Diverse voltage-sensitive dyes modulate GABAA receptor function

Voltage-sensitive dyes (VSDs) are important tools for assessing network and single-cell excitability, but an untested premise in most cases is that the dyes do not interfere with the parameters (membrane potential, excitability) that they are designed to measure. We found that popular members of several different families of voltage-sensitive dyes modulate GABA(A) receptor with maximum efficacy and potency similar to clinically used GABA(A) receptor modulators. Di-4-ANEPPS and DiBAC4(3) potentiated GABA function with micromolar and high nanomolar potency respectively and yielded strong maximum effects similar to barbiturates and neurosteroids. Newer blue oxonols had biphasic effects on GABA(A) receptor function at nanomolar and micromolar concentrations, with maximum potentiation comparable to that of saturating benzodiazepine effects. ANNINE 6 and ANNINE 6plus had no detectable effect on GABA(A) receptor function. Even dyes with no activity on GABA(A) receptors at baseline induced photodynamic enhancement of GABA(A) receptors. The basal effects of dyes were sufficient to prolong IPSCs and to dampen network activity in multielectrode array recordings. Therefore, the dual effects of voltage-sensitive dyes on GABAergic inhibition require caution in dye use for studies of excitability and network activity

Constellation Program (CxP) Crew Exploration Vehicle (CEV) Project Integrated Landing System

Crew Exploration Vehicle (CEV) Chief Engineer requested a risk comparison of the Integrated Landing System design developed by NASA and the design developed by Contractor- referred to as the LM 604 baseline. Based on the results of this risk comparison, the CEV Chief engineer requested that the NESC evaluate identified risks and develop strategies for their reduction or mitigation. The assessment progressed in two phases. A brief Phase I analysis was performed by the Water versus Land-Landing Team to compare the CEV Integrated Landing System proposed by the Contractor against the NASA TS-LRS001 baseline with respect to risk. A phase II effort examined the areas of critical importance to the overall landing risk, evaluating risk to the crew and to the CEV Crew Module (CM) during a nominal land-landing. The findings of the assessment are contained in this report

EEG dynamical correlates of focal and diffuse causes of coma

Background: Rapidly determining the causes of a depressed level of consciousness (DLOC) including coma is a common clinical challenge. Quantitative analysis of the electroencephalogram (EEG) has the potential to improve DLOC assessment by providing readily deployable, temporally detailed characterization of brain activity in such patients. While used commonly for seizure detection, EEG-based assessment of DLOC etiology is less well-established. As a first step towards etiological diagnosis, we sought to distinguish focal and diffuse causes of DLOC through assessment of temporal dynamics within EEG signals. Methods: We retrospectively analyzed EEG recordings from 40 patients with DLOC with consensus focal or diffuse culprit pathology. For each recording, we performed a suite of time-series analyses, then used a statistical framework to identify which analyses (features) could be used to distinguish between focal and diffuse cases. Results: Using cross-validation approaches, we identified several spectral and non-spectral EEG features that were significantly different between DLOC patients with focal vs. diffuse etiologies, enabling EEG-based classification with an accuracy of 76%. Conclusions: Our findings suggest that DLOC due to focal vs. diffuse injuries differ along several electrophysiological parameters. These results may form the basis of future classification strategies for DLOC and coma that are more etiologically-specific and therefore therapeutically-relevant. Electronic supplementary material The online version of this article (doi: 10.1186/s12883-017-0977-0) contains supplementary material, which is available to authorized users

Identifying uncertainties in Arctic climate change projections

Wide ranging climate changes are expected in the Arctic by the end of the 21st century, but projections of the size of these changes vary widely across current global climate models. This variation represents a large source of uncertainty in our understanding of the evolution of Arctic climate. Here we systematically quantify and assess the model uncertainty in Arctic climate changes in two CO2 doubling experiments: a multimodel ensemble (CMIP3) and an ensemble constructed using a single model (HadCM3) with multiple parameter perturbations (THC-QUMP). These two ensembles allow us to assess the contribution that both structural and parameter variations across models make to the total uncertainty and to begin to attribute sources of uncertainty in projected changes. We find that parameter uncertainty is an major source of uncertainty in certain aspects of Arctic climate. But also that uncertainties in the mean climate state in the 20th century, most notably in the northward Atlantic ocean heat transport and Arctic sea ice volume, are a significant source of uncertainty for projections of future Arctic change. We suggest that better observational constraints on these quantities will lead to significant improvements in the precision of projections of future Arctic climate change

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Learn from the past, prepare for the future: Impacts of education and experience on disaster preparedness in the Philippines and Thailand

This study aims at understanding the role of education in promoting disaster preparedness. Strengthening resilience to climate-related hazards is an urgent target of Goal 13 of the Sustainable Development Goals. Preparing for a disaster such as stockpiling of emergency supplies or having a family evacuation plan can substantially minimize loss and damages from natural hazards. However, the levels of household disaster preparedness are often low even in disaster-prone areas. Focusing on determinants of personal disaster preparedness, this paper investigates: (1) pathways through which education enhances preparedness; and (2) the interplay between education and experience in shaping preparedness actions. Data analysis is based on face-to-face surveys of adults aged ≥15 years in Thailand (N = 1,310) and the Philippines (N = 889, female only). Controlling for socio-demographic and contextual characteristics, we find that formal education raises the propensity to prepare against disasters. Using the KHB method to further decompose the education effects, we find that the effect of education on disaster preparedness is mainly mediated through social capital and disaster risk perception in Thailand whereas there is no evidence that education is mediated through observable channels in the Philippines. This suggests that the underlying mechanisms explaining the education effects are highly context-specific. Controlling for the interplay between education and disaster experience, we show that education raises disaster preparedness only for those households that have not been affected by a disaster in the past. Education improves abstract reasoning and anticipation skills such that the better educated undertake preventive measures without needing to first experience the harmful event and then learn later. In line with recent efforts of various UN agencies in promoting education for sustainable development, this study provides a solid empirical evidence showing positive externalities of education in disaster risk reduction

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN. We present a computational study determining the frequency and extent of alterations of the MYC network across the 33 human cancers of TCGA. These data, together with MYC, positively correlated pathways as well as mutually exclusive cancer genes, will be a resource for understanding MYC-driven cancers and designing of therapeutics

A case study of voltage-gated potassium channel antibody-related limbic encephalitis with PET/MRI findings

Preclinical and clinical studies have demonstrated the significance of inflammation and autoantibodies in epilepsy, and the use of immunotherapies in certain situations has become an established practice. Temporal lobe epilepsy can follow paraneoplastic or nonparaneoplastic limbic encephalitis associated with antibodies directed against brain antigens. Here, we focus on a patient with worsening confusion and temporal lobe seizures despite treatment with antiepileptic medications. Serial brain MRIs did not conclusively reveal structural abnormalities, so the patient underwent brain PET/MRI to simultaneously evaluate brain structure and function, revealing bitemporal abnormalities. The patient was diagnosed with voltage-gated potassium channel antibody-related limbic encephalitis based on clinical presentation, imaging findings, and antibody testing. Treatment included the addition of a second antiepileptic agent and oral steroids. His seizures and cognitive deficits improved and stabilized