The apolipoprotein E gene plays an important role in the pathogenesis of Alzheimer's disease , and amyloid plaque comprised mostly of the amyloid-beta peptide ) is one of the major hallmarks of AD. However, the relationship between these two important molecules is poorly understood. We examined how A treatment affects APOE expression in cultured cells and tested the role of the transcription factor NF-B in APOE gene regulation. To delineate NF-B's role, we have characterized a 1098 nucleotide (...) segment containing the 5'-flanking region of the human APOE gene . Sequence analysis of this region suggests the presence of two potential NF-B elements. To demonstrate promoter activity, the region was cloned upstream of a promoterless luciferase gene. This segment was able to drive expression of luciferase in transient transfections of human fetal glial cells. Promoter activity was stimulated twofold by A treatment. Pretreatment with double-stranded DNA decoy oligonucleotides against NF-B reduced A stimulation. Deletion and mutagenetic analyses demonstrated that the distal NF-B element was functional and showed a strong DNA-protein complex band in gel shift analysis, similar to that from control NF-B consensus element. An anti-inflammatory and anti-NF-B drug, sodium salicylate, significantly blocked A-induced APOE promoter function. Our data provide evidence that upregulation of APOE by A in astroglial cells is mediated by an NF-B-element present in the 5'-flanking region of the APOE gene. (shrink)

Amyloid-beta peptide plaque in the brain is the primary diagnostic criterion of Alzheimer's disease . The physiological role of Abeta are poorly understood. We have previously determined an Abeta interacting domain in the promoters of AD-associated genes . This AbetaID interacts in a DNA sequence-specific manner with Abeta. We now demonstrate novel Abeta activity as a possible transcription factor. Herein, we detected Abeta-chromatin interaction in cell culture by ChIP assay. We observed that human neuroblastoma cells treated with FITC (...) conjugated Abeta1-40 localized Abeta to the nucleus in the presence of H2O2-mediated oxidative stress. Furthermore, primary rat fetal cerebrocortical cultures were transfected with APP and BACE1 promoter-luciferase fusions, and rat PC12 cultures were transfected with polymorphic APP promoter-CAT fusion clones. Transfected cells were treated with different Abeta peptides and/or H2O2. Abeta treatment of cell cultures produced a DNA sequence-specific response in cells transfected with polymorphic APP clones. Our results suggest the Abeta peptide may regulate its own production through feedback on its precursor protein and BACE1, leading to amyloidogenesis in AD. (shrink)

BackgroundStory recall tests have shown variable sensitivity to rate of cognitive decline in individuals with Alzheimer’s disease biomarkers. Although SR tasks are typically scored by obtaining a sum of items recalled, item-level analyses may provide additional sensitivity to change and AD processes. Here, we examined the difficulty and discrimination indices of each item from the Logical Memory SR task, and determined if these metrics differed by recall conditions, story version, lexical categories, serial position, and amyloid status.Methodsn = 1,141 participants (...) from the Wisconsin Registry for Alzheimer’s Prevention longitudinal study who had item-level data were included in these analyses, as well as a subset of n = 338 who also had amyloid positron emission tomography imaging. LM data were categorized into four lexical categories, and by serial position. We calculated difficulty and discriminability/memorability by item, category, and serial position and ran separate repeated measures ANOVAs for each recall condition, lexical category, and serial position. For the subset with amyloid imaging, we used a two-sample t-test to examine whether amyloid positive and amyloid negative groups differed in difficulty or discrimination for the same summary metrics.ResultsIn the larger sample, items were more difficult in the delayed recall condition across both story A and story B. Item discrimination was higher at delayed than immediate recall, and proper names had better discrimination than any of the other lexical categories or serial position groups. In the subsample with amyloid PET imaging, proper names were more difficult for Aβ+ than Aβ−; items in the verb and “other” lexical categories and all serial positions from delayed recall were more discriminate for the Aβ+ group compared to the Aβ− group.ConclusionThis study provides empirical evidence that both LM stories are effective at discriminating ability levels and amyloid status, and that individual items vary in difficulty and discrimination by amyloid status, while total scores do not. These results can be informative for the future development of sensitive tasks or composite scores for early detection of cognitive decline. (shrink)

BACKGROUND: Alzheimer's disease is intimately tied to amyloid-beta peptide. Extraneuronal brain plaques consisting primarily of Abeta aggregates are a hallmark of AD. Intraneuronal Abeta subunits are strongly implicated in disease progression. Protein sequence mutations of the Abeta precursor protein account for a small proportion of AD cases, suggesting that regulation of the associated gene may play a more important role in AD etiology. The APP promoter possesses a novel 30 nucleotide sequence, or "proximal regulatory element" , at -76/-47, (...) from the +1 transcription start site that confers cell type specificity. This PRE contains sequences that make it vulnerable to epigenetic modification and may present a viable target for drug studies. We examined PRE-nuclear protein interaction by gel electrophoretic mobility shift assay and PRE mutant EMSA. This was followed by functional studies of PRE mutant/reporter gene fusion clones. RESULTS: EMSA probed with the PRE showed DNA-protein interaction in multiple nuclear extracts and in human brain tissue nuclear extract in a tissue-type specific manner. We identified transcription factors that are likely to bind the PRE, using competition gel shift and gel supershift: Activator protein 2 , nm23 nucleoside diphosphate kinase/metastatic inhibitory protein , and specificity protein 1 . These sites crossed a known single nucleotide polymorphism . EMSA with PRE mutants and promoter/reporter clone transfection analysis further implicated PuF in cells and extracts. Functional assays of mutant/reporter clone transfections were evaluated by ELISA of reporter protein levels. EMSA and ELISA results correlated by meta-analysis. CONCLUSIONS: We propose that PuF may regulate the APP gene promoter and that AD risk may be increased by interference with PuF regulation at the PRE. PuF is targeted by calcium/calmodulin-dependent protein kinase II inhibitor 1, which also interacts with the integrins. These proteins are connected to vital cellular and neurological functions. In addition, the transcription factor PuF is a known inhibitor of metastasis and regulates cell growth during development. Given that APP is a known cell adhesion protein and ferroxidase, this suggests biochemical links among cell signaling, the cell cycle, iron metabolism in cancer, and AD in the context of overall aging. (shrink)

Major hallmarks of Alzheimer's disease include brain deposition of the amyloid-beta peptide , which is proteolytically cleaved from a large Abeta precursor protein by beta and gamma- secretases. A transmembrane aspartyl protease, beta-APP cleaving enzyme , has been recognized as the beta-secretase. We review the structure and function of the BACE1 protein, and of 4129 bp of the 5'-flanking region sequence of the BACE1 gene and its interaction with various transcription factors involved in cell signaling. (...) The promoter region and 5'-untranslated region contain multiple transcription factor binding sites, such as AP-1, CREB and MEF2. A 91 bp fragment is the shortest region with significant reporter gene activity and constitutes the minimal promoter element for BACE1. The BACE1 promoter contains six unique functional domains and three structural domains of increasing sequence complexity as the "ATG" start codon is approached. Notably, the BACE1 gene promoter contains basal regulatory elements, inducible features and sites for regulation by various important transcription factors. Herein, we also discuss and speculate how the interaction of these transcription factors with the BACE1 promoter can modulate synaptic plasticity, neuronal apoptosis and oxidative stress, which are pertinent to the pathogenesis and progression of AD. (shrink)

Most prions (infectious proteins) are self‐propagating amyloids (filamentous protein multimers), and have been found in both mammals and fungal species. The prions [URE3] and [PSI+] of yeast are disease agents of Saccharomyces cerevisiae while [Het‐s] of Podospora anserina may serve a normal cellular function. The parallel in‐register beta‐sheet structure shown by prion amyloids makes possible a templating action at the end of filaments which explains the faithful transmission of variant differences in these molecules. This property of self‐reproduction, in turn, (...) allows these proteins to act as de facto genes, encoding heritable information. BioEssays 30:955–964, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Increased amyloid beta (Aβ) production by sequential cleavage of the amyloid precursor protein (APP) by the β‐ and γ‐secretases contributes to the etiological basis of Alzheimer's disease (AD). This process requires APP and the secretases to be in the same subcellular compartments, such as the endosomes. Since all membrane organelles in the endomembrane system are kinetically and functionally linked, any defects in the trafficking and sorting machinery would be expected to change the functional properties of the whole (...) system. The Golgi is a primary organelle for protein trafficking, sorting and modifications, and Golgi defects have been reported in AD. Here we hypothesize that Golgi fragmentation in AD accelerates APP trafficking and Aβ production. Furthermore, Golgi defects may perturb the proper trafficking and processing of many essential neuronal proteins, resulting in compromised neuronal function. Therefore, molecular tools that can restore Golgi structure and function could prove useful as potential drugs for AD treatment. (shrink)

Name der Zeitschrift: Byzantinische Zeitschrift Jahrgang: 107 Heft: 1 Seiten: 37-50.

Amyloid beta precursor protein (APP) and prion protein (PrP) are cell membrane elements implicated in neurodegenerative diseases. Both proteins undergo endoproteolysis. Evidence is adduced from the literature hinting that the process in the two proteins could be related, their functions may overlap and their distributions coincide. It is proposed that PrP catalyses its own cleavage, the C-terminal fragment functions as an α secretase and the N-terminal segment chaperones the active site; the α secretase releases anticoagulant and neurotrophic ectodomains (...) from APP. The proposals explain some features of spongiform encephalopathies. BioEssays 23:456–462, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Recently opposing effects of cysteine protease inhibitors, the human cystatins, on neurodegeneration have been reported. Human cystatin C is a risk factor for late‐onset Alzheimer's disease (AD), whereas human stefin B (cystatin B) has no direct involvement in AD. Conflicting data show that their target protease, cathepsin B, might be anti‐amyloidogenic, helping in amyloid‐beta (Aβ) clearance or, instead, might be involved in Aβ production. Some reports claim that cystatin C binds soluble Aβ, making transgenic animals healthier, others, in (...) contrast, that deleting cystatins genes may contribute to amyloid pathology in animal models of AD. (shrink)

Concerns about the possibility of a sharp rise in the prevalence of Alzheimer’s disease in Western nations have led to both the significant deployment of resources and the development of national research and healthcare plans. Although often focused on treatment, substantial efforts have also been dedicated toward preventing or delaying AD onset. As a result, recent technological and biomedical advances have greatly improved the understanding of AD pathophysiology. While some new tests can assess only risk ), some tests for certain (...) biomarkers (e.g., amyloid beta accumulation in the brain detected via positron... (shrink)

Alzheimer's disease (AD) is a neurodegenerative disease exhibiting amyloid beta (Aβ) peptide accumulation as a key characteristic. Autophagy, which is dysregulated in AD, participates in the metabolism of Aβ. Unexpectedly, we recently found that autophagy, in addition to its degradative function, also mediates the secretion of Aβ. This finding adds Aβ to an increasing number of biomolecules, the secretion of which is mediated by autophagy. We also showed that inhibition of Aβ secretion through genetic deletion of autophagy leads (...) to intracellular Aβ accumulation, which enhanced neurodegeneration induced by autophagy deficiency. Hence, autophagy may play a central role in two pathological hallmarks of AD: Aβ amyloidosis and neurodegeneration. Herein, we summarize the role of autophagy in AD with focus on Aβ metabolism in light of the recently established role of autophagy in protein secretion. We discuss potential routes for autophagy‐mediated Aβ secretion and suggest experimental approaches to further elucidate its mechanisms. (shrink)

Alzheimer's disease is characterized by amyloid-beta peptide -loaded plaques in the brain. Abeta is a cleavage fragment of amyloid-beta protein precursor and over production of APP may lead to amyloidogenesis. The regulatory region of the APP gene contains consensus sites recognized by the transcription factor, specificity protein 1 , which has been shown to be required for the regulation of APP and Abeta. To understand the role of SP1 in APP biogenesis, herein we have characterized the (...) relative distribution and localization of SP1, APP, and Abeta in various brain regions of rodent and primate models using immunohistochemistry. We observed that overall distribution and cellular localization of SP1, APP, and Abeta are similar and neuronal in origin. Their distribution is abundant in various layers of neocortex, but restricted to the Purkinje cell layer of the cerebellum, and the pyramidal cell layer of hippocampus. These findings suggest that overproduction of Abeta in vivo may be associated with transcriptional pathways involving SP1 and the APP gene. (shrink)

The present review highlights an association between autism, Alzheimer disease , and fragile X syndrome . We propose a conceptual framework involving the amyloid-beta peptide , Abeta precursor protein , and fragile X mental retardation protein based on experimental evidence. The anabolic effect of the secreted alpha form of the amyloid-beta precursor protein may contribute to the state of brain overgrowth implicated in autism and FXS. Our previous report demonstrated that higher plasma sAPPalpha levels associate with (...) more severe symptoms of autism, including aggression. This molecular effect could contribute to intellectual disability due to repression of cell-cell adhesion, promotion of dense, long, thin dendritic spines, and the potential for disorganized brain structure as a result of disrupted neurogenesis and migration. At the molecular level, APP and FMRP are linked via the metabotropic glutamate receptor 5 . Specifically, mGluR5 activation releases FMRP repression of APP mRNA translation and stimulates sAPP secretion. The relatively lower sAPPalpha level in AD may contribute to AD symptoms that significantly contrast with those of FXS and autism. Low sAPPalpha and production of insoluble Abeta would favor a degenerative process, with the brain atrophy seen in AD. Treatment with mGluR antagonists may help repress APP mRNA translation and reduce secretion of sAPP in FXS and perhaps autism. (shrink)

Alzheimer's disease is characterized by plaques of amyloid-beta peptide, cleaved from amyloid-beta protein precursor . Our hypothesis is that lifespan profiles of AD-associated mRNA and protein levels in monkeys would differ from mice and that differential lifespan expression profiles would be useful to understand human AD pathogenesis. We compared profiles of AbetaPP mRNA, AbetaPP protein, and Abeta levels in rodents and primates. We also tracked a transcriptional regulator of the AbetaPP gene, specificity protein 1 , and (...) the beta amyloid precursor cleaving enzyme . In mice, AbetaPP and SP1 mRNA and their protein products were elevated late in life; Abeta levels declined in old age. In monkeys, SP1, AbetaPP, and BACE1 mRNA declined in old age, while protein products and Abeta levels rose. Proteolytic processing in both species did not match production of Abeta. In primates, AbetaPP and SP1 mRNA levels coordinate, but an inverse relationship exists with corresponding protein products as well as Abeta levels. Comparison of human DNA and mRNA sequences to monkey and mouse counterparts revealed structural features that may explain differences in transcriptional and translational processing. These findings are important for selecting appropriate models for AD and other age-related diseases. (shrink)

Type 2 diabetes mellitus is associated with cognitive impairment in many domains. There are several pieces of evidence that changes in neuronal neuropathies and metabolism have been observed in T2DM. Structural and functional MRI shows that abnormal connections and synchronization occur in T2DM brain circuits and related networks. Neuroplasticity and energy metabolism appear to be principal effector systems, which may be related to amyloid beta deposition, although there is no unified explanation that includes the complex etiology of T2DM (...) with cognitive impairment. Herein, we assume that cognitive impairment in diabetes may lead to abnormalities in neuroplasticity and energy metabolism in the brain, and those reflected to MRI structural connectivity and functional connectivity, respectively. (shrink)

Background and Aims Progress towards validating amyloid beta as an early indicator of Alzheimer’s disease (AD) heightens the need for evaluation of stakeholders’ perspectives of the benefits and harms of preclinical testing in asymptomatic individuals. Methods Investigators conducted and analyzed 14 semi-structured interviews with family members of patients diagnosed with AD. Results Participants reported benefits, including the potential to seek treatment, make lifestyle changes, and prepare for cognitive impairment. Participants identified harms, including social harms, adverse life decisions, and (...) psychological harms. Nine participants reported either a “positive global perspective” or a “positive global perspective (qualified).” Conclusion Results from this study characterized stakeholders’ perspectives on the potential benefits and harms of clinical use of preclinical testing for AD. Investigators used data from this study to develop a framework that contributes to ongoing discussions that will evaluate widespread adoption of preclinical testing and will inform future research. (shrink)

Cognitive dysfunction in Alzheimer’s disease is caused by disturbances in neuronal circuits of the brain underpinned by synapse loss, neuronal dysfunction and neuronal death. Amyloid beta and tau protein cause these pathological changes and enhance neuroinflammation, which in turn modifies disease progression and severity. Vagal nerve stimulation, via activation of the locus coeruleus, results in the release of catecholamines in the hippocampus and neocortex, which can enhance synaptic plasticity and reduce inflammatory signalling. Vagal nerve stimulation has shown promise (...) to enhance cognitive ability in animal models. Research in rodents has shown that VNS can have positive effects on basal synaptic function and synaptic plasticity, tune inflammatory signalling, and limit the accumulation of amyloid plaques. Research in humans with invasive and non-invasive VNS devices has shown promise for the modulation of cognition. However, the direct stimulation of the vagus nerve afforded with the invasive procedure carries surgical risks. In contrast, non-invasive VNS has the potential to be a broadly available therapy to manage cognitive symptoms in early AD, however, the magnitude and specificity of its effects remains to be elucidated, and the non-inferiority of the effects of non-invasive VNS as compared with invasive VNS still needs to be established. Ongoing clinical trials with healthy individuals and patients with early AD will provide valuable information to clarify the potential benefits of non-invasive VNS in cognition and AD. Whether invasive or non-invasive VNS can produce a significant improvement on memory function and whether its effects can modify the progression of AD will require further investigation. (shrink)

Alzheimer's disease is characterized by formation of neuritic plaque primarily composed of a small filamentous protein called amyloid-beta peptide . The rate-limiting step in the production of Abeta is the processing of Abeta precursor protein by beta-site APP-cleaving enzyme . Hence, BACE1 activity plausibly plays a rate-limiting role in the generation of potentially toxic Abeta within brain and the development of AD, thereby making it an interesting drug target. A phase II trial of the promising LY2886721 inhibitor (...) of BACE1 was suspended in June 2013 by Eli Lilly and Co., due to possible liver toxicity. This outcome was apparently a surprise to the study's team, particularly since BACE1 knockout mice and mice treated with the drug did not show such liver toxicity. Lilly proposed that the problem was not due to LY2886721 anti-BACE1 activity. We offer an alternative hypothesis, whereby anti-BACE1 activity may induce apparent hepatotoxicity through inhibiting BACE1's processing of beta-galactoside alpha-2,6-sialyltransferase I . In knockout mice, paralogues, such as BACE2 or cathepsin D, could partially compensate. Furthermore, the short duration of animal studies and short lifespan of study animals could mask effects that would require several decades to accumulate in humans. Inhibition of hepatic BACE1 activity in middle-aged humans would produce effects not detectable in mice. We present a testable model to explain the off-target effects of LY2886721 and highlight more broadly that so-called off-target drug effects might actually represent off-site effects that are not necessarily off-target. Consideration of this concept in forthcoming drug design, screening, and testing programs may prevent such failures in the future. (shrink)

The sporadic nature of Alzheimer's disease argues for an environmental link that may drive AD pathogenesis; however, the triggering factors and the period of their action are unknown. Recent studies in rodents have shown that exposure to lead during brain development predetermined the expression and regulation of the amyloid precursor protein and its amyloidogenic beta-amyloid product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 ] as well as their transcriptional regulator were (...) elevated in aged monkeys exposed to Pb as infants. Furthermore, developmental exposure to Pb altered the levels, characteristics, and intracellular distribution of Abeta staining and amyloid plaques in the frontal association cortex. These latent effects were accompanied by a decrease in DNA methyltransferase activity and higher levels of oxidative damage to DNA, indicating that epigenetic imprinting in early life influenced the expression of AD-related genes and promoted DNA damage and pathogenesis. These data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD. (shrink)

Oxidative damage to DNA has been associated with neurodegenerative diseases. Developmental exposure to lead has been shown to elevate the Alzheimer's disease related beta-amyloid peptide , which is known to generate reactive oxygen species in the aging brain. This study measures the lifetime cerebral 8-hydroxy-2'-deoxyguanosine levels and the activity of the DNA repair enzyme 8-oxoguanine DNA glycosylase in rats developmentally exposed to Pb. Oxo8dG was transiently modulated early in life , but was later elevated 20 months after exposure (...) to Pb had ceased, while Ogg1 activity was not altered. Furthermore, an age-dependent loss in the inverse correlation between Ogg1 activity and oxo8dG accumulation was observed. The effect of Pb on oxo8dG levels did not occur if animals were exposed to Pb in old age. These increases in DNA damage occurred in the absence of any Pb-induced changes in copper/zinc-superoxide dismutase , manganese-SOD , and reduced-form glutathion . These data suggest that oxidative damage and neurodegeneration in the aging brain could be impacted by the developmental disturbances. (shrink)

Amyloid fibril formation plays a central role in the pathogenesis of a number of neurodegenerative diseases, including Alzheimer and Parkinson diseases. Transient prefibrillar oligomers forming during the aggregation process, exhibiting a small size and a large hydrophobic surface, can aberrantly interact with a number of molecular targets on neurons, including the lipid bilayer of plasma membranes, resulting in a fatal outcome for the cells. By contrast, the mature fibrils, despite presenting generally a high hydrophobic surface, are endowed with a (...) low diffusion rate and poorly penetrate the interior of the lipid bilayer. However, increasing evidence shows that both intracellular α‐synuclein fibrils, as well and as extracellular amyloid‐β and β2‐microglobulin fibrils, can release oligomers over time that quickly diffuse to reach the membrane of the neighboring cells. The persistent leakage of harmful oligomers from fibrils triggers an ongoing cascade of events resulting in a sustained injury to neurons and glia and also provides aggregates with the ability to cross biological membranes and diffuse between cells or cellular compartments. (shrink)

This paper aims to enhance security in IoT device networks through a visual tool that utilizes three projection techniques, including Beta Hebbian Learning (BHL), t-distributed Stochastic Neighbor Embedding (t-SNE) and ISOMAP, in order to facilitate the identification of network attacks by human experts. This work research begins with the creation of a testing environment with IoT devices and web clients, simulating attacks over Message Queuing Telemetry Transport (MQTT) for recording all relevant traffic information. The unsupervised algorithms chosen provide a (...) set of projections that enable human experts to visually identify most attacks in real-time, making it a powerful tool that can be implemented in IoT environments easily. (shrink)

Noradrenergic pathways are involved in mediating the central and peripheral effects of physiological arousal. The aim of the present study was to investigate the role of noradrenergic transmission in moral decision-making. We studied the effects in healthy volunteers of propranolol (a noradrenergic beta-adrenoceptor antagonist) on moral judgement in a set of moral dilemmas pitting utilitarian outcomes (e.g., saving five lives) against highly aversive harmful actions (e.g., killing an innocent person) in a double-blind, placebo-controlled, parallel group design. Propranolol (40 mg (...) orally) significantly reduced heart rate, but had no effect on self-reported mood. Importantly, propranolol made participants more likely to judge harmful actions as morally unacceptable, but only in dilemmas where harms were ‘up close and personal’. In addition, longer response times for such personal dilemmas were only found for the placebo group. Finally, judgments in personal dilemmas by the propranolol group were more decisive. These findings indicate that noradrenergic pathways play a role in responses to moral dilemmas, in line with recent work implicating emotion in moral decision-making. However, contrary to current theorising, these findings also suggest that aversion to harming is not driven by emotional arousal. Our findings are also of significant practical interest given that propranolol is a widely used drug in different settings, and is currently being considered as a potential treatment for post-traumatic stress disorder in military and rescue service personnel. (shrink)

The Protein Ontology (PRO) is designed as a formal and principled Open Biomedical Ontologies (OBO) Foundry ontology for proteins. The components of PRO extend from a classification of proteins on the basis of evolutionary relationships at the homeomorphic level to the representation of the multiple protein forms of a gene, including those resulting from alternative splicing, cleavage and/or posttranslational modifications. Focusing specifically on the TGF-beta signaling proteins, we describe the building, curation, usage and dissemination of PRO. PRO provides a (...) framework for the formal representation of protein classes and protein forms in the OBO Foundry. It is designed to enable data retrieval and integration and machine reasoning at the molecular level of proteins, thereby facilitating cross-species comparisons, pathway analysis, disease modeling and the generation of new hypotheses. (shrink)

In three recent articles it was shown that β‐catenin is crucial for the establishment and the maintenance of the overall polarity and especially for the character ‘posterior’ in planarians. If the transcription of the β‐catenin gene was silenced by RNA interference, the overall polarity is lost, and in regenerating fragments a posterior blastema displays anterior characters by forming eyes and anterior ganglia. An attempt is made to integrate these new data, well‐known older observations, and observations from other regenerating systems into (...) an outline of a model that will clarify our current understanding as well as highlight areas still to be developed. (shrink)

Neurosteroid 17 beta-estradiol (E2) is a steroid synthesized de novo in the nervous system that might influence neuronal activity and behavior. Nevertheless, the impact of E2 on the functioning of those neural systems in which it is slightly synthesized is less questioned. The vestibulo-ocular reflex (VOR) adaptation, may provide an ideal arena for investigating this issue. Indeed, E2 modulates cerebellar parallel fiber-Purkinje cell synaptic plasticity that underlies encoding of VOR adaptation. Moreover, aromatase expression in the cerebellum of adult rodents (...) is maintained at very low levels and localized to Purkinje cells. The significance of age-related maintenance of low levels of aromatase expression in the cerebellum on behavior, however, has yet to be explored. Our aim in this study was to determine whether E2 synthesis exerts an effective and persistent modulation of VOR adaptation in adult male rats. To answer this question, we investigated the acute effect of blocking E2 synthesis on gain increases and decreases in VOR adaptation using an oral dose (2.5 mg/kg) of the aromatase inhibitor Letrozole in peri-pubertal and post-pubertal male rats. We found that Letrozole acutely impaired gain increases and decreases in VOR adaptation without altering basal ocular-motor performance and that these effects were similar in peri-pubertal and post-pubertal rats. Thus, in adult male rats neurosteroid E2 effectively modulates VOR adaptation in both of the periods studied. These findings imply that the adult cerebellum uses E2 synthesis for modulating motor memory formation and suggest that low and extremely localized E2 production may play a role in adaptive phenomena. (shrink)

Stroke remains one of the leading causes of various disabilities, including debilitating motor and language impairments. Though various treatments exist, post-stroke impairments frequently become chronic, dramatically reducing daily life quality, and requiring specific rehabilitation. A critical goal of chronic stroke rehabilitation is to induce, usually through behavioral training, experience-dependent plasticity processes in order to promote functional recovery. However, the efficiency of such interventions is typically modest, and very little is known regarding the neural dynamics underpinning recovery processes and possible biomarkers (...) of their efficiency. Some studies have emphasized specific alterations of excitatory–inhibitory balance within distributed neural networks as an important recovery correlate. Neural processes sensitive to these alterations, such as task-dependent oscillatory activity in beta as well as alpha bands, may be candidate biomarkers of chronic stroke functional recovery. In this review, we discuss the results of studies on motor and language recovery with a focus on oscillatory processes centered around the beta band and their modulations during functional recovery in chronic stroke. The discussion is based on a framework where task-dependent modulations of beta and alpha oscillatory activity, generated by the deep cortical excitatory–inhibitory microcircuits, serve as a neural mechanism of domain-general top-down control processes. We discuss the findings, their limitations, and possible directions for future research. (shrink)

As it is well known, mobile phones have become a basic gadget for any individual that usually stores sensitive information. This mainly motivates the increase in the number of attacks aimed at jeopardizing smartphones, being an extreme concern above all on Android OS, which is the most popular platform in the market. Consequently, a strong effort has been devoted for mitigating mentioned incidents in recent years, even though few researchers have addressed the application of visualization techniques for the analysis of (...) malware. Within this field, the present work proposes the extension of a new technique called Hybrid Unsupervised Exploratory Plots to visualize Android malware datasets. More precisely, the novel Beta-Hebbian Learning (BHL) method is applied for the first time and validated under the frame of Hybrid Unsupervised Exploratory Plots, in conjunction with clustering methods. The informative visualization achieved provides a picture of the structure of the malware families, allowing subsequent analysis of their organization. To validate the Hybrid Unsupervised Exploratory Plot extension and its tuning, the popular Android Malware Genome dataset has been used in the experimental setting. Promising results have been obtained, suggesting that BHL applied in combination with clustering techniques in Hybrid Unsupervised Exploratory Plots are a viable resource for the visualization of malware families. (shrink)

The beta thymosins are a highly conserved family of strongly polar 5 kDa polypeptides that are widely distributed among vertebrate classes; most are now known to bind to monomeric actin and inhibit its polymerization. One beta thymosin, beta four, (Tβ4) is the predominant form in mammalian cells, present at up to 0.5 mM. Many species are known to produce at least two beta thymosin isoforms, in some cases in the same cell. Their expression can be separately (...) regulated. When present outside the cell, the N‐terminal tetrapeptide of beta four appears to affect cell cycle regulation; beta thymosins or smaller fragments derived from them may have additional regulatory functions. We suggest that many developmental changes in beta thymosin levels within cells and tissues may be related to changes in G‐actin pool size. (shrink)

Phi Beta Kappa Romanell Lectures, given at Michigan State University, February 2008.

Alpha-beta pruning is a technique for pruning trees in artificial intelligence game-playing. This note draws an analogy between the technique, which is, in essence, an application of many-valued logic to the cut-off of the evaluation of conditionals in computer programs (for efficiency).

Modal contingentists face a dilemma: there are two attractive principles of which they can only accept one. In this paper I show that the most natural way of resolving the dilemma leads to expressive limitations. I then develop an alternative resolution. In addition to overcoming the expressive limitations, the alternative picture allows for an attractive account of arithmetic and for a style of semantic theorizing that can be helpful to contingentists.

More than 15 million people have been affected by coronavirus disease 2019 (COVID‐19) and it has caused 640 016 deaths as of July 26, 2020. Currently, no effective treatment option is available for COVID‐19 patients. Though many drugs have been proposed, none of them has shown particular efficacy in clinical trials. In this article, the relationship between the Adrenergic system and the renin‐angiotensin‐aldosterone system (RAAS) is focused in COVID‐19 and a vicious circle consisting of the Adrenergic system‐RAAS‐Angiotensin converting enzyme 2 (...) (ACE2)‐severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) (which is referred to as the “ARAS loop”) is proposed. Hyperactivation of the ARAS loop may be the underlying pathophysiological mechanism in COVID‐19, and beta‐adrenergic blockers are proposed as a potential treatment option. Beta‐adrenergic blockers may decrease the SARS‐CoV‐2 cellular entry by decreasing ACE2 receptors expression and cluster of differentiation 147 (CD147) in various cells in the body. Beta‐adrenergic blockers may decrease the morbidity and mortality in COVID‐19 patients by preventing or reducing acute respiratory distress syndrome (ARDS) and other complications. Retrospective and prospective clinical trials should be conducted to check the validity of the hypothesis. Also see the video abstract here https://youtu.be/uLoy7do5ROo. (shrink)

Logicians have strongly preferred first-order natural deductive systems over Peirce's Beta Graphs even though both are equivalent to each other. One of the main reasons for this preference, I claim, is that inference rules for Beta Graphs are hard to understand, and, therefore, hard to apply for deductions. This paper reformulates the Beta rules to show more fine-grained symmetries built around visual features of the Beta system, which makes the rules more natural and easier to use (...) and understand. Noting that the rules of a natural deductive system are natural in a different sense, this case study shows that the naturalness and the intuitiveness of rules depends on the type of representation system to which they belong. In a diagrammatic system, when visual features are discovered and fully used, we have a more efficacious deductive system. I will also show that this project not only helps us to apply these rules more easily but to understand the validity of the system at a more intuitive level. (shrink)