Discriminative Stimulus Effects of Magnesium Chloride: Substitution Studies with Monoamine Uptake Inhibitors and N-Methyl-D-Aspartate Antagonists 1

ABSTRACT Previous studies suggest that magnesium chloride may have discriminative stimulus effects that partially overlap with those of noncompetitive N-methyl-D-aspartate antagonists as well as certain monoamine uptake inhibitors. In our study, rats were trained to discriminate 100 mg/kg magnesium chloride from saline and its discriminative stimulus effects were characterized with respect to N-methyl-D-aspartate receptor and monoamine transporter functions in substitution tests. The discriminative stimulus effects of magnesium chloride were acquired within a moderate number of training sessions and showed dose-related substitution after either subcutaneous (3-300 mg/kg) or intracerebroventricular (0.3-300 g) administration. The intracerebroventricular administration of magnesium chloride was over 4000 times more potent than its s.c. administration. The monoamine uptake inhibitors cocaine, GBR 12909, talsupram and citalopram fully substituted (Ն90% magnesium-appropriate responses) for magnesium chloride in the majority of subjects tested and the group averages reached a maximum of 72 to 82% responses on the magnesium-appropriate lever. Based on relative potency analysis, the rank order of potency of these four drugs for producing magnesium-appropriate responses was talsupram ϭ cocaine Ͼ citalopram ϭ GBR 12909. The N-methyl-D-aspartate receptor antagonists dizocilpine, phencyclidine and NPC 17742 engendered maximum group averages of 49 to 65% responses on the magnesium-appropriate lever. The results suggest that the centrally mediated discriminative stimulus effects of magnesium chloride may be more directly related to interactions with monoamine neurotransmitter functions than to N-methyl-D-aspartate receptor blockade

Strategic considerations for invasive species managers in the utilization of environmental DNA (eDNA): Steps for incorporating this powerful surveillance tool

Invasive species surveillance programs can utilize environmental DNA sampling and analysis to provide information on the presence of invasive species. Wider utilization of eDNA techniques for invasive species surveillance may be warranted. This paper covers topics directed towards invasive species managers and eDNA practitioners working at the intersection of eDNA techniques and invasive species surveillance. It provides background information on the utility of eDNA for invasive species management and points to various examples of its use across federal and international programs. It provides information on 1) why an invasive species manager should consider using eDNA, 2) deciding if eDNA can help with the manager’s surveillance needs, 3) important components to operational implementation, and 4) a high-level overview of the technical steps necessary for eDNA analysis. The goal of this paper is to assist invasive species managers in deciding if, when, and how to use eDNA for surveillance. If eDNA use is elected, the paper provides guidance on steps to ensure a clear understanding of the strengths and limitation of the methods and how results can be best utilized in the context of invasive species surveillance

Conceptualizing Ecological Responses to Dam Removal: If You Remove It, What’s to Come?

One of the desired outcomes of dam decommissioning and removal is the recovery of aquatic and riparian ecosystems. To investigate this common objective, we synthesized information from empirical studies and ecological theory into conceptual models that depict key physical and biological links driving ecological responses to removing dams. We define models for three distinct spatial domains: upstream of the former reservoir, within the reservoir, and downstream of the removed dam. Emerging from these models are response trajectories that clarify potential pathways of ecological transitions in each domain. We illustrate that the responses are controlled by multiple causal pathways and feedback loops among physical and biological components of the ecosystem, creating recovery trajectories that are dynamic and nonlinear. In most cases, short-term effects are typically followed by longer-term responses that bring ecosystems to new and frequently predictable ecological condition, which may or may not be similar to what existed prior to impoundment

The National COVID Cohort Collaborative (N3C): Rationale, design, infrastructure, and deployment.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) poses societal challenges that require expeditious data and knowledge sharing. Though organizational clinical data are abundant, these are largely inaccessible to outside researchers. Statistical, machine learning, and causal analyses are most successful with large-scale data beyond what is available in any given organization. Here, we introduce the National COVID Cohort Collaborative (N3C), an open science community focused on analyzing patient-level data from many centers. MATERIALS AND METHODS: The Clinical and Translational Science Award Program and scientific community created N3C to overcome technical, regulatory, policy, and governance barriers to sharing and harmonizing individual-level clinical data. We developed solutions to extract, aggregate, and harmonize data across organizations and data models, and created a secure data enclave to enable efficient, transparent, and reproducible collaborative analytics. RESULTS: Organized in inclusive workstreams, we created legal agreements and governance for organizations and researchers; data extraction scripts to identify and ingest positive, negative, and possible COVID-19 cases; a data quality assurance and harmonization pipeline to create a single harmonized dataset; population of the secure data enclave with data, machine learning, and statistical analytics tools; dissemination mechanisms; and a synthetic data pilot to democratize data access. CONCLUSIONS: The N3C has demonstrated that a multisite collaborative learning health network can overcome barriers to rapidly build a scalable infrastructure incorporating multiorganizational clinical data for COVID-19 analytics. We expect this effort to save lives by enabling rapid collaboration among clinicians, researchers, and data scientists to identify treatments and specialized care and thereby reduce the immediate and long-term impacts of COVID-19

Evolution and Survival on Eutherian Sex Chromosomes

Since the two eutherian sex chromosomes diverged from an ancestral autosomal pair, the X has remained relatively gene-rich, while the Y has lost most of its genes through the accumulation of deleterious mutations in nonrecombining regions. Presently, it is unclear what is distinctive about genes that remain on the Y chromosome, when the sex chromosomes acquired their unique evolutionary rates, and whether X-Y gene divergence paralleled that of paralogs located on autosomes. To tackle these questions, here we juxtaposed the evolution of X and Y homologous genes (gametologs) in eutherian mammals with their autosomal orthologs in marsupial and monotreme mammals. We discovered that genes on the X and Y acquired distinct evolutionary rates immediately following the suppression of recombination between the two sex chromosomes. The Y-linked genes evolved at higher rates, while the X-linked genes maintained the lower evolutionary rates of the ancestral autosomal genes. These distinct rates have been maintained throughout the evolution of X and Y. Specifically, in humans, most X gametologs and, curiously, also most Y gametologs evolved under stronger purifying selection than similarly aged autosomal paralogs. Finally, after evaluating the current experimental data from the literature, we concluded that unique mRNA/protein expression patterns and functions acquired by Y (versus X) gametologs likely contributed to their retention. Our results also suggest that either the boundary between sex chromosome strata 3 and 4 should be shifted or that stratum 3 should be divided into two strata

Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk.

We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer

Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data.

Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a "phenotype first" approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands

BMC Psychiatry

BACKGROUND: Suicidal ideation and suicidal risk assessment are major concerns for health professionals. The perception of a low level of parental support is a risk factor for suicidal tendencies among adolescents, but little is known about its long-term impact on the vulnerability to suicidal behavior in young adults. We investigated whether the perceived level of parental support during childhood and adolescence was associated with current suicidal ideation in young adults. METHODS: We retrieved data collected in the i-Share study from February 1st, 2013 through January 30, 2017. This cross-sectional study included 10,015 French students, aged 18-24 years that completed an on-line self-reported questionnaire about suicidal ideation in the last 12 months and their perceived parental support in childhood and adolescence. We performed multinomial logistic regressions and sensitivity analyses to assess associations between the degree of perceived parental support and the frequency suicidal thoughts, after adjusting for the main known risk factors of suicidal ideation. We employed multiple imputations to account for missing data. RESULTS: The study sample included 7539 female (75.7%) and 2436 male (24.3%) students (mean [SD] age 20.0 [1.8] years). About one in five students reported occasional suicidal thoughts (n = 1775, 17.7%) and 368 students (3.7%) reported frequent suicidal thoughts. The adjusted multinomial logistic regression revealed a significant negative association between perceived parental support and suicidal thoughts. A lack of perceived parental support in childhood and adolescence was associated with > 4-fold elevated risk of occasional (adjusted OR, 4.55; 95% CI: 2.97-6.99) and nearly 9-fold elevated risk of frequent (adjusted OR, 8.58; 95% CI: 4.62-15.96) suicidal thoughts, compared to individuals that perceived extremely strong parental support. This association was strongest among students with no personal history of depression or suicide attempts. CONCLUSIONS: Students that perceived low levels of past parental support had a higher risk of suicidal ideation. Past perceived parental support appeared to be a potent marker of suicidal risk in young adults. This marker should be routinely collected in studies on suicidal risk in young adults, and it could be considered an additional screening tool

Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, abeta, and alzheimer's disease.

Background: The insulin-degrading enzyme gene (IDE) is a strong functional and positional candidate for late onset Alzheimer's disease (LOAD). Methodology/Principal findings: We examined conserved regions of IDE and its 10 kb flanks in 269 AD cases and 252 controls thereby identifying 17 putative functional polymorphisms. These variants formed eleven haplotypes that were tagged with ten variants. Four of these showed significant association with IDE transcript levels in samples from 194 LOAD cerebella. The strongest, rs6583817, which has not previously been reported, showed unequivocal association (p = 1.5x10(-8), fold-increase = 2.12,); the eleven haplotypes were also significantly associated with transcript levels (global p = 0.003). Using an in vitro dual luciferase reporter assay, we found that rs6583817 increases reporter gene expression in Be(2)-C (p = 0.006) and HepG2 (p = 0.02) cell lines. Furthermore, using data from a recent genome-wide association study of two Croatian isolated populations (n = 1,879), we identified a proxy for rs6583817 that associated significantly with decreased plasma Abeta40 levels (ss = -0.124, p = 0.011) and total measured plasma Abeta levels (b = -0.130, p = 0.009). Finally, rs6583817 was associated with decreased risk of LOAD in 3,891 AD cases and 3,605 controls. (OR = 0.87, p = 0.03), and the eleven IDE haplotypes (global p = 0.02) also showed significant association. Conclusions: Thus, a previously unreported variant unequivocally associated with increased IDE expression was also associated with reduced plasma Ass40 and decreased LOAD susceptibility. Genetic association between LOAD and IDE has been difficult to replicate. Our findings suggest that targeted testing of expression SNPs (eSNPs) strongly associated with altered transcript levels in autopsy brain samples may be a powerful way to identify genetic associations with LOAD that would otherwise be difficult to detect