Impact of Heterocycle Annulation on NIR Absorbance in Quinoid Thioacene Derivatives

The synthesis and characterisation of a homologous series of quinoid sulfur-containing imidazolyl-substituted heteroacenes is described. The optoelectronic and magnetic properties were investigated by UV/vis, fluorescence and EPR spectroscopy as well as quantum-chemical calculations, and were compared to those of the corresponding benzo congener. The room-temperature and atmospherically stable quinoids display strong absorption in the NIR region between 678 and 819 nm. The dithieno[3,2-b:2′,3′-d]thiophene and the thieno[2′,3′:4,5]thieno[3,2-b]thieno[2,3-d]thiophene derivatives were EPR active at room temperature. For the latter, variable-temperature EPR spectroscopy revealed the presence of a thermally accessible triplet state, with a singlet-triplet separation of 14.1 kJ mol$^{-1}$

African isolates show a high proportion of multiple copies of the Plasmodium falciparum plasmepsin-2 gene, a piperaquine resistance marker

Background: Today, the development of new and well-tolerated anti-malarial drugs is strongly justifed by the emer‑ gence of Plasmodium falciparum resistance. In 2014–2015, a phase 2b clinical study was conducted to evaluate the efcacy of a single oral dose of Artefenomel (OZ439)–piperaquine (PPQ) in Asian and African patients presenting with uncomplicated falciparum malaria. Methods: Blood samples collected before treatment ofered the opportunity to investigate the proportion of mul‑ tidrug resistant parasite genotypes, including P. falciparum kelch13 mutations and copy number variation of both P. falciparum plasmepsin 2 (Pfpm2) and P. falciparum multidrug resistance 1 (Pfmdr1) genes. Results: Validated kelch13 resistance mutations including C580Y, I543T, P553L and V568G were only detected in parasites from Vietnamese patients. In Africa, isolates with multiple copies of the Pfmdr1 gene were shown to be more frequent than previously reported (21.1%, range from 12.4% in Burkina Faso to 27.4% in Uganda). More strikingly, high proportions of isolates with multiple copies of the Pfpm2 gene, associated with piperaquine (PPQ) resistance, were frequently observed in the African sites, especially in Burkina Faso and Uganda (>30%). Conclusions: These fndings were considered to sharply contrast with the recent description of increased sensitivity to PPQ of Ugandan parasite isolates. This emphasizes the necessity to investigate in vitro susceptibility profles to PPQ of African isolates with multiple copies of the Pfpm2 gene and estimate the risk of development of PPQ resistance in Africa

Efficacy of Felpreva®, a new spot-on formulation containing tigolaner, emodepside and praziquantel, applied as a single application to cats artificially infested with ear mites (Otodectes cynotis)

The efficacy of Felpreva® (Vetoquinol), a new spot-on application containing the novel acaricide and insecticide tigolaner in combination with emodepside and praziquantel, was evaluated in cats artificially infested with ear mites (Otodectes cynotis). A total of three pivotal dose confirmation studies were conducted, two of them designed as non-interference studies. Cats were artificially infested with O. cynotis mites and randomly allocated into groups of 8 cats based on pre-treatment mite counts. Cats were treated once on Day 0, either with Felpreva® (14.5 ​mg/kg tigolaner, 3 ​mg/kg emodepside and 12 ​mg/kg praziquantel) or with placebo. Studies with a non-interference design included two additional groups of cats, treated with Profender® spot-on solution (Vetoquinol) (3 ​mg/kg emodepside and 12 ​mg/kg praziquantel) and tigolaner as a mono product (14.5 ​mg/kg tigolaner). Efficacy was evaluated on Day 28/Day 30 based on total live mite counts after ear flushing. Efficacy was claimed when: (i) at least six control cats per group were adequately infested with mites; (ii) calculated efficacy was ≥ 90% based on geometric mean mite counts; and (iii) the difference in mite counts between Felpreva®-treated cats and control cats was statistically significant (P ​≤ ​0.05). In two of the three studies, Felpreva®-treated cats were mite-free (100% efficacy) on Day 28/Day 30 and almost full efficacy (99.6%) was seen in the third study. The difference in mite counts between Felpreva®-treated cats and control cats was significant (P ​< ​0.0001) in all three studies. All control cats were adequately infested in all three studies. The efficacy of Felpreva® against ear mite (Otodectes cynotis) infection in cats was confirmed

African isolates show a high proportion of multiple copies of the Plasmodium falciparum plasmepsin-2 gene, a piperaquine resistance marker

Background: Today, the development of new and well-tolerated anti-malarial drugs is strongly justifed by the emer‑ gence of Plasmodium falciparum resistance. In 2014–2015, a phase 2b clinical study was conducted to evaluate the efcacy of a single oral dose of Artefenomel (OZ439)–piperaquine (PPQ) in Asian and African patients presenting with uncomplicated falciparum malaria. Methods: Blood samples collected before treatment ofered the opportunity to investigate the proportion of mul‑ tidrug resistant parasite genotypes, including P. falciparum kelch13 mutations and copy number variation of both P. falciparum plasmepsin 2 (Pfpm2) and P. falciparum multidrug resistance 1 (Pfmdr1) genes. Results: Validated kelch13 resistance mutations including C580Y, I543T, P553L and V568G were only detected in parasites from Vietnamese patients. In Africa, isolates with multiple copies of the Pfmdr1 gene were shown to be more frequent than previously reported (21.1%, range from 12.4% in Burkina Faso to 27.4% in Uganda). More strikingly, high proportions of isolates with multiple copies of the Pfpm2 gene, associated with piperaquine (PPQ) resistance, were frequently observed in the African sites, especially in Burkina Faso and Uganda (>30%). Conclusions: These fndings were considered to sharply contrast with the recent description of increased sensitivity to PPQ of Ugandan parasite isolates. This emphasizes the necessity to investigate in vitro susceptibility profles to PPQ of African isolates with multiple copies of the Pfpm2 gene and estimate the risk of development of PPQ resistance in Africa

Rab14 specifies the apical membrane through Arf6-mediated regulation of lipid domains and Cdc42

The generation of cell polarity is essential for the development of multi-cellular organisms as well as for the function of epithelial organs in the mature animal. Small GTPases regulate the establishment and maintenance of polarity through effects on cytoskeleton, membrane trafficking, and signaling. Using short-term 3-dimensional culture of MDCK cells, we find that the small GTPase Rab14 is required for apical membrane specification. Rab14 knockdown results in disruption of polarized lipid domains and failure of the Par/aPKC/Cdc42 polarity complex to localize to the apical membrane. These effects are mediated through tight control of lipid localization, as overexpression of the phosphatidylinositol 4-phosphate 5-kinase a [PtdIns(4) P5K] activator Arf6 or PtdIns(4) P5K alone, or treatment with the phosphatidylinositol 3-kinase (PtdInsI3K) inhibitor wortmannin, rescued the multiple-apical domain phenotype observed after Rab14 knockdown. Rab14 also co-immunoprecipitates and colocalizes with the small GTPase Cdc42, and Rab14 knockdown results in increased Cdc42 activity. Furthermore, Rab14 regulates trafficking of vesicles to the apical domain, mitotic spindle orientation, and midbody position, consistent with Rab14' s reported localization to the midbody as well as its effects upon Cdc42. These results position Rab14 at the top of a molecular cascade that regulates the establishment of cell polarity.National Institutes of Health [RO1 DK84047]This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: A worldwide collaborative project

PURPOSE:: To achieve clinical validation of cutoff values for newborn screening by tandem mass spectrometry through a worldwide collaborative effort. METHODS:: Cumulative percentiles of amino acids and acylcarnitines in dried blood spots of approximately 25-30 million normal newborns and 10,742 deidentified true positive cases are compared to assign clinical significance, which is achieved when the median of a disorder range is, and usually markedly outside, either the 99th or the 1st percentile of the normal population. The cutoff target ranges of analytes and ratios are then defined as the interval between selected percentiles of the two populations. When overlaps occur, adjustments are made to maximize sensitivity and specificity taking all available factors into consideration. RESULTS:: As of December 1, 2010, 130 sites in 45 countries have uploaded a total of 25,114 percentile data points, 565,232 analyte results of true positive cases with 64 conditions, and 5,341 cutoff values. The average rate of submission of true positive cases between December 1, 2008, and December 1, 2010, was 5.1 cases/day. This cumulative evidence generated 91 high and 23 low cutoff target ranges. The overall proportion of cutoff values within the respective target range was 42% (2,269/5,341). CONCLUSION:: An unprecedented level of cooperation and collaboration has allowed the objective definition of cutoff target ranges for 114 markers to be applied to newborn screening of rare metabolic disorders. © 2011 Lippincott Williams &amp; Wilkins