561 research outputs found
Evolutionary Dilemmas in a Social Network
We simulate the prisoner's dilemma and hawk-dove games on a real social
acquaintance network. Using a discrete analogue of replicator dynamics, we show
that surprisingly high levels of cooperation can be achieved, contrary to what
happens in unstructured mixing populations. Moreover, we empirically show that
cooperation in this network is stable with respect to invasion by defectors.Comment: 13 pages, 9 figures; to be published in Lecture Notes in Computer
Science 200
Tubulin and Tubulin Posttranslational Modifications in Alzheimer’s Disease and Vascular Dementia
Copyright \ua9 2021 Santiago-Mujika, Luthi-Carter, Giorgini, Kalaria and Mukaetova-Ladinska. Alzheimer’s disease (AD) and vascular dementia (VaD) are the two most common forms of dementia in older people. Although these two dementia types differ in their etiology, they share many pathophysiological and morphological features, including neuronal loss, which is associated with the microtubule (MT) destabilization. Stabilization of MTs is achieved in different ways: through interactions with MT binding proteins (MTBP) or by posttranslational modifications (PTMs) of tubulin. Polyglutamylation and tyrosination are two foremost PTMs that regulate the interaction between MTs and MTBPs, and play, therefore, a role in neurodegeneration. In this review, we summarize key information on tubulin PTMs in relation to AD and VaD and address the importance of studying further the tubulin code to reveal sites of potential intervention in development of novel and effective dementia therapy
The value of PET, CT and in-line PET/CT in patients with gastrointestinal stromal tumours: long-term outcome of treatment with imatinib mesylate
Purpose: Gastrointestinal stromal tumours (GIST) are mesenchymal neoplasms of the gastrointestinal tract that are unresponsive to standard sarcoma chemotherapy. Imaging of GIST patients is done with structural and functional methods such as contrast-enhanced helical computed tomography (ceCT) and positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG). The aim of this study was to compare the prognostic power of PET and ceCT and to evaluate the clinical role of PET/CT imaging. Methods: All patients with GIST undergoing PET or PET/CT examinations were prospectively included in this study, and the median overall survival, time to progression and treatment duration were documented. The prognostic significance of PET and ceCT criteria of treatment response was assessed and PET/CT was compared with PET and ceCT imaging. Data for 34 patients (19 male, 15 female, 21-76 years) undergoing PET or PET/CT for staging or restaging were analysed. Results: In 28 patients, PET/CT and ceCT were available after introduction of treatment with the tyrosine kinase inhibitor imatinib mesylate (Gleevec; Novartis, Basel, Switzerland). Patients without FDG uptake after the start of treatment had a better prognosis than patients with residual activity. In contrast, ceCT criteria provided insufficient prognostic power. However, more lesions were found on ceCT images than on PET images, and FDG uptake was sometimes very variable. PET/CT delineated active lesions better than did the combination of PET and ceCT imaging. Conclusion: Both PET and PET/CT provide important prognostic information and have an impact on clinical decision-making in GIST patients. PET/CT precisely delineates lesions and thus allows for the correct planning of surgical intervention
Thermal expansion, heat capacity and magnetostriction of RAl (R = Tm, Yb, Lu) single crystals
We present thermal expansion and longitudinal magnetostriction data for cubic
RAl3 (R = Tm, Yb, Lu) single crystals. The thermal expansion coefficient for
YbAl3 is consistent with an intermediate valence of the Yb ion, whereas the
data for TmAl3 show crystal electric field contributions and have strong
magnetic field dependencies. de Haas-van Alphen-like oscillations were observed
in the magnetostriction data of YbAl3 and LuAl3, several new extreme orbits
were measured and their effective masses were estimated. Zero and 140 kOe
specific heat data taken on both LuAl3 and TmAl3 for T < 200 K allow for the
determination of a CEF splitting scheme for TmAl3
In vivo cell-autonomous transcriptional abnormalities revealed in mice expressing mutant huntingtin in striatal but not cortical neurons
Huntington's disease (HD), caused by a CAG repeat expansion in the huntingtin (HTT) gene, is characterized by abnormal protein aggregates and motor and cognitive dysfunction. Htt protein is ubiquitously expressed, but the striatal medium spiny neuron (MSN) is most susceptible to dysfunction and death. Abnormal gene expression represents a core pathogenic feature of HD, but the relative roles of cell-autonomous and non-cell-autonomous effects on transcription remain unclear. To determine the extent of cell-autonomous dysregulation in the striatum in vivo, we examined genome-wide RNA expression in symptomatic D9-N171-98Q (a.k.a. DE5) transgenic mice in which the forebrain expression of the first 171 amino acids of human Htt with a 98Q repeat expansion is limited to MSNs. Microarray data generated from these mice were compared with those generated on the identical array platform from a pan-neuronal HD mouse model, R6/2, carrying two different CAG repeat lengths, and a relatively high degree of overlap of changes in gene expression was revealed. We further focused on known canonical pathways associated with excitotoxicity, oxidative stress, mitochondrial dysfunction, dopamine signaling and trophic support. While genes related to excitotoxicity, dopamine signaling and trophic support were altered in both DE5 and R6/2 mice, which may be either cell autonomous or non-cell autonomous, genes related to mitochondrial dysfunction, oxidative stress and the peroxisome proliferator-activated receptor are primarily affected in DE5 transgenic mice, indicating cell-autonomous mechanisms. Overall, HD-induced dysregulation of the striatal transcriptome can be largely attributed to intrinsic effects of mutant Htt, in the absence of expression in cortical neuron
Decreased Striatal RGS2 Expression Is Neuroprotective in Huntington's Disease (HD) and Exemplifies a Compensatory Aspect of HD-Induced Gene Regulation
The molecular phenotype of Huntington's disease (HD) is known to comprise highly reproducible changes in gene expression involving striatal signaling genes. Here we test whether individual changes in striatal gene expression are capable of mitigating HD-related neurotoxicity.We used protein-encoding and shRNA-expressing lentiviral vectors to evaluate the effects of RGS2, RASD2, STEP and NNAT downregulation in HD. Of these four genes, only RGS2 and RASD2 modified mutant htt fragment toxicity in cultured rat primary striatal neurons. In both cases, disease modulation was in the opposite of the predicted direction: whereas decreased expression of RGS2 and RASD2 was associated with the HD condition, restoring expression enhanced degeneration of striatal cells. Conversely, silencing of RGS2 or RASD2 enhanced disease-related changes in gene expression and resulted in significant neuroprotection. These results indicate that RGS2 and RASD2 downregulation comprises a compensatory response that allows neurons to better tolerate huntingtin toxicity. Assessment of the possible mechanism of RGS2-mediated neuroprotection showed that RGS2 downregulation enhanced ERK activation. These results establish a novel link between the inhibition of RGS2 and neuroprotective modulation of ERK activity.Our findings both identify RGS2 downregulation as a novel compensatory response in HD neurons and suggest that RGS2 inhibition might be considered as an innovative target for neuroprotective drug development
Cell loss in the motor and cingulate cortex correlates with symptomatology in Huntington's disease
Huntington's disease is an autosomal dominant inherited neurodegenerative disease with motor symptoms that are variably co-expressed with mood and cognitive symptoms, and in which variable neuronal degeneration is also observed in the basal ganglia and the cerebral cortex. We have recently shown that the variable symptomatology in Huntington's disease correlates with the variable compartmental pattern of GABAA receptor and cell loss in the striatum. To determine whether the phenotypic variability in Huntington's disease is also related to variable neuronal degeneration in the cerebral cortex, we undertook a double-blind study using unbiased stereological cell counting methods to determine the pattern of cell loss in the primary motor and anterior cingulate cortices in the brains of 12 cases of Huntington's disease and 15 controls, and collected detailed data on the clinical symptomatology of the patients with Huntington's disease from family members and clinical records. The results showed a significant association between: (i) pronounced motor dysfunction and cell loss in the primary motor cortex; and (ii) major mood symptomatology and cell loss in the anterior cingulate cortex. This association held for both total neuronal loss (neuronal N staining) and pyramidal cell loss (SMI32 staining), and also correlated with marked dystrophic changes in the remaining cortical neurons. There was also an association between cortical cell loss and striatal neuropathological grade, but no significant association with CAG repeat length in the Huntington's disease gene. These findings suggest that the heterogeneity in clinical symptomatology that characterizes Huntington's disease is associated with variation in the extent of cell loss in the corresponding functional regions of the cerebral cortex whereby motor dysfunction correlates with primary motor cortex cell loss and mood symptomatology is associated with cell loss in the cingulate corte
Multipole Ordering and Fluctuations in f-Electron Systems
We investigate effects of multipole moments in f-electron systems both from
phenomenological and microscopic viewpoints. First, we discuss significant
effects of octupole moment on the magnetic susceptibility in a paramagnetic
phase. It is found that even within mean-field approximation, the magnetic
susceptibility deviates from the Curie-Weiss law due to interactions between
dipole and octupole moments. Next, we proceed to a microscopic theory for
multipole ordering on the basis of a j-j coupling scheme. After brief
explanation of a method to derive multipole interactions from the -electron
model, we discuss several multipole ordered phases depending on lattice
structure. Finally, we show our new development of the microscopic approach to
the evaluation of multipole response functions. We apply fluctuation exchange
approximation to the f-electron model, and evaluate multipole response
functions.Comment: 7 pages, 4 figures, Proceedings of ASR-WYP-200
Caldag-Gefi Down-Regulation in the Striatum as a Neuroprotective Change in Huntington's Disease.
Huntingtin protein (Htt) is ubiquitously expressed, yet Huntington’s disease (HD), a fatal
neurologic disorder produced by expansion of an Htt polyglutamine tract, is
characterized by neurodegeneration that occurs primarily in the striatum and cerebral
cortex. Such discrepancies between sites of expression and pathology occur in multiple
neurodegenerative disorders associated with expanded polyglutamine tracts. One
possible reason is that disease-modifying factors are tissue-specific. Here we show that
the striatum-enriched protein, CalDAG-GEFI, is severely down-regulated in the striatum
of mouse HD models and is down-regulated in HD individuals. In the R6/2 transgenic
mouse model of HD, striatal neurons with the largest aggregates of mutant Htt have the
lowest levels of CalDAG-GEFI. In a brain-slice explant model of HD, knock-down of CalDAG-GEFI expression rescues striatal neurons from pathology induced by transfection of polyglutamine-expanded Htt exon 1. These findings suggest that the striking down-regulation of CalDAG-GEFI in HD could be a protective mechanism that mitigates Htt-induced degeneration.Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (R01-HD28341)National Institute of Mental Health (U.S.) (F32-MH065815)Wellcome Trust (London, England)Cure Huntington’s Disease Initiative, Inc.MGH/MIT Morris Udall Center of Excellence in Parkinson Disease Research (P50-NS038372
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