Sequence motifs are responsible for ensuring the proper assembly of transmembrane (TM) helices in the lipid bilayer. To understand the mechanism by which the affinity of a common TM-TM interactive ...motif is controlled at the sequence level, we compared two well characterized GXXXG motif-containing homodimers, those formed by human erythrocyte protein glycophorin A (GpA, high-affinity dimer) and those formed by bacteriophage M13 major coat protein (MCP, low affinity dimer). In both constructs, the GXXXG motif is necessary for TM-TM association. Although the remaining interfacial residues (underlined) in GpA (LIXXGVXXGVXXT) differ from those in MCP (VVXXGAXXGIXXF), molecular modeling performed here indicated that GpA and MCP dimers possess the same overall fold. Thus, we could introduce GpA interfacial residues, alone and in combination, into the MCP sequence to help decrypt the determinants of dimer affinity. Using both in vivo TOXCAT assays and SDS-PAGE gel migration rates of synthetic peptides derived from TM regions of the proteins, we found that the most distal interfacial sites, 12 residues apart (and ∼18 Å in structural space), work in concert to control TM-TM affinity synergistically.
Abstract
Introduction
Non-compressible torso hemorrhage accounts for 70% of battlefield deaths. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is an emerging technology used to ...mitigate massive truncal hemorrhage. Use of REBOA on the battlefield is limited by the need for radiographic guided balloon placement. Radiofrequency identification (RFID) is a simple, portable, real-time technology utilized to detect retained sponges during surgery. We investigated the feasibility of RFID to confirm the placement of ER-REBOA.
Materials and Methods
This was a single-arm prospective proof-of-concept experimental study approved by the institutional review board at Naval Medical Center San Diego. The ER-REBOA (Prytime Medical Devices, Inc, Boerne, TX, USA) was modified by placement of a RFID tag. The tagged ER-REBOA was placed in zone I or zone III of the aorta in a previously perfused cadaver. Exact location was documented with X-ray. Five blinded individuals used the RF Assure Detection System (Medtronic, Minneapolis, MN, USA) handheld detection wand to predict catheter tip location from the xiphoid process (zone I) or pubic tubercle (zone III).
Results
In zone I, actual distance (Da) of the catheter tip was 11 cm from the xiphoid process. Mean predicted distance (Dp) from Da was 1.52 cm (95% CI 1.19–1.85). In zone III, Da was 14 cm from the pubic tubercle. Mean Dp from Da was 4.11 cm (95% CI 3.68–4.54). Sensitivity of detection was 100% in both zones. Specificity (Defined as Dp within 2 cm of Da) was 86% in zone I and 16% in zone III.
Conclusions
Using RFID to confirm the placement of ER-REBOA is feasible with specificity highest in zone I. Future work should focus on refining this technology for the forward-deployed setting.
Changes in iron supply to oceanic plankton are thought to have a significant effect on concentrations of atmospheric carbon dioxide by altering rates of carbon sequestration, a theory known as the ...'iron hypothesis'. For this reason, it is important to understand the response of pelagic biota to increased iron supply. Here we report the results of a mesoscale iron fertilization experiment in the polar Southern Ocean, where the potential to sequester iron-elevated algal carbon is probably greatest. Increased iron supply led to elevated phytoplankton biomass and rates of photosynthesis in surface waters, causing a large drawdown of carbon dioxide and macronutrients, and elevated dimethyl sulphide levels after 13 days. This drawdown was mostly due to the proliferation of diatom stocks. But downward export of biogenic carbon was not increased. Moreover, satellite observations of this massive bloom 30 days later, suggest that a sufficient proportion of the added iron was retained in surface waters. Our findings demonstrate that iron supply controls phytoplankton growth and community composition during summer in these polar Southern Ocean waters, but the fate of algal carbon remains unknown and depends on the interplay between the processes controlling export, remineralisation and timescales of water mass subduction.
The use of anti-tumour necrosis factor (TNF) agents has expanded significantly over the past few years, particularly for rheumatological diseases and Crohn’s disease. A number of associated ...opportunistic infections have been observed as a result of suppression of T cell-mediated immunity, the most frequent being tuberculosis. We report the first case of pulmonary actinomycosis in a patient receiving regular infusions of infliximab, an anti-TNF agent, for Crohn’s disease.
Abstract Background Neuropsychological (NP) performance is a consistent correlate of everyday functioning in schizophrenia, but it is unclear whether relationships between individual NP ability areas ...and domains of everyday functioning are general or specific. Assessments of real-world everyday functioning may be influenced by environmental and social factors (e.g., social security, disability status, opportunities and restrictions in living situations). This study examined the specificity of the relationships between different NP abilities and performance-based measures of social and living skills. Methods 181 ambulatory older (age> 50) patients with schizophrenia were examined with NP tests measuring episodic and working memory, executive functioning, verbal fluency, and processing speed. All subjects performed tasks examining social (Social Skills Performance Assessment: SSPA) and everyday living (UCSD Performance Based Skills Assessment: UPSA) skills. Results Using canonical analysis, the NP variables were used to predict the functional capacity measures. The analysis found that 37% of the variance in the functional capacity and NP measures was shared, X2 (54) = 106.29, p < .001. Two canonical roots described the cognitive variables and the roots were differentially associated with everyday living and social skills. The root loading on processing speed, episodic memory, and executive functions were associated with UPSA scores, while the root loading on working and episodic memory and verbal fluency were associated most strongly with social competence. Implications Social and everyday living skills deficits in patients with schizophrenia may reflect generally independent domains of functional outcome, linked through cognitive performance. The data suggest that somewhat different cognitive processes are associated with these two domains of functional capacity, although there appears to be some overlap, which may be due to the nature of the NP tests employed.
Bipolar Disorder (BD) is the 4
leading cause of disability worldwide among young people ages 10-24 years. Although the diagnosis is largely defined by the mood episodes associated with the illness, ...cognitive deficits are among the most persistent and disabling symptoms of illness and have a profound impact on clinical course and functional outcome. Specifically, trait-like impairment is common in the domains of attention, verbal learning, and executive function; these deficits contribute to functional disability and are targets for emerging treatments and preventions. Although considerable progress has been made over the past two decades, our understanding of the underlying causes of the cognitive deficits in BD remains surprisingly limited. As such, there are no approved treatments for this disabling symptom specific to BD. This article is protected by copyright. All rights reserved.
•A revised Hodgkin-Huxley type model is considered to show that cerebellar stellate cells exhibit type I excitability with a SNIC.•Model captures temporal changes in excitability (termed runup) ...during whole-cell patch-clamped configuration.•Model explains how transient single spikes during pre- and post-runup are produced when sub-threshold step currents are applied.•A slow region (ghost of SNIC) generated by the model produces biphasic first-spike latency.•Model exhibits switching in response to a pair of dynamic inhibitory/excitatory inputs.
Cerebellar stellate cells are inhibitory molecular interneurons that regulate the firing properties of Purkinje cells, the sole output of cerebellar cortex. Recent evidence suggests that these cells exhibit temporal increase in excitability during whole-cell patch-clamp configuration in a phenomenon termed runup. They also exhibit a non-monotonic first-spike latency profile as a function of the holding potential in response to a fixed step-current. In this study, we use modeling approaches to unravel the dynamics of runup and categorize the firing behavior of cerebellar stellate cells as either type I or type II oscillators. We then extend this analysis to investigate how the non-monotonic latency profile manifests itself during runup. We employ a previously developed, but revised, Hodgkin–Huxley type model to show that stellate cells are indeed type I oscillators possessing a saddle node on an invariant cycle (SNIC) bifurcation. The SNIC in the model acts as a “threshold” for tonic firing and produces a slow region in the phase space called the ghost of the SNIC. The model reveals that (i) the SNIC gets left-shifted during runup with respect to Iapp=Itest in the current-step protocol, and (ii) both the distance from the stable limit cycle along with the slow region produce the non-monotonic latency profile as a function of holding potential. Using the model, we elucidate how latency can be made arbitrarily large for a specific range of holding potentials close to the SNIC during pre-runup (post-runup). We also demonstrate that the model can produce transient single spikes in response to step-currents entirely below ISNIC, and that a pair of dynamic inhibitory and excitatory post-synaptic inputs can robustly evoke action potentials, provided that the magnitude of the inhibition is either low or high but not intermediate. Our results show that the topology of the SNIC is the key to explaining such behaviors.
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