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There has been significant progress in understanding the role of neurotransmitters in normal and pathologic brain function. However, preclinical trials aimed at improving therapeutic interventions do not take advantage of real-time in vivo neurochemical changes in dynamic brain processes such as disease progression and response to pharmacologic, cognitive, behavioral, and neuromodulation therapies. This is due in part to a lack of flexible research tools that allow in vivo measurement of the dynamic changes in brain chemistry. Here, we present a research platform, WINCS Harmoni , which can measure in vivo neurochemical activity simultaneously across multiple anatomical targets to study normal and pathologic brain function. In addition, WINCS Harmoni can provide real-time neurochemical feedback for closed-loop control of neurochemical levels via its synchronized stimulation and neurochemical sensing capabilities. We demonstrate these and other key features of this platform in non-human primate, swine, and rodent models of deep brain stimulation (DBS). Ultimately, systems like the one described here will improve our understanding of the dynamics of brain physiology in the context of neurologic disease and therapeutic interventions, which may lead to the development of precision medicine and personalized therapies for optimal therapeutic efficacy.

Essential tremor is often markedly reduced during deep brain stimulation simply by implanting the stimulating electrode before activating neurostimulation. Referred to as the microthalamotomy effect, the mechanisms of this unexpected consequence are thought to be related to microlesioning targeted brain tissue, that is, a microscopic version of tissue ablation in thalamotomy. An alternate possibility is that implanting the electrode induces immediate neurochemical release. Herein, we report the experiment performing with real-time fast-scan cyclic voltammetry to quantify neurotransmitter concentrations in human subjects with essential tremor during deep brain stimulation. The results show that the microthalamotomy effect is accompanied by local neurochemical changes, including adenosine release.

We describe the sources of stray light and thermal background that affect JWST observations; report actual backgrounds as measured from commissioning and early science observations; compare those background levels to pre-launch predictions; estimate the impact of the backgrounds on science performance; and explore how the backgrounds probe the achieved configuration of the deployed observatory. We find the observatory is limited by the irreducible astrophysical backgrounds, rather than scattered stray light and thermal self-emission, for all wavelengths λ<12.5 micron, thus meeting the level 1 requirement. This result was not assured given the open architecture and thermal challenges of JWST, and is the result of meticulous attention to stray light and thermal issues in the design, construction, integration, and test phases. From background considerations alone, JWST will require less integration time in the near-infrared compared to a system that just met the stray light requirements; as such, JWST will be even more powerful than expected for deep imaging at 1--5 micron. In the mid-infrared, the measured thermal backgrounds closely match pre-launch predictions. The background near 10 micron is slightly higher than predicted before launch, but the impact on observations is mitigated by the excellent throughput of MIRI, such that instrument sensitivity will be as good as expected pre-launch. These measured background levels are fully compatible with JWST's science goals and the Cycle 1 science program currently underway.

We describe the sources of stray light and thermal background that affect JWST observations, report actual backgrounds as measured from commissioning and early-science observations, compare these background levels to prelaunch predictions, estimate the impact of the backgrounds on science performance, and explore how the backgrounds probe the achieved configuration of the deployed observatory. We find that for almost all applications, the observatory is limited by the irreducible astrophysical backgrounds, rather than scattered stray light and thermal self-emission, for all wavelengths λ < 12.5 μm, thus meeting the level 1 requirement. This result was not assured given the open architecture and thermal challenges of JWST, and it is the result of meticulous attention to stray light and thermal issues in the design, construction, integration, and test phases. From background considerations alone, JWST will require less integration time in the near-infrared compared to a system that just met the stray-light requirements; as such, JWST will be even more powerful than expected for deep imaging at 1-5 μm. In the mid-infrared, the measured thermal backgrounds closely match prelaunch predictions. The background near 10 μm is slightly higher than predicted before launch, but the impact on observations is mitigated by the excellent throughput of MIRI, such that instrument sensitivity will be as good as expected prelaunch. These measured background levels are fully compatible with JWST’s science goals and the Cycle 1 science program currently underway.

BackgroundProdromal Huntington's disease (prHD) is associated with a myriad of cognitive changes but the domains that best predict time to clinical diagnosis have not been studied. This is a notable gap because some domains may be more sensitive to cognitive decline, which would inform clinical trials.ObjectivesThe present study sought to characterise cognitive domains underlying a large test battery and for the first time, evaluate their ability to predict time to diagnosis.MethodsParticipants included gene negative and gene positive prHD participants who were enrolled in the PREDICT-HD study. The CAG–age product (CAP) score was the measure of an individual's genetic signature. A factor analysis of 18 tests was performed to identify sets of measures or latent factors that elucidated core constructs of tests. Factor scores were then fit to a survival model to evaluate their ability to predict time to diagnosis.ResultsSix factors were identified: (1) speed/inhibition, (2) verbal working memory, (3) motor planning/speed, (4) attention–information integration, (5) sensory–perceptual processing and (6) verbal learning/memory. Factor scores were sensitive to worsening of cognitive functioning in prHD, typically more so than performances on individual tests comprising the factors. Only the motor planning/speed and sensory–perceptual processing factors predicted time to diagnosis, after controlling for CAP scores and motor symptoms.ConclusionsThe results suggest that motor planning/speed and sensory–perceptual processing are important markers of disease prognosis. The findings also have implications for using composite indices of cognition in preventive Huntington's disease trials where they may be more sensitive than individual tests.

Cardiac allograft vasculopathy (CAV) is a leading cause of late graft failure and mortality following heart transplantation, with limited therapeutic options. Endothelial cells (ECs), at the interface between the donor graft and host immune system, play a central role in CAV development. However, the molecular mechanisms driving endothelial dysfunction and vascular remodeling in chronic heart transplant rejection remain poorly understood. To characterize endothelial alterations associated with CAV, we isolated nuclei from cardiac tissues of four human donor groups: (1) early post-transplant CAV-negative surveillance biopsies, (2) CAV-negative explanted grafts with acute cellular rejection (ACR), (3) late-stage CAV-positive explanted grafts, and (4) naïve non-transplanted control hearts. We applied intranuclear cellular indexing of transcriptomes and epitopes (inCITE-seq) to profile endothelial gene expression together with nuclear protein levels of splice factor polypyrimidine tract-binding protein 1 (PTBP1), a key post-transcriptional regulator of endothelial inflammatory responses. Functional relevance of PTBP1 was assessed using endothelial-specific deletion of in an F1 hybrid murine model of CAV. In human CAV, endothelial cells exhibited increased transforming growth factor-β (TGF-β) signaling and reduced oxidative phosphorylation (OxPhos) transcripts. Nuclear PTBP1 protein levels were markedly elevated in CAV endothelium and were associated with TGF-β-responsive transcriptional programs and correlated with clinical indices of cardiac dysfunction. In murine heart transplants, endothelial-specific deletion of markedly reduced hallmarks of CAV, including neointimal hyperplasia, fibrosis, and lymphocyte activation. At the molecular level, endothelial deletion prevented suppression of mitochondrial transcripts and preserved mitochondrial content and integrity under hypoxic stress, attenuating interferon signaling in endothelial cells. These findings identify PTBP1 as a central endothelial regulator linking pro-fibrotic stress to mitochondrial dysfunction and immune activation in chronic cardiac allograft rejection. Targeting endothelial PTBP1 may represent a strategy to limit chronic graft injury while minimizing systemic immunosuppression.

Lymph nodes and other secondary lymphoid organs play critical roles in immune surveillance and immune activation in mammals, but the deep internal locations of these organs make it challenging to image and study them in living animals. Here, we describe a previously uncharacterized external immune organ in the zebrafish ideally suited for studying immune cell dynamics , the axillary lymphoid organ (ALO). This small, translucent organ has an outer cortex teeming with immune cells, an inner medulla with a mesh-like network of fibroblastic reticular cells along which immune cells migrate, and a network of lymphatic vessels draining to a large adjacent lymph sac. Noninvasive high-resolution imaging of transgenically marked immune cells can be carried out in the lobes of living animals, and the ALO is readily accessible to external treatment. This newly discovered tissue provides a superb model for dynamic live imaging of immune cells and their interaction with pathogens and surrounding tissues, including blood and lymphatic vessels.

Objective: A work function measure specific for persons with prodromal Huntington disease (HD) was created to assist with workplace accommodations. Methods: A self-report HD Work Function (HDWF) measure was developed from focus group and expert validation. Results: Pilot studies with 238 people with prodromal HD, and 185 companions; and 89 people without prodromal HD, and 70 companions indicate that HDWF has acceptable internal consistency (Cronbach α = 0.77), acceptable interrater reliability (r = 0.58), and acceptable convergent validity with selected items from the Endicott Work Productivity Scale (r = -0.56), Social Adjustment Scale-Self Report (r = -0.29), and Everyday Cognition (r = -0.70). The HDWF can distinguish between people with prodromal HD and people with an HD family history who do not have prodromal HD (P < 0.0001). Conclusions: The HDWF is a brief self-assessment that may be used to monitor work function.

The James Webb Space Telescope ( Webb) is the largest space telescope realized to-date, with a 6.5 m segmented primary mirror that must be folded to fit within its Ariane 5 launcher fairing. This infrared telescope is passively cooled using a five-layer sunshield that will keep the optical telescope and its four science instruments in the shade throughout the lifetime of the mission in an L2 orbit. Webb's science instruments include near- and mid­ infrared imagers and spectrometers that cover the spectral range from 0.6-28.5 µm. The Webb mission has a long history with numerous first of its kind technology developments, ground support equipment innovations, and algorithmic characterization advances. This conference proceeding summarizes the technical progress over the past two years, from the Spacecraft Element environmental testing to the Observatory integration and testing, and the final Observatory test plans leading up to launch, on-orbit commissioning, and science operations.

We derive an experimentally testable criterion for the teleportation of quantum states of continuous variables. This criterion is especially relevant to the recent experiment of Furusawa et al. [Science 282, 706-709 (1998)] where an input-output fidelity of \\(0.58 \\pm 0.02\\) was achieved for optical coherent states. Our derivation demonstrates that fidelities greater than 1/2 could not have been achieved through the use of a classical channel alone; quantum entanglement was a crucial ingredient in the experiment.