Dodecyl Maltoside Protects Membrane Proteins In Vacuo

Molecular dynamics simulations have been used to characterize the effects of transfer from aqueous solution to a vacuum to inform our understanding of mass spectrometry of membrane-protein-detergent complexes. We compared two membrane protein architectures (an α-helical bundle versus a β-barrel) and two different detergent types (phosphocholines versus an alkyl sugar) with respect to protein stability and detergent packing. The β-barrel membrane protein remained stable as a protein-detergent complex in vacuum. Zwitterionic detergents formed conformationally destabilizing interactions with an α-helical membrane protein after detergent micelle inversion driven by dehydration in vacuum. In contrast, a nonionic alkyl sugar detergent resisted micelle inversion, maintaining the solution-phase conformation of the protein. This helps to explain the relative stability of membrane proteins in the presence of alkyl sugar detergents such as dodecyl maltoside.     

PIK3R1 Mutations Cause Syndromic Insulin Resistance with Lipoatrophy

Short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay (SHORT) syndrome is a developmental disorder with an unknown genetic cause and hallmarks that include insulin resistance and lack of subcutaneous fat. We ascertained two unrelated individuals with SHORT syndrome, hypothesized that the observed phenotype was most likely due to de novo mutations in the same gene, and performed whole-exome sequencing in the two probands and their unaffected parents. We then confirmed our initial observations in four other subjects with SHORT syndrome from three families, as well as 14 unrelated subjects presenting with syndromic insulin resistance and/or generalized lipoatrophy associated with dysmorphic features and growth retardation. Overall, we identified in nine affected individuals from eight families de novo or inherited PIK3R1 mutations, including a mutational hotspot (c.1945C>T [p.Arg649Trp]) present in four families. PIK3R1 encodes the p85α, p55α, and p50α regulatory subunits of class IA phosphatidylinositol 3 kinases (PI3Ks), which are known to play a key role in insulin signaling. Functional data from fibroblasts derived from individuals with PIK3R1 mutations showed severe insulin resistance for both proximal and distal PI3K-dependent signaling. Our findings extend the genetic causes of severe insulin-resistance syndromes and provide important information with respect to the function of PIK3R1 in normal development and its role in human diseases, including growth delay, Rieger anomaly and other ocular affections, insulin resistance, diabetes, paucity of fat, and ovarian cysts.     

Dual effect of chemokine CCL7/MCP-3 in the development of renal tubulointerstitial fibrosis

Most end-stage renal disease kidneys display accumulation of extracellular matrix (ECM) in the renal tubular compartment (tubular interstitial fibrosis – TIF) which is strongly correlated with the future loss of renal function. Although inflammation is a key event in the development of TIF, it can also have a beneficial anti-fibrotic role depending in particular on the stage of the pathology. Chemokines play an important role in monocyte extravasation in the inflammatory process. CCL2 has already been shown to be involved in the development of TIF but CCL7, a close relative of CCL2 and able to bind to similar receptors, has not been studied in renal disease. We therefore studied chemokine CCL7 in a model of unilateral ureteral obstruction (UUO)-induced TIF. We observed that the role of CCL7 differs depending on the stage of the pathology. In early stages (0–8 days), CCL7 deficient (CCL7-KO) mice displayed attenuated TIF potentially involving two mechanisms: an early (0–3 days) decrease of inflammatory cell infiltration followed (3–8 days) by a decrease in tubular ECM production independent of inflammation. In contrast, during later stages of obstruction (10–14 days), CCL7-KO mice displayed increased TIF which was again associated with reduced inflammation. Interestingly, the switch between this anti- to profibrotic effect was accompanied by an increased influx of immunosuppressive regulatory T cells. In conclusion, these results highlight for the first time a dual role for CCL7 in the development of renal TIF, deleterious in early stages but beneficial during later stages.     

Eumelanin‐based colouration reflects local survival of juvenile feral pigeons in an urban pigeon house

Urbanisation introduces deep changes in habitats, eventually creating new urban ecosystems where ecological functions are driven by human activities. The higher frequency of some phenotypes in urban vs rural/wild areas has led to the assumption that directional selection in urban habitats occurs, which may thereby favour some behavioural and physiological traits in urban animal populations compared to rural ones. However, empirical evidence of directional selection on phenotypic traits in urban areas remains scarce. In this study we tested whether eumelanin‐based colouration could be linked to survival in two urban populations of the feral pigeon Columba livia. A number of studies in different cities pointed out a higher frequency of darker individuals in more urbanised areas compared to rural ones. To investigate whether directional selection through survival on this highly heritable trait could explain such patterns, we conducted mark–recapture studies on two populations of feral pigeons in highly urbanized areas. We predicted that darker coloured individuals would exhibit higher survival and/or philopatry (integrated into ‘local survival’) than paler coloured ones. No difference in local survival was found between adults of different colouration intensities. However, on one site, we found that darker juveniles had a higher local survival probability than light ones. Juvenile local survival on that site was also negatively correlated with the number of chicks born. This suggests the existence of colour‐ and/or density‐dependent selection processes acting on juvenile feral pigeons in urban environments, acting through differential mortality and/or dispersal.     

Stereospecific assignments in proteins using exact NOEs

Recently developed methods to measure distances in proteins with high accuracy by “exact” nuclear Overhauser effects (eNOEs) make it possible to determine stereospecific assignments, which are particularly important to fully exploit the accuracy of the eNOE distance measurements. Stereospecific assignments are determined by comparing the eNOE-derived distances to protein structure bundles calculated without stereospecific assignments, or an independently determined crystal structure. The absolute and relative CYANA target function difference upon swapping the stereospecific assignment of a diastereotopic group yields the respective stereospecific assignment. We applied the method to the eNOE data set that has recently been obtained for the third immunoglobulin-binding domain of protein G (GB3). The 884 eNOEs provide relevant data for 47 of the total of 75 diastereotopic groups. Stereospecific assignments could be established for 45 diastereotopic groups (96 %) using the X-ray structure, or for 27 diastereotopic groups (57 %) using structures calculated with the eNOE data set without stereospecific assignments, all of which are in agreement with those determined previously. The latter case is relevant for structure determinations based on eNOEs. The accuracy of the eNOE distance measurements is crucial for making stereospecific assignments because applying the same method to the traditional NOE data set for GB3 with imprecise upper distance bounds yields only 13 correct stereospecific assignments using the X-ray structure or 2 correct stereospecific assignments using NMR structures calculated without stereospecific assignments.     

Phylogenetic plant community structure along elevation is lineage specific

The trend of closely related taxa to retain similar environmental preferences mediated by inherited traits suggests that several patterns observed at the community scale originate from longer evolutionary processes. While the effects of phylogenetic relatedness have been previously studied within a single genus or family, lineage‐specific effects on the ecological processes governing community assembly have rarely been studied for entire communities or flora. Here, we measured how community phylogenetic structure varies across a wide elevation gradient for plant lineages represented by 35 families, using a co‐occurrence index and net relatedness index (NRI). We propose a framework that analyses each lineage separately and reveals the trend of ecological assembly at tree nodes. We found prevailing phylogenetic clustering for more ancient nodes and overdispersion in more recent tree nodes. Closely related species may thus rapidly evolve new environmental tolerances to radiate into distinct communities, while older lineages likely retain inherent environmental tolerances to occupy communities in similar environments, either through efficient dispersal mechanisms or the exclusion of older lineages with more divergent environmental tolerances. Our study illustrates the importance of disentangling the patterns of community assembly among lineages to better interpret the ecological role of traits. It also sheds light on studies reporting absence of phylogenetic signal, and opens new perspectives on the analysis of niche and trait conservatism across lineages.     

Patient oriented graph-based image segmentation

Despite increased image quality including medical imaging, image segmentation continues to represent a major bottleneck in practical applications due to noise and lack of contrast. In this paper, we present a new methodology to segment noisy, low contrast medical images, with a view to developing practical applications. Firstly, the contrast of the image is enhanced and then a modified graph-based method is followed. This paper has mainly two contributions: (1) a contrast enhancement stage performed by suitably utilizing the noise present in the medical data. This step is achieved through stochastic resonance theory applied in the wavelet domain and (2) a new weighting function is proposed for traditional graph-based approaches. Both qualitative (by our clinicians/radiologists) and quantitative evaluation performed on publicly available computed tomography (CT) (MICCAI 2007 Grand Challenge workshop database) and cardiac magnetic resonance (CMR) databases reflect the potential of the proposed method even in the presence of tumors/papillary muscles.     

Accounting for Age Uncertainty in Growth Modeling,the Case Study of Yellowfin Tuna (Thunnus albacares) of the Indian Ocean

Age estimates, typically determined by counting periodic growth increments in calcified structures of vertebrates, are the basis of population dynamics models used for managing exploited or threatened species. In fisheries research, the use of otolith growth rings as an indicator of fish age has increased considerably in recent decades. However, otolith readings include various sources of uncertainty. Current ageing methods, which converts an average count of rings into age, only provide periodic age estimates in which the range of uncertainty is fully ignored. In this study, we describe a hierarchical model for estimating individual ages from repeated otolith readings. The model was developed within a Bayesian framework to explicitly represent the sources of uncertainty associated with age estimation, to allow for individual variations and to include knowledge on parameters from expertise. The performance of the proposed model was examined through simulations, and then it was coupled to a two-stanza somatic growth model to evaluate the impact of the age estimation method on the age composition of commercial fisheries catches. We illustrate our approach using the saggital otoliths of yellowfin tuna of the Indian Ocean collected through large-scale mark-recapture experiments. The simulation performance suggested that the ageing error model was able to estimate the ageing biases and provide accurate age estimates, regardless of the age of the fish. Coupled with the growth model, this approach appeared suitable for modeling the growth of Indian Ocean yellowfin and is consistent with findings of previous studies. The simulations showed that the choice of the ageing method can strongly affect growth estimates with subsequent implications for age-structured data used as inputs for population models. Finally, our modeling approach revealed particularly useful to reflect uncertainty around age estimates into the process of growth estimation and it can be applied to any study relying on age estimation.     

Combined MRI and 31P-MRS Investigations of the ACTA1(H40Y) Mouse Model of Nemaline Myopathy Show Impaired Muscle Function and Altered Energy Metabolism

Nemaline myopathy (NM) is the most common disease entity among non-dystrophic skeletal muscle congenital diseases. Mutations in the skeletal muscle α-actin gene (ACTA1) account for ∼25% of all NM cases and are the most frequent cause of severe forms of NM. So far, the mechanisms underlying muscle weakness in NM patients remain unclear. Additionally, recent Magnetic Resonance Imaging (MRI) studies reported a progressive fatty infiltration of skeletal muscle with a specific muscle involvement in patients with ACTA1 mutations. We investigated strictly noninvasively the gastrocnemius muscle function of a mouse model carrying a mutation in the ACTA1 gene (H40Y). Skeletal muscle anatomy (hindlimb muscles and fat volumes) and energy metabolism were studied using MRI and ³¹Phosphorus magnetic resonance spectroscopy. Skeletal muscle contractile performance was investigated while applying a force-frequency protocol (from 1–150 Hz) and a fatigue protocol (80 stimuli at 40 Hz). H40Y mice showed a reduction of both absolute (−40%) and specific (−25%) maximal force production as compared to controls. Interestingly, muscle weakness was associated with an improved resistance to fatigue (+40%) and an increased energy cost. On the contrary, the force frequency relationship was not modified in H40Y mice and the extent of fatty infiltration was minor and not different from the WT group. We concluded that the H40Y mouse model does not reproduce human MRI findings but shows a severe muscle weakness which might be related to an alteration of intrinsic muscular properties. The increased energy cost in H40Y mice might be related to either an impaired mitochondrial function or an alteration at the cross-bridges level. Overall, we provided a unique set of anatomic, metabolic and functional biomarkers that might be relevant for monitoring the progression of NM disease but also for assessing the efficacy of potential therapeutic interventions at a preclinical level.