Increased markers of cardiac vagal activity in leucine-rich repeat kinase 2-associated Parkinson's disease.

PurposeCardiac autonomic dysfunction manifests as reduced heart rate variability (HRV) in idiopathic Parkinson's disease (PD), but no significant reduction has been found in PD patients who carry the LRRK2 mutation. Novel HRV features have not been investigated in these individuals. We aimed to assess cardiac autonomic modulation through standard and novel approaches to HRV analysis in individuals who carry the LRRK2 G2019S mutation.MethodsShort-term electrocardiograms were recorded in 14 LRRK2-associated PD patients, 25 LRRK2-non-manifesting carriers, 32 related non-carriers, 20 idiopathic PD patients, and 27 healthy controls. HRV measures were compared using regression modeling, controlling for age, sex, mean heart rate, and disease duration. Discriminant analysis highlighted the feature combination that best distinguished LRRK2-associated PD from controls.ResultsBeat-to-beat and global HRV measures were significantly increased in LRRK2-associated PD patients compared with controls (e.g., deceleration capacity of heart rate: p = 0.006) and idiopathic PD patients (e.g., 8th standardized moment of the interbeat interval distribution: p = 0.0003), respectively. LRRK2-associated PD patients also showed significantly increased irregularity of heart rate dynamics, as quantified by Rényi entropy, when compared with controls (p = 0.002) and idiopathic PD patients (p = 0.0004). Ordinal pattern statistics permitted the identification of LRRK2-associated PD individuals with 93% sensitivity and 93% specificity. Consistent results were found in a subgroup of LRRK2-non-manifesting carriers when compared with controls.ConclusionsIncreased beat-to-beat HRV in LRRK2 G2019S mutation carriers compared with controls and idiopathic PD patients may indicate augmented cardiac autonomic cholinergic activity, suggesting early impairment of central vagal feedback loops in LRRK2-associated PD

Resolving Decades of Periodic Spirals from the Wolf-Rayet Dust Factory WR 112

WR 112 is a dust-forming carbon-rich Wolf-Rayet (WC) binary with a dusty circumstellar nebula that exhibits a complex asymmetric morphology, which traces the orbital motion and dust formation in the colliding winds of the central binary. Unraveling the complicated circumstellar dust emission around WR 112 therefore provides an opportunity to understand the dust formation process in colliding-wind WC binaries. In this work, we present a multi-epoch analysis of the circumstellar dust around WR 112 using seven high spatial resolution (FWHM $\sim0.3-0.4''$) N-band ($\lambda \sim12$ $\mu$m) imaging observations spanning almost 20 years and includes newly obtained images from Subaru/COMICS in Oct 2019. In contrast to previous interpretations of a face-on spiral morphology, we observe clear evidence of proper motion of the circumstellar dust around WR 112 consistent with a nearly edge-on spiral with a $\theta_s=55^\circ$ half-opening angle and a $\sim20$-yr period. The revised near edge-on geometry of WR 112 reconciles previous observations of highly variable non-thermal radio emission that was inconsistent with a face-on geometry. We estimate a revised distance to WR 112 of $d = 3.39^{+0.89}_{-0.84}$ kpc based on the observed dust expansion rate and a spectroscopically derived WC terminal wind velocity of $v_\infty= 1230\pm260$ km s$^{-1}$. With the newly derived WR 112 parameters we fit optically-thin dust spectral energy distribution models and determine a dust production rate of $\dot{M}_d=2.7^{+1.0}_{-1.3}\times10^{-6}$ M$_\odot$ yr$^{-1}$, which demonstrates that WR 112 is one of the most prolific dust-making WC systems known.Comment: 17 pages, 9 figures, 1 animated gif, accepted for publication in Ap

Resolving Decades of Periodic Spirals from the Wolf–Rayet Dust Factory WR 112

WR 112 is a dust-forming carbon-rich Wolf–Rayet (WC) binary with a dusty circumstellar nebula that exhibits a complex asymmetric morphology, which traces the orbital motion and dust formation in the colliding winds of the central binary. Unraveling the complicated circumstellar dust emission around WR 112 therefore provides an opportunity to understand the dust formation process in colliding-wind WC binaries. In this work, we present a multi-epoch analysis of the circumstellar dust around WR 112 using seven high spatial resolution (FWHM ~ 0farcs3–0farcs4) N-band (λ ~ 12 μm) imaging observations spanning almost 20 yr and that includes images obtained from Subaru/COMICS in 2019 October. In contrast to previous interpretations of a face-on spiral morphology, we observe clear evidence of proper motion of the circumstellar dust around WR 112 consistent with a nearly edge-on spiral with a θ_s = 55° half-opening angle and a ~20 yr period. The revised near edge-on geometry of WR 112 reconciles previous observations of highly variable nonthermal radio emission that was inconsistent with a face-on geometry. We estimate a revised distance to WR 112 of d = 3.39_(-0.84)^(+0.89) kpc based on the observed dust expansion rate and a spectroscopically derived WC terminal wind velocity of v_∞ = 1230 ± 260 km s⁻¹. With the newly derived WR 112 parameters, we fit optically thin dust spectral energy distribution models and determine a dust production rate of Ṁ_d = 2.7_(-1.3)^(+1.0) x 10⁻⁶ M_⊙ yr⁻¹, which demonstrates that WR 112 is one of the most prolific dust-making WC systems known

Using bond-length dependent transferable force constants to predict vibrational entropies in Au-Cu, Au-Pd, and Cu-Pd alloys

A model is tested to rapidly evaluate the vibrational properties of alloys with site disorder. It is shown that length-dependent transferable force constants exist, and can be used to accurately predict the vibrational entropy of substitutionally ordered and disordered structures in Au-Cu, Au-Pd, and Cu-Pd. For each relevant force constant, a length- dependent function is determined and fitted to force constants obtained from first-principles pseudopotential calculations. We show that these transferable force constants can accurately predict vibrational entropies of L1$_{2}$-ordered and disordered phases in Cu$_{3}$Au, Au$_{3}$Pd, Pd$_{3}$Au, Cu$_{3}$Pd, and Pd$_{3}$Au. In addition, we calculate the vibrational entropy difference between L1$_{2}$-ordered and disordered phases of Au$_{3}$Cu and Cu$_{3}$Pt.Comment: 9 pages, 6 figures, 3 table

Placebos without Deception: A Randomized Controlled Trial in Irritable Bowel Syndrome

Background: Placebo treatment can significantly influence subjective symptoms. However, it is widely believed that response to placebo requires concealment or deception. We tested whether open-label placebo (non-deceptive and non-concealed administration) is superior to a no-treatment control with matched patient-provider interactions in the treatment of irritable bowel syndrome (IBS). Methods: Two-group, randomized, controlled three week trial (August 2009-April 2010) conducted at a single academic center, involving 80 primarily female (70%) patients, mean age 47±18 with IBS diagnosed by Rome III criteria and with a score ≥150 on the IBS Symptom Severity Scale (IBS-SSS). Patients were randomized to either open-label placebo pills presented as “placebo pills made of an inert substance, like sugar pills, that have been shown in clinical studies to produce significant improvement in IBS symptoms through mind-body self-healing processes” or no-treatment controls with the same quality of interaction with providers. The primary outcome was IBS Global Improvement Scale (IBS-GIS). Secondary measures were IBS Symptom Severity Scale (IBS-SSS), IBS Adequate Relief (IBS-AR) and IBS Quality of Life (IBS-QoL). Findings: Open-label placebo produced significantly higher mean (±SD) global improvement scores (IBS-GIS) at both 11-day midpoint (5.2±1.0 vs. 4.0±1.1, p<.001) and at 21-day endpoint (5.0±1.5 vs. 3.9±1.3, p = .002). Significant results were also observed at both time points for reduced symptom severity (IBS-SSS, p = .008 and p = .03) and adequate relief (IBS-AR, p = .02 and p = .03); and a trend favoring open-label placebo was observed for quality of life (IBS-QoL) at the 21-day endpoint (p = .08). Conclusion: Placebos administered without deception may be an effective treatment for IBS. Further research is warranted in IBS, and perhaps other conditions, to elucidate whether physicians can benefit patients using placebos consistent with informed consent. Trial Registration ClinicalTrials.gov NCT0101019

The Translation Regulatory Subunit eIF3f Controls the Kinase-Dependent mTOR Signaling Required for Muscle Differentiation and Hypertrophy in Mouse

The mTORC1 pathway is required for both the terminal muscle differentiation and hypertrophy by controlling the mammalian translational machinery via phosphorylation of S6K1 and 4E-BP1. mTOR and S6K1 are connected by interacting with the eIF3 initiation complex. The regulatory subunit eIF3f plays a major role in muscle hypertrophy and is a key target that accounts for MAFbx function during atrophy. Here we present evidence that in MAFbx-induced atrophy the degradation of eIF3f suppresses S6K1 activation by mTOR, whereas an eIF3f mutant insensitive to MAFbx polyubiquitination maintained persistent phosphorylation of S6K1 and rpS6. During terminal muscle differentiation a conserved TOS motif in eIF3f connects mTOR/raptor complex, which phosphorylates S6K1 and regulates downstream effectors of mTOR and Cap-dependent translation initiation. Thus eIF3f plays a major role for proper activity of mTORC1 to regulate skeletal muscle size

Effect of Anesthesia on Microelectrode Recordings during Deep Brain Stimulation Surgery in Tourette Syndrome Patients

Background: Deep brain stimulation (DBS) is an accepted treatment for patients with medication-resistant Tourette syndrome (TS). Sedation is commonly required during electrode implantation to attenuate anxiety, pain, and severe tics. Anesthetic agents potentially impair the quality of microelectrode recordings (MER). Little is known about the effect of these anesthetics on MER in patients with TS. We describe our experience with different sedative regimens on MER and tic severity in patients with TS. Methods: The clinical records of all TS patients who underwent DBS surgery between 2010 and 2018 were reviewed. Demographic data, stimulation targets, anesthetic agents, perioperative complications, and MER from each hemisphere were collected and analyzed. Single-unit activity was identified by filtering spiking activity from broadband MER data and principal component analysis with K-means clustering. Vocal and motor tics which caused artifacts in the MER data were manually selected using visual and auditory inspection. Results: Six patients underwent bilateral DBS electrode implantation. In all patients, the target was the anterior internal globus pallidus. Patient comfort and hemodynamic and respiratory stability were maintained with conscious sedation with one or more of the following anesthetic drugs: propofol, midazolam, remifentanil, clonidine, and dexmedetomidine. Good quality MER and clinical testing were obtained in 9 hemispheres of 6 patients. In 3 patients, MER quality was poor on one side. Conclusion: Cautiously applied sedative drugs can provide patient comfort, hemodynamic and respiratory stability, and suppress severe tics, with minimal interference with MER. (C) 2019 The Author(s) Published by S. Karger AG, Base

The Effect of Lattice Vibrations on Substitutional Alloy Thermodynamics

A longstanding limitation of first-principles calculations of substitutional alloy phase diagrams is the difficulty to account for lattice vibrations. A survey of the theoretical and experimental literature seeking to quantify the impact of lattice vibrations on phase stability indicates that this effect can be substantial. Typical vibrational entropy differences between phases are of the order of 0.1 to 0.2 k_B/atom, which is comparable to the typical values of configurational entropy differences in binary alloys (at most 0.693 k_B/atom). This paper describes the basic formalism underlying ab initio phase diagram calculations, along with the generalization required to account for lattice vibrations. We overview the various techniques allowing the theoretical calculation and the experimental determination of phonon dispersion curves and related thermodynamic quantities, such as vibrational entropy or free energy. A clear picture of the origin of vibrational entropy differences between phases in an alloy system is presented that goes beyond the traditional bond counting and volume change arguments. Vibrational entropy change can be attributed to the changes in chemical bond stiffness associated with the changes in bond length that take place during a phase transformation. This so-called ``bond stiffness vs. bond length'' interpretation both summarizes the key phenomenon driving vibrational entropy changes and provides a practical tool to model them.Comment: Submitted to Reviews of Modern Physics 44 pages, 6 figure