The Wadi Faynan Project, Southern Jordan: a Preliminary Report on Geomorphology and Landscape Archaeology

Reproduced with permission of the publisher. © 1997 Council for British Research in the Levant. Details of the publication are available at: http://www.cbrl.org.uk/Publications/publications_default.shtmThe Wadi Faynan Project of the British Institute at Amman for Archaeology and History (BIAAH) has as its principal objective the provision of a detailed case study in the relationship between environmental change and human history in the arid zone, from prehistory to the present day. This report describes the preliminary findings of an initial campaign of fieldwork in geomorphology and landscape archaeology conducted by an inter-disciplinary team in 1996. A preliminary sequence of fluvial events has been established, represented by the Ghuwayr and Shayqar Beds dated to the Late Pleistocene, and the Faynan and Dana Beds dated to the Holocene. Methodologies have been trialed for recording, dating and interpreting the ancient field system assumed to be of Nabataean, Roman and Byzantine date; initial findings confirm its longevity of use and complexity of purpose. There are also indications that floodwater farming began in the Wadi Faynan in the Chalcolithic or Early Bronze Ag

Diversity and impact of rare variants in genes encoding the platelet G protein-coupled receptors

Platelet responses to activating agonists are influenced by common population variants within or near G protein-coupled receptor (GPCR) genes that affect receptor activity. However, the impact of rare GPCR gene variants is unknown. We describe the rare single nucleotide variants (SNVs) in the coding and splice regions of 18 GPCR genes in 7,595 exomes from the 1,000-genomes and Exome Sequencing Project databases and in 31 cases with inherited platelet function disorders (IPFDs). In the population databases, the GPCR gene target regions contained 740 SNVs (318 synonymous, 410 missense, 7 stop gain and 6 splice region) of which 70 % had global minor allele frequency (MAF) < 0.05 %. Functional annotation using six computational algorithms, experimental evidence and structural data identified 156/740 (21 %) SNVs as potentially damaging to GPCR function, most commonly in regions encoding the transmembrane and C-terminal intracellular receptor domains. In 31 index cases with IPFDs (Gi-pathway defect n=15; secretion defect n=11; thromboxane pathway defect n=3 and complex defect n=2) there were 256 SNVs in the target regions of 15 stimulatory platelet GPCRs (34 unique; 12 with MAF< 1 % and 22 with MAF≥ 1 %). These included rare variants predicting R122H, P258T and V207A substitutions in the P2Y12 receptor that were annotated as potentially damaging, but only partially explained the platelet function defects in each case. Our data highlight that potentially damaging variants in platelet GPCR genes have low individual frequencies, but are collectively abundant in the population. Potentially damaging variants are also present in pedigrees with IPFDs and may contribute to complex laboratory phenotypes

Impact of long-term erythromycin therapy on the oropharyngeal microbiome and resistance gene reservoir in non-cystic fibrosis bronchiectasis

Published 18 April 2018Long-term macrolide therapy reduces rates of pulmonary exacerbation in bronchiectasis. However, little is known about the potential for macrolide therapy to alter the composition and function of the oropharyngeal commensal microbiota or to increase the carriage of transmissible antimicrobial resistance. We assessed the effect of long-term erythromycin on oropharyngeal microbiota composition and the carriage of transmissible macrolide resistance genes in 84 adults with bronchiectasis, enrolled in the Bronchiectasis and Low-dose Erythromycin Study (BLESS) 48-week placebo-controlled trial of twice-daily erythromycin ethylsuccinate (400 mg). Oropharyngeal microbiota composition and macrolide resistance gene carriage were determined by 16S rRNA gene amplicon sequencing and quantitative PCR, respectively. Long-term erythromycin treatment was associated with a significant increase in the relative abundance of oropharyngeal Haemophilus parainfluenzae (P = 0.041) and with significant decreases in the relative abundances of Streptococcus pseudopneumoniae (P = 0.024) and Actinomyces odontolyticus (P = 0.027). Validation of the sequencing results by quantitative PCR confirmed a significant decrease in the abundance of Actinomyces spp. (P = 0.046). Erythromycin treatment did not result in a significant increase in the number of subjects who carried erm(A), erm(B), erm(C), erm(F), mef(A/E), and msrA macrolide resistance genes. However, the abundance of erm(B) and mef(A/E) gene copies within carriers who had received erythromycin increased significantly (P < 0.05). Our findings indicate that changes in oropharyngeal microbiota composition resulting from long-term erythromycin treatment are modest and are limited to a discrete group of taxa. Associated increases in levels of transmissible antibiotic resistance genes within the oropharyngeal microbiota highlight the potential for this microbial system to act as a reservoir for resistance.IMPORTANCE Recent demonstrations that long-term macrolide therapy can prevent exacerbations in chronic airways diseases have led to a dramatic increase in their use. However, little is known about the wider, potentially adverse impacts of these treatments. Substantial disruption of the upper airway commensal microbiota might reduce its contribution to host defense and local immune regulation, while increases in macrolide resistance carriage would represent a serious public health concern. Using samples from a randomized controlled trial, we show that low-dose erythromycin given over 48 weeks influences the composition of the oropharyngeal commensal microbiota. We report that macrolide therapy is associated with significant changes in the relative abundances of members of the Actinomyces genus and with significant increases in the carriage of transmissible macrolide resistance. Determining the clinical significance of these changes, relative to treatment benefit, now represents a research priority.Jocelyn M. Choo, Guy C. J. Abell, Rachel Thomson, Lucy Morgan, Grant Waterer, David L. Gordon, Steven L. Taylor, Lex E. X. Leong, Steve L. Wesselingh, Lucy D. Burr, Geraint B. Roger

A CsI(Tl) Scintillating Crystal Detector for the Studies of Low Energy Neutrino Interactions

Scintillating crystal detector may offer some potential advantages in the low-energy, low-background experiments. A 500 kg CsI(Tl) detector to be placed near the core of Nuclear Power Station II in Taiwan is being constructed for the studies of electron-neutrino scatterings and other keV-MeV range neutrino interactions. The motivations of this detector approach, the physics to be addressed, the basic experimental design, and the characteristic performance of prototype modules are described. The expected background channels and their experimental handles are discussed.Comment: 34 pages, 11 figures, submitted to Nucl. Instrum. Method

Quantitative N- or C-Terminal Labelling of Proteins with Unactivated Peptides by Use of Sortases and a d-Aminopeptidase

Quantitative and selective labelling of proteins is widely used in both academic and industrial laboratories, and catalytic labelling of proteins using transpeptidases, such as sortases, has proved to be a popular strategy for such selective modification. A major challenge for this class of enzymes is that the majority of procedures require an excess of the labelling reagent or, alternatively, activated substrates rather than simple commercially sourced peptides. We report the use of a coupled enzyme strategy which enables quantitative N- and C-terminal labelling of proteins using unactivated labelling peptides. The use of an aminopeptidase in conjunction with a transpeptidase allows sequence-specific degradation of the peptide by-product, shifting the equilibrium to favor product formation, which greatly enhances the reaction efficiency. Subsequent optimisation of the reaction allows N-terminal labelling of proteins using essentially equimolar ratios of peptide label to protein and C-terminal labelling with only a small excess. Minimizing the amount of substrate required for quantitative labelling has the potential to improve industrial processes and facilitate the use of transpeptidation as a method for protein labelling

Association between early oral β-blocker therapy and risk for in-hospital major bleeding after percutaneous coronary intervention for acute coronary syndrome: findings from CCC-ACS project

Aims: Information regarding β-blocker use and bleeding risk in patients on antithrombotic therapy in contemporary practice is limited. We examined the association between early (within the first 24 hours) oral β-blocker therapy and major in-hospital bleeds among acute coronary syndrome (ACS) patients treated with percutaneous coronary intervention (PCI). Methods and results: In the Improving Care for Cardiovascular Disease in China-ACS project, among patients without contraindications to β-blocker, we examined the association between early oral β-blocker exposure [users/non-users, dosing, and type (metoprolol vs. bisoprolol)] and major in-hospital bleeds. Of the 43 640 eligible patients, 36.0% patients received early oral β-blocker and 637 major bleeds were recorded. Compared with non-users, early oral β-blocker was associated reduced risks for major bleeds [odds ratio (OR): 0.48; 95% confidence interval (CI): 0.38-0.61] and in-hospital mortality (OR: 0.47; 95% CI: 0.34-0.64) in multivariable-adjusted logistic regression models. Early oral β-blocker use associated reduction in major bleeding was evident both in high-dose (defined by metoprolol-equivalent dose &ge;50 mg/day) users (OR: 0.47; 95% CI: 0.33-0.68) and in low-dose users (metoprolol-equivalent dose <50 mg/day; OR: 0.61; 95% CI: 0.47-0.79). No significant difference was observed between metoprolol and bisoprolol in terms of reductions in major bleeding and mortality. Analyses based on inverse-probability-of-treatment-weighted regression adjustment and propensity-score matching yielded consistent findings. Conclusion: In this retrospective study based on the nationwide ACS registry, among patients treated by PCI, in addition to a reduction in in-hospital mortality, oral β-blocker therapy initiated within the first 24 hours was associated with a reduced risk for major in-hospital bleeds. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT0230661