Dimerization mechanism of an inverted-topology ion channel in membranes

Many ion channels are multisubunit complexes where oligomerization is an obligatory requirement for function as the binding axis forms the charged permeation pathway. However, the mechanisms of in-membrane assembly of thermodynamically stable channels are largely unknown. Here, we demonstrate a key advance by reporting the dimerization equilibrium reaction of an inverted-topology, homodimeric fluoride channel Fluc in lipid bilayers. While the wild-type channel is a long-lived dimer, we leverage a known mutation, N43S, that weakens N

Cortical and subcortical brain structure in generalized anxiety disorder: findings from 28 research sites in the ENIGMA-Anxiety Working Group

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5–90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology

Cortical and subcortical brain structure in generalized anxiety disorder: findings from 28 research sites in the enigma-anxiety working group

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5–90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

MR imaging in the triage of pregnant patients with acute abdominal and pelvic pain

To retrospectively assess the performance of MR imaging in the evaluation and triage of pregnant patients presenting with acute abdominal or pelvic pain. MRI studies of pregnant patients who were referred for acute abdominal pain between 2001 and 2007 were included. MR images were retrospectively reviewed and compared with surgical and pathologic findings and clinical follow-up data. Analysis of imaging findings included evaluation of the visceral organs, bowel and mesentery, appendix (for presence of appendicitis), ovaries (detection and adnexal masses were evaluated), focal inflammation, presence of abscesses, and any other abnormal findings. A total of 118 pregnant patients were included. MR findings were inconclusive in 2 patients and were positive for acute appendicitis in 11 patients (n = 9 confirmed by surgery, n = 2 improved without surgery). One patient with inconclusive MR had surgically confirmed appendicitis; the other patient with inconclusive MR had surgically confirmed adnexal torsion. Other surgical/interventional diagnoses suggested by MR imaging were adnexal torsion (n = 4), abscess (n = 4), acute cholecystitis (n = 1), and gastric volvulus (n = 1). Two patients with MR diagnosis of torsion improved without surgery. One patient with MR diagnosis of abscess had biliary cystadenoma at surgery. The rest of the MR diagnoses above were confirmed surgically or interventionally. MR imaging was normal in 67 patients and demonstrated medically treatable etiology in 28 patients: adnexal lesions (n = 9), urinary pathology (n = 6), cholelithiasis (n = 4), degenerating fibroid (n = 3), DVT (n = 2), hernia (n = 1), colitis (n = 1), thick terminal ileum (n = 1), rectus hematoma (n = 1). Three of these patients had negative surgical exploration and one had adnexal mass excision during pregnancy. Other patients were discharged with medical treatment. The sensitivity, specificity, accuracy, positive predictive values (ppv), and negative predictive values (npv) of MR imaging for acute appendicitis, and surgical/ interventional diagnoses were 90.0% vs. 88.9%, 98.1% vs. 95.0%, 97.5% vs. 94.1%, 81.8% vs. 76.2%, 99.1% vs. 97.9%, respectively. MR imaging is an excellent modality for diagnosis of acute appendicitis and exclusion of diseases requiring surgical/interventional treatment. Therefore MR imaging is useful for triage of pregnant patients with acute abdominal and pelvic pain