Modulation of the surface proteome through multiple ubiquitylation pathways in African Trypanosomes

Recently we identified multiple suramin-sensitivity genes with a genome wide screen in Trypanosoma brucei that includes the invariant surface glycoprotein ISG75, the adaptin-1 (AP-1) complex and two deubiquitylating enzymes (DUBs) orthologous to ScUbp15/HsHAUSP1 and pVHL-interacting DUB1 (type I), designated TbUsp7 and TbVdu1, respectively. Here we have examined the roles of these genes in trafficking of ISG75, which appears key to suramin uptake. We found that, while AP-1 does not influence ISG75 abundance, knockdown of TbUsp7 or TbVdu1 leads to reduced ISG75 abundance. Silencing TbVdu1 also reduced ISG65 abundance. TbVdu1 is a component of an evolutionarily conserved ubiquitylation switch and responsible for rapid receptor modulation, suggesting similar regulation of ISGs in T. brucei. Unexpectedly, TbUsp7 knockdown also blocked endocytosis. To integrate these observations we analysed the impact of TbUsp7 and TbVdu1 knockdown on the global proteome using SILAC. For TbVdu1, ISG65 and ISG75 are the only significantly modulated proteins, but for TbUsp7 a cohort of integral membrane proteins, including the acid phosphatase MBAP1, that is required for endocytosis, and additional ISG-related proteins are down-regulated. Furthermore, we find increased expression of the ESAG6/7 transferrin receptor and ESAG5, likely resulting from decreased endocytic activity. Therefore, multiple ubiquitylation pathways, with a complex interplay with trafficking pathways, control surface proteome expression in trypanosomes

Can Research Assessments Themselves Cause Bias in Behaviour Change Trials? A Systematic Review of Evidence from Solomon 4-Group Studies

BACKGROUND: The possible effects of research assessments on participant behaviour have attracted research interest, especially in studies with behavioural interventions and/or outcomes. Assessments may introduce bias in randomised controlled trials by altering receptivity to intervention in experimental groups and differentially impacting on the behaviour of control groups. In a Solomon 4-group design, participants are randomly allocated to one of four arms: (1) assessed experimental group; (2) unassessed experimental group (3) assessed control group; or (4) unassessed control group. This design provides a test of the internal validity of effect sizes obtained in conventional two-group trials by controlling for the effects of baseline assessment, and assessing interactions between the intervention and baseline assessment. The aim of this systematic review is to evaluate evidence from Solomon 4-group studies with behavioural outcomes that baseline research assessments themselves can introduce bias into trials. METHODOLOGY/PRINCIPAL FINDINGS: Electronic databases were searched, supplemented by citation searching. Studies were eligible if they reported appropriately analysed results in peer-reviewed journals and used Solomon 4-group designs in non-laboratory settings with behavioural outcome measures and sample sizes of 20 per group or greater. Ten studies from a range of applied areas were included. There was inconsistent evidence of main effects of assessment, sparse evidence of interactions with behavioural interventions, and a lack of convincing data in relation to the research question for this review. CONCLUSIONS/SIGNIFICANCE: There were too few high quality completed studies to infer conclusively that biases stemming from baseline research assessments do or do not exist. There is, therefore a need for new rigorous Solomon 4-group studies that are purposively designed to evaluate the potential for research assessments to cause bias in behaviour change trials

Effects of barefoot and shod running on lower extremity joint loading, a musculoskeletal simulation study

PURPOSE: The aim of the current investigation was to utilize a musculoskeletal simulation based approach, to examine the effects of barefoot and shod running on lower extremity joint loading during the stance phase. METHODS: Twelve male runners, ran over an embedded force plate at 4.0 m/s, in both barefoot and shod conditions. Kinematics of the lower extremities were collected using an eight camera motion capture system. Lower extremity joint loading was also explored using a musculoskeletal simulation and mathematical modelling approach, and differences between footwear conditions were examined using paired samples t-tests. RESULTS: Peak Achilles tendon force was significantly larger (P=0.039) when running barefoot (6.85 BW) compared to shod (6.07 BW). In addition, both medial (P=0.013) and lateral (P=0.007) tibiofemoral instantaneous load rates were significantly larger in the barefoot (medial = 289.17 BW/s & lateral = 179.59 BW/s) in relation to the shod (medial = 167.57 BW/s & lateral = 116.40 BW/s) condition. Finally, the barefoot condition (9.70 BW) was associated with a significantly larger (P=0.037) peak hip force compared to running shod (8.51 BW). CONCLUSIONS: The current investigation indicates that running barefoot may place runners at increased risk from the biomechanical factors linked to the aetiology of chronic lower extremity pathologies. However, future analyses using habitual barefoot runners, are required before more definitive affirmations regarding injury predisposition can be made

Structured ambivalence in grandchild care and the quality of life among European grandparents

This study employs the concept of structured ambivalence to analyse the effect of grandchild care on quality of life (QoL) in different cultural contexts. We define structured ambivalence as the contradiction between behaviour and cultural norms. The analysis is based on the Survey of Health, Ageing and Retirement in Europe with 14 countries in the sample. We focus on grandparents aged 50 and over with at least one grandchild 12 years old or younger (n = 12,740). In countries with high grandparent obligations, grandparents who did not look after their grandchildren reported a lower quality of life. Compliance with such grandparental obligations (e.g. providing grandchild care in a country with high grandparent obligations) was found to increase the QoL of grandparents. Family policy should consider family practices that better match the realities of current grandparents’ lives in order to reduce structured ambivalence and increase the QoL of grandparents