Bitter Taste Receptor Agonists Mitigate Features of Allergic Asthma in Mice.

Asthma is characterized by airway inflammation, mucus secretion, remodeling and hyperresponsiveness (AHR). Recent research has established the bronchodilatory effect of bitter taste receptor (TAS2R) agonists in various models. Comprehensive pre-clinical studies aimed at establishing effectiveness of TAS2R agonists in disease models are lacking. Here we aimed to determine the effect of TAS2R agonists on features of asthma. Further, we elucidated a mechanism by which TAS2R agonists mitigate features of asthma. Asthma was induced in mice using intranasal house dust mite or aerosol ova-albumin challenge, and chloroquine or quinine were tested in both prophylactic and treatment models. Allergen challenge resulted in airway inflammation as evidenced by increased immune cells infiltration and release of cytokines and chemokines in the lungs, which were significantly attenuated in TAS2R agonists treated mice. TAS2R agonists attenuated features of airway remodeling including smooth muscle mass, extracellular matrix deposition and pro-fibrotic signaling, and also prevented mucus accumulation and development of AHR in mice. Mechanistic studies using human neutrophils demonstrated that inhibition of immune cell chemotaxis is a key mechanism by which TAS2R agonists blocked allergic airway inflammation and exerted anti-asthma effects. Our comprehensive studies establish the effectiveness of TAS2R agonists in mitigating multiple features of allergic asthma

Diverse sapovirus genotypes identified in children hospitalised with gastroenteritis in selected regions of South Africa

BACKGROUND : Sapoviruses (SaVs) are recognised as causative agents of gastroenteritis worldwide. How-ever, data on the genetic diversity of this virus in Africa are lacking, particularly in the form of currentlong-term studies. OBJECTIVE : To determine the genetic diversity of SaVs in children hospitalised with gastroenteritis in SouthAfrica (SA). STUDY DESIGN : From April 2009 to December 2013, SaVs were characterised from stool specimens fromchildren hospitalised with gastroenteritis in four provinces of SA.RESULTS : Fourteen different SaV genotypes were identified from the 221 strains that were characterised.Genogroup (G) IV predominated overall and was detected in 24% (53/221) of specimens. The other iden-tified genotypes included six belonging to GI (GI.1–GI.3, GI.5, GI.6, and GI.7) and seven belonging to GII(GII.1–GII.7). CONCLUSION : This study has provided the first comprehensive data on the genetic diversity of SaVs in aclinical setting in SA, contributing to the global knowledge of this virus.http://www.elsevier.com/locate/jcv2017-03-31hb2016Medical Virolog

Orphan Nuclear Receptor Nur77 Inhibits Cardiac Hypertrophic Response to Beta-Adrenergic Stimulation.

The orphan nuclear receptor Nur77 plays critical roles in cardiovascular diseases, and its expression is markedly induced in the heart after beta-adrenergic receptor (β-AR) activation. However, the functional significance of Nur77 in β-AR signaling in the heart remains unclear. By using Northern blot, Western blot, and immunofluorescent staining assays, we showed that Nur77 expression was markedly upregulated in cardiomyocytes in response to multiple hypertrophic stimuli, including isoproterenol (ISO), phenylephrine (PE), and endothelin-1 (ET-1). In a time- and dose-dependent manner, ISO increases Nur77 expression in the nuclei of cardiomyocytes. Overexpression of Nur77 markedly inhibited ISO-induced cardiac hypertrophy by inducing nuclear translocation of Nur77 in cardiomyocytes. Furthermore, cardiac overexpression of Nur77 by intramyocardial injection of Ad-Nur77 substantially inhibited cardiac hypertrophy and ameliorated cardiac dysfunction after chronic infusion of ISO in mice. Mechanistically, we demonstrated that Nur77 functionally interacts with NFATc3 and GATA4 and inhibits their transcriptional activities, which are critical for the development of cardiac hypertrophy. These results demonstrate for the first time that Nur77 is a novel negative regulator for the β-AR-induced cardiac hypertrophy through inhibiting the NFATc3 and GATA4 transcriptional pathways. Targeting Nur77 may represent a potentially novel therapeutic strategy for preventing cardiac hypertrophy and heart failure

Epidemiology of human astroviruses among children younger than 5 years : prospective hospital‐based sentinel surveillance in South Africa, 2009‐2014

BACKGROUND : The epidemiology of human astroviruses (HAstVs) in hospitalised patients less than 5 years of age from selected sites in South Africa was investigated. Diarrheagenic stool specimens collected from April 2009 to May 2014 were screened retrospectively for selected viruses, bacteria and parasites. METHOD : Patient data were analysed to identify epidemiologic factors most frequently detected with HAstV infections. The following case‐comparisons were investigated; HAstV‐positive and HAstV‐negative children, human immunodeficiency virus (HIV)‐infected and HIV‐uninfected (HAstV‐positive) children and HIV‐exposed and unexposed (HAstV‐positive HIV‐uninfected) children. RESULTS : Astrovirus was identified in 7.0% (234/3340) of cases and most frequently in ages 7 to 12 months (9.2%; 90/975) compared with 5.8% to 6.6% in other 6‐month age groups. No seasonal trends were observed. More HAstVs were detected in children from homes that used outdoor water sources (7.6%) compared to indoor sources [5.7%; adjusted odds ratio (aOR), 1.5; 95% CI, 1.1‐2.1; P = 0.009]. Astroviruses were detected in 8.4% (67/799) of HIV‐uninfected patients that were exposed to HIV compared with 5.9% (74/1257) of HIV‐unexposed patients ( P = 0.032). CONCLUSION : Astroviruses were most prevalent in children aged 7 to 12 months and were detected throughout the study period. The study was limited as only hospitalised patients were investigated and no comparisons were made to diarrhoea‐free control groups. Future HAstV surveillance should include community‐based studies and children presenting at outpatient facilities.The Rotavirus Sentinel Surveillance Program was funded by GlaxoSmithKline (E‐Track 200238). Research was supported by a National Health Laboratory Service Research (004_94494) (SN) and the Poliomyelitis Research Foundation (15/22) (NAP).http://wileyonlinelibrary.com/journal/jmv2020-02-01hj2018Medical Virolog

A pilot study of transrectal endoscopic ultrasound elastography in inflammatory bowel disease

BACKGROUND: Using standard diagnostic algorithms it is not always possible to establish the correct phenotype of inflammatory bowel disease which is essential for therapeutical decisions. Endoscopic ultrasound elastography is a new endoscopic procedure which can differentiate the stiffness of normal and pathological tissue by ultrasound. Therefore, we aimed to investigate the role of transrectal ultrasound elastography in distiction between Crohn's disease and ulcerative colitis. ----- METHODS: A total 30 Crohn's disease, 25 ulcerative colitis, and 28 non-inflammatory bowel disease controls were included. Transrectal ultrasound elastography was performed in all patients and controls. In all ulcerative coltis patients and 80% of Crohn's disease patients endoscopy was performed to assess disease activity in the rectum. ----- RESULTS: Significant difference in rectal wall thickness and strain ratio was detected between patients with Crohn's disease and controls (p = 0.0001). CD patients with active disease had higher strain ratio than patients in remission (p = 0.02). In ulcerative colitis group a significant difference in rectal wall thickness was found between controls and patients with active disease (p = 0.03). A significant difference in rectal wall thickness (p = 0.02) and strain ratio (p = 0.0001) was detected between Crohn's disease and ulcerative colitis patient group. Crohn's disease patients with active disease had a significantly higher strain ratio compared to ulcerative colitis patients with active disease (p = 0.0001). ----- CONCLUSION: Transrectal ultrasound elastography seems to be a promising new diagnostic tool in the field of inflammatory bowel disease. Further study on a larger cohort of patients is needed to definitely assess the role of transrectal ultrasound elastography in inflammatory bowel disease

Thermal-elastic stresses and the criticality of the continental crust

Heating or cooling can lead to high stresses in rocks due to the different thermal-elastic properties of minerals. In the upper 4 km of the crust, such internal stresses might cause fracturing. Yet it is unclear if thermal elasticity contributes significantly to critical stresses and failure deeper in Earth's continental crust, where ductile creep causes stress relaxation. We combined a heating experiment conducted in a Synchrotron microtomograph (Advanced Photon Source, USA) with numerical simulations to calculate the grain-scale stress field in granite generated by slow burial. We find that deviatoric stresses >100 MPa can be stored during burial, with relaxation times from 100's to 1000's ka, even in the ductile crust. Hence, grain-scale thermal-elastic stresses may serve as nuclei for instabilities, thus rendering the continental crust close to criticality

Sapovirus prevalence in children less than five years of age hospitalised for diarrhoeal disease in South Africa, 2009-2013

BACKGROUND : Although sapovirus (SaV) has been detected in 2.2–12.7% of gastroenteritis cases globally,there are limited data on SaV epidemiology. OBJECTIVES : Describe the epidemiology, clinical characteristics and factors associated with SaV gastroen-teritis in hospitalised children <5 years of age in South Africa.Study design: Between 2009 and 2013 during prospective diarrhoeal surveillance, stool specimens werecollected from four sites and screened for SaVs and associated enteric pathogens using ELISA, microscopy,conventional and real-time PCR. Epidemiological and clinical data were compared in patients withor without SaV. Odds ratios were assessed by bivariate and stepwise multivariable logistic regressionanalysis. RESULTS : Sapoviruses were detected in 7.7% (238/3103) of children admitted to hospital and 11.4% (9/79)of deaths. Sapovirus was detected more commonly in children 19–24 months compared to <6 months(aOR = 2.3; p = 0.018) and in males (aOR = 2.0; p = 0.001). Additional factors associated with SaV detectionincluded residing with ≥ 7 inhabitants compared to ≤3 (aOR = 2.2; p = 0.011) and concomitant norovirusinfections (aOR = 3.0; p = 0.003). HIV-infected children with SaV were more likely to have bloody stools(aOR = 16.8; p < 0.001), low birth weight (<2.5 kg; aOR = 5.8; p = 0.007) and live in environments withoutflush toilets (aOR = 8.1; p = 0.003) compared to HIV-uninfected children. CONCLUSIONS : Sapoviruses, which are perceived to cause mild diarrhoea, were detected in hospitalisedchildren and diarrhoeal deaths in South Africa. Determinants increasing the odds of SaV included over-crowding and concomitant infections while HIV-infected children with SaV displayed bloody stools, lowbirth weight and reduced access to proper sanitation. Mitigation strategies against SaV infections includeimproved sanitation.GlaxoSmithKline.http://www.elsevier.com/locate/jcv2017-05-31hb2016Medical VirologySchool of Health Systems and Public Health (SHSPH

Evolutionary changes between pre- and post- vaccine South African group A G2P[4] rotavirus strains, 2003-2017

The transient upsurge of G2P[4] group A rotavirus (RVA) after Rotarix vaccine introduction in several countries has been a matter of concern. To gain insight into the diversity and evolution of G2P[4] strains in South Africa pre- and post-RVA vaccination introduction, whole-genome sequencing was performed for RVA positive faecal specimens collected between 2003 and 2017 and samples previously sequenced were obtained from GenBank (n=103; 56 pre- and 47 post-vaccine). Pre-vaccine G2 sequences predominantly clustered within sub-lineage IVa-1. In contrast, post-vaccine G2 sequences clustered mainly within sub-lineage IVa-3, whereby a radical amino acid (AA) substitution, S15F, was observed between the two sub-lineages. Pre-vaccine P[4] sequences predominantly segregated within sub-lineage IVa while post-vaccine sequences clustered mostly within sub-lineage IVb, with a radical AA substitution R162G. Both S15F and R162G occurred outside recognised antigenic sites. The AA residue at position 15 is found within the signal sequence domain of Viral Protein 7 (VP7) involved in translocation of VP7 into endoplasmic reticulum during infection process. The 162 AA residue lies within the hemagglutination domain of Viral Protein 4 (VP4) engaged in interaction with sialic acid-containing structure during attachment to the target cell. Free energy change analysis on VP7 indicated accumulation of stable point mutations in both antigenic and non-antigenic regions. The segregation of South African G2P[4] strains into pre- and post-vaccination sub-lineages is likely due to erstwhile hypothesized stepwise lineage/sub-lineage evolution of G2P[4] strains rather than RVA vaccine introduction. Our findings reinforce the need for continuous whole-genome RVA surveillance and investigation of contribution of AA substitutions in understanding the dynamic G2P[4] epidemiology

The Arab rural economy in Mandate Palestine, 1921-1947 Peasants under colonial rule

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