Interactions among Toxins That Inhibit N-type and P-type Calcium Channels

A number of peptide toxins from venoms of spiders and cone snails are high affinity ligands for voltage-gated calcium channels and are useful tools for studying calcium channel function and structure. Using whole-cell recordings from rat sympathetic ganglion and cerebellar Purkinje neurons, we studied toxins that target neuronal N-type (CaV2.2) and P-type (CaV2.1) calcium channels. We asked whether different toxins targeting the same channels bind to the same or different sites on the channel. Five toxins (ω-conotoxin-GVIA, ω-conotoxin MVIIC, ω-agatoxin-IIIA, ω-grammotoxin-SIA, and ω-agatoxin-IVA) were applied in pairwise combinations to either N- or P-type channels. Differences in the characteristics of inhibition, including voltage dependence, reversal kinetics, and fractional inhibition of current, were used to detect additive or mutually occlusive effects of toxins. Results suggest at least two distinct toxin binding sites on the N-type channel and three on the P-type channel. On N-type channels, results are consistent with blockade of the channel pore by ω-CgTx-GVIA, ω-Aga-IIIA, and ω-CTx-MVIIC, whereas grammotoxin likely binds to a separate region coupled to channel gating. ω-Aga-IIIA produces partial channel block by decreasing single-channel conductance. On P-type channels, ω-CTx-MVIIC and ω-Aga-IIIA both likely bind near the mouth of the pore. ω-Aga-IVA and grammotoxin each bind to distinct regions associated with channel gating that do not overlap with the binding region of pore blockers. For both N- and P-type channels, ω-CTx-MVIIC binding produces complete channel block, but is prevented by previous partial channel block by ω-Aga-IIIA, suggesting that ω-CTx-MVIIC binds closer to the external mouth of the pore than does ω-Aga-IIIA

Planck Constraints and Gravitational Wave Forecasts for Primordial Black Hole Dark Matter Seeded by Multifield Inflation

We perform a Markov Chain Monte Carlo (MCMC) analysis of a simple yet generic multifield inflation model characterized by two scalar fields coupled to each other and nonminimally coupled to gravity, fit to Planck 2018 cosmic microwave background (CMB) data. In particular, model parameters are constrained by data on the amplitude of the primordial power spectrum of scalar curvature perturbations on CMB scales $A_s$, the spectral index $n_s$, and the ratio of power in tensor to scalar modes $r$, with a prior that the primordial power spectrum should also lead to primordial black hole (PBH) production sufficient to account for the observed dark matter (DM) abundance. We find that $n_s$ in particular controls the constraints on our model. Whereas previous studies of PBH formation from an ultra-slow-roll phase of inflation have highlighted the need for at least one model parameter to be highly fine-tuned, we identify a degeneracy direction in parameter space such that shifts by $\sim 10\%$ of one parameter can be compensated by comparable shifts in other parameters while preserving a close fit between model predictions and observations. Furthermore, we find this allowed parameter region produces observable gravitational wave (GW) signals in the frequency ranges to which upcoming experiments are projected to be sensitive, including Advanced LIGO and Virgo, the Einstein Telescope (ET), Cosmic Explorer (CE), DECIGO, and LISA.Comment: 27 pages, 10 figures, 2 tables. Minor edits and references added to match published version (forthcoming in Physical Review D), including an additional appendix to discuss effects on the power spectrum from a phase of ultra-slow-roll evolutio

Plasticity of microvascular oxygenation control in rat fast-twitch muscle: effects of experimental creatine depletion

Aging, heart failure and diabetes each compromise the matching of O2 delivery (QO2)-to-metabolic requirements (O2 uptake, VO2) in skeletal muscle such that the O2 pressure driving blood-myocyte O2 flux (microvascular PO2, PmvO2) is reduced and contractile function impaired. In contrast, β-guanidinopropionic acid (β-GPA) treatment improves muscle contractile function, primarily in fast-twitch muscle (Moerland and Kushmerick, 1994). We tested the hypothesis that β-GPA (2% wt/BW in rat chow, 8 wk; n=14) would improve QO2-to-VO2 matching (elevated PmvO2) during contractions (4.5 V @ 1 Hz) in mixed (MG) and white (WG) portions of the gastrocnemius, both predominantly fast-twitch). Compared with control (CON), during contractions PmvO2 fell less following β-GPA (MG -54%, WG -26%, p<0.05), elevating steady-state PmvO2 (CON, MG: 10±2, WG: 9±1; β-GPA, MG 16±2, WG 18±2 mmHg, P<0.05). This reflected an increased QO2/VO2 ratio due primarily to a reduced VO2 in β-GPA muscles. It is likely that this adaptation helps facilitate the β-GPA-induced enhancement of contractile function in fast-twitch muscles

The Critical Coupling Likelihood Method: A new approach for seamless integration of environmental and operating conditions of gravitational wave detectors into gravitational wave searches

Any search effort for gravitational waves (GW) using interferometric detectors like LIGO needs to be able to identify if and when noise is coupling into the detector's output signal. The Critical Coupling Likelihood (CCL) method has been developed to characterize potential noise coupling and in the future aid GW search efforts. By testing two hypotheses about pairs of channels, CCL is able to identify undesirable coupled instrumental noise from potential GW candidates. Our preliminary results show that CCL can associate up to $\sim 80$ of observed artifacts with $SNR \geq 8$, to local noise sources, while reducing the duty cycle of the instrument by $\lesssim 15$. An approach like CCL will become increasingly important as GW research moves into the Advanced LIGO era, going from the first GW detection to GW astronomy.Comment: submitted CQ

Non-Fermi Liquid Behavior in Dilute Quadrupolar System Prx_{x}La1−x_{1-x}Pb3_3 with xx≤\le0.05

We have studied the low-temperature properties of Pr$_{x}$La$_{1-x}$Pb$_{3}$ with non-Kramers $\Gamma_{3}$ quadrupolar moments of the crystal-electric-field ground state, for a wide concentration range of Pr ions. For $x$$\le$0.05, the specific heat $C/T$ increases monotonically below $T$=1.5 K, which can be scaled with a characteristic temperature $T^{*}$ defined at each concentration $x$. The electrical resistivity $\rho$$(T)$ in the corresponding temperature region shows a marked decrease deviating from a Fermi-liquid behavior $\rho$$(T)$$\propto$$T^{2}$. The Kondo effect arising from the correlation between the dilute $\Gamma_{3}$ moments and the conduction electrons may give rise to such anomalous behavior

Assessing physiotherapists’ communication skills for promoting patient autonomy for self-management: reliability and validity of the communication evaluation in rehabilitation tool

Purpose: To assess the inter-rater reliability and concurrent validity of the Communication Evaluation in Rehabilitation Tool, which aims to externally assess physiotherapists competency in using Self-Determination Theory-based communication strategies in practice. Materials and methods: Audio recordings of initial consultations between 24 physiotherapists and 24 patients with chronic low back pain in four hospitals in Ireland were obtained as part of a larger randomised controlled trial. Three raters, all of whom had Ph.Ds in psychology and expertise in motivation and physical activity, independently listened to the 24 audio recordings and completed the 18-item Communication Evaluation in Rehabilitation Tool. Inter-rater reliability between all three raters was assessed using intraclass correlation coefficients. Concurrent validity was assessed using Pearson’s r correlations with a reference standard, the Health Care Climate Questionnaire. Results: The total score for the Communication Evaluation in Rehabilitation Tool is an average of all 18 items. Total scores demonstrated good inter-rater reliability (Intraclass Correlation Coefficient (ICC)?=?0.8) and concurrent validity with the Health Care Climate Questionnaire total score (range: r?=?0.7–0.88). Item-level scores of the Communication Evaluation in Rehabilitation Tool identified five items that need improvement. Conclusion: Results provide preliminary evidence to support future use and testing of the Communication Evaluation in Rehabilitation Tool.Implications for RehabilitationPromoting patient autonomy is a learned skill and while interventions exist to train clinicians in these skills there are no tools to assess how well clinicians use these skills when interacting with a patient. The lack of robust assessment has severe implications regarding both the fidelity of clinician training packages and resulting outcomes for promoting patient autonomy.This study has developed a novel measurement tool Communication Evaluation in Rehabilitation Tool and a comprehensive user manual to assess how well health care providers use autonomy-supportive communication strategies in real world-clinical settings.This tool has demonstrated good inter-rater reliability and concurrent validity in its initial testing phase.The Communication Evaluation in Rehabilitation Tool can be used in future studies to assess autonomy-supportive communication and undergo further measurement property testing as per our recommendations

Accuracy of ED Bedside Ultrasound for Identification of gallstones: retrospective analysis of 575 studies

Study Objective: To determine the ability of emergency department (ED) physicians to diagnose cholelithiasis with bedside ultrasound. Methods: ED gallbladder ultrasounds recorded over 37 months were compared to radiology ultrasound interpretation. Results: Of 1,690 ED gallbladder ultrasound scans performed during this period, radiology ultrasound was performed in 575/1690 (34%) cases. ED physician bedside interpretation was 88% sensitive [95% CI, 84-91] and 87% specific [95% CI, 82-91], while positive predictive value (PPV) was 91% [88- 94%] and negative predictive value (NPV) was 83% [78-87%], using radiology interpretation as the criterion reference. Conclusion: ED physician ultrasound of the gallbladder for cholelithiasis is both sensitive and specific

Educational Assessment of Medical Student Rotation in Emergency Ultrasound

Background: Medical student ultrasound education is sparse. In 2002, we began the first medical student rotation in emergency ultrasound. Objective: To evaluate if medical students can learn and retain sonographic skills during a two- or four-week elective. Methods: We gave students an exam on the first and last days of the rotation. Six months later, students took the exam a third time. A control group was used for comparison. Results: Over a 19-month period, we enrolled 45 students (25 on the two-week and 20 on the four-week elective). The four-week student post-test score was significantly better than the two- week posttest score (81% vs. 72%, p=0.003). On the six-month exam, the four-week student post-test score was significantly better than the two-week post-test score (77% vs 69%, p=0.008). The control group did not statistically improve. Conclusion: Medical students can learn bedside ultrasound interpretation with clinical integration and retain the knowledge six months later

Regulation of Lipid Biosynthesis in Saccharomyces cerevisiae by Fumonisin B\u3csub\u3e1\u3c/sub\u3e

The regulation of lipid biosynthesis in the yeast Saccharomyces cerevisiae by fumonisin B1 was examined. Fumonisin B1 inhibited the growth of yeast cells. Cells supplemented with fumonisin B1 accumulated free sphinganine and phytosphingosine in a dose-dependent manner. The cellular concentration of ceramide was reduced in fumonisin B1-supplemented cells. Ceramide synthase activity was found in yeast cell membranes and was inhibited by fumonisin B1. Fumonisin B1 inhibited the synthesis of the inositol-containing sphingo-lipids inositol phosphorylceramide, mannosylinositol phosphorylceramide, and mannosyldiinositol phosphorylceramide. Fumonisin B1 also caused a decrease in the synthesis of the major phospholipids synthesized via the CDP-diacylglycerol-dependent pathway and the synthesis of neutral lipids. The effects of fumonisin B1 and sphingoid bases on the activities of enzymes in the pathways leading to the synthesis of sphingolipids, phospholipids, and neutral lipids were also examined. Other than ceramide synthase, fumonisin B1 did not affect the activities of any of the enzymes examined. However, sphinganine and phytosphingosine inhibited the activities of inositol phosphorylceramide synthase, phosphatidylserine synthase, and phosphatidate phosphatase. These are key enzymes responsible for the synthesis of lipids in yeast. The data reported here indicated that the biosynthesis of sphingolipids, phospholipids and neutral lipids was coordinately regulated by fumonisin B1 through the regulation of lipid biosynthetic enzymes by sphingoid bases