Lawrencekarlsson2025

PURPOSE/OBJECTIVES This phase I/II, multi-institutional trial explored the tolerance and efficacy of stepwise increasingly hypofractionation radiation therapy regimens for fraction sizes up to 4.3 Gy in localized prostate cancer. UPF 1069 purchase MATERIALS/METHODS Three escalating dose-per-fraction schedules were designed to yield similar predicted tumor control while maintaining equivalent predicted late toxicity. Hypofractionation levels I, II, and III were carried out sequentially and delivered schedules of 64.7Gy/22 fx/2.94Gy; 58.08Gy/16 f/3.63Gy and 51.6/Gy12/4.3Gy, respectively with next level escalations contingent upon acceptable GI toxicity. The primary endpoints were biochemical control and toxicity. RESULTS A total of 347 patients were accrued by 5 institutions with 101, 111 and 135 patients treated on HPFX Levels I, II and III with median follow-ups of 100, 85.5 and 61.7 months, respectively (83.2 months combined). The NCCN low/intermediate risk group distribution was 46%/54%. Sixteen percent of patients, primarilventionally fractionated radiation therapy for prostate cancer. Every second we inhale a danger in the air; many particles in the atmosphere can influence our lives. Outdoor air pollution, especially particulate matter is the largest environmental risk factor and has been associated with many cardiovascular and lung diseases. Importantly, air pollution has recently been discovered to also impact the brain. Here, we review the effects of air pollution on glial cells of the brain, astrocytes and microglia, and the tightly controlled interplay between these cell types. We focus on how traffic related air pollutants which include both gaseous and particulate emissions and their secondary products influence the intercellular communication of microglia and astrocytes. Finally, we place these air pollution and glial interactions in a larger context by discussing their impact on neurodegeneration. The hippocampus has a well-known role in mediating learning and memory, and its function can be directly regulated by both stress and glucocorticoid receptor activation. Hippocampal contributions to learning are thought to be dependent on changes in the plasticity of synapses within specific subregions, and these functional changes are accompanied by morphological changes in the number and shape of dendritic spines, the physical correlates of these glutamatergic synapses. Serum- and glucocorticoid-inducible kinase 1 (SGK1) regulates dendritic spine morphology in the prefrontal cortex, and modulation of SGK1 expression in mouse hippocampus regulates learning. However, the role of SGK1 in dendritic spine morphology within the CA1 and dentate gyrus regions of the hippocampus are unknown. Thus, herpes simplex viral vectors expressing GFP and various SGK1 constructs, including wild type SGK1, a catalytically inactive version of SGK1 (K127Q), and a phospho-defective version of SGK1 (S78A), were infused into the hippocampus of adult mice and confocal fluorescent microscopy was used to visualize dendritic spines. We show that increasing expression of SGK1 in the dentate gyrus increased the total number of spines, driven primarily by an increase in mushroom spines, while decreasing SGK1 activity (K127Q) in the CA1 region increased the total number of dendritic spines, driven by a significant increase in mushroom and stubby spines. The differential effects of SGK1 in these regions may be mediated by the interactions of SGK1 with multiple pathways required for spine formation and stability. As the formation of mature synapses is a crucial component of learning and memory, this indicates that SGK1 is a potential target in the pathway underlying stress-associated changes in cognition and memory. High rates of hip fracture (HF) in long-term care (LTC) lead to increased hospitalization and greater risk of death. Supplementation of residents with vitamin D3 (vitD) has been recommended, but may be infrequently acted upon. Using a prospective cohort design, we explored use of vitD at doses ≥800 IU for hip fractures (HF) and for mortality among permanent LTC residents in Saskatchewan between 2008 and 2012, using provincial administrative health databases (N = 23178). We used stepwise backward regression with Cox proportional hazard multivariate analysis for time to first HF or to death upon entry into LTC (excluding the first three months), the association of daily vitD (determined during the first three months), age, sex, age*sex interaction, prior HF, osteoporosis diagnosis and Charlson Comormidity Score (CCS) was determined. Users of VitD were more likely older, women and those with previous HF. For HF, no significant impact of vitD or CCS was found. Models for mortality, stratified by sex, showed in women only, that vitD use resulted in a significant inverse association with time to death [HR (0.91(0.87-0.96)]; for men it was 0.94(0.88-1.01). The impact of VitD supplementation in LTC deserves further investigation, however, the mechanisms for its effect on mortality remain unclear. BACKGROUND Real-world illumination challenges both autonomous sensing and displays, because scene luminance can vary by up to 109-to-1, whereas vision models have limited ability to generalize beyond 100-to-1 luminance contrast. Brain mechanisms automatically normalize the visual input based on feature context, but they remain poorly understood because of the limitations of commercially available displays. NEW METHOD Here, we describe procedures for setup, calibration, and precision check of an HDR display system, based on a JVC DLA-RS600U reference projector, with over 100,000-to-1 luminance dynamic range (636-0.006055 cd/m2), pseudo 11 bit grayscale precision, and 3 ms temporal precision in the MATLAB/Psychtoolbox software environment. The setup is synchronized with electroencephalography (EEG) and infrared eye-tracking measurements. RESULTS We show display metrics including light scatter versus average display luminance (ADL), spatial uniformity, and spatial uniformity at high spatial frequency. We also show a luminance normalization phenomenon, contextual facilitation of a high contrast target, whose discovery required HDR display. COMPARISON WITH EXISTING METHODS This system provides 100-fold greater dynamic range than standard 1000-to-1 contrast displays and increases the number of gray levels from 256 or 1024 (8 or 10 bits) to 2048 (pseudo 11 bits), enabling the study of mesopic-to-photopic vision, at the expense of spatial non-uniformities. CONCLUSIONS This HDR research capability opens new questions of how visual perception is resilient to real-world luminance dynamics and will lead to improved visual modeling of dense urban and forest environments and of mixed indoor-outdoor environments such as cockpits and augmented reality. Our display metrics code can be found at https//github.com/USArmyResearchLab/ARL-Display-Metrics-and-Average-Display-Luminance. Published by Elsevier B.V.BACKGROUND Our understanding of the neural systems that subserve navigation and spatial processing can be greatly improved through access to experimental approaches that allow for precise spatial and temporal control of the sensory information that inform these systems. Furthermore, paradigms that incorporate concurrent behavioral metrics of navigation performance in the presence of experimental manipulations provide an additional dimension in which to understand neurobiological findings. NEW METHOD We investigate the use of a novel behavioral apparatus, the Instantaneous Cue Rotation (ICR) arena, which utilizes an augmented reality system to allow for rapid remote control of all symmetry breaking visual cues in the environment as rats perform a real-world visual cue-based navigation task. RESULTS We present behavioral data collected using two different reward delivery systems (fixed or mobile). Rats' behavior was assessed with respect to the degree and timing with which their navigation strategies changed in response to an instantaneous rotation of all orienting visual cues in the arena. We show that rats were able to utilize projected visual cues to navigate to a cue-aligned goal both before and after the cues were rotated, and that the mobile feeder version was optimal. COMPARISON WITH EXISTING METHODS In contrast to commonly used existing approaches for investigating environmental cues in spatial processing, the ICR does not require interrupting ongoing navigation behavior or rely on virtual reality systems that limit self-motion feedback. CONCLUSIONS The ICR is an effective new method for dissociating the role of self-motion and environmental cues in navigation. V.Oxytocin regulates social behaviours, pair bonding and hippocampal neurogenesis but most studies have used adult males. Our study investigated the effects of oxytocin on social investigation and adult hippocampal neurogenesis in male and female rats. Oxytocin has poor penetration of the blood-brain barrier, therefore we tested a nanoparticle drug, TRIOZAN™ (Ovensa Inc.), which permits greater blood-brain-barrier penetration. Adult male and female rats were injected daily (i.p.) for 10 days with either oxytocin in PBS (0.5 or 1.0 mg/kg), oxytocin in TRIOZAN™ (0.5 or 1.0 mg/kg), or vehicle (PBS) and tested for social investigation. Oxytocin decreased body mass and increased social investigation and number of oxytocin-immunoreactive cells in the supraoptic nucleus (SON) of the hypothalamus in male rats only. In both sexes, oxytocin decreased the number of immature neurons (doublecortin+ cells) in the ventral hippocampus and reduced plasma 17β-estradiol levels in a dose- and delivery-dependent way. Oxytocin in TRIOZAN™ reduced "sedation" observed post-injection and increased certain central effects (oxytocin levels in the hypothalamus and neurogenesis in the ventral hippocampus) relative to oxytocin in PBS, indicating that the nanoparticle may be used as an alternative brain delivery system. We showed that oxytocin has sex-specific effects on social investigation, body mass, "sedation", and the oxytocin system. In contrast, similar effects were observed in both sexes in neurogenesis and plasma 17β-estradiol. Our work suggests that sex differences in oxytocin regulation of brain endpoints is region-specific (hypothalamus versus hippocampus) and that oxytocin does not promote social investigation in females. G protein-coupled receptors (GPCRs), key regulators of a variety of critical biological processes, are attractive targets for insecticide development. Given the importance of these receptors in many organisms, including humans, it is critical that novel pesticides directed against GPCRs are designed to be species-specific. Here, we present characterization of an interfering RNA pesticide (IRP) targeting the mosquito GPCR-encoding dopamine 1 receptor (dop1) genes. A small interfering RNA corresponding to dop1 was identified in a screen for IRPs that kill Aedes aegypti during both the adult and larval stages. The 25 bp sequence targeted by this IRP is conserved in the dop1 genes of multiple mosquito species, but not in non-target organisms, indicating that it could function as a biorational mosquito insecticide. Aedes aegypti adults treated through microinjection or attractive toxic sugar bait delivery of small interfering RNA corresponding to the target site exhibited severe neural and behavioral defects and high levels of adult mortality.