Variance Reduced Stochastic Gradient Descent with Neighbors

Stochastic Gradient Descent (SGD) is a workhorse in machine learning, yet its slow convergence can be a computational bottleneck. Variance reduction techniques such as SAG, SVRG and SAGA have been proposed to overcome this weakness, achieving linear convergence. However, these methods are either based on computations of full gradients at pivot points, or on keeping per data point corrections in memory. Therefore speed-ups relative to SGD may need a minimal number of epochs in order to materialize. This paper investigates algorithms that can exploit neighborhood structure in the training data to share and re-use information about past stochastic gradients across data points, which offers advantages in the transient optimization phase. As a side-product we provide a unified convergence analysis for a family of variance reduction algorithms, which we call memorization algorithms. We provide experimental results supporting our theory.Comment: Appears in: Advances in Neural Information Processing Systems 28 (NIPS 2015). 13 page

Mitophagy in the aging nervous system

Aging is characterised by the progressive accumulation of cellular dysfunction, stress, and inflammation. A large body of evidence implicates mitochondrial dysfunction as a cause or consequence of age-related diseases including metabolic disorders, neuropathies, various forms of cancer and neurodegenerative diseases. Because neurons have high metabolic demands and cannot divide, they are especially vulnerable to mitochondrial dysfunction which promotes cell dysfunction and cytotoxicity. Mitophagy neutralises mitochondrial dysfunction, providing an adaptive quality control strategy that sustains metabolic homeostasis. Mitophagy has been extensively studied as an inducible stress response in cultured cells and short-lived model organisms. In contrast, our understanding of physiological mitophagy in mammalian aging remains extremely limited, particularly in the nervous system. The recent profiling of mitophagy reporter mice has revealed variegated vistas of steady-state mitochondrial destruction across different tissues. The discovery of patients with congenital autophagy deficiency provokes further intrigue into the mechanisms that underpin neural integrity. These dimensions have considerable implications for targeting mitophagy and other degradative pathways in age-related neurological disease.Peer reviewe

Monitoring autophagy in cancer : From bench to bedside

Autophagy refers to an essential mechanism that evolved to sustain eukaryotic homeostasis and metabolism during instances of nutrient deprivation. During autophagy, intracellular cargo is encapsulated and delivered to the lysosome for elimination. Loss of basal autophagy in vivo negatively impacts cellular proteostasis, metabolism and tissue integrity. Accordingly, many drug development strategies are focused on modulating autophagic capacity in various pathophysiological states, from cancer to neurodegenerative disease. The role of autophagy in cancer is particularly complicated, as either augmenting or attenuating this process can have variable outcomes on cellular survival, proliferation and transformation. This complexity is compounded by the emergence of several selective autophagy pathways, which act to eliminate damaged or superfluous cellular components in a targeted fashion. The advent of sensitive tools to monitor autophagy pathways in vivo holds promise to clarify their importance in cancer pathophysiology. In this review, we provide an overview of autophagy in cancer biology and outline how the development of tools to study autophagy in vivo could enhance our understanding of its function for translational benefit.Peer reviewe

Lipid droplets promote efficient mitophagy

Mitophagy neutralizes defective mitochondria via lysosomal elimination. Increased levels of mitophagy hallmark metabolic transitions and are induced by iron depletion, yet its metabolic basis has not been studied in-depth. How mitophagy integrates with different homeostatic mechanisms to support metabolic integrity is incompletely understood. We examined metabolic adaptations in cells treated with deferiprone (DFP), a therapeutic iron chelator known to induce PINK1-PRKN-independent mitophagy. We found that iron depletion profoundly rewired the cellular metabolome, remodeling lipid metabolism within minutes of treatment. DGAT1-dependent lipid droplet biosynthesis occurs upstream of mitochondrial turnover, with many LDs bordering mitochondria upon iron chelation. Surprisingly, DGAT1 inhibition restricts mitophagy in vitro by lysosomal dysfunction. Genetic depletion of mdy/DGAT1 in vivo impairs neuronal mitophagy and locomotor function in Drosophila, demonstrating the physiological relevance of our findings.Non peer reviewe

Life in lights:tracking mitochondrial delivery to lysosomes in vivo

The past decade has seen an intensive and concerted research effort into the molecular regulation of mitophagy, the selective autophagy of mitochondria. Cell-based studies have implicated mitophagy in the pathology of diverse conditions ranging from cancer to neurodegeneration. However, a definitive link between mitophagy and the etiology of human disease remains to be demonstrated. Moreover, we do not know how pervasive mammalian mitophagy is in vivo and fundamental questions remain unanswered. For example, is mitophagy common to all tissues under basal conditions or does it only occur in highly oxidative tissues under stress? This paucity of knowledge is largely due to a lack of experimentally tractable tools that can measure and monitor mitophagy in tissues. Our recent work describes the development of mito-QC, a mouse model to study mitophagy at single cell resolution in vivo

Ultrasonic locating devices for central venous cannulation: meta-analysis

OBJECTIVES: To assess the evidence for the clinical effectiveness of ultrasound guided central venous cannulation. DATA SOURCES: 15 electronic bibliographic databases, covering biomedical, science, social science, health economics, and grey literature. DESIGN: Systematic review and meta-analysis of randomised controlled trials. POPULATIONS: Patients scheduled for central venous access. INTERVENTION REVIEWED: Guidance using real time two dimensional ultrasonography or Doppler needles and probes compared with the anatomical landmark method of cannulation. DATA EXTRACTION: Risk of failed catheter placement (primary outcome), risk of complications from placement, risk of failure on first attempt at placement, number of attempts to successful catheterisation, and time (seconds) to successful catheterisation. DATA SYNTHESIS: 18 trials (1646 participants) were identified. Compared with the landmark method, real time two dimensional ultrasound guidance for cannulating the internal jugular vein in adults was associated with a significantly lower failure rate both overall (relative risk 0.14, 95% confidence interval 0.06 to 0.33) and on the first attempt (0.59, 0.39 to 0.88). Limited evidence favoured two dimensional ultrasound guidance for subclavian vein and femoral vein procedures in adults (0.14, 0.04 to 0.57 and 0.29, 0.07 to 1.21, respectively). Three studies in infants confirmed a higher success rate with two dimensional ultrasonography for internal jugular procedures (0.15, 0.03 to 0.64). Doppler guided cannulation of the internal jugular vein in adults was more successful than the landmark method (0.39, 0.17 to 0.92), but the landmark method was more successful for subclavian vein procedures (1.48, 1.03 to 2.14). No significant difference was found between these techniques for cannulation of the internal jugular vein in infants. An indirect comparison of relative risks suggested that two dimensional ultrasonography would be more successful than Doppler guidance for subclavian vein procedures in adults (0.09, 0.02 to 0.38). CONCLUSIONS: Evidence supports the use of two dimensional ultrasonography for central venous cannulation

Comment on "mt-Keima detects PINK1-PRKN mitophagy in vivo with greater sensitivity than mito-QC"

Peer reviewe