Central Nervous System Pathology Progresses Independently of KC and CXCR2 in Globoid-Cell Leukodystrophy

Globoid-cell Leukodystrophy (GLD; Krabbe’s disease) is a rapidly progressing inherited demyelinating disease caused by a deficiency of the lysosomal enzyme Galactosylceramidase (GALC). Deficiency of GALC leads to altered catabolism of galactosylceramide and the cytotoxic lipid, galactosylsphingosine (psychosine). This leads to a rapidly progressive fatal disease with spasticity, cognitive disability and seizures. The murine model of GLD (Twitcher; GALC−/−) lacks the same enzyme and has similar clinical features. The deficiency of GALC leads to oligodendrocyte death, profound neuroinflammation, and the influx of activated macrophages into the CNS. We showed previously that keratinocyte chemoattractant factor (KC) is highly elevated in the CNS of untreated Twitcher mice and significantly decreases after receiving a relatively effective therapy (bone marrow transplantation combined with gene therapy). The action of KC is mediated through the CXCR2 receptor and is a potent chemoattractant for macrophages and microglia. KC is also involved in oligodendrocyte migration and proliferation. Based on the commonalities between the disease presentation and the functions of KC, we hypothesized that KC and/or CXCR2 contribute to the pathogenesis of GLD. Interestingly, the course of the disease is not significantly altered in KC- or CXCR2-deficient Twitcher mice. There is also no alteration in inflammation or demyelination patterns in these mice. Furthermore, transplantation of CXCR2-deficient bone marrow does not alter the progression of the disease as it does in other models of demyelination. This study highlights the role of multiple redundant cytokines and growth factors in the pathogenesis of GLD.     

Wrangling Phosphoproteomic Data to Elucidate Cancer Signaling Pathways

The interpretation of biological data sets is essential for generating hypotheses that guide research, yet modern methods of global analysis challenge our ability to discern meaningful patterns and then convey results in a way that can be easily appreciated. Proteomic data is especially challenging because mass spectrometry detectors often miss peptides in complex samples, resulting in sparsely populated data sets. Using the R programming language and techniques from the field of pattern recognition, we have devised methods to resolve and evaluate clusters of proteins related by their pattern of expression in different samples in proteomic data sets. We examined tyrosine phosphoproteomic data from lung cancer samples. We calculated dissimilarities between the proteins based on Pearson or Spearman correlations and on Euclidean distances, whilst dealing with large amounts of missing data. The dissimilarities were then used as feature vectors in clustering and visualization algorithms. The quality of the clusterings and visualizations were evaluated internally based on the primary data and externally based on gene ontology and protein interaction networks. The results show that t-distributed stochastic neighbor embedding (t-SNE) followed by minimum spanning tree methods groups sparse proteomic data into meaningful clusters more effectively than other methods such as k-means and classical multidimensional scaling. Furthermore, our results show that using a combination of Spearman correlation and Euclidean distance as a dissimilarity representation increases the resolution of clusters. Our analyses show that many clusters contain one or more tyrosine kinases and include known effectors as well as proteins with no known interactions. Visualizing these clusters as networks elucidated previously unknown tyrosine kinase signal transduction pathways that drive cancer. Our approach can be applied to other data types, and can be easily adopted because open source software packages are employed.     

An Invasive Fish and the Time-Lagged Spread of Its Parasite across the Hawaiian Archipelago

Efforts to limit the impact of invasive species are frustrated by the cryptogenic status of a large proportion of those species. Half a century ago, the state of Hawai''i introduced the Bluestripe Snapper, Lutjanus kasmira, to O''ahu for fisheries enhancement. Today, this species shares an intestinal nematode parasite, Spirocamallanus istiblenni, with native Hawaiian fishes, raising the possibility that the introduced fish carried a parasite that has since spread to naïve local hosts. Here, we employ a multidisciplinary approach, combining molecular, historical, and ecological data to confirm the alien status of S. istiblenni in Hawai''i. Using molecular sequence data we show that S. istiblenni from Hawai''i are genetically affiliated with source populations in French Polynesia, and not parasites at a geographically intermediate location in the Line Islands. S. istiblenni from Hawai''i are a genetic subset of the more diverse source populations, indicating a bottleneck at introduction. Ecological surveys indicate that the parasite has found suitable intermediate hosts in Hawai''i, which are required for the completion of its life cycle, and that the parasite is twice as prevalent in Hawaiian Bluestripe Snappers as in source populations. While the introduced snapper has spread across the entire 2600 km archipelago to Kure Atoll, the introduced parasite has spread only half that distance. However, the parasite faces no apparent impediments to invading the entire archipelago, with unknown implications for naïve indigenous Hawaiian fishes and the protected Papahānaumokuākea Marine National Monument.     

Active Video Games and Health Indicators in Children and Youth: A Systematic Review

Background

Active video games (AVGs) have gained interest as a way to increase physical activity in children and youth. The effect of AVGs on acute energy expenditure (EE) has previously been reported; however, the influence of AVGs on other health-related lifestyle indicators remains unclear.

Objective

This systematic review aimed to explain the relationship between AVGs and nine health and behavioural indicators in the pediatric population (aged 0–17 years).

Data sources

Online databases (MEDLINE, EMBASE, psycINFO, SPORTDiscus and Cochrane Central Database) and personal libraries were searched and content experts were consulted for additional material.

Data selection

Included articles were required to have a measure of AVG and at least one relevant health or behaviour indicator: EE (both habitual and acute), adherence and appeal (i.e., participation and enjoyment), opportunity cost (both time and financial considerations, and adverse events), adiposity, cardiometabolic health, energy intake, adaptation (effects of continued play), learning and rehabilitation, and video game evolution (i.e., sustainability of AVG technology).

Results

51 unique studies, represented in 52 articles were included in the review. Data were available from 1992 participants, aged 3–17 years, from 8 countries, and published from 2006–2012. Overall, AVGs are associated with acute increases in EE, but effects on habitual physical activity are not clear. Further, AVGs show promise when used for learning and rehabilitation within special populations. Evidence related to other indicators was limited and inconclusive.

Conclusions

Controlled studies show that AVGs acutely increase light- to moderate-intensity physical activity; however, the findings about if or how AVG lead to increases in habitual physical activity or decreases in sedentary behaviour are less clear. Although AVGs may elicit some health benefits in special populations, there is not sufficient evidence to recommend AVGs as a means of increasing daily physical activity.     

Paclitaxel-Induced Apoptosis Is BAK-Dependent,but BAX and BIM-Independent in Breast Tumor

Paclitaxel (Taxol)-induced cell death requires the intrinsic cell death pathway, but the specific participants and the precise mechanisms are poorly understood. Previous studies indicate that a BH3-only protein BIM (BCL-2 Interacting Mediator of cell death) plays a role in paclitaxel-induced apoptosis. We show here that BIM is dispensable in apoptosis with paclitaxel treatment using bim^−/− MEFs (mouse embryonic fibroblasts), the bim^−/− mouse breast tumor model, and shRNA-mediated down-regulation of BIM in human breast cancer cells. In contrast, both bak ^−/− MEFs and human breast cancer cells in which BAK was down-regulated by shRNA were more resistant to paclitaxel. However, paclitaxel sensitivity was not affected in bax^−/− MEFs or in human breast cancer cells in which BAX was down-regulated, suggesting that paclitaxel-induced apoptosis is BAK-dependent, but BAX-independent. In human breast cancer cells, paclitaxel treatment resulted in MCL-1 degradation which was prevented by a proteasome inhibitor, MG132. A Cdk inhibitor, roscovitine, blocked paclitaxel-induced MCL-1 degradation and apoptosis, suggesting that Cdk activation at mitotic arrest could induce subsequent MCL-1 degradation in a proteasome-dependent manner. BAK was associated with MCL-1 in untreated cells and became activated in concert with loss of MCL-1 expression and its release from the complex. Our data suggest that BAK is the mediator of paclitaxel-induced apoptosis and could be an alternative target for overcoming paclitaxel resistance.     

Does Learning or Instinct Shape Habitat Selection?

Habitat selection is an important behavioural process widely studied for its population-level effects. Models of habitat selection are, however, often fit without a mechanistic consideration. Here, we investigated whether patterns in habitat selection result from instinct or learning for a population of grizzly bears (Ursus arctos) in Alberta, Canada. We found that habitat selection and relatedness were positively correlated in female bears during the fall season, with a trend in the spring, but not during any season for males. This suggests that habitat selection is a learned behaviour because males do not participate in parental care: a genetically predetermined behaviour (instinct) would have resulted in habitat selection and relatedness correlations for both sexes. Geographic distance and home range overlap among animals did not alter correlations indicating that dispersal and spatial autocorrelation had little effect on the observed trends. These results suggest that habitat selection in grizzly bears are partly learned from their mothers, which could have implications for the translocation of wildlife to novel environments.     

Evaluating Hemorrhage in Renal Cell Carcinoma Using Susceptibility Weighted Imaging

Background

Intratumoral hemorrhage is a frequent occurrence in renal cell carcinoma and is an indicator of tumor subtype. We hypothesize that susceptibility weighted imaging (SWI) is sensitive to hemorrhage in renal cell carcinoma and can give a more diagnostic image when compared to conventional imaging techniques.

Materials and Methods

A retrospective review of 32 patients with clear cell renal cell carcinoma was evaluated. All patients underwent magnetic resonance imaging (MRI) and 22 out of 32 patients also underwent a computed tomography (CT) scan. Hemorrhage was classified into 3 different categories according to shape and distribution. Histopathology was obtained from all masses by radical nephrectomy. The ability to detect the presence of hemorrhage using CT, non-contrast conventional MRI and SWI was evaluated, and the patterns of hemorrhage were compared.

Results

Using pathologic results as the gold standard, the sensitivities of non-contrast conventional MRI, SWI and CT in detecting hemorrhage in clear cell renal cell carcinoma were 65.6%, 100% and 22.7%, respectively. Accuracy of non-contrast conventional MRI and SWI in evaluating hemorrhagic patterns were 31.3% and 100%, respectively.

Conclusion

These results demonstrate that SWI can better reveal hemorrhage and characterize the pattern more accurately than either non-contrast conventional MRI or CT. This suggests that SWI is the technique of choice for detecting hemorrhagic lesions in patients with renal cancer.     

Monitoring of Pb Exposure in Waterfowl Ten Years after a Mine Spill through the Use of Noninvasive Sampling

Lead exposure in waterfowl was studied using noninvasive fecal sampling in the Guadalquivir Marshes in Spain, an area affected by the 1998 Aznalcóllar mine disaster. Feces of greylag geese (Anser anser, n = 191) and purple gallinule (Porphyrio porphyrio, n = 91) were collected from three different impacted sites (Entremuros, Caracoles and Cerro de los Ánsares) during the winters of 2004 to 2008. Lead and aluminium (an indicator of sediment ingestion) and Pb isotope signatures (to discriminate between sources of Pb exposure) were analyzed in freeze-dried, acid digested samples. The concentrations of fecal porphyrins and biliverdin were determined as noninvasive biomarkers to study Pb exposure effects. Results showed a decrease in Pb exposure over time in wintering greylag geese. In contrast, for purple gallinule resident in the Entremuros a clear trend was not evident. For both species, sediment ingestion appeared to be the main source of exposure to Pb. In the Entremuros, some samples from purple gallinule were detected with higher Pb levels than expected for simple soil ingestion, and these had Pb isotopic profiles compatible with mining sludge or Pb shot. Whilst fecal Pb isotopic profiles were effective in differentiating between samples from sites with different levels and sources of pollution, the combined use of element ratios (such as Pb/Al) and other non-traditional stable isotope signatures may also prove worthwhile. Overall, the fecal Pb levels detected were below those described in feces for waterfowl from other uncontaminated areas(<10 µg/g d.w.). Despite this, for both species fecal Pb levels were positively correlated with porphyrin excretion, and for purple gallinule, with the coproporphyrin III/I ratio, suggesting some subtle effects on heme synthesis in birds. Ten years after the mine spill, Pb contamination in birds by this pollution source was still detectable and subtlethal effects may persist.     

Association between Gender,Process of Care Measures,and Outcomes in ACS in India: Results from the Detection and Management of Coronary Heart Disease (DEMAT) Registry

Background

Studies from high-income countries have shown that women receive less aggressive diagnostics and treatment than men in acute coronary syndromes (ACS), though their short-term mortality does not appear to differ from men. Data on gender differences in ACS presentation, management, and outcomes are sparse in India.

Methods and Results

The Detection and Management of Coronary Heart Disease (DEMAT) Registry collected data from 1,565 suspected ACS patients (334 women; 1,231 men) from ten tertiary care centers throughout India between 2007–2008. We evaluated gender differences in presentation, in-hospital and discharge management, and 30-day death and major adverse cardiovascular event (MACE; death, re-hospitalization, and cardiac arrest) rates. Women were less likely to present with STEMI than men (38% vs. 55%, p<0.001). Overall inpatient diagnostics and treatment patterns were similar between men and women after adjustment for potential confounders. Optimal discharge management with aspirin, clopidogrel, beta-blockers, and statin therapy was lower for women than men, (58% vs. 65%, p = 0.03), but these differences were attenuated after adjustment (OR = 0.86 (0.62, 1.19)). Neither the outcome of 30-day mortality (OR = 1.40 (0.62, 3.16)) nor MACE (OR = 1.00 (0.67, 1.48)) differed significantly between men and women after adjustment.

Conclusions

ACS in-hospital management, discharge management, and 30-day outcomes did not significantly differ between genders in the DEMAT registry, though consistently higher treatment rates and lower event rates in men compared to women were seen. These findings underscore the importance of further investigation of gender differences in cardiovascular care in India.     

Spatial Heterogeneity in Ecologically Important Climate Variables at Coarse and Fine Scales in a High-Snow Mountain Landscape

Climate plays an important role in determining the geographic ranges of species. With rapid climate change expected in the coming decades, ecologists have predicted that species ranges will shift large distances in elevation and latitude. However, most range shift assessments are based on coarse-scale climate models that ignore fine-scale heterogeneity and could fail to capture important range shift dynamics. Moreover, if climate varies dramatically over short distances, some populations of certain species may only need to migrate tens of meters between microhabitats to track their climate as opposed to hundreds of meters upward or hundreds of kilometers poleward. To address these issues, we measured climate variables that are likely important determinants of plant species distributions and abundances (snow disappearance date and soil temperature) at coarse and fine scales at Mount Rainier National Park in Washington State, USA. Coarse-scale differences across the landscape such as large changes in elevation had expected effects on climatic variables, with later snow disappearance dates and lower temperatures at higher elevations. However, locations separated by small distances (∼20 m), but differing by vegetation structure or topographic position, often experienced differences in snow disappearance date and soil temperature as great as locations separated by large distances (>1 km). Tree canopy gaps and topographic depressions experienced later snow disappearance dates than corresponding locations under intact canopy and on ridges. Additionally, locations under vegetation and on topographic ridges experienced lower maximum and higher minimum soil temperatures. The large differences in climate we observed over small distances will likely lead to complex range shift dynamics and could buffer species from the negative effects of climate change.