N-substituted bis-C-alkyloxadiazolones as dual effectors: Efficient intermediates to amidoximes or amidines and prodrug candidates of potent antimalarials

A convenient route to N-substituted bis-C-alkylamidines possessing antiplasmodial activity and their oxadiazolone and amidoxime prodrug candidates, is described. These three families of compounds were available after a key N-alkylation step of the parent oxadiazolone 1a. Testing of the three compound classes in vitro and in vivo is also presented.     

Incorporation of neutral C-terminal residues in 3-amidinophenylalanine-derived matriptase inhibitors

A novel series of matriptase inhibitors based on previously identified tribasic 3-amidinophenylalanine derivatives was prepared. The C-terminal basic group was replaced by neutral residues to reduce the hydrophilicity of the inhibitors. The most potent compound 22 inhibits matriptase with a K_i value of 0.43 nM, but lacks selectivity towards factor Xa. By combination with neutral N-terminal sulfonyl residues several potent thrombin inhibitors were identified, which had reduced matriptase affinity.     

Kea Nestor notabilis mothers produce nest-specific calls with low amplitude and high entropy

Vocal behaviour of nesting altricial birds is subject to selection pressure from several sources. Offspring beg to attract parents’ attention, thus increasing the chances of being fed, but also increasing the chances of being detected by predators. Research on passerines has shown that parents may reduce the risk of nest predation by alarm calling to warn nestlings to be quiet, and by producing food calls which solicit begging when parents are present to defend the nestlings. Both nestlings and parents may reduce the risk of predator detection by producing calls of low amplitude and high entropy which are acoustically difficult to locate. Although extensive research has been undertaken on nesting passerine vocalizations, little is known about parrots in this regard, and studies are needed to determine whether parrots show similar adaptations. We investigated the calling behaviour of Kea Nestor notabilis mothers during the nesting period to determine whether maternal vocalizations were adapted in a way that could increase the chance of brood success. A microphone was installed inside the nest to record calls produced both inside the nest and in the direct vicinity. Our prediction was that calls outside the nest would be easy to locate and could function as alarm calls to alert conspecifics or distract the predator, whereas calls inside the nest would be difficult to locate and could serve to communicate with nestlings without alerting predators. Our results accorded with these predictions. Calls produced outside the nest were loud and tonal, and corresponded to previously described Kea alarm calls. Calls produced inside the nest, however, were high-entropy and low-amplitude calls, and formed a distinct structural category. We thus provide the first evidence that a parrot species has a vocal category for communication inside the nest, and that calls within this category are structured in a way that could reduce the risk of nest predation.     

呼吸道菌群种类和数量与小儿毛细支气管炎的关系

目的 分析呼吸道菌群定植种类和数量与小儿毛细支气管炎之间的关联性.方法 选择2017年5月至2018年5月我院收治的296例毛细支气管炎患儿,将患儿按照疾病严重程度分为重症毛细支气管炎组(n=92)和轻症毛细支气管炎组(n=204),另纳入同期在我院体检的62例健康儿童为对照组,分析各组对象呼吸道菌群的种类及数量.结果...     

RGS9 modulates dopamine signaling in the basal ganglia

Regulators of G protein signaling (RGS) modulate heterotrimeric G proteins in part by serving as GTPase-activating proteins for Galpha subunits. We examined a role for RGS9-2, an RGS subtype highly enriched in striatum, in modulating dopamine D2 receptor function. Viral-mediated overexpression of RGS9-2 in rat nucleus accumbens (ventral striatum) reduced locomotor responses to cocaine (an indirect dopamine agonist) and to D2 but not to D1 receptor agonists. Conversely, RGS9 knockout mice showed heightened locomotor and rewarding responses to cocaine and related psychostimulants. In vitro expression of RGS9-2 in Xenopus oocytes accelerated the off-kinetics of D2 receptor-induced GIRK currents, consistent with the in vivo data. Finally, chronic cocaine exposure increased RGS9-2 levels in nucleus accumbens. Together, these data demonstrate a functional interaction between RGS9-2 and D2 receptor signaling and the behavioral actions of psychostimulants and suggest that psychostimulant induction of RGS9-2 represents a compensatory adaptation that diminishes drug responsiveness.     

A mathematical model of the impact of infused targeted cytotoxic agents on brain tumours: implications for detection,design and delivery

Abstract. Motivated by the recent development of highly specific agents for brain tumours, we develop a mathematical model of the spatio-temporal dynamics of a brain tumour that receives an infusion of a highly specific cytotoxic agent (e.g. IL-4-PE, a cytotoxin comprised of IL-4 and a mutated form of Pseudomonas exotoxin). We derive an approximate but accurate mathematical formula for the tumour cure probability in terms of the tumour characteristics (size at time of detection, proliferation rate, diffusion coefficient), drug design (killing rate, loss rate and convection constants for tumour and tissue), and drug delivery (infusion rate, infusion duration). Our results suggest that high specificity is necessary but not sufficient to cure malignant gliomas; a nondispersed spatial profile of pretreatment tumour cells and/or good drug penetration are also required. The most important levers to improve tumour cure appear to be earlier detection, higher infusion rate, lower drug clearance rate and better convection into tumour, but not tissue. In contrast, the tumour cure probability is less sensitive to a longer infusion duration and enhancements in drug potency and drug specificity.     

The structure of Ro 09-0198 in different environments.

The constitution and configuration of Ro 09-0198 (cinnamycin) have been determined in DMSO. Further investigations in aqueous solution, in SDS micelles and in a lipid bilayer have been done to study the influence of different environments on the conformation of the peptide. It turned out that in spite of the polycyclic structure of the molecule, the conformation is drastically changed going from water to SDS micelles. Ro 09-0198 orients itself in lipid bilayers as expected from its amphiphilic structure. According to a nuclear Overhauser effect spectroscopy experiment under magic angle spinning (MAS) conditions, the molecule is incorporated into the membrane with its hydrophobic part inside the bilayer.     

Wading bird use of established and newly created reactor cooling reservoirs at the Savannah River Site,near Aiken,South Carolina,USA

We compared wading bird use of a newly created 405-ha reactor cooling reservoir (L-Lake) at the Savannah River Site, near Aiken, South Carolina, with that of two similar > 25-year-old reservoirs (1130-ha Par Pond and 87-ha Pond B) at the same site. L-Lake was constructed in 1984–1985 and filled in late 1985. Approximately 25% of the shoreline of L-Lake was planted with lacustrine vegetation in early 1987 in an attempt to speed the establishment of a self-sustaining balanced biological community (BBC) at the reservoir. Even so, during the course of our studies, L-Lake had considerably less wetland vegetation, especially floating-leaved species such as yellow nelumbo (Nelumbo lutea), than did either of the two older reservoirs.Sixty-three surveys of the avian communities using the three reservoirs were conducted between fall of 1987 and summer of 1989. These surveys indicated that (1) at least seven species of wading birds (order: Ciconiiformes) used L-Lake, (2) wading bird density was higher at L-Lake than at the other two reservoirs, (3) wading birds represented a higher proportion of the total avian community at L-Lake than at the other two, older reservoirs, and (4) wading birds at L-Lake used planted portions of the shoreline more than unplanted portions. We suggest that the inter-reservoir differences we observed represent a trophic upsurge (sensu O'Brien, 1990) resulting from the increased availability of fishes at L-Lake compared with the two older reservoirs.Work was performed at the University of Georgia's Savannah River Ecology Laboratory, Aiken, South Carolina 29802.     

Analyzing Personalized Policies for Online Biometric Verification

Motivated by India’s nationwide biometric program for social inclusion, we analyze verification (i.e., one-to-one matching) in the case where we possess similarity scores for 10 fingerprints and two irises between a resident’s biometric images at enrollment and his biometric images during his first verification. At subsequent verifications, we allow individualized strategies based on these 12 scores: we acquire a subset of the 12 images, get new scores for this subset that quantify the similarity to the corresponding enrollment images, and use the likelihood ratio (i.e., the likelihood of observing these scores if the resident is genuine divided by the corresponding likelihood if the resident is an imposter) to decide whether a resident is genuine or an imposter. We also consider two-stage policies, where additional images are acquired in a second stage if the first-stage results are inconclusive. Using performance data from India’s program, we develop a new probabilistic model for the joint distribution of the 12 similarity scores and find near-optimal individualized strategies that minimize the false reject rate (FRR) subject to constraints on the false accept rate (FAR) and mean verification delay for each resident. Our individualized policies achieve the same FRR as a policy that acquires (and optimally fuses) 12 biometrics for each resident, which represents a five (four, respectively) log reduction in FRR relative to fingerprint (iris, respectively) policies previously proposed for India’s biometric program. The mean delay is sec for our proposed policy, compared to 30 sec for a policy that acquires one fingerprint and 107 sec for a policy that acquires all 12 biometrics. This policy acquires iris scans from 32–41% of residents (depending on the FAR) and acquires an average of 1.3 fingerprints per resident.