Validity of weight loss to estimate improvement in body composition in individuals attending a wellness center

The accuracy of weight loss in estimating successful changes in body composition (BC), namely fat mass (FM) loss, is not known and was addressed in our study. To assess the correlation between change in body weight and change in FM, fat% and fat‐free mass (FFM), 465 participants (41% male; 41 ± 13 years), who met the criteria for weight change assessment at a wellness center, underwent air‐displacement plethysmography (ADP). Body weight and BC were measured at the same time. We categorized the change in body weight, FM and FFM as an increase if there was >1 kg gain, a decrease if there was >1 kg loss and no change if the difference was ≤1 kg. We estimated the diagnostic performance of weight change to identify improvement in BC. After a median time of 132 days, there was a mean weight change was 2.4 kg. From the 255 people who lost >1 kg of weight, 216 (84.7%) had lost >1 kg of FM, but 69 (27.1%) had lost >1 kg of FFM. Of the 143 people with no weight change, 42 (29.4%) had actually lost >1 kg of FM. Of the 67 who gained >1 kg of weight at follow‐up, in 23 (34.3%) this was due to an increase in FFM but not in FM. Weight change had a NPV of 73%. Our results indicate that favorable improvements in BC may go undetected in almost one‐third of people whose weight remains the same and in one‐third of people who gain weight after attending a wellness center. These results underscore the potential role of BC measurements in people attempting lifestyle changes.     

A novel synthetic smoothened antagonist transiently inhibits pancreatic adenocarcinoma xenografts in a mouse model

Background

Hedgehog (Hh) signaling is over-activated in several solid tumors where it plays a central role in cell growth, stroma recruitment and tumor progression. In the Hh signaling pathway, the Smoothened (SMO) receptor comprises a primary drug target with experimental small molecule SMO antagonists currently being evaluated in clinical trials.

Principal Findings

Using Shh-Light II (Shh-L2) and alkaline phosphatase (AP) based screening formats on a “focused diversity” library we identified a novel small molecule inhibitor of the Hh pathway, MS-0022 (2-bromo-N-(4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl)benzamide). MS-0022 showed effective Hh signaling pathway inhibition at the level of SMO in the low nM range, and Hh pathway inhibition downstream of Suppressor of fused (SUFU) in the low µM range. MS-0022 reduced growth in the tumor cell lines PANC-1, SUIT-2, PC-3 and FEMX in vitro. MS-0022 treatment led to a transient delay of tumor growth that correlated with a reduction of stromal Gli1 levels in SUIT-2 xenografts in vivo.

Significance

We document the in vitro and in vivo efficacy and bioavailability of a novel small molecule SMO antagonist, MS-0022. Although MS-0022 primarily interferes with Hh signaling at the level of SMO, it also has a downstream inhibitory effect and leads to a stronger reduction of growth in several tumor cell lines when compared to related SMO antagonists.     

Gene flow and population structure of a common agricultural wild species (Microtus agrestis) under different land management regimes

The impact of landscape structure and land management on dispersal of populations of wild species inhabiting the agricultural landscape was investigated focusing on the field vole (Microtus agrestis) in three different areas in Denmark using molecular genetic markers. The main hypotheses were the following: (i) organic farms act as genetic sources and diversity reservoirs for species living in agricultural areas and (ii) gene flow and genetic structure in the agricultural landscape are influenced by the degree of landscape complexity and connectivity. A total of 443 individual voles were sampled within 2 consecutive years from two agricultural areas and one relatively undisturbed grassland area. As genetic markers, 15 polymorphic microsatellite loci (nuclear markers) and the central part of the cytochrome-b (mitochondrial sequence) were analysed for all samples. The results indicate that management (that is, organic or conventional management) was important for genetic population structure across the landscape, but that landscape structure was the main factor shaping gene flow and genetic diversity. More importantly, the presence of organically managed areas did not act as a genetic reservoir for conventional areas, instead the most important predictor of effective population size was the amount of unmanaged available habitat (core area). The relatively undisturbed natural area showed a lower level of genetic structuring and genetic diversity compared with the two agricultural areas. These findings altogether suggest that political decisions for supporting wildlife friendly land management should take into account both management and landscape structure factors.     

Functional limits of agreement applied as a novel method comparison tool for accuracy and precision of inertial measurement unit derived displacement of the distal limb in horses

Over ground motion analysis in horses is limited by a small number of strides and restraints of the indoor gait laboratory. Inertial measurement units (IMUs) are transforming the knowledge of human motion and objective clinical assessment through the opportunity to obtain clinically relevant data under various conditions. When using IMUs on the limbs of horses to determine local position estimates, conditions with high dynamic range of both accelerations and rotational velocities prove particularly challenging. Here we apply traditional method agreement and suggest a novel method of functional data analysis to compare motion capture with IMUs placed over the fetlock joint in seven horses. We demonstrate acceptable accuracy and precision at less than or equal to 5% of the range of motion for detection of distal limb mounted cranio-caudal and vertical position. We do not recommend the use of the latero-medial position estimate of the distal metacarpus/metatarsus during walk where the average error is 10% and the maximum error 111% of the range. We also show that functional data analysis and functional limits of agreement are sensitive methods for comparison of cyclical data and could be applied to differentiate changes in gait for individuals across time and conditions.     

Protein stability, flexibility and function

Proteins rely on flexibility to respond to environmental changes, ligand binding and chemical modifications. Potentially, a perturbation that changes the flexibility of a protein may interfere with its function. Millions of mutations have been performed on thousands of proteins in quests for a delineation of the molecular details of their function. Several of these mutations interfered with the binding of a specific ligand with a concomitant effect on the stability of the protein scaffold. It has been ambiguous and not straightforward to recognize if any relationships exist between the stability of a protein and the affinity for its ligand. In this review, we present examples of proteins where changes in stability results in changes in affinity and of proteins where stability and affinity are uncorrelated. We discuss the possibility for a relationship between stability and binding. From the data presented is it clear that there are specific sites (flexibility hotspots) in proteins that are important for both binding and stability. This article is part of a Special Issue entitled: Protein Dynamics: Experimental and Computational Approaches.     

Egg‐size plasticity in Apis mellifera: Honey bee queens alter egg size in response to both genetic and environmental factors

Social evolution has led to distinct life‐history patterns in social insects, but many colony‐level and individual traits, such as egg size, are not sufficiently understood. Thus, a series of experiments was performed to study the effects of genotypes, colony size and colony nutrition on variation in egg size produced by honey bee (Apis mellifera) queens. Queens from different genetic stocks produced significantly different egg sizes under similar environmental conditions, indicating standing genetic variation for egg size that allows for adaptive evolutionary change. Further investigations revealed that eggs produced by queens in large colonies were consistently smaller than eggs produced in small colonies, and queens dynamically adjusted egg size in relation to colony size. Similarly, queens increased egg size in response to food deprivation. These results could not be solely explained by different numbers of eggs produced in the different circumstances but instead seem to reflect an active adjustment of resource allocation by the queen in response to colony conditions. As a result, larger eggs experienced higher subsequent survival than smaller eggs, suggesting that honey bee queens might increase egg size under unfavourable conditions to enhance brood survival and to minimize costly brood care of eggs that fail to successfully develop, and thus conserve energy at the colony level. The extensive plasticity and genetic variation of egg size in honey bees has important implications for understanding life‐history evolution in a social context and implies this neglected life‐history stage in honey bees may have trans‐generational effects.