Search

Cannabinoid CB2 agonists show therapeutic efficacy without unwanted CB1-mediated side effects. The G protein-biased CB2 receptor agonist LY2828360 attenuates the maintenance of chemotherapy-induced neuropathic nociception in male mice and blocks development of morphine tolerance in this model. However, the cell types involved in this phenomenon are unknown and whether this therapeutic profile is observed in female mice has never been investigated. We used conditional deletion of CB2 receptors to determine the cell population(s) mediating the anti-allodynic and morphine-sparing effects of CB2 agonists. Anti-allodynic effects of structurally distinct CB2 agonists (LY2828360 and AM1710) were present in paclitaxel-treated CB2f/f mice and in mice lacking CB2 receptors in CX3CR1 expressing microglia/macrophages (CX3CR1CRE/+; CB2f/f), but were absent in mice lacking CB2 receptors in peripheral sensory neurons (AdvillinCRE/+; CB2f/f). The morphine-sparing effect of LY28282360 occurred in a sexually-dimorphic manner, being present in male, but not female, mice. LY2828360 treatment (3 mg/kg per day i.p. x 12 days) blocked the development of morphine tolerance in male CB2f/f and CX3CR1CRE/+; CB2f/f mice with established paclitaxel-induced neuropathy but was absent in male (or female) AdvillinCRE/+; CB2f/f mice. Co-administration of morphine with a low dose of LY2828360 (0.1 mg/kg per day i.p. x 6 days) reversed morphine tolerance in paclitaxel-treated male CB2f/f mice, but not AdvillinCRE/+; CB2f/f mice of either sex. LY2828360 (3 mg/kg per day i.p. x 8 days) delayed, but did not prevent, the development of paclitaxel-induced mechanical or cold allodynia in either CB2f/f or CX3CR1CRE/+; CB2f/f mice of either sex. Our findings have potential clinical implications.

Background: This study examined the relationship between gastrointestinal disease and post-traumatic stress disorder in U.S. military Veterans. Based on literature and clinical practice data sources from the U.S. Veterans Administration, gastrointestinal disease and post-traumatic stress disorder were hypothesized to be positively correlated in Veterans. Objectives: This study aimed to determine the frequency with which gastrointestinal disease and post-traumatic stress disorder are diagnosed comorbidities, a diagnosis of gastrointestinal disease accompanies a diagnosis of post-traumatic stress disorder, and a diagnosis of post-traumatic stress disorder accompanies a diagnosis of a gastrointestinal disease. Methods: The methodology was a retrospective, correlational design using data collected from the U.S. Department of Veterans Affairs patient database. Results: The results were that post-traumatic stress disorder is bi-directionally correlated with the gastrointestinal diseases of gastroesophageal reflux disease, peptic ulcer disease, functional dyspepsia, Crohn’s disease, diverticular disease, irritable bowel syndrome, and the symptoms of constipation and nausea/vomiting within Veterans who served during wartime periods. The study also found that post-traumatic stress disorder is not correlated with ulcerative colitis in Veterans. Conclusions: The conclusions are that clinicians who see a presentation of post-traumatic stress disorder should be screening for gastrointestinal disease, while primary care and gastroenterology providers treating gastrointestinal disease should be screening for a history of trauma, as improved diagnosis rates may lead to improved treatment.

Abstract Quantifying the interconnected impacts of climate change and irrigation on surface water flows is critical for the proactive management of our water resources and the ecosystem services they provide. Changes in streamflow across the Western U.S. have generally been attributed to an aridifying climate, but in many basins flows can also be highly impacted by irrigation. We developed a 35-year dataset consisting of streamflow, climate, irrigated area, and crop water use to quantify the effects of both climate change and irrigation water use on streamflow across 221 basins in the Colorado, Columbia, and Missouri River systems. We demonstrate that flows have been altered beyond observed climate-related changes and that many of these changes are attributable to irrigation. Further, our results indicate that increases in irrigation water use have occurred over much of the study area, a finding that contradicts government-reported irrigation statistics. Increases in crop consumption have enhanced fall and winter flows in some portions of the Upper Missouri and northern Columbia River basins, and have exacerbated climate change-induced flow declines in parts of the Colorado basin. We classify each basin’s water resources sustainability in terms of flow and irrigation trends and link irrigation-induced flow changes to irrigation infrastructure modernization and differences in basin physiographic setting. These results provide a basis for determining where modern irrigation systems benefit basin water supply, and where less efficient systems contribute to return flows and relieve ecological stress.

Abstract Structural repair of the intestinal epithelium is strongly correlated with disease remission in inflammatory bowel disease (IBD); however, ulcer healing is not addressed by existing therapies. To address this need, this study reports the use of a small molecule prolyl hydroxylase (PHD) inhibitor (DPCA) to upregulate hypoxia‐inducible factor one‐alpha (HIF‐1α) and induce mammalian regeneration. Sustained delivery of DPCA is achieved through subcutaneous injections of a supramolecular hydrogel, formed through the self‐assembly of PEG‐DPCA conjugates. Pre‐treatment of mice with PEG‐DPCA is shown to protect mice from epithelial erosion and symptoms of dextran sodium sulfate (DSS)‐induced colitis. Surprisingly, a single subcutaneous dose of PEG‐DPCA, administered after disease onset, leads to accelerated weight gain and complete restoration of healthy tissue architecture in colitic mice. Rapid DPCA‐induced restoration of the intestinal barrier is likely orchestrated by increased expression of HIF‐1α and associated targets leading to an epithelial‐to‐mesenchymal transition. Further investigation of DPCA as a potential adjunctive or stand‐alone restorative treatment to combat active IBD is warranted.

Climate has changed over the last century, yet this change is seldom accounted for in drought assessment. This study quantifies drought bias due to climate change and suggests adjustment to align monitoring with contemporary risk.

There is heterogeneity inherent in the immune responses of individual mice in murine models of food allergy, including anaphylaxis, similar to the clinical heterogeneity observed in humans with food allergies to a defined food. One major driver of this heterogeneity may be differences in the microbiome between sensitized individuals. Our laboratory and others have reported that disruption of the microbiome (dysbiosis) by broad spectrum antibiotics and/or yeast colonization can alter systemic immunity and favor the development of mucosal Type 2 immunity to aeroallergens. Our objective was to use a well-characterized murine model (Balb/c mice) of food allergies (chicken egg ovalbumin, OVA) and determine if antibiotic-mediated dysbiosis (including C. albicans colonization) could enhance the manifestation of food allergies. Furthermore, we sought to identify elements of the microbiome and host response that were associated with this heterogeneity in the anaphylactic reaction between individual food allergen-sensitized mice. In our dataset, the intensity of the anaphylactic reactions was most strongly associated with a disrupted microbiome that included colonization by C. albicans, loss of a specific Lachnoclostridium species (tentatively, Lachnoclostridium YL32), development of a highly polarized Type 2 response in the intestinal mucosa and underlying tissue, and activation of mucosal mast cells. Serum levels of allergen-specific IgE were not predictive of the response and a complete absence of a microbiome did not fully recapitulate the response. Conventionalization of germ-free mice resulted in Akkermansia muciniphila outgrowth and a higher degree of heterogeneity in the allergic response. C57BL/6 mice remained resistant even under the same dysbiosis-inducing antibiotic regimens, while changes in the microbiome markedly altered the reactivity of Balb/c mice to OVA, as noted above. Strikingly, we also observed that genetically identical mice from different rooms in our vivarium develop different levels of a Type 2 response, as well as anaphylactic reactions. The intestinal microbiome in these mice also differed between rooms. Thus, our data recapitulate the heterogeneity in anaphylactic reactions, ranging from severe to none, seen in patients that have circulating levels of food allergen-reactive IgE and support the concept that alterations in the microbiome can be one factor underlying this heterogeneity.

Synergistic amino-catechol adhesives have attracted attention; however the topological relationship is still poorly understood. Here, the authors report on a study into the adhesion of a library of DOPA-lysine peptides to organic and inorganic surfaces and demonstrate the effects of spacers for energy dissipation.

Objectives: There are currently no reliable estimates of the prevalence of gastrointestinal disease in the US Military Veterans. Hence, the study aims to determine its prevalence in military Veterans in the United States. Methods: This study utilized a retrospective, correlational design using a patient record database from the Department of Veteran’s Affairs. The participants in the study were Veterans diagnosed with gastrointestinal disease. Specific gastrointestinal diseases include more than 500,000 ambulatory care visits annually in the United States, which included peptic ulcer disease, gastroesophageal reflux disease, diverticular disease, ulcerative colitis, Crohn’s disease, irritable bowel syndrome, and functional dyspepsia, as well as the symptoms of constipation and nausea/vomiting. This study revealed the exact prevalence of gastrointestinal disease diagnosed in Veterans served in outpatient settings by the Veterans Health Administration and broke down this prevalence over time and by the Veteran period of service. Results: Findings revealed that gastrointestinal disease prevalence among Veterans varied according to their period of service. Conclusions: Findings may help improve screening for Veterans with this increased risk factor. However, further research should be performed to verify the prevalence of gastrointestinal disease in Veterans as compared to the general American population.

Recognition of personally familiar faces is remarkably efficient, effortless and robust. We asked if feature-based face processing facilitates detection of familiar faces by testing the effect of face inversion on a visual search task for familiar and unfamiliar faces. Because face inversion disrupts configural and holistic face processing, we hypothesized that inversion would diminish the familiarity advantage to the extent that it is mediated by such processing. Subjects detected personally familiar and stranger target faces in arrays of two, four, or six face images. Subjects showed significant facilitation of personally familiar face detection for both upright and inverted faces. The effect of familiarity on target absent trials, which involved only rejection of unfamiliar face distractors, suggests that familiarity facilitates rejection of unfamiliar distractors as well as detection of familiar targets. The preserved familiarity effect for inverted faces suggests that facilitation of face detection afforded by familiarity reflects mostly feature-based processes.

Fibrous materials have garnered much interest in the field of biomedical engineering due to their high surface-area-to-volume ratio, porosity, and tunability. Specifically, in the field of tissue engineering, fiber meshes have been used to create biomimetic nanostructures that allow for cell attachment, migration, and proliferation, to promote tissue regeneration and wound healing, as well as controllable drug delivery. In addition to the properties of conventional, synthetic polymer fibers, fibers made from natural polymers, such as proteins, can exhibit enhanced biocompatibility, bioactivity, and biodegradability. Of these proteins, keratin, collagen, silk, elastin, zein, and soy are some the most common used in fiber fabrication. The specific capabilities of these materials have been shown to vary based on their physical properties, as well as their fabrication method. To date, such fabrication methods include electrospinning, wet/dry jet spinning, dry spinning, centrifugal spinning, solution blowing, self-assembly, phase separation, and drawing. This review serves to provide a basic knowledge of these commonly utilized proteins and methods, as well as the fabricated fibers’ applications in biomedical research.

Supramolecular self-assemblies of hydrophilic macromolecules functionalized with hydrophobic, structure-directing components have long been used for drug delivery. In these systems, loading of poorly soluble compounds is typically achieved through physical encapsulation during or after formation of the supramolecular assembly, resulting in low encapsulation efficiencies and limited control over release kinetics, which are predominately governed by diffusion and carrier degradation. To overcome these limitations, amphiphilic prodrugs that leverage a hydrophobic drug as both the therapeutic and structure-directing component can be used to create supramolecular materials with higher loading and controlled-release kinetics using biodegradable or enzymatically cleavable linkers. Here, we report the design, synthesis, and characterization of a library of supramolecular polymer prodrugs based on poly(ethylene glycol) (PEG) and the proregenerative drug 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (DPCA). Structure-property relationships were elucidated through experimental characterization of prodrug behavior in both the wet and dry states using scattering techniques and electron microscopy and corroborated by coarse-grained modeling. Molecular architecture and the hydrophobic-to-hydrophilic ratio of PEG-DPCA conjugates strongly influenced their physical state in water, ranging from fully soluble to supramolecular spherical assemblies and nanofibers. Molecular design and supramolecular structure, in turn, were shown to dramatically alter hydrolytic and enzymatic release and cellular transport of DPCA. In addition to potentially expanding therapeutic options for DPCA through control of supramolecular assemblies, the design principles elaborated here may inform the development of other supramolecular prodrugs based on hydrophobic small-molecule compounds.

Historically, the field of regenerative medicine has aimed to heal damaged tissue through the use of biomaterials scaffolds or delivery of foreign progenitor cells. Despite 30 years of research, however, translation and commercialization of these techniques has been limited. To enable mammalian regeneration, a more practical approach may instead be to develop therapies that evoke endogenous processes reminiscent of those seen in innate regenerators. Recently, investigations into tadpole tail regrowth, zebrafish limb restoration, and the super-healing Murphy Roths Large (MRL) mouse strain, have identified ancient oxygen-sensing pathways as a possible target to achieve this goal. Specifically, upregulation of the transcription factor, hypoxia-inducible factor one alpha (HIF-1α) has been shown to modulate cell metabolism and plasticity, as well as inflammation and tissue remodeling, possibly priming injuries for regeneration. Since HIF-1α signaling is conserved across species, environmental or pharmacological manipulation of oxygen-dependent pathways may elicit a regenerative response in non-healing mammals. In this review, we will explore the emerging role of HIF-1α in mammalian healing and regeneration, as well as attempts to modulate protein stability through hyperbaric oxygen treatment, intermittent hypoxia therapy, and pharmacological targeting. We believe that these therapies could breathe new life into the field of regenerative medicine.

The mussel byssus has long been a source of inspiration for the adhesion community. Recently, adhesive synergy between flanking lysine (Lys, K) and 3,4-Dihydroxyphenylalanine (DOPA, Y) residues in the mussel foot proteins (Mfps) has been highlighted. However, the complex topological relationship of DOPA and Lys as well as the interfacial adhesive roles of other amino acids have been understudied. Herein, we study adhesion of Lys and DOPA-containing peptides to organic and inorganic substrates using single-molecule force spectroscopy (SMFS). We show that a modest increase in peptide length, from KY to (KY)3, increases adhesion strength to TiO2. Surprisingly, further increase in peptide length offers no additional benefit. Additionally, comparison of adhesion of dipeptides containing Lys and either DOPA (KY) or phenylalanine (KF) shows that DOPA is stronger and more versatile. We furthermore demonstrate that incorporating a nonadhesive spacer between (KY) repeats can mimic the hidden length in the Mfp and act as an effective strategy to dissipate energy.

Initial imaging evaluation of hydronephrosis of unknown etiology is a complex subject and is dependent on clinical context. In asymptomatic patients, it is often best conducted via CT urography (CTU) without and with contrast, MR urography (MRU) without and with contrast, or scintigraphic evaluation with mercaptoacetyltriglycine (MAG3) imaging. For symptomatic patients, CTU without and with contrast, MRU without and with contrast, MAG3 scintigraphy, or ultrasound of the kidneys and bladder with Doppler imaging are all viable initial imaging studies. In asymptomatic pregnant patients, nonionizing imaging with US of the kidneys and bladder with Doppler imaging is preferred. Similarly, in symptomatic pregnant patients, US of the kidneys and bladder with Doppler imaging or MRU without contrast is the imaging study of choice, as both ionizing radiation and gadolinium contrast are avoided in pregnancy. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation. [ABSTRACT FROM AUTHOR]

As the field of nursing moves toward competency-based education, faculty need to adapt teaching and learning strategies to meet standards for assessing core behaviors of graduate psychiatric mental health nurse practitioner students. This article reviews a psychotherapy skills-based learning assignment at Frontier Nursing University that was adapted to meet developing competency-based learning standards. The assignment utilizes prerecorded video scenarios to provide students with opportunities to reinforce psychotherapy skills during didactic coursework. Assessment is conducted via an analytic rubric and specific feedback is given to each student in writing. [ABSTRACT FROM AUTHOR]

The Labrador Trough in northern Quebec and Labrador is a 900 km long Rhyacian-Orosirian orogenic belt containing mixed sedimentary-volcanic successions. Despite having been studied intensively since the 1940s, relatively few chemostratigraphic studies have been conducted. To improve our understanding of the Labrador Trough in the context of Earth history, and better constrain the local record of the Lomagundi-Jatuli carbon isotope excursion, high-resolution sampling and carbon isotope analyses of the Le Fer and Denault formations were conducted. Carbonate carbon isotopes ([delta] [.sup.13]C) in the Le Fer Formation record a large range in values from -4.4[per thousand] to +6.9[per thousand]. This large range is likely attributable to a combination of post-depositional alteration and variable abundance of authigenic carbonate minerals; elemental ratios suggest that the most [.sup.13]C-enriched samples reflect the composition of the water column at the time of deposition. Cumulatively, these data suggest that the Lomagundi-Jatuli Excursion was ongoing during deposition of the Le Fer Formation, approximately 2 km higher in the stratigraphy than previously recognised. However, the possibility of a post-Lomagundi-Jatuli Excursion carbon isotope event cannot conclusively be ruled out. The directly overlying Denault Formation records a range in [delta] [.sup.13]C values, from -0.5[per thousand] to +4.3[per thousand], suggesting that it was deposited after the conclusion of the Lomagundi-Jatuli Excursion and that the contact between the Le Fer and Denault formations occurred sometime during the transition out of the Lomagundi-Jatuli Excursion, ca. 2106 to 2057 Ma. Key words: Lomagundi Excursion, Lomagundi-Jatuli Excursion, Labrador Trough, Le Fer Formation, Denault Formation, carbon isotopes. La fosse du Labrador, dans le nord du Quebec et au Labrador, est une ceinture orogenique rhyacienne-orosirienne de 900 km de long renfermant des sequences sedimentaires-volcaniques mixtes. Bien qu'elle ait fait l'objet de nombreuses etudes depuis les annees 1940, relativement peu d'etudes chimiostratigraphiques s'y sont interessees. Afin d'ameliorer la comprehension de la fosse du Labrador dans le contexte de l'histoire de la Terre et de mieux delimiter le registre local de l'excursion Lomagundi-Jatuli des isotopes du carbone, un echantillonnage de haute resolution et des analyses des isotopes du carbone des Formations de Le Fer et de Denault ont ete effectues. Les isotopes du carbone ([delta][.sup.13]C) de carbonates dans la Formation de Le Fer presentent une grande fourchette de valeurs allant de -4,4[per thousand] à +6,9[per thousand], vraisemblablement attribuable à une combinaison d'alteration post-depot et d'abondance variable de carbonates authigenes; les rapports elementaires donnent à penser que les echantillons les plus enrichis en [.sup.13]C refletent la composition de la colonne d'eau au moment du depot. Collectivement, ces donnees indiqueraient que l'excursion Lomagundi-Jatuli etait en cours durant le depot de la Formation de Le Fer, ce qui la place environ 2 km plus haut dans la colonne stratigraphique que sa position reconnue auparavant. La possibilite d'un evenement enregistre par les isotopes de carbone qui serait posterieur à l'excursion Lomagundi-Jatuli ne peut toutefois être exclue avec certitude. La Formation de Denault immediatement au-dessus presente une fourchette de valeurs de [delta][.sup.13]C allant de -0,5[per thousand] à +4,3[per thousand], ce qui indiquerait qu'elle a ete deposee apres la fin de l'excursion Lomagundi-Jatuli et que le contact entre les Formations de Le Fer et de Denault s'est produit durant la transition au sortir de l'excursion Lomagundi-Jatuli, vers 2106 Ma à 2057 Ma. [Traduit par la Redaction] Mots-cles: excursion Lomagundi, excursion Lomagundi-Jatuli, fosse du Labrador, Formation de Le Fer, Formation de Denault, isotopes du carbone., Introduction The ca. 2.2-1.8 Ga Labrador Trough (Fig. 1) has been studied nearly continuously since the 1940s, yet its geochronology and tectonic history remain poorly constrained, in large part due [...]

Abstract Emory University has had a long relationship with His Holiness the Dalai Lama through the Emory-Tibet Science Initiative. Recently the Tenzin Gyatso Science Scholars, who are Tibetan Buddhist monastics that reside and take courses on Emory’s campus, were enrolled in a novel science research course designed and taught by undergraduate students at Emory. The goal of this study was to build a research community of Buddhist monastics who worked alongside undergraduate and graduate mentors to complete projects in R1 research laboratories, and the course was designed as preparation for these efforts. The course covered aspects of the scientific method and focused on enhancing engagement and motivation of the Scholars to pursue science research. Knowledge acquisition was assessed through quizzes, affect changes were assessed through focus group interviews, and overall course success was measured through Principal Investigator surveys. Conceptual knowledge and overall average improvement increased significantly week-to-week. Changes in affect for self-efficacy, belonging, knowledge, and future applications/drive trended towards improvement in each respective category. Finally, all seven Monastic Scholars who participated in the research curriculum were enrolled in R1 research experiences after conclusion of the course, and their principal investigators positively evaluated the preparedness and motivation of the monastics. The curriculum detailed here and its implementation facilitated cross-cultural education and successfully transitioned students from the classroom into research laboratories.