Cultural evolution: A review of theoretical challenges.

The rapid growth of cultural evolutionary science, its expansion into numerous fields, its use of diverse methods, and several conceptual problems have outpaced corollary developments in theory and philosophy of science. This has led to concern, exemplified in results from a recent survey conducted with members of the Cultural Evolution Society, that the field lacks 'knowledge synthesis', is poorly supported by 'theory', has an ambiguous relation to biological evolution and uses key terms (e.g. 'culture', 'social learning', 'cumulative culture') in ways that hamper operationalization in models, experiments and field studies. Although numerous review papers in the field represent and categorize its empirical findings, the field's theoretical challenges receive less critical attention even though challenges of a theoretical or conceptual nature underlie most of the problems identified by Cultural Evolution Society members. Guided by the heterogeneous 'grand challenges' emergent in this survey, this paper restates those challenges and adopts an organizational style requisite to discussion of them. The paper's goal is to contribute to increasing conceptual clarity and theoretical discernment around the most pressing challenges facing the field of cultural evolutionary science. It will be of most interest to cultural evolutionary scientists, theoreticians, philosophers of science and interdisciplinary researchers.

Inpatient EHR User Experience and Hospital EHR Safety Performance.

IMPORTANCE: Despite the broad adoption and optimization of electronic health record (EHR) systems across the continuum of care, serious usability and safety problems persist. OBJECTIVE: To assess whether EHR safety performance is associated with EHR frontline user experience in a national sample of hospitals. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study included all US adult hospitals that used the National Quality Forum Leapfrog Health IT Safety Measure and also used the ARCH Collaborative EHR User experience survey from January 1, 2017, to January 1, 2019. Data analysis was performed from September 2020 to November 2022. MAIN OUTCOMES AND MEASURES: The primary outcomes were hospital performance on the Leapfrog Health IT Safety measure (overall and 10 subcomponents) and the ARCH collaborative frontline user experience scores (overall and 8 subcomponents). Ordinary least squares models with survey responses clustered by hospital were used to assess associations between the overall measures and their subcomponents. RESULTS: There were 112 hospitals and 5689 frontline user surveys included in the study. Hospitals scored a mean of 0.673 (range, 0.297-0.973) on the Leapfrog Health IT safety measure; the mean ARCH EHR user experience score was 3.377 (range, 1 [best] to 5 [worst]). The adjusted ß coefficient between the overall safety score and overall user experience score was 0.011 (95% CI, 0.006-0.016). The ARCH overall score was also significantly associated with 10 subcategory scores of the Leapfrog Health IT safety score, and the overall Leapfrog score was associated with the 8 subcategory scores of the ARCH user experience score. CONCLUSIONS AND RELEVANCE: This cross-sectional study found a positive association between frontline user-rated EHR usability and EHR safety performance. This finding suggests that improving EHR usability, which is a current well-known pain point for EHR users, could have direct benefits in terms of improved EHR safety.

Host-diet-gut microbiome interactions influence human energy balance: a randomized clinical trial.

The gut microbiome is emerging as a key modulator of human energy balance. Prior studies in humans lacked the environmental and dietary controls and precision required to quantitatively evaluate the contributions of the gut microbiome. Using a Microbiome Enhancer Diet (MBD) designed to deliver more dietary substrates to the colon and therefore modulate the gut microbiome, we quantified microbial and host contributions to human energy balance in a controlled feeding study with a randomized crossover design in young, healthy, weight stable males and females (NCT02939703). In a metabolic ward where the environment was strictly controlled, we measured energy intake, energy expenditure, and energy output (fecal and urinary). The primary endpoint was the within-participant difference in host metabolizable energy between experimental conditions [Control, Western Diet (WD) vs. MBD]. The secondary endpoints were enteroendocrine hormones, hunger/satiety, and food intake. Here we show that, compared to the WD, the MBD leads to an additional 116 ± 56 kcals (P < 0.0001) lost in feces daily and thus, lower metabolizable energy for the host (89.5 ± 0.73%; range 84.2-96.1% on the MBD vs. 95.4 ± 0.21%; range 94.1-97.0% on the WD; P < 0.0001) without changes in energy expenditure, hunger/satiety or food intake (P > 0.05). Microbial 16S rRNA gene copy number (a surrogate of biomass) increases (P < 0.0001), beta-diversity changes (whole genome shotgun sequencing; P = 0.02), and fermentation products increase (P < 0.01) on an MBD as compared to a WD along with significant changes in the host enteroendocrine system (P < 0.0001). The substantial interindividual variability in metabolizable energy on the MBD is explained in part by fecal SCFAs and biomass. Our results reveal the complex host-diet-microbiome interplay that modulates energy balance.

Evaluating Adherence to Diabetic Retinopathy Care in an Urban Ophthalmology Clinic Utilizing the Compliance With Annual Diabetic Eye Exams Survey.

Introduction The objective of this study was to identify barriers that affect adherence to the management of diabetic retinopathy (DR) in an urban ophthalmology clinic. Patient beliefs regarding diabetic eye care, transportation to the eye clinic, the COVID-19 pandemic, and treatment with panretinal photocoagulation (PRP) or anti-vascular endothelial growth factor (anti-VEGF) injections were investigated. Materials and methods The original Compliance with Annual Diabetic Eye Exams Survey (CADEES) included 44 statements designed with a 5-point Likert scale to assess patients' beliefs and understanding of their eye health and the importance of diabetic eye examinations. This survey was modified to include additional statements regarding the COVID-19 pandemic and free-response questions about transportation barriers and patients' subjective experiences with PRP or anti-VEGF injections. A total of 365 patients with a diagnosis of any stage of DR from SLUCare Ophthalmology were identified as potential participants to complete the telephone survey. Patients were classified as non-adherent if they did not have a dilated eye examination within the past year, missed a scheduled follow-up appointment for DR care within the past year, or missed an appointment for anti-VEGF injections or PRP. The mean Likert scores for each CADEES statement were compared between the adherent and non-adherent groups using independent samples t-tests. Demographics and clinical indicators were also reported and compared between the two groups. Results Out of 365 patients, 68 completed the modified CADEES. Twenty-nine patients were adherent, and 39 patients were non-adherent. Results from six of the 54 CADEES statements were significantly different between the adherent and non-adherent groups. These statements addressed patients' perception of their eye health, self-confidence in making an eye appointment, knowing someone with diabetic eye complications, self-confidence in controlling blood sugar, ability to use public transportation during the COVID-19 pandemic, and prioritizing eye health during the pandemic. There were no significant differences in clinical indicators or demographics between the adherent and non-adherent groups. Of the participants, 39.7% offered reasons for why transportation to the eye clinic was difficult. Patients suggested three novel reasons for missing eye appointments that were not specifically addressed in the CADEES. Fourteen unique barriers were reported for non-adherence with PRP or anti-VEGF injections. Conclusions The CADEES is a thorough tool for evaluating social barriers impacting adherence with DR appointments in an urban ophthalmology clinic. The survey did not identify any clinical or demographic risk factors for non-adherence in this patient population. Decreased patient self-efficacy may lead to non-adherence with the management of DR. The COVID-19 pandemic impacted the adherence of a small percentage of patients.

Reprogramming the Human Gut Microbiome Reduces Dietary Energy Harvest.

The gut microbiome is emerging as a key modulator of host energy balance1. We conducted a quantitative bioenergetics study aimed at understanding microbial and host factors contributing to energy balance. We used a Microbiome Enhancer Diet (MBD) to reprogram the gut microbiome by delivering more dietary substrates to the colon and randomized healthy participants into a within-subject crossover study with a Western Diet (WD) as a comparator. In a metabolic ward where the environment was strictly controlled, we measured energy intake, energy expenditure, and energy output (fecal, urinary, and methane)2. The primary endpoint was the within-participant difference in host metabolizable energy between experimental conditions. The MBD led to an additional 116 ± 56 kcals lost in feces daily and thus, lower metabolizable energy for the host by channeling more energy to the colon and microbes. The MBD drove significant shifts in microbial biomass, community structure, and fermentation, with parallel alterations to the host enteroendocrine system and without altering appetite or energy expenditure. Host metabolizable energy on the MBD had quantitatively significant interindividual variability, which was associated with differences in the composition of the gut microbiota experimentally and colonic transit time and short-chain fatty acid absorption in silico. Our results provide key insights into how a diet designed to optimize the gut microbiome lowers host metabolizable energy in healthy humans.

Red cell exchange transfusions increase cerebral capillary transit times and may alter oxygen extraction in sickle cell disease.

Persons with sickle cell disease (SCD) suffer from chronic hemolytic anemia, reduced blood oxygen content, and lifelong risk of silent and overt stroke. Major conventional stroke risk factors are absent in most individuals with SCD, yet nearly 50% have evidence of brain infarcts by the age of 30 years, indicating alternative etiologies for ischemia. We investigated whether radiological evidence of accelerated blood water transit through capillaries, visible on arterial spin labeling (ASL) magnetic resonance imaging, reduces following transfusion-induced increases in hemoglobin and relates to oxygen extraction fraction (OEF). Neurological evaluation along with anatomical and hemodynamic imaging with cerebral blood flow (CBF)-weighted pseudocontinuous ASL and OEF imaging with T2 -relaxation-under-spin-tagging were applied in sequence before and after blood transfusion therapy (n = 32) and in a comparator cohort of nontransfused SCD participants on hydroxyurea therapy scanned at two time points to assess stability without interim intervention (n = 13). OEF was calculated separately using models derived from human hemoglobin-F, hemoglobin-A, and hemoglobin-S. Gray matter CBF and dural sinus signal, indicative of rapid blood transit, were evaluated at each time point and compared with OEF using paired statistical tests (significance: two-sided p < 0.05). No significant change in sinus signal was observed in nontransfused participants (p = 0.650), but a reduction was observed in transfused participants (p = 0.034), consistent with slower red cell transit following transfusion. The dural sinus signal intensity was inversely associated with OEF pretransfusion (p = 0.011), but not posttransfusion. Study findings suggest that transfusion-induced increases in total hemoglobin may lengthen blood transit times through cerebral capillaries and alter cerebral OEF in SCD.

Advancing School Behavioral Health at Multiple Levels of Scale.

There is a national movement to advance school behavioral health, involving the mental health system partnering with schools' multitiered systems of support. This article underscores the critical need for school behavioral health and presents strategies to advance effective programming at district, state, and regional levels. Themes include diverse stakeholder involvement, teaming, data-based decision-making, implementation of evidence-based practices, screening, coaching and implementation support, progress monitoring and outcome evaluation, and using findings to scale-up effective programming. Implications for research, practice, and policy are reviewed along with ideas for the future development of this field.

Community perspectives on the racial disparity in perinatal outcomes.

OBJECTIVE: The United States' infant and maternal mortality rates are significantly higher among non-Hispanic Black women and infants than women and infants of other races, independent of educational attainment or socioeconomic status. The purpose of this research was to understand conditions that lead to these disparities and propose practices for addressing them through community perspectives. METHOD: Researchers conducted six focus groups with African American women who had been pregnant previously (n = 27) and performed inductive thematic analysis looking at the interaction between race and health. RESULTS: Major themes included barriers to quality healthcare and support. Women perceived that healthcare professionals provided substandard care based on implicit biases and felt that asking questions of providers led to loss of autonomy.Conclusions and relevance: The perceived quality of a woman's perinatal experience is affected by women's relationships with their healthcare providers, their social support, and their sense of autonomy in decision-making. To improve the relationships between African American women and their providers, participants expressed that racism and implicit bias must be recognized and addressed. While this should be addressed in individual interactions, this study also suggests the role of policy change and system-level modifications that should be considered to effectively decrease the racial disparity in perinatal outcomes.

Developing a model for estimating the activity of colonic microbes after intestinal surgeries.

BACKGROUND: The large intestine provides a compensatory role in energy recovery when surgical interventions such as extensive small intestinal resections or bypass operations lower the efficiency of nutrient absorption in the upper gastrointestinal (GI) tract. While microorganisms in the colon are known to play vital roles in recovering energy, their contributions remain to be qualified and quantified in the small intestine resection. OBJECTIVE: We develop a mathematical model that links nutrient absorption in the upper and lower GI tract in two steps. METHODS: First, we describe the effects of small intestine resection on the ileocecal output (ICO), which enters the colon and provides food for microbes. Second, we describe energy recovered by the colon's microorganisms via short-chain fatty acid (SCFA) production. We obtain model parameters by performing a least-squares regression analysis on clinical data for subjects with normal physiology and those who had undergone small intestine resection. RESULTS: For subjects with their intestines intact, our model provided a metabolizable energy value that aligns well with the traditional Atwater coefficients. With removal of the small intestine, physiological absorption became less efficient, and the metabolizable energy decreased. In parallel, the inefficiencies in physiological absorption by the small intestine are partly compensated by production of short-chain fatty acids (SCFA) from proteins and carbohydrates by microorganisms in the colon. The colon recovered more than half of the gross energy intake when the entire small intestine was removed. Meanwhile, the quality of energy absorbed changed, because microbe-derived SCFAs, not the original components of food, become the dominant form of absorbed energy. CONCLUSION: The mathematical model developed here provides an important framework for describing the effect of clinical interventions on the colon's microorganisms.

Neonatal heart transplant outcomes: A single institutional experience.

OBJECTIVE: Neonatal orthotopic heart transplantation was introduced in the 1980s as a treatment for complex congenital heart disease. Progress in single-ventricle palliation and biventricular correction has resulted in a decline in neonatal heart transplant volume. However, limited reports on neonatal heart transplants have demonstrated favorable outcomes. We report the long-term outcomes of patients with neonatal heart transplants at our institution spanning nearly 30 years. METHODS: A retrospective analysis of neonatal heart transplants and neonates listed for transplant was performed at Children's Hospital Colorado. Primary outcomes were early and late survival. Secondary outcomes were rejection episodes, retransplantation, and development of cardiac allograft vasculopathy or post-transplant lymphoproliferative disease. RESULTS: A total of 21 neonates underwent orthotopic heart transplantation at our institution. Among these, 10 neonates were transplanted from 1991 to 2000, 8 neonates were transplanted from 2001 to 2010, and 3 neonates were transplanted from 2011 to 2020. The average age of these patients was 17 days, and the average weight was 3.43 kg. Early survival was 95.2%. Survival at 1 and 5 years was 85.7% (confidence interval [CI], 61.9%-95.2%) and 75% (CI, 45.6%-85.5%), respectively. Of eligible patients, the 10-year and 20-year survival was 72.2% (CI, 45.1%-85.3%) and 50% (CI, 25.9%-70.1%), respectively. CONCLUSIONS: Our institution reports favorable outcomes of neonatal heart transplantation. These results should be considered within the context of outcomes for patients awaiting transplant and the limited donor availability. However, the successful nature of these procedures suggest it may be necessary to reevaluate the indications for neonatal heart transplantation, particularly where risk of mortality and morbidity with palliative or corrective surgery is high.

Chemical Oxygen Demand Can Be Converted to Gross Energy for Food Items Using a Linear Regression Model.

BACKGROUND: Human and microbial metabolism are distinct disciplines. Terminology, metrics, and methodologies have been developed separately. Therefore, combining the 2 fields to study energetic processes simultaneously is difficult. OBJECTIVES: When developing a mechanistic framework describing gut microbiome and human metabolism interactions, energy values of food and digestive materials that use consistent and compatible metrics are required. As an initial step toward this goal, we developed and validated a model to convert between chemical oxygen demand (COD) and gross energy (${E_g}$) for >100 food items and ingredients. METHODS: We developed linear regression models to relate (and be able to convert between) theoretical gross energy (${E_g}^{\prime}$) and chemical oxygen demand (COD'); the latter is a measure of electron equivalents in the food's carbon. We developed an overall regression model for the food items as a whole and separate regression models for the carbohydrate, protein, and fat components. The models were validated using a sample set of computed ${E_g}^{\prime}$ and COD' values, an experimental sample set using measured ${E_g}$ and COD values, and robust statistical methods. RESULTS: The overall linear regression model and the carbohydrate, protein, and fat regression models accurately converted between COD and ${E_g}$, and the component models had smaller error. Because the ratios of COD per gram dry weight were greatest for fats and smallest for carbohydrates, foods with a high fat content also had higher ${E_g}$ values in terms of kcal · g dry weight-1. CONCLUSION: Our models make it possible to analyze human and microbial energetic processes in concert using a single unit of measure, which fills an important need in the food-nutrition-metabolism-microbiome field. In addition, measuring COD and using the regressions to calculate ${E_g}$ can be used instead of measuring ${E_g}$ directly using bomb calorimetry, which saves time and money.

Integrative and quantitative bioenergetics: Design of a study to assess the impact of the gut microbiome on host energy balance.

The literature is replete with clinical studies that characterize the structure, diversity, and function of the gut microbiome and correlate the results to different disease states, including obesity. Whether the microbiome has a direct impact on obesity has not been established. To address this gap, we asked whether the gut microbiome and its bioenergetics quantitatively change host energy balance. This paper describes the design of a randomized crossover clinical trial that combines outpatient feeding with precisely controlled metabolic phenotyping in an inpatient metabolic ward. The target population was healthy, weight-stable individuals, age 18-45 and with a body mass index ≤30 kg/m2. Our primary objective was to determine within-participant differences in energy balance after consuming a control Western Diet versus a Microbiome Enhancer Diet intervention specifically designed to optimize the gut microbiome for positive impacts on host energy balance. We assessed the complete energy-balance equation via whole-room calorimetry, quantified energy intake, fecal energy losses, and methane production. We implemented conditions of tight weight stability and balance between metabolizable energy intake and predicted energy expenditure. We explored key factors that modulate the balance between host and microbial nutrient accessibility by measuring enteroendocrine hormone profiles, appetite/satiety, gut transit and gastric emptying. By integrating these clinical measurements with future bioreactor experiments, gut microbial ecology analysis, and mathematical modeling, our goal is to describe initial cause-and-effect mechanisms of gut microbiome metabolism on host energy balance. Our innovative methods will enable subsequent studies on the interacting roles of diet, the gut microbiome, and human physiology. CLINICALTRIALSGOV IDENTIFIER: NCT02939703. The present study reference can be found here: https://clinicaltrials.gov/ct2/show/NCT02939703.

Cryptic Species Account for the Seemingly Idiosyncratic Secondary Metabolism of Sarcophyton glaucum Specimens Collected in Palau.

Sarcophyton glaucum is one of the most abundant and chemically studied soft corals with over 100 natural products reported in the literature, primarily cembrane diterpenoids. Yet, wide variation in the chemistry observed from S. glaucum over the past 50 years has led to its reputation as a capricious producer of bioactive metabolites. Recent molecular phylogenetic analysis revealed that S. glaucum is not a single species but a complex of at least seven genetically distinct species not distinguishable using traditional taxonomic criteria. We hypothesized that perceived intraspecific chemical variation observed in S. glaucum was actually due to differences between cryptic species (interspecific variation). To test this hypothesis, we collected Sarcophyton samples in Palau, performed molecular phylogenetic analysis, and prepared chemical profiles of sample extracts using gas chromatography-flame ionization detection. Both unsupervised (principal component analysis) and supervised (linear discriminant analysis) statistical analyses of these profiles revealed a strong relationship between cryptic species membership and chemical profiles. Liquid chromatography with tandem mass spectrometry-based analysis using feature-based molecular networking permitted identification of the chemical drivers of this difference between clades, including cembranoid diterpenes (2R,11R,12R)-isosarcophytoxide (5), (2S,11R,12R)-isosarcophytoxide (6), and isosarcophine (7). Our results suggest that early chemical studies of Sarcophyton may have unknowingly conflated different cryptic species of S. glaucum, leading to apparently idiosyncratic chemical variation.

Cerebellar mutism after posterior fossa tumor resection in children: a multicenter international retrospective study to determine possible modifiable factors.

PURPOSE: A preliminary survey of pediatric neurosurgeons working at different centers around the world suggested differences in clinical practice resulting in variation in the risk of pediatric cerebellar mutism (CM) and cerebellar mutism syndrome (CMS) after posterior fossa (PF) tumor resection. The purposes of this study were (1) to determine the incidence and severity of CM and CMS after midline PF tumor resection in children treated at these centers and (2) to identify potentially modifiable factors related to surgical management (rather than tumor biology) that correlate with the incidence of CM/CMS. METHODS: Attending pediatric neurosurgeons at British Columbia's Children's Hospital (BCCH) and neurosurgeons who completed a pediatric neurosurgery fellowship at BCCH were invited to provide data from the center where they currently practiced. Children aged from birth to less than 18 years who underwent initial midline PF tumor resection within a contemporary, center-selected 2-year period were included. Data was obtained by retrospective chart and imaging review. Modifiable surgical factors that were assessed included pre-resection surgical hydrocephalus treatment, surgical positioning, ultrasonic aspirator use, intraoperative external ventricular drain (EVD) use, surgical access route to the tumor, and extent of resection. CM was defined as decreased or absent speech output postoperatively and CMS as CM plus new or worsened irritability. RESULTS: There were 263 patients from 11 centers in 6 countries (Canada, Germany, the Netherlands, India, Indonesia, and the USA). Median age at surgery was 6 years (range < 1 to 17 years). The overall incidence of postoperative CM was 23.5% (range 14.7-47.6% for centers with data on ≥ 20 patients). The overall incidence of CMS was 6.5% (range 0-10.3% for centers contributing data on ≥ 20 patients). A multivariate logistic regression on the full data set showed no significant association between pre-resection surgical hydrocephalus treatment, prone position, ultrasonic aspirator use, EVD use, telovelar approach, complete or near total resection, or treating center and either postoperative CM or CMS. CONCLUSIONS: While there was variation in surgical management of midline PF tumors among centers participating in this study, the factors in management that were examined did not predict postoperative CM or CMS.

Growth arrest-specific protein-6/AXL signaling induces preeclampsia in rats†.

Preeclampsia (PE) is a complicated obstetric complication characterized by increased blood pressure, decreased trophoblast invasion, and inflammation. The growth arrest-specific 6 (Gas6) protein is known to induce dynamic cellular responses and is elevated in PE. Gas6 binds to the AXL tyrosine kinase receptor and AXL-mediated signaling is implicated in proliferation and migration observed in several tissues. Our laboratory utilized Gas6 to induce preeclamptic-like conditions in pregnant rats. Our objective was to determine the role of Gas6/AXL signaling as a possible model of PE. Briefly, pregnant rats were divided into three groups that received daily intraperitoneal injections (from gestational day 7.5 to 17.5) of phosphate buffered saline (PBS), Gas6, or Gas6 + R428 (an AXL inhibitor administered from gestational day 13.5 to 17.5). Animals dispensed Gas6 experienced elevated blood pressure, increased proteinuria, augmented caspase-3-mediated placental apoptosis, and diminished trophoblast invasion. Gas6 also enhanced expression of several PE-related genes and a number of inflammatory mediators. Gas6 further enhanced placental oxidative stress and impaired mitochondrial respiration. Each of these PE-related characteristics was ameliorated in dams and/or their placentae when AXL inhibition by R428 occurred in tandem with Gas6 treatment. We conclude that Gas6 signaling is capable of inducing PE and that inhibition of AXL prevents disease progression in pregnant rats. These results provide insight into pathways associated with PE that could be useful in the clarification of potential therapeutic approaches.

Overexpression of neuropeptide Y decreases responsiveness to neuropeptide Y.

Neuropeptide Y (NPY) is an endogenous neuropeptide that is abundantly expressed in the central nervous system. NPY is involved in various neurological processes and neuropsychiatric disorders, including fear learning and anxiety disorders. Reduced levels of NPY are reported in Post-Traumatic Stress Disorder (PTSD) patients, and NPY has been proposed as a potential therapeutic target for PTSD. It is therefore important to understand the effects of chronic enhancement of NPY on anxiety and fear learning. Previous studies have shown that acute elevation of NPY reduces anxiety, fear learning and locomotor activity. Models of chronic NPY overexpression have produced mixed results, possibly caused by ectopic NPY expression. NPY is expressed primarily by a subset of GABAergic interneurons, providing specific spatiotemporal release patterns. Administration of exogenous NPY throughout the brain, or overexpression in cells that do not normally release NPY, can have detrimental side effects, including memory impairment. In order to determine the effects of boosting NPY only in the cells that normally release it, we utilized a transgenic mouse line that overexpresses NPY only in NPY+ cells. We tested for effects on anxiety related behaviors in adolescent mice, an age with high incidence of anxiety disorders in humans. Surprisingly, we did not observe the expected reduction in anxiety-like behavior in NPY overexpression mice. There was no change in fear learning behavior, although there was a deficit in nest building. The effect of exogenous NPY on synaptic transmission in acute hippocampal slices was also diminished, indicating that the function of NPY receptors is impaired. Reduced NPY receptor function could contribute to the unexpected behavioral outcomes. We conclude that overexpression of NPY, even in cells that normally express it, can lead to reduced responsiveness of NPY receptors, potentially affecting the ability of NPY to function as a long-term therapeutic.

RAGE and AXL expression following secondhand smoke (SHS) exposure in mice.

Aim and Purpose: Tobacco exposure is one of the top three global health risks leading to the development of chronic obstructive pulmonary disease (COPD). Although there is extensive research into the effects of cigarette smoke, the effect of secondhand smoke (SHS) in the lung remains limited. SHS induces receptors for advanced glycation end-products (RAGE) and an inflammatory response that leads to COPD characteristics. Semi-synthetic glycosaminoglycan ethers (SAGEs) are sulfated polysaccharides derived from hyaluronic acid that inhibit RAGE signaling. The growth arrest-specific 6 (Gas6) protein is known to induce dynamic cellular responses and is correlated with cell function. Gas6 binds to the AXL tyrosine kinase receptor and AXL-mediated signaling is implicated in proliferation and inflammation. This project's purpose was to study the correlation between RAGE, AXL, and Gas6 during SHS exposure in the lung. Methods: C57Bl/6 mice were exposed to SHS alone or SHS + SAGEs for 4 weeks and compared to control animals exposed to room air (RA). Results: Compared to controls we observed: 1) increased RAGE mRNA and protein expression in SHS-exposed lungs which was decreased by SAGEs; 2) decreased expression of total AXL, but highly elevated pAXL expression following exposure; 3) highly elevated Gas6 expression when RAGE was targeted by SAGEs during SHS exposure; 4) SHS-mediated BALF cellularity and inflammatory molecule elaboration; and 5) the induction of both RAGE and AXL by Gas6 in cell culture models. Conclusions: Our results suggest that there is a possible correlation between RAGE and AXL during SHS exposure. Additional research is critically needed that dissects the molecular interplay between these two important signaling cascades. At this point, the current studies provide insight into tobacco-mediated effects in the lung and clarify possible avenues for alleviating complications that could arise during SHS exposure such as those observed during COPD exacerbations.

Learning Implicit Brain MRI Manifolds with Deep Learning.

An important task in image processing and neuroimaging is to extract quantitative information from the acquired images in order to make observations about the presence of disease or markers of development in populations. Having a low-dimensional manifold of an image allows for easier statistical comparisons between groups and the synthesis of group representatives. Previous studies have sought to identify the best mapping of brain MRI to a low-dimensional manifold, but have been limited by assumptions of explicit similarity measures. In this work, we use deep learning techniques to investigate implicit manifolds of normal brains and generate new, high-quality images. We explore implicit manifolds by addressing the problems of image synthesis and image denoising as important tools in manifold learning. First, we propose the unsupervised synthesis of T1-weighted brain MRI using a Generative Adversarial Network (GAN) by learning from 528 examples of 2D axial slices of brain MRI. Synthesized images were first shown to be unique by performing a cross-correlation with the training set. Real and synthesized images were then assessed in a blinded manner by two imaging experts providing an image quality score of 1-5. The quality score of the synthetic image showed substantial overlap with that of the real images. Moreover, we use an autoencoder with skip connections for image denoising, showing that the proposed method results in higher PSNR than FSL SUSAN after denoising. This work shows the power of artificial networks to synthesize realistic imaging data, which can be used to improve image processing techniques and provide a quantitative framework to structural changes in the brain.

CIP2A immunosensor comprised of vertically-aligned carbon nanotube interdigitated electrodes towards point-of-care oral cancer screening.

Vertically aligned carbon nanotube array (VANTA) coatings have recently garnered significant attention due in part to their unique material properties including light absorption, chemical inertness, and electrical conductivity. Herein we report the first use of VANTAs grown via chemical vapor deposition in a 2D interdigitated electrode (IDE) footprint with a high height-to-width aspect ratio (3:1 or 75:25 µm). The VANTA-IDEs were functionalized with an antibody (Ab) specific to the human cancerous inhibitor PP2A (CIP2A)-an oncoprotein that is associated with a variety of malignancies such as oral, breast, and multiple myeloma cancers. The resultant label-free immunosensor was capable of detecting CIP2A across a wide linear sensing range (1-100 pg/mL) with a detection limit of 0.24 pg/mL within saliva supernatant-a range that is more sensitive than the corresponding CIP2A enzyme linked immunosorbent assay (ELISA). These results help pave the way for rapid cancer screening tests at the point-of-care (POC) such as for the early-stage diagnosis of oral cancer at a dentist's office.