Post-transcriptional circadian regulation in macrophages organizes temporally distinct immunometabolic states.

Our core timekeeping mechanism, the circadian clock, plays a vital role in immunity. Although the mechanics of circadian control over the immune response is generally explained by transcriptional activation or repression derived from this clock's transcription-translation negative-feedback loop, research suggests that some regulation occurs beyond transcriptional activity. We comprehensively profiled the transcriptome and proteome of murine bone marrow-derived macrophages and found that only 15% of the circadian proteome had corresponding oscillating mRNA, suggesting post-transcriptional regulation influences macrophage clock regulatory output to a greater extent than any other tissue previously profiled. This regulation may be explained by the robust temporal enrichment we identified for proteins involved in degradation and translation. Extensive post-transcriptional temporal-gating of metabolic pathways was also observed and further corresponded with daily variations in ATP production, mitochondrial morphology, and phagocytosis. The disruption of this circadian post-transcriptional metabolic regulation impaired immune functionality. Our results demonstrate that cell-intrinsic post-transcriptional regulation is a primary driver of circadian output in macrophages and that this regulation, particularly of metabolic pathways, plays an important role in determining their response to immune stimuli.

Perspectives on Cognitive Phenotypes and Models of Vascular Disease.

Clinical investigations have established that vascular-associated medical conditions are significant risk factors for various kinds of dementia. And yet, we are unable to associate certain types of vascular deficiencies with specific cognitive impairments. The reasons for this are many, not the least of which are that most vascular disorders are multi-factorial and the development of vascular dementia in humans is often a multi-year or multi-decade progression. To better study vascular disease and its underlying causes, the National Heart, Lung, and Blood Institute of the National Institutes of Health has invested considerable resources in the development of animal models that recapitulate various aspects of human vascular disease. Many of these models, mainly in the mouse, are based on genetic mutations, frequently using single-gene mutations to examine the role of specific proteins in vascular function. These models could serve as useful tools for understanding the association of specific vascular signaling pathways with specific neurological and cognitive impairments related to dementia. To advance the state of the vascular dementia field and improve the information sharing between the vascular biology and neurobehavioral research communities, National Heart, Lung, and Blood Institute convened a workshop to bring in scientists from these knowledge domains to discuss the potential utility of establishing a comprehensive phenotypic cognitive assessment of a selected set of existing mouse models, representative of the spectrum of vascular disorders, with particular attention focused on age, sex, and rigor and reproducibility. The workshop highlighted the potential of associating well-characterized vascular disease models, with validated cognitive outcomes, that can be used to link specific vascular signaling pathways with specific cognitive and neurobehavioral deficits.

Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial.

Importance: There are limited efficacious treatments for Alzheimer disease. Objective: To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque. Design, Setting, and Participants: Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023). Interventions: Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met. Main Outcomes and Measures: The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes. Results: Among 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was -6.02 (95% CI, -7.01 to -5.03) in the donanemab group and -9.27 (95% CI, -10.23 to -8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P < .001) in the low/medium tau population and -10.2 (95% CI, -11.22 to -9.16) with donanemab and -13.1 (95% CI, -14.10 to -12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P < .001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, -0.67 [95% CI, -0.95 to -0.40]; P < .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, -0.7 [95% CI, -0.95 to -0.45]; P < .001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related. Conclusions and Relevance: Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population. Trial Registration: ClinicalTrials.gov Identifier: NCT04437511.

ECHO: an application for detection and analysis of oscillators identifies metabolic regulation on genome-wide circadian output.

MOTIVATION: Time courses utilizing genome scale data are a common approach to identifying the biological pathways that are controlled by the circadian clock, an important regulator of organismal fitness. However, the methods used to detect circadian oscillations in these datasets are not able to accommodate changes in the amplitude of the oscillations over time, leading to an underestimation of the impact of the clock on biological systems. RESULTS: We have created a program to efficaciously identify oscillations in large-scale datasets, called the Extended Circadian Harmonic Oscillator application, or ECHO. ECHO utilizes an extended solution of the fixed amplitude oscillator that incorporates the amplitude change coefficient. Employing synthetic datasets, we determined that ECHO outperforms existing methods in detecting rhythms with decreasing oscillation amplitudes and in recovering phase shift. Rhythms with changing amplitudes identified from published biological datasets revealed distinct functions from those oscillations that were harmonic, suggesting purposeful biologic regulation to create this subtype of circadian rhythms. AVAILABILITY AND IMPLEMENTATION: ECHO's full interface is available at https://github.com/delosh653/ECHO. An R package for this functionality, echo.find, can be downloaded at https://CRAN.R-project.org/package=echo.find. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Acid exposure disrupts mucus secretion and impairs mucociliary transport in neonatal piglet airways.

Tenacious mucus produced by tracheal and bronchial submucosal glands is a defining feature of several airway diseases, including cystic fibrosis (CF). Airway acidification as a driving force of CF airway pathology has been controversial. Here we tested the hypothesis that transient airway acidification produces pathologic mucus and impairs mucociliary transport. We studied pigs challenged with intra-airway acid. Acid had a minimal effect on mucus properties under basal conditions. However, cholinergic stimulation in acid-challenged pigs revealed retention of mucin 5B (MUC5B) in the submucosal glands, decreased concentrations of MUC5B in the lung lavage fluid, and airway obstruction. To more closely mimic a CF-like environment, we also examined mucus secretion and transport following cholinergic stimulation under diminished bicarbonate and chloride transport conditions ex vivo. Under these conditions, airways from acid-challenged pigs displayed extensive mucus films and decreased mucociliary transport. Pretreatment with diminazene aceturate, a small molecule with ability to inhibit acid detection through blockade of the acid-sensing ion channel (ASIC) at the doses provided, did not prevent acid-induced pathologic mucus or transport defects but did mitigate airway obstruction. These findings suggest that transient airway acidification early in life has significant impacts on mucus secretion and transport properties. Furthermore, they highlight diminazene aceturate as an agent that might be beneficial in alleviating airway obstruction.

Airway cholinergic history modifies mucus secretion properties to subsequent cholinergic challenge in diminished chloride and bicarbonate conditions.

NEW FINDINGS: What is the central question of this study? What is the impact of airway cholinergic history on the properties of airway mucus secretion in a cystic fibrosis-like environment? What is the main finding and its importance? Prior cholinergic challenge slightly modifies the characteristics of mucus secretion in response to a second cholinergic challenge in a diminished bicarbonate and chloride transport environment. Such modifications might lead to retention of mucus on the airway surface, thereby potentiating exacerbations of airway disease. ABSTRACT: Viral infections precipitate exacerbations in many airway diseases, including asthma and cystic fibrosis. Although viral infections increase cholinergic transmission, few studies have examined how cholinergic history modifies subsequent cholinergic responses in the airway. In our previous work, we found that airway resistance in response to a second cholinergic challenge was increased in young pigs with a history of airway cholinergic stimulation. Given that mucus secretion is regulated by the cholinergic nervous system and that abnormal airway mucus contributes to exacerbations of airway disease, we hypothesized that prior cholinergic challenge would also modify subsequent mucus responses to a secondary cholinergic challenge. Using our established cholinergic challenge-rechallenge model in pigs, we atomized the cholinergic agonist bethanechol or saline control to pig airways. Forty-eight hours later, we removed tracheas and measured mucus secretion properties in response to a second cholinergic stimulation. The second cholinergic stimulation was conducted in conditions of diminished chloride and bicarbonate transport to mimic a cystic fibrosis-like environment. In pigs previously challenged with bethanechol, a second cholinergic stimulation produced a mild increase in sheet-like mucus films; these films were scarcely observed in animals originally challenged with saline control. The subtle increase in mucus films was not associated with changes in mucociliary transport. These data suggest that prior cholinergic history might modify mucus secretion characteristics with subsequent stimulation in certain environmental conditions or disease states. Such modifications and/or more repetitive stimulation might lead to retention of mucus on the airway surface, thereby potentiating exacerbations of airway disease.

Sex-specific airway hyperreactivity and sex-specific transcriptome remodeling in neonatal piglets challenged with intra-airway acid.

Acute airway acidification is a potent stimulus of sensory nerves and occurs commonly with gastroesophageal reflux disease, cystic fibrosis, and asthma. In infants and adults, airway acidification can acutely precipitate asthma-like symptoms, and treatment-resistant asthma can be associated with gastroesophageal reflux disease. Airway protective behaviors, such as mucus secretion and airway smooth muscle contraction, are often exaggerated in asthma. These behaviors are manifested through activation of neural circuits. In some populations, the neural response to acid might be particularly important. For example, the immune response in infants is relatively immature compared with adults. Infants also have a high frequency of gastroesophageal reflux. Thus, in the current study, we compared the transcriptomes of an airway-nervous system circuit (e.g., tracheal epithelia, nodose ganglia, and brain stem) in neonatal piglets challenged with intra-airway acid. We hypothesized that the identification of parallel changes in the transcriptomes of two neutrally connected tissues might reveal the circuit response, and, hence, molecules important for the manifestation of asthma-like features. Intra-airway acid induced airway hyperreactivity and airway obstruction in male piglets. In contrast, female piglets displayed airway obstruction without airway hyperreactivity. Pairwise comparisons revealed parallel changes in genes directly implicated in airway hyperreactivity ( scn10a) in male acid-challenged piglets, whereas acid-challenged females exhibited parallel changes in genes associated with mild asthma ( stat 1 and isg15). These findings reveal sex-specific responses to acute airway acidification and highlight distinct molecules within a neural circuit that might be critical for the manifestation of asthma-like symptoms in pediatric populations.

Evolutionary considerations on 5-HT2 receptors.

Serotonin is a neurotransmitter widely conserved from ancient organisms lacking nervous systems through man, and its presence precedes the appearance of nervous systems on both developmental and evolutionary time scales. Serotonin receptor subtypes diversified approximately at the time period during which vertebrates diverged from invertebrates. The biological and clinical importance of serotonin receptors, may benefit from studies on their evolution. Although potentially informative about their pathophysiological functions, reviews on this topic are sparse. Several observations support basic functions mediated by serotonin, both in periphery and central nervous system. In particular, 5-HT2B receptors have been implicated in embryonic development, including cell proliferation, survival, and/or differentiation, in either neural crest cell derivatives, myeloid cell lineage, or heart embryogenesis. In this review, we collected existing data about the genomic association between the RPN2 proteasome subunit gene Psmd1 and the 5-HT2B receptor gene Htr2b. We discuss about the possibility that, during genome duplications, a single copy of this pair of genes has been conserved, suggesting a strong selective pressure. Many basic physiological functions in which serotonin system is involved could be linked to the early association of these two genes in pre-vertebrates. Their evolutionary association highlights the possibility that the 5-HT2B receptor gene, Htr2b, is the common ancestor of 5-HT2A/2B/2C-receptor subfamily. Disentangling these possibilities could bring new understanding of the respective importance of these receptors in pathophysiology of serotonin.

Two observational studies examining the effect of a social norm and a health message on the purchase of vegetables in student canteen settings.

There is some evidence from laboratory-based studies that descriptive social-norm messages are associated with increased consumption of vegetables, but evidence of their effectiveness in real-world settings is limited. In two observational field studies taking an ecological approach, a vegetable-related social norm (e.g. "Did you know that most students here choose to eat vegetables with their meal?"), and a health message (e.g. "Did you know that students who choose to eat vegetables have a lower risk of heart disease?") were displayed in two different student canteens. Purchases were observed during three stages: baseline, intervention (when the posters were displayed) and immediate post-intervention (when the posters had been removed). Study 1 (n = 7598) observed the purchase of meals containing a portion of vegetables and Study 2 (n = 4052) observed the purchase of side portions of vegetables. In Study 1, relative to baseline, the social-norms intervention was associated with an increase in purchases of vegetables (from 63% to 68% of meals; OR = 1.24, CI = 1.03-1.49), which was sustained post-intervention (67% of meals; OR = 0.96, CI = 0.80-1.15). There was no effect of the health message (75% of meals at baseline, and 74% during the intervention; OR = 0.98, CI = 0.83-1.15). In Study 2, relative to baseline, there was an effect of both the social norm (22.9% of meals at baseline, rising to 32.5% during the intervention; OR = 1.62, CI = 1.27-2.05) and health message (rising from 43.8% at baseline to 52.8%; OR = 0.59, CI = 0.46-0.75). The increase was not sustained post-intervention for the social norm intervention (22.1%; OR = 0.59, CI = 0.46-0.75), but was sustained for the health intervention (48.1%; OR = 0.83, CI = 0.67-1.02). These results support further testing of the effectiveness of such messages in encouraging healthier eating and indicate the need for larger-scale testing at multiple sites using a randomised-controlled design.

Discovery and confirmation of a protein biomarker panel with potential to predict response to biological therapy in psoriatic arthritis.

OBJECTIVE: Biological therapies, which include antitumour necrosis factor-α and T-cell inhibitors, are potentially effective treatments for psoriatic arthritis (PsA) but are costly and may induce a number of side effects. Response to treatment in PsA is variable and difficult to predict. Here, we sought to identify a panel of protein biomarkers that could be used to predict which patients diagnosed with PsA will respond to biologic treatment. METHODS: An integrated discovery to targeted proteomics approach was used to investigate the protein profiles of good and non-responders to biological treatments in patients with PsA. Reverse-phase liquid chromatography coupled to tandem mass spectrometry was used to generate protein profiles of synovial tissue obtained at baseline from 10 patients with PsA. Targeted proteomics using multiple reaction monitoring (MRM) was used to confirm and prevalidate a potential protein biomarker panel in 18 and 7 PsA patient samples, respectively. RESULTS: A panel of 107 proteins was selected, and targeted mass spectrometry MRM assays were successfully developed for 57 of the proteins. The 57 proteins include S100-A8, S100-A10, Ig kappa chain C fibrinogen-α and γ, haptoglobin, annexin A1 and A2, collagen alpha-2, vitronectin, and alpha-1 acid glycoprotein. The proteins were measured simultaneously and confirmed to be predictive of response to treatment with an area under the curve of 0.76. In a blinded study using a separate cohort of patients, the panel was able to predict response to treatment. CONCLUSIONS: The approach reported here and the initial data provide evidence that a multiplexed protein assay of a panel of biomarkers that predict response to treatment could be developed. TRIAL REGISTRATION NUMBER: ISRCTN23328456.

Sequential Combination Therapy Versus Monotherapy: A Lack of Benefit in Time to Inflammatory Bowel Disease-Related Surgery.

BACKGROUND: The benefits of combination therapy with infliximab and azathioprine have been demonstrated in clinical trials of patients with ulcerative colitis (UC) and Crohn's disease (CD). Concerns remain regarding the ideal duration and benefits of adding therapies in a sequential manner. AIMS: We aim to compare long-term outcomes among patients with inflammatory bowel disease (IBD) treated with sequentially added combination therapy or monotherapy strategies . METHODS: We performed a retrospective cohort study involving adult patients with UC and CD. One cohort included patients treated with infliximab, adalimumab, or a thiopurine as monotherapy. A second cohort included patients treated with sequentially added combination therapy including infliximab or adalimumab and a thiopurine. The primary outcome was the rate of IBD-related surgery. RESULTS: Among 462 patients, 181 (39 %) were treated with combination therapy. 12 % of patients treated with combination therapy underwent an IBD-related surgery compared to 18 % of patients treated with monotherapy (p = 0.091), with no overall difference in time to IBD-related surgery demonstrated (log-rank test, p = 0.063). When evaluating the subtypes of IBD, there was a significant benefit in time to IBD-related surgery among patients with CD treated with sequentially added combination therapy (HR 0.46, 95 % CI 0.25-0.85) but not UC (HR 0.82, 95 % CI 0.30-2.22). CONCLUSIONS: The benefits of sequentially added combination therapy seem blunted when evaluating long-term clinical outcomes. This may be due to a decreased effectiveness of sequential combination therapy, a loss of benefit over time, or a differential effect between subtypes of IBD.

Translational Pharmacodynamics of Calcitonin Gene-Related Peptide Monoclonal Antibody LY2951742 in a Capsaicin-Induced Dermal Blood Flow Model.

LY2951742, a monoclonal antibody targeting calcitonin gene-related peptide (CGRP), is being developed for migraine prevention and osteoarthritis pain. To support the clinical development of LY2951742, capsaicin-induced dermal blood flow (DBF) was used as a target engagement biomarker to assess CGRP activity in nonhuman primates and healthy volunteers. Inhibition of capsaicin-induced DBF in nonhuman primates, measured with laser Doppler imaging, was dose dependent and sustained for at least 29 days after a single intravenous injection of the CGRP antibody. This information was used to generate a pharmacokinetic/pharmacodynamic model, which correctly predicted inhibition of capsaicin-induced DBF in humans starting at a single subcutaneous 5-mg dose. As expected, the degree of inhibition in capsaicin-induced DBF increased with higher LY2951742 plasma concentrations. Utilization of this pharmacodynamic biomarker with pharmacokinetic data collected in phase I studies provided the dose-response relationship that assisted in dose selection for the phase II clinical development of LY2951742.

A review of the flortaucipir literature for positron emission tomography imaging of tau neurofibrillary tangles.

Alzheimer's disease is defined by the presence of ß-amyloid plaques and neurofibrillary tau tangles potentially preceding clinical symptoms by many years. Previously only detectable post-mortem, these pathological hallmarks are now identifiable using biomarkers, permitting an in vivo definitive diagnosis of Alzheimer's disease. 18F-flortaucipir (previously known as 18F-T807; 18F-AV-1451) was the first tau positron emission tomography tracer to be introduced and is the only Food and Drug Administration-approved tau positron emission tomography tracer (Tauvid™). It has been widely adopted and validated in a number of independent research and clinical settings. In this review, we present an overview of the published literature on flortaucipir for positron emission tomography imaging of neurofibrillary tau tangles. We considered all accessible peer-reviewed literature pertaining to flortaucipir through 30 April 2022. We found 474 relevant peer-reviewed publications, which were organized into the following categories based on their primary focus: typical Alzheimer's disease, mild cognitive impairment and pre-symptomatic populations; atypical Alzheimer's disease; non-Alzheimer's disease neurodegenerative conditions; head-to-head comparisons with other Tau positron emission tomography tracers; and technical considerations. The available flortaucipir literature provides substantial evidence for the use of this positron emission tomography tracer in assessing neurofibrillary tau tangles in Alzheimer's disease and limited support for its use in other neurodegenerative disorders. Visual interpretation and quantitation approaches, although heterogeneous, mostly converge and demonstrate the high diagnostic and prognostic value of flortaucipir in Alzheimer's disease.

The Feasibility and Efficacy of Warrior Health and Fitness: A 3-Month Fitness and Nutrition Program for Veterans.

INTRODUCTION: Veterans are at risk for mental and physical health problems but may not seek traditional health care services. Wellness-based interventions, including exercise and nutrition, have been associated with improvements in physical and mental health among this population. This study explores the acceptability, feasibility, and efficacy of a 3-month health and fitness program for veterans. MATERIALS AND METHODS: Participants in 2 time-based cohorts from 2019 to 2023 (cohort 1: n = 261; cohort 2: n = 256) were cleared by a physician to participate. Participants then completed a fitness test and self-reported surveys (e.g., quality of life, sleep, and pain) before and after the 3-month program. Participants were recruited to participate at one of three sites: Boston, MA Fort Myers, FL, or Tampa, FL. The 3-month program consisted of weekly, supervised group fitness and one-on-one sessions, nutritional consultations, yoga, and other wellness activities. Primary program outcomes were measured by fitness assessments, self-report surveys, program completion, and program satisfaction. Fitness assessments included measures of weight, body mass index, grip strength, waist to hip ratio, body fat, lean mass, fat mass, heart rate, and blood pressure (BP). Self-report measures included quality of life, depression, loneliness, sleep quality, pain intensity, and pain interference. RESULTS: In cohort 1, significant improvements were found for measures of weight (P = .01), left-handed grip strength (P < .01), body fat percent (P < .01), and quality of life (P < .01). In cohort 2, significant improvements were found for measures of waist:hip ratio (P = .02), right and left-handed grip strength (P < .01), body mass index (P = .02), body fat percent (P < .01), and quality of life (P = .02). For both cohorts, pain intensity (cohort 1: P = .01, cohort 2: P < .001) and pain interference (cohort 1: P = .02, cohort 2: P < .001) increased significantly. CONCLUSIONS: These data suggest that a 3-month health and fitness program for veterans is acceptable and feasible and may improve physical and mental health outcomes. Considerations for program retention and assessment completion are discussed.

Glycosylation status of serum in inflammatory arthritis in response to anti-TNF treatment.

OBJECTIVE: Glycosylation is the most common post-translational modification and is altered in disease. The typical glycosylation change in patients with inflammatory arthritis (IA) is a decrease in galactosylation levels on IgG. The aim of this study is to evaluate the effect of anti-TNF therapy on whole serum glycosylation from IA patients and determine whether these alterations in the glycome change upon treatment of the disease. METHODS: Serum samples were collected from 54 IA patients before treatment and at 1 and 12 months after commencing anti-TNF therapy. N-linked glycans from whole serum samples were analysed using a high-throughput hydrophilic interaction liquid chromatography-based method. RESULTS: Glycosylation on the serum proteins of IA patients changed significantly with anti-TNF treatment. We observed an increase in galactosylated glycans from IgG, also an increase in core-fucosylated biantennary galactosylated glycans and a decrease in sialylated triantennary glycans with and without outer arm fucose. This increase in galactosylated IgG glycans suggests a reversing of the N-glycome towards normal healthy profiles. These changes are strongly correlated with decreasing CRP, suggesting a link between glycosylation changes and decreases in inflammatory processes. CONCLUSION: Glycosylation changes in the serum of IA patients on anti-TNF therapy are strongly associated with a decrease in inflammatory processes and reflect the effect of anti-TNF on the immune system.

Sign Language Studies with Chimpanzees in Sanctuary.

Adult chimpanzees Tatu and Loulis lived at the Fauna Foundation sanctuary. They had acquired signs of American Sign Language (ASL) while young and continued to use them as adults. Caregivers with proficiency in ASL maintained daily sign language records during interactions and passive observation. Sign checklists were records of daily vocabulary use. Sign logs were records of signed interactions with caregivers and other chimpanzees. This study reports sign use from eight years of these records. Tatu and Loulis used a majority of their base vocabularies consistently over the study period. They used signs that they had acquired decades earlier and new signs. Their utterances served a variety of communicative functions, including responses, conversational devices, requests, and descriptions. They signed to caregivers, other chimpanzees, including those who did not use signs, and to themselves privately. This indicates the importance of a stimulating and interactive environment to understand the scope of ape communication and, in particular, their use of sign language.

Neurorehabilitation robotics: how much control should therapists have?

Robotic technologies for rehabilitating motor impairments from neurological injuries have been the focus of intensive research and capital investment for more than 30 years. However, these devices have failed to convincingly demonstrate greater restoration of patient function compared to conventional therapy. Nevertheless, robots have value in reducing the manual effort required for physical therapists to provide high-intensity, high-dose interventions. In most robotic systems, therapists remain outside the control loop to act as high-level supervisors, selecting and initiating robot control algorithms to achieve a therapeutic goal. The low-level physical interactions between the robot and the patient are handled by adaptive algorithms that can provide progressive therapy. In this perspective, we examine the physical therapist's role in the control of rehabilitation robotics and whether embedding therapists in lower-level robot control loops could enhance rehabilitation outcomes. We discuss how the features of many automated robotic systems, which can provide repeatable patterns of physical interaction, may work against the goal of driving neuroplastic changes that promote retention and generalization of sensorimotor learning in patients. We highlight the benefits and limitations of letting therapists physically interact with patients through online control of robotic rehabilitation systems, and explore the concept of trust in human-robot interaction as it applies to patient-robot-therapist relationships. We conclude by highlighting several open questions to guide the future of therapist-in-the-loop rehabilitation robotics, including how much control to give therapists and possible approaches for having the robotic system learn from therapist-patient interactions.

Tau as a diagnostic instrument in clinical trials to predict amyloid in Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is characterized by the presence of both amyloid and tau pathology. In vivo diagnosis can be made with amyloid and tau positron emission tomography (PET) imaging. Emergent evidence supports that amyloid and tau accumulation are associated and that amyloid accumulation may precede that of tau. This report further investigates the relationship between amyloid and tau to assess whether elevated cortical tau can predict elevated amyloid in participants with early symptomatic AD. METHODS: Florbetapir F18 and flortaucipir F18 uptake were evaluated from baseline PET scans collected in three multi-center studies with cognitively impaired participants, including A05 (N = 306; NCT02016560), TB (N = 310; TRAILBLAZER-ALZ; NCT03367403), and TB2 (N = 1165; TRAILBLAZER-ALZ 2; NCT04437511). Images were assessed using visual and quantitative approaches to establish amyloid (A+) and tau (T+) positivity, as well as a combination method (tauVQ) to establish T+. Associations between global amyloid and tau were evaluated with positive and negative predictive values (PPV, NPV) and likelihood ratios (LR+, LR-). Predictive values within subgroups according to ethnicity, race, cognitive score, age, and sex were also evaluated. The relationship between regional tau (four target and two reference regions were tested) and global amyloid was investigated in A05 participant scans using receiver-operating characteristic (ROC) curves. RESULTS: PPV for amyloid positivity was ≥93% for all three trials using various A+ and T+ definitions, including visual, quantitative, and combination methods. Population characteristics did not have an impact on A+ predictability. Regional analyses (early tau (Eτ) volume of interest (VOI), temporal, parietal, frontal) revealed significant area under the ROC curve in Eτ VOI compared to frontal region, regardless of reference region and consistent among visual and quantitative A+ definitions (p < 0.001). DISCUSSION: These findings suggest that a positive tau PET scan is associated (≥93%) with amyloid positivity in individuals with early symptomatic AD, with the potential benefits of reducing clinical trial and health care expenses, radiation exposure, and participant time. Highlights: Positron emission tomography (PET) evaluates candidates for Alzheimer's disease (AD) research. A positive tau PET scan is associated (≥93%) with amyloid positivity.A positive amyloid PET is not necessarily associated with tau positivity.Tau PET could be the sole diagnostic tool to confirm candidates for AD trials.

TRPA1 Antagonist LY3526318 Inhibits the Cinnamaldehyde-Evoked Dermal Blood Flow Increase: Translational Proof of Pharmacology.

Transient receptor potential Ankyrin 1 (TRPA1) is an ion channel expressed by sensory neurons, where it mediates pain signaling. Consequently, it has emerged as a promising target for novel analgesics, yet, to date, no TRPA1 antagonists have been approved for clinical use. In the present translational study, we utilized dermal blood flow changes evoked by TRPA1 agonist cinnamaldehyde as a target engagement biomarker to investigate the in vivo pharmacology of LY3526318, a novel TRPA1 antagonist. In rats, LY3526318 (1, 3, and 10 mg/kg, p.o.) dose-dependently reduced the cutaneous vasodilation typically observed following topical application of 10% v/v cinnamaldehyde. The inhibition was significant at the site of cinnamaldehyde application and also when including an adjacent area of skin. Similarly, in a cohort of 16 healthy human volunteers, LY3526318 administration (10, 30, and 100 mg, p.o.) dose-dependently reduced the elevated blood flow surrounding the site of 10% v/v cinnamaldehyde application, with a trend toward inhibition at the site of application. Comparisons between both species reveal that the effects of LY3526318 on the cinnamaldehyde-induced dermal blood flow are greater in rats relative to humans, even when adjusting for cross-species differences in potency of the compound at TRPA1. Exposure-response relationships suggest that a greater magnitude response may be observed in humans if higher antagonist concentrations could be achieved. Taken together, these results demonstrate that cinnamaldehyde-evoked changes in dermal blood flow can be utilized as a target engagement biomarker for TRPA1 activity and that LY3526318 antagonizes the ion channel both in rats and humans.

Porcine sperm bind to specific 6-sialylated biantennary glycans to form the oviduct reservoir.

After mating, many female mammals store a subpopulation of sperm in the lower portion of the oviduct, forming a reservoir. The reservoir lengthens sperm lifespan, regulates sperm capacitation, controls polyspermy, and selects normal sperm. It is believed that sperm bind to glycans on the oviduct epithelium to form the reservoir, but the specific adhesion molecules that retain sperm are unclear. Herein, using a glycan array to test 377 glycans for their ability to bind porcine sperm, we found two glycan motifs in common among all glycans with sperm-binding ability: the Lewis X trisaccharide and biantennary structures containing a mannose core with 6-sialylated lactosamine at one or more termini. Binding to both motifs was specific; isomers of each motif did not bind sperm. Further work focused on sialylated lactosamine. Sialylated lactosamine was found abundantly on the apical side of epithelial cells collected from the oviduct isthmus, among N-linked and O-linked glycans. Sialylated lactosamine bound to the head of sperm, the region that interacts with the oviduct epithelium. After capacitation, sperm lost affinity for sialylated lactosamine. Receptor modification may contribute to release from the reservoir so that sperm can move to the site of fertilization. Sialylated lactosamine was required for sperm to bind oviduct cells. Simbucus nigra agglutinin or an antibody specific to sialylated lactosamine with a preference for Neu5Acalpha2-6Gal rather than Neu5Acalpha2-3Gal reduced sperm binding to oviduct isthmic cells, as did occupying putative receptors on sperm with sialylated biantennary glycans. These results demonstrate that sperm binding to oviduct 6-sialylated biantennary glycans is necessary for normal adhesion to the oviduct.