RAC1mutation is not a predictive biomarker for PI3’‐kinase‐β‐selective pathway‐targeted therapy

Mutational activation of RAC1 is detected in ~7% of cutaneous melanoma, with the most frequent mutation (RAC1^C85T) encoding for RAC1^P29S. RAC1^P29S is a fast‐cycling GTPase that leads to accumulation of RAC1^P29S‐GTP, which has potentially pleiotropic regulatory functions in melanoma cell signaling and biology. However, the precise mechanism by which mutationally activated RAC1^P29S propagates its pro‐tumorigenic effects remains unclear. RAC1‐GTP is reported to activate the beta isoform of PI3’‐kinase (PIK3CB/PI3Kβ) leading to downstream activation of PI3’‐lipid signaling. Hence, we employed both genetic and isoform‐selective pharmacological inhibitors to test if RAC1^P29S propagates its oncogenic signaling in melanoma through PI3Kβ. We observed that RAC1^P29S‐expressing melanoma cells were largely insensitive to inhibitors of PI3Kβ. Furthermore, RAC1^P29S melanoma cell lines showed variable sensitivity to pan‐class 1 (α/β/γ/δ) PI3’‐kinase inhibitors, suggesting that RAC1‐mutated melanoma cells may not rely on PI3’‐lipid signaling for their proliferation. Lastly, we observed that RAC1^P29S‐expressing cell lines also showed variable sensitivity to pharmacological inhibition of the RAC1 → PAK1 signaling pathway, questioning the relevance of inhibitors of this pathway for the treatment of patients with RAC1‐mutated melanoma.     

Nine new polymorphic microsatellite loci for the amplification of archived otolith DNA of Atlantic cod,Gadus morhua L.

Nine out of 22 microsatellite primers tested were successfully amplified on three samples of cod Gadus morhua L. (two contemporary and one archived otolith samples). All loci were polymorphic (5–23 alleles/locus). The average observed heterozygosity across loci and samples was 0.625, ranging from 0.294 to 0.895 at each locus. All loci were under Hardy–Weinberg equilibrium, except PGmo56 that showed significant excess of heterozygotes in all studied samples. The isolated loci were suitable for degraded DNA and therefore useful for conducting a long‐term temporal study with DNA obtained from archived otoliths of cod.     

Unusual anchor of a motor complex (MyoD-MLC2) to the plasma membrane of Toxoplasma gondii

Toxoplasma gondii possesses 11 rather atypical myosin heavy chains. The only myosin light chain described to date is MLC1, associated with myosin A, and contributing to gliding motility. In this study, we examined the repertoire of calmodulin-like proteins in Apicomplexans, identified six putative myosin light chains and determined their subcellular localization in T. gondii and Plasmodium falciparum. MLC2, only found in coccidians, is associated with myosin D via its calmodulin (CaM)-like domain and anchored to the plasma membrane of T. gondii via its N-terminal extension. Molecular modeling suggests that the MyoD-MLC2 complex is more compact than the reported structure of Plasmodium MyoA-myosin A tail-interacting protein (MTIP) complex. Anchorage of this MLC2 to the plasma membrane is likely governed by palmitoylation.     

Hierarchical regulation of pelagic invertebrates in lakes of the northern Great Plains: a novel model for interdecadal effects of future climate change on lakes

Endorheic lakes of the northern Great Plains encompass a wide range of environmental parameters (e.g., salinity, pH, DOC, Ca, nutrients, depth) that vary 1000‐fold among sites and through the past 2000 years due to variation in basin hydrology and evaporative forcing. However, while many environmental parameters are known to individually influence zooplankton diversity and taxonomic composition, relatively little is known of the hierarchical relationships among potential controls or of how regulatory mechanisms may change in response to climate variation on diverse scales. To address these issues, we surveyed 70 lakes within a 100 000 km² prairie region to simulate the magnitude of environmental change expected to occur over 100–1000 years and to quantify the unique and interactive effects of diverse environmental parameters in regulating pelagic invertebrate community structure at that scale. Multivariate analyses showed that salinity was the principal correlate of changes in invertebrate composition among lakes, with a sequential loss of taxa between salinities of 4 and 50 g total dissolved solids L^?1 until one to two species predominated in highly saline systems. In contrast, changes in the concentrations of Ca²⁺ and other mineral nutrients exerted secondary controls of invertebrate assemblages independent of salinity, whereas lake depth provided a tertiary regulatory mechanism structuring species composition. In contrast to these large‐scale hierarchical patterns, seasonal surveys (May, July, September) of a subset of 21 lakes in each of 2003–2005 revealed that annual meteorological variation had no measurable effect on pelagic invertebrates, despite large differences in temperature, precipitation, and evaporation arising from regional droughts. Together these findings show that pelagic invertebrate communities in saline lakes are resilient to interannual variability in climate, but suggest that lakes of the northern Great Plains may provide a sensitive model to forecast centennial effects of future climate change.     

Resisting resistance

This month's Genome Watch describes how knowledge of the malaria parasite genome can be used to better understand and mitigate the emergence of drug resistance.     

Skull shape variation in extant and extinct Testudinata and its relation to habitat and feeding ecology

Turtles (Testudinata) are a diverse group of reptiles that conquered a broad set of habitats and feeding ecologies over the course of their well‐documented evolutionary history. We here investigate the cranial shape of 171 representatives of the turtle lineage and the relationship of shape to different habitat and diet preferences using two‐dimensional geometric morphometrics. The skull shape of extant turtles correlates with both ecological proxies, but is more affected by habitat than diet. However, the application of these correlations to extinct turtles produces mostly flawed results, as least when compared to external data such as sedimentary environment, highlighting that the morphospace held by extant turtles is not necessarily the optimal location in tree space for a particular ecology. The inability of this study to correctly predict the ecology of extinct turtles is likely related to the fact that the shape of turtle skulls is dominated by the emarginations and jaw closure mechanisms, two shape features unrelated to habitat or feeding ecology. This indicates that various specializations that are apparent in the skull only contribute little to overall shape.     

A Dutch guideline for the treatment of scoliosis in neuromuscular disorders

Background

Children with neuromuscular disorders with a progressive muscle weakness such as Duchenne Muscular Dystrophy and Spinal Muscular Atrophy frequently develop a progressive scoliosis. A severe scoliosis compromises respiratory function and makes sitting more difficult. Spinal surgery is considered the primary treatment option for correcting severe scoliosis in neuromuscular disorders. Surgery in this population requires a multidisciplinary approach, careful planning, dedicated surgical procedures, and specialized after care.

Methods

The guideline is based on scientific evidence and expert opinions. A multidisciplinary working group representing experts from all relevant specialties performed the research. A literature search was conducted to collect scientific evidence in answer to specific questions posed by the working group. Literature was classified according to the level of evidence.

Results

For most aspects of the treatment scientific evidence is scarce and only low level cohort studies were found. Nevertheless, a high degree of consensus was reached about the management of patients with scoliosis in neuromuscular disorders. This was translated into a set of recommendations, which are now officially accepted as a general guideline in the Netherlands.

Conclusion

In order to optimize the treatment for scoliosis in neuromuscular disorders a Dutch guideline has been composed. This evidence-based, multidisciplinary guideline addresses conservative treatment, the preoperative, perioperative, and postoperative care of scoliosis in neuromuscular disorders.