On the atomic structure of cocaine in solution

Cocaine is an amphiphilic drug which has the ability to cross the blood–brain barrier (BBB). Here, a combination of neutron diffraction and computation has been used to investigate the atomic scale structure of cocaine in aqueous solutions. Both the observed conformation and hydration of cocaine appear to contribute to its ability to cross hydrophobic layers afforded by the BBB, as the average conformation yields a structure which might allow cocaine to shield its hydrophilic regions from a lipophilic environment. Specifically, the carbonyl oxygens and amine group on cocaine, on average, form ~5 bonds with the water molecules in the surrounding solvent, and the top 30% of water molecules within 4 Å of cocaine are localized in the cavity formed by an internal hydrogen bond within the cocaine molecule. This water mediated internal hydrogen bonding suggests a mechanism of interaction between cocaine and the BBB that negates the need for deprotonation prior to interaction with the lipophilic portions of this barrier. This finding also has important implications for understanding how neurologically active molecules are able to interact with both the blood stream and BBB and emphasizes the use of structural measurements in solution in order to understand important biological function.Peer ReviewedPostprint (author's final draft

High-accuracy Casimir-Polder force calculations using the Discontinuous Galerkin Time-Domain method

We describe a numerical time-domain approach for high-accuracy calculations of Casimir-Polder forces near micro-structured materials. The use of a time-domain formulation enables the investigation of a broad range of materials described by advanced material models, including nonlocal response functions. We validate the method by a number of example calculations for which we thoroughly investigate the convergence properties of the method, and comparing to analytical reference calculations, we find average relative errors as low as a few parts in a million. As an application example, we investigate the anisotropy-induced repulsive behavior of the Casimir-Polder force near a sharp gold wedge described by a hydrodynamic Drude model.Comment: 17 pages, 11 figure

Nanostructured In3SbTe2 antennas enable switching from sharp dielectric to broad plasmonic resonances

Phase-change materials (PCMs) allow for non-volatile resonance tuning of nanophotonic components. Upon switching, they offer a large dielectric contrast between their amorphous and crystalline phases. The recently introduced “plasmonic PCM” In3SbTe2 (IST) additionally features in its crystalline phase a sign change of its permittivity over a broad infrared spectral range. While optical resonance switching in unpatterned IST thin films has been investigated before, nanostructured IST antennas have not been studied, yet. Here, we present numerical and experimental investigations of nanostructured IST rod and disk antennas. By crystallizing the IST with microsecond laser pulses, we switched individual antennas from narrow dielectric to broad plasmonic resonances. For the rod antennas, we demonstrated a resonance shift of up to 1.2 µm (twice the resonance width), allowing on/off switching of plasmonic resonances with a contrast ratio of 2.7. With the disk antennas, we realized an increase of the resonance width by more than 800% from 0.24 µm to 1.98 µm while keeping the resonance wavelength constant. Further, we demonstrated intermediate switching states by tuning the crystallization depth within the resonators. Our work empowers future design concepts for nanophotonic applications like active spectral filters, tunable absorbers, and switchable flat optics

Chemoreflex Mediated Arrhythmia during Apnea at 5050m in Low but not High Altitude Natives

Peripheral chemoreflex mediated increases in both parasympathetic and sympathetic drive under chronic hypoxia may evoke bradyarrhythmias during apneic periods. We determined whether 1) voluntary apnea unmasks arrhythmia at low (344 m) and high (5,050 m) altitude, 2) high-altitude natives (Nepalese Sherpa) exhibit similar cardiovagal responses at altitude, and 3) bradyarrhythmias at altitude are partially chemoreflex mediated. Participants were grouped as Lowlanders ( n = 14; age = 27 ± 6 yr) and Nepalese Sherpa ( n = 8; age = 32 ± 11 yr). Lowlanders were assessed at 344 and 5,050 m, whereas Sherpa were assessed at 5,050 m. Heart rate (HR) and rhythm (lead II ECG) were recorded during rest and voluntary end-expiratory apnea. Peripheral chemoreflex contributions were assessed in Lowlanders ( n = 7) at altitude after 100% oxygen. Lowlanders had higher resting HR at altitude (70 ± 15 vs. 61 ± 15 beats/min; P &lt; 0.01) that was similar to Sherpa (71 ± 5 beats/min; P = 0.94). High-altitude apnea caused arrhythmias in 11 of 14 Lowlanders [junctional rhythm ( n = 4), 3° atrioventricular block ( n = 3), sinus pause ( n = 4)] not present at low altitude and larger marked bradycardia (nadir −39 ± 18 beats/min; P &lt; 0.001). Sherpa exhibited a reduced bradycardia response during apnea compared with Lowlanders ( P &lt; 0.001) and did not develop arrhythmias. Hyperoxia blunted bradycardia (nadir −10 ± 14 beats/min; P &lt; 0.001 compared with hypoxic state) and reduced arrhythmia incidence (3 of 7 Lowlanders). Degree of bradycardia was significantly related to hypoxic ventilatory response (HVR) at altitude and predictive of arrhythmias ( P &lt; 0.05). Our data demonstrate apnea-induced bradyarrhythmias in Lowlanders at altitude but not in Sherpa (potentially through cardioprotective phenotypes). The chemoreflex is an important mechanism in genesis of bradyarrhythmias, and the HVR may be predictive for identifying individual susceptibility to events at altitude. NEW &amp; NOTEWORTHY The peripheral chemoreflex increases both parasympathetic and sympathetic drive under chronic hypoxia. We found that this evoked bradyarrhythmias when combined with apneic periods in Lowlanders at altitude, which become relieved through supplemental oxygen. In contrast, high-altitude residents (Nepalese Sherpa) do not exhibit bradyarrhythmias during apnea at altitude through potential cardioprotective adaptations. The degree of bradycardia and bradyarrhythmias was related to the hypoxic ventilatory response, demonstrating that the chemoreflex plays an important role in these findings. </jats:p

Increased frequency of Tim-3 expressing T cells is associated with symptomatic West Nile virus infection

More than a decade after West Nile virus (WNV) entered North America, and despite a significant increase in reported cases during the 2012 and 2013 seasons, no treatment or vaccine for humans is available. Although antiviral T cells contribute to the control of WNV, little is known about their regulation during acute infection. We analyzed the expression of Tim-3 and PD-1, two recently identified T cell negative immune checkpoint receptors, over the course of WNV infection. Symptomatic WNV+ donors exhibited higher frequencies of Tim-3+ cells than asymptomatic subjects within naïve/early differentiated CD28+/-CD57-CD4+ and differentiated CD28-CD57-CD8+ T cells. Our study links Tim-3-expression on T cells during acute WNV infection with the development of symptomatic disease, suggesting Tim-3 and its ligands could be targeted therapeutically to alter anti-WNV immunity and improve disease outcome

Whole-Genome Analysis of the SHORT-ROOT Developmental Pathway in Arabidopsis

Stem cell function during organogenesis is a key issue in developmental biology. The transcription factor SHORT-ROOT (SHR) is a critical component in a developmental pathway regulating both the specification of the root stem cell niche and the differentiation potential of a subset of stem cells in the Arabidopsis root. To obtain a comprehensive view of the SHR pathway, we used a statistical method called meta-analysis to combine the results of several microarray experiments measuring the changes in global expression profiles after modulating SHR activity. Meta-analysis was first used to identify the direct targets of SHR by combining results from an inducible form of SHR driven by its endogenous promoter, ectopic expression, followed by cell sorting and comparisons of mutant to wild-type roots. Eight putative direct targets of SHR were identified, all with expression patterns encompassing subsets of the native SHR expression domain. Further evidence for direct regulation by SHR came from binding of SHR in vivo to the promoter regions of four of the eight putative targets. A new role for SHR in the vascular cylinder was predicted from the expression pattern of several direct targets and confirmed with independent markers. The meta-analysis approach was then used to perform a global survey of the SHR indirect targets. Our analysis suggests that the SHR pathway regulates root development not only through a large transcription regulatory network but also through hormonal pathways and signaling pathways using receptor-like kinases. Taken together, our results not only identify the first nodes in the SHR pathway and a new function for SHR in the development of the vascular tissue but also reveal the global architecture of this developmental pathway

Responsible Human-Robot Interaction with Anthropomorphic Service Robots: State of the Art of an Interdisciplinary Research Challenge

Anthropomorphic service robots are on the rise. The more capable they become and the more regular they are applied in real-world settings, the more critical becomes the responsible design of human-robot interaction (HRI) with special attention to human dignity, transparency, privacy, and robot compliance. In this paper we review the interdisciplinary state of the art relevant for the responsible design of HRI. Furthermore, directions for future research on the responsible design of HRI with anthropomorphic service robots are suggested

Global REACH: Assessment of brady-arrhythmias in Andeans and Lowlanders during apnea at 4330m

BACKGROUND: Ascent to altitude increases the prevalence of arrhythmogenesis in low-altitude dwelling populations (Lowlanders). High altitude populations (ie. Nepalese Sherpa) may have arrhythmias resistant adaptations that prevent arrhythmogenesis at altitude, though this has not been documented in other High altitude groups, including those diagnosed with chronic mountain sickness (CMS). We investigated whether healthy (CMS-) and CMS afflicted (CMS+) Andeans exhibit cardiac arrhythmias under acute apneic stress at altitude. METHODS AND RESULTS: Electrocardiograms (lead II) were collected in CMS- (N=9), CMS+ (N=8), and Lowlanders (N= 13) following several days at 4330m (Cerro de Pasco, Peru). ECG rhythm and HR were assessed at both rest and during maximal volitional apnea (End-Expiratory [EXP]). Both CMS- and CMS+ had similar basal HR (69 ± 8 beats/min vs. 62 ± 11 beats/min), while basal HR was higher in Lowlanders (77 ± 18 beats/min; P<0.05 versus CMS+). Apnea elicited significant bradycardia (nadir -32 ± 15 beats/min; P<0.01) and the development of arrhythmias in 8/13 Lowlanders (junctional rhythm, 3° atrio-venticular block, sinus pause). HR was preserved was prior to volitional breakpoint in both CMS- (nadir -6 ± 1 beat/min) and CMS+ (1 ±12 beats/min), with 2/17 Andeans developing arrhythmias ( 1 CMS+ and 1 CMS-; both Premature Atrial Contraction) prior to breakpoint. CONCLUSIONS: Andeans showed an absence of arrhythmias and preserved HR response to volitional apnea at altitude, demonstrating that potential cardio-resistant adaptations to arrhythmogenesis exist across permanent HA populations. Acclimatized Lowlanders have further demonstrated an increased prevalence of arrhythmias at altitude