bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effects of a Warm or Chilly Climate Toward Socioeconomic Diversity on Academic Motivation and Self-Concept
Authors: Browman Alexander S. , Destin Mesmin
Published: December 2015

Persistent academic achievement gaps exist between university students from high and low socioeconomic status (SES) backgrounds. The current research proposes that the extent to which a university is perceived as actively supporting versus passively neglecting students from diverse socioeconomic backgrounds can influence low-SES students’ academic motivation and self-concepts. In Experiments 1 and 2, low-SES students exposed to cues suggestive of an institution’s warmth toward socioeconomic diversity demonstrated greater academic efficacy, expectations, and implicit associations with high academic achievement compared with those exposed to cues indicating institutional chilliness. Exploring the phenomenology underlying these effects, Experiment 3 demonstrated that warmth cues led low-SES students to perceive their socioeconomic background as a better match with the rest of the student body and to perceive the university as more socioeconomically diverse than did chilliness cues. Contributions to our understanding of low-SES students’ psychological experiences in academic settings and practical implications for academic institutions are discussed.
Overview of ICRP Committee 1: radiation effects
Authors: Morgan W.F.
Published: December 2015

This paper does not necessarily reflect the views of the International Commission on Radiological Protection. The author passed away on 13 November 2015. Committee 1 of the International Commission on Radiological Protection (ICRP) addresses issues pertinent to tissue reactions, risks of cancer and heritable diseases, radiation dose responses, effects of dose rate, and radiation quality. In addition, it reviews data on the effects of radiation on the embryo/fetus, genetic factors in radiation response, and uncertainties in providing judgements on radiation-induced health effects. Committee 1 advises the Main Commission on the biological basis of radiation-induced health effects, and how epidemiological, experimental, and theoretical data can be combined to make quantitative judgements on health risks to humans. The emphasis is on low radiation doses, in the form of detriment-adjusted nominal risk coefficients, where there are considerable uncertainties in terms of the biology and the epidemiology. Furthermore, Committee 1 reviews data from radiation epidemiology studies and publications on the molecular and cellular effects of ionising radiation relevant to updating the basis of the 2007 Recommendations published in ICRP Publication 103. This paper will provide an overview of the activities of Committee 1, the updated work of the Task Groups and Working Parties, and the future activities being pursued.
‘Ideology’ and media research
Authors: Corner John
Published: December 2015

This commentary reviews the continuing discussion about the use of the concept of ‘ideology’ in media research, connecting back to earlier dimensions of the debate and the problems that developed around its varying usage. It engages with the attempt to reinstate the idea as an organising concept in the analysis of power, looking at some of the ways in which the media’s work in the brokering of power relations remains in need of further understanding.
Exploring performance of clustering methods on document sentiment analysis
Authors: Ma Baojun , Yuan Hua , Wu Ye
Published: December 2015

Clustering is a powerful unsupervised tool for sentiment analysis from text. However, the clustering results may be affected by any step of the clustering process, such as data pre-processing strategy, term weighting method in Vector Space Model and clustering algorithm. This paper presents the results of an experimental study of some common clustering techniques with respect to the task of sentiment analysis. Different from previous studies, in particular, we investigate the combination effects of these factors with a series of comprehensive experimental studies. The experimental results indicate that, first, the K-means-type clustering algorithms show clear advantages on balanced review datasets, while performing rather poorly on unbalanced datasets by considering clustering accuracy. Second, the comparatively newly designed weighting models are better than the traditional weighting models for sentiment clustering on both balanced and unbalanced datasets. Furthermore, adjective and adverb words extraction strategy can offer obvious improvements on clustering performance, while strategies of adopting stemming and stopword removal will bring negative influences on sentiment clustering. The experimental results would be valuable for both the study and usage of clustering methods in online review sentiment analysis.
Predicting Partner Enhancement in Marital Relationships: The Family of Origin, Attachment, and Social Network Approval
Authors: Busby Dean M. , Boden Jeremy , Niehuis Sylvia , Reifman Alan , Fitzpatrick Jacki
Published: December 2015

Partner enhancement is an important relational process that has been linked to better relationship outcomes in existing research. However, little is known about variables that might be associated with the practice of partner enhancement. In this study, we utilized an ecosystemic model with a sample of 1,432 couples and an actor/partner interdependence model to explore whether the family of origin, attachment avoidance and anxiety, and social network approval predicted partner enhancement scores. The results indicated that the family of origin was only indirectly associated with partner enhancement through attachment and social network approval. The best predictors of partner enhancement were attachment avoidance and social network approval. Higher scores on actor attachment avoidance were related to higher scores on partner enhancement contrary to expectations. Curiously, partner effects for attachment avoidance were the opposite in that higher scores were associated with lower levels of partner enhancement. Attachment anxiety was associated with lower scores on partner enhancement for both actor and partner effects, and social network approval was associated with higher scores on partner enhancement.
A general model to calculate the spin-lattice (T1) relaxation time of blood, accounting for haematocrit, oxygen saturation and magnetic field strength
Authors: Hales Patrick W , Kirkham Fenella J , Clark Christopher A
Published: December 2015

Many MRI techniques require prior knowledge of the T1-relaxation time of blood ( T1 bl). An assumed/fixed value is often used; however, T1 bl is sensitive to magnetic field ( B0), haematocrit ( Hct), and oxygen saturation ( Y). We aimed to combine data from previous in vitro measurements into a mathematical model, to estimate T1 bl as a function of B0, Hct, and Y. The model was shown to predict T1 bl from in vivo studies with a good accuracy (±87 ms). This model allows for improved estimation of T1 bl between 1.5–7.0 T while accounting for variations in Hct and Y, leading to improved accuracy of MRI-derived perfusion measurements.
Sensory-parietal cortical stimulation improves motor recovery in severe capsular infarct
Authors: Kim Ra Gyung , Cho Jongwook , Ree Jinkyue , Kim Hyung-Sun , Rosa-Neto Pedro , Kim Jin-Myung , Lee Min-Cheol , Kim Hyoung-Ihl
Published: December 2015

The prevalence of subcortical white matter strokes in elderly patients is on the rise, but these patients show mixed responses to conventional rehabilitative interventions. To examine whether cortical electrical stimulation can promote motor recovery after white matter stroke, we delivered stimulation to a small or wide region of sensory-parietal cortex for two weeks in a rodent model of circumscribed subcortical capsular infarct. The sham-operated group (SOG) showed persistent and severe motor impairments together with decreased activation in bilateral sensorimotor cortices and striatum. In contrast, sensory-parietal cortex stimulation significantly improved motor recovery: final recovery levels were 72.9% of prelesion levels in the wide stimulation group (WSG) and 37% of prelesion levels in the small stimulation group (SSG). The microPET imaging showed reversal of cortical diaschisis in both groups: in both hemispheres for the WSG, and in the hemisphere ipsilateral to stimulation in the SSG. In addition, we observed activation of the corpus callosum and subcortical corticostriatal structures after stimulation. The results from the c-Fos mapping study were grossly consistent with the microPET imaging. Sensory-parietal cortex stimulation may therefore be a useful strategy for overcoming the limits of rehabilitative training in patients with severe forms of subcortical capsular infarct.
The influence of gender on ‘tissue at risk’ in acute stroke: A diffusion-weighted magnetic resonance imaging study in a rat model of focal cerebral ischaemia
Authors: Baskerville Tracey A , Macrae I Mhairi , Holmes William M , McCabe Christopher
Published: December 2015

This is the first study to assess the influence of sex on the evolution of ischaemic injury and penumbra. Permanent middle cerebral artery occlusion was induced in male (n = 9) and female (n = 10) Sprague-Dawley rats. Diffusion-weighted imaging was acquired over 4 h and infarct determined from T2 images at 24 h post-permanent middle cerebral artery occlusion. Penumbra was determined retrospectively from serial apparent diffusion coefficient lesions and T2-defined infarct. Apparent diffusion coefficient lesion volume was significantly smaller in females from 0.5 to 4 h post permanent middle cerebral artery occlusion as was infarct volume. Penumbral volume, and its loss over time, was not significantly different despite the sex difference in acute and final lesion volumes.
Long-term dynamics of somatosensory activity in a stroke model of distal middle cerebral artery oclussion
Authors: Barios Juan A , Pisarchyk Liudmila , Fernandez-Garcia Laura , Barrio Luis C , Ramos Milagros , Martinez-Murillo Ricardo , Gonzalez-Nieto Daniel
Published: December 2015

A constant challenge in experimental stroke is the use of appropriate tests to identify signs of recovery and adverse effects linked to a particular therapy. In this study, we used a long-term longitudinal approach to examine the functional brain changes associated with cortical infarction in a mouse model induced by permanent ligation of the middle cerebral artery (MCA). Sensorimotor function and somatosensory cortical activity were evaluated with fault-foot and forelimb asymmetry tests in combination with somatosensory evoked potentials. The stroke mice exhibited both long-term deficits in the functional tests and impaired responses in the infarcted and intact hemispheres after contralateral and ipsilateral forepaw stimulation. In the infarcted hemisphere, reductions in the amplitudes of evoked responses were detected after contralateral and ipsilateral stimulation. In the intact hemisphere, and similar to cortical stroke patients, a gradual hyperexcitability was observed after contralateral stimulation but no parallel evidence of a response was detected after ipsilateral stimulation. Our results suggest the existence of profound and persistent changes in the somatosensory cortex in this specific mouse cortical stroke model. The study of evoked potentials constitutes a feasible and excellent tool for evaluating the fitness of the somatosensory cortex in relation to functional recovery after preclinical therapeutic intervention.
Reduction of the neuroprotective transcription factor Npas4 results in increased neuronal necrosis, inflammation and brain lesion size following ischaemia
Authors: Choy Fong Chan , Klarić Thomas S , Leong Wai Khay , Koblar Simon A , Lewis Martin D
Published: December 2015

Stroke is the second leading cause of death and the most frequent cause of adult disability. Neuronal Per-Arnt-Sim domain protein 4 (Npas4) is an activity-dependent transcription factor whose expression is induced in various brain insults, including cerebral ischaemia. Although previous studies have demonstrated that Npas4 plays a critical role in protecting neurons against neurodegenerative insults, the neuroprotective effect of Npas4 in response to ischaemic brain injury remains unknown. In this study, we used a loss-of-function approach to examine the neuroprotective potential of Npas4 in the context of ischaemic damage. Using oxygen and glucose deprivation, we demonstrated that the knockdown of Npas4 in mouse cortical neurons resulted in increased susceptibility to cell death. The protective effect of Npas4 was further investigated in vivo using a photochemically-induced stroke model in mice. We found a significantly larger lesion size and increased neurodegeneration in Npas4 knockout mice as compared to wild-type mice. Moreover, we also showed that ablation of Npas4 caused an increase in activated astrocytes and microglia, pro-inflammatory cytokines interleukin-6 and tumour necrosis factor alpha levels and a switch from apoptotic to necrotic cell death. Taken together, these data suggest that Npas4 plays a neuroprotective role in ischaemic stroke by limiting progressive neurodegeneration and neuroinflammation.
CD200 restrains macrophage attack on oligodendrocyte precursors via toll-like receptor 4 downregulation
Authors: Hayakawa Kazuhide , Pham Loc-Duyen D , Seo Ji Hae , Miyamoto Nobukazu , Maki Takakuni , Terasaki Yasukazu , Sakadžić Sava , Boas David , van Leyen Klaus , Waeber Christian , Kim Kyu-Won , Arai Ken , Lo Eng H
Published: December 2015

There are numerous barriers to white matter repair after central nervous system injury and the underlying mechanisms remain to be fully understood. In this study, we propose the hypothesis that inflammatory macrophages in damaged white matter attack oligodendrocyte precursor cells via toll-like receptor 4 signaling thus interfering with this endogenous progenitor recovery mechanism. Primary cell culture experiments demonstrate that peritoneal macrophages can attack and digest oligodendrocyte precursor cells via toll-like receptor 4 signaling, and this phagocytosis of oligodendrocyte precursor cells can be inhibited by using CD200-Fc to downregulate toll-like receptor 4. In an in vivo model of white matter ischemia induced by endothelin-1, treatment with CD200-Fc suppressed toll-like receptor 4 expression in peripherally circulating macrophages, thus restraining macrophage phagocytosis of oligodendrocyte precursor cells and leading to improved myelination. Taken together, these findings suggest that deleterious macrophage effects may occur after white matter ischemia, whereby macrophages attack oligodendrocyte precursor cells and interfere with endogenous recovery responses. Targeting this pathway with CD200 may offer a novel therapeutic approach to amplify endogenous oligodendrocyte precursor cell-mediated repair of white matter damage in mammalian brain.
Optogenetic fMRI in the mouse hippocampus: Hemodynamic response to brief glutamatergic stimuli
Authors: Lebhardt Philipp , Hohenberg Christian Clemm von , Weber-Fahr Wolfgang , Kelsch Wolfgang , Sartorius Alexander
Published: December 2015

The combination of optogenetics with functional magnetic resonance imaging is a promising tool to study the causal relationship between specific neuronal populations and global brain activity. We employed this technique to study the brain response to recruitment of glutamatergic neurons in the mouse hippocampus. The light-sensitive protein channelrhodopsin-2 was expressed in α-CamKII-positive glutamatergic neurons in the left hippocampus (N = 10). Functional magnetic resonance imaging was performed during local laser stimulation, with stimulus duration of 1 second. The hemodynamic response to these stimuli was analyzed on a whole-brain level. In a secondary analysis, we examined the impact of the stimulation locus on the dorso-ventral axis within the hippocampal formation. The hemodynamic response in the mouse hippocampus had an earlier peak and a shorter duration compared to those observed in humans. Photostimulation was associated with significantly increased blood oxygen level-dependent signal in group statistics: bilaterally in the hippocampus, frontal lobe and septum, ipsilaterally in the nucleus accumbens and contralaterally in the striatum. More dorsal position of the laser fiber was associated with a stronger activation in projection regions (insular cortex and striatum). The characterization of brain-region-specific hemodynamic response functions may enable more precise interpretation of future functional magnetic resonance imaging experiments.
Regulation of P-glycoprotein expression in brain capillaries in Huntington’s disease and its impact on brain availability of antipsychotic agents risperidone and paliperidone
Authors: Kao Yu-Han , Chern Yijuang , Yang Hui-Ting , Chen Hui-Mei , Lin Chun-Jung
Published: December 2015

Huntington’s disease (HD) is a neurodegenerative disease marked by an expanded polyglutamine (polyQ) tract on the huntingtin (HTT) protein that may cause transcriptional dysfunction. This study aimed to investigate the regulation and function of P-glycoprotein, an important efflux transporter, in brain capillaries in HD. The results showed that, compared with the littermate controls, R6/2 HD transgenic mice with the human mutant HTT gene had higher levels of P-glycoprotein mRNA and protein and enhanced NF-κB activity in their brain capillaries. Higher P-glycoprotein expression was also observed in the brain capillaries of human HD patients. Consistent with this enhanced P-glycoprotein expression, brain extracellular levels and brain-to-plasma ratios of the antipsychotic agents risperidone and paliperidone were significantly lower in R6/2 mice than in their littermate controls. Exogenous expression of human mutant HTT protein with expanded polyQ (mHTT-109Q) in HEK293T cells enhanced the levels of P-glycoprotein transcripts and NF-κB activity compared with cells expressing normal HTT-25Q. Treatment with the IKK inhibitor, BMS-345541, decreased P-glycoprotein mRNA level in cells transfected with mHTT-109Q or normal HTT-25Q. In conclusion, mutant HTT altered the expression of P-glycoprotein through the NF-κB pathway in brain capillaries in HD and markedly affected the availability of P-glycoprotein substrates in the brain.
Adult human dental pulp stem cells promote blood–brain barrier permeability through vascular endothelial growth factor-a expression
Authors: Winderlich Joshua N , Kremer Karlea L , Koblar Simon A
Published: December 2015

Stem cell therapy is a promising new treatment option for stroke. Intravascular administration of stem cells is a valid approach as stem cells have been shown to transmigrate the blood–brain barrier. The mechanism that causes this effect has not yet been elucidated. We hypothesized that stem cells would mediate localized discontinuities in the blood–brain barrier, which would allow passage into the brain parenchyma. Here, we demonstrate that adult human dental pulp stem cells express a soluble factor that increases permeability across an in vitro model of the blood–brain barrier. This effect was shown to be the result of vascular endothelial growth factor-a. The effect could be amplified by exposing dental pulp stem cell to stromal-derived factor 1, which stimulates vascular endothelial growth factor-a expression. These findings support the use of dental pulp stem cell in therapy for stroke.
Stroke neuroprotection revisited: Intra-arterial verapamil is profoundly neuroprotective in experimental acute ischemic stroke
Authors: Maniskas Michael E , Roberts Jill M , Aron Ishi , Fraser Justin F , Bix Gregory J
Published: December 2015

While clinical trials have now solidified the role of thrombectomy in emergent large vessel occlusive stroke, additional therapies are needed to optimize patient outcome. Using our previously described experimental ischemic stroke model for evaluating adjunctive intra-arterial drug therapy after vessel recanalization, we studied the potential neuroprotective effects of verapamil. A calcium channel blocker, verapamil is often infused intra-arterially by neurointerventionalists to treat cerebral vasospasm. Such a direct route of administration allows for both focused targeting of stroke-impacted brain tissue and minimizes potential systemic side effects. Intra-arterial administration of verapamil at a flow rate of 2.5 µl/min and injection volume of 10 µl immediately after middle cerebral artery recanalization in C57/Bl6 mice was shown to be profoundly neuroprotective as compared to intra-arterial vehicle-treated stroke controls. Specifically, we noted a significant (P ≤ 0.05) decrease in infarct volume, astrogliosis, and cellular apoptosis as well as a significant increase in neuronal survival and functional outcome over seven days. Furthermore, intra-arterial administration of verapamil was well tolerated with no hemorrhage, systemic side effects, or increased mortality. Thus, verapamil administered intra-arterially immediately following recanalization in experimental ischemic stroke is both safe and neuroprotective and merits further study as a potential therapeutic adjunct to thrombectomy.
Ultrastructural analysis of blood–brain barrier breakdown in the peri-infarct zone in young adult and aged mice
Authors: Nahirney Patrick C , Reeson Patrick , Brown Craig E
Published: December 2015

Following ischemia, the blood–brain barrier is compromised in the peri-infarct zone leading to secondary injury and dysfunction that can limit recovery. Currently, it is uncertain what structural changes could account for blood–brain barrier permeability, particularly with aging. Here we examined the ultrastructure of early and delayed changes (3 versus 72 h) to the blood–brain barrier in young adult and aged mice (3–4 versus 18 months) subjected to photothrombotic stroke. At both time points and ages, permeability was associated with a striking increase in endothelial caveolae and vacuoles. Tight junctions were generally intact although small spaces were detected in a few cases. In young mice, ischemia led to a significant increase in pericyte process area and vessel coverage whereas these changes were attenuated with aging. Stroke led to an expansion of the basement membrane region that peaked at 3 h and partially recovered by 72 h in both age groups. Astrocyte endfeet and their mitochondria were severely swollen at both times points and ages. Our results suggest that blood–brain barrier permeability in young and aged animals is mediated by transcellular pathways (caveolae/vacuoles), rather than tight junction loss. Further, our data indicate that the effects of ischemia on pericytes and basement membrane are affected by aging.
Time delay processing of hypercapnic fMRI allows quantitative parameterization of cerebrovascular reactivity and blood flow delays
Authors: Donahue Manus J , Strother Megan K , Lindsey Kimberly P , Hocke Lia M , Tong Yunjie , Frederick Blaise deB
Published: December 2015

Blood oxygenation level-dependent fMRI contrast depends on the volume and oxygenation of blood flowing through the circulatory system. The effects on image intensity depend temporally on the arrival of blood within a voxel, and signal can be monitored during the time course of such blood flow. It has been previously shown that the passage of global endogenous variations in blood volume and oxygenation can be tracked as blood passes through the brain by determining the strength and peak time lag of their cross-correlation with blood oxygenation level-dependent data. By manipulating blood composition using transient hypercarbia and hyperoxia, we can induce much larger oxygenation and volume changes in the blood oxygenation level-dependent signal than result from natural endogenous fluctuations. This technique was used to examine cerebrovascular parameters in healthy subjects (n = 8) and subjects with intracranial stenosis (n = 22), with a subgroup of intracranial stenosis subjects scanned before and after surgical revascularization (n = 6). The halfwidth of cross-correlation lag times in the brain was larger in IC stenosis subjects (21.21 ± 14.22 s) than in healthy control subjects (8.03 ± 3.67), p < 0.001, and was subsequently reduced in regions that co-localized with surgical revascularization. These data show that blood circulatory timing can be measured robustly and longitudinally throughout the brain using simple respiratory challenges.
Apicobasal polarity of brain endothelial cells
Authors: Worzfeld Thomas , Schwaninger Markus
Published: December 2015

Normal brain homeostasis depends on the integrity of the blood–brain barrier that controls the access of nutrients, humoral factors, and immune cells to the CNS. The blood–brain barrier is composed mainly of brain endothelial cells. Forming the interface between two compartments, they are highly polarized. Apical/luminal and basolateral/abluminal membranes differ in their lipid and (glyco-)protein composition, allowing brain endothelial cells to secrete or transport soluble factors in a polarized manner and to maintain blood flow. Here, we summarize the basic concepts of apicobasal cell polarity in brain endothelial cells. To address potential molecular mechanisms underlying apicobasal polarity in brain endothelial cells, we draw on investigations in epithelial cells and discuss how polarity may go awry in neurological diseases.
Nanoliposomes protect against human arteriole endothelial dysfunction induced by β-amyloid peptide
Authors: Truran Seth , Weissig Volkmar , Madine Jillian , Davies Hannah A , Guzman-Villanueva Diana , Franco Daniel A , Karamanova Nina , Burciu Camelia , Serrano Geidy , Beach Thomas G , Migrino Raymond Q
Published: December 2015

We tested whether nanoliposomes containing phosphatidylcholine, cholesterol and phosphatidic acid (NLPA) prevent β-amyloid 1-42 (Aβ42) fibrillation and Aβ42-induced human arteriole endothelial dysfunction. NLPA abolished Aβ42 fibril formation (thioflavin-T fluorescence/electron microscopy). In ex-vivo human adipose and leptomeningeal arterioles, Aβ42 impaired dilator response to acetylcholine that was reversed by NLPA; this protection was abolished by L-NG-nitroarginine methyl ester. Aβ42 reduced human umbilical vein endothelial cell NO production that was restored by NLPA. Nanoliposomes prevented Aβ42 amyloid formation, reversed Aβ42-induced human microvascular endothelial dysfunction and may be useful in Alzheimer’s disease.
Genetic ablation of soluble tumor necrosis factor with preservation of membrane tumor necrosis factor is associated with neuroprotection after focal cerebral ischemia
Authors: Madsen Pernille M , Clausen Bettina H , Degn Matilda , Thyssen Stine , Kristensen Lotte K , Svensson Martina , Ditzel Nicholas , Finsen Bente , Deierborg Tomas , Brambilla Roberta , Lambertsen Kate L
Published: December 2015

Microglia respond to focal cerebral ischemia by increasing their production of the neuromodulatory cytokine tumor necrosis factor, which exists both as membrane-anchored tumor necrosis factor and as cleaved soluble tumor necrosis factor forms. We previously demonstrated that tumor necrosis factor knockout mice display increased lesion volume after focal cerebral ischemia, suggesting that tumor necrosis factor is neuroprotective in experimental stroke. Here, we extend our studies to show that mice with intact membrane-anchored tumor necrosis factor, but no soluble tumor necrosis factor, display reduced infarct volumes at one and five days after stroke. This was associated with improved functional outcome after experimental stroke. No changes were found in the mRNA levels of tumor necrosis factor and tumor necrosis factor-related genes (TNFR1, TNFR2, TACE), pro-inflammatory cytokines (IL-1β, IL-6) or chemokines (CXCL1, CXCL10, CCL2); however, protein expression of TNF, IL-1β, IL-6 and CXCL1 was reduced in membrane-anchored tumor necrosis factorΔ/Δ compared to membrane-anchored tumor necrosis factorwt/wt mice one day after experimental stroke. This was paralleled by reduced MHCII expression and a reduction in macrophage infiltration in the ipsilateral cortex of membrane-anchored tumor necrosis factorΔ/Δ mice. Collectively, these findings indicate that membrane-anchored tumor necrosis factor mediates the protective effects of tumor necrosis factor signaling in experimental stroke, and therapeutic strategies specifically targeting soluble tumor necrosis factor could be beneficial in clinical stroke therapy.
What is a pericyte?
Authors: Attwell David , Mishra Anusha , Hall Catherine N , O’Farrell Fergus M , Dalkara Turgay
Published: December 2015

Pericytes, spatially isolated contractile cells on capillaries, have been reported to control cerebral blood flow physiologically, and to limit blood flow after ischaemia by constricting capillaries and then dying. Paradoxically, a recent paper dismisses the idea of pericytes controlling cerebral blood flow, despite confirming earlier data showing a role for pericytes. We show that these discrepancies are apparent rather than real, and depend on the new paper defining pericytes differently from previous reports. An objective definition of different sub-classes of pericyte along the capillary bed is needed to develop novel therapeutic approaches for stroke and disorders caused by pericyte malfunction.
A benchmarking tool to evaluate computer tomography perfusion infarct core predictions against a DWI standard
Authors: Cereda Carlo W , Christensen Søren , Campbell Bruce CV , Mishra Nishant K , Mlynash Michael , Levi Christopher , Straka Matus , Wintermark Max , Bammer Roland , Albers Gregory W , Parsons Mark W , Lansberg Maarten G
Published: December 2015

Differences in research methodology have hampered the optimization of Computer Tomography Perfusion (CTP) for identification of the ischemic core. We aim to optimize CTP core identification using a novel benchmarking tool. The benchmarking tool consists of an imaging library and a statistical analysis algorithm to evaluate the performance of CTP. The tool was used to optimize and evaluate an in-house developed CTP-software algorithm. Imaging data of 103 acute stroke patients were included in the benchmarking tool. Median time from stroke onset to CT was 185 min (IQR 180-238), and the median time between completion of CT and start of MRI was 36 min (IQR 25-79). Volumetric accuracy of the CTP-ROIs was optimal at an rCBF threshold of <38%; at this threshold, the mean difference was 0.3 ml (SD 19.8 ml), the mean absolute difference was 14.3 (SD 13.7) ml, and CTP was 67% sensitive and 87% specific for identification of DWI positive tissue voxels. The benchmarking tool can play an important role in optimizing CTP software as it provides investigators with a novel method to directly compare the performance of alternative CTP software packages.
Non-invasive tracking of CD4+ T cells with a paramagnetic and fluorescent nanoparticle in brain ischemia
Authors: Jin Wei-Na , Yang Xiaoxia , Li Zhiguo , Li Minshu , Shi Samuel Xiang-Yu , Wood Kristofer , Liu Qingwei , Fu Ying , Han Wei , Xu Yun , Shi Fu-Dong , Liu Qiang
Published: December 2015

Recent studies have demonstrated that lymphocytes play a key role in ischemic brain injury. However, there is still a lack of viable approaches to non-invasively track infiltrating lymphocytes and reveal their key spatiotemporal events in the inflamed central nervous system (CNS). Here we describe an in vivo imaging approach for sequential monitoring of brain-infiltrating CD4+ T cells in experimental ischemic stroke. We show that magnetic resonance imaging (MRI) or Xenogen imaging combined with labeling of SPIO-Molday ION Rhodamine-B (MIRB) can be used to monitor the dynamics of CD4+ T cells in a passive transfer model. MIRB-labeled CD4+ T cells can be longitudinally visualized in the mouse brain and peripheral organs such as the spleen and liver after cerebral ischemia. Immunostaining of tissue sections showed similar kinetics of MIRB-labeled CD4+ T cells when compared with in vivo observations. Our results demonstrated the use of MIRB coupled with in vivo imaging as a valid method to track CD4+ T cells in ischemic brain injury. This approach will facilitate future investigations to identify the dynamics and key spatiotemporal events for brain-infiltrating lymphocytes in CNS inflammatory diseases.
The potassium channel KCa3.1 constitutes a pharmacological target for neuroinflammation associated with ischemia/reperfusion stroke
Authors: Chen Yi-Je , Nguyen Hai M , Maezawa Izumi , Grössinger Eva M , Garing April L , Köhler Ralf , Jin Lee-Way , Wulff Heike
Published: December 2015

Activated microglia/macrophages significantly contribute to the secondary inflammatory damage in ischemic stroke. Cultured neonatal microglia express the K+ channels Kv1.3 and KCa3.1, both of which have been reported to be involved in microglia-mediated neuronal killing, oxidative burst and cytokine production. However, it is questionable whether neonatal cultures accurately reflect the K+ channel expression of activated microglia in the adult brain. We here subjected mice to middle cerebral artery occlusion with eight days of reperfusion and patch-clamped acutely isolated microglia/macrophages. Microglia from the infarcted area exhibited higher densities of K+ currents with the biophysical and pharmacological properties of Kv1.3, KCa3.1 and Kir2.1 than microglia from non-infarcted control brains. Similarly, immunohistochemistry on human infarcts showed strong Kv1.3 and KCa3.1 immunoreactivity on activated microglia/macrophages. We next investigated the effect of genetic deletion and pharmacological blockade of KCa3.1 in reversible middle cerebral artery occlusion. KCa3.1 −/− mice and wild-type mice treated with the KCa3.1 blocker TRAM-34 exhibited significantly smaller infarct areas on day-8 after middle cerebral artery occlusion and improved neurological deficit. Both manipulations reduced microglia/macrophage activation and brain cytokine levels. Our findings suggest KCa3.1 as a pharmacological target for ischemic stroke. Of potential, clinical relevance is that KCa3.1 blockade is still effective when initiated 12 h after the insult.
Blood metabolite markers of cognitive performance and brain function in aging
Authors: Simpson Brittany N , Kim Min , Chuang Yi-Fang , Beason-Held Lori , Kitner-Triolo Melissa , Kraut Michael , Lirette Seth T , Windham B Gwen , Griswold Michael E , Legido-Quigley Cristina , Thambisetty Madhav
Published: December 2015

We recently showed that Alzheimer's disease patients have lower plasma concentrations of the phosphatidylcholines (PC16:0/20:5; PC16:0/22:6; and PC18:0/22:6) relative to healthy controls. We now extend these findings by examining associations between plasma concentrations of these PCs with cognition and brain function (measured by regional resting state cerebral blood flow; rCBF) in non-demented older individuals. Within the Baltimore Longitudinal Study of Aging neuroimaging substudy, participants underwent cognitive assessments and brain 15O-water positron emission tomography. Plasma phosphatidylcholines concentrations (PC16:0/20:5, PC16:0/22:6, and PC18:0/22:6), cognition (California Verbal Learning Test (CVLT), Trail Making Test A&B, the Mini-Mental State Examination, Benton Visual Retention, Card Rotation, and Fluencies—Category and Letter), and rCBF were assessed. Lower plasma phosphatidylcholine concentrations were associated with lower baseline memory performance (CVLT long delay recall task—PC16:0/20:5: −2.17–1.39−0.60 p = 0.001 (β with 95% confidence interval subscripts)) and lower rCBF in several brain regions including those associated with memory performance and higher order cognitive processes. Our findings suggest that lower plasma concentrations of PC16:0/20:5, PC16:0/22:6, and PC18:0/22:6 are associated with poorer memory performance as well as widespread decreases in brain function during aging. Dysregulation of peripheral phosphatidylcholine metabolism may therefore be a common feature of both Alzheimer's disease and age-associated differences in cognition.
Neuronal NCX1 overexpression induces stroke resistance while knockout induces vulnerability via Akt
Authors: Molinaro Pasquale , Sirabella Rossana , Pignataro Giuseppe , Petrozziello Tiziana , Secondo Agnese , Boscia Francesca , Vinciguerra Antonio , Cuomo Ornella , Philipson Kenneth D , De Felice Mario , Di Lauro Roberto , Di Renzo Gianfranco , Annunziato Lucio
Published: December 2015

Three different Na+/Ca2+ exchanger (NCX) isoforms, NCX1, NCX2, and NCX3, are expressed in brain where they play a relevant role in maintaining Na+ and Ca2+ homeostasis. Although the neuroprotective roles of NCX2 and NCX3 in stroke have been elucidated, the relevance of NCX1 is still unknown because of embryonic lethality of its knocking-out, heart dysfunctions when it is overexpressed, and the lack of selectivity in currently available drugs. To overcome these limitations we generated two conditional genetically modified mice that upon tamoxifen administration showed a selective decrease or increase of NCX1 in cortical and hippocampal neurons. Interestingly, in cortex and hippocampus NCX1 overexpression increased, where NCX1 knock-out reduced, both exchanger activity and Akt1 phosphorylation, a neuronal survival signaling. More important, mice overexpressing NCX1 showed a reduced ischemic volume and an amelioration of focal and general deficits when subjected to transient middle cerebral artery occlusion. Conversely, NCX1-knock-out mice displayed a worsening of brain damage, focal and neurological deficits with a decrease in Akt phosphorylation. These results support the idea that NCX1 overexpression/activation may represent a feasible therapeutic opportunity in stroke intervention.
Infarct prediction by intraoperative laser speckle imaging in patients with malignant hemispheric stroke
Authors: Hecht Nils , Müller Marc-Michael , Sandow Nora , Pinczolits Alexandra , Vajkoczy Peter , Woitzik Johannes
Published: December 2015

Currently, a reliable method for real-time prediction of ischemia in the human brain is not available. Here, we took a first step towards validating non-invasive intraoperative laser speckle imaging (iLSI) for prediction of infarction in 22 patients undergoing decompressive surgery for treatment of malignant hemispheric stroke. During surgery, cortical perfusion was visualized and recorded in real-time with iLSI. The true morphological infarct extension within the iLSI imaging field was superimposed onto the iLSI blood flow maps according to a postoperative MRI (16 h [95% CI: 13, 19] after surgery) with three-dimensional magnetization-prepared rapid gradient-echo and diffusion-weighted imaging reconstruction. Based on the frequency distribution of iLSI perfusion values within the infarcted and non-infarcted territories, probability curves and perfusion thresholds of normalized cerebral blood flow predictive of eventual infarction or non-infarction were calculated. Intraoperative LSI predicted and excluded cortical ischemia with 95% probability at normalized perfusion levels below 40% and above 110%, respectively, which represented 73% of the entire cortical surface area. Together, our results suggest that iLSI is valid for (pseudo-) quantitative assessment of blood flow in the human brain and may be used to identify tissue at risk for infarction at a given time-point in the course of ischemic stroke.
Regulation of cerebral metabolism during cortical spreading depression
Authors: Feuerstein Delphine , Backes Heiko , Gramer Markus , Takagaki Masatoshi , Gabel Paula , Kumagai Tetsuya , Graf Rudolf
Published: December 2015

We analyzed the metabolic response to cortical spreading depression that drastically increases local energy demand to restore ion homeostasis. During single and multiple cortical spreading depressions in the rat cortex, we simultaneously monitored extracellular levels of glucose and lactate using rapid sampling microdialysis and glucose influx using 18 F-fluorodeoxyglucose positron emission tomography while tracking cortical spreading depression using laser speckle imaging. Combining the acquired data with steady-state requirements we developed a mass-conserving compartment model including neurons and glia that was consistent with the observed data. In summary, our findings are: (1) Early breakdown of glial glycogen provides a major source of energy during increased energy demand and leaves 80% of blood-borne glucose to neurons. (2) Lactate is used solely by neurons and only if extracellular lactate levels are >80% above normal. (3) Although the ratio of oxygen and glucose consumption transiently reaches levels <3, the major part (>90%) of the overall energy supply is from oxidative metabolism. (4) During cortical spreading depression, brain release of lactate exceeds its consumption suggesting that lactate is only a circumstantial energy substrate. Our findings provide a general scenario for the metabolic response to increased cerebral energy demand.
Mice deficient in endothelial α5 integrin are profoundly resistant to experimental ischemic stroke
Authors: Roberts Jill , de Hoog Leon , Bix Gregory J
Published: December 2015

Stroke is a disease in dire need of better therapies. We have previously shown that a fragment of the extracellular matrix proteoglycan, perlecan, has beneficial effects following cerebral ischemia via the α5β1 integrin receptor. We now report that endothelial cell selective α5 integrin deficient mice (α5 KO) are profoundly resistant to ischemic infarct after transient middle cerebral artery occlusion. Specifically, α5 KOs had little to no infarct 2–3 days post-stroke, whereas controls had an increase in mean infarct volume over the same time period as expected. Functional outcome is also improved in the α5 KOs compared with controls. Importantly, no differences in cerebrovascular anatomy or collateral blood flow were noted that could account for this difference in ischemic injury. Rather, we demonstrate that α5 KOs have increased blood-brain barrier integrity (increased expression of claudin-5, and absent brain parenchymal IgG extravasation) after stroke compared with controls, which could explain their resistance to ischemic injury. Additionally, inhibition of α5 integrin in vitro leads to decreased permeability of brain endothelial cells following oxygen-glucose deprivation. Together, these findings indicate endothelial cell α5 integrin plays an important role in stroke outcome and blood-brain barrier integrity, suggesting that α5 integrin could be a novel therapeutic target for stroke.
Assessing sensory versus optogenetic network activation by combining (o)fMRI with optical Ca2+ recordings
Authors: Schmid Florian , Wachsmuth Lydia , Schwalm Miriam , Prouvot Pierre-Hugues , Jubal Eduardo Rosales , Fois Consuelo , Pramanik Gautam , Zimmer Claus , Faber Cornelius , Stroh Albrecht
Published: December 2015

Encoding of sensory inputs in the cortex is characterized by sparse neuronal network activation. Optogenetic stimulation has previously been combined with fMRI (ofMRI) to probe functional networks. However, for a quantitative optogenetic probing of sensory-driven sparse network activation, the level of similarity between sensory and optogenetic network activation needs to be explored. Here, we complement ofMRI with optic fiber-based population Ca2+ recordings for a region-specific readout of neuronal spiking activity in rat brain. Comparing Ca2+ responses to the blood oxygenation level-dependent signal upon sensory stimulation with increasing frequencies showed adaptation of Ca2+ transients contrasted by an increase of blood oxygenation level-dependent responses, indicating that the optical recordings convey complementary information on neuronal network activity to the corresponding hemodynamic response. To study the similarity of optogenetic and sensory activation, we quantified the density of cells expressing channelrhodopsin-2 and modeled light propagation in the tissue. We estimated the effectively illuminated volume and numbers of optogenetically stimulated neurons, being indicative of sparse activation. At the functional level, upon either sensory or optogenetic stimulation we detected single-peak short-latency primary Ca2+ responses with similar amplitudes and found that blood oxygenation level-dependent responses showed similar time courses. These data suggest that ofMRI can serve as a representative model for functional brain mapping.
Pharmacology in cerebrovascular disease research: Pharmacokinetics–pharmacodynamics to the rescue
Authors: Feuerstein Giora Z
Published: December 2015

Pharmacological tools (compounds) have an important role in validation of biological molecular targets for their role in disease processes and their prospective development for therapeutic objectives. Effective utilization of such pharmacological tools impacts on the veracity of the information by which decisions regarding target validation is reached, and investment in clinical development is committed. This commentary addresses frequent gaps in effective utilization of pharmacological principles and practices of pharmacokinetics and pharmacodynamics in experimental pre-clinical research, which if more rigorously implemented could contribute to eventual success in drug development for stroke and neurotrauma.
Safflower Yellow regulates microglial polarization and inhibits inflammatory response in LPS-stimulated Bv2 cells
Authors: Yang Xing-Wang , Li Yan-Hua , Zhang Hui , Zhao Yong-Fei , Ding Zhi-Bin , Yu Jie-Zhong , Liu Chun-Yun , Liu Jian-Chun , Jiang Wei-Jia , Feng Qian-Jin , Xiao Bao-Guo , Ma Cun-Gen
Published: December 2015

Activated microglia, especially polarized M1 cells, produce pro-inflammatory cytokines and free radicals, thereby contributing directly to neuroinflammation and various brain disorders. Given that excessive or chronic neuroinflammation within the central nervous system (CNS) exacerbates neuronal damage, molecules that modulate neuroinflammation are candidates as neuroprotective agents. In this study, we provide evidence that Safflor yellow (SY), the main active component in the traditional Chinese medicine safflower, modulates inflammatory responses by acting directly on BV2 microglia. LPS stimulated BV2 cells to upregulate expression of TLR4-Myd88 and MAPK-NF-κB signaling pathways and to release IL-1β, IL-6, TNF-α, and COX-2. However, SY treatment inhibited expression of TLR4-Myd88 and p-38/p-JNK-NF-κB, downregulated expression of iNOS, CD16/32, and IL-12, and upregulated CD206 and IL-10. In conclusion, our results demonstrate that SY exerts an anti-inflammatory effect on BV2 microglia, possibly through TLR-4/p-38/p-JNK/NF-κB signaling pathways and the conversion of microglia from inflammatory M1 to an anti-inflammatory M2 phenotype.