Atomoxetine (ATX), a drug for treatment of depression and ADHD, has a high affinity for the norepinephrine transporter (NET); however, our previous study showed it had a blocking effect similar to ...fluoxetine on binding of 11CDASB, a selective serotonin transporter (SERT) ligand. Whether the therapeutic effects of ATX are due to inhibition of either or both transporters is not known. Here we report our comparative PET imaging studies with 11CMRB (a NET ligand) and 11CAFM (a SERT ligand) to evaluate in vivo IC50 values of ATX in monkeys.
Rhesus monkeys were scanned up to four times with each tracer with up to four doses of ATX. ATX or saline (placebo) infusion began 2h before each PET scan, lasting until the end of the 2-h scan. The final infusion rates were 0.01–0.12mg/kg/h and 0.045–1.054mg/kg/h for the NET and SERT studies, respectively. ATX plasma levels and metabolite-corrected arterial input functions were measured. Distribution volumes (VT) and IC50 values were estimated.
ATX displayed dose-dependent occupancy on both NET and SERT, with a higher occupancy on NET: IC50 of 31±10 and 99±21ng/mL plasma for NET and SERT, respectively. At a clinically relevant dose (1.0–1.8mg/kg, approx. 300–600ng/mL plasma), ATX would occupy >90% of NET and >85% of SERT. This extrapolation assumes comparable free fraction of ATX in humans and non-human primates.
Our data suggests that ATX at clinically relevant doses greatly occupies both NET and SERT. Thus, therapeutic modes of ATX action for treatment of depression and ADHD may be more complex than selective blockade of NET.
•We examine the in vivo selectivity of atomoxetine (ATX) with PET.•11CMRB and 11CAFM were used to evaluate ATX IC50 values for NET & SERT.•ATX at clinically relevant doses greatly occupies both NET and SERT.•ATX for treatment of depression and ADHD may be more complex than current thinking.•The implications on the therapeutic mechanisms of ATX are discussed.
The worm Caenorhabditis elegans is a model system for studying many aspects of biology, including host responses to bacterial pathogens, but it is not known to support replication of any virus. ...Plants and insects encode multiple Dicer enzymes that recognize distinct precursors of small RNAs and may act cooperatively. However, it is not known whether the single Dicer of worms and mammals is able to initiate the small RNA-guided RNA interference (RNAi) antiviral immunity as occurs in plants and insects. Here we show complete replication of the Flock house virus (FHV) bipartite, plus-strand RNA genome in C. elegans. We show that FHV replication in C. elegans triggers potent antiviral silencing that requires RDE-1, an Argonaute protein essential for RNAi mediated by small interfering RNAs (siRNAs) but not by microRNAs. This immunity system is capable of rapid virus clearance in the absence of FHV B2 protein, which acts as a broad-spectrum RNAi inhibitor upstream of rde-1 by targeting the siRNA precursor. This work establishes a C. elegans model for genetic studies of animal virus-host interactions and indicates that mammals might use a siRNA pathway as an antiviral response.
Aqueous rechargeable zinc metal batteries promise attractive advantages including safety, high volumetric energy density, and low cost; however, such benefits cannot be unlocked unless Zn ...reversibility meets stringent commercial viability. Herein, we report remarkable improvements on Zn reversibility in aqueous electrolytes when phosphonium‐based cations are used to reshape interfacial structures and interphasial chemistries, particularly when their ligands contain an ether linkage. This novel aqueous electrolyte supports unprecedented Zn reversibility by showing dendrite‐free Zn plating/stripping for over 6400 h at 0.5 mA cm−2, or over 280 h at 2.5 mA cm−2, with coulombic efficiency above 99 % even with 20 % Zn utilization per cycle. Excellent full cell performance is demonstrated with Na2V6O16⋅1.63 H2O cathode, which cycles for 2000 times at 300 mA g−1. The microscopic characterization and modeling identify the mechanism of unique interphase chemistry from phosphonium and its functionalities as the key factors responsible for dictating reversible Zn chemistry
The addition of phosphonium‐based supporting salts and a subtle difference in their ligand chemistry remarkably improves the reversibility of aqueous Zn electrolytes. By promoting interphase formation, P444(2O1)‐TFSI supports a Zn coulombic efficiency above 99 % even at 1.17 mA cm−2 with 20 % Zn utilization per cycle, and a stable Zn∥Na2V6O16⋅1.63 H2O cell cycling.
Long-distance quantum communication and networking require quantum memory nodes with efficient optical interfaces and long memory times. We report the realization of an integrated two-qubit network ...node based on silicon-vacancy centers (SiVs) in diamond nanophotonic cavities. Our qubit register consists of the SiV electron spin acting as a communication qubit and the strongly coupled silicon-29 nuclear spin acting as a memory qubit with a quantum memory time exceeding 2 seconds. By using a highly strained SiV, we realize electron-photon entangling gates at temperatures up to 1.5 kelvin and nucleus-photon entangling gates up to 4.3 kelvin. We also demonstrate efficient error detection in nuclear spin–photon gates by using the electron spin as a flag qubit, making this platform a promising candidate for scalable quantum repeaters.
A robust quantum network node
The ability to develop quantum networks and communicate quantum information over long distances requires quantum memory nodes with efficient optical interfaces and long memory times. Because of their long coherence times and efficient optical interface, color centers in diamond are promising candidates to achieve this goal. Stas
et al
. use silicon vacancies in diamond and integrated the properties into a single device (see the Perspective by Gangloff). The authors demonstrate a quantum memory with a lifetime exceeding 2 seconds and full optical control of the quantum states of the two-qubit register. With the capability of built-in error detection, such a platform is promising for the development of scalable quantum networks. —ISO
A quantum network node combining a long-lived memory, robust optical interface, and integrated error detection is realized.
Divertor detachment offers a promising solution to the challenge of plasma-wall interactions for steady-state operation of fusion reactors. Here, we demonstrate the excellent compatibility of ...actively controlled full divertor detachment with a high-performance (β
~ 3, H
~ 1.5) core plasma, using high-β
(poloidal beta, β
> 2) scenario characterized by a sustained core internal transport barrier (ITB) and a modest edge transport barrier (ETB) in DIII-D tokamak. The high-β
high-confinement scenario facilitates divertor detachment which, in turn, promotes the development of an even stronger ITB at large radius with a weaker ETB. This self-organized synergy between ITB and ETB, leads to a net gain in energy confinement, in contrast to the net confinement loss caused by divertor detachment in standard H-modes. These results show the potential of integrating excellent core plasma performance with an efficient divertor solution, an essential step towards steady-state operation of reactor-grade plasmas.
While immunosuppression poses a theoretical increase in the risk of COVID-19, the nature of this relationship is yet to be ascertained.
To determine whether immunosuppressed patients are at higher ...risk of COVID-19 to help inform the management of patients receiving immunosuppressant therapies during the pandemic.
We performed a random-effects meta-analysis of data from studies that reported on the prevalence of immunosuppression among patient cohorts with COVID-19.
Sixty full-text publications were identified. In total, six individual studies were included in the final analysis, contributing a total of 10 049 patients with COVID-19 disease. The prevalence of immunosuppressed patients among the study cohorts with COVID-19 ranged from 0.126% to 1.357%. In the pooled cohort a total of 64/10 049 (0.637%) patients with COVID-19 disease was immunosuppressed. Observed to expected ratios were used to compare the prevalence of immunosuppression in cohorts with confirmed COVID-19 disease to the background prevalence of immunosuppression in the general community. The observed to expected ratio of immunosuppression among patients with COVID-19 illness, relative to the general community, was 0.12 (95% confidence interval: 0.05-0.27).
Compared to the general population, immunosuppressed patients were not at significantly increased risk of COVID-19 infection. This finding provides support for current expert consensus statements, which have recommended the continuation of immunosuppressant therapy in the absence of COVID-19.
Recent advances in MRI and increasing knowledge on the characterization and anatomical variability of medial temporal lobe (MTL) anatomy have paved the way for more specific subdivisions of the MTL ...in humans. In addition, recent studies suggest that early changes in many neurodegenerative and neuropsychiatric diseases are better detected in smaller subregions of the MTL rather than with whole structure analyses. Here, we developed a new protocol using 7 Tesla (T) MRI incorporating novel anatomical findings for the manual segmentation of entorhinal cortex (ErC), perirhinal cortex (PrC; divided into area 35 and 36), parahippocampal cortex (PhC), and hippocampus; which includes the subfields subiculum (Sub), CA1, CA2, as well as CA3 and dentate gyrus (DG) which are separated by the endfolial pathway covering most of the long axis of the hippocampus. We provide detailed instructions alongside slice-by-slice segmentations to ease learning for the untrained but also more experienced raters. Twenty-two subjects were scanned (19-32 yrs, mean age = 26 years, 12 females) with a turbo spin echo (TSE) T2-weighted MRI sequence with high-resolution oblique coronal slices oriented orthogonal to the long axis of the hippocampus (in-plane resolution 0.44 × 0.44 mm
) and 1.0 mm slice thickness. The scans were manually delineated by two experienced raters, to assess intra- and inter-rater reliability. The Dice Similarity Index (DSI) was above 0.78 for all regions and the Intraclass Correlation Coefficients (ICC) were between 0.76 to 0.99 both for intra- and inter-rater reliability. In conclusion, this study presents a fine-grained and comprehensive segmentation protocol for MTL structures at 7 T MRI that closely follows recent knowledge from anatomical studies. More specific subdivisions (e.g. area 35 and 36 in PrC, and the separation of DG and CA3) may pave the way for more precise delineations thereby enabling the detection of early volumetric changes in dementia and neuropsychiatric diseases.
In order to study how the statistical properties of the observational quantities of the turbulent molecular cloud models vary with different turbulence parameters, I use the artificially generated ...random numerical models based on Gaussian fields created by the code pyfc with different values of the 1D density Fourier spectral index β
n
, the turbulence driving parameter, i.e. the b parameter and the 1D Fourier velocity power spectral index β
v
. Then I calculate the line profiles of 13CO emission on every sight line. I derive the statistical properties of column density N, line intensity W, peak intensity T
peak and velocity dispersion V
rms on every sight line. I discover that as β
n
increases, (1) the standard deviations σln (N/〈N〉) and σln (W/〈W〉) of the logarithmic column density ln (N/〈N〉) and the logarithmic integrated intensity ln (W/〈W〉) increase; (2) the number of the low T
peak values becomes larger; (3) the probability distribution function (PDF) of V
rms inclines to left a little. As the b parameter increases, (1) the values of both σln (N/〈N〉) and σln (W/〈W〉) increase; (2) the numbers of both the low T
peak values and the saturated T
peak values become larger; (3) the PDF of V
rms inclines to left obviously. As β
v
increases, (1) the PDF of ln (W/〈W〉) remains generally unchanged; (2) the PDF of T
peak remains generally unchanged; (3) the PDF of V
rms inclines to left obviously. I also discuss the relationship among σ
N/〈N〉, Mach number, the b parameter and β
n
.
Myeloid cells constitute a significant part of the immune system in the context of cancer, exhibiting both immunostimulatory effects, through their role as antigen presenting cells, and ...immunosuppressive effects, through their polarization to myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages. While they are rarely sufficient to generate potent anti-tumor effects on their own, myeloid cells have the ability to interact with a variety of immune populations to aid in mounting an appropriate anti-tumor immune response. Therefore, myeloid therapies have gained momentum as a potential adjunct to current therapies such as immune checkpoint inhibitors (ICIs), dendritic cell vaccines, oncolytic viruses, and traditional chemoradiation to enhance therapeutic response. In this review, we outline critical pathways involved in the recruitment of the myeloid population to the tumor microenvironment and in their polarization to immunostimulatory or immunosuppressive phenotypes. We also emphasize existing strategies of modulating myeloid recruitment and polarization to improve anti-tumor immune responses. We then summarize current preclinical and clinical studies that highlight treatment outcomes of combining myeloid targeted therapies with other immune-based and traditional therapies. Despite promising results from reports of limited clinical trials thus far, there remain challenges in optimally harnessing the myeloid compartment as an adjunct to enhancing anti-tumor immune responses. Further large Phase II and ultimately Phase III clinical trials are needed to elucidate the treatment benefit of combination therapies in the fight against cancer.
Speckle noise reduces the image contrast significantly making the highly scattering structures boundaries difficult to distinguish. This has limited the usage of optical coherence tomography (OCT) ...images in clinical routine and hindered its potential by depriving clinicians from assessing useful information that are needed in disease monitoring, treatment, progression, and decision making. To overcome this limitation, we propose a fast and robust OCT image enhancement framework using non-linear statistical parametric technique. In the proposed framework, we utilize prior statistical information to model the image to follow Gaussian distribution. After which, a newly designed dual-parametric sigmoid function (DPSF) is utilized to control the dynamic range and contrast level of the image. To balance the intensity range and contrast level, both linear and non-linear normalization operations are performed, then followed by a mapping operation to obtain the enhanced image. Experimentation results on the three OCT vendors show that the proposed method obtained high values in EME, PSNR, SSIM,
ρ
, and low value in MSE of 36.72, 38.87, 0.87, 0.98, and 25.12 for Cirrus; 40.77, 41.84, 0.89, 0.98, and 22.15 for Spectralis; and 30.81, 32.10, 0.81, 0.96, and 28.55 for Topcon OCT devices, respectively. The proposed DPSF framework performs better than the state-of-the-art methods and improves the interpretability and perception of the OCT images, which can provide clinicians and computer vision program with good quantitative and qualitative information.
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