Exposure to Kynurenic Acid during Adolescence Increases Sign-Tracking and Impairs Long-Term Potentiation in Adulthood

Changes in brain reward systems are thought to contribute significantly to the cognitive and behavioral impairments of schizophrenia, as well as the propensity to develop co-occurring substance abuse disorders. Presently, there are few treatments for persons with a dual diagnosis and little is known about the neural substrates that underlie co-occurring schizophrenia and substance abuse. One goal of the present study was to determine if a change in the concentration of kynurenic acid (KYNA), a tryptophan metabolite that is increased in the brains of people with schizophrenia, affects reward-related behavior. KYNA is an endogenous antagonist of NMDA glutamate receptors and α7 nicotinic acetylcholine receptors, both of which are critically involved in neurodevelopment, plasticity, and behavior. In Experiment 1, rats were treated throughout adolescence with L-kynurenine (L-KYN), the precursor of KYNA. As adults, the rats were tested drug-free in an autoshaping procedure in which a lever was paired with food. Rats treated with L-KYN during adolescence exhibited increased sign-tracking behavior (lever pressing) when they were tested as adults. Sign-tracking is thought to reflect the lever acquiring incentive salience (motivational value) as a result of its pairing with reward. Thus, KYNA exposure may increase the incentive salience of cues associated with reward, perhaps contributing to an increase in sensitivity to drug-related cues in persons with schizophrenia. In Experiment 2, we tested the effects of exposure to KYNA during adolescence on hippocampal long-term potentiation (LTP). Rats treated with L-KYN exhibited no LTP after a burst of high-frequency stimulation that was sufficient to produce robust LTP in vehicle-treated rats. This finding represents the first demonstrated consequence of elevated KYNA concentration during development and provides insight into the basis for cognitive and behavioral deficits that result from exposure to KYNA during adolescence

The use of virtual reality and augmented reality to enhance cardio-pulmonary resuscitation: a scoping review.

Background and objective Virtual reality (VR) and augmented reality (AR) have been proposed as novel methods to enhance cardio-pulmonary resuscitation (CPR) performance and increase engagement with CPR training. A scoping review was conducted to map the global evolution of these new approaches to CPR training, to assess their efficacy and determine future directions to meet gaps in current knowledge. Methods A standardised five-stage scoping methodology was used to (1) identify the research question, (2) identify relevant studies, (3) select the studies, (4) chart the data and (5) summarise the findings. The Kirkpatrick model levels of evidence were used to chart and assess the efficacy of each intervention reported. A multi-pronged search term strategy was used to search the Web of Science, PubMed, CINAHL and EMBASE databases up to June 2020. Results A total of 42 articles were included in this review. The first relevant paper identified was published in 2009 and based on VR, from 2014 onwards there was a large increase in the volume of work being published regarding VR and AR uses in CPR training. This review reports Kirkpatrick level one to three evidence for the use of VR/AR–CPR. Inconsistencies in the specific language, keywords used and methodologies are highlighted. Conclusion VR and AR technologies have shown great potential in the area of CPR, and there is continuing evidence of new novel applications and concepts. As VR/AR research into CPR reaches an inflection point, it is key to bring collaboration and consistency to the wider research community, to enable the growth of the area and ease of access to the wider medical community

Supporting 'design for reuse' with modular design

Engineering design reuse refers to the utilization of any knowledge gained from the design activity to support future design. As such, engineering design reuse approaches are concerned with the support, exploration, and enhancement of design knowledge prior, during, and after a design activity. Modular design is a product structuring principle whereby products are developed with distinct modules for rapid product development, efficient upgrades, and possible reuse (of the physical modules). The benefits of modular design center on a greater capacity for structuring component parts to better manage the relation between market requirements and the designed product. This study explores the capabilities of modular design principles to provide improved support for the engineering design reuse concept. The correlations between modular design and 'reuse' are highlighted, with the aim of identifying its potential to aid the little-supported process of design for reuse. In fulfilment of this objective the authors not only identify the requirements of design for reuse, but also propose how modular design principles can be extended to support design for reuse

Spurious Shear in Weak Lensing with LSST

The complete 10-year survey from the Large Synoptic Survey Telescope (LSST) will image $\sim$ 20,000 square degrees of sky in six filter bands every few nights, bringing the final survey depth to $r\sim27.5$, with over 4 billion well measured galaxies. To take full advantage of this unprecedented statistical power, the systematic errors associated with weak lensing measurements need to be controlled to a level similar to the statistical errors. This work is the first attempt to quantitatively estimate the absolute level and statistical properties of the systematic errors on weak lensing shear measurements due to the most important physical effects in the LSST system via high fidelity ray-tracing simulations. We identify and isolate the different sources of algorithm-independent, \textit{additive} systematic errors on shear measurements for LSST and predict their impact on the final cosmic shear measurements using conventional weak lensing analysis techniques. We find that the main source of the errors comes from an inability to adequately characterise the atmospheric point spread function (PSF) due to its high frequency spatial variation on angular scales smaller than $\sim10'$ in the single short exposures, which propagates into a spurious shear correlation function at the $10^{-4}$--$10^{-3}$ level on these scales. With the large multi-epoch dataset that will be acquired by LSST, the stochastic errors average out, bringing the final spurious shear correlation function to a level very close to the statistical errors. Our results imply that the cosmological constraints from LSST will not be severely limited by these algorithm-independent, additive systematic effects.Comment: 22 pages, 12 figures, accepted by MNRA

Effect of Phosphorus and Strontium Additions on Formation Temperature and Nucleation Density of Primary Silicon in Al-19 Wt Pct Si Alloy and Their Effect on Eutectic Temperature

The influence of P and Sr additions on the formation temperature and nucleation density of primary silicon in Al-19 wt pct Si alloy has been determined, for small volumes of melt solidified at cooling rates _T of ~0.3 and 1 K/s. The proportion of ingot featuring primary silicon decreased progressively with increased Sr addition, which also markedly reduced the temperature for first formation of primary silicon and the number of primary silicon particles per unit volume �Nv: When combined with previously published results, the effects of amount of P addition and cooling rate on �Nv are in reasonable accord with �Nv� _T ¼ ðp=6fÞ1=2 109 [250 � 215 (wt pct P)0.17]�3, where �Nv is in mm�3, _T is in K/s, and f is volume fraction of primary silicon. Increased P addition reduces the eutectic temperature, while increased Sr appears to generate a minimum in eutectic temperature at about 100 ppmw Sr

Mortality in pulmonary arterial hypertension in the modern era: Early insights from the Pulmonary Hypertension Association Registry

Background Current mortality data for pulmonary arterial hypertension (PAH) in the United States are based on registries that enrolled patients prior to 2010. We sought to determine mortality in PAH in the modern era using the PHAR (Pulmonary Hypertension Association Registry). Methods and Results We identified all adult patients with PAH enrolled in the PHAR between September 2015 and September 2020 (N=935). We used Kaplan-Meier survival analysis and Cox proportional hazards models to assess mortality at 1, 2, and 3 years. Patients were stratified based on disease severity by 3 validated risk scores. In treatment-naïve patients, we compared survival based on initial treatment strategy. The median age was 56 years (44-68 years), and 76% were women. Of the 935 patients, 483 (52%) were ≤6 months from PAH diagnosis. There were 121 deaths (12.9%) during a median follow-up time of 489 days (281-812 days). The 1-, 2-, and 3-year mortality was 8% (95% CI, 6%-10%), 16% (95% CI, 13%-19%), and 21% (95% CI, 17%-25%), respectively. When stratified into low-, intermediate-, and high-risk PAH, the mortality at 1, 2, and 3 years was 1%, 4% to 6%, and 7% to 11% for low risk; 7% to 8%, 11% to 16%, and 18% to 20% for intermediate risk; and 12% to 19%, 22% to 38%, and 28% to 55% for high risk, respectively. In treatment-naïve patients, initial combination therapy was associated with better 1-year survival (adjusted hazard ratio, 0.43 [95% CI, 0.19-0.95]

Financing Direct Democracy: Revisiting the Research on Campaign Spending and Citizen Initiatives

The conventional view in the direct democracy literature is that spending against a measure is more effective than spending in favor of a measure, but the empirical results underlying this conclusion have been questioned by recent research. We argue that the conventional finding is driven by the endogenous nature of campaign spending: initiative proponents spend more when their ballot measure is likely to fail. We address this endogeneity by using an instrumental variables approach to analyze a comprehensive dataset of ballot propositions in California from 1976 to 2004. We find that both support and opposition spending on citizen initiatives have strong, statistically significant, and countervailing effects. We confirm this finding by looking at time series data from early polling on a subset of these measures. Both analyses show that spending in favor of citizen initiatives substantially increases their chances of passage, just as opposition spending decreases this likelihood

Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease

The worldwide burden of sickle cell disease is enormous, with over 200,000 infants born with the disease each year in Africa alone. Induction of fetal hemoglobin is a validated strategy to improve symptoms and complications of this disease. The development of targeted therapies has been limited by the absence of discrete druggable targets. We developed a unique bead-based strategy for the identification of inducers of fetal hemoglobin transcripts in primary human erythroid cells. A small-molecule screen of bioactive compounds identified remarkable class-associated activity among histone deacetylase (HDAC) inhibitors. Using a chemical genetic strategy combining focused libraries of biased chemical probes and reverse genetics by RNA interference, we have identified HDAC1 and HDAC2 as molecular targets mediating fetal hemoglobin induction. Our findings suggest the potential of isoform-selective inhibitors of HDAC1 and HDAC2 for the treatment of sickle cell disease