Mitochondrial complex I activity in microglia sustains neuroinflammation.

Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis1. Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells2. However, how these metabolic features act to perpetuate inflammation of the central nervous system is unclear. Here, using a multiomics approach, we identify a molecular signature that sustains the activation of microglia through mitochondrial complex I activity driving reverse electron transport and the production of reactive oxygen species. Mechanistically, blocking complex I in pro-inflammatory microglia protects the central nervous system against neurotoxic damage and improves functional outcomes in an animal disease model in vivo. Complex I activity in microglia is a potential therapeutic target to foster neuroprotection in chronic inflammatory disorders of the central nervous system3.

Activation of NFAT signaling establishes a tumorigenic microenvironment through cell autonomous and non-cell autonomous mechanisms.

NFAT (the nuclear factor of activated T cells) upregulation has been linked to cellular transformation intrinsically, but it is unclear whether and how tissue cells with NFAT activation change the local environment for tumor initiation and progression. Direct evidence showing NFAT activation initiates primary tumor formation in vivo is also lacking. Using inducible transgenic mouse systems, we show that tumors form in a subset of, but not all, tissues with NFATc1 activation, indicating that NFAT oncogenic effects depend on cell types and tissue contexts. In NFATc1-induced skin and ovarian tumors, both cells with NFATc1 activation and neighboring cells without NFATc1 activation have significant upregulation of c-Myc and activation of Stat3. Besides known and suspected NFATc1 targets, such as Spp1 and Osm, we have revealed the early upregulation of a number of cytokines and cytokine receptors, as key molecular components of an inflammatory microenvironment that promotes both NFATc1(+) and NFATc1(-) cells to participate in tumor formation. Cultured cells derived from NFATc1-induced tumors were able to establish a tumorigenic microenvironment, similar to that of the primary tumors, in an NFATc1-dependent manner in nude mice with T-cell deficiency, revealing an addiction of these tumors to NFATc1 activation and downplaying a role for T cells in the NFATc1-induced tumorigenic microenvironment. These findings collectively suggest that beyond the cell autonomous effects on the upregulation of oncogenic proteins, NFATc1 activation has non-cell autonomous effects through the establishment of a promitogenic microenvironment for tumor growth. This study provides direct evidence for the ability of NFATc1 in inducing primary tumor formation in vivo and supports targeting NFAT signaling in anti-tumor therapy.

Psychosocial and functional correlates of nutrition among community-dwelling older adults in Ireland.

OBJECTIVES: To examine psychosocial and functional correlates of nutrition in a nonrandom sample of Irish community-dwelling older adults. DESIGN: Cross-sectional observational study. SETTING: Technology Research for Independent Living (TRIL) Clinic, a comprehensive geriatric assessment facility in St James's Hospital, Dublin. Data were collected from participants by medical personnel (physical assessments) and psychologists (questionnaires), between August 2007 and May 2009. PARTICIPANTS: 556 participants (388 females; 168 males) ranging in age from 60-92 years (Mean 72.5 years, SD 7.1). All were community-dwelling and provided informed consent. MEASUREMENTS: The Nestlé Mini-Nutritional Assessment (MNA®), Time to get up and go (TUG) and the Lubben Social Network Scale-18 (LSNS-18) were used to assess nutrition, functional mobility and social support. METHODS: Multivariate binary logistic regression was used to examine the association between social support or mobility and nutritional status, whilst controlling for possible confounders (age, gender, living alone and material deprivation). RESULTS: The strongest predictors of abnormal nutritional status were mobility (p < 0.001) and social support (p = 0.005). Other significant predictors of nutritional risk were age (p = 0.032) and deprivation (p = 0.018). CONCLUSION: The results emphasise the importance of mobility and social supports in mediating nutritional outcomes in Irish community-dwelling older adults.

Psychosocial correlates of aspects of sleep quality in community-dwelling Irish older adults.

OBJECTIVES: While it is known that psychosocial factors affect overall sleep quality, there is little consensus on the factors that affect different aspects of sleep. The Pittsburgh Sleep Quality Index (PSQI) provides a means of examining these separate aspects of sleep. METHOD: This study investigated whether the different components of the PSQI are affected by different psychosocial factors, or whether all aspects of sleep are associated with the same factors. 505 community-dwelling older adults took part in this study. Psychosocial status, comprising of measures of depression, anxiety, perceived stress, social and emotional loneliness and personality, was assessed for each participant. Health-related factors (pain, comorbidities, polypharmacy) as well as age and gender were also measured. RESULTS: Neuroticism, depression, anxiety and age accounted for overall sleep quality. Further analyses revealed that different psychosocial and health-related factors such as pain, loneliness and personality accounted for scores in the different components. CONCLUSION: Interventions for poor sleep quality may depend on the aspect of sleep affected in the individual, and treatment may be contingent on a number of different psychosocial variables. Future research could focus on developing personalised treatment programs for older adults with sleep complaints.