A deletion containing a CTCF-element in intron 8 of the Bbs7 gene is partially responsible for juvenile obesity in the Berlin Fat Mouse

Mammalian Genome - The Berlin Fat Mouse Inbred (BFMI) line is a model for juvenile obesity. Previous studies on crosses between BFMI and C57Bl/6N (B6N) have identified a recessive defect causing...     

Genetic determinants for intramuscular fat content and water-holding capacity in mice selected for high muscle mass

Intramuscular fat content and water-holding capacity are important traits in livestock as they influence meat quality, nutritive value of the muscle, and animal health. As a model for livestock, two inbred lines of the Berlin Muscle Mouse population, which had been long-term selected for high muscle mass, were used to identify genomic regions affecting intramuscular fat content and water-holding capacity. The intramuscular fat content of the Musculus longissimus was on average 1.4 times higher in BMMI806 than in BMMI816 mice. This was accompanied by a 1.5 times lower water-holding capacity of the Musculus quadriceps in BMMI816 mice. Linkage analyses with 332 G₃ animals of reciprocal crosses between these two lines revealed quantitative trait loci for intramuscular fat content on chromosome 7 and for water-holding capacity on chromosome 2. In part, the identified loci coincide with syntenic regions in pigs in which genetic effects for the same traits were found. Therefore, these muscle-weight-selected mouse lines and the produced intercross populations are valuable genetic resources to identify genes that could also contribute to meat quality in other species.     

Poor trail making test performance is directly associated with altered dual task prioritization in the elderly--baseline results from the TREND study

Background

Deterioration of executive functions in the elderly has been associated with impairments in walking performance. This may be caused by limited cognitive flexibility and working memory, but could also be caused by altered prioritization of simultaneously performed tasks. To disentangle these options we investigated the associations between Trail Making Test performance—which specifically measures cognitive flexibility and working memory—and dual task costs, a measure of prioritization.

Methodology and Principal Findings

Out of the TREND study (Tuebinger evaluation of Risk factors for Early detection of Neurodegenerative Disorders), 686 neurodegeneratively healthy, non-demented elderly aged 50 to 80 years were classified according to their Trail Making Test performance (delta TMT; TMT-B minus TMT-A). The subjects performed 20 m walks with habitual and maximum speed. Dual tasking performance was tested with walking at maximum speed, in combination with checking boxes on a clipboard, and subtracting serial 7 s at maximum speeds. As expected, the poor TMT group performed worse when subtracting serial 7 s under single and dual task conditions, and they walked more slowly when simultaneously subtracting serial 7 s, compared to the good TMT performers. In the walking when subtracting serial 7 s condition but not in the other 3 conditions, dual task costs were higher in the poor TMT performers (median 20%; range −6 to 58%) compared to the good performers (17%; −16 to 43%; p<0.001). To the contrary, the proportion of the poor TMT performance group that made calculation errors under the dual tasking situation was lower than under the single task situation, but higher in the good TMT performance group (poor performers, −1.6%; good performers, +3%; p = 0.035).

Conclusion

Under most challenging conditions, the elderly with poor TMT performance prioritize the cognitive task at the expense of walking velocity. This indicates that poor cognitive flexibility and working memory are directly associated with altered prioritization.     

Micro-CT based experimental liver imaging using a nanoparticulate contrast agent: a longitudinal study in mice

Background

Micro-CT imaging of liver disease in mice relies on high soft tissue contrast to detect small lesions like liver metastases. Purpose of this study was to characterize the localization and time course of contrast enhancement of a nanoparticular alkaline earth metal-based contrast agent (VISCOVER ExiTron nano) developed for small animal liver CT imaging.

Methodology

ExiTron nano 6000 and ExiTron nano 12000, formulated for liver/spleen imaging and angiography, respectively, were intravenously injected in C57BL/6J-mice. The distribution and time course of contrast enhancement were analysed by repeated micro-CT up to 6 months. Finally, mice developing liver metastases after intrasplenic injection of colon carcinoma cells underwent longitudinal micro-CT imaging after a single injection of ExiTron nano.

Principal Findings

After a single injection of ExiTron nano the contrast of liver and spleen peaked after 4–8 hours, lasted up to several months and was tolerated well by all mice. In addition, strong contrast enhancement of abdominal and mediastinal lymph nodes and the adrenal glands was observed. Within the first two hours after injection, particularly ExiTron nano 12000 provided pronounced contrast for imaging of vascular structures. ExiTron nano facilitated detection of liver metastases and provided sufficient contrast for longitudinal observation of tumor development over weeks.

Conclusions

The nanoparticulate contrast agents ExiTron nano 6000 and 12000 provide strong contrast of the liver, spleen, lymph nodes and adrenal glands up to weeks, hereby allowing longitudinal monitoring of pathological processes of these organs in small animals, with ExiTron nano 12000 being particularly optimized for angiography due to its very high initial vessel contrast.     

Reduced food intake and body weight in mice deficient for the G protein-coupled receptor GPR82

G protein-coupled receptors (GPCR) are involved in the regulation of numerous physiological functions. Therefore, GPCR variants may have conferred important selective advantages during periods of human evolution. Indeed, several genomic loci with signatures of recent selection in humans contain GPCR genes among them the X-chromosomally located gene for GPR82. This gene encodes a so-called orphan GPCR with unknown function. To address the functional relevance of GPR82 gene-deficient mice were characterized. GPR82-deficient mice were viable, reproduced normally, and showed no gross anatomical abnormalities. However, GPR82-deficient mice have a reduced body weight and body fat content associated with a lower food intake. Moreover, GPR82-deficient mice showed decreased serum triacylglyceride levels, increased insulin sensitivity and glucose tolerance, most pronounced under Western diet. Because there were no differences in respiratory and metabolic rates between wild-type and GPR82-deficient mice our data suggest that GPR82 function influences food intake and, therefore, energy and body weight balance. GPR82 may represent a thrifty gene most probably representing an advantage during human expansion into new environments.     

Expansion of the Multi-Link Frontier™ coronary bifurcation stent: micro-computed tomographic assessment in human autopsy and porcine heart samples

Background

Treatment of coronary bifurcation lesions remains challenging, beyond the introduction of drug eluting stents. Dedicated stent systems are available to improve the technical approach to the treatment of these lesions. However dedicated stent systems have so far not reduced the incidence of stent restenosis. The aim of this study was to assess the expansion of the Multi-Link (ML) Frontier™ stent in human and porcine coronary arteries to provide the cardiologist with useful in-vitro information for stent implantation and selection.

Methodology/Principal Findings

Nine ML Frontier™ stents were implanted in seven human autopsy heart samples with known coronary artery disease and five ML Frontier™ stents were implanted in five porcine hearts. Proximal, distal and side branch diameters (PD, DD, SBD, respectively), corresponding opening areas (PA, DA, SBA) and the mean stent length (L) were assessed by micro-computed tomography (micro-CT). PD and PA were significantly smaller in human autopsy heart samples than in porcine heart samples (3.54±0.47 mm vs. 4.04±0.22 mm, p = 0.048; 10.00±2.42 mm² vs. 12.84±1.38 mm², p = 0.034, respectively) and than those given by the manufacturer (3.54±0.47 mm vs. 4.03 mm, p = 0.014). L was smaller in human autopsy heart samples than in porcine heart samples, although data did not reach significance (16.66±1.30 mm vs. 17.30±0.51 mm, p = 0.32), and significantly smaller than that given by the manufacturer (16.66±1.30 mm vs. 18 mm, p = 0.015).

Conclusions/Significance

Micro-CT is a feasible tool for exact surveying of dedicated stent systems and could make a contribution to the development of these devices. The proximal diameter and proximal area of the stent system were considerably smaller in human autopsy heart samples than in porcine heart samples and than those given by the manufacturer. Special consideration should be given to the stent deployment procedure (and to the follow-up) of dedicated stent systems, considering final intravascular ultrasound or optical coherence tomography to visualize (and if necessary optimize) stent expansion.     

The solution structure of the SODD BAG domain reveals additional electrostatic interactions in the HSP70 complexes of SODD subfamily BAG domains

The solution structure of an N-terminally extended construct of the SODD BAG domain was determined by nuclear magnetic resonance spectroscopy. A homology model of the SODD-BAG/HSP70 complex reveals additional possible interactions that are specific for the SODD subfamily of BAG domains while the overall geometry of the complex remains the same. Relaxation rate measurements show that amino acids N358-S375 of SODD which were previously assigned to its BAG domain are not structured in our construct. The SODD BAG domain is thus indeed smaller than the homologous domain in Bag1 defining a new subfamily of BAG domains.     

Human high temperature requirement serine protease A1 (HTRA1) degrades tau protein aggregates

Protective proteases are key elements of protein quality control pathways that are up-regulated, for example, under various protein folding stresses. These proteases are employed to prevent the accumulation and aggregation of misfolded proteins that can impose severe damage to cells. The high temperature requirement A (HtrA) family of serine proteases has evolved to perform important aspects of ATP-independent protein quality control. So far, however, no HtrA protease is known that degrades protein aggregates. We show here that human HTRA1 degrades aggregated and fibrillar tau, a protein that is critically involved in various neurological disorders. Neuronal cells and patient brains accumulate less tau, neurofibrillary tangles, and neuritic plaques, respectively, when HTRA1 is expressed at elevated levels. Furthermore, HTRA1 mRNA and HTRA1 activity are up-regulated in response to elevated tau concentrations. These data suggest that HTRA1 is performing regulated proteolysis during protein quality control, the implications of which are discussed.