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Digital health and virtual care (DH/VC) interventions have been rapidly transforming healthcare systems, offering enormous potential to bridge gaps in healthcare access and deliver person-centred interventions to equity-deserving populations. Working in partnership with patients, caregivers and communities to meaningfully integrate lived experience perspectives into DH/VC interventions can help ensure that diverse needs are met. In this commentary, we propose a consolidated set of principles for co-designing equity-informed DH/VC interventions. We also identify how these principles can be leveraged through resources and opportunities offered by Healthcare Excellence Canada and others.
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Salud Digital , Humanos , CanadáRESUMEN
Stimulation of adipocyte ß-adrenergic receptors (ß-ARs) induces expression of uncoupling protein 1 (UCP1), promoting nonshivering thermogenesis. Association of ß-ARs with a lysine-myristoylated form of A kinase-anchoring protein 12 (AKAP12, also known as gravin-α) is required for downstream signaling that culminates in UCP1 induction. Conversely, demyristoylation of gravin-α by histone deacetylase 11 (HDAC11) suppresses this pathway. Whether inhibition of HDAC11 in adipocytes is sufficient to drive UCP1 expression independently of ß-ARs is not known. Here, we demonstrate that adipocyte-specific deletion of HDAC11 in mice leads to robust induction of UCP1 in adipose tissue (AT), resulting in increased body temperature. These effects are mimicked by treating mice in vivo or human AT ex vivo with an HDAC11-selective inhibitor, FT895. FT895 triggers biphasic, gravin-α myristoylation-dependent induction of UCP1 protein expression, with a noncanonical acute response that is posttranscriptional and independent of protein kinase A (PKA), and a delayed response requiring PKA activity and new Ucp1 mRNA synthesis. Remarkably, HDAC11 inhibition promotes UCP1 expression even in models of adipocyte catecholamine resistance where ß-AR signaling is blocked. These findings define cell-autonomous, multimodal roles for HDAC11 as a suppressor of thermogenesis, and highlight the potential of inhibiting HDAC11 to therapeutically alter AT phenotype independently of ß-AR stimulation.
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Adipocitos , Catecolaminas , Inhibidores de Histona Desacetilasas , Histona Desacetilasas , Animales , Humanos , Ratones , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Tejido Adiposo Pardo/metabolismo , Catecolaminas/farmacología , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Termogénesis/genética , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Inhibidores de Histona Desacetilasas/farmacologíaRESUMEN
Kinesin-5 crosslinks and slides apart microtubules to assemble, elongate, and maintain the mitotic spindle. Kinesin-5 is a tetramer, where two N-terminal motor domains are positioned at each end of the motor, and the coiled-coil stalk domains are organized into a tetrameric bundle through the bipolar assembly (BASS) domain. To dissect the function of the individual structural elements of the motor, we constructed a minimal kinesin-5 tetramer (mini-tetramer). We determined the x-ray structure of the extended, 34-nm BASS domain. Guided by these structural studies, we generated active bipolar kinesin-5 mini-tetramer motors from Drosophila melanogastor and human orthologues which are half the length of native kinesin-5. We then used these kinesin-5 mini-tetramers to examine the role of two unique structural adaptations of kinesin-5: 1) the length and flexibility of the tetramer, and 2) the C-terminal tails which interact with the motor domains to coordinate their ATPase activity. The C-terminal domain causes frequent pausing and clustering of kinesin-5. By comparing microtubule crosslinking and sliding by mini-tetramer and full-length kinesin-5, we find that both the length and flexibility of kinesin-5 and the C-terminal tails govern its ability to crosslink microtubules. Once crosslinked, stiffer mini-tetramers slide antiparallel microtubules more efficiently than full-length motors.
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Cinesinas , Microtúbulos , Humanos , Animales , Huso Acromático , Análisis por Conglomerados , DrosophilaRESUMEN
Stimulation of adipocyte ß-adrenergic receptors (ß-ARs) induces expression of uncoupling protein 1 (UCP1), promoting non-shivering thermogenesis. Association of ß-ARs with a lysine myristoylated form of A-kinase anchoring protein 12 (AKAP12)/gravin-α is required for downstream signaling that culminates in UCP1 induction. Conversely, demyristoylation of gravin-α by histone deacetylase 11 (HDAC11) suppresses this pathway. Whether inhibition of HDAC11 in adipocytes is sufficient to drive UCP1 expression independently of ß-ARs is not known. Here, we demonstrate that adipocyte-specific deletion of HDAC11 in mice leads to robust induction of UCP1 in adipose tissue (AT), resulting in increased body temperature. These effects are mimicked by treating mice in vivo or human AT ex vivo with an HDAC11-selective inhibitor, FT895. FT895 triggers biphasic, gravin-α myristoylation-dependent induction of UCP1 protein expression, with a non-canonical acute response that is post-transcriptional and independent of protein kinase A (PKA), and a delayed response requiring PKA activity and new Ucp1 mRNA synthesis. Remarkably, HDAC11 inhibition promotes UCP1 expression even in models of adipocyte catecholamine resistance where ß-AR signaling is blocked. These findings define cell autonomous, multi-modal roles for HDAC11 as a suppressor of thermogenesis, and highlight the potential of inhibiting HDAC11 to therapeutically alter AT phenotype independently of ß-AR stimulation.
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Dementia is a growing concern in Canada, affecting peoples' health and raising the cost of care. Between June and October 2019, we conducted an environmental scan to identify primary care models, strategies, and resources for dementia care from 11 pre-selected countries and assess their impact on quality-of-life measures. Search strategies included a rapid scoping review, grey literature search, and discussions with stakeholders. Eighteen primary care-based models of dementia care were identified. Common factors include team-based care, centralized care/case coordination, individual treatment plans, a stepped-care approach, and support for care partners. Five provinces had released a dementia strategy. Evidence of positive outcomes supported primary care-based models for dementia care, although only one model demonstrated evidence of impact on quality of life. Although these findings are encouraging, further research is needed to identify primary care-based models of dementia care that demonstrably improve quality of life for people living with dementia and their care partners.
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Demencia , Calidad de Vida , Humanos , Cuidadores , Canadá , Atención Primaria de Salud , Demencia/terapiaRESUMEN
Passive stiffness of the heart is determined largely by extracellular matrix and titin, which functions as a molecular spring within sarcomeres. Titin stiffening is associated with the development of diastolic dysfunction (DD), while augmented titin compliance appears to impair systolic performance in dilated cardiomyopathy. We found that myofibril stiffness was elevated in mice lacking histone deacetylase 6 (HDAC6). Cultured adult murine ventricular myocytes treated with a selective HDAC6 inhibitor also exhibited increased myofibril stiffness. Conversely, HDAC6 overexpression in cardiomyocytes led to decreased myofibril stiffness, as did ex vivo treatment of mouse, rat, and human myofibrils with recombinant HDAC6. Modulation of myofibril stiffness by HDAC6 was dependent on 282 amino acids encompassing a portion of the PEVK element of titin. HDAC6 colocalized with Z-disks, and proteomics analysis suggested that HDAC6 functions as a sarcomeric protein deacetylase. Finally, increased myofibril stiffness in HDAC6-deficient mice was associated with exacerbated DD in response to hypertension or aging. These findings define a role for a deacetylase in the control of myofibril function and myocardial passive stiffness, suggest that reversible acetylation alters titin compliance, and reveal the potential of targeting HDAC6 to manipulate the elastic properties of the heart to treat cardiac diseases.
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Miofibrillas , Sarcómeros , Animales , Conectina/química , Conectina/genética , Conectina/metabolismo , Histona Desacetilasa 6/genética , Histona Desacetilasa 6/metabolismo , Humanos , Ratones , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Miofibrillas/metabolismo , Ratas , Sarcómeros/metabolismoRESUMEN
The production effect is the superior memory for items read aloud as opposed to silently at the time of study. The distinctiveness account holds that produced items benefit from the encoding of additional elements associated with the act of production. If so, then that benefit should be consistent regardless of item type. Three experiments, using three different sets of materials and three different methods, tested this hypothesis. Experiment 1, using recognition testing, showed consistent production benefits for high and low frequency words. Experiment 2, using free recall, showed consistent production increments for pictures and words. Experiment 3, using incidental learning, showed consistent production benefits for recognition of nonwords and words. Taken together, these results fit with the distinctiveness account: Production at encoding dependably adds information to the memory record, regardless of item type or method of testing, producing a consistently reliable memory benefit.
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Recuerdo Mental , Reconocimiento en Psicología , Humanos , Aprendizaje , LecturaRESUMEN
N-myristoylation on glycine is an irreversible modification that has long been recognized to govern protein localization and function. In contrast, the biological roles of lysine myristoylation remain ill-defined. We demonstrate that the cytoplasmic scaffolding protein, gravin-α/A kinase-anchoring protein 12, is myristoylated on two lysine residues embedded in its carboxyl-terminal protein kinase A (PKA) binding domain. Histone deacetylase 11 (HDAC11) docks to an adjacent region of gravin-α and demyristoylates these sites. In brown and white adipocytes, lysine myristoylation of gravin-α is required for signaling via ß2- and ß3-adrenergic receptors (ß-ARs), which are G protein-coupled receptors (GPCRs). Lysine myristoylation of gravin-α drives ß-ARs to lipid raft membrane microdomains, which results in PKA activation and downstream signaling that culminates in protective thermogenic gene expression. These findings define reversible lysine myristoylation as a mechanism for controlling GPCR signaling and highlight the potential of inhibiting HDAC11 to manipulate adipocyte phenotypes for therapeutic purposes.
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Adipocitos/metabolismo , Histona Desacetilasas/metabolismo , Lisina/metabolismo , Células 3T3-L1 , Acilación , Animales , Regulación de la Expresión Génica , Histona Desacetilasas/genética , Humanos , Lisina/química , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Pulmonary arterial hypertension (PAH) is a devastating disease of the cardiopulmonary system caused by the narrowing of the pulmonary arteries, leading to increased vascular resistance and pressure. This leads to right ventricle remodeling, dysfunction, and eventually, death. While conventional therapies have largely focused on targeting vasodilation, other pathological features of PAH including aberrant inflammation, mitochondrial dynamics, cell proliferation, and migration have not been well explored. Thus, despite some recent improvements in PAH treatment, the life expectancy and quality of life for patients with PAH remains poor. Showing many similarities to cancers, PAH is characterized by increased pulmonary arterial smooth muscle cell proliferation, decreased apoptotic signaling pathways, and changes in metabolism. The recent successes of therapies targeting epigenetic modifiers for the treatment of cancer has prompted epigenetic research in PAH, revealing many new potential therapeutic targets. In this minireview we discuss the emergence of epigenetic dysregulation in PAH and highlight epigenetic-targeting compounds that may be effective for the treatment of PAH.
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Epigénesis Genética , Genoma Humano , Pulmón/metabolismo , Hipertensión Arterial Pulmonar , Arteria Pulmonar/metabolismo , Calidad de Vida , Animales , Apoptosis , Humanos , Inflamación/genética , Inflamación/metabolismo , Inflamación/terapia , Pulmón/patología , Hipertensión Arterial Pulmonar/genética , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/terapia , Transducción de SeñalRESUMEN
OBJECTIVES: To evaluate the impact of a multicenter intervention to reduce potentially inappropriate antipsychotic use in Canadian nursing homes at the individual and facility levels. DESIGN: Longitudinal, population-based cohort study to evaluate the Canadian Foundation for Healthcare Improvement's Spreading Healthcare Innovations Initiative to reduce potentially inappropriate antipsychotic use in 6 provinces/territories. SETTING AND PARTICIPANTS: Adults in nursing homes in 6 provinces/territories in Canada between 2014 and 2016. The sample involved 4927 residents in 45 intervention homes and 122,570 residents in 1193 control homes in the first quarter of the study. MEASURES: Assessment data based on the Resident Assessment Instrument 2.0 were used in both settings to track antipsychotic use and to obtain risk-adjusters for a quality indicator on potentially inappropriate use. INTERVENTION: Quality improvement teams in participating organizations were provided with education, training, and support to implement localized strategies intended to reduce antipsychotic medication use in residents without diagnosis of psychosis. RESULTS: At the resident level, we found that the odds of remaining on potentially inappropriate antipsychotics were 0.75 in intervention compared with control homes after adjusting for age, sex, aggressive behavior, and cognition. These findings were evident within the pooled Canadian data as well as within provinces. At the facility level, the intervention homes had greater improvements in risk-adjusted quality indicator performance than the control homes, and this was true for the worst, median, and best-performing homes at baseline. There was no major change in the quality indicator for worsening of behavior symptoms. CONCLUSIONS/IMPLICATIONS: The Canadian Foundation for Healthcare Improvement intervention was associated with a reduction in potentially inappropriate antipsychotic use at both the individual and facility levels of analysis. This improvement in performance was independent of secular trends toward reduced antipsychotic use in participating provinces. This suggests that substantial improvements in medication use may be achieved through targeted, collaborative quality improvement initiatives in long-term care.
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Antipsicóticos , Adulto , Antipsicóticos/uso terapéutico , Canadá , Estudios de Cohortes , Humanos , Cuidados a Largo Plazo , Casas de SaludRESUMEN
High-density lipoprotein (HDL) metabolism is facilitated in part by scavenger receptor class B, type 1 (SR-B1) that mediates HDL uptake into cells. Higher levels of HDL have been associated with protection in other diseases, however, its role in prostate cancer is not definitive. SR-B1 is up-regulated in prostate cancer tissue, suggesting a possible role of this receptor in tumor progression. Here, we report that knockout (KO) of SR-B1 in both human and mouse prostate cancer cell lines through CRISPR/Cas9-mediated genome editing reduces HDL uptake into the prostate cancer cells and reduces their proliferation in response to HDL. In vivo studies using syngeneic SR-B1 WT (SR-B1+/+) and SR-B1 KO (SR-B1-/-) prostate cancer cells in WT and apolipoprotein-AI KO (apoA1-KO) C57BL/6J mice revealed that WT hosts, containing higher levels of total and HDL-cholesterol, grew larger tumors than apoA1-KO hosts with lower levels of total and HDL-cholesterol. Furthermore, SR-B1-/- prostate cancer cells formed smaller tumors in WT hosts than SR-B1+/+ cells in the same host model. Increased tumor volume was overall associated with reduced survival. We conclude that knocking out SR-B1 in prostate cancer tumors reduces HDL-associated increases in prostate cancer cell proliferation and disease progression.
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Progresión de la Enfermedad , Lipoproteínas HDL/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Receptores Depuradores de Clase B/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Colesterol/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones Endogámicos C57BL , Neoplasias de la Próstata/genética , Regulación hacia Arriba/genéticaRESUMEN
Alzheimer's disease (AD) is a debilitating neurodegenerative disorder affecting millions worldwide. Currently, there are only four approved treatments for AD, which improve symptoms modestly. AD is believed to be caused by the formation of intercellular plaques and intracellular tangles in the brain, but thus far all new drugs which target these pathologies have failed clinical trials. New research highlights the link between AD and Type II Diabetes (T2D), and some believe that AD is actually a brain specific form of it termed Type III Diabetes (T3D). Drugs which are currently approved for the treatment of T2D, such as metformin, have shown promising results in improving cognitive function and even preventing the development of AD in diabetic patients. Recent studies shed light on the relationship between the brain and cardiovascular system in which the brain and heart communicate with one another via the vasculature to regulate fluid and nutrient homeostasis. This line of research reveals how the brain-heart axis regulates hypertension and diabetes, both of which can impact cognitive function. In this review we survey past and ongoing research and clinical trials for AD, and argue that AD is a complex and systemic disorder which requires comprehensive approaches beyond the brain for effective prevention and/or treatment.
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Kinesin-5 motors organize mitotic spindles by sliding apart microtubules. They are homotetramers with dimeric motor and tail domains at both ends of a bipolar minifilament. Here, we describe a regulatory mechanism involving direct binding between tail and motor domains and its fundamental role in microtubule sliding. Kinesin-5 tails decrease microtubule-stimulated ATP-hydrolysis by specifically engaging motor domains in the nucleotide-free or ADP states. Cryo-EM reveals that tail binding stabilizes an open motor domain ATP-active site. Full-length motors undergo slow motility and cluster together along microtubules, while tail-deleted motors exhibit rapid motility without clustering. The tail is critical for motors to zipper together two microtubules by generating substantial sliding forces. The tail is essential for mitotic spindle localization, which becomes severely reduced in tail-deleted motors. Our studies suggest a revised microtubule-sliding model, in which kinesin-5 tails stabilize motor domains in the microtubule-bound state by slowing ATP-binding, resulting in high-force production at both homotetramer ends.
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Cinesinas/metabolismo , Microtúbulos/metabolismo , Adenosina Difosfato/metabolismo , Adenosina Trifosfato/metabolismo , Microscopía por Crioelectrón , Humanos , Hidrólisis , Cinesinas/química , Cinesinas/ultraestructura , Cinética , Unión Proteica , Dominios Proteicos , Huso Acromático/metabolismoRESUMEN
Over the past two decades, it has become increasingly evident that microRNAs (miRNA) play a major role in human diseases such as cancer and cardiovascular diseases. Moreover, their easy detection in circulation has made them a tantalizing target for biomarkers of disease. This surge in interest has led to the accumulation of a vast amount of miRNA expression data, prediction tools, and repositories. We used the Human microRNA Disease Database (HMDD) to discover miRNAs which shared expression patterns in the related diseases of ischemia/reperfusion injury, coronary artery disease, stroke, and obesity as a model to identify miRNA candidates for biomarker and/or therapeutic intervention in complex human diseases. Our analysis identified a single miRNA, hsa-miR-21, which was casually linked to all four pathologies, and numerous others which have been detected in the circulation in more than one of the diseases. Target analysis revealed that hsa-miR-21 can regulate a number of genes related to inflammation and cell growth/death which are major underlying mechanisms of these related diseases. Our study demonstrates a model for researchers to use HMDD in combination with gene analysis tools to identify miRNAs which could serve as biomarkers and/or therapeutic targets of complex human diseases.
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The sarcolemmal membrane associated proteins (SLMAPs) belong to the super family of tail anchored membrane proteins which serve diverse roles in biology including cell growth, protein trafficking and ion channel regulation. Mutations in human SLMAP have been linked to Brugada syndrome with putative deficits in trafficking of the sodium channel (Nav1.5) to the cell membrane resulting in aberrant electrical activity and heart function. Three main SLMAP isoforms (SLMAP1 (35 kDa), SLMAP2 (45 kDa), and SLMAP3 (91 kDa)) are expressed in myocardium but their precise role remains to be defined. Here we generated transgenic (Tg) mice with cardiac-specific expression of the SLMAP3 isoform during postnatal development which present with a significant decrease (20%) in fractional shortening and (11%) in cardiac output at 5 weeks of age. There was a lack of any notable cardiac remodeling (hypertrophy, fibrosis or fetal gene activation) in Tg hearts but the electrocardiogram indicated a significant increase (14%) in the PR interval and a decrease (43%) in the R amplitude. Western blot analysis indicated a selective and significant decrease (55%) in protein levels of Nav1.5 while 45% drop in its transcript levels were detectable by qRT-PCR. Significant decreases in the protein and transcript levels of the calcium transport system of the sarcoplasmic reticulum (SERCA2a/PLN) were also evident in Tg hearts. These data reveal a novel role for SLMAP3 in the selective regulation of important ion transport proteins at the level of gene expression and suggest that it may be a unique target in cardiovascular function and disease.
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Corazón/fisiología , Proteínas de la Membrana/fisiología , Miocardio/metabolismo , Animales , Femenino , Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Contracción Miocárdica/genética , Contracción Miocárdica/fisiología , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismoRESUMEN
BACKGROUND: It is widely recognized that the prevalence of obesity and comorbidities including prediabetes and type 2 diabetes continue to increase worldwide. Results from a 24-week Diabetes Prevention Program (DPP) fully mobile pilot intervention were previously published showing promising evidence of the usefulness of DPP-based eHealth interventions on weight loss. OBJECTIVE: This pilot study extends previous findings to evaluate weight loss results of core (up to week 16) and maintenance (postcore weeks) DPP interventions at 65 weeks from baseline. METHODS: Originally, 140 participants were invited and 43 overweight or obese adult participants with a diagnosis of prediabetes signed up to receive a 24-week virtual DPP with human coaching through a mobile platform. At 65 weeks, this pilot study evaluates weight loss and engagement in maintenance participants by means of repeated measures analysis of variances and backward multiple linear regression to examine predictors of weight loss. Last observation carried forward was used for endpoint measurements. RESULTS: At 65 weeks, mean weight loss was 6.15% in starters who read 1 or more lessons per week on 4 or more core weeks, 7.36% in completers who read 9 or more lessons per week on core weeks, and 8.98% in maintenance completers who did any action in postcore weeks (all P<.001). Participants were highly engaged, with 80% (47/59) of the sample completing 9 lessons or more and 69% (32/47) of those completing the maintenance phase. In-app actions related to self-monitoring significantly predicted weight loss. CONCLUSIONS: In comparison to eHealth programs, this pilot study shows that a fully mobile DPP can produce transformative weight loss. A fully mobile DPP intervention resulted in significant weight loss and high engagement during the maintenance phase, providing evidence for long-term potential as an alternative to in-person DPP by removing many of the barriers associated with in-person and other forms of virtual DPP.
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Numerous posttranslational modifications have been described in kinesins, but their consequences on motor mechanics are largely unknown. We investigated one of these-acetylation of lysine 146 in Eg5-by creating an acetylation mimetic lysine to glutamine substitution (K146Q). Lysine 146 is located in the α2 helix of the motor domain, where it makes an ionic bond with aspartate 91 on the neighboring α1 helix. Molecular dynamics simulations predict that disrupting this bond enhances catalytic site-neck linker coupling. We tested this using structural kinetics and single-molecule mechanics and found that the K146Q mutation increases motor performance under load and coupling of the neck linker to catalytic site. These changes convert Eg5 from a motor that dissociates from the microtubule at low load into one that is more tightly coupled and dissociation resistant-features shared by kinesin 1. These features combined with the increased propensity to stall predict that the K146Q Eg5 acetylation mimetic should act in the cell as a "brake" that slows spindle pole separation, and we have confirmed this by expressing this modified motor in mitotically active cells. Thus, our results illustrate how a posttranslational modification of a kinesin can be used to fine tune motor behavior to meet specific physiological needs.
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Cinesinas/química , Cinesinas/metabolismo , Mitosis/fisiología , Secuencia de Aminoácidos , Fenómenos Biomecánicos , Células HeLa , Humanos , Modelos Moleculares , Mutación , Conformación ProteicaRESUMEN
The E2F/Rb pathway regulates cell growth, differentiation, and death. In particular, E2F1 promotes apoptosis in all cells including those of the heart. E2F6, which represses E2F activity, was found to induce dilated cardiomyopathy in the absence of apoptosis in murine post-natal heart. Here we evaluate the anti-apoptotic potential of E2F6 in neonatal cardiomyocytes (NCM) from E2F6-Tg hearts which showed significantly less caspase-3 cleavage, a lower Bax/Bcl2 ratio, and improved cell viability in response to CoCl2 exposure. This correlated with a decrease in the pro-apoptotic E2F3 protein levels. In contrast, no difference in apoptotic markers or cell viability was observed in response to Doxorubicin (Dox) treatment between Wt and Tg-NCM. Dox caused a rapid and dramatic loss of the E2F6 protein in Tg-NCM within 6h and was undetectable after 12h. The level of e2f6 transcript was unchanged in Wt NCM, but was dramatically decreased in Tg cells in response to both Dox and CoCl2. This was related to an impact of the drugs on the α-myosin heavy chain promoter used to drive the E2F6 transgene. By comparison in HeLa, Dox induced apoptosis through upregulation of endogenous E2F1 involving post-transcriptional mechanisms, while E2F6 was down regulated with induction of the Checkpoint kinase-1 and proteasome degradation. These data imply that E2F6 serves to modulate E2F activity and protect cells including cardiomyocytes from apoptosis and improve survival. Strategies to modulate E2F6 levels may be therapeutically useful to mitigate cell death associated disorders.