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OBJECTIVES/SPECIFIC AIMS: Women with pulmonary arterial hypertension (PAH) exhibit superior right ventricular (RV) function and survival compared with men, a phenomenon attributed to poorly understood cardioprotective effects of 17β-estradiol (E2). We hypothesize that E2, through ERα, attenuates PH-induced RV dysfunction by upregulating the pro-contractile and pro-angiogenic peptide apelin. This ERα-mediated increase in apelin is mediated by the myocardial remodeling effector bone morphogenetic protein receptor 2 (BMPR2). METHODS/STUDY POPULATION: ERα, BMPR2, and apelin were measured (western blot) in RVs from patients with PAH-induced RV failure and in RV homogenates from male or female Sprague-Dawley rats with sugen/hypoxia (SuHx) or monocrotaline (MCT)-induced PH. H9c2 rat cardiomyoblasts and cardiac endothelial cells were stressed with TNF-α (10 ng/mL) or staurosporine (50 nM)±E2 (100 nM; 24 h). ERα-, BMPR2-, and apelin-dependence were evaluated by siRNA (5 pM). Downstream apelin target and pro-survival factor ERK1/2 expression was measured (western blot). p<0.05 by ANOVA was considered significant. RESULTS/ANTICIPATED RESULTS: ERα correlated positively with BMPR2 and apelin expression in SuHx-RVs and human RVs. Treatment of SuHx-PH rats with E2 or ERα agonist increased RV BMPR2 and apelin, whereas RV apelin was decreased in E2-treated hypoxic ERα knockout mice (p<0.05), but not in ERβ knockout mice. In H9c2 cells, E2 or ERα agonist attenuated TNF-α- or staurosporine-induced decreases in BMPR2, apelin, and phospho-ERK1/2 (p<0.05 for all endpoints). E2 protection was lost in presence of siRNA directed against ERα, BMPR2, or apelin (p<0.05). ERα was necessary for E2-mediated increases in BMPR2, apelin, and ERK1/2, and BMPR2 was required for the E2-mediated increase in apelin (p<0.05 for siRNA vs. scramble). ERα, BMPR2, and apelin protein was increased in decompensated human RVs but downstream phospho-ERK signaling was disrupted. DISCUSSION/SIGNIFICANCE OF IMPACT: E2, via ERα, increases BMPR2 and apelin in the failing RV and in stressed rat cardiomyoblasts. The E2-mediated increase in apelin is BMPR2-dependent and likely occurs through direct binding of ERα to the BMPR2 promoter. Harnessing this E2-ERα-BMPR2-apelin axis during RV compensation may lead to novel, RV-targeted therapies for PAH patients of either sex.
We have discovered a well-defined extended conformation of double-stranded DNA, which we call Σ-DNA, using laser-tweezers force-spectroscopy experiments. At a transition force corresponding to free energy change ΔG = 1·57 ± 0·12 kcal (mol base pair)−1 60 or 122 base-pair long synthetic GC-rich sequences, when pulled by the 3′−3′ strands, undergo a sharp transition to the 1·52 ± 0·04 times longer Σ-DNA. Intriguingly, the same degree of extension is also found in DNA complexes with recombinase proteins, such as bacterial RecA and eukaryotic Rad51. Despite vital importance to all biological organisms for survival, genome maintenance and evolution, the recombination reaction is not yet understood at atomic level. We here propose that the structural distortion represented by Σ-DNA, which is thus physically inherent to the nucleic acid, is related to how recombination proteins mediate recognition of sequence homology and execute strand exchange. Our hypothesis is that a homogeneously stretched DNA undergoes a ‘disproportionation’ into an inhomogeneous Σ-form consisting of triplets of locally B-like perpendicularly stacked bases. This structure may ensure improved fidelity of base-pair recognition and promote rejection in case of mismatch during homologous recombination reaction. Because a triplet is the length of a gene codon, we speculate that the structural physics of nucleic acids may have biased the evolution of recombinase proteins to exploit triplet base stacks and also the genetic code.
This paper presents the impact of three undergraduate research projects focusing on constructability assessment of adhesive-based wood-concrete composite structural members, on a solar heating technology that can be utilized in conjunction with this system and how these projects relate to engineering education and program development at Metropolitan State University of Denver (MSU Denver). The sustainable structures topic was pursued within senior project classes offered in summer 2013 and 2014 at MSU Denver. The first project addressed new members, while the second dealt with retrofits. These projects were motivated by faculty research in developing new sustainable construction systems using composites. Since underlining faculty research is on an international scale, students had direct access to researchers world-wide. Such research was used as an instrument in the “Experimental Methods in Structural Engineering” course. The students were also exposed to a broader-range of diverse ideas within the field of research by attending an international conference on timber bridges. The solar furnace project was run in parallel, providing students an opportunity to conduct research targeted at design and performance optimization of the heating units with the intention to assess the benefits of incorporating these devices into future buildings using the sustainable structural system technology. Experiences gained through the undergraduate research activities were applied in the design of a proposed Sustainable Systems Engineering degree program.
To assess recovery of cognitive effects, we investigated neuropsychological performance after 1 month of monitored abstinence in teens with histories of heavy episodic drinking, protracted marijuana use, or concomitant use of alcohol and marijuana. Adolescents (ages 16–18 years) with histories of heavy episodic drinking (HED; n=24), marijuana use (MJ; n=20), both heavy alcohol and marijuana use (HED+MJ; n=29), and socio-demographically similar control teens (CON; n=55) completed a neuropsychological battery following 4 weeks of monitored abstinence. Groups were similar on 5th grade standardized test scores, suggesting comparable academic functioning before onset of substance use. Relative to CON, HED showed poorer cognitive flexibility (p=.006), verbal recall (p=.024), semantic clustering (p=.011), and reading skills (p=.018). MJ performed worse than CON on inhibition task accuracy (p=.015), cued verbal memory (p=.031), and psychomotor speed (p=.027). Similar to HED youth, HED+MJ showed differences relative to CON on cognitive flexibility (p=.024) and verbal recall (p=.049). As with MJ teens, HED+MJ showed poorer task accuracy (p=.020). Unique to the HED+MJ group was poorer working memory (p=.012) relative to CON. For all substance using participants, worse performance across domains correlated with more lifetime use of alcohol and of marijuana, more withdrawal symptoms from alcohol, and earlier age of onset of marijuana use (ps<.05). Heavy alcohol use, marijuana use, and concomitant use of both substances during adolescence appear to be associated with decrements in cognitive functioning, and each substance (or combination of substances) may be linked to poorer performance in specific cognitive domains (JINS, 2014, 20, 784–795).
The present study investigated the rate and pattern of neuropsychological recovery in heavy episodic drinking teens during the initial days to weeks of abstinence from alcohol. Adolescents (ages, 16–18 years) with histories of heavy episodic drinking (HED; N = 39) and socio-demographically similar control teens (CON; N = 26) were recruited from San Diego area schools. HED and CON were comparable on 5th grade standardized math and language arts test performance to ensure similar functioning before onset of substance use. Participants were administered three neuropsychological test batteries with 2-week intervals during a 4-week monitored abstinence period. HED teens performed worse overall than CON on tests of prospective memory (p = .005), cognitive switching (p = .039), inhibition task accuracy (p = .001), verbal memory (p's < .045), visuospatial construction (p's < .043), and language and achievement (p's < .008). The statistically significant group × time interaction for block design demonstrated normalization within the 4 weeks of abstinence for the HED (p = .009). This study identified cognitive performance deficits associated with heavy episodic drinking in adolescence during early abstinence and with sustained 4-week abstention. These findings suggest alcohol-related influences on several underlying brain systems that may predate the onset of alcohol abuse or dependence or take longer than 4 weeks to recover. (JINS, 2014, 20, 218–229)
As part of the Bcool project, over 150 solar-type stars chosen mainly from planet search databases have been observed between 2006 and 2013 using the NARVAL and ESPaDOnS spectropolarimeters on the Telescope Bernard Lyot (Pic du Midi, France) and the Canada France Hawaii Telescope (Mauna Kea, USA), respectively. These single “snapshot” observations have been used to detect the presence of magnetic fields on 40% of our sample, with the highest detection rates occurring for the youngest stars. From our observations we have determined the mean surface longitudinal field (or an upper limit for stars without detections) and the chromospheric surface fluxes, and find that the upper envelope of the absolute value of the mean surface longitudinal field is directly correlated to the chromospheric emission from the star and increases with rotation rate and decreases with age.
A strong consensus is building on the need to slow the rate of climate change. Emissions must be reduced, and where emission reductions are not financially feasible, mechanisms need to be in place to allow investment in reductions in neighboring areas, neighboring countries, and across the Earth. Forests have a large potential role to play in this system, and the environmental, social, and economic benefits of investing in forests are high. However, challenges exist if we are to maximize the potential of forests to affect climate change.
What Are Offsets?
Greenhouse gas (GHG) emissions regulations typically place a cap on permitted emissions. It is unrealistic to expect industries and companies to immediately and drastically decrease GHG emissions. As a result, a system exists that allows entities that cannot sufficiently reduce their own emissions to invest elsewhere to stimulate emission reductions or increases in sequestration. The financial instrument is typically known as an offset and is measured by Mg carbon dioxide (CO2), or a carbon dioxide equivalent for non-CO2 GHGs (Mg CO2e), which have varying potentials to cause global warming.
Strabismus represents a complex oculomotor disorder characterized by the deviation of one or both eyes and poor vision. A more sophisticated understanding of the genetic liability of strabismus is required to guide searches for associated molecular variants. In this classical twin study of 1,462 twin pairs, we examined the relative influence of genes and environment in comitant strabismus, and the degree to which these influences can be explained by factors in common with refractive error. Participants were examined for the presence of latent (‘phoria’) and manifest (‘tropia’) strabismus using cover–uncover and alternate cover tests. Two phenotypes were distinguished: eso-deviation (esophoria and esotropia) and exo-deviation (exophoria and exotropia). Structural equation modeling was subsequently employed to partition the observed phenotypic variation in the twin data into specific variance components. The prevalence of eso-deviation and exo-deviation was 8.6% and 20.7%, respectively. For eso-deviation, the polychoric correlation was significantly greater in monozygotic (MZ) (r = 0.65) compared to dizygotic (DZ) twin pairs (r = 0.33), suggesting a genetic role (p = .003). There was no significant difference in polychoric correlation between MZ (r = 0.55) and DZ twin pairs (r = 0.53) for exo-deviation (p = .86), implying that genetic factors do not play a significant role in the etiology of exo-deviation. The heritability of an eso-deviation was 0.64 (95% CI 0.50–0.75). The additive genetic correlation for eso-deviation and refractive error was 0.13 and the bivariate heritability (i.e., shared variance) was less than 1%, suggesting negligible shared genetic effect. This study documents a substantial heritability of 64% for eso-deviation, yet no corresponding heritability for exo-deviation, suggesting that the genetic contribution to strabismus may be specific to eso-deviation. Future studies are now needed to identify the genes associated with eso-deviation and unravel their mechanisms of action.
Consumption of fruits and vegetables has been investigated for their role in the prevention of many chronic conditions. Among the fruits, mango provides numerous bioactive compounds such as carotenoids, vitamin C and phenolic compounds, which have been shown to have antioxidant and anti-inflammatory properties. The present study examined the effects of dietary supplementation of freeze-dried mango pulp, in comparison with the hypolipidaemic drug, fenofibrate, and the hypoglycaemic drug, rosiglitazone, in reducing adiposity and alterations in glucose metabolism and lipid profile in mice fed a high-fat (HF) diet. Male C57BL/6J mice were randomly divided into six treatment groups (eight to nine/group): control (10 % energy from fat); HF (60 % energy from fat); HF+1 or 10 % freeze-dried mango (w/w); HF+fenofibrate (500 mg/kg diet); HF+rosiglitazone (50 mg/kg diet). After 8 weeks of treatment, mice receiving the HF diet had a higher percentage body fat (P = 0·0205) and epididymal fat mass (P = 0·0037) compared with the other treatment groups. Both doses of freeze-dried mango, similar to fenofibrate and rosiglitazone, prevented the increase in epididymal fat mass and the percentage of body fat. Freeze-dried mango supplementation at the 1 % dose improved glucose tolerance as shown by approximately 35 % lower blood glucose area under the curve compared with the HF group. Moreover, freeze-dried mango lowered insulin resistance, as indicated by the homeostasis model assessment of insulin resistance, to a similar extent as rosiglitazone and modulated NEFA. The present findings demonstrate that incorporation of freeze-dried mango in the diet of mice improved glucose tolerance and lipid profile and reduced adiposity associated with a HF diet.
A key outcome of the Yuendumu studies has been a new way of conceptualising what constitutes so-called normal occlusal development and function in humans. This new view has important implications for dentistry and the management of dental problems. This chapter provides an overview of some of the main findings arising from the studies of Yuendumu Aboriginal people and highlights their implications for dental science and practice.
Anthropologists have extensively recorded population differences in the dentition in studies of comparative anatomy, human evolution and palaeo-pathology. Dentists must also consider the great variation in dental structures exhibited by members of a single population and by relatives within a family. The source of this variation is the interaction between genes and environment during the initial formation and subsequent growth of the masticatory structures. Even in the same individual, the arrangement of teeth within the dental arches and the manner in which they contact do not remain static throughout life but continually change in response to normal growth processes, environmental influences, dental treatment, pathology and ageing. Changes of this nature have particular relevance for the clinical dentist. Although significant advances in masticatory physiology have occurred in recent years, many concepts of dental occlusion retain an element of 19th century teleological thought. As Brace (1977) put it, “the idea of the perfect occlusion has shimmered in the imagination of the dental profession somewhat like the Holy Grail of Arthurian legend – the unattainable height of earthly aspiration”.
The end of field trips to Yuendumu and the post-1970 years
The early stages of the Yuendumu Growth Study received research funding from The University of Adelaide. From April 1964, the project received substantial support for a further seven years until March 1971 from a Public Health Service Grant of the United States Department of Health, Education and Welfare. The National Institute of Dental Research, Bethesda, Maryland, approved this grant.
Towards the end of the 1960s it was becoming apparent to Barrett and Brown that a decision was needed about whether to continue the yearly visits to Yuendumu after the grant expired or to stop and concentrate more on data analysis. Time was always a precious commodity, and so much of it was required to make the field trips worthwhile. The extensive organisation needed to plan the trips and the costs involved made it increasingly difficult to justify further visits to Yuendumu after the 1971 expedition. They reached the decision to stop the field trips after considering several factors. First and foremost was the vast accumulation of field records awaiting further analysis: 1,717 sets of dental casts representing 446 participants, 1169 sets of radiographs representing 288 individuals, as well as somatometric observations, family histories, photographs, and film and sound recordings.
Table 8.1 indicates the “longitudinality” of the records obtained between 1961 and 1971. For example, the third row shows that 31 children were 6 years of age at first examination.