Microbial Drug Resistance , Vol. 0, No. 0.
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Παρασκευή 1 Δεκεμβρίου 2017
PBP2a in β-Lactam–Resistant Laboratory Mutants and Clinical Isolates: Disruption Versus Reduced Penicillin Affinity
ASPP2 Inhibits the Profibrotic Effects of Transforming Growth Factor-β1 in Hepatic Stellate Cells by Reducing Autophagy
Abstract
Background
Apoptosis-stimulating protein of p53-2 (ASPP2) is a damage-inducible P53-binding protein that enhances damage-induced apoptosis. Fibrosis is a wound-healing response, and hepatic stellate cells (HSCs) are key players in liver fibrogenesis. However, little is known about the relationship between ASPP2 and hepatic fibrosis.
Aims
We investigated the effects of ASPP2 overexpression in HSCs and the role of ASPP2 in mouse liver fibrogenesis.
Methods
Human HSCs (LX-2 cells) were pre-incubated with GFP adenovirus (Ad) or ASPP2 adenovirus (AdASPP2) for 24 h and then treated with or without TGF-β1. ASPP2+/− and ASPP2+/+ Balb/c mice were used to examine the effects of ASPP2 on liver fibrosis in vivo. ASPP2+/+ Balb/c mice were generated by injecting AdASPP2 into the tail vein of ASPP2 WT Balb/c mice; all mice received intraperitoneal injections of carbon tetrachloride.
Results
In this study, ASPP2 was found to markedly inhibit TGF-β1-induced fibrogenic activation of LX-2 cells. Further experiments using an autophagic flux assay confirmed that ASPP2 reduced the fibrogenic activation of LX-2 cells by inhibiting autophagy. Moreover, we found that ASPP2 overexpression attenuated the anti-apoptotic effects of TGF-β1 in LX-2 cells. The extent of liver fibrosis was markedly reduced in ASPP2+/+ mouse liver tissue compared with control mice; however, in ASPP2+/− mice, hepatic collagen deposition was significantly increased.
Conclusion
These results suggest that TGF-β1-induced autophagy is required for the fibrogenic response in LX-2 cells and that ASPP2 may both inhibit TGF-β1-induced autophagy and decrease liver fibrosis.
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Powerful Inference with the D-Statistic on Low-Coverage Whole-Genome Data
The detection of ancient gene flow between human populations is an important issue in population genetics. A common tool for detecting ancient admixture events is the D-statistic. The D-statistic is based on the hypothesis of a genetic relationship that involves four populations, whose correctness is assessed by evaluating specific coincidences of alleles between the groups. When working with high throughput sequencing data calling genotypes accurately is not always possible, therefore the D-statistic currently samples a single base from the reads of one individual per population. This implies ignoring much of the information in the data, an issue especially striking in the case of ancient genomes. We provide a significant improvement to overcome the problems of the D-statistic by considering all reads from multiple individuals in each population. We also apply type-specific error correction to combat the problems of sequencing errors and show a way to correct for introgression from an external population that is not part of the supposed genetic relationship, and how this leads to an estimate of the admixture rate.\\ We prove that the D-statistic is approximated by a standard normal. Furthermore we show that our method outperforms the traditional D-statistic in detecting admixtures. The power gain is most pronounced for low/medium sequencing depth (1-10X) and performances are as good as with perfectly called genotypes at a sequencing depth of 2X. We show the reliability of error correction on scenarios with simulated errors and ancient data, and correct for introgression in known scenarios to estimate the admixture rates.
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Pas de deux: An Intricate Dance of Anther Smut and Its Host
The successful interaction between pathogen/parasite and host requires a delicate balance between fitness of the former and survival of the latter. To optimize fitness a parasite/pathogen must effectively create an environment conducive to reproductive success, while simultaneously avoiding or minimizing detrimental host defense response. The association between Microbotryum lychnidis-dioicae and its host, Silene latifolia, serves as an excellent model to examine such interactions. This fungus is part of a species complex that infects species of the Caryophyllaceae, replacing pollen with the fungal spores. In the current study, transcriptome analyses of the fungus and its host were conducted during discrete stages of bud development so as to identify changes in fungal gene expression that lead to spore development and to identify changes associated with infection in the host plant. In contrast to early biotrophic phase stages of infection for the fungus, the latter stages involve tissue necrosis and in the case of infected female flowers, further changes in the developmental program in which the ovary aborts and a pseudoanther is produced. Transcriptome analysis via Illumina RNA sequencing revealed enrichment of fungal genes encoding small secreted proteins, with hallmarks of effectors and genes found to be relatively unique to the Microbotryum species complex. Host gene expression analyses also identified interesting sets of genes up-regulated, including those involving stress response, host defense response and several agamous-like MADS-box genes (AGL61 and AGL80), predicted to interact and be involved in male gametophyte development.
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Utah responders leave naloxone kits with families of overdose patients
The Unified Fire Authority will also teach everyone how to use the kit in an effort to teach the public how to reverse overdoses
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Elevated serum antiphospholipid antibodies in adults with celiac disease
An increased incidence of thrombosis is suggested in celiac disease. We explored serum levels of antiphospholipid antibodies in untreated and treated adult celiac disease patients.
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Efficacy and safety of SIC-8000 (Eleview®) for submucosal injection for Endoscopic Mucosal Resection and Endoscopic Submucosal Dissection in an in vivo porcine model
Submucosal injection is generally required for both endoscopic-mucosal resection (EMR) and submucosal dissection (ESD). SIC-8000 (Eleview™) is a new FDA 510 (k) cleared and CE marked liquid composition for submucosal injection, containing a biocompatible polymer as a cushioning agent.
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Retraction of: Tumor Protein D52-Like 2 Contributes to Proliferation of Breast Cancer Cells; 10.1089/cbr.2014.1723
Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.
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Retraction of: Tumor Protein D52-Like 2 Accelerates Gastric Cancer Cell Proliferation; 10.1089/cbr.2014.1766
Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.
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Groundwater chemistry and radon-222 distribution in Jerba Island, Tunisia
Source:Journal of Environmental Radioactivity, Volume 182
Author(s): Faten Telahigue, Belgacem Agoubi, Fayza Souid, Adel Kharroubi
The present study integrates hydrogeological, hydrochemical and radiogenic data of groundwater samples taken from the Plio-Quaternary unconfined aquifer of Jerba Island, southeastern Tunisia, in order to interpret the spatial variations of the groundwater quality and identify the main hydrogeochemical factors responsible for the high ion concentrations and radon-222 content in the groundwater analysed. Thirty-nine groundwater samples were collected from open wells widespread on the island. Physical parameters (EC, pH, TDS and T °) were measured, major ions (Ca2+, Mg2+, Na+, K+, Cl−, SO42−, NO3− and HCO3−) were analysed and 222Rn concentrations were determined using a RAD7-H2O. Hydrogeochemical characterisation revealed that groundwater from the Jerba aquifer has several origins. Basically, two water types exist in the island. The first one, characterized by a low to moderate salinity with a chemical facies CaMgClSO4, characterizes the central part of Jerba (a recharge area) due to carbonate and gypsum dissolution. The second water type with high salinities, dominated by NaKCl type, was observed in coastal areas and some parts having low topographic and piezometric levels. These areas seem to be affected by the seawater intrusion process. The 222Rn concentrations in groundwater samples in Jerba varied from 0 Bq.L−1 to 2860 Bq.L−1 with an average of 867 Bq.L−1.The highest values were registered in the western coastal wells and near the fault of Guellala. However, the central and eastern wells showed low radon levels. Compared to 222Rn activity in some countries with the same lithology, radon concentrations in the Jerba unconfined aquifer have higher values influenced by the structure of the aquifer and by seawater inflow enriched with 222Rn resulting from the decay of uranium derived from phosphogypsum deposits in the gulf of Gabes. The EC and 222Rn spatial variability in the study area were mapped using ARC Map 10.3 software. Hydrochemical results in addition to geological data and radon activities confirm the existence of vertical communication between the Miocene aquifer and the unconfined Plio-Quaternary aquifer through fault system and a lateral communication with the sea via seawater intrusion.
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Fate of 137Cs, 90Sr and 239+240Pu in soil profiles at a water recharge site in Basel, Switzerland
Source:Journal of Environmental Radioactivity, Volume 182
Author(s): Johannes Abraham, Katrin Meusburger, Judith Kobler Waldis, Michael E. Ketterer, Markus Zehringer
An important process in the production of drinking water is the recharge of the withdrawn ground water with river water at protected recharge fields. While it is well known that undisturbed soils are efficiently filtering and adsorbing radionuclides, the goal of this study was to investigate their behaviour in an artificial recharge site that may receive rapid and additional input of radionuclides by river water (particularly when draining a catchment including nuclear power plants (NPP)). Soil profiles of recharge sites were drilled and analysed for radionuclides, specifically radiocesium (137Cs), radiostrontium (90Sr) and plutonium (239+240Pu). The distribution of the analysed radionuclides were compared with an uncultivated reference soil outside the recharge site. The main activity of 137Cs was located in the top soil (4.5–7.5 cm) and reached down to a depth of 84 cm and 48 cm for the recharge and the reference site, respectively. The found activities of 239+240Pu originate from the global fallout after 1950. 239+240Pu appeared to be strongly adsorbed onto soil particles. The shape of the depth profile was similar to 137Cs, but also similar between the recharge and the reference site. In contrast, 90Sr showed a uniform distribution over the entire depth of the recharge and reference profiles indicating that 90Sr already entered the gravel zone and the ground water. Elevated inventories of the radionuclides were observed for the recharge site. The soil of the recharge field exhibited a threefold higher activity of 137Cs compared to the reference soil. Also for 239+240Pu higher inventories where observed for the recharge sites (40%). 90Sr behaved differently, showing similar inventories between reference and recharge site. We estimate that 75–89% of the total inventory of 137Cs in the soil at the recharge site (7.000 Bq/m2) originated from the fallout of the Chernobyl accident and from emissions of Swiss NPPs. This estimate is based on the actual activity ratio of 137Cs/239+240Pu of 22 for global fallout. The investigations identified radiostrontium as potential threat to the ground water.
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Case Series: Slowing Alpha Rhythm in Late-Stage ALS Patients
To this date, the cognitive abilities of patients in the final stage of Amyotrophic Lateral Sclerosis (ALS) are largely unknown. Residing in a completely locked-in state (CLIS) makes interaction by regular means impossible. Many attempts were made to establish communication through Brain-computer interfaces (BCIs), but success has been very limited (Marchetti and Priftis, 2015). It has been theorized that the loss of motor-functions leads to an extinction of both goal directed thinking and physiological control, leaving only reflex-like responses to fundamental, personal questions (Gallegos-Ayala et al., 2014; Chaudhary et al., 2017).
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GABA transporters regulate tonic and synaptic GABAA receptor-mediated currents in the suprachiasmatic nucleus neurons
GABA is a principal neurotransmitter in the hypothalamic suprachiasmatic nucleus (SCN) that contributes to intercellular communication between individual circadian oscillators within the SCN network and the stability and precision of the circadian rhythms. GABA transporters (GAT) regulate the extracellular GABA concentration and modulate GABAA receptor (GABAAR)-mediated currents. GABA transport inhibitors were applied to study how GABAAR-mediated currents depend on the expression and function of GAT. Nipecotic acid inhibits GABA transport and induced an inward tonic current in concentration-dependent manner during whole cell patch-clamp recordings from SCN neurons. Application of either the selective GABA transporter 1 (GAT1) inhibitors NNC-711 or SKF-89976A, or the GABA transporter 3 (GAT3) inhibitor SNAP-5114, produced only small changes of the baseline current. Coapplication of GAT1 and GAT3 inhibitors induced a significant GABAAR-mediated tonic current that was blocked by gabazine. GAT inhibitors decreased the amplitude and decay time constant and increased the rise time of spontaneous GABAAR-mediated postsynaptic currents. However, inhibition of GAT did not alter the expression of either GAT1 or GAT3 in the hypothalamus. Thus GAT1 and GAT3 functionally complement each other to regulate the extracellular GABA concentration and GABAAR-mediated synaptic and tonic currents in the SCN. Coapplication of SKF-89976A and SNAP-5114 (50 µM each) significantly reduced the circadian period of Per1 expression in the SCN by 1.4 h. Our studies demonstrate that GAT are important regulators of GABAAR-mediated currents and the circadian clock in the SCN.
NEW & NOTEWORTHY In the suprachiasmatic nucleus (SCN), the GABA transporters GAT1 and GAT3 are expressed in astrocytes. Inhibition of these GABA transporters increased a tonic GABA current and reduced the circadian period of Per1 expression in SCN neurons. GAT1 and GAT3 showed functional cooperativity: inhibition of one GAT increased the activity but not the expression of the other. Our data demonstrate that GABA transporters are important regulators of GABAA receptor-mediated currents and the circadian clock.
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The divisive normalization model of V1 neurons: a comprehensive comparison of physiological data and model predictions
The physiological responses of simple and complex cells in the primary visual cortex (V1) have been studied extensively and modeled at different levels. At the functional level, the divisive normalization model (DNM; Heeger DJ. Vis Neurosci 9: 181–197, 1992) has accounted for a wide range of single-cell recordings in terms of a combination of linear filtering, nonlinear rectification, and divisive normalization. We propose standardizing the formulation of the DNM and implementing it in software that takes static grayscale images as inputs and produces firing rate responses as outputs. We also review a comprehensive suite of 30 empirical phenomena and report a series of simulation experiments that qualitatively replicate dozens of key experiments with a standard parameter set consistent with physiological measurements. This systematic approach identifies novel falsifiable predictions of the DNM. We show how the model simultaneously satisfies the conflicting desiderata of flexibility and falsifiability. Our key idea is that, while adjustable parameters are needed to accommodate the diversity across neurons, they must be fixed for a given individual neuron. This requirement introduces falsifiable constraints when this single neuron is probed with multiple stimuli. We also present mathematical analyses and simulation experiments that explicate some of these constraints.
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Evidence for the representation of movement kinematics in the discharge of F5 mirror neurons during the observation of transitive and intransitive actions
Mirror neurons (MirNs) are sensorimotor neurons that fire both when an animal performs a goal-directed action and when the same animal observes another agent performing the same or a similar transitive action. It has been claimed that the observation of intransitive actions does not activate MirNs in a monkey's brain. Prompted by recent evidence indicating that the discharge of MirNs is modulated also by non-object-directed actions, we investigated thoroughly the efficacy of intransitive actions to trigger MirNs' discharge. Using representational similarity analysis, we also studied whether the elements constituting the visual scene presented to the monkey during the observation of actions (both transitive and intransitive) are represented in the discharge of MirNs. For this purpose, the moving hand was modeled by its kinematics and the object by features of its geometry. We found that MirNs respond to the observation of both transitive and intransitive actions and that the discharge differences evoked by the observation of object- and non-object-directed actions are correlated more with the kinematic differences of these actions than with the differences of the objects' features. These findings support the view that observed action kinematics contribute to action mirroring.
NEW & NOTEWORTHY Mirror neurons in the monkey brain are thought to respond exclusively to the observation of object-directed actions. Here, we show that mirror neurons also respond to the observation of intransitive actions and that the kinematics of the observed movements are represented in their discharge. This finding supports the view that mirror neurons provide also a kinematics-based representation of actions.
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Feature-coding transitions to conjunction-coding with progression through human visual cortex
Identifying an object and distinguishing it from similar items depends upon the ability to perceive its component parts as conjoined into a cohesive whole, but the brain mechanisms underlying this ability remain elusive. The ventral visual processing pathway in primates is organized hierarchically: Neuronal responses in early stages are sensitive to the manipulation of simple visual features, whereas neuronal responses in subsequent stages are tuned to increasingly complex stimulus attributes. It is widely assumed that feature-coding dominates in early visual cortex whereas later visual regions employ conjunction-coding in which object representations are different from the sum of their simple feature parts. However, no study in humans has demonstrated that putative object-level codes in higher visual cortex cannot be accounted for by feature-coding and that putative feature codes in regions prior to ventral temporal cortex are not equally well characterized as object-level codes. Thus the existence of a transition from feature- to conjunction-coding in human visual cortex remains unconfirmed, and if a transition does occur its location remains unknown. By employing multivariate analysis of functional imaging data, we measure both feature-coding and conjunction-coding directly, using the same set of visual stimuli, and pit them against each other to reveal the relative dominance of one vs. the other throughout cortex. Our results reveal a transition from feature-coding in early visual cortex to conjunction-coding in both inferior temporal and posterior parietal cortices. This novel method enables the use of experimentally controlled stimulus features to investigate population-level feature and conjunction codes throughout human cortex.
NEW & NOTEWORTHY We use a novel analysis of neuroimaging data to assess representations throughout visual cortex, revealing a transition from feature-coding to conjunction-coding along both ventral and dorsal pathways. Occipital cortex contains more information about spatial frequency and contour than about conjunctions of those features, whereas inferotemporal and parietal cortices contain conjunction coding sites in which there is more information about the whole stimulus than its component parts.
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Comparison of three models of saccade disconjugacy in strabismus
In pattern strabismus the horizontal and vertical misalignments vary with eye position along the orthogonal axis. The disorder is typically described in terms of overaction or underaction of oblique muscles. Recent behavioral studies in humans and monkeys, however, have reported that such actions are insufficient to fully explain the patterns of directional and amplitude disconjugacy of saccades. There is mounting evidence that the oculomotor abnormalities associated with strabismus are at least partially attributable to neurophysiological abnormalities. A number of control systems models have been developed to simulate the kinematic characteristics of saccades in normal primates. In the present study we sought to determine whether these models could simulate the abnormalities of saccades in strabismus by making two assumptions: 1) in strabismus the burst generator gains differ for the two eyes and 2) abnormal crosstalk exists between the horizontal and vertical saccadic circuits in the brain stem. We tested three models, distinguished by the location of the horizontal-vertical crosstalk. All three models were able to simulate amplitude and directional saccade disconjugacy, postsaccadic drift, and a pattern strabismus for static fixation, but they made different predictions about the dynamics of saccades. By assuming that crosstalk occurs at multiple nodes, the Distributed Crosstalk Model correctly predicted the dynamics of saccades. These new models make additional predictions that can be tested with future neurophysiological experiments.
NEW & NOTEWORTHY Over the past several decades, numerous control systems models have been devised to simulate the known kinematic features of saccades in normal primates. These models have proven valuable to neurophysiology, as a means of generating testable predictions. The present manuscript, as far as we are aware, is the first to present control systems models to simulate the known abnormalities of saccades in strabismus.
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Contribution of sensory feedback to plantar flexor muscle activation during push-off in adults with cerebral palsy
Exaggerated sensory activity has been assumed to contribute to functional impairment following lesion of the central motor pathway. However, recent studies have suggested that sensory contribution to muscle activity during gait is reduced in stroke patients and children with cerebral palsy (CP). We investigated whether this also occurs in CP adults and whether daily treadmill training is accompanied by alterations in sensory contribution to muscle activity. Seventeen adults with CP and 12 uninjured individuals participated. The participants walked on a treadmill while a robotized ankle-foot orthosis applied unload perturbations at the ankle, thereby removing sensory feedback naturally activated during push-off. Reduction of electromyographic (EMG) activity in the soleus muscle caused by unloads was compared and related to kinematics and ankle joint stiffness measurements. Similar measures were obtained after 6 wk of gait training. We found that sensory contribution to soleus EMG activation was reduced in CP adults compared with uninjured adults. The lowest contribution of sensory feedback was found in participants with lowest maximal gait speed. This was related to increased ankle plantar flexor stiffness. Six weeks of gait training did not alter the contribution of sensory feedback. We conclude that exaggerated sensory activity is unlikely to contribute to impaired gait in CP adults, because sensory contribution to muscle activity during gait was reduced compared with in uninjured individuals. Increased passive stiffness around the ankle joint is likely to diminish sensory feedback during gait so that a larger part of plantar flexor muscle activity must be generated by descending motor commands.
NEW & NOTEWORTHY Findings suggest that adults with cerebral palsy have less contribution of sensory feedback to ongoing soleus muscle activation during push-off than uninjured individuals. Increased passive stiffness around the ankle joint is likely to diminish sensory feedback during gait, and/or sensory feedback is less integrated with central motor commands in the activation of spinal motor neurons. Consequently, muscle activation must to a larger extent rely on descending drive, which is already decreased because of the cerebral lesion.
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Stability of hand force production. I. Hand level control variables and multifinger synergies
We combined the theory of neural control of movement with referent coordinates and the uncontrolled manifold hypothesis to explore synergies stabilizing the hand action in accurate four-finger pressing tasks. In particular, we tested a hypothesis on two classes of synergies, those among the four fingers and those within a pair of control variables, stabilizing hand action under visual feedback and disappearing without visual feedback. Subjects performed four-finger total force and moment production tasks under visual feedback; the feedback was later partially or completely removed. The "inverse piano" device was used to lift and lower the fingers smoothly at the beginning and at the end of each trial. These data were used to compute pairs of hypothetical control variables. Intertrial analysis of variance within the finger force space was used to quantify multifinger synergies stabilizing both force and moment. A data permutation method was used to quantify synergies among control variables. Under visual feedback, synergies in the spaces of finger forces and hypothetical control variables were found to stabilize total force. Without visual feedback, the subjects showed a force drift to lower magnitudes and a moment drift toward pronation. This was accompanied by disappearance of the four-finger synergies and strong attenuation of the control variable synergies. The indexes of the two types of synergies correlated with each other. The findings are interpreted within the scheme with multiple levels of abundant variables.
NEW & NOTEWORTHY We extended the idea of hierarchical control with referent spatial coordinates for the effectors and explored two types of synergies stabilizing multifinger force production tasks. We observed synergies among finger forces and synergies between hypothetical control variables that stabilized performance under visual feedback but failed to stabilize it after visual feedback had been removed. Indexes of two types of synergies correlated with each other. The data suggest the existence of multiple mechanisms stabilizing motor actions.
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Extracellular H+ fluxes from tiger salamander Müller (glial) cells measured using self-referencing H+-selective microelectrodes
Self-referencing H+-selective electrodes were used to measure extracellular H+ fluxes from Müller (glial) cells isolated from the tiger salamander retina. A novel chamber enabled stable recordings using H+-selective microelectrodes in a self-referencing format using bicarbonate-based buffer solutions. A small basal H+ flux was observed from the end foot region of quiescent cells bathed in 24 mM bicarbonate-based solutions, and increasing extracellular potassium induced a dose-dependent increase in H+ flux. Barium at 6 mM also increased H+ flux. Potassium-induced extracellular acidifications were abolished when bicarbonate was replaced by 1 mM HEPES. The carbonic anhydrase antagonist benzolamide potentiated the potassium-induced extracellular acidification, while 300 μM DIDS, 300 μM SITS, and 30 μM S0859 significantly reduced the response. Potassium-induced extracellular acidifications persisted in solutions lacking extracellular calcium, although potassium-induced changes in intracellular calcium monitored with Oregon Green were abolished. Exchange of external sodium with choline also eliminated the potassium-induced extracellular acidification. Removal of extracellular sodium by itself induced a transient alkalinization, and replacement of sodium induced a transient acidification, both of which were blocked by 300 μM DIDS. Recordings at the apical portion of the cell showed smaller potassium-induced extracellular H+ fluxes, and removal of the end foot region further decreased the H+ flux, suggesting that the end foot was the major source of acidifications. These studies demonstrate that self-referencing H+-selective electrodes can be used to monitor H+ fluxes from retinal Müller cells in bicarbonate-based solutions and confirm the presence of a sodium-coupled bicarbonate transporter, the activity of which is largely restricted to the end foot of the cell.
NEW & NOTEWORTHY The present study uses self-referencing H+-selective electrodes for the first time to measure H+ fluxes from Müller (glial) cells isolated from tiger salamander retina. These studies demonstrate bicarbonate transport as a potent regulator of extracellular levels of acidity around Müller cells and point toward a need for further studies aimed at addressing how such glial cell pH regulatory mechanisms may shape neuronal signaling.
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Contribution of spiking activity in the primary auditory cortex to detection in noise
A fundamental problem in hearing is detecting a "target" stimulus (e.g., a friend's voice) that is presented with a noisy background (e.g., the din of a crowded restaurant). Despite its importance to hearing, a relationship between spiking activity and behavioral performance during such a "detection-in-noise" task has yet to be fully elucidated. In this study, we recorded spiking activity in primary auditory cortex (A1) while rhesus monkeys detected a target stimulus that was presented with a noise background. Although some neurons were modulated, the response of the typical A1 neuron was not modulated by the stimulus- and task-related parameters of our task. In contrast, we found more robust representations of these parameters in population-level activity: small populations of neurons matched the monkeys' behavioral sensitivity. Overall, these findings are consistent with the hypothesis that the sensory evidence, which is needed to solve such detection-in-noise tasks, is represented in population-level A1 activity and may be available to be read out by downstream neurons that are involved in mediating this task.
NEW & NOTEWORTHY This study examines the contribution of A1 to detecting a sound that is presented with a noisy background. We found that population-level A1 activity, but not single neurons, could provide the evidence needed to make this perceptual decision.
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The effect of prior knowledge and intelligibility on the cortical entrainment response to speech
It has been suggested that cortical entrainment plays an important role in speech perception by helping to parse the acoustic stimulus into discrete linguistic units. However, the question of whether the entrainment response to speech depends on the intelligibility of the stimulus remains open. Studies addressing this question of intelligibility have, for the most part, significantly distorted the acoustic properties of the stimulus to degrade the intelligibility of the speech stimulus, making it difficult to compare across "intelligible" and "unintelligible" conditions. To avoid these acoustic confounds, we used priming to manipulate the intelligibility of vocoded speech. We used EEG to measure the entrainment response to vocoded target sentences that are preceded by natural speech (nonvocoded) prime sentences that are either valid (match the target) or invalid (do not match the target). For unintelligible speech, valid primes have the effect of restoring intelligibility. We compared the effect of priming on the entrainment response for both 3-channel (unintelligible) and 16-channel (intelligible) speech. We observed a main effect of priming, suggesting that the entrainment response depends on prior knowledge, but not a main effect of vocoding (16 channels vs. 3 channels). Furthermore, we found no difference in the effect of priming on the entrainment response to 3-channel and 16-channel vocoded speech, suggesting that for vocoded speech, entrainment response does not depend on intelligibility.
NEW & NOTEWORTHY Neural oscillations have been implicated in the parsing of speech into discrete, hierarchically organized units. Our data suggest that these oscillations track the acoustic envelope rather than more abstract linguistic properties of the speech stimulus. Our data also suggest that prior experience with the stimulus allows these oscillations to better track the stimulus envelope.
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The neural code for tactile roughness in the somatosensory nerves
Roughness is the most salient perceptual dimension of surface texture but has no well-defined physical basis. We seek to determine the neural determinants of tactile roughness in the somatosensory nerves. Specifically, we record the patterns of activation evoked in tactile nerve fibers of anesthetized Rhesus macaques to a large and diverse set of natural textures and assess what aspect of these patterns of activation can account for psychophysical judgments of roughness, obtained from human observers. We show that perceived roughness is determined by the variation in the population response, weighted by fiber type. That is, a surface will feel rough to the extent that the activity varies across nerve fibers and varies across time within nerve fibers. We show that this variation-based neural code can account not only for magnitude estimates of roughness but also for roughness discrimination performance.
NEW & NOTEWORTHY Our sense of touch endows us with an exquisite sensitivity to the microstructure of surfaces, the most salient aspect of which is roughness. We analyze the responses evoked in tactile fibers of monkeys by natural textures and compare them to judgments of roughness obtained for the same textures from human observers. We then describe how texture signals from three populations of nerve fibers are integrated to culminate in a percept of roughness.
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Acute and Chronic Kidney Injury in a Non-Human Primate Model of Partial-Body Irradiation with Bone Marrow Sparing
Radiation Research, Volume 188, Issue 6, Page 661-671, December 2017.
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The Impact of Hypoxia on Out-of-Field Cell Survival after Exposure to Modulated Radiation Fields
Radiation Research, Volume 188, Issue 6, Page 636-644, December 2017.
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Activation of mTORC1 Signaling is Required for Timely Hair Follicle Regeneration from Radiation Injury
Radiation Research, Volume 188, Issue 6, Page 681-689, December 2017.
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Lung Cancer Risk from Plutonium: A Pooled Analysis of the Mayak and Sellafield Worker Cohorts
Radiation Research, Volume 188, Issue 6, Page 645-660, December 2017.
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Organ Doses Associated with Partial-Body Irradiation with 2.5% Bone Marrow Sparing of the Non-Human Primate: A Retrospective Study
Radiation Research, Volume 188, Issue 6, Page 615-625, December 2017.
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Urinary miRNAs as Biomarkers for Noninvasive Evaluation of Radiation-Induced Renal Tubular Injury
Radiation Research, Volume 188, Issue 6, Page 626-635, December 2017.
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Long-Term Deficits in Behavior Performances Caused by Low- and High-Linear Energy Transfer Radiation
Radiation Research, Volume 188, Issue 6, Page 672-680, December 2017.
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Tumor Cell Invasion Induced by Radiation in Balb/C Mouse is Prevented by the Cox-2 Inhibitor NS-398
Radiation Research, Volume 188, Issue 6, Page 605-614, December 2017.
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Measurement of DNA-Dependent Protein Kinase Phosphorylation Using Flow Cytometry Provides a Reliable Estimate of DNA Repair Capacity
Radiation Research, Volume 188, Issue 6, Page 597-604, December 2017.
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Nanodosimetric Simulation of Direct Ion-Induced DNA Damage Using Different Chromatin Geometry Models
Radiation Research, Volume 188, Issue 6, Page 690-703, December 2017.
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Oesophageal or transgastric views for estimating mean pulmonary artery pressure with transoesophageal echocardiography?
BACKGROUND Recent data suggest that in cardiac surgical patients, the pulmonary artery acceleration time (PAT) is useful for estimating mean pulmonary artery pressure (MPAP) noninvasively with transoesophageal echocardiography (TOE). The pulmonary valve can be visualised from multiple echocardiographic windows, but it is unclear which, if any, view correlates best with MPAP. OBJECTIVE(S) To compare the PAT measured with TOE from oesophageal and transgastric views with MPAP obtained invasively with a pulmonary artery catheter. DESIGN A prospective observational study. SETTING St. Vincent's Hospital, Melbourne, a university tertiary referral centre in Australia. PATIENTS Sixty-three patients having cardiac surgery were included in our study. All patients had insertion of both a TOE probe and pulmonary artery catheter; this is the routine standard of care in our centre. INTERVENTION(S) Nil. MAIN OUTCOME MEASURES During a period of haemodynamic stability, the PAT was measured first from an oesophageal view and then immediately after from a transgastric view. The results were then compared with the invasively measured MPAP. RESULTS Simultaneous measurements of MPAP and PAT were taken in 63 patients. In two patients, these measurements were not possible in the transgastric position due to an inability to visualise the right ventricular outflow tract and pulmonary valve. A Bland–Altman analysis of the PAT measured from the upper oesophageal and transgastric views showed a mean difference of 1 ms and limits of agreement of −18 to 16 ms. The area under the receiver operating curves for predicting pulmonary hypertension with PAT were upper oesophageal view 0.99 [95% confidence interval (CI), 0.98 to 1.00] and transgastric view 0.99 (95% CI, 0.97 to 1.00). The agreement between the results from these two views in the diagnosis of pulmonary hypertension (defined as PAT 25 mmHg) with a sensitivity of 94.7% and specificity of 97.6%. The transgastric view predicted pulmonary hypertension with a sensitivity of 89.4% and specificity of 95.2%. CONCLUSION Oesophageal and transgastric measurements of PAT have close agreement and a similar high ability to discriminate between people with and without pulmonary hypertension. The transgastric measurement was unobtainable in a small percentage of patients and required more probe manipulation. We would recommend PAT measurement in the upper oesophageal view. Correspondence to Dr Brian Cowie, Staff Anaesthetist, Department of Anaesthesia, St. Vincent's Hospital, Melbourne, Melbourne, Victoria, Australia E-mail: brian.cowie@svha.org.au © 2017 European Society of Anaesthesiology
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Oslo University Hospital and Sopra Steria win the Microsoft 2017 Health Innovation Award
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Oslo University Hospital and Sopra Steria win the Microsoft 2017 Health Innovation Award
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Oslo University Hospital and Sopra Steria win the Microsoft 2017 Health Innovation Award
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The availability of water associated with glycogen during dehydration: a reservoir or raindrop?
Abstract
Purpose
This study evaluated whether glycogen-associated water is a protected entity not subject to normal osmotic homeostasis. An investigation into practical and theoretical aspects of the functionality of this water as a determinant of osmolality, dehydration, and glycogen concentration was undertaken.
Methods
In vitro experiments were conducted to determine the intrinsic osmolality of glycogen–potassium phosphate mixtures as would be found intra-cellularly at glycogen concentrations of 2% for muscle and 5 and 10% for liver. Protected water would not be available to ionic and osmotic considerations, whereas free water would obey normal osmotic constraints. In addition, the impact of 2 L of sweat loss in situations of muscle glycogen repletion and depletion was computed to establish whether water associated with glycogen is of practical benefit (e.g., to increase "available total body water").
Results
The osmolality of glycogen–potassium phosphate mixtures is predictable at 2% glycogen concentration (predicted 267, measured 265.0 ± 4.7 mOsmol kg−1) indicating that glycogen-associated water is completely available to all ions and is likely part of the greater osmotic system of the body. At higher glycogen concentrations (5 and 10%), there was a small amount of glycogen water (~ 10–20%) that could be considered protected. However, the majority of the glycogen-associated water behaved to normal osmotic considerations. The theoretical exercise of selective dehydration (2 L) indicated a marginal advantage to components of total body water such as plasma volume (1.57% or 55 mL) when starting exercise glycogen replete.
Conclusion
Glycogen-associated water does not appear to be a separate reservoir and is not able to uniquely replete water loss during dehydration.
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Pole lengths influence O 2 -cost during double poling in highly trained cross-country skiers
Abstract
Purpose
In elite cross-country skiing, double poling is used in different terrain. This study compared O2-cost and kinematics during double poling with four different pole lengths [self-selected (SS), SS − 5 cm, SS + 5 cm, SS + 10 cm] at Low versus Moderate incline.
Methods
Thirteen highly trained male cross-country skiers (mean ± SD 23 ± 3 years; 182 ± 4 cm; 77 ± 6 kg) completed eight submaximal trials with roller skis on a treadmill at two conditions: "Low incline" (1.7°; 4.5 m s−1) and "Moderate incline" (4.5°; 2.5 m s−1) with each of the four pole lengths. O2-cost and 3D body kinematics were assessed in each trial.
Results
In Low incline, SS + 10 cm induced a lower O2-cost than all the other pole lengths [P < 0.05; effect size (ES) 0.5–0.8], whereas no differences were found between the remaining pole lengths (P > 0.05; ES 0.2–0.4). In Moderate incline, significant differences between all pole lengths were found for O2-cost, with SS − 5 cm > SS > SS + 5 cm > SS + 10 cm (P < 0.05; ES 0.6–1.8). The relative differences in O2-cost between SS and the other pole lengths were greater in Moderate incline than Low incline (SS − 5 cm; 1.5%, ES 0.8, SS + 5 cm; 1.3%, ES 1.0, and SS + 10 cm; 1.9%, ES 1.0, all P < 0.05). No difference was found in cycle, poling or reposition times between pole lengths. However, at both conditions a smaller total vertical displacement of center of mass was observed with SS + 10 cm compared to the other pole lengths.
Conclusion
Increasing pole length from SS − 5 cm to SS + 10 cm during double poling induced lower O2-cost and this advantage was greater in Moderate compared to Low incline.
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Body position influences arterial occlusion pressure: implications for the standardization of pressure during blood flow restricted exercise
Abstract
Purpose
Arterial occlusion pressure (AOP) measured in a supine position is often used to set cuff pressures for blood flow restricted exercise (BFRE). However, supine AOP may not reflect seated or standing AOP, thus potentially influencing the degree of occlusion. The primary aim of the study was to investigate the effect of body position on AOP. A secondary aim was to investigate predictors of AOP using wide and narrow cuffs.
Methods
Twenty-four subjects underwent measurements of thigh circumference, skinfold and blood pressure, followed by assessments of thigh AOP in supine and seated positions with a wide and a narrow cuff, respectively, using Doppler ultrasound.
Results
In the supine position, AOP was 148 ± 19 and 348 ± 94 mmHg with the wide and narrow cuff, respectively. This increased to 177 ± 20 and 409 ± 101 mmHg in the seated position, with correlations between supine and seated AOP of R 2 = 0.81 and R 2 = 0.50 for the wide and narrow cuff, respectively. For both cuff widths, thigh circumference constituted the strongest predictor of AOP, with diastolic blood pressure explaining additional variance with the wide cuff. The predictive strength of these variables did not differ between body positions.
Conclusion
Our results indicate that body position strongly influences lower limb AOP, especially with narrow cuffs, yielding very high AOP (≥ 500–600 mmHg) in some subjects. This should be taken into account in the standardization of cuff pressures used during BFRE to better control the physiological effects of BFRE.
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Effects of mating on host selection by female small white butterflies Pieris rapae (Lepidoptera: Pieridae)
Abstract
Mating might significantly affect the host selection behaviors of phytophagous insects. Here, we investigated the post-mating changes in behavioral and antennal responses of Pieris rapae (Lepidoptera: Pieridae) females to host plant volatiles. In two-choice bioassays using artificial plant models, mated females visited the model scented with synthetic blends (15-, 9-, or 6-components) of cabbage plant volatiles more frequently than the unscented control, whereas virgin females did not exhibit this preference. Because single compounds and the 3-component blend did not induce preferential visiting, mated females apparently utilized complex odor blends as their host-finding cue. Moreover, 2- to 4-day-old mated females visited the models, scented and unscented, more frequently than did their virgin counterparts. Therefore, mating enhanced the host-finding behavior of young females and their responsiveness to plant volatiles. Gas chromatography–electroantennographic detector analysis revealed that eight of the 15 compounds in the cabbage plant volatiles elicited responses from female antennae. However, post-mating and age-dependent changes in antennal responses were not detected. Because female peripheral (antennal) sensitivity to volatiles remained practically unchanged after emergence, post-mating changes in host selection might be attributed to changes in the central nervous system.
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3 key considerations for improving EMS workplace safety
How can EMS agencies prepare for the future and ensure the safest possible workplace for their employees?
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Oslo University Hospital and Sopra Steria win the Microsoft 2017 Health Innovation Award
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Diversity in spatial scope of contrast adaptation among mouse retinal ganglion cells
Retinal ganglion cells adapt to changes in visual contrast by adjusting their response kinetics and sensitivity. While much work has focused on the time scales of these adaptation processes, less is known about the spatial scale of contrast adaptation. For example, do small, localized contrast changes affect a cell's signal processing across its entire receptive field? Previous investigations have provided conflicting evidence, suggesting that contrast adaptation occurs either locally within subregions of a ganglion cell's receptive field or globally over the receptive field in its entirety. Here, we investigated the spatial extent of contrast adaptation in ganglion cells of the isolated mouse retina through multielectrode-array recordings. We applied visual stimuli so that ganglion cell receptive fields contained regions where the average contrast level changed periodically as well as regions with constant average contrast level. This allowed us to analyze temporal stimulus integration and sensitivity separately for stimulus regions with and without contrast changes. We found that the spatial scope of contrast adaptation depends strongly on cell identity, with some ganglion cells displaying clear local adaptation, whereas others, in particular large transient ganglion cells, adapted globally to contrast changes. Thus, the spatial scope of contrast adaptation in mouse retinal ganglion cells appears to be cell-type specific. This could reflect differences in mechanisms of contrast adaptation and may contribute to the functional diversity of different ganglion cell types.
NEW & NOTEWORTHY Understanding whether adaptation of a neuron in a sensory system can occur locally inside the receptive field or whether it always globally affects the entire receptive field is important for understanding how the neuron processes complex sensory stimuli. For mouse retinal ganglion cells, we here show that both local and global contrast adaptation exist and that this diversity in spatial scope can contribute to the functional diversity of retinal ganglion cell types.
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Influence of biases in numerical magnitude allocation on human prosocial decision making
Over the past decade neuroscientific research has attempted to probe the neurobiological underpinnings of human prosocial decision making. Such research has almost ubiquitously employed tasks such as the dictator game or similar variations (i.e., ultimatum game). Considering the explicit numerical nature of such tasks, it is surprising that the influence of numerical cognition on decision making during task performance remains unknown. While performing these tasks, participants typically tend to anchor on a 50:50 split that necessitates an explicit numerical judgement (i.e., number-pair bisection). Accordingly, we hypothesize that the decision-making process during the dictator game recruits overlapping cognitive processes to those known to be engaged during number-pair bisection. We observed that biases in numerical magnitude allocation correlated with the formulation of decisions during the dictator game. That is, intrinsic biases toward smaller numerical magnitudes were associated with the formulation of less favorable decisions, whereas biases toward larger magnitudes were associated with more favorable choices. We proceeded to corroborate this relationship by subliminally and systematically inducing biases in numerical magnitude toward either higher or lower numbers using a visuo-vestibular stimulation paradigm. Such subliminal alterations in numerical magnitude allocation led to proportional and corresponding changes to an individual's decision making during the dictator game. Critically, no relationship was observed between neither intrinsic nor induced biases in numerical magnitude on decision making when assessed using a nonnumerical-based prosocial questionnaire. Our findings demonstrate numerical influences on decisions formulated during the dictator game and highlight the necessity to control for confounds associated with numerical cognition in human decision-making paradigms.
NEW & NOTEWORTHY We demonstrate that intrinsic biases in numerical magnitude can directly predict the amount of money donated by an individual to an anonymous stranger during the dictator game. Furthermore, subliminally inducing perceptual biases in numerical-magnitude allocation can actively drive prosocial choices in the corresponding direction. Our findings provide evidence for numerical influences on decision making during performance of the dictator game. Accordingly, without the implementation of an adequate control for numerical influences, the dictator game and other tasks with an inherent numerical component (i.e., ultimatum game) should be employed with caution in the assessment of human behavior.
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Diversity of molecularly defined spinal interneurons engaged in mammalian locomotor pattern generation
Mapping the expression of transcription factors in the mouse spinal cord has identified ten progenitor domains, four of which are cardinal classes of molecularly defined, ventrally located interneurons that are integrated in the locomotor circuitry. This review focuses on the properties of these interneuronal populations and their contribution to hindlimb locomotor central pattern generation. Interneuronal populations are categorized based on their excitatory or inhibitory functions and their axonal projections as predictors of their role in locomotor rhythm generation and coordination. The synaptic connectivity and functions of these interneurons in the locomotor central pattern generators (CPGs) have been assessed by correlating their activity patterns with motor output responses to rhythmogenic neurochemicals and sensory and descending fibers stimulations as well as analyzing kinematic gait patterns in adult mice. The observed complex organization of interneurons in the locomotor CPG circuitry, some with seemingly similar physiological functions, reflects the intricate repertoire associated with mammalian motor control and is consistent with high transcriptional heterogeneity arising from cardinal interneuronal classes. This review discusses insights derived from recent studies to describe innovative approaches and limitations in experimental model systems and to identify missing links in current investigational enterprise.
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Impact of prior errors on visuomotor adaptation and savings: experimental considerations and clinical implications
The motor system retains learning from visuomotor adaptation tasks in the form of "savings" to enable faster readaptation to similar perturbations in the future. Leow et al. (J Neurophysiol 116: 1603–1614, 2016) suggest that the experience of prior errors during relearning is necessary for savings while repetition of prior actions may not be sufficient. These findings provide novel insight into factors that contribute to visuomotor adaptation and can be applied to future experimental and clinical research.
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Anatomy and physiology of phrenic afferent neurons
Large-diameter myelinated phrenic afferents discharge in phase with diaphragm contraction, and smaller diameter fibers discharge across the respiratory cycle. In this article, we review the phrenic afferent literature and highlight areas in need of further study. We conclude that 1) activation of both myelinated and nonmyelinated phrenic sensory afferents can influence respiratory motor output on a breath-by-breath basis; 2) the relative impact of phrenic afferents substantially increases with diaphragm work and fatigue; 3) activation of phrenic afferents has a powerful impact on sympathetic motor outflow, and 4) phrenic afferents contribute to diaphragm somatosensation and the conscious perception of breathing. Much remains to be learned regarding the spinal and supraspinal distribution and synaptic contacts of myelinated and nonmyelinated phrenic afferents. Similarly, very little is known regarding the potential role of phrenic afferent neurons in triggering or modulating expression of respiratory neuroplasticity.
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Characterization of ion channels and O2 sensitivity in gill neuroepithelial cells of the anoxia-tolerant goldfish (Carassius auratus)
The neuroepithelial cell (NEC) of the fish gill is an important model for O2 sensing in vertebrates; however, a complete picture of the chemosensory mechanisms in NECs is lacking, and O2 chemoreception in vertebrates that are tolerant to anoxia has not yet been explored. Using whole cell patch-clamp recording, we characterized four types of ion channels in NECs isolated from the anoxia-tolerant goldfish. A Ca2+-dependent K+ current (IKCa) peaked at ~20 mV, was potentiated by increased intracellular Ca2+, and was reduced by 100 μM Cd2+. A voltage-dependent inward current in Ba2+ solution, with peak at 0 mV, confirmed the presence of Ca2+ channels. A voltage-dependent K+ current (IKV) was inhibited by 20 mM tetraethylammonium and 5 mM 4-aminopyridine, revealing a background K+ current (IKB) with open rectification. Mean resting membrane potential of –45.2 ± 11.6 mV did not change upon administration of hypoxia (Po2 = 11 mmHg), nor were any of the K+ currents sensitive to changes in Po2 during whole cell recording. By contrast, when the membrane and cytosol were left undisturbed during fura-2 or FM 1-43 imaging experiments, hypoxia increased intracellular Ca2+ concentration and initiated synaptic vesicle activity. 100 μM Cd2+ and 50 μM nifedipine eliminated uptake of FM 1-43. We conclude that Ca2+ influx via L-type Ca2+ channels is correlated with vesicular activity during hypoxic stimulation. In addition, we suggest that expression of IKCa in gill NECs is species specific and, in goldfish, may contribute to an attenuated response to acute hypoxia.
NEW & NOTEWORTHY This study provides the first physiological characterization of oxygen chemoreceptors from an anoxia-tolerant vertebrate. Neuroepithelial cells (NECs) from the gills of goldfish displayed L-type Ca2+ channels and three types of K+ channels, one of which was dependent upon intracellular Ca2+. Although membrane currents were not inhibited by hypoxia during patch-clamp recording, this study is the first to show that NECs with an undisturbed cytosol responded to hypoxia with increased intracellular Ca2+ and synaptic vesicle activity.
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Effect of M-current modulation on mammalian vestibular responses to transient head motion
The precise role and mechanisms underlying efferent modulation of peripheral vestibular afferent function are not well understood in mammals. Clarifying the details of efferent action may lead to new strategies for clinical management of debilitating disturbances in vestibular and balance function. Recent evidence in turtle indicates that efferent modulation of M-currents is likely one mechanism for modifying afferent discharge. M-currents depend in part on KCNQ potassium conductances (Kv7), which can be adjusted through efferent activation of M1, M3, and/or M5 muscarinic acetylcholine receptors (mAChRs). How KCNQ channels and altered M-currents affect vestibular afferent function in vivo is unclear, and whether such a mechanism operates in mammals is unknown. In this study we used the KCNQ antagonist XE991 and the KCNQ activator retigabine in anesthetized mice to evaluate the effects of M-current modulation on peripheral vestibular responses to transient head motion. At low doses of XE991, responses were modestly enhanced, becoming larger in amplitude and shorter in latency. Higher doses of XE991 produced transient response enhancement, followed by steady-state suppression where latencies and thresholds increased and amplitudes decreased. Retigabine produced opposite effects. Auditory function was also impacted, based on results of companion auditory brain stem response testing. We propose that closure of KCNQ channels transforms vestibular afferent behavior by suppressing responses to transient high-frequency stimuli while simultaneously enhancing responses to sustained low-frequency stimulation. Our results clearly demonstrate that KCNQ channels are critical for normal mammalian vestibular function and suggest that efferent action may utilize these mechanisms to modulate the dynamic characteristics and gain of vestibular afferent responses.
NEW & NOTEWORTHY The role of calyceal KCNQ channels and associated M-current in normal mammalian vestibular function is unknown. Our results show that calyceal KCNQ channels are critical for normal vestibular function in the intact mammal. The findings provide evidence that efferent modulation of M-currents may act normally to differentially adjust the sensitivity of vestibular neurons to transient and tonic stimulation and that such mechanisms may be targeted to achieve effective clinical management of vestibular disorders.
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Hyperpolarization-activated cyclic-nucleotide-gated channels potentially modulate axonal excitability at different thresholds
Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels mediate differences in sensory and motor axonal excitability at different thresholds in animal models. Importantly, HCN channels are responsible for voltage-gated inward rectifying (Ih) currents activated during hyperpolarization. The Ih currents exert a crucial role in determining the resting membrane potential and have been implicated in a variety of neurological disorders, including neuropathic pain. In humans, differences in biophysical properties of motor and sensory axons at different thresholds remain to be elucidated and could provide crucial pathophysiological insights in peripheral neurological diseases. Consequently, the aim of this study was to characterize sensory and motor axonal function at different threshold. Median nerve motor and sensory axonal excitability studies were undertaken in 15 healthy subjects (45 studies in total). Tracking targets were set to 20, 40, and 60% of maximum for sensory and motor axons. Hyperpolarizing threshold electrotonus (TEh) at 90–100 ms was significantly increased in lower threshold sensory axons times (F = 11.195, P < 0.001). In motor axons, the hyperpolarizing current/threshold (I/V) gradient was significantly increased in lower threshold axons (F = 3.191, P < 0.05). The minimum I/V gradient was increased in lower threshold motor and sensory axons. In conclusion, variation in the kinetics of HCN isoforms could account for the findings in motor and sensory axons. Importantly, assessing the function of HCN channels in sensory and motor axons of different thresholds may provide insights into the pathophysiological processes underlying peripheral neurological diseases in humans, particularly focusing on the role of HCN channels with the potential of identifying novel treatment targets.
NEW & NOTEWORTHY Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels, which underlie inward rectifying currents (Ih), appear to mediate differences in sensory and motor axonal properties. Inward rectifying currents are increased in lower threshold motor and sensory axons, although different HCN channel isoforms appear to underlie these changes. While faster activating HCN channels seem to underlie Ih changes in sensory axons, slower activating HCN isoforms appear to be mediating the differences in Ih conductances in motor axons of different thresholds. The differences in HCN gating properties could explain the predilection for dysfunction of sensory and motor axons in specific neurological diseases.
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Transcriptome analysis of the threatened snail Ellobium chinense reveals candidate genes for adaptation and identifies SSRs for conservation genetics
Abstract
Ellobium chinense (Pfeiffer, 1854) is a brackish pulmonate species that inhabits the bases of mangrove trees and is most commonly found in salt grass meadows. Threats to mangrove ecosystems due to habitat degradation and overexploitation have threatened the species with extinction. In South Korea, E. chinense has been assessed as vulnerable, but there are limited data on its population structure and distribution. The nucleotide and protein sequences for this species are not available in databases, which limits the understanding of adaptation-related traits. We sequenced an E. chinense cDNA library using the Illumina platform, and the subsequent bioinformatics analysis yielded 227,032 unigenes. Of these unigenes, 69,088 were annotated to matched protein and nucleotide sequences in databases, for an annotation rate of 30.42%. Among the predominant gene ontology terms, cellular and metabolic processes (under the biological process category), membrane and cell (under the cellular component category), and binding and catalytic activity (under the molecular function category) were noteworthy. In addition, 4850 unigenes were distributed to 15 Kyoto Encyclopaedia of Genes and Genomes based enrichment categories. Among the candidate genes related to adaptation, angiotensin I converting enzyme, adenylate cyclase activating polypeptide, and AMP-activated protein kinase were the most prominent. A total of 15,952 simple sequence repeats (SSRs) were identified in sequences of > 1 kb in length. The di- and trinucleotide repeat motifs were the most common. Among the repeat motif types, AG/CT, AC/GT, and AAC/GTT dominated. Our study provides the first comprehensive genomics dataset for E. chinense, which favors conservation programs for the restoration of the species and provides sufficient evidence for genetic variability among the wild populations.
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Incomplete penetrance, variable expressivity, or dosage insensitivity in four families with directly transmitted unbalanced chromosome abnormalities
The direct transmission of microscopically visible unbalanced chromosome abnormalities (UBCAs) is rare and usually has phenotypic consequences. Here we report four families in which a normal phenotype was initially found in one or more family members. Each UBCA was interpreted with regard to overlapping examples and factors previously associated with transmitted imbalances including incidental ascertainment, low gene density, benign copy number variation (CNV) content, and gene relatedness. A 4.56 Mb deletion of 8p23.1-p23.2 was thought to be causal in the affected proband but showed incomplete penetrance in her mother and sibling (Family 1). Incomplete penetrance was also associated with a 10.88 Mb duplication of 13q21.31-q22.1 (Family 3) and dosage insensitivity with a 17.6 Mb deletion of 22pter-q11.21 (Family 4) that were both ascertained at prenatal diagnosis and each found in 4 unaffected family members. The 22pter-q11.21 deletion is part of a region with high benign CNV content and supports the mapping of cat eye syndrome to a 600 kb interval of 22q11.1-q11.21. Low gene densities of less than 2.0 genes/Mb were found in each of these three families but only after segmentally duplicated genes were excluded from the deletions of 8p and 22q. In contrast, gene density was average and variable expressivity associated with a 3.59 Mb duplication of 8p23.1 incidentally ascertained for paternal infertility (Family 2). Our results indicate that a greater degree of direct parental transmission, incomplete penetrance, and variable expression are features of both sub-microscopic CNVs and UBCAs with relatively low gene and high benign CNV content.
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Acute hypoxia in a simulated high-altitude airdrop scenario due to oxygen system failure
High-Altitude High Opening (HAHO) is a military operational procedure in which parachute jumps are performed at high altitude requiring supplemental oxygen, putting personnel at risk of acute hypoxia in the event of oxygen equipment failure. This study was initiated by the Norwegian Army to evaluate potential outcomes during failure of oxygen supply, and to explore physiology during acute severe hypobaric hypoxia. A simulated HAHO without supplemental oxygen was carried out in a hypobaric chamber with decompression to 30,000 ft (9,144 m) and then recompression to ground level with a descent rate of 1,000 ft/min (305 m/min). Nine subjects were studied. Repeated arterial blood gas samples were drawn throughout the entire hypoxic exposure. Additionally, pulse oximetry, cerebral oximetry, and hemodynamic variables were monitored. Desaturation evolved rapidly and the arterial oxygen tensions are among the lowest ever reported in volunteers during acute hypoxia. PaO2 decreased from baseline 18.4 (17.3–19.1) kPa, 138.0 (133.5–143.3) mmHg, to a minimum value of 3.3 (2.9–3.7) kPa, 24.8 (21.6–27.8) mmHg, after 180 (60–210) s, [median (range)], N = 9. Hyperventilation with ensuing hypocapnia was associated with both increased arterial oxygen saturation and cerebral oximetry values, and potentially improved tolerance to severe hypoxia. One subject had a sharp drop in heart rate and cardiac index and lost consciousness 4 min into the hypoxic exposure. A simulated high-altitude airdrop scenario without supplemental oxygen results in extreme hypoxemia and may result in loss of consciousness in some individuals.
NEW & NOTEWORTHY This is the first study to investigate physiology and clinical outcome of oxygen system failure in a simulated HAHO scenario. The acquired knowledge is of great value to make valid risk-benefit analyses during HAHO training or operations. The arterial oxygen tensions reported in this hypobaric chamber study are among the lowest ever reported during acute hypoxia.
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Effect of a patent foramen ovale in humans on thermal responses to passive cooling and heating
Humans with a patent foramen ovale (PFO) have a higher esophageal temperature (Tesoph) than humans without a PFO (PFO–). Thus the presence of a PFO might also be associated with differences in thermal responsiveness to passive cooling and heating such as shivering and hyperpnea, respectively. The purpose of this study was to determine whether thermal responses to passive cooling and heating are different between PFO– subjects and subjects with a PFO (PFO+). We hypothesized that compared with PFO– subjects PFO+ subjects would cool down more rapidly and heat up slower and that PFO+ subjects who experienced thermal hyperpnea would have a blunted increase in ventilation. Twenty-seven men (13 PFO+) completed two trials separated by >48 h: 1) 60 min of cold water immersion (19.5 ± 0.9°C) and 2) 30 min of hot water immersion (40.5 ± 0.2°C). PFO+ subjects had a higher Tesoph before and during cold water and hot water immersion (P < 0.05). However, the rate of temperature change was similar between groups for each condition. Within a subset of 18 subjects (8 PFO+) who experienced thermal hyperpnea, PFO+ subjects experienced thermal hyperpnea at a higher absolute Tesoph but with a blunted magnitude compared with PFO– subjects. These data suggest that PFO+ subjects have a higher Tesoph at rest and have blunted thermal hyperpnea during passive heating.
NEW & NOTEWORTHY Patent foramen ovale (PFO) is found in ~25–40% of the population. The presence of a PFO appears to be associated with a greater core body temperature and blunted ventilatory responses during passive heating. The reason for this blunted ventilatory response to passive heating is unknown but may suggest differences in thermal sensitivity in PFO+ subjects compared with PFO– subjects.
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Shifting gears: dynamic muscle shape changes and force-velocity behavior in the medial gastrocnemius
When muscles contract, they bulge in thickness or in width to maintain a (nearly) constant volume. These dynamic shape changes are tightly linked to the internal constraints placed on individual muscle fibers and play a key functional role in modulating the mechanical performance of skeletal muscle by increasing its range of operating velocities. Yet to date we have a limited understanding of the nature and functional implications of in vivo dynamic muscle shape change under submaximal conditions. This study determined how the in vivo changes in medial gastrocnemius (MG) fascicle velocity, pennation angle, muscle thickness, and subsequent muscle gearing varied as a function of force and velocity. To do this, we obtained recordings of MG tendon length, fascicle length, pennation angle, and thickness using B-mode ultrasound and muscle activation using surface electromyography during cycling at a range of cadences and loads. We found that that increases in contractile force were accompanied by reduced bulging in muscle thickness, reduced increases in pennation angle, and faster fascicle shortening. Although the force and velocity of a muscle contraction are inversely related due to the force-velocity effect, this study has shown how dynamic muscle shape changes are influenced by force and not influenced by velocity.
NEW & NOTEWORTHY During movement, skeletal muscles contract and bulge in thickness or width. These shape changes play a key role in modulating the performance of skeletal muscle by increasing its range of operating velocities. Yet to date the underlying mechanisms associated with muscle shape change remain largely unexplored. This study identified muscle force, and not velocity, as the mechanistic driving factor to allow for muscle gearing to vary depending on the contractile conditions during human cycling.
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Increased tissue oxygenation explains the attenuation of hyperemia upon repetitive pneumatic compression of the lower leg
The rapid hyperemia evoked by muscle compression is short lived and was recently shown to undergo a rapid decrease even in spite of continuing mechanical stimulation. The present study aims at investigating the mechanisms underlying this attenuation, which include local metabolic mechanisms, desensitization of mechanosensitive pathways, and reduced efficacy of the muscle pump. In 10 healthy subjects, short sequences of mechanical compressions (n = 3–6; 150 mmHg) of the lower leg were delivered at different interstimulus intervals (ranging from 20 to 160 s) through a customized pneumatic device. Hemodynamic monitoring included near-infrared spectroscopy, detecting tissue oxygenation and blood volume in calf muscles, and simultaneous echo-Doppler measurement of arterial (superficial femoral artery) and venous (femoral vein) blood flow. The results indicate that 1) a long-lasting (>100 s) increase in local tissue oxygenation follows compression-induced hyperemia, 2) compression-induced hyperemia exhibits different patterns of attenuation depending on the interstimulus interval, 3) the amplitude of the hyperemia is not correlated with the amount of blood volume displaced by the compression, and 4) the extent of attenuation negatively correlates with tissue oxygenation (r = –0,78, P < 0.05). Increased tissue oxygenation appears to be the key factor for the attenuation of hyperemia upon repetitive compressive stimulation. Tissue oxygenation monitoring is suggested as a useful integration in medical treatments aimed at improving local circulation by repetitive tissue compression.
NEW & NOTEWORTHY This study shows that 1) the hyperemia induced by muscle compression produces a long-lasting increase in tissue oxygenation, 2) the hyperemia produced by subsequent muscle compressions exhibits different patterns of attenuation at different interstimulus intervals, and 3) the extent of attenuation of the compression-induced hyperemia is proportional to the level of oxygenation achieved in the tissue. The results support the concept that tissue oxygenation is a key variable in blood flow regulation.
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White-nose syndrome increases torpid metabolic rate and evaporative water loss in hibernating bats
Fungal diseases of wildlife typically manifest as superficial skin infections but can have devastating consequences for host physiology and survival. White-nose syndrome (WNS) is a fungal skin disease that has killed millions of hibernating bats in North America since 2007. Infection with the fungus Pseudogymnoascus destructans causes bats to rewarm too often during hibernation, but the cause of increased arousal rates remains unknown. On the basis of data from studies of captive and free-living bats, two mechanistic models have been proposed to explain disease processes in WNS. Key predictions of both models are that WNS-affected bats will show 1) higher metabolic rates during torpor (TMR) and 2) higher rates of evaporative water loss (EWL). We collected bats from a WNS-negative hibernaculum, inoculated one group with P. destructans, and sham-inoculated a second group as controls. After 4 mo of hibernation, TMR and EWL were measured using respirometry. Both predictions were supported, and our data suggest that infected bats were more affected by variation in ambient humidity than controls. Furthermore, disease severity, as indicated by the area of the wing with UV fluorescence, was positively correlated with EWL, but not TMR. Our results provide the first direct evidence that heightened energy expenditure during torpor and higher EWL independently contribute to WNS pathophysiology, with implications for the design of potential treatments for the disease.
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Use of radiotelemetry to assess perinatal cardiac function in the ovine fetus and newborn
The late gestation fetal ECG (fECG) has traditionally been difficult to characterize due to the low fECG signal relative to high maternal noise. Although new technologies have improved the feasibility of its acquisition and separation, little is known about its development in late gestation, a period in which the fetal heart undergoes extensive maturational changes. Here, we describe a method for the chronic implantation of radiotelemetry devices into late gestation ovine fetuses to characterize parameters of the fECG following surgery, throughout late gestation, and in the perinatal period. We found no significant changes in mean aortic pressure (MAP), heart rate (HR), or ECG in the 5 days following implantation; however, HR decreased in the first 24 h following the end of surgery, with associated increases in RR, PR, and QRS intervals. Over the last 14 days of fetal life, fetal MAP significantly increased, and HR significantly decreased, as expected. MAP and HR increased as labor progressed. Although there were no significant changes over time in the ECG during late gestation, the duration of the PR interval initially decreased and then increased as birth approached. These results indicate that although critical maturational changes occur in the late gestation fetal myocardium, the mechanisms that control the cardiac conduction are relatively mature in late gestation. The study demonstrates that radiotelemetry can be successfully used to assess fetal cardiac function, in particular conduction, through the process of labor and delivery, and may therefore be a useful tool for study of peripartum cardiac events.
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Optogenetics and pharmacogenetics: principles and applications
Remote and selective spatiotemporal control of the activity of neurons to regulate behavior and physiological functions has been a long-sought goal in system neuroscience. Identification and subsequent bioengineering of light-sensitive ion channels (e.g., channelrhodopsins, halorhodopsin, and archaerhodopsins) from the bacteria have made it possible to use light to artificially modulate neuronal activity, namely optogenetics. Recent advance in genetics has also allowed development of novel pharmacological tools to selectively and remotely control neuronal activity using engineered G protein-coupled receptors, which can be activated by otherwise inert drug-like small molecules such as the designer receptors exclusively activated by designer drug, a form of chemogenetics. The cutting-edge optogenetics and pharmacogenetics are powerful tools in neuroscience that allow selective and bidirectional modulation of the activity of defined populations of neurons with unprecedented specificity. These novel toolboxes are enabling significant advances in deciphering how the nervous system works and its influence on various physiological processes in health and disease. Here, we discuss the fundamental elements of optogenetics and chemogenetics approaches and some of the applications that yielded significant advances in various areas of neuroscience and beyond.
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The differential role of reactive oxygen species in early and late stages of cancer
The large doses of vitamins C and E and β-carotene used to reduce reactive oxygen species (ROS) production and oxidative damages in cancerous tissue have produced disappointing and contradictory results. This therapeutic conundrum was attributed to the double-faced role of ROS, notably, their ability to induce either proliferation or apoptosis of cancer cells. However, for a ROS-inhibitory approach to be effective, it must target ROS when they induce proliferation rather than apoptosis. On the basis of recent advances in redox biology, this review underlined a differential regulation of prooxidant and antioxidant system, respective to the stage of cancer. At early precancerous and neoplastic stages, antioxidant activity decreases and ROS appear to promote cancer initiation via inducing oxidative damage and base pair substitution mutations in prooncogenes and tumor suppressor genes, such as RAS and TP53, respectively. Whereas in late stages of cancer progression, tumor cells escape apoptosis by producing high levels of intracellular antioxidants, like NADPH and GSH, via the pentose phosphate pathway to buffer the excessive production of ROS and related intratumor oxidative injuries. Therefore, antioxidants should be prohibited in patients with advanced stages of cancer and/or undergoing anticancer therapies. Interestingly, the biochemical and biophysical properties of some polyphenols allow them to selectively recognize tumor cells. This characteristic was exploited to design and deliver nanoparticles coated with low doses of polyphenols and containing chemotherapeutic drugs into tumor-bearing animals. First results are encouraging, which may revolutionize the conventional use of antioxidants in cancer.
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The in vitro zebrafish heart as a model to investigate the chronotropic effects of vapor anesthetics
In addition to their intended clinical actions, all general anesthetic agents in common use have detrimental intrasurgical and postsurgical side effects on organs and systems, including the heart. The major cardiac side effect of anesthesia is bradycardia, which increases the probability of insufficient systemic perfusion during surgery. These side effects also occur in all vertebrate species so far examined, but the underlying mechanisms are not clear. The zebrafish heart is a powerful model for studying cardiac electrophysiology, employing the same pacemaker system and neural control as do mammalian hearts. In this study, isolated zebrafish hearts were significantly bradycardic during exposure to the vapor anesthetics sevoflurane (SEVO), desflurane (DES), and isoflurane (ISO). Bradycardia induced by DES and ISO continued during pharmacological blockade of the intracardiac portion of the autonomic nervous system, but the chronotropic effect of SEVO was eliminated during blockade. Bradycardia evoked by vagosympathetic nerve stimulation was augmented during DES and ISO exposure; nerve stimulation during SEVO exposure had no effect. Together, these results support the hypothesis that the cardiac chronotropic effect of SEVO occurs via a neurally mediated mechanism, while DES and ISO act directly upon cardiac pacemaker cells via an as yet unknown mechanism.
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Baroreflex and neurovascular responses to skeletal muscle mechanoreflex activation in humans: an exercise in integrative physiology
Cardiovascular adjustments to exercise resulting in increased blood pressure (BP) and heart rate (HR) occur in response to activation of several neural mechanisms: the exercise pressor reflex, central command, and the arterial baroreflex. Neural inputs from these feedback and feedforward mechanisms integrate in the cardiovascular control centers in the brain stem and modulate sympathetic and parasympathetic neural outflow, resulting in the increased BP and HR observed during exercise. Another specific consequence of the central neural integration of these inputs during exercise is increased sympathetic neural outflow directed to the kidneys, causing renal vasoconstriction, a key reflex mechanism involved in blood flow redistribution during increased skeletal muscle work. Studies in humans have shown that muscle mechanoreflex activation inhibits cardiac vagal outflow, decreasing the sensitivity of baroreflex control of HR. Metabolite sensitization of muscle mechanoreceptors can lead to reduced sensitivity of baroreflex control of HR, with thromboxane being one of the metabolites involved, via greater inhibition of cardiac vagal outflow without affecting baroreflex control of BP or baroreflex resetting. Muscle mechanoreflex activation appears to play a predominant role in causing renal vasoconstriction, both in isolation and in the presence of local metabolites. Limited investigations in older adults and patients with cardiovascular-related disease have provided some insight into how the influence of muscle mechanoreflex activation on baroreflex function and renal vasoconstriction is altered in these populations. However, future research is warranted to better elucidate the specific effect of muscle mechanoreflex activation on baroreflex and neurovascular responses with aging and cardiovascular-related disease.
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Variation in Akt protein kinases in human populations
The three Akt kinases are related proteins that are essential for normal growth and metabolic regulation and are implicated as key signaling mediators in many physiological and pathophysiological processes. Each Akt is activated by common biochemical signals that act downstream of growth factor and hormone receptors via phosphatidylinositol-3 kinase, and each controls several downstream pathways. The importance of Akt actions in human physiology is strengthened by the rarity of modifying mutations in their genes and by the devastating impact caused by these mutations on growth and development and in disorders such as cancer. Recent advances in genomics present unique opportunities for enhancing our understanding of human physiology and disease predisposition through the lens of population genetics, and the availability of DNA sequence data from 60,706 people in the Exome Aggregation Consortium has prompted this analysis. Results reveal a cohort of potential missense and other alterations in the coding regions of each AKT gene, but with nearly all changes being uncommon. The total number of different alleles per gene varied over an approximately threefold range, from 52 for AKT3 to 158 for AKT2, with variants distributed throughout all Akt protein domains. Previously characterized disease-causing mutations were found rarely in the general population. In contrast, a fairly prevalent amino acid substitution in AKT2 appears to be linked to increased predisposition for type 2 diabetes. Further analysis of variant Akt molecules as identified here will provide opportunities to understand the intricacies of Akt signaling and actions at a population level in human physiology and pathology.
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First Trimester Prenatal Care Initiation Among Hispanic Women Along the U.S.-Mexico Border
Abstract
Background First trimester prenatal care (FTPNC) is associated with improved birth outcomes. U.S.-Mexico border Hispanic women have lower FTPNC than non-border or non-Hispanic women. This study aimed to identify (1) what demographic, knowledge and care-seeking factors influence FTPNC among Hispanic women in border counties served by five Healthy Start sites, and (2) what FTPNC barriers may be unique to this target population. Healthy Starts work to eliminate disparities in perinatal health in areas with high poverty and poor birth outcomes. Methods 403 Hispanic women of reproductive age in border communities of California, Arizona, New Mexico and Texas were surveyed on knowledge and behaviors related to prenatal care (PNC) and basic demographic information. Chi square analyses and logistic regressions were used to identify important relationships. Results Chi square analyses revealed that primiparous women were significantly less likely to start FTPNC than multiparous women (χ2 = 6.8372, p = 0.0089). Women with accurate knowledge about FTPNC were more likely to obtain FTPNC (χ2 = 29.280, p < .001) and more likely to have seen a doctor within the past year (χ2 = 5.550, p = .018). Logistic regression confirmed that multiparity was associated with FTPNC and also that living in Texas was negatively associated with FTPNC (R2 = 0.066, F(9,340) = 2.662, p = .005). Among 27 women with non-FTPNC, barriers included late pregnancy recognition (n = 19) and no medical insurance (n = 5). Conclusions This study supports research that first time pregnancies have lower FTPNC, and demonstrated a strong association between delayed PNC and late pregnancy recognition. Strengthened investments in preconception planning could improve FTPNC in this population.
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Genetic association of molecular traits: a help to identify causative variants in complex diseases
Abstract
In the past 15 years, major progresses have been made in the understanding of the genetic basis of regulation of gene expression. These new insights have revolutionized our approach to resolve the genetic variation underlying complex diseases. Gene transcript levels were the first expression phenotypes that were studied. They are heritable and therefore amenable to genome-wide association studies (GWAS). The genetic variants that modulate them are called expression quantitative trait loci (eQTL). Their study has been extended to other molecular quantitative trait loci (molQTL) that regulate gene expression at the various levels, from chromatin state to cellular responses. Altogether, these studies have generated a wealth of basic information on the genome-wide patterns of gene expression and their inter-individual variation. Most importantly, molQTLs have become an invaluable asset in the genetic study of complex diseases. Although the identification of the disease-causing variants on the basis of their overlap with molQTLs requires caution, molQTLs can help prioritize the relevant candidate gene(s) in the disease-associated regions and bring a functional interpretation of the associated variants, therefore bridging the gap between genotypes and clinical phenotypes.
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Endothelial Piezo1 channels as sensors of exercise
Abstract
Piezo1 channels are newly discovered ion channels which have come to the fore as players in endothelial biology. They have a key role as sensors of shear stress, a frictional force which arises in vascular biology because of blood flow. Endothelial Piezo1 channels are critical in murine embryonic development, just after the heart starts to beat and drive blood into the nascent endothelial network. In contrast they are not critical at the adult stage but they are important for performance in whole body physical activity where they have a vascular bed-specific effect to cause mesenteric resistance artery vasoconstriction, achieved through opposition to the vasodilatory mechanism of endothelium-derived hyperpolarization. These are our first insights into the relevance of endothelial Piezo1 channels and there is clearly much more to be done to understand the significance and underlying molecular mechanisms. The suggestion that they constitute an exercise sensor by virtue of their shear stress-sensing capability is intriguing and could open the way to better understanding of the molecular basis of the response to exercise and determination of how the health benefits of exercise arise. Enhanced Piezo1 channel activity has been demonstrated in response to the Yoda1 molecule and this suggests the possibility for developing tools which probe and manipulate this aspect of the exercise system. Whether such agents might progress to "exercise pills" and whether the existence of such pills would be desirable are matters for further work and debate.
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