Effects of the mGluR2/3 agonist LY354740 on computerized tasks of attention and working memory in marmoset monkeys

Rationale: LY354740 is a recently developed metabotropic glutamatergic receptor 2 and 3 (mGluR2/3) agonist. A high density of mGluR2 has been reported in terminal fields of the perforant path in rodents and humans, suggesting its involvement in cognitive functions mediated by the temporal lobe, including memory. A small number of in vivo studies in rodents have assessed the effects of LY354740 on memory tasks, reporting the induction of impaired memory for spatial orientation in a water maze task and for delayed match and non-match to position in an operant version of these tasks. Objective: In the present primate study, we used radioautography to describe the distribution and intensity of 3H-LY354740 binding in the hippocampal formation of the common marmoset monkey (Callithrix jacchus) relative to the rat. In the major, in vivo part of the study, the effects of systemic LY354740 on computerized tasks of attention and memory were investigated. Methods: Adult common marmosets were trained to perform a five-choice serial reaction time (5-CSRT) task and a concurrent delayed match-to-position (CDMP) task from the Cambridge Neuropsychological Automated test Battery (CANTAB). Filter tests of LY354740 effects on motor dexterity and motivation for reward revealed high inter-individual variation in sensitivity; therefore, on the 5-CSRT, subjects were tested at a dose range of 3-10mg/kg, and on the CDMP, subjects were tested at 1-3 or 3-10mg/kg. Results: Radioautography revealed a relatively low level of 3H-LY354740 binding in the marmoset hippocampal formation compared to the rat. Despite low binding, LY354740 reduced sustained-attention accuracy in the 5-CSRT, and reduced accuracy in two stages of the CDMP. Conclusions: The current study provides novel evidence for the importance of mGluR2/3 in the regulation of primate cognitive functionin

Oxytocin attenuates phencyclidine hyperactivity and increases social interaction and nucleus accumben dopamine release in rats

The pituitary neuropeptide oxytocin promotes social behavior, and is a potential adjunct therapy for social deficits in schizophrenia and autism. Oxytocin may mediate pro-social effects by modulating monoamine release in limbic and cortical areas, which was investigated herein using in vivo microdialysis, after establishing a dose that did not produce accompanying sedative or thermoregulatory effects that could concomitantly influence behavior. The effects of oxytocin (0.03–0.3 mg/kg subcutaneous) on locomotor activity, core body temperature, and social behavior (social interaction and ultrasonic vocalizations) were examined in adult male Lister-hooded rats, using selective antagonists to determine the role of oxytocin and vasopressin V1a receptors. Dopamine and serotonin efflux in the prefrontal cortex and nucleus accumbens of conscious rats were assessed using microdialysis. 0.3 mg/kg oxytocin modestly reduced activity and caused hypothermia but only the latter was attenuated by the V1a receptor antagonist, SR49059 (1 mg/kg intraperitoneal). Oxytocin at 0.1 mg/kg, which did not alter activity and had little effect on temperature, significantly attenuated phencyclidine-induced hyperactivity and increased social interaction between unfamiliar rats without altering the number or pattern of ultrasonic vocalizations. In the same rats, oxytocin (0.1 mg/kg) selectively elevated dopamine overflow in the nucleus accumbens, but not prefrontal cortex, without influencing serotonin efflux. Systemic oxytocin administration attenuated phencyclidine-induced hyperactivity and increased pro-social behavior without decreasing core body temperature and selectively enhanced nucleus accumbens dopamine release, consistent with activation of mesocorticolimbic circuits regulating associative/reward behavior being involved. This highlights the therapeutic potential of oxytocin to treat social behavioral deficits seen in psychiatric disorders such as schizophrenia

Rethinking a rare-species conservation strategy in an urban landscape: the case of the valley elderberry longhorn beetle

Reflecting the lack of critical information for most protected species, recovery plans for organisms listed as threatened or endangered under the U.S. Endangered Species Act tend to oversimplify habitat descriptions. Here we present our approach for improving the definition of habitat for rare and patchily distributed listed species. The valley elderberry longhorn beetle (Desmocerus californicus dimorphus) occurs in riparian and scrub communities in California's Central Valley. Habitat quality for the species currently is defined essentially exclusively in terms of presence and abundance of its larval host plant, elderberry (Sambucus spp.). Using detailed measures of physical and biological attributes at diverse sites occupied by the beetle, we characterized and defined habitat quality on the basis of not only host plants, but on an array of biotic and abiotic environmental characteristics. We identified four geomorphically distinct habitat associations: alluvial plain, narrow riparian corridor, upper riparian plain, and non-riparian scrub. Depending on habitat type, the environmental characteristics most strongly associated with beetle presence were host plant availability, topography and proximity to habitat edge. Increased local population size of beetles was associated with higher elderberry density and the presence of larger, more mature plants. Stochasticity in site occupancy over space and time confounds our ability to identify sites that are most able to contribute to long-term beetle survival, while underscoring the importance of unoccupied habitat to the beetle. Adopting a multivariate definition of habitat may facilitate more effective identification of locations critical to the recovery of the valley elderberry longhorn beetle, and prioritization of those management actions that can contribute effectively to meeting conservation goals for the species

Reversible vancomycin susceptibility within emerging ST1421 Enterococcus faecium strains is associated with rearranged vanA-gene clusters and increased vanA plasmid copy number

Vancomycin variable enterococci (VVE) are van-positive enterococci with a vancomycin-susceptible phenotype (VVE-S) that can convert to a resistant phenotype (VVE-R) and be selected for during vancomycin exposure. VVE-R outbreaks have been reported in Canada and Scandinavian countries. The aim of this study was to examine the presence of VVE in whole genome sequenced (WGS) Australian bacteremia Enterococcus faecium (Efm) isolates collected through the Australian Group on Antimicrobial resistance (AGAR) network. Eight potential VVEAus isolates, all identified as Efm ST1421, were selected based on the presence of vanA and a vancomycin-susceptible phenotype. During vancomycin selection, two potential VVE-S harboring intact vanHAX genes, but lacking the prototypic vanRS and vanZ genes, reverted to a resistant phenotype (VVEAus-R). Spontaneous VVEAus-R reversion occurred at a frequency of 4-6 × 10−8 resistant colonies per parent cell in vitro after 48 h and led to high-level vancomycin and teicoplanin resistance. The S to R reversion was associated with a 44-bp deletion in the vanHAX promoter region and an increased vanA plasmid copy number. The deletion in the vanHAX promoter region enables an alternative constitutive promoter for the expression of vanHAX. Acquisition of vancomycin resistance was associated with a low fitness cost compared with the corresponding VVEAus-S isolate. The relative proportion of VVEAus-R vs. VVEAus-S decreased over time in serial passages without vancomycin selection. Efm ST1421 is one of the predominant VanA-Efm multilocus sequence types found across most regions of Australia, and has also been associated with a major prolonged VVE outbreak in Danish hospitals

Oxytocin attenuates phencyclidine hyperactivity and increases social interaction and nucleus accumben dopamine release in rats

The pituitary neuropeptide oxytocin promotes social behavior, and is a potential adjunct therapy for social deficits in schizophrenia and autism. Oxytocin may mediate pro-social effects by modulating monoamine release in limbic and cortical areas, which was investigated herein using in vivo microdialysis, after establishing a dose that did not produce accompanying sedative or thermoregulatory effects that could concomitantly influence behavior. The effects of oxytocin (0.03-0.3mg/kg s.c.) on locomotor activity, core body temperature and social behavior (social interaction and ultrasonic vocalisations) were examined in adult male Lister-hooded rats, using selective antagonists to determine the role of oxytocin and vasopressin V1A receptors. Dopamine and serotonin (5-HT) efflux in the prefrontal cortex (PFC) and nucleus accumbens (NAc) of conscious rats were assessed using microdialysis. 0.3mg/kg oxytocin modestly reduced activity and caused hypothermia but only the latter was attenuated by the V1A receptor antagonist, SR49059 (1mg/kg i.p.). Oxytocin at 0.1mg/kg, which did not alter activity or temperature, significantly attenuated PCP-induced hyperactivity and increased social interaction between unfamiliar rats without altering the number or pattern of ultrasonic vocalisations. In the same rats, oxytocin (0.1 mg/kg) selectively elevated dopamine overflow in the NAc (F(1, 12)=7.983, P=0.0153), but not PFC, without influencing 5-HT efflux. Systemic oxytocin administration attenuated PCP-induced hyperactivity and increased pro-social behavior without decreasing core body temperature and selectively enhanced NAc dopamine release, consistent with activation of mesocorticolimbic circuits regulating associative/reward behavior being involved. This highlights the therapeutic potential of oxytocin to treat social behavioral deficits seen in psychiatric disorders such as schizophrenia and autism

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Perinatal cocaine reduces responsiveness to cocaine and causes alterations in exploratory behavior and visual discrimination in young-adult rats

Lister hooded female rats were exposed to either saline or cocaine (20 mg/kg s.c.) from gestational day 10 every other day until weaning (postnatal day 25). The effects of maternal cocaine exposure on novelty-induced exploration and on spontaneous and cocaine-induced motor activity were evaluated in young-adult male offspring (4 weeks after weaning). Rats exposed to cocaine during development spent less lime exploring two novel objects. Lack of habituation upon the second presentation of the objects and failure in the ability to discriminate between the novel and familiar object were also found in cocaine exposed offspring. Moreover, maternal cocaine treatment did not affect spontaneous motor activity (active time, average speed and rearing) in rats subjected to an open field test. Furthermore, perinatal exposure to cocaine significantly attenuated acute cocaine (15 mg/kg i.p.)-induced hyperactivity. These data indicate that developmental exposure to cocaine, at dose levels below those producing gross malformations and/or overt signs of neurotoxicity, causes behavioral changes characterized by an altered responsiveness to environmental and pharmacological challenges

Small Satellite Deployments From STS116 - Development Of New Manned Spaceflight Deployment Systems

The Department of Defense (DoD) Space Test Program (STP) has developed a new capability to deploy small satellites from the NASA Space Shuttle or other manned reusable space systems. For STS116, launched in December 2006, STP developed and flew two new types of small satellite deployment systems; the Space Shuttle Picosat Launcher (SSPL) and the Canister for All Payload Ejection (CAPE). Both SSPL and CAPE are designed to take advantage of very small volumes available in the Shuttle’s payload bay to launch into LEO small satellite experiments, in two different form factors. Because STP is the organization responsible for providing launch services for all of DoD’s R&D space experiments and has used the Shuttle extensively in the past for its experiments, a concerted effort began seeking means to continue use of the Shuttle despite these new limitations. STP recognized that, although the Shuttle’s payload capacity was extremely limited because of its primary use for ISS assembly and logistics, virtually every flight has some available mass and volume for small deployable payloads. To make use of this limited resource, the launchers had to be compact, require little electrical power and crew time and use only standard Shuttle interfaces, and of course, be safe for manned vehicle flight. Additionally, because of advances in micro-electronics, space experiments require less and less volume and mass. STP evaluated potential capabilities and decided that two types of launchers would be most useful. The first type would be able to deploy small satellites with a cylindrical volume of 22 by 52 inches (a Nano or Microsat class), the second type would be a Picosat class with a volume of 5 by 5 by 10 inches. This paper will present the development history and first flight results of both the SSPL and CAPE capabilities on Space Shuttle mission 116 in December of 2006. These new standard spacecraft launchers, uniquely suited to take advantage of virtually any available space on reusable manned space missions, promise to provide expanded launch opportunities for small satellites