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Aromatase is an estrogen synthetic enzyme that plays important roles in brain functions. To quantify aromatase expression in the brain by positron emission tomography (PET), we had previously developed [11C]cetrozole, which showed high specificity and affinity. To develop more efficient PET tracer(s) for aromatase imaging, we synthesized three analogs of cetrozole. selleck chemicals We synthesized meta-cetrozole, nitro-cetrozole, and iso-cetrozole, and prepared the corresponding 11C-labeled tracers. The inhibitory activities of these three analogs toward aromatase were evaluated using marmoset placenta, and PET imaging of brain aromatase was performed using the 11C-labeled tracers in monkeys. The most promising analog in the monkey study, iso-cetrozole, was evaluated in the human PET study. The highest to lowest inhibitory activity of the analogs toward aromatase in the microsomal fraction from marmoset placenta was in the following order iso-cetrozole, nitro-cetrozole, cetrozole, and meta-cetrozole. This order showed good agreement with the order of the binding potential (BP) of each 11C-labeled analog to aromatase in the rhesus monkey brain. A human PET study using [11C]iso-analog showed a similar distribution pattern of binding as that of [11C]cetrozole. The time-activity curves showed that elimination of [11C]iso-cetrozole from brain tissue was faster than that of 11C-cetrozole, indicating more rapid metabolism of [11C]iso-cetrozole. [11C]Cetrozole has preferable metabolic stability for brain aromatase imaging in humans, although [11C]iso-cetrozole might also be useful to measure aromatase level in living human brain because of its high binding potential.Growth in energy use for indoor cooling tripled between 1990 and 2016 to outpace any other end use in buildings. Part of this energy demand is wasted on excessive cooling of offices, a practice known as overcooling. Overcooling has been attributed to poorly designed or managed air-conditioning systems with thermostats that are often set below recommended comfort temperatures. Prior research has reported lower thermal comfort for women in office buildings, but there is insufficient evidence to explain the reasons for this disparity. We use two large and independent datasets from US buildings to show that office temperatures are less comfortable for women largely due to overcooling. Survey responses show that uncomfortable temperatures are more likely to be cold than hot regardless of season. Crowdsourced data suggests that overcooling is a common problem in warm weather in offices across the US. The associated impacts of this pervasive overcooling on well-being and performance are borne predominantly by women. The problem is likely to increase in the future due to growing demand for cooling in increasingly extreme climates. There is a need to rethink the approach to air-conditioning office buildings in light of this gender inequity caused by overcooling.Circulating CD4+CD8+ double-positive (DP) T cells are associated with a variety of disease states. However, unlike conventional T cells, the composition of this population is poorly understood. Here, we used single-cell RNA sequencing (scRNA-seq) to analyze the composition and characteristics of the DP T cell population circulating in the peripheral blood of cynomolgus monkeys. We found that circulating DP T cells not only contain a large number of naïve cells, but also comprise a heterogeneous population (CD4 CTL-, Eomes+ Tr1-, Th2-, Th17-, Tfh-, Treg-, CD8 CTL-, and innate-like cells) with multiple potential functions. Flow cytometry analysis revealed that a substantial number of the naïve DP T cells expressed CD8αβ, as well as CD8αα, along with high expression of CD31. Moreover, the CD4hiCD8lo and CD4hiCD8hi populations, which express high levels of the CD4 coreceptor, comprised subsets characterized by helper and regulatory functions, some of which also exhibited cytotoxic functions. By contrast, the CD4loCD8hi population with high CD8 coreceptor expression comprised a subset characterized by CD8 CTL- and innate-like properties. Taken together, the data show that scRNA-seq analysis identified a more diverse subset of the circulating DP cells than is currently known, despite this population being very small.We reveal the effects of a new microtubule-destabilizing compound in human cells. link2 C75 has a core thienoisoquinoline scaffold with several functional groups amenable to modification. Previously we found that sub micromolar concentrations of C75 caused cytotoxicity. We also found that C75 inhibited microtubule polymerization and competed with colchicine for tubulin-binding in vitro. However, here we found that the two compounds synergized suggesting differences in their mechanism of action. Indeed, live imaging revealed that C75 causes different spindle phenotypes compared to colchicine. Spindles remained bipolar and collapsed after colchicine treatment, while C75 caused bipolar spindles to become multipolar. Importantly, microtubules rapidly disappeared after C75-treatment, but then grew back unevenly and from multiple poles. The C75 spindle phenotype is reminiscent of phenotypes caused by depletion of ch-TOG, a microtubule polymerase, suggesting that C75 blocks microtubule polymerization in metaphase cells. C75 also caused an increase in the number of spindle poles in paclitaxel-treated cells, and combining low amounts of C75 and paclitaxel caused greater regression of multicellular tumour spheroids compared to each compound on their own. These findings warrant further exploration of C75's anti-cancer potential.Meningiomas are among the most frequent tumors of the central nervous system. For a total resection, shown to decrease recurrences, it is paramount to reliably discriminate tumor tissue from normal dura mater intraoperatively. Raman spectroscopy (RS) is a non-destructive, label-free method for vibrational analysis of biochemical molecules. On the microscopic level, RS was already used to differentiate meningioma from dura mater. In this study we test its suitability for intraoperative macroscopic meningioma diagnostics. link3 RS is applied to surgical specimen of intracranial meningiomas. The main purpose is the differentiation of tumor from normal dura mater, in order to potentially accelerate the diagnostic workflow. The collected meningioma and dura mater samples (n = 223 tissue samples from a total of 59 patients) are analyzed under untreated conditions using a new partially robotized RS acquisition system. Spectra (n = 1273) are combined with the according histopathological analysis for each sample. Based on this, a classifier is trained via machine learning. Our trained classifier separates meningioma and dura mater with a sensitivity of 96.06 [Formula see text] 0.03% and a specificity of 95.44 [Formula see text] 0.02% for internal fivefold cross validation and 100% and 93.97% if validated with an external test set. RS is an efficient method to discriminate meningioma from healthy dura mater in fresh tissue samples without additional processing or histopathological imaging. It is a quick and reliable complementary diagnostic tool to the neuropathological workflow and has potential for guided surgery. RS offers a safe way to examine unfixed surgical specimens in a perioperative setting.Identification of Parkinson's disease subtypes may help understand underlying disease mechanisms and provide personalized management. Although clustering methods have been previously used for subtyping, they have reported generic subtypes of limited relevance in real life practice because patients do not always fit into a single category. The aim of this study was to identify new subtypes assuming that patients could be grouped differently according to certain sets of related symptoms. To this purpose, a novel model-based multi-partition clustering method was applied on data from an international, multi-center, cross-sectional study of 402 Parkinson's disease patients. Both motor and non-motor symptoms were considered. As a result, eight sets of related symptoms were identified. Each of them provided a different way to group patients impulse control issues, overall non-motor symptoms, presence of dyskinesias and pyschosis, fatigue, axial symptoms and motor fluctuations, autonomic dysfunction, depression, and excessive sweating. Each of these groups could be seen as a subtype of the disease. Significant differences between subtypes (P less then 0.01) were found in sex, age, age of onset, disease duration, Hoehn & Yahr stage, and treatment. Independent confirmation of these results could have implications for the clinical management of Parkinson's disease patients.This study aimed to compare the analgesic effectiveness of virtual reality vs. topical anesthesia gel during the administration of local anesthesia (injections to numb the gums) in adult dental patients; as well as to determine which approach is preferred by the patients. Twenty-one adult patients received dental anesthetic injections bilaterally for their maxillary premolars area. We predicted that VR would be more effective than a topical anesthetic gel at reducing pain during injections into the gums. Using a within subject design, each patient received two injections during a single dental visit. Pain was measured after each injection. One side was of the mouth was injected under the influence of the topical anesthesia (TA) 20% benzocaine. The other side of the mouth was injected when the patient was in virtual reality (VR) watching an animated movie using an Oculus Quest® helmet to distract them during the other injection, treatment order randomized. Immediately after each injection, the patients were directed to rate their pain experience using the Wong-Baker Faces Pain-rating Scale (W-BFPS), and to choose which delivery system they preferred. Heart rates were recorded prior to and after the injections using a finger pulse oximeter. Participants reported the predicted pattern of a lower W-PFPS score (less pain intensity) during needle injection while in VR than the injection with topical anesthesia gel, however, the difference was not statistically significant. A statistically significant majority of the participants (p = 0.021) preferred VR to TA. No statistically significant difference heart rate during VR vs. TA was found. Although dental patients reported less pain during VR distraction vs. topical gel anesthetic, the difference was not significant. A statistically significant majority of patients preferred virtual reality over topical anesthesia during their future injections. However, no significant difference in heart rate was found.The identification of movement strategies in situations that are as ecologically valid as possible is essential for the understanding of lower limb interactions. This study considered the kinetic and kinematic data for the hip, knee and ankle joints from 376 block jump-landings when moving in the dominant and non-dominant directions from fourteen senior national female volleyball players. Two Machine Learning methods were used to generate the models from the dataset, Random Forest and Artificial Neural Networks. In addition, decision trees were used to detect which variables were relevant to discern the limb movement strategies and to provide a meaningful prediction. The results showed statistically significant differences when comparing the movement strategies between limb role (accuracy > 88.0% and > 89.3%, respectively), and when moving in the different directions but performing the same role (accuracy > 92.3% and > 91.2%, respectively). This highlights the importance of considering limb dominance, limb role and direction of movement during block jump-landings in the identification of which biomechanical variables are the most influential in the movement strategies.