Climate forcing reconstructions for use in PMIP simulations of the Last Millennium (v1

We update the forcings for the PMIP3 experiments for the Last Millennium to include new assessments of historical land use changes and discuss new suggestions for calibrating solar activity proxies to total solar irradiance.

On the postnatal development of the striate cortex (V1) in the tree shrew (Tupaia belangeri)

Histological serial sections, three-dimensional reconstructions and morphometry served to study the postnatal development of V1 in tree shrews. The main objectives were to evaluate the expansion of V1, the implications of its growth on the occipital cortex and, vice versa, the effects of the expanding neocortex on the topography of V1. The future V1 was identified on postnatal day 1 by its granular layer IV, covering the superior surface of the occipital cortices including the poles. A subdivision of layer IV, distinctive for the binocular part, was evident in the central region. V1 expanded continuously with age into all directions succeeded by the maturation of layering. The monocular part was recognized from day 15 onward, after the binocular part had reached its medial border. In reference to the retinotopic map of V1, regions emerged in a coherent temporo-spatial sequence delineating the retinal topography in a central to peripheral gradient beginning with the visual streak representation. The growth of V1 was greatest until tree shrews open their eyes, culminated during adolescence, and completed after a subsequent decrease in the young adult. Simultaneous expansion of the neocortex induced a shifting of V1. Translation and elongation of V1 entailed that the occipital cortex covered the superior colliculi along with a downward rotation of the poles. The enlargement of the occipital part of the hemispheres was in addition associated with the formation of a small occipital horn in the lateral ventricles, indicating an incipient 'true' occipital lobe harbouring mainly cortices involved in visual functions.

Electrophysiological properties of mouse and epitope-tagged human cardiac sodium channel Na v1.5 expressed in HEK293 cells

Background: The pore-forming subunit of the cardiac sodium channel, Na v1.5, has been previously found to be mutated in genetically determined arrhythmias. Na v1.5 associates with many proteins that regulate its function and cellular localisation. In order to identify more in situ Na v1.5 interacting proteins, genetically-modified mice with a high-affinity epitope in the sequence of Na v1.5 can be generated. Methods: In this short study, we (1) compared the biophysical properties of the sodium current (I Na) generated by the mouse Na v1.5 (mNa v1.5) and human Na v1.5 (hNa v1.5) constructs that were expressed in HEK293 cells, and (2) investigated the possible alterations of the biophysical properties of the human Na v1.5 construct that was modified with specific epitopes. Results: The biophysical properties of mNa v1.5 were similar to the human homolog. Addition of epitopes either up-stream of the N-terminus of hNa v1.5 or in the extracellular loop between the S5 and S6 transmembrane segments of domain 1, significantly decreased the amount of I Na and slightly altered its biophysical properties. Adding green fluorescent protein (GFP) to the N-terminus did not modify any of the measured biophysical properties of hNa v1.5. Conclusions: These findings have to be taken into account when planning to generate genetically-modified mouse models that harbour specific epitopes in the gene encoding mNa v1.5.

Ubiquitin-specific protease USP2-45 acts as a molecular switch to promote α2δ-1-induced downregulation of Ca v1.2 channels

Availability of voltage-gated calcium channels (Cav) at the plasma membrane is paramount to maintaining the calcium homeostasis of the cell. It is proposed that the ubiquitylation/de-ubiquitylation balance regulates the density of ion channels at the cell surface. Voltage-gated calcium channels Cav1.2 have been found to be ubiquitylated under basal conditions both in vitro and in vivo. In a previous study, we have shown that Cav1.2 channels are ubiquitylated by neuronal precursor cell-expressed developmentally downregulated 4 (Nedd4-1) ubiquitin ligases, but the identity of the counterpart de-ubiquitylating enzyme remained to be elucidated. Regarding sodium and potassium channels, it has been reported that the action of the related isoform Nedd4-2 is counteracted by the ubiquitin-specific protease (USP) 2-45. In this study, we show that USP 2-45 also de-ubiquitylates Cav channels. We co-expressed USPs and Cav1.2 channels together with the accessory subunits β2 and α2δ-1, in tsA-201 and HEK-293 mammalian cell lines. Using whole-cell current recordings and surface biotinylation assays, we show that USP2-45 specifically decreases both the amplitude of Cav currents and the amount of Cav1.2 subunits inserted at the plasma membrane. Importantly, co-expression of the α2δ-1 accessory subunit is necessary to support the effect of USP2-45. We further show that USP2-45 promotes the de-ubiquitylation of both Cav1.2 and α2δ-1 subunits. Remarkably, α2δ-1, but not Cav1.2 nor β2, co-precipitated with USP2-45. These results suggest that USP2-45 binding to α2δ-1 promotes the de-ubiquitylation of both Cav1.2 and α2δ-1 subunits, in order to regulate the expression of Cav1.2 channels at the plasma membrane.

Stimulus predictability reduces responses in primary visual cortex

In this functional magnetic resonance imaging study we tested whether the predictability of stimuli affects responses in primary visual cortex (V1). The results of this study indicate that visual stimuli evoke smaller responses in V1 when their onset or motion direction can be predicted from the dynamics of surrounding illusory motion. We conclude from this finding that the human brain anticipates forthcoming sensory input that allows predictable visual stimuli to be processed with less neural activation at early stages of cortical processing.

Imagery of a moving object: the role of occipital cortex and human MT/V5+

Visual imagery – similar to visual perception – activates feature-specific and category-specific visual areas. This is frequently observed in experiments where the instruction is to imagine stimuli that have been shown immediately before the imagery task. Hence, feature-specific activation could be related to the short-term memory retrieval of previously presented sensory information. Here, we investigated mental imagery of stimuli that subjects had not seen before, eliminating the effects of short-term memory. We recorded brain activation using fMRI while subjects performed a behaviourally controlled guided imagery task in predefined retinotopic coordinates to optimize sensitivity in early visual areas. Whole brain analyses revealed activation in a parieto-frontal network and lateral–occipital cortex. Region of interest (ROI) based analyses showed activation in left hMT/V5+. Granger causality mapping taking left hMT/V5+ as source revealed an imagery-specific directed influence from the left inferior parietal lobule (IPL). Interestingly, we observed a negative BOLD response in V1–3 during imagery, modulated by the retinotopic location of the imagined motion trace. Our results indicate that rule-based motion imagery can activate higher-order visual areas involved in motion perception, with a role for top-down directed influences originating in IPL. Lower-order visual areas (V1, V2 and V3) were down-regulated during this type of imagery, possibly reflecting inhibition to avoid visual input from interfering with the imagery construction. This suggests that the activation in early visual areas observed in previous studies might be related to short- or long-term memory retrieval of specific sensory experiences.

Callosal connections of primary visual cortex predict the spatial spreading of binocular rivalry across the visual hemifields

In binocular rivalry, presentation of different images to the separate eyes leads to conscious perception alternating between the two possible interpretations every few seconds. During perceptual transitions, a stimulus emerging into dominance can spread in a wave-like manner across the visual field. These traveling waves of rivalry dominance have been successfully related to the cortical magnification properties and functional activity of early visual areas, including the primary visual cortex (V1). Curiously however, these traveling waves undergo a delay when passing from one hemifield to another. In the current study, we used diffusion tensor imaging (DTI) to investigate whether the strength of interhemispheric connections between the left and right visual cortex might be related to the delay of traveling waves across hemifields. We measured the delay in traveling wave times (ΔTWT) in 19 participants and repeated this test 6 weeks later to evaluate the reliability of our behavioral measures. We found large interindividual variability but also good test-retest reliability for individual measures of ΔTWT. Using DTI in connection with fiber tractography, we identified parts of the corpus callosum connecting functionally defined visual areas V1-V3. We found that individual differences in ΔTWT was reliably predicted by the diffusion properties of transcallosal fibers connecting left and right V1, but observed no such effect for neighboring transcallosal visual fibers connecting V2 and V3. Our results demonstrate that the anatomical characteristics of topographically specific transcallosal connections predict the individual delay of interhemispheric traveling waves, providing further evidence that V1 is an important site for neural processes underlying binocular rivalry.

Interhemispheric connections shape subjective experience of bistable motion

The right and left visual hemifields are represented in different cerebral hemispheres and are bound together by connections through the corpus callosum. Much has been learned on the functions of these connections from split-brain patients [1-4], but little is known about their contribution to conscious visual perception in healthy humans. We used diffusion tensor imaging and functional magnetic resonance imaging to investigate which callosal connections contribute to the subjective experience of a visual motion stimulus that requires interhemispheric integration. The "motion quartet" is an ambiguous version of apparent motion that leads to perceptions of either horizontal or vertical motion [5]. Interestingly, observers are more likely to perceive vertical than horizontal motion when the stimulus is presented centrally in the visual field [6]. This asymmetry has been attributed to the fact that, with central fixation, perception of horizontal motion requires integration across hemispheres whereas perception of vertical motion requires only intrahemispheric processing [7]. We are able to show that the microstructure of individually tracked callosal segments connecting motion-sensitive areas of the human MT/V5 complex (hMT/V5+; [8]) can predict the conscious perception of observers. Neither connections between primary visual cortex (V1) nor other surrounding callosal regions exhibit a similar relationship.

Orientation-selective functional magnetic resonance imaging adaptation in primary visual cortex revisited

The processing of orientations is at the core of our visual experience. Orientation selectivity in human visual cortex has been inferred from psychophysical experiments and more recently demonstrated with functional magnetic resonance imaging (fMRI). One method to identify orientation-selective responses is fMRI adaptation, in which two stimuli—either with the same or with different orientations—are presented successively. A region containing orientation-selective neurons should demonstrate an adapted response to the “same orientation” condition in contrast to the “different orientation” condition. So far, human primary visual cortex (V1) showed orientation-selective fMRI adaptation only in experimental designs using prolonged pre-adaptation periods (∼40 s) in combination with top-up stimuli that are thought to maintain the adapted level. This finding has led to the notion that orientation-selective short-term adaptation in V1 (but not V2 or V3) cannot be demonstrated using fMRI. The present study aimed at re-evaluating this question by testing three differently timed adaptation designs. With the use of a more sensitive analysis technique, we show robust orientation-selective fMRI adaptation in V1 evoked by a short-term adaptation design.

A novel SCN5A mutation, F1344S, identified in a patient with Brugada syndrome and fever-induced ventricular fibrillation

OBJECTIVE: Brugada syndrome (BS) is an inherited electrical cardiac disorder characterized by right bundle branch block pattern and ST segment elevation in leads V1 to V3 on surface electrocardiogram that can potentially lead to malignant ventricular tachycardia and sudden cardiac death. About 20% of patients have mutations in the only so far identified gene, SCN5A, which encodes the alpha-subunit of the human cardiac voltage-dependent sodium channel (hNa(v)1.5). Fever has been shown to unmask or trigger the BS phenotype, but the associated molecular and the biophysical mechanisms are still poorly understood. We report on the identification and biophysical characterization of a novel heterozygous missense mutation in SCN5A, F1344S, in a 42-year-old male patient showing the BS phenotype leading to ventricular fibrillation during fever. METHODS: The mutation was reproduced in vitro using site-directed mutagenesis and characterized using the patch clamp technique in the whole-cell configuration. RESULTS: The biophysical characterization of the channels carrying the F1344S mutation revealed a 10 mV mid-point shift of the G/V curve toward more positive voltages during activation. Raising the temperature to 40.5 degrees C further shifted the mid-point activation by 18 mV and significantly changed the slope factor in Na(v)1.5/F1344S mutant channels from -6.49 to -10.27 mV. CONCLUSIONS: Our findings indicate for the first time that the shift in activation and change in the slope factor at a higher temperature mimicking fever could reduce sodium currents' amplitude and trigger the manifestation of the BS phenotype.

Vertebral artery dissection: presenting findings and predictors of outcome

BACKGROUND AND PURPOSE: Few data exist about clinical, radiologic findings, clinical outcome, and its predictors in patients with spontaneous vertebral artery dissection (sVAD). METHODS: Clinical characteristics, imaging findings, 3-month outcomes, and its predictors were investigated in consecutive patients with sVAD. RESULTS: One hundred sixty-nine patients with 195 sVAD were identified. Brain ischemia occurred in 131 patients (77%; ischemic stroke, n=114, 67%; transient ischemic attack, n=17, 10%). Three patients with ischemic stroke showed also signs of subarachnoid hemorrhage (SAH); 3 (2%) had SAH without ischemia. The 134 patients with brain ischemia or SAH had head and/or neck pain in 118 (88%) and pulsatile tinnitus in seven (5%) patients. The remaining 35 patients (21%) had isolated head and/or neck pain in 21 (12%) cases, asymptomatic sVAD in 13 (8%), and cervical radiculopathy in one case (1%). Location of sVAD was more often in the pars transversaria (V2; 35%) or atlas loop (V3; 34%) than in the prevertebral (V1; 20%) or intracranial (V4; 11%) segment (P=0.0001). Outcome was favorable (modified Rankin scale score 0 or 1) in 88 (82%) of 107 ischemic stroke patients with follow up. Two (2%) patients died. Low baseline National Institutes of Health Stroke Scale score (P<0.0001) and younger age (P=0.007) were independent predictors of favorable outcome. CONCLUSIONS: sVAD is predominantly located in the pars transversaria (V2) or the atlas loop (V3). Most patients show posterior circulation ischemia. Favorable outcome is observed in most ischemic strokes and independently predicted by low National Institutes of Health Stroke Scale score and younger age.

Perceptual Learning via Modification of Cortical Top-Down Signals

The primary visual cortex (V1) is pre-wired to facilitate the extraction of behaviorally important visual features. Collinear edge detectors in V1, for instance, mutually enhance each other to improve the perception of lines against a noisy background. The same pre-wiring that facilitates line extraction, however, is detrimental when subjects have to discriminate the brightness of different line segments. How is it possible to improve in one task by unsupervised practicing, without getting worse in the other task? The classical view of perceptual learning is that practicing modulates the feedforward input stream through synaptic modifications onto or within V1. However, any rewiring of V1 would deteriorate other perceptual abilities different from the trained one. We propose a general neuronal model showing that perceptual learning can modulate top-down input to V1 in a task-specific way while feedforward and lateral pathways remain intact. Consistent with biological data, the model explains how context-dependent brightness discrimination is improved by a top-down recruitment of recurrent inhibition and a top-down induced increase of the neuronal gain within V1. Both the top-down modulation of inhibition and of neuronal gain are suggested to be universal features of cortical microcircuits which enable perceptual learning.

Arginine vasopressin in vasodilatory shock: effects on metabolism and beyond

PURPOSE OF REVIEW: To describe the effects of arginine vasopressin other than its vasoconstrictive and antidiuretic potential in vasodilatory shock. RECENT FINDINGS: Arginine vasopressin influences substrate metabolism by stimulation of hepatic glucose release, gluconeogenesis, ureogenesis and fatty acid esterification. Although arginine vasopressin is a secretagogue of different hormones, only prolactin increases during arginine vasopressin therapy. Plasmatic and cellular coagulation are affected by arginine vasopressin, resulting in thrombocyte aggregation. Therefore, platelet count typically decreases following arginine vasopressin infusion in critically ill patients. In addition, arginine vasopressin reduces bile flow and may increase bilirubin concentrations. Despite its potential to decrease serum sodium, no change in electrolytes was observed in critically ill patients receiving arginine vasopressin. Although arginine vasopressin is an endogenous antipyretic, body temperature is not decreased by central venous arginine vasopressin infusion. In addition, arginine vasopressin modulates immune function through V1 receptors. Compared with norepinephrine, arginine vasopressin may have protective effects on endothelial function. Net arginine vasopressin effects on gastrointestinal motility seem to be inhibitory and are dose dependent. SUMMARY: Except for its antidiuretic and vasoconstrictive actions, the effects of arginine vasopressin in patients with vasodilatory shock have so far only been partially examined. Potential influences of arginine vasopressin on metabolism and immune, liver and mitochondrial function remain to be assessed in future studies.

Pattern and timing of the coronary sinus activation to guide rapid diagnosis of atrial tachycardia after atrial fibrillation ablation

BACKGROUND Atrial tachycardias (AT) during or after ablation of atrial fibrillation frequently pose a diagnostic challenge. We hypothesized that both the patterns and the timing of coronary sinus (CS) activation could facilitate AT mapping. METHODS AND RESULTS A total of 140 consecutive postpersistent atrial fibrillation ablation patients with sustained AT were investigated by conventional mapping. CS activation pattern was defined as chevron or reverse chevron when the activations recorded on both the proximal and the distal CS dipoles were latest or earliest, respectively. The local activation of mid-CS was timed with reference to Ppeak-Ppeak (P-P) interval in lead V1. A ratio, mid-CS activation time to AT cycle length, was computed. Of 223 diagnosed ATs, 124 were macroreentrant (56%) and 99 were centrifugal (44%). When CS activation was chevron/reverse chevron (n=44; 20%), macroreentries were mostly roof dependent. With reference to P-P interval, mid-CS activation timing showed specific consistency for peritricuspid and perimitral AT. Proximal to distal CS activation pattern and mid-CS activation at 50% to 70% of the P-P interval (n=30; 13%) diagnosed peritricuspid AT with 81% sensitivity and 89% specificity. Distal to proximal CS activation and mid-CS activation at 10% to 40% of the P-P interval (n=44; 20%) diagnosed perimitral AT with 88% sensitivity and 75% specificity. CONCLUSIONS The analysis of the patterns and timing of CS activation provides a rapid stratification of most likely macroreentrant ATs and points toward the likely origin of centrifugal ATs. It can be included in a stepwise diagnostic approach to rapidly select the most critical mapping maneuvers.