapp 39:7-23, 2018. © 2017 Wiley Periodicals, Inc.
Subject(s)
Electroencephalography/instrumentation , Neurophysiological Monitoring/instrumentation , Spectroscopy, Near-Infrared/instrumentation , Wearable Electronic Devices , Wireless Technology , Adolescent , Adult , Bicycling/physiology , Cerebral Cortex/blood supply , Cerebral Cortex/physiology , Cerebral Cortex/physiopathology , Cerebrovascular Circulation , Cognition/physiology , Drug Resistant Epilepsy/diagnosis , Drug Resistant Epilepsy/physiopathology , Female , Functional Neuroimaging/instrumentation , Humans , Language , Male , Middle Aged , Phantoms, Imaging , Stroke/diagnosis , Stroke/physiopathology , Visual Perception/physiology , Young AdultABSTRACT
Magnetic resonance fingerprinting (MRF) was recently proposed as a novel strategy for MR data acquisition and analysis. A variant of MRF called vascular MRF (vMRF) followed, that extracted maps of three parameters of physiological importance: cerebral oxygen saturation (SatO2), mean vessel radius and cerebral blood volume (CBV). However, this estimation was based on idealized 2-dimensional simulations of vascular networks using random cylinders and the empirical Bloch equations convolved with a diffusion kernel. Here we focus on studying the vascular MR fingerprint using real mouse angiograms and physiological values as the substrate for the MR simulations. The MR signal is calculated ab initio with a Monte Carlo approximation, by tracking the accumulated phase from a large number of protons diffusing within the angiogram. We first study the identifiability of parameters in simulations, showing that parameters are fully estimable at realistically high signal-to-noise ratios (SNR) when the same angiogram is used for dictionary generation and parameter estimation, but that large biases in the estimates persist when the angiograms are different. Despite these biases, simulations show that differences in parameters remain estimable. We then applied this methodology to data acquired using the GESFIDE sequence with SPIONs injected into 9 young wild type and 9 old atherosclerotic mice. Both the pre injection signal and the ratio of post-to-pre injection signals were modeled, using 5-dimensional dictionaries. The vMRF methodology extracted significant differences in SatO2, mean vessel radius and CBV between the two groups, consistent across brain regions and dictionaries. Further validation work is essential before vMRF can gain wider application.
Subject(s)
Brain/diagnostic imaging , Image Processing, Computer-Assisted/methods , Magnetic Resonance Imaging/methods , Animals , Atherosclerosis/diagnostic imaging , Brain/blood supply , Cerebral Angiography , Mice , Mice, Inbred C57BLABSTRACT
Automated analysis of diffusion tensor imaging (DTI) data is an appealing way to process large datasets in an unbiased manner. However, automation can sometimes be linked to a lack of interpretability. Two whole-brain, automated and voxelwise methods exist: voxel-based analysis (VBA) and tract-based spatial statistics (TBSS). In VBA, the amount of smoothing has been shown to influence the results. TBSS is free of this step, but a projection procedure is introduced to correct for residual misalignments. This projection assigns the local highest fractional anisotropy (FA) value to the mean FA skeleton, which represents white matter tract centers. For both methods, the normalization procedure has a major impact. These issues are well documented in humans but, to our knowledge, not in rodents. In this study, we assessed the quality of three different registration algorithms (ANTs SyN, DTI-TK and FNIRT) using study-specific templates and their impact on automated analysis methods (VBA and TBSS) in a rat pup model of diffuse white matter injury presenting large unilateral deformations. VBA and TBSS results were stable and anatomically coherent across the three pipelines. For VBA, in regions around the large deformations, interpretability was limited because of the increased partial volume effect. With TBSS, two of the three pipelines found a significant decrease in axial diffusivity (AD) at the known injury site. These results demonstrate that automated voxelwise analyses can be used in an animal model with large deformations.
Subject(s)
Diffusion Tensor Imaging/methods , Leukomalacia, Periventricular/diagnostic imaging , Algorithms , Animals , Disease Models, Animal , Rats , Rats, Sprague-Dawley , White MatterABSTRACT
Functional near-infrared spectroscopy (fNIRS) can be combined with electroencephalography (EEG) to continuously monitor the hemodynamic signal evoked by epileptic events such as seizures or interictal epileptiform discharges (IEDs, aka spikes). As estimation methods assuming a canonical shape of the hemodynamic response function (HRF) might not be optimal, we sought to model patient-specific HRF (sHRF) with a simple deconvolution approach for IED-related analysis with EEG-fNIRS data. Furthermore, a quadratic term was added to the model to account for the nonlinearity in the response when IEDs are frequent. Prior to analyzing clinical data, simulations were carried out to show that the HRF was estimable by the proposed deconvolution methods under proper conditions. EEG-fNIRS data of five patients with refractory focal epilepsy were selected due to the presence of frequent clear IEDs and their unambiguous focus localization. For each patient, both the linear sHRF and the nonlinear sHRF were estimated at each channel. Variability of the estimated sHRFs was seen across brain regions and different patients. Compared with the SPM8 canonical HRF (cHRF), including these sHRFs in the general linear model (GLM) analysis led to hemoglobin activations with higher statistical scores as well as larger spatial extents on all five patients. In particular, for patients with frequent IEDs, nonlinear sHRFs were seen to provide higher sensitivity in activation detection than linear sHRFs. These observations support using sHRFs in the analysis of IEDs with EEG-fNIRS data.
Subject(s)
Cerebral Cortex/physiopathology , Electroencephalography/methods , Epilepsy/physiopathology , Models, Neurological , Neurovascular Coupling/physiology , Spectroscopy, Near-Infrared/methods , Adolescent , Adult , Female , Humans , Male , Young AdultABSTRACT
Failure to recognize insular cortex seizures has recently been identified as a cause of epilepsy surgeries targeting the temporal, parietal, or frontal lobe. Such failures are partly due to the fact that current noninvasive localization techniques fare poorly in recognizing insular epileptic foci. Our group recently demonstrated that magnetoencephalography (MEG) is sensitive to epileptiform spikes generated by the insula. In this study, we assessed the potential of distributed source imaging and functional connectivity analyses to distinguish insular networks underlying the generation of spikes. Nineteen patients with operculo-insular epilepsy were investigated. Each patient underwent MEG as well as T1-weighted magnetic resonance imaging (MRI) as part of their standard presurgical evaluation. Cortical sources of MEG spikes were reconstructed with the maximum entropy on the mean algorithm, and their time courses served to analyze source functional connectivity. The results indicate that the anterior and posterior subregions of the insula have specific patterns of functional connectivity mainly involving frontal and parietal regions, respectively. In addition, while their connectivity patterns are qualitatively similar during rest and during spikes, couplings within these networks are much stronger during spikes. These results show that MEG can establish functional connectivity-based signatures that could help in the diagnosis of different subtypes of insular cortex epilepsy. Hum Brain Mapp 37:3250-3261, 2016. © 2016 Wiley Periodicals, Inc.
Subject(s)
Cerebral Cortex/physiopathology , Epilepsy/diagnosis , Epilepsy/physiopathology , Neural Pathways/physiopathology , Adolescent , Brain Mapping , Child , Epilepsy/surgery , Female , History, 16th Century , Humans , Magnetic Resonance Imaging , Magnetoencephalography , Male , Middle Aged , Young AdultABSTRACT
We report the design of scaffolds containing mono-, bis-, and tris-phosphonate coordinating groups, and a polyethylene glycol chain, for stabilizing superparamagnetic iron oxide nanoparticles (SPIONs), using simple and versatile chemistry. We demonstrate that the number of anchoring phosphonate sites on the ligand influence the colloidal stability, magnetic and biological properties of SPIONs, and the latter do not solely depend on attaching moieties that can enhance their aqueous dispersion. These parameters can be tailored by the number of conjugation sites on the ligand, as evidenced from dynamic light scattering at various salt concentrations, magnetic relaxivities and cell viability studies.
ABSTRACT
Maintaining wakefulness is associated with a progressive increase in the need for sleep. This phenomenon has been linked to changes in synaptic function. The synaptic adhesion molecule Neuroligin-1 (NLG1) controls the activity and synaptic localization of N-methyl-d-aspartate receptors, which activity is impaired by prolonged wakefulness. We here highlight that this pathway may underlie both the adverse effects of sleep loss on cognition and the subsequent changes in cortical synchrony. We found that the expression of specific Nlg1 transcript variants is changed by sleep deprivation in three mouse strains. These observations were associated with strain-specific changes in synaptic NLG1 protein content. Importantly, we showed that Nlg1 knockout mice are not able to sustain wakefulness and spend more time in nonrapid eye movement sleep than wild-type mice. These changes occurred with modifications in waking quality as exemplified by low theta/alpha activity during wakefulness and poor preference for social novelty, as well as altered delta synchrony during sleep. Finally, we identified a transcriptional pathway that could underlie the sleep/wake-dependent changes in Nlg1 expression and that involves clock transcription factors. We thus suggest that NLG1 is an element that contributes to the coupling of neuronal activity to sleep/wake regulation.
Subject(s)
Cell Adhesion Molecules, Neuronal/physiology , Neurons/physiology , Sleep/physiology , Wakefulness/physiology , Animals , Blotting, Western , Cell Adhesion Molecules, Neuronal/genetics , Cell Adhesion Molecules, Neuronal/metabolism , Electroencephalography , Electromyography , Gene Expression , Male , Mice , Mice, 129 Strain , Mice, Inbred AKR , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Knockout , Neurons/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Sleep/genetics , Sleep Deprivation/genetics , Sleep Deprivation/physiopathology , Species Specificity , Time Factors , Wakefulness/geneticsABSTRACT
PURPOSE: To assess the relationship between exercise intensity, cerebral HbO2 and cognitive performance (Executive and non-Executive) in young adults. METHODS: We measured reaction time (RT) and accuracy, during a computerized Stroop task, in 19 young adults (7 males and 12 females). Their mean ± SD age, height, body mass and body mass index (BMI) were 24 ± 4 years, 1.67 ± 0.07 m, 72 ± 14 kg and 25 ± 3 kg m(-2), respectively. Each subject performed the Stroop task at rest and during cycling at exercise of low intensity [40% of peak power output (PPO)], moderate intensity (60% of PPO) and high intensity (85% of PPO). Cerebral oxygenation was monitored during the resting and exercise conditions over the prefrontal cortex (PFC) using near-infrared spectroscopy (NIRS). RESULTS: High-intensity exercise slowed RT in both the Naming (p = 0.04) and the Executive condition (p = 0.04). The analysis also revealed that high-intensity exercise was associated with a decreased accuracy when compared to low-intensity exercise (p = 0.021). Neuroimaging results confirm a decrease of cerebral oxygenation during high-intensity exercise in comparison to low- (p = 0.004) and moderate-intensity exercise (p = 0.003). Correlations revealed that a lower cerebral HbO2 in the prefrontal cortex was associated with slower RT in the Executive condition only (p = 0.04, g = -0.72). CONCLUSION: Results of the present study suggest that low to moderate exercise intensity does not alter Executive functioning, but that exercise impairs cognitive functions (Executive and non-Executive) when the physical workload becomes heavy. The cerebral HbO2 correlation suggests that a lower availability of HbO2 was associated with slower RT in the Executive condition only.
Subject(s)
Brain/physiology , Cerebrovascular Circulation , Cognition , Exercise , Oxygen Consumption , Adult , Brain/growth & development , Brain/metabolism , Female , Hemoglobins/metabolism , Humans , MaleABSTRACT
PURPOSE: To investigate spatial and metabolic changes associated with frontal lobe seizures. METHODS: Functional near-infrared spectroscopy combined with electroencephalography (EEG-fNIRS) recordings of patients with confirmed nonlesional refractory frontal lobe epilepsy (FLE). KEY FINDINGS: Eighteen seizures from nine patients (seven male, mean age 27 years, range 13-46 years) with drug-refractory FLE were captured during EEG-fNIRS recordings. All seizures were coupled with significant hemodynamic variations that were greater with electroclinical than with electrical seizures. fNIRS helped in the identification of seizures in three patients with more subtle ictal EEG abnormalities. Hemodynamic changes consisted of local increases in oxygenated (HbO) and total hemoglobin (HbT) but heterogeneous deoxygenated hemoglobin (HbR) behavior. Furthermore, rapid hemodynamic alterations were observed in the homologous contralateral region, even in the absence of obvious propagated epileptic activity. The extent of HbO activation adequately lateralized the epileptogenic side in the majority of patients. SIGNIFICANCE: EEG-fNIRS reveals complex spatial and metabolic changes during focal frontal lobe seizures. Further characterization of these changes could improve seizure detection, localization, and understanding of the impact of focal seizures.
Subject(s)
Electroencephalography/methods , Epilepsy, Frontal Lobe/diagnosis , Spectroscopy, Near-Infrared/methods , Adolescent , Adult , Aged , Cerebrovascular Circulation/physiology , Child , Data Interpretation, Statistical , Drug Resistance , Epilepsy, Frontal Lobe/physiopathology , Female , Functional Laterality/physiology , Hemoglobinometry/methods , Humans , Male , Nerve Net/physiopathology , Oximetry , Seizures/diagnosis , Young AdultABSTRACT
BACKGROUND: Functional near-infrared spectroscopy (fNIRS) is a suitable tool for recording brain function in pediatric or challenging populations. As with other neuroimaging techniques, the scientific community is engaged in an evolving debate regarding the most adequate methods for performing fNIRS data analyses. NEW METHOD: We introduce LIONirs, a neuroinformatics toolbox for fNIRS data analysis, designed to follow two main goals: (1) flexibility, to explore several methods in parallel and verify results using 3D visualization; (2) simplicity, to apply a defined processing pipeline to a large dataset of subjects by using the MATLAB Batch System and available on GitHub. RESULTS: Within the graphical user interfaces (DisplayGUI), the user can reject noisy intervals and correct artifacts, while visualizing the topographical projection of the data onto the 3D head representation. Data decomposition methods are available for the identification of relevant signatures, such as brain responses or artifacts. Multimodal data recorded simultaneously to fNIRS, such as physiology, electroencephalography or audio-video, can be visualized using the DisplayGUI. The toolbox includes several functions that allow one to read, preprocess, and analyze fNIRS data, including task-based and functional connectivity measures. COMPARISON WITH EXISTING METHODS: Several good neuroinformatics tools for fNIRS data analysis are currently available. None of them emphasize multimodal visualization of the data throughout the preprocessing steps and multidimensional decomposition, which are essential for understanding challenging data. Furthermore, LIONirs provides compatibility and complementarity with other existing tools by supporting common data format. CONCLUSIONS: LIONirs offers a flexible platform for basic and advanced fNIRS data analysis, shown through real experimental examples.
Subject(s)
Data Analysis , Spectroscopy, Near-Infrared , Artifacts , Brain/diagnostic imaging , Brain/physiology , Child , Electroencephalography , Humans , Spectroscopy, Near-Infrared/methodsABSTRACT
Allergic asthma is a chronic inflammatory disease characterized by Th2-type inflammation. Although the cellular interactions are now well studied, the intracellular signaling involved in asthma development is still a developing field. Protein tyrosine kinases are one focus of such research and their inhibition shows improvement of asthmatic features. Interestingly, very little attention was given to protein tyrosine phosphatases (PTPs), the counterparts to protein tyrosine kinases, in the development of asthma. Previous studies from our laboratory showed that pharmacological inhibition of PTPs induced a transient Th1 response in the spleen. Therefore, we hypothesized that modulation of PTPs could influence asthma development. To assess PTP functions, we used the PTP inhibitor bis-peroxovanadium bpV(phen) in a murine model of asthma during either allergen sensitization or challenge. Inhibition of PTPs during allergen sensitization resulted in the reduction of key features of allergic asthma: serum IgE levels, lung tissue inflammation, eosinophilia, and airway hyperresponsiveness. Of utmost interest, PTP inhibition at allergen challenge resulted in a very similar improvement of asthmatic features. Of further importance, we observed that bpV(phen) treatment modulated cytokine expression in the spleen and, more specifically, favored Th1 cytokines while inhibiting Th2 cytokines. Collectively, we show for the first time that intact activity of PTPs is required for a complete induction of asthma in a mouse model. This clearly suggests that PTPs have a pivotal regulatory role in the development of asthmatic diseases, which opens the possibility of new therapeutic avenues.