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71.
72.
Signature of selective sweep associated with the evolution of sex-ratio drive in Drosophila simulans
In several Drosophila species, the XY Mendelian ratio is disturbed by X-linked segregation distorters (sex-ratio drive). We used a collection of recombinants between a nondistorting chromosome and a distorting X chromosome originating from the Seychelles to map a candidate sex-ratio region in Drosophila simulans using molecular biallelic markers. Our data were compatible with the presence of a sex-ratio locus in the 7F cytological region. Using sequence polymorphism at the Nrg locus, we showed that sex-ratio has induced a strong selective sweep in populations from Madagascar and Réunion, where distorting chromosomes are close to a 50% frequency. The complete association between the marker and the sex-ratio phenotype and the near absence of mutations and recombination in the studied fragment after the sweep event indicate that this event is recent. Examples of selective sweeps are increasingly reported in a number of genomes. This case identifies the causal selective force. It illustrates that all selective sweeps are not necessarily indicative of an increase in the average fitness of populations. 相似文献
73.
The calcium/calmodulin-dependent protein kinase II (CaMKII) plays a key role in the induction of long-term postsynaptic modifications following calcium entry. Experiments suggest that these long-term synaptic changes are all-or-none switch-like events between discrete states. The biochemical network involving CaMKII and its regulating protein signaling cascade has been hypothesized to durably maintain the evoked synaptic state in the form of a bistable switch. However, it is still unclear whether experimental LTP/LTD protocols lead to corresponding transitions between the two states in realistic models of such a network. We present a detailed biochemical model of the CaMKII autophosphorylation and the protein signaling cascade governing the CaMKII dephosphorylation. As previously shown, two stable states of the CaMKII phosphorylation level exist at resting intracellular calcium concentration, and high calcium transients can switch the system from the weakly phosphorylated (DOWN) to the highly phosphorylated (UP) state of the CaMKII (similar to a LTP event). We show here that increased CaMKII dephosphorylation activity at intermediate Ca2+ concentrations can lead to switching from the UP to the DOWN state (similar to a LTD event). This can be achieved if protein phosphatase activity promoting CaMKII dephosphorylation activates at lower Ca2+ levels than kinase activity. Finally, it is shown that the CaMKII system can qualitatively reproduce results of plasticity outcomes in response to spike-timing dependent plasticity (STDP) and presynaptic stimulation protocols. This shows that the CaMKII protein network can account for both induction, through LTP/LTD-like transitions, and storage, due to its bistability, of synaptic changes. 相似文献
74.
Pierce RJ Dubois-Abdesselem F Caby S Trolet J Lancelot J Oger F Bertheaume N Roger E 《Memórias do Instituto Oswaldo Cruz》2011,106(7):794-801
Only one drug is currently available for the treatment and control of schistosomiasis and the increasing risk of selecting strains of schistosome that are resistant to praziquantel means that the development of new drugs is urgent. With this objective we have chosen to target the enzymes modifying histones and in particular the histone acetyltransferases and histone deacetylases (HDAC). Inhibitors of HDACs (HDACi) are under intense study as potential anti-cancer drugs and act via the induction of cell cycle arrest and/or apoptosis. Schistosomes like other parasites can be considered as similar to tumours in that they maintain an intense metabolic activity and rate of cell division that is outside the control of the host. We have shown that HDACi can induce apoptosis and death of schistosomes maintained in culture and have set up a consortium (Schistosome Epigenetics: Targets, Regulation, New Drugs) funded by the European Commission with the aim of developing inhibitors specific for schistosome histone modifying enzymes as novel lead compounds for drug development. 相似文献
75.
76.
Vishnu Vijayakumar Yuhan Zhong Viktoriia Untilova Mounib Bahri Laurent Herrmann Laure Biniek Nicolas Leclerc Martin Brinkmann 《Liver Transplantation》2019,9(24)
Here, an effective design strategy of polymer thermoelectric materials based on structural control in doped polymer semiconductors is presented. The strategy is illustrated for two archetypical polythiophenes, e.g., poly(2,5‐bis(3‐dodecyl‐2‐thienyl)thieno[3,2‐b]thiophene) (C12‐PBTTT) and regioregular poly(3‐hexylthiophene) (P3HT). FeCl3 doping of aligned films results in charge conductivities up to 2 × 105 S cm?1 and metallic‐like thermopowers similar to iodine‐doped polyacetylene. The films are almost optically transparent and show strongly polarized near‐infrared polaronic bands (dichroic ratio >10). The comparative study of structure–property correlations in P3HT and C12‐PBTTT identifies three conditions to obtain conductivities beyond 105 S cm?1: i) achieve high in‐plane orientation of conjugated polymers with high persistence length; ii) ensure uniform chain oxidation of the polymer backbones by regular intercalation of dopant molecules in the polymer structure without disrupting alignment of π‐stacked layers; and iii) maintain a percolating nanomorphology along the chain direction. The highly anisotropic conducting polymer films are ideal model systems to investigate the correlations between thermopower S and charge conductivity σ. A scaling law S ∝ σ?1/4 prevails along the chain direction, but a different S ∝ ?ln(σ) relation is observed perpendicular to the chains, suggesting different charge transport mechanisms. The simultaneous increase of charge conductivity and thermopower along the chain direction results in a substantial improvement of thermoelectric power factors up to 2 mW m?1 K?2 in C12‐PBTTT. 相似文献
77.
Nicholas G.M. Davies Helen Browne Ben Davis Martin J. Drysdale Nicolas Foloppe Stephanie Geoffrey Ben Gibbons Terance Hart Roderick Hubbard Michael Rugaard Jensen Howard Mansell Andrew Massey Natalia Matassova Jonathan D. Moore James Murray Robert Pratt Stuart Ray Alan Robertson Stephen D. Roughley Joseph Schoepfer Paul Brough 《Bioorganic & medicinal chemistry》2012,20(22):6770-6789
Inhibitors of the Hsp90 molecular chaperone are showing promise as anti-cancer agents. Here we describe a series of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors that were identified following structure-driven optimization of purine hits revealed by NMR based screening of a proprietary fragment library. Ligand-Hsp90 X-ray structures combined with molecular modeling led to the rational displacement of a conserved water molecule leading to enhanced affinity for Hsp90 as measured by fluorescence polarization, isothermal titration calorimetry and surface plasmon resonance assays. This displacement was achieved with a nitrile group, presenting an example of efficient gain in binding affinity with minimal increase in molecular weight. Some compounds in this chemical series inhibit the proliferation of human cancer cell lines in vitro and cause depletion of oncogenic Hsp90 client proteins and concomitant elevation of the co-chaperone Hsp70. In addition, one compound was demonstrated to be orally bioavailable in the mouse. This work demonstrates the power of structure-based design for the rapid evolution of potent Hsp90 inhibitors and the importance of considering conserved water molecules in drug design. 相似文献
78.
79.
Mohamed Alburaki Sébastien Boutin Pierre-Luc Mercier Yves Loublier Madeleine Chagnon Nicolas Derome 《PloS one》2015,10(5)
Thirty-two honeybee (Apis mellifera) colonies were studied in order to detect and measure potential in vivo effects of neonicotinoid pesticides used in cornfields (Zea mays spp) on honeybee health. Honeybee colonies were randomly split on four different agricultural cornfield areas located near Quebec City, Canada. Two locations contained cornfields treated with a seed-coated systemic neonicotinoid insecticide while the two others were organic cornfields used as control treatments. Hives were extensively monitored for their performance and health traits over a period of two years. Honeybee viruses (brood queen cell virus BQCV, deformed wing virus DWV, and Israeli acute paralysis virus IAPV) and the brain specific expression of a biomarker of host physiological stress, the Acetylcholinesterase gene AChE, were investigated using RT-qPCR. Liquid chromatography-mass spectrometry (LC-MS) was performed to detect pesticide residues in adult bees, honey, pollen, and corn flowers collected from the studied hives in each location. In addition, general hive conditions were assessed by monitoring colony weight and brood development. Neonicotinoids were only identified in corn flowers at low concentrations. However, honeybee colonies located in neonicotinoid treated cornfields expressed significantly higher pathogen infection than those located in untreated cornfields. AChE levels showed elevated levels among honeybees that collected corn pollen from treated fields. Positive correlations were recorded between pathogens and the treated locations. Our data suggests that neonicotinoids indirectly weaken honeybee health by inducing physiological stress and increasing pathogen loads. 相似文献
80.
Sylvie Rodrigues-Ferreira Anne Di Tommaso Ariane Dimitrov Sylvie Cazaubon Nadège Gruel Hélène Colasson André Nicolas Nathalie Chaverot Vincent Molinié Fabien Reyal Brigitte Sigal-Zafrani Benoit Terris Olivier Delattre Fran?ois Radvanyi Franck Perez Anne Vincent-Salomon Clara Nahmias 《PloS one》2009,4(10)