Abstract Objectives Prophylactic aortic root replacement improves survival in patients with Marfan syndrome with aortic root aneurysms, but the optimal procedure remains undefined. Methods Adult ...patients with Marfan syndrome who had Bentall or aortic valve-sparing root replacement (VSRR) procedures between 1997 and 2013 were identified. Comprehensive follow-up information was obtained from hospital charts and telephone contact. Results One hundred sixty-five adult patients with Marfan syndrome (aged > 20 years) had either VSRR (n = 98; 69 reimplantation, 29 remodeling) or Bentall (n = 67) procedures. Patients undergoing Bentall procedure were older (median, 37 vs 36 years; P = .03), had larger median preoperative sinus diameter (5.5 cm vs 5.0 cm; P = .003), more aortic dissections (25.4% vs 4.1%; P < .001), higher incidence of moderate or severe aortic insufficiency (49.3% vs 14.4%; P < .001) and more urgent or emergent operations (24.6% vs 3.3%; P < .001). There were no hospital deaths and 9 late deaths in more than 17 years of follow-up (median, 7.8 deaths). Ten-year survival was 90.5% in patients undergoing Bentall procedure and 96.3% in patients undergoing VSRR ( P = .10). Multivariable analysis revealed that VSRR was associated with fewer thromboembolic or hemorrhagic events (hazard ratio, 0.16; 95% confidence interval, 0.03-0.85; P = .03). There was no independent difference in long-term survival, freedom from reoperation, or freedom from endocarditis between the 2 procedures. Conclusions After prophylactic root replacement in patients with Marfan syndrome, patients undergoing Bentall and valve-sparing procedures have similar late survival, freedom from root reoperation, and freedom from endocarditis. However, valve-sparing procedures result in significantly fewer thromboembolic and hemorrhagic events.
Loss-of-function mutations in progranulin (GRN), a secreted glycoprotein expressed by neurons and microglia, are a common autosomal dominant cause of frontotemporal dementia, a neurodegenerative ...disease commonly characterized by disrupted social and emotional behaviour. GRN mutations are thought to cause frontotemporal dementia through progranulin haploinsufficiency, therefore, boosting progranulin expression from the intact allele is a rational treatment strategy. However, this approach has not been tested in an animal model of frontotemporal dementia and it is unclear if boosting progranulin could correct pre-existing deficits. Here, we show that adeno-associated virus-driven expression of progranulin in the medial prefrontal cortex reverses social dominance deficits in Grn+/- mice, an animal model of frontotemporal dementia due to GRN mutations. Adeno-associated virus-progranulin also corrected lysosomal abnormalities in Grn+/- mice. The adeno-associated virus-progranulin vector only transduced neurons, suggesting that restoring neuronal progranulin is sufficient to correct deficits in Grn+/- mice. To further test the role of neuronal progranulin in the development of frontotemporal dementia-related deficits, we generated two neuronal progranulin-deficient mouse lines using CaMKII-Cre and Nestin-Cre. Measuring progranulin levels in these lines indicated that most brain progranulin is derived from neurons. Both neuronal progranulin-deficient lines developed social dominance deficits similar to those in global Grn+/- mice, showing that neuronal progranulin deficiency is sufficient to disrupt social behaviour. These data support the concept of progranulin-boosting therapies for frontotemporal dementia and highlight an important role for neuron-derived progranulin in maintaining normal social function.
Frontotemporal dementia (FTD) is a neurodegenerative disease with hallmark deficits in social and emotional function. Heterozygous loss-of-function mutations in GRN, the progranulin gene, are a ...common genetic cause of the disorder, but the mechanisms by which progranulin haploinsufficiency causes neuronal dysfunction in FTD are unclear. Homozygous progranulin knock-out (Grn(-/-)) mice have been studied as a model of this disorder and show behavioral deficits and a neuroinflammatory phenotype with robust microglial activation. However, homozygous GRN mutations causing complete progranulin deficiency were recently shown to cause a different neurological disorder, neuronal ceroid lipofuscinosis, suggesting that the total absence of progranulin may have effects distinct from those of haploinsufficiency. Here, we studied progranulin heterozygous (Grn(+/-)) mice, which model progranulin haploinsufficiency. We found that Grn(+/-) mice developed age-dependent social and emotional deficits potentially relevant to FTD. However, unlike Grn(-/-) mice, behavioral deficits in Grn(+/-) mice occurred in the absence of gliosis or increased expression of tumor necrosis factor-α. Instead, we found neuronal abnormalities in the amygdala, an area of selective vulnerability in FTD, in Grn(+/-) mice. Our findings indicate that FTD-related deficits resulting from progranulin haploinsufficiency can develop in the absence of detectable gliosis and neuroinflammation, thereby dissociating microglial activation from functional deficits and suggesting an important effect of progranulin deficiency on neurons.
Based on daily collections of final instar exuviae, the widespread annual cicada adult emergence of Neotibicen canicularis (Harris) (Hemiptera: Cicadidae) was studied in southeastern Wisconsin in a ...combined plot containing 15 mature trees and suburban lawns for seven successive years and in a separate plot of two trees for four years. The daily numbers of males and females were recorded. Over the entire seven years of the 15-tree plot, total female and male exuviae were equal, a summative 50:50 ratio. However, there was considerable deviation from this ratio three of the seven years. More females than males eclosed in the first two years and more males eclosed in the final year, yet the overall trend was for females to eclose later than males for the entire seven-year study of the 15-tree plot, with many more females emerging in the last twenty plus days. Although ambient temperatures varied over the study (cooler in the first two years and warmer later), they did not have any discernible effect on the timing of female and male eclosions. The overall annual emergence period was 56.7 (se 4.48) d for a seven-year total of 2967 exuviae, with the annual average emergence being 437.6 (se 34.6) per year. The average density of exuviae, an estimate of the emerging adult population, was 1.3 ± 0.09 (se) per m2. In the separate two-tree plot, a greater number of males emerged than females for all four years. ARISTOTLE ADVISES: “Male cicadas are tastier when young, but the females are preferable later when they are full of eggs.”
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Structured abstract Background Despite evidence that bilateral internal thoracic arteries (ITAs) improve long-term survival after coronary artery bypass grafting (CABG), uptake of this technique ...remains low. We directly compared bilateral ITA graft configurations and examined long-term outcomes. Methods We reviewed 762 patients who had CABG using bilateral ITA grafts at our institution between 1997 and 2014. The outcomes were mortality and a composite revascularization endpoint defined as need for percutaneous coronary intervention (PCI) or repeat CABG. Adjusted sub-group analyses were performed using propensity score-adjusted Cox proportional hazards modeling. Results The cohort was divided into four groups: in situ (IS) left ITA (LITA) anastomosed to the left anterior descending artery (LAD) with IS right ITA (RITA) anastomosed to the left coronary circulation (“LL/RL”, 239 patients); IS LITA-LAD and IS RITA-right coronary circulation (“LL/RR”, 239 patients); IS RITA-LAD with IS LITA-left coronary circulation (“RL/LL”, 185 patients); and IS LITA-LAD with a free RITA as a composite graft with inflow from the LITA or a saphenous vein graft (“composite/Y”, 99 patients). Over a median follow-up of 1128 days, there were 47 deaths, 58 late PCIs, and 7 repeat CABGs. Unadjusted Kaplan-Meier analysis revealed a difference in need for repeat revascularization among the four groups (log rank P=0.049). However, after statistical adjustment, graft configuration was not an independent predictor of repeat revascularization or death. Conclusions BITA graft configuration has no independent effect on need for repeat revascularization or long-term survival. Therefore, the simplest technique, determined by individual patient characteristics, should be selected.
Loss-of-function mutations in progranulin (GRN), most of which cause progranulin haploinsufficiency, are a major autosomal dominant cause of frontotemporal dementia (FTD). Individuals with ...loss-of-function mutations on both GRN alleles develop neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder. Progranulin is a secreted glycoprotein expressed by a variety of cell types throughout the body, including neurons and microglia in the brain. Understanding the relative importance of neuronal and microglial progranulin insufficiency in FTD pathogenesis may guide development of therapies. In this study, we used mouse models to investigate the role of neuronal and microglial progranulin insufficiency in the development of FTD-like pathology and behavioral deficits. Grn−/− mice model aspects of FTD and NCL, developing lipofuscinosis and gliosis throughout the brain, as well as deficits in social behavior. We have previously shown that selective depletion of neuronal progranulin disrupts social behavior, but does not produce lipofuscinosis or gliosis. We hypothesized that reduction of microglial progranulin would induce lipofuscinosis and gliosis, and exacerbate behavioral deficits, in neuronal progranulin-deficient mice. To test this hypothesis, we crossed Grnfl/fl mice with mice expressing Cre transgenes targeting neurons (CaMKII-Cre) and myeloid cells/microglia (LysM-Cre). CaMKII-Cre, which is expressed in forebrain excitatory neurons, reduced cortical progranulin protein levels by around 50%. LysM-Cre strongly reduced progranulin immunolabeling in many microglia, but did not reduce total brain progranulin levels, suggesting that, at least under resting conditions, microglia contribute less than neurons to overall brain progranulin levels. Mice with depletion of both neuronal and microglial progranulin failed to develop lipofuscinosis or gliosis, suggesting that progranulin from extracellular sources prevented pathology in cells targeted by the Cre transgenes. Reduction of microglial progranulin also did not exacerbate the social deficits of neuronal progranulin-insufficient mice. These results do not support the hypothesis of synergistic effects between progranulin-deficient neurons and microglia. Nearly complete progranulin deficiency appears to be required to induce lipofuscinosis and gliosis in mice, while partial progranulin insufficiency is sufficient to produce behavioral deficits.
•Depletion of neuronal progranulin reduces cortical progranulin levels by 50%.•Reduction of microglial progranulin using LysM-Cre does not substantially further reduce overall brain progranulin levels.•Reduction of both neuronal and microglial progranulin does not cause lipofuscinosis.•Depletion of neuronal progranulin causes social deficits.•Reduction of microglial progranulin elevates compulsive grooming behavior.
Transcriptional dysregulation of the MYC oncogene is among the most frequent events in aggressive tumor cells, and this is generally accomplished by acquisition of a super-enhancer somewhere within ...the 2.8 Mb TAD where MYC resides. We find that these diverse cancer-specific super-enhancers, differing in size and location, interact with the MYC gene through a common and conserved CTCF binding site located 2 kb upstream of the MYC promoter. Genetic perturbation of this enhancer-docking site in tumor cells reduces CTCF binding, super-enhancer interaction, MYC gene expression, and cell proliferation. CTCF binding is highly sensitive to DNA methylation, and this enhancer-docking site, which is hypomethylated in diverse cancers, can be inactivated through epigenetic editing with dCas9-DNMT. Similar enhancer-docking sites occur at other genes, including genes with prominent roles in multiple cancers, suggesting a mechanism by which tumor cell oncogenes can generally hijack enhancers. These results provide insights into mechanisms that allow a single target gene to be regulated by diverse enhancer elements in different cell types.
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•Tumor-specific super-enhancers loop to an enhancer-docking site at the MYC oncogene•Deletion or methylation of MYC enhancer-docking site reduces enhancer-promoter looping•MYC enhancer-docking site provides common vulnerability in diverse cancer cells•Similar docking sites for multiple enhancers occur at additional genes
Schuijers et al. show that a conserved CTCF site at the promoter of the MYC oncogene plays an important role in enhancer-promoter looping with tumor-specific super-enhancers. Perturbation of this site provides a potential therapeutic vulnerability.
Abstract
Alfalfa is a commonly grown forage in the Intermountain West region of the United States and is often included in the diet of dairy cattle. Alfalfa provides a variety of different nutrients, ...but the nutrient content of alfalfa varies depending on factors such as the soil, region, cutting, and climate. However, alfalfa leaves tend to have less variation in their nutrient content than alfalfa stems. Fractionating alfalfa may be one way to improve control of nutrients provided when developing a ration for developing dairy heifers. The purpose of this study was to determine whether including fractionated alfalfa in the diet impacts the growth or conception rates of developing dairy heifers. Heifers were allocated to one of three treatments: a control group fed a typical diet (CON; n = 8), a diet that replaced alfalfa with fractionated alfalfa leaf pellets and alfalfa stems (ProLEAF MAX + ProFiber Plus; PLM + PFP; n = 8), or a diet that replaced alfalfa with alfalfa stems (PFP; n = 8) for 85 d. Heifers were fed individually twice daily and weight, hip height (HH), and wither height (WH) were recorded every 14 d. Additionally, blood was collected every 28 d, and conception rates were recorded at the end of the trial. Heifers receiving the PFP diet consumed less dry matter (P = 0.001) than the CON treatment. Analyses were then conducted to determine nutrient intake and heifers receiving the PFP diet also consumed less neutral detergent fiber (P = 0.02), acid detergent fiber (P = 0.02), crude protein (P = 0.001), and net energy for maintenance (P = 0.001) than heifers consuming the CON diet; however, no differences (P > 0.10) were observed between heifers fed the CON and PLM + PFP diets. Analysis of body weight gain over the feeding period showed no difference (P = 0.52) among heifers consuming the different treatment diets. Additionally, treatment did not affect average daily gain (P = 0.49), gain:feed (P = 0.82), HH gain (P = 0.20), or WH gain (P = 0.44) among heifers receiving different diets. Treatment × time altered (P < 0.001) blood urea nitrogen when analyzed as a repeated measure. Total feed cost was lowest (P < 0.001) for the PFP diet and cost of gain tended (P = 0.09) to be increased for the PLM + PFP diet compared to the CON diet. Overall, these data indicate that including alfalfa stems in a developing heifer diet may decrease dry matter intake, lower input costs, and increase profitability, without negatively impacting growth.
Fractionating alfalfa into leaf pellets and stems may be an option for producers to have more control of nutrients when formulating diets for developing heifers. The results of this study suggest that including alfalfa stems in the diet of developing heifers may decrease dry matter intake and lower input costs, without negatively impacting growth or development.
Lay Summary
In the Intermountain West of the United States, alfalfa is a common feedstuff in the diet of dairy cattle. Alfalfa is a relatively nutrient-dense forage, but nutrient content varies with soil, region, cutting, and climate. However, alfalfa leaves have a less variable nutrient content than alfalfa stems. Fractionating alfalfa into leaves and stems could improve control of nutrients when formulating diets. The purpose of this research was to determine whether including fractionated alfalfa in developing dairy heifer diets impacts growth or conception rate. To test this, 24 Holstein heifers of similar age and weight were fed a typical diet, a diet including alfalfa leaf pellets and alfalfa stems, or a diet including alfalfa stems for 90 d. No differences in body growth measurements or feed efficiency were observed, but heifers getting the diet with alfalfa stems had a lower dry matter intake than those receiving the typical ration. Total feed costs were lowest for heifers getting alfalfa stems, and the cost of gain tended to be highest for heifers getting both alfalfa leaves and stems. Overall, these data show that including alfalfa stems in a developing heifer diet may decrease dry matter intake, lower input costs, and increase profitability, without negatively impacting growth.
"Young... brings the trained eye of an entomologist and an unabashed admiration for the beauty of nature to this engaging and informative account of his experiences during twenty-one years of ...fieldwork in Costa Rica's rainforests."— Publishers Weekly "A splendid read. For newcomers to the moist tropics, and for any but the most sated old-timers, it can be commended for an entertaining account of a locality where life is lived to the full—by all species, including the human observer."—Norman Myers, New Scientist The abundant insect life of the rainforests of northeastern Costa Rica is the subject of this engaging book, first published over twenty-five years ago and now including two new chapters on the rise of ecotourism in the region.
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