Rationale
The adverse consequences of human addictive drug use could be the result of either addictive drug consumption resulting in punishment (e.g., incarceration) or failure to engage in ...negative-reinforced behaviors that might compete with drug-maintained behaviors (e.g., contingency management strategies that reset payment amounts for drug free urines).
Objective
The goal of the present study was to establish a discrete-trial cocaine-vs-negative reinforcer (S
NR
) choice procedure where rats were presented with a simplified model of this conflict: choose negative reinforcement (i.e., escape or avoid foot shock) or choose an intravenous (IV) cocaine infusion followed by an inescapable shock.
Methods
Responding was maintained in male and female rats by IV cocaine infusions (0.32–1.8 mg/kg/inf) and a S
NR
(0.1–0.7 mA shock) under a discrete-trial concurrent “choice” schedule during daily sessions. Following parametric reinforcer magnitude and response requirement experiments, the effects of 12 h extended access cocaine self-administration and acute diazepam (0.32–10 mg/kg, IP) pretreatment were determined on cocaine-vs-S
NR
choice.
Results
Negative reinforcement was chosen over all cocaine doses. Lowering shock magnitude or increasing S
NR
response requirement failed to promote behavioral reallocation towards cocaine. Extended access cocaine self-administration sessions resulted in high daily cocaine intakes but failed to significantly increase cocaine choice in all (19) but one rat. Acute diazepam pretreatment also did not alter choice behavior up to doses that produced behavioral depression.
Conclusions
These results suggest that S
NR
s may be a source of reinforcement that effectively compete with and mitigate maladaptive addictive drug-maintained behaviors in the general population.
This document presents the American Thoracic Society clinical practice guidelines for the diagnosis of primary ciliary dyskinesia (PCD).
Clinicians investigating adult and pediatric patients for ...possible PCD.
Systematic reviews and, when appropriate, meta-analyses were conducted to summarize all available evidence pertinent to our clinical questions. Evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for diagnosis and discussed by a multidisciplinary panel with expertise in PCD. Predetermined conflict-of-interest management strategies were applied, and recommendations were formulated, written, and graded exclusively by the nonconflicted panelists. Three conflicted individuals were also prohibited from writing, editing, or providing feedback on the relevant sections of the manuscript.
After considering diagnostic test accuracy, confidence in the estimates for each diagnostic test, relative importance of test results studied, desirable and undesirable direct consequences of each diagnostic test, downstream consequences of each diagnostic test result, patient values and preferences, costs, feasibility, acceptability, and implications for health equity, the panel made recommendations for or against the use of specific diagnostic tests as compared with using the current reference standard (transmission electron microscopy and/or genetic testing) for the diagnosis of PCD.
The panel formulated and provided a rationale for the direction as well as for the strength of each recommendation to establish the diagnosis of PCD.
Dysregulation of lipid homeostasis is a precipitating event in the pathogenesis and progression of hepatosteatosis and metabolic syndrome. These conditions are highly prevalent in developed societies ...and currently have limited options for diagnostic and therapeutic intervention. Here, using a proteomic and lipidomic-wide systems genetic approach, we interrogated lipid regulatory networks in 107 genetically distinct mouse strains to reveal key insights into the control and network structure of mammalian lipid metabolism. These include the identification of plasma lipid signatures that predict pathological lipid abundance in the liver of mice and humans, defining subcellular localization and functionality of lipid-related proteins, and revealing functional protein and genetic variants that are predicted to modulate lipid abundance. Trans-omic analyses using these datasets facilitated the identification and validation of PSMD9 as a previously unknown lipid regulatory protein. Collectively, our study serves as a rich resource for probing mammalian lipid metabolism and provides opportunities for the discovery of therapeutic agents and biomarkers in the setting of hepatic lipotoxicity.
Pathologic immune hyperactivation is emerging as a key feature of critical illness in COVID-19, but the mechanisms involved remain poorly understood. We carried out proteomic profiling of plasma from ...cross-sectional and longitudinal cohorts of hospitalized patients with COVID-19 and analyzed clinical data from our health system database of more than 3300 patients. Using a machine learning algorithm, we identified a prominent signature of neutrophil activation, including resistin, lipocalin-2, hepatocyte growth factor, interleukin-8, and granulocyte colony-stimulating factor, which were the strongest predictors of critical illness. Evidence of neutrophil activation was present on the first day of hospitalization in patients who would only later require transfer to the intensive care unit, thus preceding the onset of critical illness and predicting increased mortality. In the health system database, early elevations in developing and mature neutrophil counts also predicted higher mortality rates. Altogether, these data suggest a central role for neutrophil activation in the pathogenesis of severe COVID-19 and identify molecular markers that distinguish patients at risk of future clinical decompensation.
•Markers of neutrophil activation (RETN, LCN2, HGF, IL-8, G-CSF) are among the most potent discriminators of critical illness in COVID-19.•Evidence of neutrophil activation precedes the onset of critical illness and predicts mortality in COVID-19.
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Cocaine use disorder occurs in an environment where cocaine and other nondrug commodities are concurrently available. Preclinical drug-vs-nondrug choice procedures are one simplified method of ...modeling this complex clinical environment. The present study established a discrete-trial cocaine-vs-social interaction choice procedure in male and female rats and determined sensitivity of choice behavior to manipulations of reinforcer magnitude and non-contingent “sample” reinforcer presentation. Rats could make up to nine discrete choices between an intravenous cocaine infusion (0.1–1.0 mg/kg/inf) and social interaction with a same-sex social “Partner” rat. Cocaine infusions were available under a progressive-ratio (PR) schedule of reinforcement, and social interaction was available under a fixed-ratio (FR) 3 schedule. Social interaction was chosen over no or small cocaine doses (saline, 0.01 mg/kg/inf) and behavior was reallocated away from social and towards cocaine at larger cocaine doses (1.0 mg/kg/inf). Manipulating social interaction time as one method to alter social reinforcer magnitude did not significantly alter cocaine-vs-social choice. Removing the non-contingent reinforcer presentations before the discrete choice trials also failed to affect cocaine-vs-social choice, suggesting the time interval was sufficient to minimize any potential influence of the non-contingent cocaine infusions on subsequent choice behavior. Overall, the present results were consistent with previous drug-vs-social choice studies and extend our knowledge of environmental factors impacting drug-vs-social choice. Future studies determining the pharmacological sensitivity of cocaine-vs-social choice will be important in expanding the preclinical utility of these procedures for candidate medication drug development.
•Cocaine was chosen over social interaction in both female and male rats.•Manipulation of social access time failed to alter cocaine-vs-social choice.•Removing non-contingent reinforcer presentations did not attenuate cocaine choice.
Hybrid speciation, or the formation of a daughter species due to interbreeding between two parental species, is a potentially important means of diversification, because it generates new forms from ...existing variation. However, factors responsible for the origin and maintenance of hybrid species are largely unknown. Here we show that the North American butterfly Papilio appalachiensis is a hybrid species, with genomic admixture from Papilio glaucus and Papilio canadensis. Papilio appalachiensis has a mosaic phenotype, which is hypothesized to be the result of combining sex-linked traits from P. glaucus and P. canadensis. We show that P. appalachiensis' Z-linked genes associated with a cooler thermal habitat were inherited from P. canadensis, whereas its W-linked mimicry and mitochondrial DNA were inherited from P. glaucus. Furthermore, genome-wide AFLP markers showed nearly equal contributions from each parental species in the origin of P. appalachiensis, indicating that it formed from a burst of hybridization between the parental species, with little subsequent backcrossing. However, analyses of genetic differentiation, clustering, and polymorphism based on molecular data also showed that P. appalachiensis is genetically distinct from both parental species. Population genetic simulations revealed P. appalachiensis to be much younger than the parental species, with unidirectional gene flow from P. glaucus and P. canadensis into P. appalachiensis. Finally, phylogenetic analyses, combined with ancestral state reconstruction, showed that the two traits that define P. appalachiensis' mosaic phenotype, obligatory pupal diapause and mimicry, evolved uniquely in P. canadensis and P. glaucus, respectively, and were then recombined through hybridization to form P. appalachiensis. These results suggest that natural selection and sex-linked traits may have played an important role in the origin and maintenance of P. appalachiensis as a hybrid species. In particular, ecological barriers associated with a steep thermal cline appear to maintain the distinct, mosaic genome of P. appalachiensis despite contact and occasional hybridization with both parental species.
Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders ...the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-κB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-κB signalling, and we observed mutual exclusivity among tumours with somatic NF-κB pathway aberrations and LMP1-overexpression, suggesting that NF-κB activation is selected for by both somatic and viral events during NPC pathogenesis.
Background & Aims Colonoscopy can decrease colorectal cancer (CRC) mortality, although performing this procedure more frequently than recommended could increase costs and risks to patients. We aimed ...to determine rates and correlates of physician non-adherence to guidelines for repeat colonoscopy screening and polyp surveillance intervals. Methods We performed a multi-center, retrospective, observational study using administrative claims, physician databases, and electronic medical records (EMR) from 1455 patients (50–64 y old) who underwent colonoscopy in the Veterans Affairs healthcare system in fiscal year 2008. Patients had no prior diagnosis of CRC or inflammatory bowel disease, and had not undergone colonoscopy examinations in the previous 10 years. We compared EMR-documented, endoscopist-recommended intervals for colonoscopies with intervals recommended by the 2008 Multi-Society Task Force guidelines. Results The overall rate of non-adherence to guideline recommendations was 36% and ranged from 3% to 80% among facilities. Non-adherence was 28% for patients who underwent normal colonoscopies, but 45%−52% after colonoscopies that identified hyperplastic or adenomatous polyps. Most of all recommendations that were not followed recommended a shorter surveillance interval. In adjusted analyses, non-adherence was significantly higher for patients whose colonoscopies identified hyperplastic (odds ratio OR = 3.1; 95% CI, 1.7–5.5) or high-risk adenomatous polyps (OR = 3.0; 95% CI, 1.2−8.0), compared to patients with normal colonoscopy examinations, but not for patients with low-risk adenomatous polyps (OR = 1.8; 95% CI, 0.9–3.7). Nonadherence was also associated with bowel preparation quality, geographic region, Charlson comorbidity score, and colonoscopy indication. Conclusions In a managed care setting with salaried physicians, endoscopists recommend repeat colonoscopy sooner than guidelines for more than one third of patients. Factors associated with non-adherence to guideline recommendations were colonoscopy findings, quality of bowel preparation, and geographic region. Targeting endoscopist about non-adherence to colonoscopy guidelines could reduce overuse of colonoscopy and associated healthcare costs.
This article presents a method for multiobjective optimization of a complex system, modelling it as a collection of components and resource flows between them. Constraints can be imposed on a ...component basis or system-wide, based on the resource flows. Optimization is performed by a genetic algorithm utilizing a variable-length genome. This specialized genome enables a more open-ended design capability than previous similar frameworks. Systems are evaluated through a user-defined simulation, and results can be presented in any trade space of interest based on the performance in the simulation. The framework is then applied to the design of a table as a simple proof of concept. In this problem, the framework was found to identify a design within 4% of the theoretical optimum 80% of the time, and within 8% of the theoretical optimum the remaining 20% of the time.
Monarch butterflies are a species of conservation priority due to declining overwintering populations in both eastern and western North America. Declines in western overwintering monarchs—more than ...99.9% since monitoring began—are especially acute. However, the degree to which western monarchs are a distinct biological entity is uncertain. In this review, we focus on phenotypic and genetic differentiation between eastern and western monarchs, with the goal of informing researchers and policy‐makers who are interested in monarch conservation. Eastern and western monarchs occupy distinct environments and show some evidence for phenotypic differentiation, particularly for migration‐associated traits, though population genetic and genomic studies suggest that they are indistinguishable from one another. We suggest future studies that could improve our understanding of differences between eastern and western monarchs. We also discuss the concept of adaptive capacity in eastern and western monarchs as well as non‐migratory populations outside of the monarch's primary North American range. Finally, we discuss the prospect of completely losing migratory monarchs from western North America and what this entails for monarch conservation.
Monarch butterflies are a species of conservation significance, and migratory western North American monarch butterflies are at especially high risk of local extirpation. This review article contextualizes the decline of western monarchs by reviewing research on their status as a distinct population from eastern monarchs, with an emphasis on studies of genetic, phenotypic, and ecological differentiation.
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