In silico modeling of the specific inhibitory potential of thiophene-2,3-dihydro-1,5-benzothiazepine against BChE in the formation of β-amyloid plaques associated with Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease, known to be associated with the gradual loss of memory, is characterized by low concentration of acetylcholine in the hippocampus and cortex part of the brain. Inhibition of acetylcholinesterase has successfully been used as a drug target to treat Alzheimer's disease but drug resistance shown by butyrylcholinesterase remains a matter of concern in treating Alzheimer's disease. Apart from the many other reasons for Alzheimer's disease, its association with the genesis of fibrils by β-amyloid plaques is closely related to the increased activity of butyrylcholinesterase. Although few data are available on the inhibition of butyrylcholinesterase, studies have shown that that butyrylcholinesterase is a genetically validated drug target and its selective inhibition reduces the formation of β-amyloid plaques.</p> <p>Rationale</p> <p>We previously reported the inhibition of cholinesterases by 2,3-dihydro-1, 5-benzothiazepines, and considered this class of compounds as promising inhibitors for the cure of Alzheimer's disease. One compound from the same series, when substituted with a hydroxy group at C-3 in ring A and 2-thienyl moiety as ring B, showed greater activity against butyrylcholinesterase than to acetylcholinesterase. To provide insight into the binding mode of this compound (Compound A), molecular docking in combination with molecular dynamics simulation of 5000 ps in an explicit solvent system was carried out for both cholinesterases.</p> <p>Conclusion</p> <p>Molecular docking studies revealed that the potential of Compound A to inhibit cholinesterases was attributable to the cumulative effects of strong hydrogen bonds, cationic-π, π-π interactions and hydrophobic interactions. A comparison of the docking results of Compound A against both cholinesterases showed that amino acid residues in different sub-sites were engaged to stabilize the docked complex. The relatively high affinity of Compound A for butyrylcholinesterase was due to the additional hydrophobic interaction between the 2-thiophene moiety of Compound A and Ile69. The involvement of one catalytic triad residue (His438) of butyrylcholinesterase with the 3'-hydroxy group on ring A increases the selectivity of Compound A. C-C bond rotation around ring A also stabilizes and enhances the interaction of Compound A with butyrylcholinesterase. Furthermore, the classical network of hydrogen bonding interactions as formed by the catalytic triad of butyrylcholinesterase is disturbed by Compound A. This study may open a new avenue for structure-based drug design for Alzheimer's disease by considering the 3D-pharmacophoric features of the complex responsible for discriminating these two closely-related cholinesterases.</p

How a slow-ovipositing parasitoid can succed as a biological control agent of the invasive mealybug Phenacoccus peruvianus: implications for future classical and conservation biological control programs

[EN] Phenaccocus peruvianus Granara de Willink (Hemiptera: pseudococcidae) is an invasive mealybug that has become a pest of ornamental plants in Europe and has recently been detected in California, USA. In this work, we studied the tritrophic interaction among this mealybug, its main parasitoid Acerophagus n. sp. near coccois (Hymenoptera: Encyrtidae) and tending ants to disclose the success of this parasitoid controlling P. peruvianus. Acerophagus n. sp. near coccois accepted mealybugs for parasitism regardless of their size but did not hostfeed. We recorded three active defenses of P. peruvianus. Host handling time-consuming process that required more than 30 min. Tending ants, Lasius grandis (Hymenoptera: Encyrtidae), reduced the time spent by parasitoids in a patch and disrupted oviposition attempts. The low numbers of ants tending mealybugs colonies in Spain and France could explain why this parasitoid, with a long handling time, is an efficient biological control agent for P. peruvianus.Beltrà Ivars, A.; Soto Sánchez, AI.; Tena Barreda, A. (2015). How a slow-ovipositing parasitoid can succed as a biological control agent of the invasive mealybug Phenacoccus peruvianus: implications for future classical and conservation biological control programs. BioControl. 60(4):473-484. https://doi.org/10.1007/s10526-015-9663-6S473484604Arakelian G (2013) Bougainvillea mealybug (Phenacoccus peruvianus). Factsheet 2013. County of Los Angeles. Department of agricultural commissioner/weights and measures, USABartlett BR (1961) The influence of ants upon parasites, predators, and scale insects. Ann Entomol Soc Am 54:543–551Bartlett BR (1978) Pseudococcidae. In: Clausen CP (ed) Introduced parasites and predators of arthropod pests and weeds: a world review, 1st edn. Agricultural Research Service USDA, Washington, USA, pp 137–170Barzman MS, Daane KM (2001) Host-handling behaviors in parasitoids of black scale, Saissetia oleae (Homoptera: Coccidae): a case for ant-mediated evolution. J Anim Ecol 70:237–247Beltrà A, Soto A, Germain JF, Matile-Ferrero D, Mazzeo G, Pellizzari G, Russo A, Franco JC, Williams DJ (2010) The Bougainvillea mealybug Phenacoccus peruvianus, a rapid invader from South America to Europe. Entomol Hell 19:137–143Beltrà A, Garcia-Marí F, Soto A (2013a) Seasonal phenology, spatial distribution, and sampling plan for the invasive mealybug Phenacoccus peruvianus (Hemiptera: Pseudococcidae). J Econ Entomol 106:1486–1494Beltrà A, Tena A, Soto A (2013b) Fortuitous biological control of the invasive mealybug Phenacoccus peruvianus in Southern Europe. BioControl 58:309–317Beltrà A, Tena A, Soto A (2013c) Reproductive strategies and food sources used by Acerophagus n. sp. near coccois, a new successful parasitoid of the invasive mealybug Phenacoccus peruvianus. J Pest Sci 86:253–259Berlinger MJ, Golberg AM (1978) The effect of the fruit sepals on the citrus mealybug population and on its parasite. Entomol Exp Appl 24:238–243Blumstein DT, Daniel JC (2007) Quantifying behavior the JWatcher way. Sinauer Associates Inc., Sunderland, UKBoavida C, Ahounou M, Vos M, Neuenschwander P, van Alphen JJM (1995) Host stage selection and sex allocation by Gyranusoidea tebygi (Hymenoptera: Encyrtidae), a parasitoid of the mango mealybug, Rastrococcus invadens (Homoptera: Pseudococcidae). Biol Control 5:487–496Bokonon-Ganta AH, Neuenschwander P, van Alphen JJM, Vos M (1995) Host stage selection and sex allocation by Anagyrus mangicola (Hymenoptera: Encyrtidae), a parasitoid of the mango mealybug, Rastrococcus invadens (Homoptera: Pseudococcidae). Biol Control 5:479–486Bugila AAA, Franco JC, Borges da Silva E, Branco M (2014a) Defense response of native and alien mealybugs (Hemiptera: Pseudococcidae) against the solitary parasitoid Anagyrus sp. nr. pseudococci (Girault) (Hymenoptera: Encyrtidae). J Insect Behav 27:439–453Bugila AAA, Branco M, Borges da Silva E, Franco JC (2014b) Host selection behavior and specificity of the solitary parasitoid of mealybugs Anagyrus sp. nr. pseudococci (Girault) (Hymenoptera, Encyrtidae). Biocontrol Sci Techn 24:22–38Bynum EK (1937) Pseudococcobius terryi Fullaway, a Hawaiian parasite of Gray Sugarcane mealybug in the United States. J Econ Entomol 30:756–761Cadée N, van Alphen JJM (1997) Host selection and sex allocation in Leptomastidea abnormis, a parasitoid of the citrus mealybug Planococcus citri. Entomol Exp Appl 83:277–284Clausen CP (1924) The parasites of Pseudococcus maritimus (Ehrhorn) in California (Hymenoptera, Chalcidoidea). Part II. Biological studies and life histories. UC Pub Entomol 3:253–288Daane KM, Barzman MS, Caltagirone LE, Hagen KS (2000) Metaphycus anneckei and Metaphycus hageni: two discrete species parasitic on black scale, Saissetia oleae. BioControl 45:269–284Daane KM, Bentley WJ, Walton VM, Malakar-Kuenen R, Millar JC, Ingels CA, Weber EA, Gispert C (2006) New controls investigated for vine mealybug. Calif Agric 60:31–38Daane KM, Sime KR, Fallon J, Cooper ML (2007) Impacts of Argentine ants on mealybugs and their natural enemies in California’s coastal vineyards. Ecol Entomol 32:583–596De Farias AM, Hopper KR (1999) Oviposition behavior of Aphelinus asychis (Hymenoptera: Aphelinidae) and Aphidius matricariae (Hymenoptera: Aphidiidae) and defense behavior of their host Diuraphis noxia (Homoptera: Aphididae). Environ Entomol 28:858–862Dorn B, Mattiacci L, Bellotti AC, Dorn S (2001) Host specificity and comparative foraging behavior of Aenasius vexans and Acerophagus coccois, two endo-parasitoids of the cassava mealybug. Entomol Exp Appl 99:331–339Eisner T, Silberglied RE (1988) A chrysopid larva that cloaks itself in mealybug wax. Psyche 95:15–20Flanders SE (1963) Predation by parasitic Hymenoptera, the basis of ant-induced outbreaks of a host species. J Econ Entomol 56:116Foldi I (1983) Structure et fonctions des glandes tégumentaires de cochenilles Pseudococcines et de leurs secretions. Ann Soc Entomol Fr 19:155–156Foldi I (1997) Defense strategies in scale insects: phylogenetic inference and evolutionary scenarios (Hemiptera, Coccoidea). In: Grandcolas P (ed) The origin of biodiversity in insects: phylogenetic tests of evolutionary scenarios, 1st edn. Muséum National d’Histoire Naturelle, Paris, France, pp 203–230Godfray HCJ (1994) Parasitoids: behavioral and evolutionary ecology. Princeton University Press, Princeton, USAGonzález-Hernández H, Johnson MW, Reimer NJ (1999) Impact of Pheidole megacephala (F.) (Hymenoptera: Formicidae) on the biological control of Dysmicoccus brevipes (Cockerell) (Homoptera: Pseudococcidae). Biol Control 15:145–152Gross P (1993) Insect behavioral and morphological defenses against parasitoids. Annu Rev Entomol 38:251–273Gullan PJ (1997) Relationships with ants. In: Ben-Dov Y, Hodgson CJ (eds) Soft scale insects—their biology natural enemies and control, 1st edn. Elsevier, Amsterdam, The Netherlands, pp 351–373Gullan PJ, Kosztarab M (1997) Adaptations in scale insects. Annu Rev Entomol 42:23–50Hcidari M, Jahan M (2000) A study of ovipositional behavior of Anagyrus pseudococci a parasitoid of mealybugs. J Agric Sci Technol 2:49–53Honda JY, Luck RF (1995) Scale morphology effects on feeding behavior and biological control potential of Rhyzobius lophanthae (Coleoptera: Coccinellidae). Ann Entomol Soc Am 88:441–450Joyce AL, Hoddle MS, Bellows TS, Gonzalez D (2001) Oviposition behavior of Coccidoxenoides peregrinus, a parasitoid of Planococcus ficus. Entomol Exp Appl 98:49–57Karamaouna F (1999) Biology of the parasitoids Leptomastix epona (Walker) and Pseudaphycus flavidulus (Brèthes) and behavioural interactions with the host mealybug Pseudococcus viburni (Signoret). Ph.D. Thesis, University of London, UK, p 333Karamaouna F, Copland MJ (2000) Oviposition behavior, influence of experience on host size selection, and niche overlap of the solitary Leptomastix epona and the gregarious Pseudaphycus flavidulus, two endoparasitoids of the mealybug Pseudococcus viburni. Entomol Exp Appl 97:301–308Klotz JH, Hansen L, Pospischil R, Rust M (2008) Urban ants of North America and Europe. Cornell University Press, Ithaca, USAMailleux AC, Deneubourg JL, Detrain C (2003) Regulation of ants foraging to resource productivity. P R Soc Lond B Bio 270:1609–1616Majerus ME, Sloggett JJ, Godeau JF, Hemptinne JL (2007) Interactions between ants and aphidophagous and coccidophagous ladybirds. Popul Ecol 49:15–27Mgocheki N, Addison P (2009) Interference of ants (Hymenoptera: Formicidae) with biological control of the vine mealybug Planococcus ficus (Signoret) (Hemiptera: Pseudococcidae). Biol Control 49:180–185Moore D (1988) Agents used for biological control of mealybugs (Pseudococcidae). Biocontrol News Inf 9:209–225Paris CI, Espadaler X (2009) Honeydew collection by the invasive garden ant Lasius neglectus versus the native ant L grandis. Arthropod Plant Interact 3:75–85Pekas A, Tena A, Aguilar A, Garcia-Marí F (2011) Spatio-temporal patterns and interactions with honeydew-producing Hemiptera of ants in a Mediterranean citrus orchard. Agric Forest Entomol 13:89–97Pennacchio F, Strand MR (2006) Evolution of developmental strategies in parasitic Hymenoptera. Annu Rev Entomol 51:233–258Pijls JW, Hofker KD, Staalduinen MJ, van Alphen JJM (1995) Interspecific host discrimination and competition in Apoanagyrus (Epidinocarsis) lopezi and A(E) diversicornis parasitoids of the cassava mealybug Phenacoccus manihoti. Ecol Entomol 20:326–332Robert Y (1987) Dispersion and migration. In: Minks AK, Harrewijn P (eds) Aphids—their biology, natural enemies and control, 1st edn. Elsevier, Amsterdam, The Netherlands, pp 299–313Sandanayaka WRM, Charles JG, Allan DJ (2009) Aspects of the reproductive biology of Pseudaphycus maculipennis (Hym: Encyrtidae), a parasitoid of obscure mealybug, Pseudococcus viburni (Hem: Pseudococcidae). Biol Control 48:30–35Sarkar D (2008) Lattice: multivariate data visualization with R. Springer, New York, USASime KR, Daane KM (2014) Rapid, non-discriminatory oviposition behaviors are favored in mealybug parasitoids when Argentine ants are present. Environ Entomol 43:995–1002Tena A, Garcia-Marí F (2008) Suitability of citricola scale Coccus pseudomagnoliarum (Hemiptera: Coccidae) as host of Metaphycus helvolus (Hymenoptera: Encyrtidae): Influence of host size and encapsulation. Biol Control 46:341–347Tena A, Hoddle CD, Hoddle MS (2013) Competition between honeydew producers in an ant–hemipteran interaction may enhance biological control of an invasive pest. Bull Entomol Res 103:714–723The R Core Team (2011) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austriavan Driesche RG, Belloti A, Herrera CJ, Castello JA (1987a) Host preferences of two encyrtid parasitoids for the Columbian Phenacoccus spp. of cassava mealybugs. Entomol Exp Appl 43:261–266van Driesche RG, Belloti A, Herrera CJ, Castello JA (1987b) Host feeding and ovipositor insertion as sources of mortality in the mealybug Phenacoccus herreni caused by two encyrtids Epidinocarsis diversicornis and Acerophagus coccois. Entomol Exp Appl 44:97–100Vet LE, Dicke M (1992) Ecology of infochemical use by natural enemies in a tritrophic context. Annu Rev Entomol 37:141–172Völkl W, Woodring J, Fischer M, Lorenz MW, Hoffmann KH (1999) Ant-aphid mutualisms: the impact of honeydew production and honeydew sugar composition on ant preferences. Oecologia 118:483–491Wajnberg E (1989) Analysis of variations of handling-time in Trichogramma maidis. Entomophaga 34:397–407Way MJ (1963) Mutualism between ants and honeydew-producing Homoptera. Annu Rev Entomol 8:307–344Weiss MR (2006) Defecation behavior and ecology of insects. Annu Rev Entomol 51:635–661Wyckhuys KAG, Stone L, Desneux N, Hoelmer KA, Hopper KR, Heimpel GE (2008) Parasitism of the soybean aphid Aphis glycines by Binodoxys communis: the role of aphid defensive behavior and parasitoid reproductive performance. Bull Entomol Res 98:361–370Zain-ul-Abdin, Arif MJ, Suhail A, Gogi MD, Arshad M, Wakil W, Abbas SK, Altaf A, Shaina H, Manzoor A (2012) Molecular analysis of the venom of mealybug parasitoid Aenasius bambawalei Hayat (Hymenoptera: Encyrtidae). Pak Entomol 34:189–193Zinna G (1959) Specializzazione entomoparassitica negli Encyrtidae: studio morfologico etologico e fisiologico del Leptomastix dactylopii. Howard Boll Lab agr Filippo Silvestri 18:1–14

Avian Influenza Virus Glycoproteins Restrict Virus Replication and Spread through Human Airway Epithelium at Temperatures of the Proximal Airways

Transmission of avian influenza viruses from bird to human is a rare event even though avian influenza viruses infect the ciliated epithelium of human airways in vitro and ex vivo. Using an in vitro model of human ciliated airway epithelium (HAE), we demonstrate that while human and avian influenza viruses efficiently infect at temperatures of the human distal airways (37°C), avian, but not human, influenza viruses are restricted for infection at the cooler temperatures of the human proximal airways (32°C). These data support the hypothesis that avian influenza viruses, ordinarily adapted to the temperature of the avian enteric tract (40°C), rarely infect humans, in part due to differences in host airway regional temperatures. Previously, a critical residue at position 627 in the avian influenza virus polymerase subunit, PB2, was identified as conferring temperature-dependency in mammalian cells. Here, we use reverse genetics to show that avianization of residue 627 attenuates a human virus, but does not account for the different infection between 32°C and 37°C. To determine the mechanism of temperature restriction of avian influenza viruses in HAE at 32°C, we generated recombinant human influenza viruses in either the A/Victoria/3/75 (H3N2) or A/PR/8/34 (H1N1) genetic background that contained avian or avian-like glycoproteins. Two of these viruses, A/Victoria/3/75 with L226Q and S228G mutations in hemagglutinin (HA) and neuraminidase (NA) from A/Chick/Italy/1347/99 and A/PR/8/34 containing the H7 and N1 from A/Chick/Italy/1347/99, exhibited temperature restriction approaching that of wholly avian influenza viruses. These data suggest that influenza viruses bearing avian or avian-like surface glycoproteins have a reduced capacity to establish productive infection at the temperature of the human proximal airways. This temperature restriction may limit zoonotic transmission of avian influenza viruses and suggests that adaptation of avian influenza viruses to efficient infection at 32°C may represent a critical evolutionary step enabling human-to-human transmission

Genome-wide DNA methylation analysis in blood cells from patients with Werner syndrome

Werner syndrome is a progeroid disorder characterized by premature age-related phenotypes. Although it is well established that autosomal recessive mutations in the WRN gene is responsible for Werner syndrome, the molecular alterations that lead to disease phenotype remain still unidentified

Scale-up of Malaria Rapid Diagnostic Tests and Artemisinin-Based Combination Therapy: Challenges and Perspectives in Sub-Saharan Africa.

Guido Bastiaens and colleagues describe barriers to achieving scale-up and appropriate use of rapid diagnostic tests and artemisinin-based combination therapy for malaria in sub-Saharan Africa. Please see later in the article for the Editors' Summary

Prevalence and Characterization of Motile Salmonella in Commercial Layer Poultry Farms in Bangladesh

Salmonella is a globally widespread food-borne pathogen having major impact on public health. All motile serovars of Salmonella enterica of poultry origin are zoonotic, and contaminated meat and raw eggs are an important source to human infections. Information on the prevalence of Salmonella at farm/holding level, and the zoonotic serovars circulating in layer poultry in the South and South-East Asian countries including Bangladesh, where small-scale commercial farms are predominant, is limited. To investigate the prevalence of Salmonella at layer farm level, and to identify the prevalent serovars we conducted a cross-sectional survey by randomly selecting 500 commercial layer poultry farms in Bangladesh. Faecal samples from the selected farms were collected following standard procedure, and examined for the presence of Salmonella using conventional bacteriological procedures. Thirty isolates were randomly selected, from the ninety obtained from the survey, for serotyping and characterized further by plasmid profiling and pulsed-field gel electrophoresis (PFGE). Results of the survey showed that the prevalence of motile Salmonella at layer farm level was 18% (95% confidence interval 15–21%), and Salmonella Kentucky was identified to be the only serovar circulating in the study population. Plasmid analysis of the S. Kentucky and non-serotyped isolates revealed two distinct profiles with a variation of two different sizes (2.7 and 4.8 kb). PFGE of the 30 S. Kentucky and 30 non-serotyped isolates showed that all of them were clonally related because only one genotype and three subtypes were determined based on the variation in two or three bands. This is also the first report on the presence of any specific serovar of Salmonella enterica in poultry in Bangladesh

The Temporal Dynamics of Voluntary Emotion Regulation

Background: Neuroimaging has demonstrated that voluntary emotion regulation is effective in reducing amygdala activation to aversive stimuli during regulation. However, to date little is known about the sustainability of these neural effects once active emotion regulation has been terminated. Methodology/Principal Findings: We addressed this issue by means of functional magnetic resonance imaging (fMRI) in healthy female subjects. We performed an active emotion regulation task using aversive visual scenes (task 1) and a subsequent passive viewing task using the same stimuli (task 2). Here we demonstrate not only a significantly reduced amygdala activation during active regulation but also a sustained regulation effect on the amygdala in the subsequent passive viewing task. This effect was related to an immediate increase of amygdala signal in task 1 once active emotion regulation has been terminated: The larger this peak postregulation signal in the amygdala in task 1, the smaller the sustained regulation effect in task 2. Conclusions/Significance: In summary, we found clear evidence that effects of voluntary emotion regulation extend beyond the period of active regulation. These findings are of importance for the understanding of emotion regulation i

3066 consecutive Gamma Nails. 12 years experience at a single centre

<p>Abstract</p> <p>Background</p> <p>Fixation of trochanteric hip fractures using the Gamma Nail has been performed since 1988 and is today well established and wide-spread. However, a number of reports have raised serious concerns about the implant's complication rate. The main focus has been the increased risk of a subsequent femoral shaft fracture and some authors have argued against its use despite other obvious advantages, when this implant is employed.</p> <p>Through access to a uniquely large patient data base available, which is available for analysis of trochanteric fractures; we have been able to evaluate the performance of the Gamma Nail over a twelve year period.</p> <p>Methods</p> <p>3066 consecutive patients were treated for trochanteric fractures using Gamma Nails between 1990 and 2002 at the Centre de Traumatologie et de l'Orthopedie (CTO), Strasbourg, France. These patients were retrospectively analysed. Information on epidemiological data, intra- and postoperative complications and patients' outcome was retrieved from patient notes. All available radiographs were assessed by a single reviewer (AJB).</p> <p>Results</p> <p>The results showed a low complication rate with the use of the Gamma Nail. There were 137 (4.5%) intraoperative fracture-related complications. Moreover 189 (6.2%) complications were detected postoperatively and during follow-up. Cut-out of the lag screw from the femoral head was the most frequent mechanical complication (57 patients, 1.85%), whereas a postoperative femoral shaft fracture occurred in 19 patients (0.6%). Other complications, such as infection, delayed healing/non-union, avascular femoral head necrosis and distal locking problems occurred in 113 patients (3.7%).</p> <p>Conclusions</p> <p>The use of the Gamma Nail in trochanteric hip fractures is a safe method with a low complication rate. In particular, a low rate of femoral shaft fractures was reported. The low complication rate reported in this series can probably be explained by strict adherence to a proper surgical technique.</p