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Patients with chronic cough are typically female and have a mean age of ~ 60 years. However, initial pharmacokinetic (PK) characterization of the P2X3-receptor antagonist gefapixant, developed to treat refractory or unexplained chronic cough, was performed in healthy participants who were predominantly younger adult males. The objective of this Phase 1 study was to assess the safety, tolerability, and PK of gefapixant in younger (18-55 years) and older (65-80 years) males and females.A randomized, double-blind, placebo-controlled study was conducted. Healthy adult participants were stratified into 4 cohorts by age and sex (younger males/females and older males/females) and randomized 4:1 (younger adults) or 3:1 (older adults) to receive gefapixant 300 mg twice daily (BID) for 1 week, followed by gefapixant 600 mg BID for 2 weeks or placebo. Safety, tolerability, and PK were assessed.Of 36 randomized and treated participants, 28 (100%) receiving gefapixant and 6 (75%) receiving placebo reported ≥ 1 adverse event (AE). The most common treatment-related AEs in the gefapixant group were taste related. Predefined renal/urologic AEs were reported by 7 (25%) participants receiving gefapixant (all mild to moderate in severity). Gefapixant exposure was generally lower in younger males compared with younger females and older adults; however, differences may have been due to estimated glomerular filtration rate.The safety profile of gefapixant 300-600 mg BID was generally consistent with previous studies. Additional characterization of gefapixant PK as a function of age and sex using population PK modeling is warranted.

Supplementary Figures 1-6. Supplementary Figure 1: RQ-PCR analyses of adhesion molecule expression in control and ETV6-RUNX1 positive Ba/F3 cells. Supplementary Figure 2: Phenotypic analyses of control and ETV6-RUNX1 positive Ba/F3 cells. Supplementary Figure 3: Analysis of the role of CCL2/CCR2 axis in the CXCL12 migratory defects of ETV6-RUNX1 positive Ba/F3 cells. Supplementary Figure 4: Analysis of the role of CXCR7, FLT3L receptor and CDC42 in the CXCL12 migratory defects of ETV6-RUNX1 positive Ba/F3 cells. Supplementary Figure 5: Phenotypic analyses of Pre-BI MIGR-GFP and MIGRETV6-RUNX1 cells. Supplementary Figure 6: Migration assay of PreBI cells towards CXCL12 in presence or not of EGF.

Although the ETV6–RUNX1 fusion is a frequent initiating event in childhood leukemia, its role in leukemogenesis is only partly understood. The main impact of the fusion itself is to generate and sustain a clone of clinically silent preleukemic B-cell progenitors (BCP). Additional oncogenic hits, occurring even several years later, are required for overt disease. The understanding of the features and interactions of ETV6–RUNX1–positive cells during this “latency” period may explain how these silent cells can persist and whether they could be prone to additional genetic changes. In this study, two in vitro murine models were used to investigate whether ETV6–RUNX1 alters the cellular adhesion and migration properties of BCP. ETV6–RUNX1–expressing cells showed a significant defect in the chemotactic response to CXCL12, caused by a block in CXCR4 signaling, as demonstrated by inhibition of CXCL12-associated calcium flux and lack of ERK phosphorylation. Moreover, the induction of ETV6–RUNX1 caused changes in the expression of cell-surface adhesion molecules. The expression of genes regulating the cytoskeleton was also affected, resulting in a block of CDC42 signaling. The abnormalities described here could alter the interaction of ETV6–RUNX1 preleukemic BCP with the microenvironment and contribute to the pathogenesis of the disease.Implications: Alterations in the expression of cytoskeletal regulatory genes and migration properties of BCP represent early events in the evolution of the disease, from the preleukemic phase to the clinical onset, and suggest new strategies for effective eradication of leukemia. Mol Cancer Res; 12(12); 1796–806. ©2014 AACR.

Plasmodium vivax malaria is much less common in Africa than the rest of the world because the parasite relies primarily on the Duffy antigen/chemokine receptor (DARC) to invade human erythrocytes, and the majority of Africans are Duffy negative. Recently, there has been a dramatic increase in the reporting of P. vivax cases in Africa, with a high number of them being in Duffy negative individuals, potentially indicating P. vivax has evolved an alternative invasion mechanism that can overcome Duffy negativity. Here, we analyzed single nucleotide polymorphism (SNP) and copy number variation (CNV) in Whole Genome Sequence (WGS) data from 44 P. vivax samples isolated from symptomatic malaria patients in southwestern Ethiopia, where both Duffy positive and Duffy negative individuals are found. A total of 123,711 SNPs were detected, of which 22.7% were nonsynonymous and 77.3% were synonymous mutations. The largest number of SNPs were detected on chromosomes 9 (24,007 SNPs; 19.4% of total) and 10 (16,852 SNPs, 13.6% of total). There were particularly high levels of polymorphism in erythrocyte binding gene candidates including merozoite surface protein 1 (MSP1) and merozoite surface protein 3 (MSP3.5, MSP3.85 and MSP3.9). Two genes, MAEBL and MSP3.8 related to immunogenicity and erythrocyte binding function were detected with significant signals of positive selection. Variation in gene copy number was also concentrated in genes involved in host-parasite interactions, including the expansion of the Duffy binding protein gene (PvDBP) on chromosome 6 and MSP3.11 on chromosome 10. Based on the phylogeny constructed from the whole genome sequences, the expansion of these genes was an independent process among the P. vivax lineages in Ethiopia. We further inferred transmission patterns of P. vivax infections among study sites and showed various levels of gene flow at a small geographical scale. The genomic features of P. vivax provided baseline data for future comparison with those in Duffy-negative individuals and allowed us to develop a panel of informative Single Nucleotide Polymorphic markers diagnostic at a micro-geographical scale., Author summary Plasmodium vivax is the most geographically widespread parasite species that causes malaria in humans. Although it occurs in Africa as a member of a mix of Plasmodium species, P. vivax is dominant in other parts of the world outside of Africa (e.g., Brazil). It was previously thought that most African populations were immune to P. vivax infections due to the absence of Duffy antigen chemokine receptor (DARC) gene expression required for erythrocyte invasion. However, several recent reports have indicated the emergence and potential spread of P. vivax across human populations in Africa. Compared to Southeast Asia and South America where P. vivax is highly endemic, data on polymorphisms in erythrocyte binding gene candidates of P. vivax from Africa is limited. Filling this knowlege gap is critical for identifying functional genes in erythrocyte invasion, biomarkers for tracking the P. vivax isolates from Africa, as well as potential gene targets for vaccine development. This paper examined the level of genetic polymorphisms in a panel of 43 potential erythrocyte binding protein genes based on whole genome sequences and described transmission patterns of P. vivax infections from different study sites in Ethiopia based on the genetic variants. Our analyses showed that chromosomes 9 and 10 of the P. vivax genomes isolated in Ethiopia had the most high-quality genetic polymorphisms. Among all erythrocyte binding protein gene candidates, the merozoite surface proteins 1 and merozoite surface protein 3 showed high levels of polymorphism. MAEBL and MSP3.8 related to immunogenicity and erythrocyte binding function were detected with significant signals of positive selection. The expansion of the Duffy binding protein and merozoite surface protein 3 gene copies was an independent process among the P. vivax lineages in Ethiopia. Various levels of gene flow were observed even at a smaller geographical scale. Our study provided baseline data for future comparison with P. vivax in Duffy negative individuals and help develop a panel of genetic markers that are informative at a micro-geographical scale.

Plasmodium vivax invasion of human erythrocytes depends on the Duffy Binding Protein (PvDBP) which interacts with the Duffy antigen. PvDBP copy number has been recently shown to vary between P. vivax isolates in Sub-Saharan Africa. However, the extent of PvDBP copy number variation, the type of PvDBP multiplications, as well as its significance across broad samples are still unclear. We determined the prevalence and type of PvDBP duplications, as well as PvDBP copy number variation among 178 Ethiopian P. vivax isolates using a PCR-based diagnostic method, a novel quantitative real-time PCR assay and whole genome sequencing. For the 145 symptomatic samples, PvDBP duplications were detected in 95 isolates, of which 81 had the Cambodian and 14 Malagasy-type PvDBP duplications. PvDBP varied from 1 to >4 copies. Isolates with multiple PvDBP copies were found to be higher in symptomatic than asymptomatic infections. For the 33 asymptomatic samples, PvDBP was detected with two copies in two of the isolates, and both were the Cambodian-type PvDBP duplication. PvDBP copy number in Duffy-negative heterozygotes was not significantly different from that in Duffy-positives, providing no support for the hypothesis that increased copy number is a specific association with Duffy-negativity, although the number of Duffy-negatives was small and further sampling is required to test this association thoroughly., Author summary Plasmodium vivax invasion of human erythrocytes relies on interaction between the Duffy antigen and P. vivax Duffy Binding Protein (PvDBP). Whole genome sequences from P. vivax field isolates in Madagascar identified a duplication of the PvDBP gene and PvDBP duplication has also been detected in non-African P. vivax-endemic countries. Two types of PvDBP duplications have been reported, termed Cambodian and Malagasy-type duplications. Our study used a combination of PCR-based diagnostic method, a novel quantitative real-time PCR assay, and whole genome sequencing to determine the prevalence and type of PvDBP duplications, as well as PvDBP copy number on a broad number of P. vivax samples in Ethiopia. We found that over 65% of P. vivax isolated from the symptomatic infections were detected with PvDBP duplications and PvDBP varied from 1 to >4 copies. The majority of PvDBP duplications belongs to the Cambodian-type while the Malagasy-type duplications was also detected. For the asymptomatic infections, despite a small sample size, the majority of P. vivax were detected with a single-copy based on both PCR and qPCR assays. There was no significant difference in PvDBP copy number between Duffy-null heterozygote and Duffy-positive homozygote/heterozygote. Further investigation is needed with expanded Duffy-null homozygotes to examine the functional significance of PvDBP expansion.

In celebration of the centenary of the first publication of the South African Journal of Chemistry, the history of the Journal is traced, with reference to the personalities involved in its development and its relationship with the South African Chemical Institute. The impact of online publishing on the format of the Journal and the ways in which the handling of submitted manuscripts have changed over time are discussed. Some statistics are presented illustrating the changing topicality of the various chemistry disciplines over time, as well as the expansion of the potential pool of authors arising from the internationalization of the scientific publishing field. Reference is also made to the quantitative measures by which the integrity and international acceptance of the Journal are judged.

Author(s): Lo, E; Bonizzoni, M; Hemming-Schroeder, E; Ford, A; Janies, DA; James, AA; Afrane, Y; Etemesi, H; Zhou, G; Githeko, A; Yan, G | Abstract: Single nucleotide polymorphisms (SNPs) have been shown to be useful in revealing population structure with continental-and regional-scale samples. In epidemiological study, a careful selection of SNPs to track disease spread in local communities would provide an important addition to traditional disease surveillance. This study used SNPs and microsatellites to examine population structure of Plasmodium falciparum at fine- scale in malaria-endemic areas of Western Kenya. A set of high performance (HP) SNPs were selected from a large SNP panel based on BELS ranking, FST values and minor allele frequency criteria. The discriminative power and assignment accuracy of different SNP panels including nonsynonymous SNPs, silent SNPs, previously published barcode SNPs, and the HP SNPs were evaluated together with microsatellites. Among all SNP panels, HP SNPs showed the highest level of differentiation and self-assignment accuracy on average among sites. Clear distinction was observed between the northern and southern P. falciparum samples, whereas samples from the south were least diverged from one another. These results were comparable to those by microsatellites. Nonsynonymous, silent, and barcode SNPs all showed similar levels of genetic variability to one another and weaker structure than the HP SNPs. We described here the procedure of selecting a set of HP SNPs from a large panel of SNPs that resolve population structure of P. falciparum between the northern and southern regions of Western Kenya. Future work is needed to determine if this procedure can result in SNPs panels capable of tracing Plasmodium spread at finer geographical scales.

The binary complexes formed between sulphur dioxide, as electron donor, and the series carbon dioxide, carbonyl sulphide and carbon disulphide, as electron acceptors, have been studied by means of ab initio molecular orbital theory. The optimized structures, the interaction energies and the vibrational spectra have been determined, and the effect of successive substitution of sulphur for oxygen atoms in the electron acceptor molecules has been established. Nitrous oxide, which is isoelectronic with carbon dioxide, has also been included among the electron acceptors, but the properties of the complex formed between sulphur dioxide and nitrous oxide are substantially different from those of the other three complexes.Keywords: Ab initio calculations, molecular complexes, sulphur dioxide, carbon dioxide, carbonyl sulphide, carbon disulphide, nitrous oxide, molecular structures, interaction energies, vibrational spectraPDF and Supplementry file attached

Boron trifluoride acts as a classical Lewis acid in forming molecular complexes with a variety of electron donors. Recent computational results on a number of complexes with some oxygen and nitrogen bases have indicated relationships between the properties of the adducts, such as the interaction energies and the wavenumber shifts of some of the modes of the boron trifluoride sub-molecule, and some physical properties of the bases. Hydroxylamine represents an example of a base containing two potential sites of electron donation, the nitrogen and the oxygen atoms. Predictions based on our earlier investigations of systems of this type suggest that hydroxylamine would bind to boron trifluoride preferentially through its nitrogen atom. Whether such a complex adopts an equilibrium structure in which the NO bond of hydroxylamine lies cis or trans to one of the BF bonds of boron trifluoride is more difficult to predict. This paper investigates the relative binding properties of N-bound versus O-bound complexes of boron trifluoride with hydroxylamine, and explores the conformational preferences and vibrational spectra of both types of adduct.

Abstract 1583 Poster Board I-609 Approximately a quarter of B cell precursor childhood acute lymphoblastic leukemia (ALL) is characterized by an ETV6-RUNX1 (TEL-AML1) fusion gene and has an overall good prognosis. The majority of these children will be treated on the standard risk arm of the United Kingdom ALL treatment protocols. Relapse usually occurs after cessation of treatment but remarkably can present many years later. The incidence of ETV6-RUNX1 at relapse has been reported to be less than or similar to de novo ALL. Molecular studies on neonatal bloodspots and on twins with concordant ALL have demonstrated the prenatal origin of major subtypes of childhood ALL, including most ETV6-RUNX1 fusion gene positive cases. In addition these investigations have suggested the existence of a preleukaemic stem cell requiring additional mutations or ‘hits’ in order to develop frank leukemia. To understand the genetic basis and clonal origin of late relapses we have compared the profiles of genome-wide copy number alterations (CNA) at relapse versus presentation in samples matched with remission DNA from 24 patients. The selected samples had tumor cell purity >75% before DNA extraction. DNA copy number alteration data was generated using the Affymetrix 500K SNP arrays. LOH analysis was performed using CNAG 3.0 and dCHIP 2008. Overall we identified 168 CNA at presentation and 252 at relapse (excluding deletions at IgH and TCR loci), equating to 6.96 and 10.3 CNA at presentation and relapse respectively. Although the number of CNA increased at relapse, no single gene or pathway was uniquely targeted in relapse. The most frequent alterations involved loss of 12p3.2 (ETV6), 9p21.3 (CDKN2A/B), 6q16.2-3 and gain of 21q22.1-22.12. A novel observation was gain of part or whole of chromosome 16 (2 patients at presentation, 5 at relapse) and deletion of the oncogene Plasmocytoma Variant Translocation 1 (PVT1) in 3 patients. Pathway analysis demonstrated frequent involvement at presentation and relapse of genes implicated in both B cell development (44 versus 46%) and cell cycle control (46 versus 71%). In order to study the clonal origin of relapse, we devised a classification describing the change in CNA between presentation and relapse in each individual patient. The clonal relationship between the presentation and relapse clone was established by the persistence of both the ETV6-RUNX1 fusion and at least 1 Ig and/or TCR rearrangement. We used a classification focussed on ‘driver’ CNA, defined as CNA that target genes functionally involved in leukemogenesis or CNA that are recurrently targeted as described in the literature. The four categories of relapse were type 1 (the dominant clone at presentation presented unchanged at relapse), type 2 (the relapse clone was derived from the major subclone at presentation with additional CNA), type 3 (the relapse clone was derived from a minor clone at presentation with gains and losses of CNA) and type 4 (the relapse clone is derived from an ancestral or preleukemic clone at initial presentation with all CNA gained). Twenty-one of the 24 patients were classifiable in this way (Figure 1). Although comparative relapse / presentation CNA profiles cannot identify precise clonal origins of relapse, the data indicate that irrespective of time to relapse (5 years) derived from pre-leukemic cells lacking CNA. This data indicate diverse clonal origins of relapse and extended periods of dormancy, possibly via quiescence, for stem cells in ETV6-RUNX1+ ALL. Relapse type Remission duration (years) < 2 2 - 5 > 5 1 • • 2 • ••••••• •• 3 •• •• ••• 4 •• Figure 1. Each patient is represented by a black dot. Each patient is classified on the basis of the relapse type and remission duration. Disclosures No relevant conflicts of interest to declare.

Giovanni Bononcini was born at Modena on 18 July 1670. Not long after the death of his father in 1678 he moved to Bologna, where he completed his musical education, held his first posts as a church musician and published his first eight collections, largely of instrumental music. He left Bologna for Rome in 1691 and composed there his first operas, beginning with Xerse in January 1694. To this period also belongs the opera Il trionfo di Camilla, Regina de' Volsci which was first performed at Naples on 27 December 1696, and achieved international renown. By 1699 he had moved to Vienna where he wrote music for 21 dramatic works of various sorts between that year and 1710, including ten full-length operas. Two serenatas for Berlin and one opera and part of a pasticcio for Italy also date from this period.

Three tests for the presence of occult blood in the stools of children were examined; the orthotolidine test, the guaiacum resin test, and a modified reduced phenolphthalain test. The stools of 71 neonates, 33 normal children, and 8 children with suspected gastrointestinal pathology were examined. The 1% orthotolidine test and the guaiacum resin test produced a high number of false positive results in healthy children eating a meat-containing diet. It is concluded that a positive result by these tests is of little diagnostic value in children eating a normal diet.

Epidermal proliferation was studied in the guinea-pig ear in vivo using the incorporation of [3H]thymidine into DNA as a measure of cell proliferation. Twenty-four-hour pretreatment of the skin topically with nanomolar amounts of either leukotriene B4 (LTB4), 12-hydroxyeicosatetraenoic acid, ionophore A23187, or the epidermal mitogen 12-O-tetradecanoylphorbol-13-acetate induced dose-dependent increases in epidermal proliferation. The stimulatory effect of LTB4 was stereospecific since a number of biologically inactive LTB4 stereoisomers had no effect.

The chemical modification of the ability of C. parvum to activate macrophages has been studied. It was shown to be possible to decrease this activity in C. parvum by a phenol extraction procedure. Macrophages attracted to the peritoneal cavity by the phenol extract were weakly cytotoxic to tumour cells.

In 1978, the 3rd International Sun–Earth Explorer (ISEE-3) became the first libration-point mission, about the Sun–Earth L1 point. Four years later, a complex series of lunar swingbys and small propulsive maneuvers ejected ISEE-3 from the Earth–Moon system, to fly by a comet (Giacobini–Zinner) for the first time in 1985, as the rechristened International Cometary Explorer (ICE). In its heliocentric orbit, ISEE-3/ICE slowly drifted around the Sun to return to the Earth׳s vicinity in 2014. Maneuvers in 1986 targeted a 2014 August 10th lunar swingby to recapture ISEE-3 into Earth orbit. In 1999, ISEE-3/ICE passed behind the Sun; after that, tracking of the spacecraft ceased and its control center at Goddard was shut down. In 2013, meetings were held to assess the viability of “re-awakening” ISEE-3. The goal was to target the 2014 lunar swingby, to recapture the spacecraft back into a halo-like Sun–Earth L1 orbit. However, special hardware for communicating with the spacecraft via NASA׳s Deep Space Network stations was discarded after 1999, and NASA had no funds to reconstruct the lost equipment. After ISEE-3׳s carrier signal was detected on March 1st with the 20 m antenna at Bochum, Germany, Skycorp, Inc. decided to initiate the ISEE-3 Reboot Project, to use software-defined radio with a less costly S-band transmitter that was purchased with a successful RocketHub crowdsourcing effort. NASA granted Skycorp permission to command the spacecraft. Commanding was successfully accomplished using the 300 m radio telescope at Arecibo. New capture trajectories were computed, including trajectories that would target the August lunar swingby and use a second ΔV (velocity change) that could target later lunar swingbys that would allow capture into almost any desired final orbit, including orbits about either the Sun–Earth L1 or L2 points, a lunar distant retrograde orbit, or targeting a flyby of the Earth-approaching active Comet Wirtanen in 2018. A tiny spinup maneuver was performed on July 2nd, the first since 1987. A 7 m/s ΔV maneuver was attempted on July 8th, to target the August lunar swingby. But the maneuver failed; telemetry showed that only about 0.15 m/s of ΔV was accomplished, then the thrust quickly decayed. The telemetry indicated that the nitrogen pressurant was gone so hydrazine could not be forced to the thrusters. The experience showed how a spacecraft can survive 30 years of space weather. The spacecraft flew 18 thousand km from the Moon, resulting in a heliocentric orbit that will return near the Earth in 2029.