G protein-coupled receptors are dynamic regulators of digestion and targets for digestive diseases

G protein-coupled receptors (GPCRs) are the largest family of transmembrane signaling proteins. Within the gastrointestinal tract, GPCRs expressed by epithelial cells sense contents of the lumen, and GPCRs expressed by epithelial cells, myocytes, neurons, and immune cells participate in communication amongst cells. GPCRs control digestion, mediate digestive diseases, and coordinate repair and growth. GPCRs are the target of over one third of therapeutic drugs, including many drugs used to treat digestive diseases. Recent advances in structural, chemical, and cell biology research have revealed that GPCRs are not static binary switches that operate from the plasma membrane to control a defined set of intracellular signals. Rather, GPCRs are dynamic signaling proteins that adopt distinct conformations and subcellular distributions when associated with different ligands and intracellular effectors. An understanding of the dynamic nature of GPCRs has provided insights into the mechanism of activation and signaling of GPCRs, and has revealed opportunities for drug discovery. We review the allosteric modulation, biased agonism, oligomerization, and compartmentalized signaling of GPCRs that control digestion and digestive diseases. We highlight the implications of these concepts for the development of selective and effective drugs to treat diseases of the gastrointestinal tract

The Segond fracture occurs at the site of lowest sub-entheseal trabecular bone volume fraction on the tibial plateau.

In a series of human cadaveric experiments, Dr. Paul Segond first described the avulsion injury occurring at the anterolateral tibial plateau that later took his name. The fracture is thought to arise as a consequence of excessive tibia internal rotation which often also elicits damage to other connective tissue of the knee. The exact mechanism behind the avulsion is, however, unclear. A number of ligamentous structures have been proposed in separate studies to insert into the Segond fragment. Suggestions include the iliotibial band (ITB), biceps femoris and the controversial 'anterolateral ligament' (ALL). Despite increasing knowledge of tibial plateau bony microarchitecture in both healthy and disease states, no studies have yet, to our knowledge, considered the role of tibial sub-entheseal bone structure in pathogenesis of the Segond fracture. The goal of this study was thus to elucidate the differences in trabecular properties at regions across the tibial plateau in order to provide an explanation for the susceptibility of the anterolateral region to avulsion injury. Twenty human tibial plateaus from cadaveric donors were dissected and imaged using a Nikon-XTH225-μCT scanner with <80 μm isotropic voxel size. Scans were reconstructed using MicroView 3D Image Viewer and Analysis Tool. Subsequent virtual biopsy at ten anatomically defined regions of interest (ROI) generated estimates of bone volume fraction ('bone volume divided by total volume' (BV/TV)). The overall mean BV/TV value across all 20 tibiae and all 10 ROIs was 0.271. Univariate repeated-measurements ANOVA demonstrated that BV/TV values differed between ROIs. BV/TV values at the Segond site (Sα, Sβ or Sγ) were lower than all other ROIs at 0.195, 0.192 and 0.193, respectively. This suggests that, notwithstanding inter- and intra-specimen variation, the Segond site tends to have a lower trabecular bone volume fraction than entheseal sites elsewhere on the tibia. Since BV/TV correlates with tensile and torsional strength, the lower BV/TV at the Segond site could equate to a region of local weakness in certain individuals which predisposes them to an avulsion injury following the application of force from excessive internal rotation. The low BV/TV recorded at the Segond site also challenges the idea that the fracture occurs due to pull from a discrete 'anterolateral ligament', as the tension exerted focally would be expected to elicit a hypertrophic response in line with Frost's Mechanostat hypothesis. Our data would instead agree with the aforementioned reports of the fibrous band at the Segond site being part of a broader insertion of an 'anterolateral complex'

Six Military and Patriotic Illustrated Songs. Elaborately Colored. In a novel form. Series No. 1.

This publication contains the lyrics to six songs, each accompanied by a color illustration, and an advertisement on the last page. 1. Our Grandfathers\u27 Days 2. The Captain with his Whiskers 3. Want — A Substitute 4. Dixie\u27s Land 5. Young American and ould Ireland 6. Kingdom Cominghttps://digitalcommons.wofford.edu/littlejohnmss/1325/thumbnail.jp

The Progress of Tobacco Control Research in Sub-Saharan Africa in the Past 50 Years: A Systematic Review of the Design and Methods of the Studies

Over one billion of the world’s population are smokers, with increasing tobacco use in low-and middle-income countries. However, information about the methodology of studies on tobacco control is limited. We conducted a literature search to examine and evaluate the methodological designs of published tobacco research in Sub-Saharan Africa (SSA) over the past 50 years. The first phase was completed in 2015 using PubMed, Embase, CINAHL, and Cochrane Central Register of Controlled Trials. An additional search was completed in February 2017 using PubMed. Only tobacco/smoking research in SSA countries with human subjects and published in English was selected. Out of 1796 articles, 447 met the inclusion criteria and were from 26 countries, 11 of which had one study each. Over half of the publications were from South Africa and Nigeria. The earliest publication was in 1968 and the highest number of publications was in 2014 (n = 46). The majority of publications used quantitative methods (91.28%) and were cross-sectional (80.98%). The commonest data collection methods were self-administered questionnaires (38.53%), interviews (32.57%), and observation (20.41%). Around half of the studies were among adults and in urban settings. We conclud that SSA remains a “research desert” and needs more investment in tobacco control research and training

Transcriptional memory-like imprints and enhanced functional activity in gamma delta T cells following resolution of malaria infection

Gamma delta T cells play an essential role in the immune response to many pathogens, including Plasmodium. However, long-lasting effects of infection on the gamma delta T cell population still remain inadequately understood. This study focused on assessing molecular and functional changes that persist in the gamma delta T cell population following resolution of malaria infection. We investigated transcriptional changes and memory-like functional capacity of malaria pre-exposed gamma delta T cells using a Plasmodium chabaudi infection model. We show that multiple genes associated with effector function (chemokines, cytokines and cytotoxicity) and antigen-presentation were upregulated in P. chabaudi-exposed gamma delta T cells compared to gamma delta T cells from naive mice. This transcriptional profile was positively correlated with profiles observed in conventional memory CD8(+) T cells and was accompanied by enhanced reactivation upon secondary encounter with Plasmodium-infected red blood cells in vitro. Collectively our data demonstrate that Plasmodium exposure result in "memory-like imprints" in the gamma delta T cell population and also promotes gamma delta T cells that can support antigen-presentation during subsequent infections

Heterogeneities in systems with quenched disorder

We study the strong role played by structural (quenched) heterogeneities on static and dynamic properties of the Frustrated Ising Lattice Gas in two dimensions, already in the liquid phase. Differently from the dynamical heterogeneities observed in other glass models in this case they may have infinite lifetime and be spatially pinned by the quenched disorder. We consider a measure of local frustration, show how it induces the appearance of spatial heterogeneities and how this reflects in the observed behavior of equilibrium density distributions and dynamic correlation functions.Comment: 8 page

Internet-based psychoeducation for bipolar disorder: a qualitative analysis of feasibility, acceptability and impact

&lt;p&gt;Background: In a recent exploratory randomised trial we found that a novel, internet-based psychoeducation programme for bipolar disorder (Beating Bipolar) was relatively easy to deliver and had a modest effect on psychological quality of life. We sought to explore the experiences of participants with respect to feasibility, acceptability and impact of Beating Bipolar.&lt;/p&gt; &lt;p&gt;Methods: Participants were invited to take part in a semi-structured interview. Thematic analysis techniques were employed; to explore and describe participants’ experiences, the data were analysed for emerging themes which were identified and coded.&lt;/p&gt; &lt;p&gt;Results: The programme was feasible to deliver and acceptable to participants where they felt comfortable using a computer. It was found to impact upon insight into illness, health behaviour, personal routines and positive attitudes towards medication. Many participants regarded the programme as likely to be most beneficial for those recently diagnosed.&lt;/p&gt; &lt;p&gt;Conclusions: An online psychoeducation package for bipolar disorder, such as Beating Bipolar, is feasible and acceptable to patients, has a positive impact on self-management behaviours and may be particularly suited to early intervention. Alternative (non-internet) formats should also be made available to patients.&lt;/p&gt

Peripheral Determinants of Oxygen Utilization in Heart Failure With Preserved Ejection Fraction

The aim of this study was to determine the arteriovenous oxygen content difference (ΔAVO2) in adult subjects with and without heart failure with preserved ejection fraction (HFpEF) during systemic and forearm exercise. Subjects with HFpEF had reduced ΔAVO2. Forearm diffusional conductance for oxygen, a lumped conductance parameter that incorporates all impediments to the movement of oxygen from red blood cells in skeletal muscle capillaries into the mitochondria within myocytes, was estimated. Forearm diffusional conductance for oxygen was not different among adults with HFpEF, those with hypertension, and healthy control subjects; therefore, diffusional conductance cannot explain the reduced forearm ΔAVO2. Instead, adiposity was strongly associated with ΔAVO2, suggesting an active role for adipose tissue in reducing exercise capacity in patients with HFpEF

Near-Ultraviolet Properties of a Large Sample of Type Ia Supernovae as Observed with the Swift UVOT

We present ultraviolet (UV) and optical photometry of 26 Type Ia supernovae (SNe~Ia) observed from March 2005 to March 2008 with the NASA {\it Swift} Ultraviolet and Optical Telescope (UVOT). The dataset consists of 2133 individual observations, making it by far the most complete study of the UV emission from SNe~Ia to date. Grouping the SNe into three subclasses as derived from optical observations, we investigate the evolution of the colors of these SNe, finding a high degree of homogeneity within the normal subclass, but dramatic differences between that group and the subluminous and SN 2002cx-like groups. For the normal events, the redder UV filters on UVOT ($u$, $uvw1$) show more homogeneity than do the bluer UV filters ($uvm2$, $uvw2$). Searching for purely UV characteristics to determine existing optically based groupings, we find the peak width to be a poor discriminant, but we do see a variation in the time delay between peak emission and the late, flat phase of the light curves. The UV light curves peak a few days before the $B$ band for most subclasses (as was previously reported by Jha et al. 2006a), although the SN 2002cx-like objects peak at a very early epoch in the UV. That group also features the bluest emission observed among SNe~Ia. As the observational campaign is ongoing, we discuss the critical times to observe, as determined by this study, in order to maximize the scientific output of future observations.Comment: Accepted to Astrophysical Journa