Δευτέρα 30 Οκτωβρίου 2017

rSalvador: An R Package for the Fluctuation Experiment

The past few years saw a surge of novel applications of the Luria-Delbruck fluctuation assay protocol in bacterial research.  Appropriate analysis of fluctuation assay data often requires computational methods that are unavailable in the popular web tool FALCOR. This paper introduces an R packages named rSalvador to bring improvements to the field. The paper focuses on rSalvador's capabilities to alleviate three kinds of problems found in recent investigations: (i) resorting to partial plating without properly accounting for the effects of partial plating; (ii) conducting attendant fitness assays without incorporating mutants' relative fitness in subsequent data analysis; and (iii) comparing mutation rates using methods that are in general inapplicable to fluctuation assay data. In addition, the paper touches on rSalvador's capabilities to estimate sample size and the difficulties related to parameter non-identifiability.



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Use of Mental Health Services by Adolescents After Traumatic Brain Injury: A Secondary Analysis of a Randomized Controlled Triala

Mental health problems are common after pediatric traumatic brain injury (TBI). Many patients in need of mental health services do not receive them, but studies have not consistently used prospective and objective methods or followed samples for more than 1 year.

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The effects of an 8-week stabilization exercise program on lumbar multifidus muscle thickness and activation as measured with ultrasound imaging in patients with low back pain: An exploratory study

Lumbar statilization exercise programs (LSEP) produce positive effects on clinical outcomes, but the underlying mechanisms remain fairly unexplored. Psychological and neuromuscular mechanisms can be involved such as a better activation of the lumbar multifidus which represents one possibility.

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Interaction of Glutamate Receptors and GABA Neurons in the Central Nervous System

This review summarizes data on the interaction of effects arising as a result of activation of receptors for the main neurotransmitters in the CNS – glutamate and GABA. Reports on the structures and functions of the receptors for these signal substances are presented, and questions of their colocalization in synapses and interactions between the effects of activation of both ionotropic and metabotropic receptors for these neurotransmitters at the postsynaptic level are discussed.



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Morphological Changes and Characteristics of the Expression of Serine Racemase in the Rat Hippocampus in Combined Stress

Structural changes in the ventral segment of the hippocampus and the characteristics of the expression of serine racemase were studied in rats aged 12 and 24 months exposed to combined stress. Four groups of 10 animals were formed: group 1 were control rats aged 12 months; group 2 were control rats aged 24 months; group 3 were 12-month rats subjected to 30-min stress daily for seven days; group 4 were 24-month rats subjected to stress. Stress was applied in a special apparatus consisting of six isolated sectors of identical volume and allowing the combination of different types of stress to be applied (pulsing light, loud noise, vibration). The ventral segment of the hippocampus of experimental animals showed an increase in the specific number of shrunken hyperchromic neurons in field CA3 and decreases in neuron density, accompanied by pericellular edema, cytoplasmic vacuolization, and decreased serine racemase expression in the neuropil of the radial layer of fields CA1 and CA3. Stressed animals showed changes in neurons in the pyramidal layer of field CA3, which were combined with a decrease in the level of expression of serine racemase in dendrites in the radial layer of fields CA1 and CA3, which is taken as a sign of impairment to NMDA receptor-mediated transmission of nerve spikes in the hippocampus.



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The Role of GABAergic Interneurons in the Cortex and Hippocampus in the Development of Epilepsy

This review analyzes contemporary data on the possible roles of different classes of interneurons in the hippocampus and cortex in the pathogenesis of temporal epilepsy in humans – one of the commonest forms of epilepsy. Data obtained from humans (results of post mortem morphological investigation of patients' brain tissues and electrophysiological experiments on brain slices collected at neurosurgical procedures) are considered, along with results from studies of in vivo and in vitro animal models of temporal epilepsy. Systematic analysis of impairments to inhibitory processes in temporal epilepsy show that these result from the selective death of particular interneuron populations and from functional impairments to the operation of important interneurons. Understanding of the concrete roles of different classes of interneurons in epilepsy is required for the development of new and effective treatment methods for this disease.



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Effects of Cognitive Loading on the Development of Muscle Fatigue

The aim of the present work was to study the effects of cognitive loading requiring activation of the attention systems on the development of muscle fatigue. The dynamics of measures of arm muscle fatigue were evaluated in two sessions, separated by 5 min, consisting of 250 maximum-strength dynamometer compressions in response to acoustic target signals in three tasks with different levels of cognitive loading. The first experiment used only the target signals; in experiment two, the subjects had to discriminate the target signal from an equal number (250) of nontarget signals, which required voluntary attention. In experiment three, the proportions of target stimuli were 17 and 83%, respectively, i.e., the target stimulus was random (deviant), activating not only voluntary attention, but also involuntary attention. Measurements of grip strength, maximum voluntary contraction strength, and subjective assessments of fatigue before and after the motor tasks showed that experiments involving voluntary and involuntary attention to sound stimuli produced a smaller rate of development of muscle fatigue. Activation of involuntary attention, accompanied by the appearance of mismatch negativity on the EEG, enhanced the effect of voluntary attention.



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Acquisition of a Conditioned Fear Reaction to a Light Stimulus in Mice: Comparison with Learning in Response to a Sound Stimulus

Currently the model of associative memory in mammals most frequently used in neurobiological studies consists of acquisition of a conditioned reflex freezing reaction. As most studies address the mechanisms of learning in response to a sound stimulus, the question of the extent to which the patterns of forming associative memory are universal and apply to other conditioned stimuli remains open. The aim of the present work was to compare the dynamics of the formation and reproduction of a memory in mice on acquisition of a conditioned freezing reaction to light and sound conditioned stimuli. Training using a light stimulus was found to occur in this model significantly more slowly than using a sound signal. In addition, the dynamics of memory reproduction differed in animals trained using sound and light stimuli, being slower using light stimuli, which may reflect different consolidation or extraction processes for these types of memory. The results of this study are critically important for understanding the common and specific conditions for the formation of associative memory in this model.



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Long-Term Consequences of Perinatal Hypoxia and Their Possible Pharmacological Correction: Responses of Neocortical Nerve Cells and Synapses

The morphological characteristics of neurons and synaptic contacts in the neocortex following acute perinatal hypoxia and subsequent use of Saliphene were studied in later ontogeny (days 80–90) in 28 Wistar rats. Controls consisted of intact animals of the same age. Light and electron microscopy studies were performed, along with immunocytochemical detection of synaptophysin and morphometric studies. These investigations showed that hypoxia in the perinatal period leads to structural rearrangements in neocortical neurons in adult animals. Degeneration of some large pyramidal neurons in layer V was seen, with decreases in the density of synaptic contacts (almost twofold) in the deep layers of the neocortex. These impairments were probably due to modifications to the developmental program for structures and interneuronal contacts. The data obtained here provide evidence that the Russian formulation "Saliphene" has protective actions on neurons and their differentiation and synaptogenesis after hypoxia. This suggests that this formulation is clinically effective and provides grounds for continuing studies in this direction.



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Association of the GRIN2B Gene Polymorphism with Verbal Fluency and Impairments to Abstract Thought in Schizophrenia

Objective. This study was conducted to seek associations between the GRIN2B gene and signs of impairments to thought and speech in schizophrenia, which may be based on access to the mental lexicon. Materials and methods. A group 552 patients with schizophrenia spectrum disorders were studied to establish associations between the rs7301328 polymorphism of the GRIN2B gene and semantic verbal fluency and five symptoms of impairments to thought and speech on the Positive and Negative Syndrome Scale (PANSS). Results and conclusions. Associations between the GRIN2B gene and verbal fluency (p = 0.013) and impairment to abstract thought (p = 0.012) were found. Verbal fluency was not found to have a mediatory role in the association between the gene and the impairment to thought. These results suggest that the GRIN2B gene has a modifying action on language processes extracting information from the mental lexicon on the basis of semantic features and, furthermore, that it makes a contribution to the variability of clinically marked impairments to abstract thought in patients with schizophrenia. The heterozygous genotype may be protective in relation to the development of thought and speech pathology.



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Permeability of the Dura Mater of the Spinal Cord in Dogs for Low Molecular Weight Substances in Serum

The permeability of the dura mater (DM) of the dog spinal cord for low molecular weight serum components – urea, creatinine, glucose, lactate, cholesterol, calcium, and inorganic phosphate – was studied in in vitro conditions. DM permeability for a high molecular weight serum component – albumin – was assessed as a reference compound. Most of the study components had permeabilities of 8–15%. The greatest DM permeability was for lactate (33.6%) and the lowest was for cholesterol (1.3%). Values for urea and creatinine were 8.0 and 7.5%, respectively; there was a nonlinear relationship between permeability and the initial substrate concentration in the serum. The DM permeability threshold for urea was 4.83 mM and that for creatinine was 97 μM. The functional characteristics of DM permeability may be determined by its structural features – dense packing of fibrillar connective tissues structures, high content of sulfated and the absence of nonsulfated glycosaminoglycans.



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Individual Features of Viewing Emotionally Significant Images

Experimental data on the individual features of eye movements on viewing affective images from the IAPS database are presented. The results provide evidence that the viewing trajectory in each subject (n = 20) persisted on presentation of images with different emotional coloration. The whole cohort of subjects showed a significant correlation between the numbers of tests in which areas of interest were detected, in three combinations: between negative and positive images, between negative and neutral, and between positive and neutral (r = 0.84, 0.78, and 0.77, respectively). Analogous correlations were seen for the duration of gaze fixations (r = 0.90, 0.82, and 0.90). The number of fixation points in areas of interest, the size of the areas examined, and the duration of fixations were found to differ significantly between two groups of subjects (with dominance of focal or scanning gaze trajectories). The potential for using emotionally significant images for assessing the dominant type of visual attention in terms of eye movement parameters in individual humans is discussed.



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Changes in the Ethogram in Rats Due to Contagion Behavior

Experiments were performed using a model of contagion behavior based on drinking behavior in rats. Observer rats without the drinking motivation, in the presence of a familiar conspecific with drinking motivation who demonstrated drinking behavior (demonstrator rats), displayed behavioral signs of the drinking motivation, i.e., signs of contagion behavior. Analysis of transition probability matrixes to investigate changes in the ethogram in observer rats demonstrated contagion behavior. Decreases in the frequency of aggressive and defensive behavioral patterns were seen in these animals, along with simultaneous increases in the frequency of exploratory activity, drinking, and exploratory approaches to bottles as compared with the ethograms of observer rats not displaying signs of contagion behavior on testing in the presence of a familiar conspecific demonstrator without the drinking motivation.



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The Role of Treatment Motivation Subsystems in the Overall Structure of Compliance in Patients Undergoing Psychopharmacotherapy

Objective. To identify interactions in the structure of treatment motivation and compliance in patients in a psychiatric clinic. Materials and methods. A questionnaire and compliance scales were used to assess treatment motivation in 104 patients in the Department of Integrative Pharmaco- and Psychotherapy. These included 67 patients with schizophrenia and schizoaffective spectrum disorders, 15 with affective disorders, 13 with personality disorders and neurotic disorders, and nine with organic lesions. Results and conclusions. The key role in forming the overall level of treatment compliance is played by the motivation mechanism based on subjective experience of suffering from the disorder. Occurrence of amotivation syndrome has disastrous effects on the formation of compliance. Passive agreement by the patient to accept treatment leads to a degradation in the treatment alliance, which is worsened by cognitive deficit in patients and reduced insight into the condition. Predominance of external motivation to receive treatment, determined by the pressure of the patient's immediate environment, also had adverse impact on the compliance subsystem linked with the surroundings. Pressure from relatives was often not transformed into adequate social support. Extremely low levels of internal motivation based on an understanding of the nature of the disorder, led to decreases in compliance associated with attitudes to treatment with medication.



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The Content of c-Fos-Positive Neurons in the Cerebral Cortex and Striatum and Behavioral Characteristics in Rats on Cutaneous Application of Antiseptic Dorogov’s Stimulator Paste

Experiments were performed on three groups of male Sprague–Dawley rats, each of six animals. Group 1 consisted of intact animals; group 2 of animals given zinc paste, and group 3 of animals given fraction 3 of antiseptic Dorogov's stimulator (ASD-3) by application to the skin on the back. Detection of c-Fos-positive neurons in different parts of the brain and studies of behavioral responses demonstrated activation of neurons in the cingulate, motor, and piriform areas of the cerebral cortex and the striatum, with increases in motor and ultrasound activity; there was a correlation between behavioral reactions and activation of neurons in these brain areas. These results provide evidence of the concomitant regulation of behavior by multiple brain structures and that ASD-3 has neurotropic properties.



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“Unpredictable Stress”: Ambiguity of Stress Reactivity in Studies of Long-Term Plasticity

Data on the influences of stress on the function of long-term synaptic plasticity are analyzed. Using longterm potentiation (LTP) as an example, stress has been shown to have both stimulatory and inhibitory influences on the effectiveness of the induction of long-term modifications, the effect depending on the nature, duration, and intensity of the stress, the observation time point, the brain structure being studied, and, thus, the involvement in the stress response of the different mechanisms underlying LTP. Stress-induced increases in glucocorticoid levels did not obligately correlate with changes in long-term plasticity, while application of corticosterone in vivo and in vitro could lead to both activation and inhibition of LTP. Existing data provide evidence that changes in LTP are determined by the ratio of mineralocorticoid and glucocorticoid receptors, activation of the latter not so much impairing the mechanisms of generation as increasing the threshold of induction of LTP, regulating the metaplasticity of synapses. The unpredictability of the effects of stress is related in particular to the involvement of other transmitter systems regulating metaplasticity whose actions depend on the animal's individual experience in the stress reaction. The range of individual differences stimulates the ongoing search for significant factors determining the stress reactivity of longterm plasticity underlying stress resistance or susceptibility to its pathological consequences. Differences in the processing of signals arriving at neurons and their molecular mediation may constitute such a factor.



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Cognitive Impairments in Stroke: Potential for Medication-Based Correction

Objective. To assess the efficacy and safety of Cellex for the correction of cognitive disorders in the acute period of ischemic stroke (IS). Materials and methods. The study included 246 patients in the acute period of IS. Patients were divided by random selection into two groups given Cellex or placebo for 10 days on the background of standard basal treatment. Patients were assessed dynamically in terms of neuropsychological status. Results and conclusions. This study showed that in patients with IS, mild and moderate cognitive impairments underwent faster and more marked regression when Cellex was prescribed (p < 0.05).



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Increasing the Efficacy of the Psychopharmacotherapy of Late Depression: Optimization of Treatment Duration

Objective. This study was performed to analyze the potential for using different methods to increase the efficacy of the psychopharmacotherapy of late depression, particularly by increasing the duration of treatment. Materials and methods. The study included 378 patients aged 50–82 (mean 60.6 ± 8.4) years. Treatment duration effects were studied by dividing patients into groups with short (4–8 weeks), intermediate (12 weeks), and long (20–24 weeks) durations of psychopharmacotherapy. Results and conclusions. Treatment results for durations of less than 8 weeks were significantly worse than those obtained with treatment duration greater than 12 weeks (these groups were not comparable because the initial cohorts were not comparable). By week 24, treatment responses were obtained in 63.9% of patients who had not responded to treatment by week 12, and 43.4% achieved remission. Partial responses and stable positive improvements by 12 weeks (about half the patients achieved remission) were predictors of responses with treatment durations of up to 24 weeks. These data were used to develop algorithms for selection of therapeutic tactics in patients with late depression depending on the results obtained at the first 12 weeks of psychopharmacotherapy.



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Systematics and Characteristics of the Development of Mental Disorders in Patients with HIV Infection

Objective. To study and systematize the features of the development of mental disorders seen in HIV infection. Materials and methods. A total of 250 HIV-infected patients and 50 consumers of injected narcotics aged 18–50 years were studied. Most HIV-infected patients were aged 21–40 years. The study used a general clinical method to investigate patients for psychopathology in addition to lab tests and experimental psychological investigations. Results and conclusions. Mental disorders seen in HIV-infected patients formed three groups of impairments: psychogenic-reactive, exogenous-organic, and personality disorders. The dynamics of these disorders were found to result from the complex actions of somatogenic, nosogenic, and premorbid personality factors.



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Event-Related Potentials to Faces Presented in an Emotional Context

The ability to recognize faces is a key skill forming our social behavior. Much attention has been focused on studies of the perception of emotional faces and expressions, though the question of the effects of context on the face recognition process has received little study. Subjects in the studies reported here watched a video clip, after which EEG recordings were made as they performed a task with photographs of the neutral faces of the characters in the film and photographs of the neutral faces of fillers (characters not appearing in the film). Studies were performed using event-related potentials (ERP). Differences were found in the amplitude of the P200 component in responses to presentation of the faces of culprits and victims, which may be associated with the different subjective significance of these stimuli for the person watching the video clip. Correlations were also found between the subjects' personality characteristics (anxiety, aggressivity, hostility) and increases in the amplitude of the P200 component in response to the faces of victims as compared with fillers. Further studies of the effects of emotional context on the perception of faces are required.



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Long-Term Effects of Stressors during the Neonatal Period of Development on the Nociceptive System and Psychoemotional Behavior

The long-term effects of peripheral inflammatory pain, transient maternal separation stress, and the combination of these factors on days 1 and 2 of life or on days 7 and 8 of life were studied in relation to measures of baseline pain (in the absence of an inflammatory process), prolonged responses to reinitiation of inflammation in the formalin test, levels of anxiety, extents of depressive behavior, and spatial learning ability when the animals reached adult age (90 days). In adult rats, study parameters showed changes depending on the type of early treatment and the age at which it was applied: inflammatory pain induced hypoalgesia in the hotplate test and degraded spatial learning ability in the Morris maze; maternal separation stress on days 1–2 but not days 7–8 increased pain responses in the formalin test. Regardless of the age at which the rat pups were subjected to treatments, repeated induction of inflammatory foci induced increased pain responses when animals reached adulthood. In the forced swimming test, immobility was increased in rats subjected to any of the treatments. The effects of combined pain and stress did not increase the influences of each applied alone. These new data contribute to the further development of our understanding of the longterm influences of harmful pain and stressors and their interactions in the neonatal period of development on the functional activity of the tonic nociception system and psychoemotional behavior.



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The impact of menstrual phase on brachial artery flow-mediated dilation during handgrip exercise in healthy premenopausal women

Abstract

Flow-mediated dilation (FMD) in response to a sustained shear stress stimulus (e.g. via handgrip exercise; HGEX) is emerging as a useful tool for assessing endothelial function; however, the impact of menstrual phase on HGEX-FMD is unknown. The purpose of this study was to determine whether HGEX-FMD fluctuates with cyclical changes in estrogen levels over two discrete phases (low and high estrogen) of the menstrual cycle. Brachial artery (BA) diameter and blood velocity were assessed with 2D and Doppler ultrasound, respectively. Shear stress was estimated using shear rate (SR = BA blood velocity/BA diameter). Participants (12 healthy, regularly cycling women 21 ± 2 yrs) completed two experimental visits: (1) low estrogen (early follicular, EF) and (2) high estrogen (late follicular, LF). Reactive hyperemia stimulated FMD (RH-FMD) and HGEX-FMD (6-minutes of handgrip exercise) were assessed each visit. Results are mean ± SD. Estrogen increased from the EF to LF phase (EF: 33 ± 9 pg mL−1; LF: 161 ± 113 pg mL−1, P = 0.003). However, neither the SR stimuli (HGEX P = 0.501; RH P = 0.173), nor the FMD responses differed between phases (EF vs. LF: HGEX-FMD: 4.8 ± 2.8% vs. 4.6 ± 2.2%, P = 0.601; RH-FMD: 7.9 ± 4.3% vs. 6.4 ± 3.1%, P = 0.071). These results extend existing RH-FMD findings indicating that not all women experience fluctuations in FMD with the menstrual cycle. Further research is needed to investigate the mechanisms that underlie variability in the impact of menstrual phase on FMD.

This article is protected by copyright. All rights reserved



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Transcription: Promoters dictate termination mode

Transcription: Promoters dictate termination mode

Nature Reviews Genetics, Published online: 30 October 2017; doi:10.1038/nrg.2017.93



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Human gene essentiality

Human gene essentiality

Nature Reviews Genetics, Published online: 30 October 2017; doi:10.1038/nrg.2017.75

Characterizing the essentiality of human genes provides insights into gene function and genome evolution and facilitates the clinical interpretation of genetic variants. This article analyses essentiality metrics based on the statistical intolerance to loss-of-function mutations in human population sequencing studies and discusses commonalities and distinctions relative to data sets from knockout mice and functional genomics screens in human cell culture. Implications for disease genetics and extrapolation to non-coding regions are also discussed.



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Human gene essentiality



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Transcription: Promoters dictate termination mode



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