Circumventing antivector immunity: potential use of nonhuman adenoviral vectors

Adenoviruses are efficient gene delivery vectors based on their ability to transduce a wide variety of cell types and drive high-level transient transgene expression. While there have been advances in modifying human adenoviral (HAdV) vectors to increase their safety profile, there are still pitfalls that need to be further addressed. Preexisting humoral and cellular immunity against common HAdV serotypes limits the efficacy of gene transfer and duration of transgene expression. As an alternative, nonhuman AdV (NHAdV) vectors can circumvent neutralizing antibodies against HAdVs in immunized mice and monkeys and in human sera, suggesting that NHAdV vectors could circumvent preexisting humoral immunity against HAdVs in a clinical setting. Consequently, there has been an increased interest in developing NHAdV vectors for gene delivery in humans. In this review, we outline the recent advances and limitations of HAdV vectors for gene therapy and describe examples of NHAdV vectors focusing on their immunogenicity, tropism, and potential as effective gene therapy vehicles

Carnegie Supernova Project-II: Extending the Near-Infrared Hubble Diagram for Type Ia Supernovae to z∼0.1z\sim0.1

The Carnegie Supernova Project-II (CSP-II) was an NSF-funded, four-year program to obtain optical and near-infrared observations of a "Cosmology" sample of $\sim100$ Type Ia supernovae located in the smooth Hubble flow ($0.03 \lesssim z \lesssim 0.10$). Light curves were also obtained of a "Physics" sample composed of 90 nearby Type Ia supernovae at $z \leq 0.04$ selected for near-infrared spectroscopic time-series observations. The primary emphasis of the CSP-II is to use the combination of optical and near-infrared photometry to achieve a distance precision of better than 5%. In this paper, details of the supernova sample, the observational strategy, and the characteristics of the photometric data are provided. In a companion paper, the near-infrared spectroscopy component of the project is presented.Comment: 43 pages, 10 figures, accepted for publication in PAS

Correlates and Predictors of Symptom Severity Over Time in People Under Investigation for Postural Orthostatic Tachycardia Syndrome

Objective: Postural orthostatic tachycardia syndrome (POTS) is a poorly understood chronic disorder characterized by an unexplained excessive increase in heartbeat upon standing. The aim of this study was to investigate psychosocial and physiological correlates and predictors of symptom severity over time in patients presenting with POTS-like symptoms.Methods: Longitudinal cohort study of patients under investigation for POTS (n = 149). Patients completed questionnaires at 1 month preclinic appointment and 6 months later. Diagnosis, blood pressure (BP), and heart rate (HR) measures were collected from medical records.Data were analyzed using hierarchical linear multiple regression.Results: Orthostatic and small fiber neuropathy (SFN) symptoms remainedstable over time and were significantly correlated with distress, cardiac anxiety, threatening views of the illness, and cognitivebehavioral responses to symptoms, but not with emotional reactivity or social support. Baseline psychosocial factors collectively explained 48% (F = 5.37, p < .001) of the variance in orthostatic symptoms, and 35%(F = 3.49, p < .001) of the variance of SFN symptoms at baseline, but a nonsignificant amount of variance in symptoms at 6 monthswhen controlling for baseline symptoms. Hemodynamic measures explaineda significant 4% (F = 3.37, p = .026) of variance of orthostatic symptoms at 6 months.Conclusion: Symptomburden in patientswith suspected POTS remained high over 6 months. Psychosocial factors explained a large amount of the variance in symptoms at baseline. As symptoms did not change/improve over time, baseline symptoms accounted for most of the variance in symptoms at 6 months. An integrated approach addressing psychosocial factors alongside medical treatments may promote adjustment to the condition and lessen symptom burden for this group

Breathlessness and dysfunctional breathing in patients with postural orthostatic tachycardia syndrome (POTS):The impact of a physiotherapy intervention

Postural orthostatic tachycardia syndrome (POTS) is a chronic, multifactorial syndrome with complex symptoms of orthostatic intolerance. Breathlessness is a prevalent symptom, however little is known about the aetiology. Anecdotal evidence suggests that breathless POTS patients commonly demonstrate dysfunctional breathing/hyperventilation syndrome (DB/HVS). There are, however, no published data regarding DB/HVS in POTS, and whether physiotherapy/breathing retraining may improve patients' breathing pattern and symptoms. The aim of this study was to explore the potential impact of a physiotherapy intervention involving education and breathing control on DB/HVS in POTS. A retrospective observational cohort study of all patients with POTS referred to respiratory physiotherapy for treatment of DB/HVS over a 20-month period was undertaken. 100 patients (99 female, mean (standard deviation) age 31 (12) years) with a clinical diagnosis of DB/HV were referred, of which data was available for 66 patients pre – post intervention. Significant improvements in Nijmegen score, respiratory rate and breath hold time (seconds) were observed following treatment. These data provide a testable hypothesis that breathing retraining may provide breathless POTS patients with some symptomatic relief, thus improving their health-related quality of life. The intervention can be easily protocolised to ensure treatment fidelity. Our preliminary findings provide a platform for a subsequent randomised controlled trial of breathing retraining in POTS.</p

The Grizzly, February 12, 1988

Harassment Runs Rampant • Security Tips for Safe Driving • Tapping the Task Force • Schroeder for Press • Sex Still Religiously Private • Letter: Commencing the Issue • Restructuring the Ursinus Tradition: Task Force Transcends Past Goals • Speech Exam Announced • Participants Model the U.N. • Winner-Take-All in Ursinus-Moravian Showdown • Hoopsters Vastly Improved • Reckless Wrestlers Rustlin\u27 Victory • The Bigger Doesn\u27t Mean the Better • Beam Breakin\u27 Benner • \u27Mers Keep Victory Abreast • Conwell Cuts the Cake • Reflect: Success Promising • Dole Doles out Compromise • Can\u27t a Person Change His Mind? • Race for the White House: The Candidateshttps://digitalcommons.ursinus.edu/grizzlynews/1204/thumbnail.jp

Macrophage metabolism in the intestine is compartment specific and regulated by the microbiota

Intestinal macrophages play a vital role in the maintenance of gut homeostasis through signals derived from the microbiota. We previously demonstrated that microbial-derived metabolites can shape the metabolic functions of macrophages. Here, we show that antibiotic-induced disruption of the intestinal microbiota dramatically alters both the local metabolite environment and the metabolic functions of macrophages in the colon. Broad-spectrum antibiotic administration in mice increased the expression of the large neutral amino acid transporter LAT1 and accordingly, amino acid uptake. Subsequently, antibiotic administration enhanced the metabolic functions of colonic macrophages, increasing phosphorylation of components of mammalian/mechanistic target of rapamycin signalling pathways, with increased expression of genes involved in glycolysis and oxidative phosphorylation (OXPHOS), increased mitochondrial function, increased rate of extracellular acidification (ECAR; measure of glycolysis) and increased rate of oxygen consumption (OCR; measure of OXPHOS). Small bowel macrophages were less metabolically active than their colonic counterparts, with macrophage metabolism in the small intestine being independent of the microbiota. Finally, we reveal tissue-resident Tim4+ CD4+ macrophages exhibit enhanced fatty acid uptake alongside reduced fatty acid synthesis compared to recruited macrophages. Thus, the microbiota shapes gut macrophage metabolism in a compartment-specific manner, with important implications for monocyte recruitment and macrophage differentiation