Mitigating Computer Limitations in Replicating Numerical Simulations of a Neural Network Model With Hodgkin-Huxley-Type Neurons.

Computational experiments have been very important to numerically simulate real phenomena in several areas. Many studies in computational biology discuss the necessity to obtain numerical replicability to accomplish new investigations. However, even following well-established rules in the literature, numerical replicability is unsuccessful when it takes the computer's limitations for representing real numbers into consideration. In this study, we used a previous published recurrent network model composed by Hodgkin-Huxley-type neurons to simulate the neural activity during development. The original source code in C/C++ was carefully refactored to mitigate the lack of replicability; moreover, it was re-implemented to other programming languages/software (XPP/XPPAUT, Python and Matlab) and executed under two operating systems (Windows and Linux). The commutation and association of the input current values during the summation of the pre-synaptic activity were also analyzed. A total of 72 simulations which must obtain the same result were executed to cover these scenarios. The results were replicated when the high floating-point precision (supplied by third-party libraries) was used. However, using the default floating-point precision type, none of the results were replicated when compared with previous results. Several new procedures were proposed during the source code refactorization; they allowed replicating only a few scenarios, regardless of the language and operating system. Thus, the generated computational "errors" were the same. Even using a simple computational model, the numerical replicability was very difficult to be achieved, requiring people with computational expertise to be performed. After all, the research community must be aware that conducting analyses with numerical simulations that use real number operations can lead to different conclusions.

Cyclic alternation of quiet and active sleep states in the octopus.

Previous observations suggest the existence of 'Active sleep' in cephalopods. To investigate in detail the behavioral structure of cephalopod sleep, we video-recorded four adult specimens of Octopus insularis and quantified their distinct states and transitions. Changes in skin color and texture and movements of eyes and mantle were assessed using automated image processing tools, and arousal threshold was measured using sensory stimulation. Two distinct states unresponsive to stimulation occurred in tandem. The first was a 'Quiet sleep' state with uniformly pale skin, closed pupils, and long episode durations (median 415.2 s). The second was an 'Active sleep' state with dynamic skin patterns of color and texture, rapid eye movements, and short episode durations (median 40.8 s). 'Active sleep' was periodic (60% of recurrences between 26 and 39 min) and occurred mostly after 'Quiet sleep' (82% of transitions). These results suggest that cephalopods have an ultradian sleep cycle analogous to that of amniotes.

Geographic Variability and Pathogen-Specific Considerations in the Diagnosis and Management of Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) is a rare but serious primary immunodeficiency with varying prevalence and rates of X-linked and autosomal recessive disease worldwide. Functional defects in the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex predispose patients to a relatively narrow spectrum of bacterial and fungal infections that are sometimes fastidious and often difficult to identify. When evaluating and treating patients with CGD, it is important to consider their native country of birth, climate, and living situation, which may predispose them to types of infections that are atypical to your routine practice. In addition to recurrent and often severe infections, patients with CGD and X-linked female carriers are also susceptible to developing many non-infectious complications including tissue granuloma formation and autoimmunity. The DHR-123 oxidation assay is the gold standard for making the diagnosis and it along with genetic testing can help predict the severity and prognosis in patients with CGD. Disease management focuses on prophylaxis with antibacterial, antifungal, and immunomodulatory medications, prompt identification and treatment of acute infections, and prevention of secondary granulomatous complications. While hematopoietic stem-cell transplantation is the only widely available curative treatment for patients with CGD, recent advances in gene therapy may provide a safer, more direct alternative.

Food Allergies.

Food allergy is 1 of the 4 manifestations of the "atopic march," along with eczema, allergic rhinitis, and asthma. Depending on the pathophysiologic immune mechanisms behind a food allergy, it can be classified as immunoglobulin E-mediated, non-immunoglobulin E-mediated, or mixed. The prevalence of food allergies has risen worldwide during the past few decades, becoming a significant global health concern. Patients experiencing food allergies and their caregivers are heavily burdened personally, socially, emotionally, and financially. The health-care system is also considerably affected. Pediatricians, as primary health-care providers, are often challenged with these patients, becoming the first-line for the recognition and management of food allergies. The purpose of this review is to provide a comprehensive summary of food allergies, including the most up-to-date information, recent guidelines, and recommendations.

Non-replicability circumstances in a neural network model with Hodgkin-Huxley-type neurons.

Building upon previous experiments can be used to accomplish new goals. In computing, it is imperative to reuse computer code to continue development on specific projects. Reproducibility is a fundamental building block in science, and experimental reproducibility issues have recently been of great concern. It may be surprising that reproducibility is also of concern in computational science. In this study, we used a previously published code to investigate neural network activity and we were unable to replicate our original results. This led us to investigate the code in question, and we found that several different aspects, attributable to floating-point arithmetic, were the cause of these replicability issues. Furthermore, we uncovered other manifestations of this lack of replicability in other parts of the computation with this model. The simulated model is a standard system of ordinary differential equations, very much like those commonly used in computational neuroscience. Thus, we believe that other researchers in the field should be vigilant when using such models and avoid drawing conclusions from calculations if their qualitative results can be substantially modified through non-reproducible circumstances.

Hippocampal functional organization: A microstructure of the place cell network encoding space.

A clue to hippocampal function has been the discovery of place cells, leading to the 'spatial map' theory. Although the firing attributes of place cells are well documented, little is known about the organization of the spatial map. Unit recording studies, thus far, have reported a low coherence between neighboring cells and geometric space, leading to the prevalent view that the spatial map is not topographically organized. However, the number of simultaneously recorded units is severely limited, rendering construction of the spatial map nearly impossible. To visualize the functional organization of place cells, we used the activity-dependent immediate-early gene Zif268 in combination with behavioral, pharmacological and electrophysiological methods, in mice and rats exploring an environment. Here, we show that in animals confined to a small part of a maze, principal cells in the CA1/CA3 subfields of the dorsal hippocampus immunoreactive (IR) for Zif268 adhere to a 'cluster-type' organization. Unit recordings confirmed that the Zif268 IR clusters correspond to active place cells, while blockade of NMDAR (which alters place fields) disrupted the Zif268 IR clusters. Contrary to the prevalent view that the spatial map consists of a non-topographic neural network, our results provide evidence for a 'cluster-type' functional organization of hippocampal neurons encoding for space.

Gain of transcription factor binding sites is associated to changes in the expression signature of human brain and testis and is correlated to genes with higher expression breadth.

The gain of transcription factor binding sites (TFBS) is believed to represent one of the major causes of biological innovation. Here we used strategies based on comparative genomics to identify 21,822 TFBS specific to the human lineage (TFBS-HS), when compared to chimpanzee and gorilla genomes. More than 40% (9,206) of these TFBS-HS are in the vicinity of 1,283 genes. A comparison of the expression pattern of these genes and the corresponding orthologs in chimpanzee and gorilla identified genes differentially expressed in human tissues. These genes show a more divergent expression pattern in the human testis and brain, suggesting a role for positive selection in the fixation of TFBS gains. Genes associated with TFBS-HS were enriched in gene ontology categories related to transcriptional regulation, signaling, differentiation/development and nervous system. Furthermore, genes associated with TFBS-HS present a higher expression breadth when compared to genes in general. This biased distribution is due to a preferential gain of TFBS in genes with higher expression breadth rather than a shift in the expression pattern after the gain of TFBS.

Computational models of memory consolidation and long-term synaptic plasticity during sleep.

The brain stores memories by persistently changing the connectivity between neurons. Sleep is known to be critical for these changes to endure. Research on the neurobiology of sleep and the mechanisms of long-term synaptic plasticity has provided data in support of various theories of how brain activity during sleep affects long-term synaptic plasticity. The experimental findings - and therefore the theories - are apparently quite contradictory, with some evidence pointing to a role of sleep in the forgetting of irrelevant memories, whereas other results indicate that sleep supports the reinforcement of the most valuable recollections. A unified theoretical framework is in need. Computational modeling and simulation provide grounds for the quantitative testing and comparison of theoretical predictions and observed data, and might serve as a strategy to organize the rather complicated and diverse pool of data and methodologies used in sleep research. This review article outlines the emerging progress in the computational modeling and simulation of the main theories on the role of sleep in memory consolidation.

The Effects of GABAergic Polarity Changes on Episodic Neural Network Activity in Developing Neural Systems.

Early in development, neural systems have primarily excitatory coupling, where even GABAergic synapses are excitatory. Many of these systems exhibit spontaneous episodes of activity that have been characterized through both experimental and computational studies. As development progress the neural system goes through many changes, including synaptic remodeling, intrinsic plasticity in the ion channel expression, and a transformation of GABAergic synapses from excitatory to inhibitory. What effect each of these, and other, changes have on the network behavior is hard to know from experimental studies since they all happen in parallel. One advantage of a computational approach is that one has the ability to study developmental changes in isolation. Here, we examine the effects of GABAergic synapse polarity change on the spontaneous activity of both a mean field and a neural network model that has both glutamatergic and GABAergic coupling, representative of a developing neural network. We find some intuitive behavioral changes as the GABAergic neurons go from excitatory to inhibitory, shared by both models, such as a decrease in the duration of episodes. We also find some paradoxical changes in the activity that are only present in the neural network model. In particular, we find that during early development the inter-episode durations become longer on average, while later in development they become shorter. In addressing this unexpected finding, we uncover a priming effect that is particularly important for a small subset of neurons, called the "intermediate neurons." We characterize these neurons and demonstrate why they are crucial to episode initiation, and why the paradoxical behavioral change result from priming of these neurons. The study illustrates how even arguably the simplest of developmental changes that occurs in neural systems can present non-intuitive behaviors. It also makes predictions about neural network behavioral changes that occur during development that may be observable even in actual neural systems where these changes are convoluted with changes in synaptic connectivity and intrinsic neural plasticity.

Electrophysiological Evidence That the Retrosplenial Cortex Displays a Strong and Specific Activation Phased with Hippocampal Theta during Paradoxical (REM) Sleep.

It is widely accepted that cortical neurons are similarly more activated during waking and paradoxical sleep (PS; aka REM) than during slow-wave sleep (SWS). However, we recently reported using Fos labeling that only a few limbic cortical structures including the retrosplenial cortex (RSC) and anterior cingulate cortex (ACA) contain a large number of neurons activated during PS hypersomnia. Our aim in the present study was to record local field potentials and unit activity from these two structures across all vigilance states in freely moving male rats to determine whether the RSC and the ACA are electrophysiologically specifically active during basal PS episodes. We found that theta power was significantly higher during PS than during active waking (aWK) similarly in the RSC and hippocampus (HPC) but not in ACA. Phase-amplitude coupling between HPC theta and gamma oscillations strongly and specifically increased in RSC during PS compared with aWK. It did not occur in ACA. Further, 68% and 43% of the units recorded in the RSC and ACA were significantly more active during PS than during aWK and SWS, respectively. In addition, neuronal discharge of RSC but not of ACA neurons increased just after the peak of hippocampal theta wave. Our results show for the first time that RSC neurons display enhanced spiking in synchrony with theta specifically during PS. We propose that activation of RSC neurons specifically during PS may play a role in the offline consolidation of spatial memories, and in the generation of vivid perceptual scenery during dreaming.SIGNIFICANCE STATEMENT Fifty years ago, Michel Jouvet used the term paradoxical to define REM sleep because of the simultaneous occurrence of a cortical activation similar to waking accompanied by muscle atonia. However, we recently demonstrated using functional neuroanatomy that only a few limbic structures including the retrosplenial cortex (RSC) and anterior cingulate cortex (ACA) are activated during PS. In the present study, we show for the first time that the RSC and ACA contain neurons firing more during PS than in any other state. Further, RSC neurons are firing in phase with the hippocampal theta rhythm. These data indicate that the RSC is very active during PS and could play a key role in memory consolidation taking place during this state.

Stabilization of collapsing scroll waves in systems with random heterogeneities.

In three-dimensional reaction-diffusion systems, excitation waves may form and rotate around a one-dimensional phase singularity called the filament. If the filament forms a closed curve, it will shrink over time and eventually collapse. However, filaments may pin to non-reactive objects present in the medium, reducing their rate of collapse or even allowing them to persist indefinitely. We use numerical simulations to study how different arrangements of non-reactive spheres affect the dynamics of circular filaments. As the filament contracts, it gets closer to and eventually touches and pins to objects in its path. This causes two possible behaviors. The filament can detach from the spheres in its path, slowing down the rate of contraction, or it can remain pinned to a collection of spheres. In general, more or larger spheres increase the chance that the filament remains pinned, but there are exceptions. It is possible for a small number of small spheres to support the filament and possible for the filament to pass through a large number of large spheres. Our work yields insights into the pinning of scroll waves in excitable tissue such as cardiac muscle, where scar tissue acts in a way similar to the non-reactive domains.

Synaptic Homeostasis and Restructuring across the Sleep-Wake Cycle.

Sleep is critical for hippocampus-dependent memory consolidation. However, the underlying mechanisms of synaptic plasticity are poorly understood. The central controversy is on whether long-term potentiation (LTP) takes a role during sleep and which would be its specific effect on memory. To address this question, we used immunohistochemistry to measure phosphorylation of Ca2+/calmodulin-dependent protein kinase II (pCaMKIIα) in the rat hippocampus immediately after specific sleep-wake states were interrupted. Control animals not exposed to novel objects during waking (WK) showed stable pCaMKIIα levels across the sleep-wake cycle, but animals exposed to novel objects showed a decrease during subsequent slow-wave sleep (SWS) followed by a rebound during rapid-eye-movement sleep (REM). The levels of pCaMKIIα during REM were proportional to cortical spindles near SWS/REM transitions. Based on these results, we modeled sleep-dependent LTP on a network of fully connected excitatory neurons fed with spikes recorded from the rat hippocampus across WK, SWS and REM. Sleep without LTP orderly rescaled synaptic weights to a narrow range of intermediate values. In contrast, LTP triggered near the SWS/REM transition led to marked swaps in synaptic weight ranking. To better understand the interaction between rescaling and restructuring during sleep, we implemented synaptic homeostasis and embossing in a detailed hippocampal-cortical model with both excitatory and inhibitory neurons. Synaptic homeostasis was implemented by weakening potentiation and strengthening depression, while synaptic embossing was simulated by evoking LTP on selected synapses. We observed that synaptic homeostasis facilitates controlled synaptic restructuring. The results imply a mechanism for a cognitive synergy between SWS and REM, and suggest that LTP at the SWS/REM transition critically influences the effect of sleep: Its lack determines synaptic homeostasis, its presence causes synaptic restructuring.

Dream characteristics in a Brazilian sample: an online survey focusing on lucid dreaming.

During sleep, humans experience the offline images and sensations that we call dreams, which are typically emotional and lacking in rational judgment of their bizarreness. However, during lucid dreaming (LD), subjects know that they are dreaming, and may control oneiric content. Dreaming and LD features have been studied in North Americans, Europeans and Asians, but not among Brazilians, the largest population in Latin America. Here we investigated dreams and LD characteristics in a Brazilian sample (n = 3,427; median age = 25 years) through an online survey. The subjects reported recalling dreams at least once a week (76%), and that dreams typically depicted actions (93%), known people (92%), sounds/voices (78%), and colored images (76%). The oneiric content was associated with plans for the upcoming days (37%), memories of the previous day (13%), or unrelated to the dreamer (30%). Nightmares usually depicted anxiety/fear (65%), being stalked (48%), or other unpleasant sensations (47%). These data corroborate Freudian notion of day residue in dreams, and suggest that dreams and nightmares are simulations of life situations that are related to our psychobiological integrity. Regarding LD, we observed that 77% of the subjects experienced LD at least once in life (44% up to 10 episodes ever), and for 48% LD subjectively lasted less than 1 min. LD frequency correlated weakly with dream recall frequency (r = 0.20, p < 0.01), and LD control was rare (29%). LD occurrence was facilitated when subjects did not need to wake up early (38%), a situation that increases rapid eye movement sleep (REMS) duration, or when subjects were under stress (30%), which increases REMS transitions into waking. These results indicate that LD is relatively ubiquitous but rare, unstable, difficult to control, and facilitated by increases in REMS duration and transitions to wake state. Together with LD incidence in USA, Europe and Asia, our data from Latin America strengthen the notion that LD is a general phenomenon of the human species.

Dual roles of telomere dysfunction in initiation and suppression of tumorigenesis.

Human carcinomas arise through the acquisition of genetic changes that endow precursor cancer cells with a critical threshold of cancer-relevant genetic lesions. This complex genomic alterations confer upon precursor cancer cells the ability to grow indefinitely and to metastasize to distant sites. One important mechanism underlying a cell's tumorigenic potential is the status of its telomere. Telomeres are G-rich simple repeat sequences that serve to prevent chromosomal ends from being recognized as DNA double-strand breaks (DSBs). Dysfunctional telomeres resemble DSBs, leading to the formation of dicentric chromosomes that fuel high degrees of genomic instability. In the setting of an intact p53 pathway, this instability promotes cellular senescence, a potent tumor suppressor mechanism. However, rare cells that stochastically lose p53 function emerge from this sea of genomic instability and progress towards cancer. In this review, we describe the use of mouse models to probe the impact of dysfunctional telomeres on tumor initiation and suppression.

Dysfunctional telomeres activate an ATM-ATR-dependent DNA damage response to suppress tumorigenesis.

The POT1 (protection of telomeres) protein binds the single-stranded G-rich overhang and is essential for both telomere end protection and telomere length regulation. Telomeric binding of POT1 is enhanced by its interaction with TPP1. In this study, we demonstrate that mouse Tpp1 confers telomere end protection by recruiting Pot1a and Pot1b to telomeres. Knockdown of Tpp1 elicits a p53-dependent growth arrest and an ATM-dependent DNA damage response at telomeres. In contrast to depletion of Trf2, which activates ATM, removal of Pot1a and Pot1b from telomeres initiates an ATR-dependent DNA damage response (DDR). Finally, we show that telomere dysfunction as a result of Tpp1 depletion promotes chromosomal instability and tumorigenesis in the absence of an ATM-dependent DDR. Our results uncover a novel ATR-dependent DDR at telomeres that is normally shielded by POT1 binding to the single-stranded G-overhang. In addition, our results suggest that loss of ATM can cooperate with dysfunctional telomeres to promote cellular transformation and tumor formation in vivo.

Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53-dependent cellular senescence.

Dysfunctional telomeres induce p53-dependent cellular senescence and apoptosis, but it is not known which function is more important for tumour suppression in vivo. We used the p53 ( R172P ) knock-in mouse, which is unable to induce apoptosis but retains intact cell-cycle arrest and cellular senescence pathways, to show that spontaneous tumorigenesis is potently repressed in Terc -/- p53 ( R172P ) mice. Tumour suppression is accompanied by global induction of p53, p21 and the senescence marker senescence-associated-beta-galactosidase. By contrast, cellular senescence was unable to suppress chemically induced skin carcinomas. These results indicate that suppression of spontaneous tumorigenesis by dysfunctional telomeres requires the activation of the p53-dependent cellular senescence pathway.

POT1b protects telomeres from end-to-end chromosomal fusions and aberrant homologous recombination.

POT1 (protection of telomere 1) is a highly conserved single-stranded telomeric binding protein that is essential for telomere end protection. Here, we report the cloning and characterization of a second member of the mouse POT family. POT1b binds telomeric DNA via conserved DNA binding oligonucleotide/oligosaccharide (OB) folds. Compared to POT1a, POT1b OB-folds possess less sequence specificity for telomeres. In contrast to POT1a, truncated POT1b possessing only the OB-folds can efficiently localize to telomeres in vivo. Overexpression of a mutant Pot1b allele that cannot bind telomeric DNA initiated a DNA damage response at telomeres that led to p53-dependent senescence. Furthermore, a reduction of the 3' G-rich overhang, increased chromosomal fusions and elevated homologous recombination (HR) were observed at telomeres. shRNA mediated depletion of endogenous Pot1b in Pot1a deficient cells resulted in increased chromosomal aberrations. Our results indicate that POT1b plays important protective functions at telomeres and that proper maintenance of chromosomal stability requires both POT proteins.

Pot1 deficiency initiates DNA damage checkpoint activation and aberrant homologous recombination at telomeres.

The terminal t-loop structure adopted by mammalian telomeres is thought to prevent telomeres from being recognized as double-stranded DNA breaks by sequestering the 3' single-stranded G-rich overhang from exposure to the DNA damage machinery. The POT1 (protection of telomeres) protein binds the single-stranded overhang and is required for both chromosomal end protection and telomere length regulation. The mouse genome contains two POT1 orthologs, Pot1a and Pot1b. Here we show that conditional deletion of Pot1a elicits a DNA damage response at telomeres, resulting in p53-dependent replicative senescence. Pot1a-deficient cells exhibit overall telomere length and 3' overhang elongation as well as aberrant homologous recombination (HR) at telomeres, manifested as increased telomere sister chromatid exchanges and formation of telomere circles. Telomeric HR following Pot1a loss requires NBS1. Pot1a deletion also results in chromosomal instability. Our results suggest that POT1a is crucial for the maintenance of both telomere integrity and overall genomic stability.