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(1) Summarize revisions made to the implantable resonator (IR) design and results of testing to characterize biocompatibility; (2) Demonstrate safety of implantation and feasibility of deep tissue oxygenation measurement using electron paramagnetic resonance (EPR) oximetry. In vitro testing of the revised IR and in vivo implantation in rabbit brain and leg tissues. Revised IRs were fabricated with 1–4 OxyChips with a thin wire encapsulated with two biocompatible coatings. Biocompatibility and chemical characterization tests were performed. Rabbits were implanted with either an IR with 2 oxygen sensors or a biocompatible-control sample in both the brain and hind leg. The rabbits were implanted with IRs using a catheter-based, minimally invasive surgical procedure. EPR oximetry was performed for rabbits with IRs. Cohorts of rabbits were euthanized and tissues were obtained at 1 week, 3 months, and 9 months after implantation and examined for tissue reaction. Biocompatibility and toxicity testing of the revised IRs demonstrated no abnormal reactions. EPR oximetry from brain and leg tissues were successfully executed. Blood work and histopathological evaluations showed no significant difference between the IR and control groups. IRs were functional for up to 9 months after implantation and provided deep tissue oxygen measurements using EPR oximetry. Tissues surrounding the IRs showed no more tissue reaction than tissues surrounding the control samples. This pre-clinical study demonstrates that the IRs can be safely implanted in brain and leg tissues and that repeated, non-invasive, deep-tissue oxygen measurements can be obtained using in vivo EPR oximetry.

Computational methods for image-based profiling are under active development, but their success hinges on assays that can capture a wide range of phenotypes. We have developed a multiplex cytological profiling assay that \"paints the cell\" with as many fluorescent markers as possible without compromising our ability to extract rich, quantitative profiles in high throughput. The assay detects seven major cellular components. In a pilot screen of bioactive compounds, the assay detected a range of cellular phenotypes and it clustered compounds with similar annotated protein targets or chemical structure based on cytological profiles. The results demonstrate that the assay captures subtle patterns in the combination of morphological labels, thereby detecting the effects of chemical compounds even though their targets are not stained directly. This image-based assay provides an unbiased approach to characterize compound- and disease-associated cell states to support future probe discovery.

Oligodendrocyte precursor cells (OPCs) account for 5% of the resident parenchymal central nervous system glial cells. OPCs are not only a back-up for the loss of oligodendrocytes that occurs due to brain injury or inflammation-induced demyelination (remyelination) but are also pivotal in plastic processes such as learning and memory (adaptive myelination). OPC differentiation into mature myelinating oligodendrocytes is controlled by a complex transcriptional network and depends on high metabolic and mitochondrial demand. Mounting evidence shows that OPC dysfunction, culminating in the lack of OPC differentiation, mediates the progression of neurodegenerative disorders such as multiple sclerosis, Alzheimer’s disease and Parkinson’s disease. Importantly, neurodegeneration is characterised by oxidative and carbonyl stress, which may primarily affect OPC plasticity due to the high metabolic demand and a limited antioxidant capacity associated with this cell type. The underlying mechanisms of how oxidative/carbonyl stress disrupt OPC differentiation remain enigmatic and a focus of current research efforts. This review proposes a role for oxidative/carbonyl stress in interfering with the transcriptional and metabolic changes required for OPC differentiation. In particular, oligodendrocyte (epi)genetics, cellular defence and repair responses, mitochondrial signalling and respiration, and lipid metabolism represent key mechanisms how oxidative/carbonyl stress may hamper OPC differentiation in neurodegenerative disorders. Understanding how oxidative/carbonyl stress impacts OPC function may pave the way for future OPC-targeted treatment strategies in neurodegenerative disorders.

To examine the relationship between postoperative pain and opioid use and the development of postoperative delirium (POD), with attention to the preoperative opioid use status of patients. This was a secondary analysis of data from a prospective observational study of patients (N = 219; ≥70 years old) scheduled to undergo elective spine surgery. Maximal daily pain scores (0-10) and postoperative morphine milligram equivalents per hour (MME/hr) were determined for postoperative days 1-3 (D1-3). POD was assessed by daily in-person interviews using the Confusion Assessment Method and chart review. Patients who reported regular preoperative opioid use (n = 58, 27%) reported significantly greater maximal daily pain scores, despite also requiring greater daily opioids (MME/hr) in the first 3 days after surgery. These patients were also more likely to develop POD. Interestingly, while postoperative pain scores were significantly higher in patients who developed POD, postoperative opioid consumption was not significantly higher in this group. POD was associated with greater postoperative pain, but not with postoperative opioid consumption. While postoperative opioid consumption is often blamed for delirium, these findings suggest that uncontrolled pain may actually be a more important factor, particularly among patients who are opioid tolerant. These findings underscore the importance of employing multimodal perioperative analgesic management, especially among older patients who have a predilection to developing POD and baseline tolerance to opioids.

Understanding how DNA binding proteins control global gene expression and chromosomal maintenance requires knowledge of the chromosomal locations at which these proteins function in vivo. We developed a microarray method that reveals the genome-wide location of DNA-bound proteins and used this method to monitor binding of gene-specific transcription activators in yeast. A combination of location and expression profiles was used to identify genes whose expression is directly controlled by Gal4 and Ste12 as cells respond to changes in carbon source and mating pheromone, respectively. The results identify pathways that are coordinately regulated by each of the two activators and reveal previously unknown functions for Gal4 and Ste12. Genome-wide location analysis will facilitate investigation of gene regulatory networks, gene function, and genome maintenance.

Purpose: Loneliness increased during the COVID-19 pandemic and social distancing guidelines, potentially exacerbating negative cognitions about pain. The present study investigated the longitudinal relationship between loneliness, assessed during the early weeks of the pandemic, and pain catastrophizing, assessed after living in the pandemic for approximately 1 year, among chronic pain patients. We also examined whether severity of depressive symptoms mediated this association. Methods: This prospective longitudinal study recruited individuals with chronic pain (N=93) from Massachusetts using an online convenience sampling method via the platform Rally. Participants completed an initial survey early after the onset of social distancing (4/28/20-6/17/20; Time 1) and a follow-up survey 1 year later (5/21/21-6/7/21; Time 2). Participants completed validated assessments of loneliness (T1), pain catastrophizing (T2), and depression (T2). Spearman correlations and Mann--Whitney U-tests were used to explore associations among psychosocial, pain, and participant characteristics. A mediation analysis was conducted to test whether the association between loneliness and pain catastrophizing was mediated by depression. Results: Participants had a mean age of 40.6 years and were majority female (80%) and White (82%). Greater loneliness was associated with subsequent higher pain catastrophizing (6=1.23, 95% CI [0.03, 2.44]). Mediation analysis showed a significant indirect effect (6=0.57, 95% CI [0.10, 1.18) of loneliness (T1) on catastrophizing (T2) through depression (T2) while accounting for several important covariates. The direct effect of loneliness on catastrophizing was no longer significant when depression was included in the model (6=0.66, 95% CI [-0.54, 1.87]). Conclusion: Findings suggest that greater loneliness during the pandemic was associated with higher pain catastrophizing 1 year later, and severity of depression after living in the pandemic mediated this association. As loneliness, depression, and catastrophizing can all be modified with behavioral interventions, understanding the temporal associations among these variables is important for the employment of future empirically supported treatments. Keywords: loneliness, pain catastrophizing, depression, chronic pain, COVID-19

Using a diverse collection of small molecules generated from a variety of sources, we measured protein-binding activities of each individual compound against each of 100 diverse (sequence-unrelated) proteins using small-molecule microarrays. We also analyzed structural features, including complexity, of the small molecules. We found that compounds from different sources (commercial, academic, natural) have different protein-binding behaviors and that these behaviors correlate with general trends in stereochemical and shape descriptors for these compound collections. Increasing the content of sp³-hybridized and stereogenic atoms relative to compounds from commercial sources, which comprise the majority of current screening collections, improved binding selectivity and frequency. The results suggest structural features that synthetic chemists can target when synthesizing screening collections for biological discovery. Because binding proteins selectively can be a key feature of high-value probes and drugs, synthesizing compounds having features identified in this study may result in improved performance of screening collections.

Mature pollen is covered by durable cell walls, principally composed of sporopollenin, an evolutionary conserved, highly resilient, but not fully characterized, biopolymer of aliphatic and aromatic components. Here, we report that ABORTED MICROSPORES (AMS) acts as a master regulator coordinating pollen wall development and sporopollenin biosynthesis in Arabidopsis thaliana. Genome-wide coexpression analysis revealed 98 candidate genes with specific expression in the anther and 70 that showed reduced expression in ams. Among these 70 members, we showed that AMS can directly regulate 23 genes implicated in callose dissociation, fatty acids elongation, formation of phenolic compounds, and lipidie transport putatively involved in sporopollenin precursor synthesis. Consistently, ams mutants showed defective microspore release, a lack of sporopollenin deposition, and a dramatic reduction in total phenolic compounds and cutin monomers. The functional importance of the AMS pathway was further demonstrated by the observation of impaired pollen wall architecture in plant lines with reduced expression of several AMS targets: the abundant pollen coat protein extracellular lipases (EXL5 and EXL6), and CYP98A8 and CYP98A9, which are enzymes required for the production of phenolic precursors. These findings demonstrate the central role of AMS in coordinating sporopollenin biosynthesis and the secretion of materials for pollen wall patterning.

Many white dwarf stars show signs of having accreted smaller bodies, implying that they may host planetary systems. A small number of these systems contain gaseous debris discs, visible through emission lines.We report a stable 123.4-minute periodic variation in the strength and shape of the Ca II emission line profiles originating from the debris disc around the white dwarf SDSS J122859.93+104032.9. We interpret this short-period signal as the signature of a solid-body planetesimal held together by its internal strength.

Chronic postsurgical pain (CPSP) is a cause of new chronic pain, with a wide range of reported incidence. Previous longitudinal studies suggest that development of CPSP may depend more on the constellation of risk factors around a patient (pre-existing pain phenotype) rather than on the extent of surgical injury itself. The biopsychosocial model of pain outlines a broad array of factors that modulate the severity, longevity, and impact of pain. Biological variables associated with CPSP include age, sex, baseline pain sensitivity, and opioid tolerance. Psychological factors, including anxiety, depression, somatization, sleep disturbance, catastrophizing, and resilience, and social factors, like education and social support, may also importantly modulate CPSP. Prevention efforts have targeted acute pain reduction using multimodal analgesia (regional anesthesia and intraoperative analgesic adjuvant medications). However, studies that do not measure or take phenotypic risk factors into account (either using them for enrichment or statistically as effect modifiers) likely suffer from underpowering, and thus, fail to discern subgroups of patients that preventive measures may be most helpful to. Early preoperative identification of a patient’s pain phenotype allows estimation of their constellation of risk factors and may greatly enhance successful, personalized prevention of postoperative pain. Effective preoperative employment of behavioral interventions like cognitive–behavioral therapy, stress reduction, and physical and mental prehabilitation may particularly require knowledge of a patient’s pain phenotype. Preoperative assessment of patients’ pain phenotypes will not only inform high-quality personalized perioperative care clinically, but it will enable enriched testing of novel therapies in future scientific studies.