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OBJECTIVES/GOALS: We aim to discover safer and more effective therapeutics for CNS disorders. Current therapeutic development is hindered by dosing out drugs for safe consumption. By identifying proteins with narrow functional roles in the brain (i.e., behavioral control), we can develop drugs targeting these proteins for improved treatment safety and efficacy. METHODS/STUDY POPULATION: We focused on an evolutionarily new, non-neuronal, non-synaptic glutamate signaling mechanism, system xc- (Sxc). Sxc activity was eliminated by mutating the gene Slc7a11 through pronuclear injection of zinc-finger nucleases into Sprague Dawley rat embryos to create a line of rats lacking Sxc (MSxc). To confirm Sxc mutation, we verified that tissue from MSxc rats had a complete lack of xCT, which is the regulatory subunit of Sxc that is encoded by Slc7a11. We also verified that astrocyte cultures generated from MSxc tissue lacked cystine-evoked glutamate release. Next, we measured development (body weight), CNS regulation of metabolism, and other indicators of generalized, non-specific brain function as well as behaviors that are reliant on behavioral control, such as impulse control and response inhibition. RESULTS/ANTICIPATED RESULTS: Eliminating Sxc was not lethal and did not impair development or produce widespread changes in brain function as is commonly observed when deleting other glutamate mechanisms. MSxc rats did not differ from wildtype in growth rate, central regulation of metabolism as reflected by absolute or diurnal changes in core body temperature, locomotor activity in a familiar or novel environment, or simple forms of cognition such as novel object recognition, or operant responding (food and cocaine-reinforced). In contrast, behaviors that rely on behavioral control were impaired. MSxc rats displayed deficits in impulse control and behavioral flexibility. We hypothesize that MSxc rats will also show deficits in response inhibition using the stop signal reaction time task, a common metric used in clinical populations. DISCUSSION/SIGNIFICANCE: Eliminating Sxc activity in rats produced deficits in behaviors reliant on impulse control, without impacting development or simple brain function. These results show the potential of targeting Sxc to restore behavioral control without generating therapeutically limiting adverse effects resulting from non-specific changes in brain function.
OBJECTIVES/GOALS: We aim to determine whether non-neuronal, non-synaptic glutamate signaling mechanisms can be targeted to produce highly specific, narrow changes in brain function that would benefit CNS disorders. To do this, we investigated cognitive changes produced through manipulating the activity of the astrocytic glutamate release mechanism system xc-. METHODS/STUDY POPULATION: System xc- (Sxc) activity was eliminated by mutating the gene Slc7a11 through pronuclear injection of zinc-finger nucleases into Sprague Dawley rat embryos to create a line of rats lacking Sxc (MSxc rats). To confirm a lack of Sxc activity, we verified that tissue from MSxc rats had a complete lack of xCT, which is the regulatory subunit of Sxc that is encoded by Slc7a11. We also verified that astrocyte cultures generated from MSxc tissue lacked cystine-evoked glutamate release. Next, we measured development (body weight), CNS regulation of metabolism, and other indicators of generalized, non-specific brain function as well as behaviors that are reliant on executive function, such as cognitive flexibility, impulse control, decision-making, and response inhibition. RESULTS/ANTICIPATED RESULTS: Eliminating Sxc was not lethal and did not impair development or produce widespread changes in brain function as is commonly observed when deleting other glutamate mechanisms. MSxc rats did not differ from wildtype in growth rate, central regulation of metabolism as reflected by absolute or diurnal changes in core body temperature, locomotor activity in a familiar or novel environment, or simple forms of cognition such as novel object recognition, or operant responding (food and cocaine-reinforced). In contrast, behaviors that rely on executive function were impaired. MSxc rats displayed deficits in cocaine reinstatement and attentional set-shifting. We anticipate MSxc rats to also show impairments in decision-making in the rat gambling task and response inhibition in the stop-signal reaction time task. DISCUSSION/SIGNIFICANCE: Eliminating Sxc activity in rats produced deficits in behaviors reliant on executive function without impacting development or simple brain function. These results highlight the potential of targeting Sxc to enhance cognition without generating therapeutically limiting adverse effects resulting from non-specific changes in brain function.
Given the relatively small industry scale of cow-calf operations in New York to other regions of the country, little is known about differences in determinant values for feeder cattle. Using auction prices and quality characteristics over 7 years, differences in market, lot, and quality parameters suggest opportunities for improved marketing performance. A delta profit model is constructed to inform timing of marketing decisions for producers. The results indicate a relatively high potential for producers to increase farm returns by delaying sales of lighter-weight feeder cattle from the fall to spring auction months, given sufficient rates of gain and reasonable overwintering costs.
An early economic evaluation to inform the translation into clinical practice of a spectroscopic liquid biopsy for the detection of brain cancer. Two specific aims are (1) to update an existing economic model with results from a prospective study of diagnostic accuracy and (2) to explore the potential of brain tumor-type predictions to affect patient outcomes and healthcare costs.
A cost-effectiveness analysis from a UK NHS perspective of the use of spectroscopic liquid biopsy in primary and secondary care settings, as well as a cost–consequence analysis of the addition of tumor-type predictions was conducted. Decision tree models were constructed to represent simplified diagnostic pathways. Test diagnostic accuracy parameters were based on a prospective validation study. Four price points (GBP 50-200, EUR 57-228) for the test were considered.
In both settings, the use of liquid biopsy produced QALY gains. In primary care, at test costs below GBP 100 (EUR 114), testing was cost saving. At GBP 100 (EUR 114) per test, the ICER was GBP 13,279 (EUR 15,145), whereas at GBP 200 (EUR 228), the ICER was GBP 78,300 (EUR 89,301). In secondary care, the ICER ranged from GBP 11,360 (EUR 12,956) to GBP 43,870 (EUR 50,034) across the range of test costs.
The results demonstrate the potential for the technology to be cost-effective in both primary and secondary care settings. Additional studies of test use in routine primary care practice are needed to resolve the remaining issues of uncertainty—prevalence in this patient population and referral behavior.
Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990–1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.
Introduction: Despite the public health relevance of smoking in adolescents and emerging adults, this group remains understudied and underserved. High technology utilisation among this group may be harnessed as a tool for better understanding of smoking, yet little is known regarding the acceptability of mobile health (mHealth) integration.
Methods: Participants (ages 14–21 years) enrolled in a smoking cessation clinical trial provided feedback on their technology utilisation, perceptions, and attitudes; and interest in remote monitoring for smoking. Characteristics that predicted greater technology acceptability for smoking treatment were also explored.
Results: Participants (N = 87) averaged 19 years old and were mostly male (67%). Technology utilisation was high for smart phone ownership (93%), Internet use (98%), and social media use (94%). Despite this, only one-third of participants had ever searched the Internet for cessation tips or counselling (33%). Participants showed interest in mHealth-enabled treatment (48%) and felt that it could be somewhat helpful (83%). Heavier smokers had more favourable attitudes toward technology-based treatment, as did those with smartphones and unlimited data.
Conclusions: Our results demonstrate high technology utilisation, favourable attitudes towards technology, and minimal concerns. Technology integration among this population should be pursued, though in a tailored fashion, to accomplish the goal of providing maximally effective, just-in-time interventions.
A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.
For over 100 years, the genetics of human anthropometric traits has attracted scientific interest. In particular, height and body mass index (BMI, calculated as kg/m2) have been under intensive genetic research. However, it is still largely unknown whether and how heritability estimates vary between human populations. Opportunities to address this question have increased recently because of the establishment of many new twin cohorts and the increasing accumulation of data in established twin cohorts. We started a new research project to analyze systematically (1) the variation of heritability estimates of height, BMI and their trajectories over the life course between birth cohorts, ethnicities and countries, and (2) to study the effects of birth-related factors, education and smoking on these anthropometric traits and whether these effects vary between twin cohorts. We identified 67 twin projects, including both monozygotic (MZ) and dizygotic (DZ) twins, using various sources. We asked for individual level data on height and weight including repeated measurements, birth related traits, background variables, education and smoking. By the end of 2014, 48 projects participated. Together, we have 893,458 height and weight measures (52% females) from 434,723 twin individuals, including 201,192 complete twin pairs (40% monozygotic, 40% same-sex dizygotic and 20% opposite-sex dizygotic) representing 22 countries. This project demonstrates that large-scale international twin studies are feasible and can promote the use of existing data for novel research purposes.
Mutations in the progranulin gene (GRN) are a common cause of familial frontotemporal dementia. We used a comprehensive neuropsychological battery to investigate whether early cognitive changes could be detected in GRN mutation carriers before dementia onset. Twenty-four at-risk members from six families with known GRN mutations underwent detailed neuropsychological testing. Group differences were investigated by domains of attention, language, visuospatial function, verbal memory, non-verbal memory, working memory and executive function. There was a trend for mutation carriers (n=8) to perform more poorly than non-carriers (n=16) across neuropsychological domains, with significant between group differences for visuospatial function (p<.04; d=0.92) and working memory function (p<.02; d=1.10). Measurable cognitive differences exist before the development of frontotemporal dementia in subjects with GRN mutations. The neuropsychological profile of mutation carriers suggests early asymmetric, right hemisphere brain dysfunction that is consistent with recent functional imaging data from our research group and the broader literature. (JINS, 2014, 20, 1–10)
During an unusually massive filament eruption on 7 June 2011, SDO/AIA imaged for the first time significant EUV emission around a magnetic reconnection region in the solar corona. The reconnection occurred between magnetic fields of the laterally expanding CME and a neighbouring active region. A pre-existing quasi-separatrix layer was activated in the process. This scenario is supported by data-constrained numerical simulations of the eruption. Observations show that dense cool filament plasma was re-directed and heated in situ, producing coronal-temperature emission around the reconnection region. These results provide the first direct observational evidence, supported by MHD simulations and magnetic modelling, that a large-scale re-configuration of the coronal magnetic field takes place during solar eruptions via the process of magnetic reconnection.
In 1991, McNabb introduced the concept of mean action time (MAT) as a finite measure of the time required for a diffusive process to effectively reach steady state. Although this concept was initially adopted by others within the Australian and New Zealand applied mathematics community, it appears to have had little use outside this region until very recently, when in 2010 Berezhkovskii and co-workers [A. M. Berezhkovskii, C. Sample and S. Y. Shvartsman, “How long does it take to establish a morphogen gradient?” Biophys. J.99 (2010) L59–L61] rediscovered the concept of MAT in their study of morphogen gradient formation. All previous work in this area has been limited to studying single-species differential equations, such as the linear advection–diffusion–reaction equation. Here we generalize the concept of MAT by showing how the theory can be applied to coupled linear processes. We begin by studying coupled ordinary differential equations and extend our approach to coupled partial differential equations. Our new results have broad applications, for example the analysis of models describing coupled chemical decay and cell differentiation processes.