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Most Cited Neurobiology of Learning and Memory Articles
The most cited articles published since 2011, extracted from Scopus.
The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's diseaseSergio T. Ferreira | William L. Klein
Volume 96, Issue 4, November 2011, Pages 529-543
Alzheimer's disease (AD) is the 3rd most costly disease and the leading cause of dementia. It can linger for many years, but ultimately is fatal, the 6th leading cause of death. Alzheimer's disease (AD) is fatal and affected individuals can sometimes linger many years. Current treatments are palliative and transient, not disease modifying. This article reviews progress in the search to identify the primary AD-causing toxins. We summarize the shift from an initial focus on amyloid plaques to the contemporary concept that AD memory failure is caused by small soluble oligomers of the Aβ peptide, toxins that target and disrupt particular synapses. Evidence is presented that links Aβ oligomers to pathogenesis in animal models and humans, with reference to seminal discoveries from cell biology and new ideas concerning pathogenic mechanisms, including relationships to diabetes and Fragile X. These findings have established the oligomer hypothesis as a new molecular basis for the cause, diagnosis, and treatment of AD. © 2011 Elsevier Inc.
An analysis of rat prefrontal cortex in mediating executive functionRaymond P. Kesner | John C. Churchwell
Volume 96, Issue 3, October 2011, Pages 417-431
While it is acknowledged that species specific differences are an implicit condition of comparative studies, rodent models of prefrontal function serve a significant role in the acquisition of converging evidence on prefrontal function across levels of analysis and research techniques. The purpose of the present review is to examine whether the prefrontal cortex (PFC) in rats supports a variety of processes associated with executive function including working memory, temporal processing, planning (prospective coding), flexibility, rule learning, and decision making. Therefore, in this review we examined changes associated with working memory processes for spatial locations, visual objects, odors, tastes, and response domains or attributes, temporal processes including temporal order, sequence learning, prospective coding, behavioral flexibility associated with reversal learning and set shifting, paired associate learning, and decision making based on effort, time discounting, and uncertainty following damage to the PFC in rats. In addition, potential parallel processes of executive function in monkeys and humans based on several theories of subregional differentiation within the PFC will be presented. Specifically, theories based on domain or attribute specificity (Goldman-Rakic, 1996), level of processing (Petrides, 1996), rule learning based on complexity (Wise, Murray, & Gerfen, 1996), executive functions based on connectivity with other brain regions associated with top-down control (Miller & Cohen, 2001), are presented and applied to PFC function in rats with the aim of understanding subregional specificity in the rat PFC. The data suggest that there is subregional specificity within the PFC of rats, monkey and humans and there are parallel cognitive functions of the different subregions of the PFC in rats, monkeys and humans. © 2011.
Cognitive dysfunction in depression: Neurocircuitry and new therapeutic strategiesJames W. Murrough | Brian Iacoviello | Alexander Neumeister | Dennis S. Charney | Dan V. Iosifescu
Volume 96, Issue 4, November 2011, Pages 553-563
Major depressive disorder (MDD) is a disabling medical condition associated with significant morbidity, mortality and public health costs. However, neurocircuitry abnormalities underlying depression remain incompletely understood and consequently current treatment options are unfortunately limited in efficacy. Recent research has begun to focus specifically on cognitive aspects of depression and potential neurobiological correlates. Two fundamental types of cognitive dysfunction observed in MDD are cognitive biases, which include distorted information processing or attentional allocation toward negative stimuli, and cognitive deficits, which include impairments in attention, short-term memory and executive functioning. In this article, we present a selective review of current research findings in these domains and examine neuroimaging research that is beginning to characterize the neurocircuitry underlying these biases and deficits. We propose that deficient cognitive functioning, attention biases and the sustained negative affect characteristic of MDD can be understood as arising in part from dysfunctional prefrontal-subcortical circuitry and related disturbances in the cognitive control of emotion. Finally, we highlight potential new pharmacological and non-pharmacological therapeutic strategies for MDD based on an evolving mechanistic understanding of the disorder. © 2011 Elsevier Inc.
The cognitive cost of sleep lostJohn G. McCoy | Robert E. Strecker
Volume 96, Issue 4, November 2011, Pages 564-582
A substantial body of literature supports the intuitive notion that a good night's sleep can facilitate human cognitive performance the next day. Deficits in attention, learning & memory, emotional reactivity, and higher-order cognitive processes, such as executive function and decision making, have all been documented following sleep disruption in humans. Thus, whilst numerous clinical and experimental studies link human sleep disturbance to cognitive deficits, attempts to develop valid and reliable rodent models of these phenomena are fewer, and relatively more recent. This review focuses primarily on the cognitive impairments produced by sleep disruption in rodent models of several human patterns of sleep loss/sleep disturbance. Though not an exclusive list, this review will focus on four specific types of sleep disturbance: total sleep deprivation, experimental sleep fragmentation, selective REM sleep deprivation, and chronic sleep restriction. The use of rodent models can provide greater opportunities to understand the neurobiological changes underlying sleep loss induced cognitive impairments. Thus, this review concludes with a description of recent neurobiological findings concerning the neuroplastic changes and putative brain mechanisms that may underlie the cognitive deficits produced by sleep disturbances. © 2011.
Chronic stress, cognitive functioning and mental healthMarie France Marin | Catherine Lord | Julie Andrews | Robert Paul Juster | Shireen Sindi | Geneviève Arsenault-Lapierre | Alexandra J. Fiocco | Sonia J. Lupien
Volume 96, Issue 4, November 2011, Pages 583-595
This review aims to discuss the evidence supporting the link between chronic stress, cognitive function and mental health. Over the years, the associations between these concepts have been investigated in different populations. This review summarizes the findings that have emerged from older populations as well as from populations suffering from pathological aging, namely Mild Cognitive Impairment and Alzheimer's Disease. Although older adults are an interesting population to study in terms of chronic stress, other stress-related diseases can occur throughout the lifespan. The second section covers some of these stress-related diseases that have recently received a great deal of attention, namely burnout, depression, and post-traumatic stress disorder. Given that chronic stress contributes to the development of certain pathologies by accelerating and/or exacerbating pre-existing vulnerabilities that vary from one individual to the other, the final section summarizes data obtained on potential variables contributing to the association between chronic stress and cognition. © 2011 Elsevier Inc.
Retrieval per se is not sufficient to trigger reconsolidation of human fear memoryDieuwke Sevenster | Tom Beckers | Merel Kindt
Volume 97, Issue 3, March 2012, Pages 338-345
Ample evidence suggests that consolidated memories, upon their retrieval, enter a labile state, in which they might be susceptible to change. It has been proposed that memory labilization allows for the integration of relevant information in the established memory trace (memory updating). Memory labilization and reconsolidation do not necessarily occur when a memory is being reactivated, but only when there is something to be learned during memory retrieval (prediction error). Thus, updating of a fear memory trace should not occur under retrieval conditions in which the outcome is fully predictable (no prediction error). Here, we addressed this issue, using a human differential fear conditioning procedure, by eliminating the very possibility of reinforcement of the reminder cue. A previously established fear memory (picture-shock pairings) was reactivated with shock-electrodes attached (Propranolol group, n= 18) or unattached (Propranolol No-Shock Expectation group, n= 19). We additionally tested a placebo-control group with the shock-electrodes attached (Placebo group, n= 18). Reconsolidation was not triggered when nothing could be learned during the reminder trial, as noradrenergic blockade did not affect expression of the fear memory 24. h later in the Propranolol No-Shock Expectation group. Only when the outcome of the retrieval cue was not fully predictable, propranolol, contrary to placebo, reduced the startle fear response and prevented the return of fear (reinstatement) the following day. In line with previous studies, skin conductance response and shock expectancies were not affected by propranolol. Remarkably, a double dissociation emerged between the emotional (startle response) and more cognitive expression (expectancies, SCR) of the fear memory. Our findings have important implications for reconsolidation blockade as treatment strategy for emotional disorders. First, fear reducing procedures that target the emotional component of fear memory do not necessarily affect the cognitive component and vice versa. Second, mere retrieval of the fear memory is not sufficient to induce its labilization and reconsolidation. © 2012 Elsevier Inc.
Cognitive neuroepigenetics: A role for epigenetic mechanisms in learning and memoryJeremy J. Day | J. David Sweatt
Volume 96, Issue 1, July 2011, Pages 2-12
Although long-lasting behavioral memories have long been thought to require equally persistent molecular changes, little is known about the biochemical underpinnings of memory storage and maintenance. Increasing evidence now suggests that long-term behavioral change may be associated with epigenetic regulation of transcription in the central nervous system. In this review, we present evidence that changes in DNA methylation contribute to memory formation and maintenance, consider how DNA methylation affects readout of memory-related genes, and discuss how these changes may be important in the large-scale context of memory circuits. Finally, we discuss potential challenges involved in examining epigenetic changes in the brain and highlight how epigenetic mechanisms may be relevant for other cognitive processes. © 2010 Elsevier Inc.
Genistein ameliorates learning and memory deficits in amyloid β(1-40) rat model of Alzheimer's diseaseMaryam Bagheri | Mohammad Taghi Joghataei | Simin Mohseni | Mehrdad Roghani
Volume 95, Issue 3, March 2011, Pages 270-276
Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by increased β-amyloid (Aβ) deposition and neuronal dysfunction leading to impaired learning and recall. Ageing, heredity, and induced oxidative stress are among proposed risk factors. The increased frequency of the disease in women also suggests a role for estrogen in development of AD. In the present study, effects of the phytoestrogen genistein (10mg/kg) on learning and memory impairments was assessed in intrahippocampal Aβ(1-40)-injected rats. The estrogen receptor antagonist fulvestrant was injected intracerebroventricularly in a group of Aβ-lesioned rats. The Aβ-injected animals exhibited the following: lower spontaneous alternation score in Y-maze tasks, impaired retention and recall capability in the passive avoidance test, and fewer correct choices and more errors in the RAM task. Genistein, but not genistein and fulvestrant, significantly improved most of these parameters. Measurements of oxidative stress markers in hippocampal tissue of Aβ-injected rats showed an elevation of malondialdehyde (MDA) and nitrite content, and a reduction of superoxide dismutase (SOD) activity. Genistein significantly attenuated the increased MDA content but did not affect the nitrite content or SOD activity. These results indicate that genistein pretreatment ameliorates Aβ-induced impairment of short-term spatial memory in rats through an estrogenic pathway and by inducing attenuation of oxidative stress. © 2010 Elsevier Inc.
MicroRNA regulation of neural plasticity and memoryTimothy W. Bredy | Quan Lin | Wei Wei | Danay Baker-Andresen | John S. Mattick
Volume 96, Issue 1, July 2011, Pages 89-94
MicroRNAs (miRNAs) are a class of endogenous, small non-coding RNAs that mediate post-transcriptional gene silencing by complementary binding to the 3′untranslated region of target mRNAs. The transient and localized expression of these small RNAs in dendrites, their capacity to respond in an activity-dependent manner, and the observation that a single miRNA can simultaneously regulate many genes, make brain-specific miRNAs ideal candidates for the fine-tuning of gene expression associated with neural plasticity and memory formation. Here we provide an overview of the current literature, which supports the proposal that non-coding RNA-mediated regulation of gene function represents an important, yet underappreciated, layer of epigenetic control that contributes to learning and memory in the adult brain. © 2011 Elsevier Inc.
Aberrant learning and memory in addictionMary M. Torregrossa | Philip R. Corlett | Jane R. Taylor
Volume 96, Issue 4, November 2011, Pages 609-623
Over the past several years, drug addiction has increasingly been accepted to be a disease of the brain as opposed to simply being due to a lack of willpower or personality flaw. Exposure to addictive substances has been shown to create enduring changes in brain structure and function that are thought to underlie the transition to addiction. Specific genetic and environmental vulnerability factors also influence the impact of drugs of abuse on the brain and can enhance the likelihood of becoming an addict. Long-lasting alterations in brain function have been found in neural circuits that are known to be responsible for normal appetitive learning and memory processes and it has been hypothesized that drugs of abuse enhance positive learning and memory about the drug while inhibiting learning about the negative consequences of drug use. Therefore, the addict's behavior becomes increasingly directed towards obtaining and using drugs of abuse, while at the same time developing a poorer ability to stop using, even when the drug is less rewarding or interferes with functioning in other facets of life. In this review we will discuss the clinical evidence that addicted individuals have altered learning and memory and describe the possible neural substrates of this dysfunction. In addition, we will explore the pre-clinical evidence that drugs of abuse cause a progressive disorder of learning and memory, review the molecular and neurobiological changes that may underlie this disorder, determine the genetic and environmental factors that may increase vulnerability to addiction, and suggest potential strategies for treating addiction through manipulations of learning and memory. © 2011 Elsevier Inc.
The role of histone acetylation in age-associated memory impairment and Alzheimer's diseaseRoman Manuel Stilling | André Fischer
Volume 96, Issue 1, July 2011, Pages 19-26
Learning and memory are cognitive processes that are tightly regulated. A proper genome-environment interaction is a pre-requisite for cognitive function. Epigenetic processes are central regulators of genome-environment interactions. In line with this, it has been shown that the epigenetic machinery is essential for cognitive function. With a specific focus on histone acetylation, we will discuss recent research in the field of epigenetic mechanisms of learning and memory. We will also specifically address the role of histone acetylation in age-associated memory impairment and Alzheimer's disease and ask the question why targeting the epigenome could be a suitable strategy for neuroprotection and neuroregeneration. © 2011 Elsevier Inc.
HDAC3 and the molecular brake pad hypothesisSusan C. McQuown | Marcelo A. Wood
Volume 96, Issue 1, July 2011, Pages 27-34
Successful transcription of specific genes required for long-term memory processes involves the orchestrated effort of not only transcription factors, but also very specific enzymatic protein complexes that modify chromatin structure. Chromatin modification has been identified as a pivotal molecular mechanism underlying certain forms of synaptic plasticity and memory. The best-studied form of chromatin modification in the learning and memory field is histone acetylation, which is regulated by histone acetyltransferases and histone deacetylases (HDACs). HDAC inhibitors have been shown to strongly enhance long-term memory processes, and recent work has aimed to identify contributions of individual HDACs. In this review, we focus on HDAC3 and discuss its recently defined role as a negative regulator of long-term memory formation. HDAC3 is part of a corepressor complex and has direct interactions with Class II HDACs that may be important for its molecular and behavioral consequences. And last, we propose the " molecular brake pad" hypothesis of HDAC function. The HDACs and associated corepressor complexes may function in neurons, in part, as " molecular brake pads." HDACs are localized to promoters of active genes and act as a persistent clamp that requires strong activity-dependent signaling to temporarily release these complexes (or brake pads) to activate gene expression required for long-term memory formation. Thus, HDAC inhibition removes the " molecular brake pads" constraining the processes necessary for long-term memory and results in strong, persistent memory formation. © 2011 Elsevier Inc.
From Pavlov to PTSD: The extinction of conditioned fear in rodents, humans, and anxiety disordersMichael B. VanElzakker | M. Kathryn Dahlgren | F. Caroline Davis | Stacey Dubois | Lisa M. Shin
Volume 113, Issue , January 2014, Pages 3-18
Nearly 100. years ago, Ivan Pavlov demonstrated that dogs could learn to use a neutral cue to predict a biologically relevant event: after repeated predictive pairings, Pavlov's dogs were conditioned to anticipate food at the sound of a bell, which caused them to salivate. Like sustenance, danger is biologically relevant, and neutral cues can take on great salience when they predict a threat to survival. In anxiety disorders such as posttraumatic stress disorder (PTSD), this type of conditioned fear fails to extinguish, and reminders of traumatic events can cause pathological conditioned fear responses for decades after danger has passed. In this review, we use fear conditioning and extinction studies to draw a direct line from Pavlov to PTSD and other anxiety disorders. We explain how rodent studies have informed neuroimaging studies of healthy humans and humans with PTSD. We describe several genes that have been linked to both PTSD and fear conditioning and extinction and explain how abnormalities in fear conditioning or extinction may reflect a general biomarker of anxiety disorders. Finally, we explore drug and neuromodulation treatments that may enhance therapeutic extinction in anxiety disorders. © 2013 Elsevier Inc.
The role of the basal ganglia in learning and memory: Insight from Parkinson's diseaseKarin Foerde | Daphna Shohamy
Volume 96, Issue 4, November 2011, Pages 624-636
It has long been known that memory is not a single process. Rather, there are different kinds of memory that are supported by distinct neural systems. This idea stemmed from early findings of dissociable patterns of memory impairments in patients with selective damage to different brain regions. These studies highlighted the role of the basal ganglia in non-declarative memory, such as procedural or habit learning, contrasting it with the known role of the medial temporal lobes in declarative memory. In recent years, major advances across multiple areas of neuroscience have revealed an important role for the basal ganglia in motivation and decision making. These findings have led to new discoveries about the role of the basal ganglia in learning and highlighted the essential role of dopamine in specific forms of learning. Here we review these recent advances with an emphasis on novel discoveries from studies of learning in patients with Parkinson's disease. We discuss how these findings promote the development of current theories away from accounts that emphasize the verbalizability of the contents of memory and towards a focus on the specific computations carried out by distinct brain regions. Finally, we discuss new challenges that arise in the face of accumulating evidence for dynamic and interconnected memory systems that jointly contribute to learning. © 2011 Elsevier Inc.
Brain insulin signaling: A key component of cognitive processes and a potential basis for cognitive impairment in type 2 diabetesEwan C. McNay | Andrew K. Recknagel
Volume 96, Issue 3, October 2011, Pages 432-442
Understanding of the role of insulin in the brain has gradually expanded, from initial conceptions of the brain as insulin-insensitive through identification of a role in regulation of feeding, to recent demonstration of insulin as a key component of hippocampal memory processes. Conversely, systemic insulin resistance such as that seen in type 2 diabetes is associated with a range of cognitive and neural deficits. Here we review the evidence for insulin as a cognitive and neural modulator, including potential effector mechanisms, and examine the impact that type 2 diabetes has on these mechanisms in order to identify likely bases for the cognitive impairments seen in type 2 diabetic patients. © 2011 Elsevier Inc.
High-fat diets impair spatial learning in the radial-arm maze in miceI. Valladolid-Acebes | P. Stucchi | V. Cano | M. S. Fernández-Alfonso | B. Merino | M. Gil-Ortega | A. Fole | L. Morales | M. Ruiz-Gayo | N. Del Olmo
Volume 95, Issue 1, January 2011, Pages 80-85
It has been suggested that hyperglycemia and insulin resistance triggered by energy-dense diets can account for hippocampal damage and deficits of cognitive behaviour. We wonder if the impairment of learning and memory processes detected in diet-induced obese (DIO) mice is linked to diet composition itself. With this purpose we have evaluated learning performance in mice undergoing a short-term high-fat (HF) treatment, which leads to a pre-obese state characterized by increased adiposity without significant changes of glucose and insulin plasma levels. C57BL/6J mice were fed either a HF (45. kcal% from fat) or control diet (10. kcal% from fat) during 8. weeks. Learning performance was evaluated by using the four-arm baited version of the eight-arm radial maze test (RAM). Mice were trained to learn the RAM protocol and then memory was tested at different time-points. Time spent to consume food placed in baited arms and errors committed to find them were measured in all sessions. DIO mice significantly spent more time in learning the task and made a greater number of errors than controls. Moreover, retention tests revealed that both working and total memory errors were also more numerous in DIO mice. The current results show that short-term DIO impairs spatial learning and suggest that impairment of hippocampal learning elicited by HF diets might be perceptible before metabolic alterations linked to obesity develop. © 2010 Elsevier Inc.
The role of REM sleep in the processing of emotional memories: Evidence from behavior and event-related potentialsS. Groch | I. Wilhelm | S. Diekelmann | J. Born
Volume 99, Issue , January 2013, Pages 1-9
Emotional memories are vividly remembered for the long-term. Rapid eye movement (REM) sleep has been repeatedly proposed to support the superior retention of emotional memories. However, its exact contribution and, specifically, whether its effect is mainly on the consolidation of the contents or the processing of the affective component of emotional memories is not clear. Here, we investigated the effects of sleep rich in slow wave sleep (SWS) or REM sleep on the consolidation of emotional pictures and the accompanying changes in affective tone, using event-related potentials (ERPs) together with subjective ratings of valence and arousal. Sixteen healthy, young men learned 50 negative and 50 neutral pictures before 3-h retention sleep intervals that were filled with either SWS-rich early or REM sleep-rich late nocturnal sleep. In accordance with our hypothesis, recognition was better for emotional pictures than neutral pictures after REM compared to SWS-rich sleep. This emotional enhancement after REM-rich sleep expressed itself in an increased late positive potential of the ERP over the frontal cortex 300-500. ms after stimulus onset for correctly classified old emotional pictures compared with new emotional and neutral pictures. Valence and arousal ratings of emotional pictures were not differentially affected by REM or SWS-rich sleep after learning. Our results corroborate that REM sleep contributes to the consolidation of emotional contents in memory, but suggest that the affective tone is preserved rather than reduced by the processing of emotional memories during REM sleep. © 2012 Elsevier Inc.
Probing the role of HDACs and mechanisms of chromatin-mediated neuroplasticityStephen J. Haggarty | Li Huei Tsai
Volume 96, Issue 1, July 2011, Pages 41-52
Advancing our understanding of neuroplasticity and the development of novel therapeutics based upon this knowledge is critical in order to improve the treatment and prevention of a myriad of nervous system disorders. Epigenetic mechanisms of neuroplasticity involve the post-translational modification of chromatin and the recruitment or loss of macromolecular complexes that control neuronal activity-dependent gene expression. While over a century after Ramón y Cajal first described nuclear subcompartments and foci that we now know correspond to sites of active transcription with acetylated histones that are under epigenetic control, the rate and extent to which epigenetic processes act in a dynamic and combinatorial fashion to shape experience-dependent phenotypic and behavioral plasticity in response to various types of neuronal stimuli over a range of time scales is only now coming into focus. With growing recognition that a subset of human diseases involving cognitive dysfunction can be classified as 'chromatinopathies', in which aberrant chromatin-mediated neuroplasticity plays a causal role in the underlying disease pathophysiology, understanding the molecular nature of epigenetic mechanisms in the nervous system may provide important new avenues for the development of novel therapeutics. In this review, we discuss the chemistry and neurobiology of the histone deacetylase (HDAC) family of chromatin-modifying enzymes, outline the role of HDACs in the epigenetic control of neuronal function, and discuss the potential relevance of these epigenetic mechanisms to the development of therapeutics aiming to enhance memory and neuroplasticity. Finally, open questions, challenges, and critical needs for the field of 'neuroepigenetics' in the years to come will be summarized. © 2011 Elsevier Inc.
Epigenetic regulation of reelin and brain-derived neurotrophic factor genes in long-term potentiation in rat medial prefrontal cortexLi Sui | Yan Wang | Li Hua Ju | Meng Chen
Volume 97, Issue 4, May 2012, Pages 425-440
Epigenetic mechanisms have recently been known to play fundamental roles in the regulation of synaptic plasticity, and learning and memory tasks in many brain regions, such as the hippocampus, the amygdala, the insular cortex. However, epigenetic mechanism in the medial prefrontal cortex (mPFC), also a crucial neural locus for the control of cognition and emotion, is not well known. The present study investigated the epigenetic regulation of two genes, . reelin and . brain-derived neurotrophic factor (. bdnf), both play important roles in neural plasticity, in the mPFC. The data showed that the levels of total DNA methyltransferase (DNMTs), total histone acetyltransferases (HATs), global acetylated histone 3 (H3) and global acetylated histone 4 (H4) were all changed with the induction of long-term potentiation (LTP) in the mPFC, implying that DNA methylation and histone acetylation may involve in synaptic plasticity in the mPFC. The present results further demonstrated that the demethylation status of . reelin and . bdnf, and acetylated H3 and acetylated H4 at the . reelin and the . bdnf promoters in the mPFC were enhanced by the delivery of LTP-inducing high-frequency stimulation (HFS). Consistently, infusion of DNMT inhibitor, 5-azacytidine (5-azaC), or histone deacetylases (HDACs) inhibitor, sodium butyrate (NaB), into the mPFC could interfere with LTP-associated demethylation and acetylation of . reelin and . bdnf genes, and the induction of LTP as well. Long-term retention of trace fear memory, which is dependent on mPFC function, was also altered by administration of these inhibitors into the mPFC. These findings suggest that epigenetic regulation of DNA demethylation and histone acetylation of target genes, such as . reelin and . bdnf, might underlie the mechanisms of synaptic plasticity and memory retention in the mPFC. © 2012 Elsevier Inc..
Forced treadmill exercise prevents oxidative stress and memory deficits following chronic cerebral hypoperfusion in the ratFernanda Cechetti | Paulo Valdeci Worm | Viviane Rostirolla Elsner | Karine Bertoldi | Eduardo Sanches | Juliana Ben | Ionara Rodrigues Siqueira | Carlos Alexandre Netto
Volume 97, Issue 1, January 2012, Pages 90-96
Physical activity impacts functional recovery following stroke in humans, however its effects in experimental animals submitted to chronic cerebral hypoperfusion have not been investigated. The aim of this study was to evaluate the therapeutic potential of exercise, as assessed by cognitive activity in the Morris water maze and the brain oxidative status, through measurement of macromolecules damage, TBARS levels and total cellular thiols, as well as antioxidant enzymes in hippocampus, striatum and cerebral cortex. Adult male Wistar rats were submitted to the modified permanent bilateral occlusion of the common carotid arteries (2VO) method, with right common carotid artery being first occluded, and tested 3. months after the ischemic event. The effects of three different exercise protocols were examined: pre-ischemia, post-ischemia and pre. +. post-ischemia. Physical exercise consisted of sessions of 20-min, 3 times per week during 12. weeks (moderate intensity). Rats were submitted to cognitive assessment, in both reference and working spatial memory and after the last testing session were sacrificed to have oxidative stress parameters determined. Hypoperfusion caused a significant cognitive deficit in both spatial water maze tasks and this effect was reversed in rats receiving exercise protocol post and pre. +. post the ischemic event. Moreover, forced regular treadmill exercise regulated oxidative damage and antioxidant enzyme activity in the hippocampus. These results suggest that physical exercise protects against cognitive and biochemical impairments caused by chronic cerebral hypoperfusion. © 2011 Elsevier Inc.
Modulatory influence of dopamine receptors on consolidation of object recognition memoryMaria Noêmia Martins de Lima | Juliana Presti-Torres | Arethuza Dornelles | Felipe Siciliani Scalco | Rafael Roesler | Vanessa Athaíde Garcia | Nadja Schröder
Volume 95, Issue 3, March 2011, Pages 305-310
The role of dopamine receptors in regulating the formation of recognition memory remains poorly understood. Here we show the effects of systemic administration of dopamine receptor agonists and antagonists on the formation of memory for novel object recognition in rats. In Experiment I, rats received an intraperitoneal (i.p.) injection of vehicle, the selective D1 receptor agonist SKF38393 (1.0 and 5.0. mg/kg), or the D2 receptor agonist quinpirole (1.0 and 5.0. mg/kg) immediately after training. In Experiment II, rats received an injection of vehicle, the dopamine receptor antagonist SCH23390 (0.1 and 0.05. mg/kg), or the D2 receptor antagonist raclopride (0.5 and 0.1. mg/kg) before training, followed by an injection of vehicle or the nonselective dopamine receptor agonist apomorphine (0.05. mg/kg) immediately after training. SKF38393 at 5. mg/kg produced an enhancement of novel object recognition memory measured at both 24 and 72. h after training, whereas the dose of 10. mg/kg impaired 24-h retention. Posttraining administration of quinpirole did not affect 24-h retention. Apomorphine enhanced memory in rats given pretraining raclopride, suggesting that the effect was mediated by selective activation of D1 receptors. The results indicate that activation of D1 receptors can enhance recognition memory consolidation. Importantly, pharmacological activation of D1 receptors enhanced novel object recognition memory even under conditions in which control rats showed significant retention. © 2010 Elsevier Inc.
Hydrogen sulfide slows down progression of experimental Alzheimer's disease by targeting multiple pathophysiological mechanismsDaniela Giuliani | Alessandra Ottani | Davide Zaffe | Maria Galantucci | Flavio Strinati | Renzo Lodi | Salvatore Guarini
Volume 104, Issue , September 2013, Pages 82-91
It has been previously reported that brain hydrogen sulfide (H2S) synthesis is severely decreased in Alzheimer's disease (AD) patients, and plasma H2S levels are negatively correlated with the severity of AD. Here we extensively investigated whether treatment with a H2S donor and spa-waters rich in H2S induces neuroprotection and slows down progression of AD. Studies with sodium hydrosulfide (a H2S donor) and Tabiano's spa-water were carried out in three experimental models of AD. Short-term and long-term treatments with sodium hydrosulfide and/or Tabiano's spa-water significantly protected against impairment in learning and memory in rat models of AD induced by brain injection of β-amyloid1-40 (Aβ) or streptozotocin, and in an AD mouse model harboring human transgenes APPSwe, PS1M146V and tauP301L (3xTg-AD mice). The improvement in behavioral performance was associated with hippocampus was size of Aβ plaques and preservation of the morphological picture, as found in AD rats. Further, lowered concentration/phosphorylation levels of proteins thought to be the central events in AD pathophysiology, namely amyloid precursor protein, presenilin-1, Aβ1-42 and tau phosphorylated at Thr181, Ser396 and Ser202, were detected in 3xTg-AD mice treated with spa-water. The excitotoxicity-triggered oxidative and nitrosative stress was counteracted in 3xTg-AD mice, as indicated by the decreased levels of malondialdehyde and nitrites in the cerebral cortex. Hippocampus reduced activity of c-jun N-terminal kinases, extracellular signal-regulated kinases and p38, which have an established role not only in phosphorylation of tau protein but also in inflammation and apoptosis, was also found. Consistently, decrease in tumor necrosis factor-α level, up-regulation of Bcl-2, and down-regulation of BAX and the downstream executioner caspase-3, also occurred in the hippocampus of 3xTg-AD mice after treatment with Tabiano's spa-water, thus suggesting that it is also able to modulate inflammation and apoptosis. Our findings indicate that appropriate treatments with H2S donors and Tabiano's spa-waters, and may be other spa-waters rich in H2S content, might represent an innovative approach to slow down AD progression in humans by targeting multiple pathophysiological mechanisms. © 2013 Elsevier Inc.
Adult mice maintained on a high-fat diet exhibit object location memory deficits and reduced hippocampal SIRT1 gene expressionFrankie D. Heyward | R. Grace Walton | Matthew S. Carle | Mark A. Coleman | W. Timothy Garvey | J. David Sweatt
Volume 98, Issue 1, July 2012, Pages 25-32
Mounting evidence has established that diet-induced obesity (DIO) is associated with deficits in hippocampus-dependent memory. The bulk of research studies dealing with this topic have utilized rats fed a high-fat diet as an experimental model. To date, there has been a paucity of research studies that have established whether the memory deficits exhibited in DIO rats can be recapitulated in mice. Moreover, the majority of experiments that have evaluated memory performance in rodent models of DIO have utilized memory tests that are essentially aversive in nature (i.e., Morris water maze). The current study sought to fill an empirical void by determining if mice maintained on a high-fat diet exhibit deficits in two non-aversive memory paradigms: novel object recognition (NOR) and object location memory (OLM). Here we report that mice fed a high-fat diet over 23. weeks exhibit intact NOR, albeit a marked impairment in hippocampus-dependent OLM. We also determined the existence of corresponding aberrations in gene expression within the hippocampus of DIO mice. DIO mice exhibited significant reductions in both SIRT1 and PP1 mRNA within the hippocampus. Our data suggest that mice maintained on a high-fat diet present with impaired hippocampus-dependent spatial memory and a corresponding alteration in the expression of genes that have been implicated in memory consolidation. © 2012 Elsevier Inc.
Epigenetic gene regulation in the adult mammalian brain: Multiple roles in memory formationFarah D. Lubin
Volume 96, Issue 1, July 2011, Pages 68-78
Brain-derived neurotrophic factor (bdnf) is one of numerous gene products necessary for long-term memory formation and dysregulation of bdnf has been implicated in the pathogenesis of cognitive and mental disorders. Recent work indicates that epigenetic-regulatory mechanisms including the markings of histone proteins and associated DNA remain labile throughout the life-span and represent an attractive molecular process contributing to gene regulation in the brain. In this review, important information will be discussed on epigenetics as a set of newly identified dynamic transcriptional mechanisms serving to regulate gene expression changes in the adult brain with particular emphasis on bdnf transcriptional readout in learning and memory formation. This review will also highlight evidence for the role of epigenetics in aberrant bdnf gene regulation in the pathogenesis of cognitive dysfunction associated with seizure disorders, Rett syndrome, Schizophrenia, and Alzheimer's disease. Such research offers novel concepts for understanding epigenetic transcriptional mechanisms subserving adult cognition and mental health, and furthermore promises novel avenues for therapeutic approach in the clinic. © 2011 Elsevier Inc.
Inhibition of mTOR by rapamycin in the amygdala or hippocampus impairs formation and reconsolidation of inhibitory avoidance memoryPaulo F C Jobim | Thiago R. Pedroso | Raissa R. Christoff | Aline Werenicz | Natasha Maurmann | Gustavo K. Reolon | Rafael Roesler
Volume 97, Issue 1, January 2012, Pages 105-112
Mammalian target of rapamycin (mTOR), a central regulator of protein synthesis in neurons, has been implicated in synaptic plasticity and memory. Here we show that mTOR inhibition by rapamycin in the basolateral amygdala (BLA) or dorsal hippocampus (DH) impairs both formation and reconsolidation of memory for inhibitory avoidance (IA) in rats. Male Wistar rats received bilateral infusions of vehicle or rapamycin into the BLA or DH before or after IA training or retrieval. Memory retention was tested at different time points after drug infusion. Rapamycin impaired long-term IA retention when given before or immediately after training or retrieval into the BLA. When infused into the DH, rapamycin produced memory impairment when given before training or immediately after retrieval. The impairing effects of post-retrieval rapamycin required memory retrieval and were not reversed by a reminder shock. The results provide the first evidence that mTOR in the BLA and DH might play a role in IA memory reconsolidation. © 2011 Elsevier Inc.


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Fire Marshal Counter Hours
Beginning January 4, 2016, the Tiburon Fire Protection District Fire Marshal will hold drop-in public counter hours at Belvedere City Hall on Mondays from 1:30 PM - 2:30 PM.
If you would like to speak with the Fire Marshal at another time, you may either email or call (415) 435-7207.
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For years eco-minded Montanans have lamented the lack of glass recycling in the state. We don't generate enough glass to lure bottling plants here, and we're generally too far away from existing plants to make hauling our glass out-of-state cost-effective. But if you're sending empty trucks out-of-state anyway, the math changes. It appears Target has figured that out.
In this week's installment: The bet that ended with a man eating his own beard (it tasted like chewing a "sponge"), a terrible way to remove a tattoo, and an MIT study on how cats drink. Meow.
Curses, Foiled Again
Police had little trouble identifying the masked woman who robbed a drug store in Manchester, N.H. A witness reported seeing the suspect flee the store and get into a car with vanity plates that read "B-USHER." Police arrested Bonnie Usher, 43, at her home with stolen money. (Boston's WCVB-TV)
New York City police investigating a murder at a Chelsea diner identified Earle Barranco, 24, as their suspect after witnesses reported the gunman wore a diamond-encrusted moneybag hanging from a gold chain—Barranco's signature bling. A week after police issued a nationwide arrest warrant, Barranco was spotted in Charlotte, N.C., on the JumboTron video screen at a Bobcats basketball game wearing the same telltale pendant. Charlotte authorities and FBI agents arrested Barranco two nights later, when he returned for another Bobcats game. (New York's Daily News)
Maybe it's the egg nog we started on first thing this morning that got us tingling with the holiday spirit. Regardless, we're on a roll and plan on marking the season in our own unique way. That's why we dedicate this Friday's Happiest Hour, our weekly ode to local watering holes, to Fred's Lounge & Casino.
Montana ski enthusiast Dave Evans launched a public beta test this week of a new text messaging service aimed at helping powder hounds throughout the region answer that important early morning question: "Is the snow deep enough, or should I stay in bed?" Skiers and snowboarders in five states and counting can now receive snow reports for individual resorts via text, eliminating the need to strip off the covers and open up the laptop.
Through his newly established website, skiingonthebrain.com, Evans is now offering snow condition updates for numerous resorts in California, Colorado, Utah, Wyoming and, of course, Montana (Discovery, Lost Trail and Snowbowl are on the list). Similar services are in the works for Alaska, Idaho, Washington and Oregon. The service is completely free, and Evans says reports are updated every day by 7 a.m. at the latest.
In other ski news, Discovery is hosting a fundraiser this Sunday for The Max Wave initiative (an effort to build a second kayak wave in Missoula in honor of Max Lentz, a local surfer who died on West Virginia's Gauley River in 2007). Day passes are only $28, with $10 from each adult pass going to benefit The Max. Wondering how great the snow is? Text 612-217-7204.
Just as quickly as Sen. Jon Tester's Forest Jobs and Recreation Act was revived earlier this week, it died—at least for the foreseeable future—last night, a casualty of Senate Majority Leader Harry Reid's decision amid bitter Republican backlash to pull the $1.2 trillion spending measure that had contained it.
A statement from Tester spokesman Aaron Murphy: "Partisan politics shot down this measure last night, but it won't keep Jon from creating Montana jobs—through middle-class tax relief, strengthening family agriculture and small businesses, and working together with Montanans on bipartisan plans like his forest jobs bill."
Find Rob Brezsny's "Free Will Astrology" online, every Wednesday, one day before it hits the Indy's printed pages.
ARIES (March 21-April 19): I vividly remember seeing singer Diamanda Galas in concert. Though classically trained, she didn't confine herself to mellifluous melodies and elegant tones. She was a whirlwind of elemental sound, veering from animalistic bellows to otherworldly chants to operatic glossolalia. It was all very entertaining, and often enjoyable. The skill with which she shaped the sound as it escaped her body was prodigious. My companion and I agreed that "she made your ears convulse and your eyes writhe and your skin prickle—but in a good way." How would you feel about inviting some similar experiences into your life, Aries? The astrological omens suggest this would be an excellent time to seek the rowdy healing that only disciplined wildness can provide.
Sen. Jon Tester's controversial Forest Jobs and Recreation Act has been lumped into a massive $1.1 trillion, 1,924-page omnibus spending bill Democrats hope to pass by year's end.
Actually, it's not called that anymore. The bill's now titled the "Montana Forest Jobs and Restoration Initiative." Here's a PDF. The initiative begins on page 893.
"Jon's pleased that his Senate colleagues agree it's time to put the Forest Jobs and Recreation Act up for a vote," spokesman Aaron Murphy said in a statement. "This is just another step in what has been a year-and-a-half long process to create jobs in Montana. Nothing is final until this bill is passed by the full Congress and is signed into law."
Tester's office says the Senate is expected to vote on the bill sometime between Thursday and Saturday.
In this week's installment: Restraining orders against Jesus (and Tim Tebow), exploding escargots and The Supreme Foie Gras burger.
Curses, Foiled Again
Randy King, 53, admitted stealing an antique wrought-iron fence from a house in Duluth, Minn., after police confronted him with the evidence: the fence itself, which King had installed around his own house, a few blocks away. Officers came looking for him because the victim told them King had tried to buy her fence the month before.
Police arriving on the scene of a hotel robbery in Lewiston, Idaho, needed mere minutes to track down suspect Donald Mosley Jr., 40. He was next door, at a bar named The Alibi.
It's Friday and you just want to kick back with a strong ale and get in the holiday mood. If you head down to the Big Sky taproom you can sip on the limited edition All Souls Ale—the subject of this week's Happiest Hour—and consider what a sweet gift good beer can be.
What you're tasting: All Souls Ale is a limited edition imperial saison. It's slightly spicy, slightly fruity and very strong at 11% ABV. That's unusual for a "saison," which means "season" in French and generally hits 5% ABV. Saisons, by the way, are light beers from French-speaking Belgium that were brewed specifically to refresh farmers when they didn't have access to water. All Souls may be strong, but it actually maintains a sort of light feel—in case you get thirsty out in those fields.
Who's behind it: Members of all Souls Missoula, an alternative Christian church, approached the brewery last summer about crafting the beer. Big Sky owner Bjorn Nabozney says he was surprised to have a church ask about brewing, and even more surprised when the group insisted the beer not seem "too churchy," so that it appeals to everyone. About 16 members of the church spent several hours helping Big Sky brewers bottle and label the ale.
Why you're supporting it: Even if you're not a churchie yourself, consider this: proceeds from sales of All Souls goes to Imagine Missoula—a non-profit that organizes volunteers to help people around town, whether it's to fix leaks and build fences, help with childcare or run errands for those who need a little neighborly assistance. Plus, who doesn't like doing community service in the form of drinking beer?
When to get it: Now. According to taproom bartenders, the ale is going fast. Big Sky Brewery ordered a limited 100 cases of the stylish, 750 milliliter bottles, which go for $14 each. There are no plans to make more, though Nabozney says the brewery will definitely team up with All Souls again next year with another recipe.
How to find the taproom: Near the airport, at 5417 Trumpeter Way.
Happiest Hour celebrates western Montana watering holes. To recommend a bar, bartender or beverage for Happiest Hour, e-mail firstname.lastname@example.com.
Perhaps it's a reflection of our altruistic, vegan, Birkenstock-wearing population that Missoula this year topped the Peace Corps' list of metropolitan areas with the highest number of volunteers per capita anywhere in the nation. According to data released by the Corps today, Missoula beat out other well-known peacenik havens such as second-ranked Burlington, Va., and third-place Boulder, Colo.
I have had some ups and downs when it comes to online dating, not stating…
The leader of Identity Evropa is a felon that served time for armed robbery. Such…
The reason the posters disappeared is due to a group called 'Missoula Anti-Fascist Action'. They…


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Baxter has entered into a definitive agreement to acquire privately-held Gambro, based in Lund, Sweden, for total consideration of SKr 26.5 billion (approximately US$4.0 billion). Gambro is a global medical technology company focused on developing, manufacturing and supplying dialysis products and therapies for patients with acute or chronic kidney disease. The acquisition will give Baxter a comprehensive dialysis product portfolio, complementing its existing home dialysis offerings.
Gambro's portfolio in the traditional chronic care segment consists of haemodynamic devices including advanced monitors, dialysers, bloodlines, cyclers and dialysis systems. The company's in-centre haemodialysis devices include the Artis and the AK 96 systems. In the acute care segment, which includes continuous renal replacement therapy and treatment for fluid overload, among others, Gambro offers the Prismaflex system used for the treatment of critically ill patients with acute kidney injury.
It is believed that the transaction will provide a number of long-term growth opportunities for Baxter worldwide. With a broad and complementary dialysis product portfolio, Baxter can accelerate product sales in established markets such as Europe, where Gambro has an extensive footprint. Baxter can also expand Gambro's reach in high-growth regions of Latin America and Asia-Pacific, where Baxter has steadily grown its peritoneal dialysis business. In addition, Baxter will also build upon its pipeline of investigational home haemodialysis and automated peritoneal dialysis systems with the addition of Gambro's monitors, dialysers, devices and dialysis systems.


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"A journey is best measured in friends rather than miles."
-Tim Cahill
Ah, depression. That fiendish feeling I frequently feel when one of my epic journeys come to an end, also known as the polar opposite of what I feel when I am about to embark on one of said epic journeys. Yeah, that's right, I'm depressed. Another PAX and another lovely trip to Washington has come and gone, placing me back square in the middle of the daily grind we have all come to know and hate.
All, however, is not lost. As with any other so-called "epic" journey I undertake, this one has left in it's a wake a bevy of cherished memories I'll never forget.
In other words, I had fun!
Please let me know if there are any problems with pictures overlapping, screwing up column widths or causing any others problems.
The Road to Nerdvana
My journey to Washington started, of course, with a trip to the airport. I very surprised to see huge signs everywhere advertising Call of Duty: Black Ops. Why here? San Antonio isn't Nerdvana. Then I saw all the people with Gamestop shirts…then I remembered that the Gamestop manager's conference was held in San Antonio during the Monday-Wednesday immediately prior to PAX. I have a friend who manages a local Gamestop store who told me about all the games and industry celebrities who were in town but forgot all about that. It's just so odd to me that San Antonio of all places hosted a videogame convention. The tech industry is nearly non-existent in this city. Lucky for me I sat next to a Gamestop manager from Vancouver on my way to my layover in Denver. That made for an enjoyable chat.
My flight path from Denver to Seattle gave me an absolutely breathtaking view of Mt. Rainier. I wasn't able to get a good shot of the mountain this year because I was on the opposite side of the plane, but I've included a picture I took last year. Seriously, the picture doesn't do it any justice. In retrospect, I find it poetic that I was welcomed to Seattle by such an awesome display of the power of nature standing tall in stark, defiant juxtaposition to the purely man-made creations I had traveled so far to see in person.
Death Mountain!
Once I made it to Seattle, I was picked up by my best friend – John – and his wife Maggy, both residents of Redmond, WA. They were the real reason I flew up to Seattle, it's just that PAX influenced my decision to fly up there during Labor Day Weekend as opposed to any other weekend. Good times and conversations were had, we spent some time catching up, I met their Chihuahua "Momo" who absolutely loves me for some reason, blah blah blah. Spending time with them was the best part of the trip, but we all know the whole reason you're even reading this blog is because you want to hear about PAX!!!
Reaching the Lair of Nerd – Day 1
After consuming a hearty breakfast of Mountain Dew, chocolate and pizza, I finally reached the vicinity of PAX Prime 2010 at around 1:30pm. Yeah, the show floor had already been open for 3.5 hours but to hell with getting up early, I was on vacation. Besides, all I was concerned with was making it to the 2:30pm 1UP alumni panel. I had to swing by registration first to pick up my disability pass (broken foot), but lucky for me the registration room and the theater in which the panel took place were both side-by-side in the Sheraton hotel.
Featuring the likes of Che Chou, Garnett Lee, Patrick Klepek, Jane Pinckard, Shane Bettenhausen and many others, this panel was an absolute joy to attend for a long-time EGM lover like myself. As I've said before, the reason I chose to start blogging at 1UP is because to me, 1UP is EGM. It was great hearing all the little stories from the crew about how great the old days were, how much fun it was to work together, etc. I was lucky to get a 2nd row seat (sitting behind other alumni Anthony Gallegos and next to current 1UP editor Alice Liang) thanks to my medical badge which offered me early access to seating for all panels:)
Throughout the panel, a few of the panelists occasionally looked like they were distracted by a piece of paper being passed around. It was a scene reminiscent of a bunch of bored high schoolers taking turns passing notes to each other during class. After the panel ended, I walked a few feet to the stage to say hi to the panelists and collect a few more signatures on a special copy of EGM I brought with me. Not only did I get those signatures, but I was also actually given the piece of paper they were doodling on! You can see the results of their handiwork to the right. 1UP's art director Mike Cruz – who happened to be standing right behind me – was highly amused and took a picture of me that was included in the alumni panel gallery. I'm not sure if I'm excited that I'm the only community member to be featured in the gallery or mortified that this will forever be my legacy on the internet.
Immediately afterwards, I had a short conversation with Mike (real cool guy) and then happened to run into the entire crew from Area 5 (minus Rick Curnutte). These are the guys who produced Revision3's Co-op, the spiritual successor to my favorite podcast ever – the 1UP Show! They together have the coolest business cards in the world.
I also ran into former 1UP editor/current Telltale employee Alan Johnson while he was standing guard in front of a full-size, fully-functional replica of the DeLorean from Back to the Future. I was shocked that he immediately recognized me from my 1UP profile pic. I'm famous! We chatted briefly before I let him get back to work. Super cool guy just like Mike and all the members of Area 5.
1UP MeetUP!
My best-friend John, his wife Maggy, me, and...could it be? Yes, it's Falcon X!
Later on that night, I attended a live taping of the Giant Bombcast (those guys are funny as hell) before heading across the street to the Taphouse Grill for the 1UP MeetUP. Lucky for me, 1UP community member Falcon X held a spot in line for me and my friends. We had never met in person before, so it was a huge pleasure to finally meet the man himself. Falcon, in case you're reading this my friends liked you a lot!
I gotta say that the Taphouse was a huge upgrade in my mind over the Gameworks in which the meetup was held last year. Gameworks didn't have a lot of wide open spaces, which made it difficult to navigate and impossible to find anyone. In contrast, the area of the Taphouse that 1UP reserved didn't seem any larger than the space they occupied last year, but it was much more wide open and very easy to find everyone. Even in my pain in the ass medical boot I was able to get around easily. I spent most of my time hanging out with and talking to Falcon, but also had a few run ins with Community Manager Tina and chatted quite a bit with Mike and Alan as well as community members Jinpei05 and TheJoetoKnow (the E3 blogger winner). I had a great time, I just wish I could've stuck around until everyone went home at 2am.
I'll go ahead and cut this blog off right here. It's already taken me a week to put this out, so instead of waiting another week or two to post the whole thing I'd rather publish part 1 now and part 2 later.
I should have the second half including photos from the show floor posted in about a week, but we'll see what my schedule permits. Work plus a ton of other side projects have left me pressed for time, and then there's that thing called Reach that just came out:)
Stay tuned, more to come (including a full photo blowout) very soon! Until then, here are some pics from my first two days in Washington including larger versions of the ones I posted above.
Sign at the airport welcoming Gamestop managers to San Antonio for some Gamestop expo. A coworker who left for a trip to Canada that morning told me the airport was filled with Gamestop employees trying to catch flights home and bitching nonstop about the long security lines.
Throw in some Cheetos™ and we'd have a full blown nerd stereotype on our hands.
Ahhhhhh! Nerds! EVERYWHERE!!!
Yeah. Picture taken by Mike Cruz.
Straight from the minds of gaming journalism's finest.
The backsides of the Area 5 members' business cards.
OMG it's THE Alan Johnson!
That's right, I took a pic with Teanah! Envy me nerds, eeeeeeenvyyyyyy!!!
We look tough don't we? In case you can't tell I was tired.
Another photo taken by Mike.
Random shot of one of the party rooms 1UP rented. I had to take it from the outside because some bitchy bar Nazi kept kicking me out for not having a wrist band. Clearly she had no sympathy for cripples nor any appreciation for my unique and dashing Asian charm/math abilities.


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Tell Tayinat
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- Morrison, Dorothy
- Dorothy is a Wiccan High Priestess of the Georgian tradition and an avid practitioner of the ancient arts for over 20 years. She teaches the Craft to students throughout the US and in Australia. Her interests include archery and bowhunting, magical herbalism,...
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- Everything you always wanted to know about the beliefs of the Founding Fathers that your Congressman will never tell you!
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- Grimassi, Raven
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- >From an early age, David Allen Hulse has made a diligent study of the alphabets of the ancient world. Even as a child, David possessed a great affinity for the alphabets of Egypt, Phoenicia, and Greece. In college, a reading of MacGregor Mathers' Kabbalah...
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- Hittite king comes to Istanbul
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Vikram Batra Early Life And Career
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- Our Pagan Village: The Importance and Persuit of Honor
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- 2.1 'Trance;' descriptive or misleading? Most of the classical notions of hypnosis have long held that hypnosis was special in some way from other types of interpersonal communication and that an induction (preparatory process considered by some to be...
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- Survivalists' Guide for the New Millennium: Chapter 2
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- The Religious Experience: A Wiccan Viewpoint
- What is religion? Religion is a set of beliefs which allow us to understand and categorize our world and our place in it. A set of beliefs which define our culture, our expectations, our views of people and behaviors we expect. I have found several different...
Religion & Philosophy >> Religions
- Pagan Mythology
- Is the traditional story presented as an historical event that serves to illustrate part of the world view of a people or explain a practice, belief, or natural phenomenon. The mythological beliefs a culture shares gives shape to its actions and choices....
Paganism & Wicca >> Holidays
- Survivalists' Guide for the New Millennium: Chapter 7
- MAKING FRIENDS WITH NATURE AND NATURAL LAW The fall of human society has not occurred overnight. It has taken many centuries, many millennia in fact, for the Divine potentials and inherent genius of the human being to degrade into the modern...
Philosophy >> Survivalists Guide for the New Millennium
Vikram Batra Early Life And Career is described in multiple online sources, as addition to our editors' articles, see section below for printable documents, Vikram Batra Early Life And Career books and related discussion.
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- Pakistan singer Adnan Sami gets Indian citizenship
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South African retailer BT Games' website has apparently outed Call of Duty: Black Ops 2's minimum PC requirements.
With developer Treyarch only confirming dedicated servers for the PC version of the shooter thus far, the possible minimum system requirements, as seen below, is strictly a rumor. That said, the retailer in question has previously leaked the existence of several games before its announcement.
- Intel CPU: Celeron E1200 Dual-Core 1.6GHzor
- AMD CPU: Athlon 64 x2 Dual Core 3600+
- Nvidia GPU: GeForce GT 120
- AMD GPU: Radeon HD 4550
- Ram: 2GB
- OS:Windows XP 32bit (or later)
- Direct X: DX9
- HDD Space: 10GB
Call of Duty: Black Ops 2 is due for a worldwide release on November 9, 2012.


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Wilkes University welcomes you to our official home page. Wilkes, located in Northeastern Pennsylvania, offers small classes with Ph.D.-level faculty and a variety of undergraduate and graduate degree programs in arts, music, applied sciences, biology, chemistry, ... (see more)
Wilkes University welcomes you to our official home page. Wilkes, located in Northeastern Pennsylvania, offers small classes with Ph.D.-level faculty and a variety of undergraduate and graduate degree programs in arts, music, applied sciences, biology, chemistry, ...
Wilkes University Students Selected for Kirby Scholarship by Allan P. Kirby Center for Free Enterprise and Entrepreneurship
Ten Wilkes University students have been selected to be Kirby Scholars by the Allan P. Kirby Center for Free Enterprise and Entrepreneurship. The Kirby Scholars are top-performers in accounting, marketing, legal, product development, and project management. The Scholars provide services to the businesses at the center's business incubator, and receive valuable experience in their field of study and formal recognition of their work.
Four Wilkes University Honor Society students recently had an opportunity to visit Hanoi, Vietnam, to learn about making positive transformations in small communities. The students attended the University Scholars Leadership Symposium, an international conference intended to raise global awareness of disenfranchised communities.
Wilkes University awarded 372 doctoral, master's and bachelor's degrees to students graduating after the completion of the summer 2016 semester.
Wilkes University would like to welcome over 700 students into the class of 2020.
Thirty Wilkes University students are participating in research projects this summer in the biology, environmental engineering and earth sciences, and geology departments.
Wilkes University recently selected Josh Hagan, Autumn Peck and Kristen Santey as drum majors to lead it's marching band. The Marching Colonels - the only collegiate marching band in the region - debuted in the fall 2014 semester.
Wilkes University Provost Dr. Anne Skleder announced the Dean's List for the Spring 2016 Semester. To be named to the Dean's List, students must obtain a minimum 3.4 grade point average and carry at least 12 credits.
Three Wilkes University students and editors of the campus newspaper, The Beacon, received regional Society of Professional Journalists (SPJ) Marks of Excellence Awards at the recent Region 1 Conference held in New Haven, Conn.
Seven Wilkes University students were inducted into Phi Alpha Theta, the national history honor society, in a ceremony on Thursday, April 21, 2016. Phi Alpha Theta students must have at least 12 semester hours of history, a 3.1 grade point average and a 3.0 overall grade point average.
Twenty Wilkes University education majors are gaining classroom experience this semester as they complete student teaching assignments at area schools. The student teaching is one of the requirements for earning teacher certification in Pennsylvania.
Wilkes University Theatre will present William Shakespeare's Twelfth Night, or What You Will on April 14-17. Performances are being held nightly at 8 p.m. in the Dorothy Dickson Darte Center, with a Sunday matinee performance at 2 p.m.
Wilkes University students chose to spend their break contributing to underprivileged communities in Costa Rica, the Dominican Republic, and rural Kentucky. In Costa Rica, students created planters, outdoor seating, and tables from recycled and painted tires and cement for Costa Rican schools.
Wilkes University junior Valerie Woods, a marketing and management double major, was recently awarded two scholarships: the Joseph D. Giampapa Scholarship and the Thomas E. Matthews Scholarship through NACA, the National Association for Campus Activities. These scholarships are awarded to students who hold important leadership positions, and through Woods' demonstrated leadership skills and ability, she is being recognized for making a significant contribution on the Wilkes campus.
Wilkes University Students Enter "Achieving Independence" Competition at Pennsylvania Pharmacists Association Annual Meeting
A team of four Wilkes University students from the Nesbitt School of Pharmacy participated in the Achieving Independence Competition at the Pennsylvania Pharmacists Association Annual Meeting. The competition challenges student teams to create a fiscally viable business plan for opening a new pharmacy in Pennsylvania or purchasing an existing pharmacy and implementing new concepts. The students presented their poster to a live panel of judges. Kim Ference, assistant professor of pharmacy practice, was faculty advisor for the project.
Wilkes University Students Foster Supportive Residential Environment, Promote Campus Community Participation as Resident Assistants
More than 45 undergraduate students at Wilkes University have accepted on-campus leadership roles as resident assistants. Resident assistants are responsible for crisis management, documenting policy violations, reporting maintenance requests and various other administrative tasks in campus residence halls where undergraduate students live.
Wilkes University Communication Studies majors are gaining firsthand experience as members of the student-run television program, Wilkes Now. As members of Wilkes Now, students produce original news and feature content each week for broadcast on channel 97 for Service Electric Cable in Wilkes-Barre.
Wilkes University Communication Studies majors are gaining firsthand experience as members of the student-run public relations agency, Zebra Communications. As members of Zebra Communications, students work with 12-15 client-partners, including not-for-profit organizations, government agencies, small businesses, campus initiatives and regional grant-funded projects, to create public relations campaigns of up to three months.
Six Wilkes University student teachers presented "Getting Ready for America" at City University College in Selangor, a suburb of Kuala Lumpur, Malaysia, on March 3 as part of an international exchange program between the two institutions. Nearly 150 college students attended the presentation on American culture and customs given by Gina Zanolini Morrison, Wilkes associate professor of undergraduate education and student teaching abroad supervisor, and the student teachers.
Forty-five undergraduate students serve the Wilkes University community as members of the student government. Student Government is the major decision- and policy-making organization for the student body at Wilkes University, providing student input on University policy and governing extracurricular life at Wilkes.
Wilkes University upperclassmen have volunteered to serve as E-Mentors for the 2013-2014 academic year. The mentors provide guidance to all First Year Students by assisting in the transition from high school to college both socially and academically. E-Mentors work with first-year students at orientation and during welcome weekend and serve as mentors throughout the first year at Wilkes. E-Mentors are assigned to first-year students based on the students' majors and help freshmen at Wilkes adapt to life at the University. E-Mentors not only guide first-year students through the adjustment to collegiate life but become the students' friends, often meeting face-to-face for lunch or at campus events. Each E-Mentor receives between 10-15 first-year student mentees.
Seven Wilkes University Air Force Reserve Officers' Training Corps graduates were awarded their second lieutenant commissions at a commissioning ceremony held before commencement in May. Graduates from your area include:


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The Big Funk by Pulitzer Prize Winner John Patrick Shanley
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An absurd comedy, The Big Funk opens to find its main characters arguing over which of them is the hero of the story. There's an apparently pregnant woman who's informed that she's due the next day; her knife-throwing, circus performer husband; his actor friend who wears a drip-dry suit so he can give a woman he's just met a bath; a soulmate-seeking campaign manager and a guy who has a thing for petroleum jelly. Each performance of this odd tale -- penned by Pulitzer Prize- and Academy Award-winning writer John Patrick Shanley (Moonstruck, Doubt: A Parable) -- features live music from The Roly Polys.
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The last date listed for The Big Funk was Sunday April 6, 2014 / 3:00pm.
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The weather was cold. I wore jeans.
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Reviews & Ratings
"The Big Funk"
Featured review from Liza Shepeleva
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A surreal experience sitting only few rows away from the action. the play makes you think about hesitations and fears and how people deal with it all in a very innovative manner.
attended Apr 03 2014
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The production "The Big Funk" was a dumbfounded comedy with unnecessary nudeness.
attended Mar 29 2014
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The performance was amazing and it was fun to see, I recommend it:)
attended Apr 01 2014
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There is full frontal nudity and also, baby powder in the air. It's an interesting play, there's a girl who gets smeared by vaseline.
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It's a week away from 2015, and I have transitioned completely away from Matlab. Julia is winning the platform attention battle. It is very easy to code in and it is very fast. I just haven't gotten around to learning python much less pyDSTool (sorry Rob). I kind of find the syntax of Python (with all the periods between words) annoying. Wally Xie and I have also been trying to implement some of our MCMC runs in Stan but we have had trouble making it work. Our model requires integrating ODEs and the ODE solutions from Stan (using our own solver) do not match our Julia code or the gold standard XPP. Maybe we are missing something obvious in the Stan syntax but our code is really very simple. Thus, we are going back to doing our Bayesian posterior estimates in Julia. However, I do plan to revisit Stan if they (or we) can write a debugger for it.
Big Data backlash
I predicted that there would be an eventual push back on Big Data and it seems that it has begun. Gary Marcus and Ernest Davis of NYU had an op-ed in the Times yesterday outlining nine issues with Big Data. I think one way to encapsulate many of the critiques is that you will never be able to do true prior free data modeling. The number of combinations in a data set grows as the factorial of the number of elements, which grows faster than an exponential. Hence, Moore's law can never catch up. At some point, someone will need to exercise some judgement in which case Big Data is not really different from the ordinary data that we deal with all the time.
Paper on compressed sensing and genomics
New paper on the arXiv. The next step after the completion of the Human Genome Project, was the search for genes associated with diseases such as autism or diabetes. However, after spending hundreds of millions of dollars, we find that there are very few common variants of genes with large effects. This doesn't mean that there aren't genes with large effect. The growth hormone gene definitely has a large effect on height. It just means that variations of genes that are common among people have small effects on the phenotype. Given the results of Fisher, Wright, Haldane and colleagues, this was probably expected as the most likely scenario and recent results measuring narrow-sense heritability directly from genetic markers (e.g. see this) confirms this view.
Current GWAS microarrays consider about a million or two markers and this is increasing rapidly. Narrow-sense heritability refers to the additive or linear genetic variance, which means the phenotype is given by the linear model , where is the phenotype vector, is the genotype matrix, are all the genetic effects we want to recover, and are all the nonadditive components including environmental effects. This is a classic linear regression problem. The problem comes when the number of coefficients far exceeds the number of people in your sample, which is the case for genomics. Compressed sensing is a field of high dimensional statistics that addresses this specific problem. People such as David Donoho, Emmanuel Candes and Terence Tao have proven under fairly general conditions that if the number of nonzero coefficients are sparse compared to the number samples, then the effects can be completely recovered using L1 penalized optimization algorithms such as the lasso or approximate message passing. In this paper, we show that these ideas can be applied to genomics.
Here is Steve Hsu's summary of the paper
Application of compressed sensing to genome wide association studies and genomic selection
We show that the signal-processing paradigm known as compressed sensing (CS) is applicable to genome-wide association studies (GWAS) and genomic selection (GS). The aim of GWAS is to isolate trait-associated loci, whereas GS attempts to predict the phenotypic values of new individuals on the basis of training data. CS addresses a problem common to both endeavors, namely that the number of genotyped markers often greatly exceeds the sample size. We show using CS methods and theory that all loci of nonzero effect can be identified (selected) using an efficient algorithm, provided that they are sufficiently few in number (sparse) relative to sample size. For heritability h2 = 1, there is a sharp phase transition to complete selection as the sample size is increased. For heritability values less than one, complete selection can still occur although the transition is smoothed. The transition boundary is only weakly dependent on the total number of genotyped markers. The crossing of a transition boundary provides an objective means to determine when true effects are being recovered. For h2 = 0.5, we find that a sample size that is thirty times the number of nonzero loci is sufficient for good recovery.
|Main paper (27 pages, 4 figures) and Supplement (5 figures) combined
|Genomics (q-bio.GN); Applications (stat.AP)
|Cite as:
|arXiv:1310.2264 [q-bio.GN]
|(or arXiv:1310.2264v1 [q-bio.GN] for this version)
MCMC and fitting models to data
As I have posted before, I never learned any statistics during my education as a theoretical physicist/applied mathematician. However, it became fairly apparent after I entered biology (although I managed to avoid it for a few years) that fitting models to data and estimating parameters is unavoidable. As I have opined multiple times previously, Bayesian inference and the Markov Chain Monte Carlo (MCMC) method is the best way to do this. I thought I would provide the details on how to implement the algorithm since most of the treatments on the subject are often couched in statistical language that may be hard to decipher for someone with a physics or dynamical systems background. I'll do this in a series of posts and in a nonstandard order. Instead of building up the entire Bayesian formalism, I thought I would show how the MCMC method can be used to do the job and then later show how it fits into the grand scheme of things to do even more.
Suppose you have data , which consists of some measurements (either a scalar or a vector) at discrete time points and a proposed model, which produces a time series , where represents a set of free parameters that changes the function. This model could be a system of differential equations or just some proposed function like a polynomial. The goal is to find the set of parameters that best fits the data and to evaluate how good the model is. Now, the correct way to do this is to use Bayesian inference and model comparison, which can be computed using the MCMC. However, the MCMC can also be used just to get the parameters in the sense of finding the best fit according to some criterion.
Slides for two talks
I just gave a seminar in the math department at the University of Iowa today. I gave a talk that was similar to the one I gave at the Mathematical Biosciences Institute on Bayesian Inference for dynamical systems. My slides are here. I was lucky I made it to give this talk. My flight from Chicago O'Hare to Cedar Rapids, Iowa was cancelled yesterday and I was rebooked on another flight tonight, which wouldn't have been of much use for my talk this afternoon. There was one fight left last evening to Cedar Rapids but bad weather cancelled several flights yesterday so there were many stranded travelers. I was number 38 on the standby list and thought I had no chance to make it out that night. However, on a whim I decided to wait it out and I started to move up the list because other people had evidently given up as well. To my great surprise and relief I was the last person to get on the plane. There was a brief scare when they asked me to get off because we exceeded the weight limitation but then they changed their mind and let us all fly. (Someone else had kindly volunteered to take my place). I learned two lessons. One is to keep close watch of your flight at all times so you can get on the standby list as soon as possible and two is that even number 38 on a plane that only seats 50 can still make it.
I also gave a talk at Northwestern University in March on the gene induction project that I described here. My slides are here.
Dollar cost averaging
It is often recommended that when investing money in a mutual fund or security to use a strategy called dollar cost averaging. This simply means you invest a fixed amount of money at periodic intervals rather than say buy a fixed number of shares at periodic intervals or invest as a lump sum. The argument is that when the price of the fund is low you buy more shares and when it is high you buy fewer shares. In this way you can ride out the fluctuations in the stock price.
Evaluating which strategy is best is a great example of how concepts in calculus and in particular Jensen's inequality enter every day life and more reasons for why an average person should learn more math. The question is how do the investment strategies compare over time. Let be the price of the fund at time . In dollar cost averaging, you would invest dollars at periodic intervals (say each week). So the number of shares you would buy each week is . Over a time period you will have purchased shares, which can be rewritten as , where is the expectation value or average. Since you have invested dollars, you have paid per share on average, which is also called the harmonic mean.
If on the other hand you decided to buy a fixed number of shares per week then it would cost . Over the time period you will have spend and have shares. Thus you have paid on average. Now the question is how does the mean compare to the harmonic mean . This is where Jensen's inequality comes in, which says that for a convex function , . A convex function is a function where a straight line joining any two points on the function is greater than or equal to the function. Since is a convex function, this means that which can be rearrange to show that . So dollar cost averaging is always better than or as good as buying the same number of shares each week. Now of course if you buy on a day when the price is below the harmonic mean of a time horizon you are looking at you will always do better .
Connecting the dots
As I posted previously, I am highly skeptical that any foolproof system can be developed to screen for potential threats. My previous argument was that in order to have a zero false negative rate for identifying terrorists, it would be impossible to not also have a relatively significant false positive rate. In other words, the only way to guarantee that a terrorist doesn't board a plane is to not let anyone board. A way to visualize this graphically is with what is called a receiver operating characteristic or ROC curve, which is a plot of the true positive rate versus the false positive rate for a binary classification test as some parameter, usually a discrimination threshold, is changed. Ideally, one would like a curve that jumps to a true positive rate of 1 for zero false positive rate. The area under the ROC curve (AROC) is the usual measure for how good a discriminator is. So a perfect discriminator has AROC = 1. In my experience with biological systems, it is pretty difficult to make a test with an AROC of greater than 90%. Additionally, ROC curves are usually somewhat smooth so that they only reach true positve rate = 1 at false positive rate = 1.
Practicalities aside, is there any mathematical reason why a perfect or near perfect discriminator couldn't be designed? This to me is the more interesting question. My guess is that deciding if a person is a terrorist is an NP hard question, which is why it is so insidious. For any NP problem, it is simple to verify the answer but hard to find one. Connecting all the dots to show that someone is a terrorist is a straightforward matter if you already know that they are a terrorist. This is also true of proving the Riemann Hypothesis or solving the 3D Ising model. The solution is obvious if you know the answer. If terrorist finding is NP hard, then that means for a large enough population and I think 5 billion qualifies, then no method nor achievable amount of computational power is sufficient to do the job perfectly.


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