Novel sphingosine-containing analogues selectively inhibit sphingosine kinase (SK) isozymes, induce SK1 proteasomal degradation and reduce DNA synthesis in human pulmonary arterial smooth muscle cells

Sphingosine 1-phosphate (S1P) is involved in hyper-proliferative diseases such as cancer and pulmonary arterial hypertension. We have synthesized inhibitors that are selective for the two isoforms of sphingosine kinase (SK1 and SK2) that catalyze the synthesis of S1P. A thiourea adduct of sphinganine (F02) is selective for SK2 whereas the 1-deoxysphinganines 55-21 and 77-7 are selective for SK1. (2S,3R)-1-Deoxysphinganine (55-21) induced the proteasomal degradation of SK1 in human pulmonary arterial smooth muscle cells and inhibited DNA synthesis, while the more potent SK1 inhibitors PF-543 and VPC96091 failed to inhibit DNA synthesis. These findings indicate that moderate potency inhibitors such as 55-21 are likely to have utility in unraveling the functions of SK1 in inflammatory and hyperproliferative disorders

Instructions not included: dementia-friendly approaches to DMI design

The development of bespoke musical tools such as many accessible digital musical instruments (ADMI) can neces- sitate specific design constraints. Within a field which of- ten promotes out of the box thinking and new interactions with experimental technologies, how do we design for user groups where these notions of interaction will be less famil- iar, and/or increasingly challenging due to the progression of cognitive decline? The relationship between age and the use of technol- ogy is understood within the wider context of human com- puter interaction (HCI), however, how this applies specifi- cally to musical interaction or contributes to a ‘dementia- friendly’ approach to digital musical instrument (DMI) de- sign is drastically underrepresented within the NIME com- munity. Following a scoping review of technology for arts activities designed for older adults with cognitive decline, we ran a series of involvement activities with a range of stakeholders living with, or caring for those living with de- mentia. Consolidating the knowledge and experience shared at these events, we propose five considerations for designing dementia-friendly digital musical instruments. We illustrate our approach with a range of new instruments co-designed to enable increased interaction with music for people living with dementia

Exploring older adult needs and preferences for technology-assisted group music-making. A qualitative analysis of data collected during the participatory user-centred design process

Purpose: Engagement with arts, recreation and leisure is highly valued by older adults, with positive links to their continued wellbeing. Despite an availability of new music technology, these devices are rarely designed with older adults in mind. This project explores the needs and preferences of older adults in residential care as they interact with digital music interfaces in a group music-making context. Materials and methods: Twenty participants at an Australian residential aged-care facility were involved in a user-centred design process (20 sessions across six months) to develop digital music interfaces suitable for group music-making. Participants’ verbal comments were audio-recorded and transcribed, supported by further written observation notes made by the activity facilitators. Results: A hybrid inductive and deductive approach to thematic analysis revealed three main themes: individual music-making, ensemble music-making and social engagement. Our results suggest that when interfaces are designed with older adults in mind, technology-assisted group music-making can facilitate bringing together residents with different experiences and abilities. Conclusions: These findings suggest implications for rehabilitation in developing a range of musical devices for older adults to account for required flexibility, whilst maintaining an appropriate and satisfyingly “rich” musical outcome.Implications for rehabilitation Older adults positively engage with music technology, showing distinct personal preferences for aspects of physical interaction, balance and quality of sound. Rehabilitation and/or wellbeing-based musical activities for older adults in residential care may benefit from considering tools that allow for personal adaptations such as these to be made. Preferences for musical interaction can be influenced by previous musical experiences, as well as physical and/or cognitive abilities. However, on any given day musical preferences can also be subject to change. Within a group music-making context, there is a significant capacity for older adults to feel agency in contributing to the overall sound; rehabilitation activities and/or technologies could be designed where this individual contribution to the group can be enhanced. Group music-making using new digital music interfaces has the potential to encourage interpersonal social connections that are most likely made over repeated sessions

Structure-activity relationships and molecular modeling of sphingosine kinase inhibitors

The design, synthesis, and evaluation of the potency of new isoform-selective inhibitors of sphingosine kinases 1 and 2 (SK1 and SK2), the enzyme that catalyzes the phosphorylation of d-erythro-sphingosine to produce the key signaling lipid, sphingosine 1-phosphate, are described. Recently, we reported that 1-(4-octylphenethyl)piperidin-4-ol (RB-005) is a selective inhibitor of SK1. Here we report the synthesis of 43 new analogues of RB-005, in which the lipophilic tail, polar headgroup, and linker region were modified to extend the structure-activity relationship profile for this lead compound, which we explain using modeling studies with the recently published crystal structure of SK1. We provide a basis for the key residues targeted by our profiled series and provide further evidence for the ability to discriminate between the two isoforms using pharmacological intervention

Effect of the sphingosine kinase 1 selective inhibitor, PF-543 on arterial and cardiac remodeling in a hypoxic model of pulmonary arterial hypertension

Recent studies have demonstrated that the expression of sphingosine kinase 1, the enzyme that catalyses formation of the bioactive lipid, sphingosine 1-phosphate, is increased in lungs from patients with pulmonary arterial hypertension. In addition, Sk1-/- mice are protected from hypoxic-induced pulmonary arterial hypertension. Therefore, we assessed the effect of the sphingosine kinase 1 selective inhibitor, PF-543 and a sphingosine kinase 1/ceramide synthase inhibitor, RB-005 on pulmonary and cardiac remodeling in a mouse hypoxic model of pulmonary arterial hypertension. Administration of the potent sphingosine kinase 1 inhibitor, PF-543 in a mouse hypoxic model of pulmonary hypertension had no effect on vascular remodeling but reduced right ventricular hypertrophy. The latter was associated with a significant reduction in cardiomyocyte death. The protection involves a reduction in the expression of p53 (that promotes cardiomyocyte death) and an increase in the expression of anti-oxidant nuclear factor (erythroid-derived 2)-like 2 (Nrf-2). In contrast, RB-005 lacked effects on right ventricular hypertrophy, suggesting that SK1 inhibition might be nullified by concurrent inhibition of ceramide synthase. Therefore, our findings with PF-543 suggest an important role for SK1 in the development of hypertrophy in PAH

Going online: successes and challenges in delivering group music instrument and aural learning for older adult novices during the COVID-19 pandemic

As a result of the COVID-19 pandemic, many cultural and artistic programs for older adults have been put on hold, despite the numerous physical, social, and emotional well-being benefits continued participation may bring. This article details a cross-section of participants (n = 13) in the Active Minds Music Ensemble—a longitudinal Australian-based research project that provides 12 months of group music instrument lessons to healthy older adult novices—who transitioned from face-to-face (F2F) to an online format. Research questions include the benefits and challenges for older adults as they cope with the technological demands of “going online,” perceived effects on teaching and older adults’ musical learning, as well as perceived effects on group learning benefits. Qualitative data were collected from three different perspectives: i) a frequently asked questions (FAQ) report from the research team documenting technological issues, ii) individual semi-structured interviews with the participants, and iii) a reflective report from the teacher. The findings confirm that online group music instrument lessons are viable for and valued by older adults, with appreciation of continued technical support. Teaching and learning changed as a result of the online format, primarily in the reduction of individual feedback and less interplay between participants; this was mitigated by use of various functions such as chat, whiteboards, and breakout rooms. Implications for older adult online music instrument lessons include providing continued technical support to learners and helping them maintain confidence with technology. Social opportunities for informal “side-chatter” may also help them to empathize with and encourage each other during music learning activities

Role of sphingosine 1-phosphate receptors, sphingosine kinases and sphingosine in cancer and inflammation

Sphingosine kinase (there are two isoforms, SK1 and SK2) catalyses the formation of sphingosine 1-phosphate (S1P), a bioactive lipid that can be released from cells to activate a family of G protein-coupled receptors, termed S1P1-5. In addition, S1P can bind to intracellular target proteins, such as HDAC1/2, to induce cell responses. There is increasing evidence of a role for S1P receptors (e.g. S1P4) and SK1 in cancer, where high expression of these proteins in ER negative breast cancer patient tumours is linked with poor prognosis. Indeed, evidence will be presented here to demonstrate that S1P4 is functionally linked with SK1 and the oncogene HER2 (ErbB2) to regulate mitogen-activated protein kinase pathways and growth of breast cancer cells. Although much emphasis is placed on SK1 in terms of involvement in oncogenesis, evidence will also be presented for a role of SK2 in both T-cell and B-cell acute lymphoblastic leukemia. In patient T-ALL lymphoblasts and T-ALL cell lines, we have demonstrated that SK2 inhibitors promote T-ALL cell death via autophagy and induce suppression of c-myc and PI3K/AKT pathways. We will also present evidence demonstrating that certain SK inhibitors promote oxidative stress and protein turnover via proteasomal degradative pathways linked with induction of p53-and p21-induced growth arrest. In addition, the SK1 inhibitor, PF-543 exacerbates disease progression in an experimental autoimmune encephalomyelitis mouse model indicating that SK1 functions in an anti-inflammatory manner. Indeed, sphingosine, which accumulates upon inhibition of SK1 activity, and sphingosine-like compounds promote activation of the inflammasome, which is linked with multiple sclerosis, to stimulate formation of the pro-inflammatory mediator, IL-1β. Such compounds could be exploited to produce antagonists that diminish exaggerated inflammation in disease. The therapeutic potential of modifying the SK-S1P receptor pathway in cancer and inflammation will therefore, be reviewed

Designing new musical technologies for wellbeing – exploring the needs and preferences of those living with dementia

Background Music has been found to provide numerous health and wellbeing benefits for people living with dementia. It is also quite open in terms of the forms of engagement it affords, offering numerous different ways to listen, play and create. Although technology has the potential to reduce barriers that people with dementia face when attempting to engage with music, little has been designed with them in mind. This study seeks to understand: i) the needs, rewards, and barriers that people with dementia and their carers face when engaging with music in their daily lives, and ii) how any specifically designed future musical interfaces will look and react. Method A survey using a mixture of qualitative and quantitative questions was distributed online to people living with mild cognitive impairment or dementia and to those that provide care for them. Questions asked about motivations and contexts for engagement, barriers and enabling factors, the comparative importance of various musical activities, and the technologies people living with dementia currently use and why. Result The main tools for listening include smartphone apps, radio, virtual assistants, and YouTube. Most participants listen to music on multiple devices, with its ease of use, accessibility, and convenience for their current listening environment frequently influencing their choice. They also presented a wide range of motivations for engaging with music, but a majority of participants agreed that “feeling like myself” is their most important motivator. Most participants thought it was very important for devices to offer choice. It should also have a simple way for them to turn it off or switch to a safe song if they hear a distressing song or it experiences signal loss. Conclusion The findings highlight that people living with dementia have diverse individual motivations for music, and they want it to perform different functions at different times (e.g. sometimes aiding in their relaxation and sometimes connecting them with others). The findings point to fruitful future directions for technology development: i) ready-to-use tools that can adapt to changing interests, and ii) tools that make it easy to access choice and variety while safeguarding against distress from unwanted or unexpected events