Autophagy-dependent alternative splicing of ribosomal protein S24 produces a more stable isoform that aids in hypoxic cell survival.

Cells remodel splicing and translation machineries to mount specialized gene expression responses to stress. Here, we show that hypoxic human cells in 2D and 3D culture models increase the relative abundance of a longer mRNA variant of ribosomal protein S24 (RPS24L) compared to a shorter mRNA variant (RPS24S) by favoring the inclusion of a 22 bp cassette exon. Mechanistically, RPS24L and RPS24S are induced and repressed, respectively, by distinct pathways in hypoxia: RPS24L is induced in an autophagy-dependent manner, while RPS24S is reduced by mTORC1 repression in a hypoxia-inducible factor-dependent manner. RPS24L produces a more stable protein isoform that aids in hypoxic cell survival and growth, which could be exploited by cancer cells in the tumor microenvironment.

Hypoxia influences polysome distribution of human ribosomal protein S12 and alternative splicing of ribosomal protein mRNAs.

Ribosomes were once considered static in their composition because of their essential role in protein synthesis and kingdom-wide conservation. The existence of tolerated mutations in select ribosomal proteins (RPs), such as in Diamond-Blackfan anemia, is evidence that not all ribosome components are essential. Heterogeneity in the protein composition of eukaryotic ribosomes is an emerging concept with evidence that different pools of ribosomes exist with transcript-specificity. Here, we show that the polysome association of ribosomal proteins is altered by low oxygen (hypoxia), a feature of the tumor microenvironment, in human cells. We quantified ribosomal protein abundance in actively translating polysomes of normoxic and hypoxic HEK293 cells by tandem mass tags mass spectrometry. Our data suggest that RPS12 (eS12) is enriched in hypoxic monosomes, which increases the heavy polysome association of structured transcripts APAF-1 and XIAP. Furthermore, hypoxia induced five alternative splicing events within a subset of RP mRNAs in cell lines. One of these events in RPS24 (eS24 protein) alters the coding sequence to produce two protein isoforms that can incorporate into ribosomes. This splicing event is greatly induced in spheroids and correlates with tumor hypoxia in human prostate cancer. Our data suggest that hypoxia may influence the composition of the human ribosome through changes in RP incorporation and the production of hypoxia-specific RP isoforms.

A value-based practice model of rehabilitation: consumers' recommendations in action.

The purpose of this paper is to present a model of rehabilitation practice that is based on the recommendations of consumers who used rehabilitation services and have a life-changing physical impairment (spinal cord injury - SCI). This value-based practice model is based on two qualitative studies. The first study developed the framework (social adaptation) for a new practice model based on values. The second study, described in this paper, used the framework to learn about recommendations for change in the rehabilitation process. Participants in the second study were 80 volunteers who live with a SCI in the community, across the province of Ontario, Canada. A snowball strategy was used to recruit interested participants. Participants were involved in face-to-face interviews which included questions on what helped and hindered their initial rehabilitation process, and their recommendations for change. In this paper, we described a model that demonstrates how consumer input is essential in shaping a comprehensive rehabilitation process. The model is based on overarching value statements that express the worthiness of all individuals, the value of the lived experience of disability and the responsibility of the rehabilitation process to enable client autonomy. Four "values in action" are articulated: caring and respect for the individual and his/her personhood; applying the lived experience of disability; fostering autonomy; and promoting hopefulness. These values have been initially described in another paper based on a specific subset of 15 women living with SCI related to body issues during rehabilitation. This paper builds on this value work and we develop key practices for a progressive rehabilitation culture and model, based on the larger study group of 80 participants (men and women with SCI). This value-based model, when integrated with traditional, physical improvement-focused rehabilitation, has the potential to create a more effective process by offering clients better support as they go through the complex process of re-building their lives and making the transition back to the community. Implications for Rehabilitation We suggest that the Values in the Action Rehabilitation Practice Model that emphasized social adaptation be used along side the physical rehabilitation approach to enhance client-based practice. That peers with disabilities work collaboratively with rehabilitation professionals within a culture that acknowledges and reimburses their knowledge and expertise. Rehabilitation professionals learn about the lived experience of disability and systemic issues by being involved in grass-roots community organizations.

'Working at the margins' or 'leading from behind'? A Canadian study of hospital-community collaboration.

Collaboration between hospitals and community organisations has been promoted over the past 20 years by various levels of government, hospital associations, health promotion advocates, and others at the state/province, national and international levels as a way to improve the 'efficiency of the system', reduce duplication, enhance effectiveness and service coordination, improve continuity of care, and enhance community capacity to address complex issues. Nevertheless, and despite a growing literature on interagency collaboration, systematic documentation and empirical analysis of hospital-community collaboration (HCC) is almost completely lacking in the literature, particularly as regards collaborations that address the determinants of health beyond the hospital walls. In this paper, we describe the methodology and key findings from a research study of HCC. The Hospital Involvement in Community Action (HICA) study undertook detailed qualitative case studies (in four urban, suburban, rural and northern locations) and a telephone survey (of 139 community organisations in a large urban centre) in order to learn about the range of collaborations and working relationships that exist between hospitals and community agencies in the province of Ontario (Canada), and the factors that influenced (enabled and/or hindered) HCC. Particular attention was paid to barriers and enablers at three nested levels of context (policy, hospital and community) and, drawing primarily on the qualitative case studies, it is this aspect that is the focus of this paper. That such collaborations continue to be widespread despite a generally unfavourable policy environment and hospital institutional culture that poses significant barriers, suggests that the extent to which HCC flourishes (or exists at all) crucially depends on the presence and ongoing enthusiasm/commitment of one or more 'champions' within the hospital, and the commitment of both parties to overcome the marked cultural differences between hospital and community. We conclude with a discussion of implications for policy and practice.