bluuebunny/crossref_metadata_2025_split huggingface dataset:
A detailed experimental study of a DNA computer with two endonucleases
Authors: Sakowski Sebastian , Krasiński Tadeusz , Sarnik Joanna , Blasiak Janusz , Waldmajer Jacek , Poplawski Tomasz 
Published: April 2017

Abstract
Great advances in biotechnology have allowed the construction of a computer from DNA. One of the proposed solutions is a biomolecular finite automaton, a simple two-state DNA computer without memory, which was presented by Ehud Shapiro’s group at the Weizmann Institute of Science. The main problem with this computer, in which biomolecules carry out logical operations, is its complexity – increasing the number of states of biomolecular automata. In this study, we constructed (in laboratory conditions) a six-state DNA computer that uses two endonucleases (e.g. AcuI and BbvI) and a ligase. We have presented a detailed experimental verification of its feasibility. We described the effect of the number of states, the length of input data, and the nondeterminism on the computing process. We also tested different automata (with three, four, and six states) running on various accepted input words of different lengths such as ab, aab, aaab, ababa, and of an unaccepted word ba. Moreover, this article presents the reaction optimization and the methods of eliminating certain biochemical problems occurring in the implementation of a biomolecular DNA automaton based on two endonucleases.
Early Social Isolation Stress and Perinatal NMDA Receptor Antagonist Treatment Induce Changes in the Structure and Neurochemistry of Inhibitory Neurons of the Adult Amygdala and Prefrontal Cortex
Authors: Castillo-Gómez Esther , Pérez-Rando Marta , Bellés María , Gilabert-Juan Javier , Llorens José Vicente , Carceller Héctor , Bueno-Fernández Clara , García-Mompó Clara , Ripoll-Martínez Beatriz , Curto Yasmina , Sebastiá-Ortega Noelia , Moltó María Dolores , Sanjuan Julio , Nacher Juan 
Published: April 2017

AbstractThe exposure to aversive experiences during early life influences brain development and leads to altered behavior. Moreover, the combination of these experiences with subtle alterations in neurodevelopment may contribute to the emergence of psychiatric disorders, such as schizophrenia. Recent hypotheses suggest that imbalances between excitatory and inhibitory (E/I) neurotransmission, especially in the prefrontal cortex and the amygdala, may underlie their etiopathology. In order to understand better the neurobiological bases of these alterations, we studied the impact of altered neurodevelopment and chronic early-life stress on these two brain regions. Transgenic mice displaying fluorescent excitatory and inhibitory neurons, received a single injection of MK801 (NMDAR antagonist) or vehicle solution at postnatal day 7 and/or were socially isolated from the age of weaning until adulthood (3 months old). We found that anxiety-related behavior, brain volume, neuronal structure, and the expression of molecules related to plasticity and E/I neurotransmission in adult mice were importantly affected by early-life stress. Interestingly, many of these effects were potentiated when the stress paradigm was applied to mice perinatally injected with MK801 ("double-hit" model). These results clearly show the impact of early-life stress on the adult brain, especially on the structure and plasticity of inhibitory networks, and highlight the double-hit model as a valuable tool to study the contribution of early-life stress in the emergence of neurodevelopmental psychiatric disorders, such as schizophrenia.
Inhibition of Drp1 Ameliorates Synaptic Depression, Aβ Deposition, and Cognitive Impairment in an Alzheimer's Disease Model
Authors: Baek Seung Hyun , Park So Jung , Jeong Jae In , Kim Sung Hyun , Han Jihoon , Kyung Jae Won , Baik Sang-Ha , Choi Yuri , Choi Bo Youn , Park Jin Su , Bahn Gahee , Shin Ji Hyun , Jo Doo Sin , Lee Joo-Yong , Jang Choon-Gon , Arumugam Thiruma V. , Kim Jongpil , Han Jeung-Whan , Koh Jae-Young , Cho Dong-Hyung , Jo Dong-Gyu 
Published: April 2017

Excessive mitochondrial fission is a prominent early event and contributes to mitochondrial dysfunction, synaptic failure, and neuronal cell death in the progression of Alzheimer's disease (AD). However, it remains to be determined whether inhibition of excessive mitochondrial fission is beneficial in mammal models of AD. To determine whether dynamin-related protein 1 (Drp1), a key regulator of mitochondrial fragmentation, can be a disease-modifying therapeutic target for AD, we examined the effects of Drp1 inhibitor on mitochondrial and synaptic dysfunctions induced by oligomeric amyloid-β (Aβ) in neurons and neuropathology and cognitive functions in Aβ precursor protein/presenilin 1 double-transgenic AD mice. Inhibition of Drp1 alleviates mitochondrial fragmentation, loss of mitochondrial membrane potential, reactive oxygen species production, ATP reduction, and synaptic depression in Aβ-treated neurons. Furthermore, Drp1 inhibition significantly improves learning and memory and prevents mitochondrial fragmentation, lipid peroxidation, BACE1 expression, and Aβ deposition in the brain in the AD model. These results provide evidence that Drp1 plays an important role in Aβ-mediated and AD-related neuropathology and in cognitive decline in an AD animal model. Therefore, inhibiting excessive Drp1-mediated mitochondrial fission may be an efficient therapeutic avenue for AD.SIGNIFICANCE STATEMENTMitochondrial fission relies on the evolutionary conserved dynamin-related protein 1 (Drp1). Drp1 activity and mitochondria fragmentation are significantly elevated in the brains of sporadic Alzheimer's disease (AD) cases. In the present study, we first demonstrated that the inhibition of Drp1 restored amyloid-β (Aβ)-mediated mitochondrial dysfunctions and synaptic depression in neurons and significantly reduced lipid peroxidation, BACE1 expression, and Aβ deposition in the brain of AD mice. As a result, memory deficits in AD mice were rescued by Drp1 inhibition. These results suggest that neuropathology and combined cognitive decline can be attributed to hyperactivation of Drp1 in the pathogenesis of AD. Therefore, inhibitors of excessive mitochondrial fission, such as Drp1 inhibitors, may be a new strategy for AD.
Selective Modulation of the Pupil Light Reflex by Microstimulation of Prefrontal Cortex
Authors: Ebitz R. Becket , Moore Tirin 
Published: April 2017

The prefrontal cortex (PFC) is thought to flexibly regulate sensorimotor responses, perhaps through modulating activity in other circuits. However, the scope of that control remains unknown: it remains unclear whether the PFC can modulate basic reflexes. One canonical example of a central reflex is the pupil light reflex (PLR): the automatic constriction of the pupil in response to luminance increments. Unlike pupil size, which depends on the interaction of multiple physiological and neuromodulatory influences, the PLR reflects the action of a simple brainstem circuit. However, emerging behavioral evidence suggests that the PLR may be modulated by cognitive processes. Although the neural basis of these modulations remains unknown, one possible source is the PFC, particularly the frontal eye field (FEF), an area of the PFC implicated in the control of attention. We show that microstimulation of the rhesus macaque FEF alters the magnitude of the PLR in a spatially specific manner. FEF microstimulation enhanced the PLR to probes presented within the stimulated visual field, but suppressed the PLR to probes at nonoverlapping locations. The spatial specificity of this effect parallels the effect of FEF stimulation on attention and suggests that FEF is capable of modulating visuomotor transformations performed at a lower level than was previously known. These results provide evidence of the selective regulation of a basic brainstem reflex by the PFC.SIGNIFICANCE STATEMENTThe pupil light reflex (PLR) is our brain's first and most fundamental mechanism for light adaptation. Although it is often described in textbooks as being an immutable reflex, converging evidence suggests that the magnitude of the PLR is modulated by cognitive factors. The neural bases of these modulations are unknown. Here, we report that microstimulation in the prefrontal cortex (PFC) modulates the gain of the PLR, changing how a simple reflex circuit responds to physically identical stimuli. These results suggest that control structures such as the PFC can add complexity and flexibility to even a basic brainstem circuit.
The Spacing Effect for Structural Synaptic Plasticity Provides Specificity and Precision in Plastic Changes
Authors: San Martin Alvaro , Rela Lorena , Gelb Bruce , Pagani Mario Rafael 
Published: April 2017

In contrast to trials of training without intervals (massed training), training trials spaced over time (spaced training) induce a more persistent memory identified as long-term memory (LTM). This phenomenon, known as the spacing effect for memory, is poorly understood. LTM is supported by structural synaptic plasticity; however, how synapses integrate spaced stimuli remains elusive. Here, we analyzed events of structural synaptic plasticity at the single-synapse level after distinct patterns of stimulation in motoneurons ofDrosophila. We found that the spacing effect is a phenomenon detected at synaptic level, which determines the specificity and the precision in structural synaptic plasticity. Whereas a single pulse of stimulation (massed) induced structural synaptic plasticity, the same amount of stimulation divided in three spaced stimuli completely prevented it. This inhibitory effect was determined by the length of the interstimulus intervals. The inhibitory effect of the spacing was lost by suppressing the activity of Ras or mitogen-activated protein kinase, whereas the overexpression of Ras-WT enhanced it. Moreover, dividing the same total time of stimulation into five or more stimuli produced a higher precision in the number of events of plasticity. Ras mutations associated with intellectual disability abolished the spacing effect and led neurons to decode distinct stimulation patterns as massed stimulation. This evidence suggests that the spacing effect for memory may result from the effect of the spacing in synaptic plasticity, which appears to be a property not limited to neurons involved in learning and memory. We propose a model of spacing-dependent structural synaptic plasticity.SIGNIFICANCE STATEMENTLong-term memory (LTM) induced by repeated trials spaced over time is known as the spacing effect, a common property in the animal kingdom. Altered mechanisms in the spacing effect have been found in animal models of disorders with intellectual disability, such as Noonan syndrome. Although LTM is sustained by structural synaptic plasticity, how synapses integrate spaced stimuli and decode them into specific plastic changes remains elusive. Here, we show that the spacing effect is a phenomenon detected at the synaptic level, which determines the properties of the response in structural plasticity, including precision of such response. Whereas suppressing or enhancing Ras/mitogen-activated protein kinase signaling changed how synapses decode a pattern of stimuli, a disease-related Ras allele abolished the spacing effect for plastic changes.
Feature-Selective Attention Adaptively Shifts Noise Correlations in Primary Auditory Cortex
Authors: Downer Joshua D. , Rapone Brittany , Verhein Jessica , O'Connor Kevin N. , Sutter Mitchell L. 
Published: April 2017

Sensory environments often contain an overwhelming amount of information, with both relevant and irrelevant information competing for neural resources. Feature attention mediates this competition by selecting the sensory features needed to form a coherent percept. How attention affects the activity of populations of neurons to support this process is poorly understood because population coding is typically studied through simulations in which one sensory feature is encoded without competition. Therefore, to study the effects of feature attention on population-based neural coding, investigations must be extended to include stimuli with both relevant and irrelevant features. We measured noise correlations (rnoise) within small neural populations in primary auditory cortex while rhesus macaques performed a novel feature-selective attention task. We found that the effect of feature-selective attention onrnoisedepended not only on the population tuning to the attended feature, but also on the tuning to the distractor feature. To attempt to explain how these observed effects might support enhanced perceptual performance, we propose an extension of a simple and influential model in which shifts inrnoisecan simultaneously enhance the representation of the attended feature while suppressing the distractor. These findings present a novel mechanism by which attention modulates neural populations to support sensory processing in cluttered environments.SIGNIFICANCE STATEMENTAlthough feature-selective attention constitutes one of the building blocks of listening in natural environments, its neural bases remain obscure. To address this, we developed a novel auditory feature-selective attention task and measured noise correlations (rnoise) in rhesus macaque A1 during task performance. Unlike previous studies showing that the effect of attention onrnoisedepends on population tuning to the attended feature, we show that the effect of attention depends on the tuning to the distractor feature as well. We suggest that these effects represent an efficient process by which sensory cortex simultaneously enhances relevant information and suppresses irrelevant information.
Dissociation of Choice Formation and Choice-Correlated Activity in Macaque Visual Cortex
Authors: Goris Robbe L.T. , Ziemba Corey M. , Stine Gabriel M. , Simoncelli Eero P. , Movshon J. Anthony 
Published: April 2017

Responses of individual task-relevant sensory neurons can predict monkeys' trial-by-trial choices in perceptual decision-making tasks. Choice-correlated activity has been interpreted as evidence that the responses of these neurons are causally linked to perceptual judgments. To further test this hypothesis, we studied responses of orientation-selective neurons in V1 and V2 while two macaque monkeys performed a fine orientation discrimination task. Although both animals exhibited a high level of neuronal and behavioral sensitivity, only one exhibited choice-correlated activity. Surprisingly, this correlation was negative: when a neuron fired more vigorously, the animal was less likely to choose the orientation preferred by that neuron. Moreover, choice-correlated activity emerged late in the trial, earlier in V2 than in V1, and was correlated with anticipatory signals. Together, these results suggest that choice-correlated activity in task-relevant sensory neurons can reflect postdecision modulatory signals.SIGNIFICANCE STATEMENTWhen observers perform a difficult sensory discrimination, repeated presentations of the same stimulus can elicit different perceptual judgments. This behavioral variability often correlates with variability in the activity of sensory neurons driven by the stimulus. Traditionally, this correlation has been interpreted as suggesting a causal link between the activity of sensory neurons and perceptual judgments. More recently, it has been argued that the correlation instead may originate in recurrent input from other brain areas involved in the interpretation of sensory signals. Here, we call both hypotheses into question. We show that choice-related activity in sensory neurons can be highly variable across observers and can reflect modulatory processes that are dissociated from perceptual decision-making.
Age-Related Effects and Sex Differences in Gray Matter Density, Volume, Mass, and Cortical Thickness from Childhood to Young Adulthood
Authors: Gennatas Efstathios D. , Avants Brian B. , Wolf Daniel H. , Satterthwaite Theodore D. , Ruparel Kosha , Ciric Rastko , Hakonarson Hakon , Gur Raquel E. , Gur Ruben C. 
Published: April 2017

Developmental structural neuroimaging studies in humans have long described decreases in gray matter volume (GMV) and cortical thickness (CT) during adolescence. Gray matter density (GMD), a measure often assumed to be highly related to volume, has not been systematically investigated in development. We used T1 imaging data collected on the Philadelphia Neurodevelopmental Cohort to study age-related effects and sex differences in four regional gray matter measures in 1189 youths ranging in age from 8 to 23 years. Custom T1 segmentation and a novel high-resolution gray matter parcellation were used to extract GMD, GMV, gray matter mass (GMM; defined as GMD × GMV), and CT from 1625 brain regions. Nonlinear models revealed that each modality exhibits unique age-related effects and sex differences. While GMV and CT generally decrease with age, GMD increases and shows the strongest age-related effects, while GMM shows a slight decline overall. Females have lower GMV but higher GMD than males throughout the brain. Our findings suggest that GMD is a prime phenotype for the assessment of brain development and likely cognition and that periadolescent gray matter loss may be less pronounced than previously thought. This work highlights the need for combined quantitative histological MRI studies.SIGNIFICANCE STATEMENTThis study demonstrates that different MRI-derived gray matter measures show distinct age and sex effects and should not be considered equivalent but complementary. It is shown for the first time that gray matter density increases from childhood to young adulthood, in contrast with gray matter volume and cortical thickness, and that females, who are known to have lower gray matter volume than males, have higher density throughout the brain. A custom preprocessing pipeline and a novel high-resolution parcellation were created to analyze brain scans of 1189 youths collected as part of the Philadelphia Neurodevelopmental Cohort. A clear understanding of normal structural brain development is essential for the examination of brain–behavior relationships, the study of brain disease, and, ultimately, clinical applications of neuroimaging.
Visually Evoked 3–5 Hz Membrane Potential Oscillations Reduce the Responsiveness of Visual Cortex Neurons in Awake Behaving Mice
Authors: Einstein Michael C. , Polack Pierre-Olivier , Tran Duy T. , Golshani Peyman 
Published: April 2017

Low-frequency membrane potential (Vm) oscillations were once thought to only occur in sleeping and anesthetized states. Recently, low-frequencyVmoscillations have been described in inactive awake animals, but it is unclear whether they shape sensory processing in neurons and whether they occur during active awake behavioral states. To answer these questions, we performed two-photon guided whole-cellVmrecordings from primary visual cortex layer 2/3 excitatory and inhibitory neurons in awake mice during passive visual stimulation and performance of visual and auditory discrimination tasks. We recorded stereotyped 3–5 HzVmoscillations where theVmbaseline hyperpolarized as theVmunderwent high amplitude rhythmic fluctuations lasting 1–2 s in duration. When 3–5 HzVmoscillations coincided with visual cues, excitatory neuron responses to preferred cues were significantly reduced. Despite this disruption to sensory processing, visual cues were critical for evoking 3–5 HzVmoscillations when animals performed discrimination tasks and passively viewed drifting grating stimuli. Using pupillometry and animal locomotive speed as indicators of arousal, we found that 3–5 Hz oscillations were not restricted to unaroused states and that they occurred equally in aroused and unaroused states. Therefore, low-frequencyVmoscillations play a role in shaping sensory processing in visual cortical neurons, even during active wakefulness and decision making.SIGNIFICANCE STATEMENTA neuron's membrane potential (Vm) strongly shapes how information is processed in sensory cortices of awake animals. Yet, very little is known about how low-frequencyVmoscillations influence sensory processing and whether they occur in aroused awake animals. By performing two-photon guided whole-cell recordings from layer 2/3 excitatory and inhibitory neurons in the visual cortex of awake behaving animals, we found visually evoked stereotyped 3–5 HzVmoscillations that disrupt excitatory responsiveness to visual stimuli. Moreover, these oscillations occurred when animals were in high and low arousal states as measured by animal speed and pupillometry. These findings show, for the first time, that low-frequencyVmoscillations can significantly modulate sensory signal processing, even in awake active animals.
Effect of oral contraceptives and/or metformin on GLP-1 secretion and reactive hypoglycaemia in polycystic ovary syndrome
Authors: Glintborg Dorte , Mumm Hanne , Holst Jens Juul , Andersen Marianne 
Published: April 2017

Context
Insulin resistance in polycystic ovary syndrome (PCOS) may increase the risk of reactive hypoglycaemia (RH) and decrease glucagon-like peptide-1 (GLP-1) secretion. The possible effects of treatment with oral contraceptives (OCP) and/or metformin on GLP-1 secretion and risk of RH in PCOS is undetermined.

Setting
Outpatient clinic.

Patients and interventions
Randomized, controlled clinical trial. Ninety women with PCOS were randomized to 12-month treatment with OCP (150 mg desogestrel + 30 mg ethinylestradiol), metformin (2 g/day) or metformin + OCP. Five-hour oral glucose tolerance tests (5-h OGTT) measuring fasting and area under the curve (AUC) for GLP-1, glucose, insulin and C-peptide were performed before and after the intervention period. Sixty-five women completed the study and 34 weight-matched healthy women were included as controls.

Main outcome measures
Changes in GLP-1, glucose, insulin and C-peptide during 5-h OGTT.

Results
Fasting GLP-1 levels increased during metformin + OCP vs OCP treatment, whereas AUC GLP-1 levels were unchanged during medical treatment. The prevalence of reactive hypoglycemia increased from 9/65 to 14/65 after intervention (P < 0.01) and was more common after treatment with metformin + OCP (increase from 3/23 to 6/23, P = 0.01). Reactive hypoglycaemia was associated with higher insulin and C-peptide levels during 5-h OGTT, but was unassociated with BMI and AUC GLP-1. GLP-1 levels were comparable in PCOS vs controls. AUC GLP-1 levels were significantly lower in obese vs lean patients and were inversely associated with BMI.

Conclusions
AUC GLP-1 levels were unchanged during treatment. Increased risk of hypoglycemia during metformin + OCP could be associated with increased insulin secretion.