The human sirtuin family: Evolutionary divergences and functions

The sirtuin family of proteins is categorised as class III histone deacetylases that play complex and important roles in ageing-related pathological conditions such as cancer and the deregulation of metabolism. There are seven members in humans, divided into four classes, and evolutionarily conserved orthologues can be found in most forms of life, including both eukaryotes and prokaryotes. The highly conserved catalytic core domain composed of a large oxidised nicotinamide adenine dinucleotide (NAD(+))-binding Rossmann fold subunit suggests that these proteins belong to a family of nutrient-sensing regulators. Along with their function in regulating cellular metabolism in response to stressful conditions, they are implicated in modifying a wide variety of substrates; this increases the complexity of unravelling the interplay of sirtuins and their partners. Over the past few years, all of these new findings have attracted the interest of researchers exploring potential therapeutic implications related to the function of sirtuins. It remains to be elucidated whether, indeed, sirtuins can serve as molecular targets for the treatment of human illnesses

Ionizing Radiation-Induced Oxidative Stress Alters miRNA Expression

). treatment, and 45 after etoposide treatment. Substantial overlap between the miRNA expression changes between agents was observed suggesting a signature miRNA response to cell stress. Changes in the expression of selected miRNA species varied in response to radiation dose and time. Finally, production of reactive oxygen species (ROS) increased with increasing doses of radiation and pre-treatment with the thiol antioxidant cysteine decreased both ROS production and the miRNA response to radiation., and etoposide. Additionally, pre-treatment with cysteine prevented radiation-induced alterations in miRNA expression which suggests that miRNAs are responsive to oxidative stress. Taken together, these results imply that miRNAs play a role in cellular defense against exogenous stress and are involved in the generalized cellular response to genotoxic oxidative stress

Dietary Restriction: Standing Up For Sirtuins

We believe that L. Fontana, L. Partridge, and V. D. Longo should have included a discussion of sirtuins in their Review “Extending healthy life span—From yeast to humans” (16 April, p. 321). We also believe that some of the references used are misleading. The authors state that the purpose of their Review is to “consider the role of nutrient-sensing signaling pathways in mediating the beneficial effects of dietary restriction.” Yet there was no mention of the sirtuins, a family of critically important nutrient-sensing proteins that promote health span from yeast to mammals, as shown by more than 1000 peer-reviewed publications from labs around the world. The authors state that “[i]t is unlikely that a single, linear pathway mediates the effects of dietary restriction in any organism,” and we agree. Indeed, the aging field now recognizes that healthy life span is under the influence of several nutrient-sensing pathways, and there is at least as much evidence for the involvement of sirtuins in the dietary restriction response as for any of the pathways discussed in the Review

Sirt3, Mitochondrial ROS, Ageing, and Carcinogenesis

One fundamental observation in cancer etiology is that the rate of malignancies in any mammalian population increases exponentially as a function of age, suggesting a mechanistic link between the cellular processes governing longevity and carcinogenesis. In addition, it is well established that aberrations in mitochondrial metabolism, as measured by increased reactive oxygen species (ROS), are observed in both aging and cancer. In this regard, genes that impact upon longevity have recently been characterized in S. cerevisiae and C. elegans, and the human homologs include the Sirtuin family of protein deacetylases. Interestingly, three of the seven sirtuin proteins are localized into the mitochondria suggesting a connection between the mitochondrial sirtuins, the free radical theory of aging, and carcinogenesis. Based on these results it has been hypothesized that Sirt3 functions as a mitochondrial fidelity protein whose function governs both aging and carcinogenesis by modulating ROS metabolism. Sirt3 has also now been identified as a genomically expressed, mitochondrial localized tumor suppressor and this review will outline potential relationships between mitochondrial ROS/superoxide levels, aging, and cell phenotypes permissive for estrogen and progesterone receptor positive breast carcinogenesis

Doing AI differently:rethinking the foundations of AI via the humanities

Artificial Intelligence is rapidly becoming global infrastructure – shaping decisions in healthcare, education, industry and everyday life. Yet current AI systems face a fundamental limitation: they are shaped by narrow operational metrics that fail to reflect the diversity, ambiguity and richness of human experience.This white paper presents a research vision that positions interpretive depth as essential to building AI systems capable of engaging meaningfully with cultural complexity – while recognising that no technical solution alone can resolve the challenges these systems face in diverse human contexts.Accompanying the white paper is a policy note and a methodology report – links to all publications can be found below.Doing AI Differently calls for a fundamental shift in AI development – one that positions the humanities, arts and qualitative social sciences as integral, rather than supplemental, to technical innovation.Three critical challenges1) The qualitative turn: AI is no longer limited to structured prediction or optimisation – it now operates in tasks that require contextual judgement, cultural nuance, and interpretive reasoning.2) The homogenisation problem: The dominance of a few AI architectures propagates design limitations across countless applications and can entrench social inequalities by reinforcing narrow models of reasoning and representation.3) The transformation of human cognition: As we engage with complex, interconnected systems of artificial and human agents, AI is reshaping human thinking and work in ways that risk diminishing rather than enhancing human agency and capabilities.The core innovations we envision:1) Interpretive technologies: AI systems that represent multiple valid perspectives rather than producing monolithic outputs, enabling more nuanced, culturally sensitive reasoning across diverse contexts.2) Alternative architectures for AI: Expanding the AI design space beyond current homogeneous approaches through diverse reasoning paradigms grounded in heterogeneous cognitive, cultural and planetary processes.3) Human-AI ensembles: Developing frameworks for sophisticated, collaborative human-AI systems that strengthen our collective intelligence and enhance rather than replace human capabilities in complex decision-making

Proceedings of the 3rd Biennial Conference of the Society for Implementation Research Collaboration (SIRC) 2015: advancing efficient methodologies through community partnerships and team science

It is well documented that the majority of adults, children and families in need of evidence-based behavioral health interventionsi do not receive them [1, 2] and that few robust empirically supported methods for implementing evidence-based practices (EBPs) exist. The Society for Implementation Research Collaboration (SIRC) represents a burgeoning effort to advance the innovation and rigor of implementation research and is uniquely focused on bringing together researchers and stakeholders committed to evaluating the implementation of complex evidence-based behavioral health interventions. Through its diverse activities and membership, SIRC aims to foster the promise of implementation research to better serve the behavioral health needs of the population by identifying rigorous, relevant, and efficient strategies that successfully transfer scientific evidence to clinical knowledge for use in real world settings [3]. SIRC began as a National Institute of Mental Health (NIMH)-funded conference series in 2010 (previously titled the “Seattle Implementation Research Conference”; $150,000 USD for 3 conferences in 2011, 2013, and 2015) with the recognition that there were multiple researchers and stakeholdersi working in parallel on innovative implementation science projects in behavioral health, but that formal channels for communicating and collaborating with one another were relatively unavailable. There was a significant need for a forum within which implementation researchers and stakeholders could learn from one another, refine approaches to science and practice, and develop an implementation research agenda using common measures, methods, and research principles to improve both the frequency and quality with which behavioral health treatment implementation is evaluated. SIRC’s membership growth is a testament to this identified need with more than 1000 members from 2011 to the present.ii SIRC’s primary objectives are to: (1) foster communication and collaboration across diverse groups, including implementation researchers, intermediariesi, as well as community stakeholders (SIRC uses the term “EBP champions” for these groups) – and to do so across multiple career levels (e.g., students, early career faculty, established investigators); and (2) enhance and disseminate rigorous measures and methodologies for implementing EBPs and evaluating EBP implementation efforts. These objectives are well aligned with Glasgow and colleagues’ [4] five core tenets deemed critical for advancing implementation science: collaboration, efficiency and speed, rigor and relevance, improved capacity, and cumulative knowledge. SIRC advances these objectives and tenets through in-person conferences, which bring together multidisciplinary implementation researchers and those implementing evidence-based behavioral health interventions in the community to share their work and create professional connections and collaborations

Abstract CN11-03: SIRT3 is a mitochrondial tumor suppressor in breast cancer

Abstract It is a well-established scientific observation that mammalian cells contain fidelity or watchdog proteins that maintain the correct function of cellular organelles. Over the past several years, the Sirtuin deacetylase family protein Sirt3 has emerged as a mitochondrial fidelity protein that directs energy generation and regulates reactive oxygen species (ROS) scavenging proteins. Genetic deletion of these fidelity proteins has been shown to create a cellular environment that is permissive for the development of cellular damage associated with processes such as aging and breast ductal cell carcinogenesis. In this regard, we have previously shown that mice lacking the mitochondrial Sirtuin-3 (Sirt3) gene develop estrogen receptor (ER+) positive, p53 wild-type, poorly differentiated invasive ductal carcinomas (IDC) (Kim et al., 2010, Cancer Cell), a subtype of malignancy similar to luminal B breast cancer that is predominantly observed in older women. Mice lacking Sirt3 also exhibit increased ROS, including superoxide due to the aberrant acetylation of manganese superoxide dismutase (MnSOD) resulting in decreased enzymatic ROS scavenging activity. In addition, over expressing a mutant deacetylated-mimic MnSOD isoform, which exhibits increased SOD enzymatic activity, reversed the tumor permissive phenotype (Tao et al, 2010, Molecular Cell) observed in breast tumor cells lacking Sirt3. Finally, in collaboration with Dr. Joe Bass (Corresponding Author, Northwestern University) a link between SIRT3 and the clock proteins, in the form of mitochondrial NAD+ concentrations has been discovered. Specifically, a clock protein loop directs SIRT3, via NAD+ bioavailability, to regulate mitochondrial glycolytic and oxidative metabolism, as well as MnSOD lysine acetylation and detoxification activity. Furthermore, NAD+ supplementation decreased MnSOD acetylation and significantly restored mitochondrial function in circadian mutant mice by a mechanism involving SIRT3 activity (Peek et al., 2013, Science). These results suggest that circadian clock proteins coordinate mitochondrial metabolism, in part via the modulation of protein acetylation, to synchronize metabolic and oxidative pathways with circadian rhythms. Citation Format: David Gius. SIRT3 is a mitochrondial tumor suppressor in breast cancer. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr CN11-03.</jats:p