Deciphering the 'fuzzy' interaction of FG nucleoporins and transport factors using SANS

The largely intrinsically disordered phenylalanine-glycine-rich nucleoporins (FG Nups) underline a selectivity mechanism, which enables the rapid translocation of transport factors (TFs) through the nuclear pore complexes (NPCs). Conflicting models of NPC transport have assumed that FG Nups undergo different conformational transitions upon interacting with TFs. To selectively characterize conformational changes in FG Nups induced by TFs we performed small-angle neutron scattering (SANS) with contrast matching. Conformational ensembles derived SANS data indicate an increase in the overall size of FG Nups is associated with TF interaction. Moreover, the organization of the FG motif in the interacting state is consistent with prior experimental analyses defining that FG motifs undergo conformational restriction upon interacting with TFs. These results provide structural insights into a highly dynamic interaction and illustrate how functional disorder imparts rapid and selective FG Nup / TF interactions.Comment: Minor revisions and reformattin

ABCG5 and ABCG8: More Than a Defense Against Xenosterols

The elucidation of the molecular basis of the rare disease, sitosterolemia, has revolutionized our mechanistic understanding of how dietary sterols are excreted and how cholesterol is eliminated from the body. Two proteins, ABCG5 and ABCG8, encoded by the sitosterolemia locus, work as obligate dimers to pump sterols out of hepatocytes and enterocytes. ABCG5/ABCG8 are key in regulating whole-body sterol trafficking, by eliminating sterols via the biliary tree as well as the intestinal tract. Importantly, these transporters keep xenosterols from accumulating in the body. The sitosterolemia locus has been genetically associated with lipid levels and downstream atherosclerotic disease, as well as formation of gallstones and the risk of gallbladder cancer. While polymorphic variants raise or lower the risks of these phenotypes, loss of function of this locus leads to more dramatic phenotypes, such as premature atherosclerosis, platelet dysfunction, and thrombocytopenia, and, perhaps, increased endocrine disruption and liver dysfunction. Whether small amounts of xenosterol exposure over a lifetime cause pathology in normal humans with polymorphic variants at the sitosterolemia locus remains largely unexplored. The purpose of this review will be to summarize the current state of knowledge, but also highlight key conceptual and mechanistic issues that remain to be explored

Methodological considerations for neuroimaging in deep brain stimulation of the subthalamic nucleus in Parkinson’s disease patients

Deep brain stimulation (DBS) of the subthalamic nucleus is a neurosurgical intervention for Parkinson’s disease patients who no longer appropriately respond to drug treatments. A small fraction of patients will fail to respond to DBS, develop psychiatric and cognitive side-effects, or incur surgery-related complications such as infections and hemorrhagic events. In these cases, DBS may require recalibration, reimplantation, or removal. These negative responses to treatment can partly be attributed to suboptimal pre-operative planning procedures via direct targeting through low-field and low-resolution magnetic resonance imaging (MRI). One solution for increasing the success and efficacy of DBS is to optimize preoperative planning procedures via sophisticated neuroimaging techniques such as high-resolution MRI and higher field strengths to improve visualization of DBS targets and vasculature. We discuss targeting approaches, MRI acquisition, parameters, and post-acquisition analyses. Additionally, we highlight a number of approaches including the use of ultra-high field (UHF) MRI to overcome limitations of standard settings. There is a trade-off between spatial resolution, motion artifacts, and acquisition time, which could potentially be dissolved through the use of UHF-MRI. Image registration, correction, and post-processing techniques may require combined expertise of traditional radiologists, clinicians, and fundamental researchers. The optimization of pre-operative planning with MRI can therefore be best achieved through direct collaboration between researchers and clinicians

Sensory gating functions of the auditory thalamus: Adaptation and modulations through noise-exposure and high-frequency stimulation in rats

The medial geniculate body (MGB) of the thalamus is an obligatory relay for auditory processing. A breakdown of adaptive filtering and sensory gating at this level may lead to multiple auditory dysfunctions, while high-frequency stimulation (HFS) of the MGB might mitigate aberrant sensory gating. To further investigate the sensory gating functions of the MGB, this study (i) recorded electrophysiological evoked potentials in response to continuous auditory stimulation, and (ii) assessed the effect of MGB HFS on these responses in noise-exposed and control animals. Pure-tone sequences were presented to assess differential sensory gating functions associated with stimulus pitch, grouping (pairing), and temporal regularity. Evoked potentials were recorded from the MGB and acquired before and after HFS (100 Hz). All animals (unexposed and noise-exposed, pre- and post-HFS) showed gating for pitch and grouping. Unexposed animals also showed gating for temporal regularity not found in noise-exposed animals. Moreover, only noise-exposed animals showed restoration comparable to the typical EP amplitude suppression pattern following MGB HFS. The current findings confirm adaptive thalamic sensory gating based on different sound characteristics and provide evidence that temporal regularity affects MGB auditory signaling

Chemical Composition and Antibacterial Activity of Essential Oils from Ferula L. Species against Methicillin-Resistant Staphylococcus aureus

WOS: 000445301800182PubMed ID: 29996498Essential oils (EOs) were obtained by hydrodistillation of various parts of Ferula ovina (Boiss.) Boiss., Ferula iliensis Krasn. ex. Korovin, and Ferula akitschkensis B. Fedtsch. ex Koso-Pol., collected in the flowering/budding and fruiting stages. Eight samples of EOs isolated from F. ovina and four samples from F. akitsckensis were analyzed by gas chromatography-mass spectrometry (GC-MS). The major constituents of F. ovina EOs were alpha-pinene (6.9-47.8%), beta-pinene (1.5-7.1%), sabinene (0.1-20.5%), beta-phellandrene (0-6.5%), trans-verbenol (0.9-7.4%), eremophilene (3.1-12%), and 6Z-2,5,5,10-tetramethyl-undeca-2,6,9-trien-8-one (0-13.7%). The major constituents of F. akitsckensis EOs were alpha-pinene (0-46.2%), beta-pinene (0-47.9%), sabinene (0-28.3%), eremophilene (0-10.6), beta-caryophyllene (0-7.5%), himachalen-7-ol (0-28.2%), and an himachalol derivative (0-8.3%). Samples of EOs from F. ovina, F. iliensis, and F. akitsckensis were evaluated for antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) pulse-field gel electrophoresis type USA300 (LAC). EOs from F. ovina exhibited the highest antibacterial activity compared to samples from other Ferula spp., with the most potent EOs being isolated from roots at the flowering and fruiting stages and stems at the fruiting stage (IC50 values of 19.1, 20.9, and 22.9 mu g/mL, respectively). Although EOs demonstrated concentration-dependent inhibition of MRSA growth, analysis of the major constituents (alpha-pinene, beta-pinene, and sabinene) showed that they had low activity, suggesting that other components were likely responsible for the observed bioactivity of the unfractionated EOs. Indeed, correlation of the GC-MS data with antibacterial activity suggested that the putative components responsible for antibacterial activity were, either individually or in combination, eremophilene and trans-verbenol. Overall, these results suggest that the EOs from F. ovina could have potential for use as alternative remedies for the treatment of infectious diseases caused by MRSA.Ministry of Education and Science of the Republic of Kazakhstan [2117/GF4]; United States National Institutes of Health IDeA Program COBRE Grant [GM110732]; United States National Institutes of Health IDeA Program CTR Grant [U54GM115371]; United States Department of Agriculture National Institute of Food and Agriculture Hatch project [1009546]; Montana University System Research Initiative [51040-MUSRI2015-03]; Montana State University Agricultural Experiment StationThis research was supported in part by Grant 2117/GF4 of the Ministry of Education and Science of the Republic of Kazakhstan; United States National Institutes of Health IDeA Program COBRE Grant GM110732 and CTR Grant U54GM115371; United States Department of Agriculture National Institute of Food and Agriculture Hatch project 1009546; Montana University System Research Initiative (51040-MUSRI2015-03); and the Montana State University Agricultural Experiment Station

Nonresonant powering of injectable nanoelectrodes enables wireless deep brain stimulation in freely moving mice

Devices that electrically modulate the deep brain have enabled important breakthroughs in the management of neurological and psychiatric disorders. Such devices are typically centimeter-scale, requiring surgical implantation and wired-in powering, which increases the risk of hemorrhage, infection, and damage during daily activity. Using smaller, remotely powered materials could lead to less invasive neuromodulation. Here, we present injectable, magnetoelectric nanoelectrodes that wirelessly transmit electrical signals to the brain in response to an external magnetic field. This mechanism of modulation requires no genetic modification of neural tissue, allows animals to freely move during stimulation, and uses nonresonant carrier frequencies. Using these nanoelectrodes, we demonstrate neuronal modulation in vitro and in deep brain targets in vivo. We also show that local subthalamic modulation promotes modulation in other regions connected via basal ganglia circuitry, leading to behavioral changes in mice. Magnetoelectric materials present a versatile platform technology for less invasive, deep brain neuromodulation

Density functional theory based screening of ternary alkali-transition metal borohydrides: A computational material design project

The dissociation of molecules, even the most simple hydrogen molecule, cannot be described accurately within density functional theory because none of the currently available functionals accounts for strong on-site correlation. This problem led to a discussion of properties that the local Kohn-Sham potential has to satisfy in order to correctly describe strongly correlated systems. We derive an analytic expression for the nontrivial form of the Kohn-Sham potential in between the two fragments for the dissociation of a single bond. We show that the numerical calculations for a one-dimensional two-electron model system indeed approach and reach this limit. It is shown that the functional form of the potential is universal, i.e., independent of the details of the two fragments.We acknowledge funding by the Spanish MEC (Grant No. FIS2007-65702-C02-01), “Grupos Consolidados UPV/EHU del Gobierno Vasco” (Grant No. IT-319-07), and the European Community through e-I3 ETSF project (Grant Agreement No. 211956).Peer reviewe

An examination of five theoretical foundations associated with localized thermosensory testing

Purpose: To assess five theoretical foundations underlying thermosensory testing using local thermal stimuli. Methods: Thermal sensation, discomfort and the confidence of thermal sensation scores were measured in 9 female and 8 male volunteers in response to 17 physical contact temperature stimuli, ranging between 18–42 °C. These were applied to their dorsal forearm and lateral torso, across two sessions. Results: Thermal sensation to physical temperature relationships followed a positive linear and sigmoidal fit at both forearm (r2 = 0.91/r2 = 0.91, respectively) and lateral torso (r2 = 0.90/ r2 = 0.91, respectively). Thermal discomfort to physical temperature relationships followed second and third-order fits at both forearm (r2 = 0.33/r2 = 0.34, respectively) and lateral torso (r2 = 0.38/r2 = 0.39, respectively) test sites. There were no sex-related or regional site differences in thermal sensation and discomfort across a wide range of physical contact temperatures. The median confidence of an individual’s thermal sensation rating was measured at 86%. Conclusion: The relation between thermal sensation and physical contact temperature was well described by both linear and sigmoidal models, i.e., the distance between the thermal sensation anchors is close to equal in terms of physical temperatures changes for the range studied. Participants rated similar thermal discomfort level in both cold and hot thermal stimuli for a given increase or decrease in physical contact temperature or thermal sensation. The confidence of thermal sensation rating did not depend on physical contact temperature