MUCKE aims to mine a large volume of images, to structure them conceptually and to use this conceptual structuring in order to improve large-scale image retrieval. The last decade witnessed important progress concerning low-level image representations. However, there are a number problems which need to be solved in order to unleash the full potential of image mining in applications. The central problem with low-level representations is the mismatch between them and the human interpretation of image content. This problem can be instantiated, for instance, by the incapability of existing descriptors to capture spatial relationships between the concepts represented or by their incapability to convey an explanation of why two images are similar in a content-based image retrieval framework. We start by assessing existing local descriptors for image classification and by proposing to use co-occurrence matrices to better capture spatial relationships in images. The main focus in MUCKE is on cleaning large scale Web image corpora and on proposing image representations which are closer to the human interpretation of images. Consequently, we introduce methods which tackle these two problems and compare results to state of the art methods. Note: some aspects of this deliverable are withheld at this time as they are pending review. Please contact the authors for a preview.

http://ieeexplore.ieee.org/iel2/4524/12820/00592460.pdf

Image Processing

Treatment with the α-glucosidase inhibitor acarbose increases median lifespan by approximately 20% in male mice and 5% in females. This longevity extension differs from dietary restriction based on a number of features, including the relatively small effects on weight and the sex-specificity of the lifespan effect. By inhibiting host digestion, acarbose increases the flux of starch to the lower digestive system, resulting in changes to the gut microbiota and their fermentation products. Given the documented health benefits of short-chain fatty acids (SCFAs), the dominant products of starch fermentation by gut bacteria, this secondary effect of acarbose could contribute to increased longevity in mice. To explore this hypothesis, we compared the fecal microbiome of mice treated with acarbose to control mice at three independent study sites. Microbial communities and the concentrations of SCFAs in the feces of mice treated with acarbose were notably different from those of control mice. At all three study sites, the bloom of a single bacterial taxon was the most obvious response to acarbose treatment. The blooming populations were classified to the largely uncultured Bacteroidales family Muribaculaceae and were the same taxonomic unit at two of the three sites. Propionate concentrations in feces were consistently elevated in treated mice, while the concentrations of acetate and butyrate reflected a dependence on study site. Across all samples, Muribaculaceae abundance was strongly correlated with propionate and community composition was an important predictor of SCFA concentrations. Cox proportional hazards regression showed that the fecal concentrations of acetate, butyrate, and propionate were, together, predictive of mouse longevity even while controlling for sex, site, and acarbose. We observed a correlation between fecal SCFAs and lifespan in mice, suggesting a role of the gut microbiota in the longevity-enhancing properties of acarbose. Treatment modulated the taxonomic composition and fermentation products of the gut microbiome, while the site-dependence of the responses illustrate the challenges facing reproducibility and interpretation in microbiome studies. These results motivate future studies exploring manipulation of the gut microbial community and its fermentation products for increased longevity, testing causal roles of SCFAs in the observed effects of acarbose.

/pdf/changes-in-the-gut-microbiome-and-fermentation-products-4azi1hjd58.pdf

Changes in the gut microbiome and fermentation products concurrent with enhanced longevity in acarbose-treated mice

With an aging population that has been increasing in recent years, the need for the development of therapeutic approaches for treatment of neurodegenerative disorders (ND) has increased ND, which are characterized by the progressive loss of the structure or function of neurons, are often associated with neuronal death In spite of screening numerous drugs, currently there is no specific treatment that can cure these diseases or slow down their progression Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Huntington's disease, and prion diseases belong to ND which affect enormous numbers of people globally There are some main possible reasons for failure in the treatment of neurodegenerative diseases such as limitations introduced by the Blood-Brain Barrier (BBB), the Blood-Cerebrospinal Fluid Barrier (BCFB) and P-glycoproteins Current advances in nanotechnology present opportunities to overcome the mentioned limitations by using nanotechnology and designing nanomaterials improving the delivery of active drug candidates Some of the basic and developing strategies to overcome drug delivery impediments are the local delivery of drugs, receptor-mediated transcytosis, physicochemical disruption of the BBB, cell-penetrating peptides and magnetic disruption Recently, the application of nanoparticles has been developed to improve the efficiency of drug delivery Nanoengineered particles as nanodrugs possess the capacity to cross the BBB and also show decreased invasiveness Examples include inorganic, magnetic, polymeric and carbonic nanoparticles that have been developed to improve drug delivery efficiency Despite numerous papers published in this filed, there are some unsolved issues that need to be addressed for successful treatment of neurodegenerative diseases These are discussed herein

Nanomaterial based drug delivery systems for the treatment of neurodegenerative diseases

All animal cells use the motor cytoplasmic dynein 1 (dynein) to transport diverse cargo toward microtubule minus ends and to organize and position microtubule arrays such as the mitotic spindle. Cargo-specific adaptors engage with dynein to recruit and activate the motor, but the molecular mechanisms remain incompletely understood. Here, we use structural and dynamic nuclear magnetic resonance (NMR) analysis to demonstrate that the C-terminal region of human dynein light intermediate chain 1 (LIC1) is intrinsically disordered and contains two short conserved segments with helical propensity. NMR titration experiments reveal that the first helical segment (helix 1) constitutes the main interaction site for the adaptors Spindly (SPDL1), bicaudal D homolog 2 (BICD2), and Hook homolog 3 (HOOK3). In vitro binding assays show that helix 1, but not helix 2, is essential in both LIC1 and LIC2 for binding to SPDL1, BICD2, HOOK3, RAB-interacting lysosomal protein (RILP), RAB11 family-interacting protein 3 (RAB11FIP3), ninein (NIN), and trafficking kinesin-binding protein 1 (TRAK1). Helix 1 is sufficient to bind RILP, whereas other adaptors require additional segments preceding helix 1 for efficient binding. Point mutations in the C-terminal helix 1 of Caenorhabditis elegans LIC, introduced by genome editing, severely affect development, locomotion, and life span of the animal and disrupt the distribution and transport kinetics of membrane cargo in axons of mechanosensory neurons, identical to what is observed when the entire LIC C-terminal region is deleted. Deletion of the C-terminal helix 2 delays dynein-dependent spindle positioning in the one-cell embryo but overall does not significantly perturb dynein function. We conclude that helix 1 in the intrinsically disordered region of LIC provides a conserved link between dynein and structurally diverse cargo adaptor families that is critical for dynein function in vivo.

/pdf/a-transient-helix-in-the-disordered-region-of-dynein-light-1ntr7lrx1j.pdf

A transient helix in the disordered region of dynein light intermediate chain links the motor to structurally diverse adaptors for cargo transport.

High concentration of cytoskeletal filaments, organelles, and proteins along with the space constraints due to the axon's narrow geometry lead inevitably to intracellular physical crowding along the axon of a neuron. Local cargo movement is essential for maintaining steady cargo transport in the axon, and this may be impeded by physical crowding. Molecular motors that mediate active transport share movement mechanisms that allow them to bypass physical crowding present on microtubule tracks. Many neurodegenerative diseases, irrespective of how they are initiated, show increased physical crowding owing to the greater number of stalled organelles and structural changes associated with the cytoskeleton. Increased physical crowding may be a significant factor in slowing cargo transport to synapses, contributing to disease progression and culminating in the dying back of the neuronal process. This review explores the idea that physical crowding can impede cargo movement along the neuronal process. We examine the sources of physical crowding and strategies used by molecular motors that might enable cargo to circumvent physically crowded locations. Finally, we describe sub-cellular changes in neurodegenerative diseases that may alter physical crowding and discuss the implications of such changes on cargo movement.

/pdf/crowd-control-effects-of-physical-crowding-on-cargo-movement-2gr1y2gomh.pdf

Crowd Control: Effects of Physical Crowding on Cargo Movement in Healthy and Diseased Neurons.

We investigate the role of axonal transport in regulating neuronal mitochondrial density. We show that the density of mitochondria in the touch receptor neuron (TRN) of adult Caenorhabditis elegans is constant. Mitochondrial density and transport are controlled both by the Kinesin heavy chain and the Dynein-Dynactin complex. However, unlike in other models, the presence of mitochondria in C. elegans TRNs depends on a Kinesin light chain as well. Mutants in the three C. elegans miro genes do not alter mitochondrial density in the TRNs. Mutants in the Kinesin-1 associated proteins, UNC-16/JIP3 and UNC-76/FEZ1, show increased mitochondrial density and also have elevated levels of both the Kinesin Heavy and Light Chains in neurons. Genetic analyses suggest that, the increased mitochondrial density at the distal end of the neuronal process in unc-16 and unc-76 depends partly on Dynein. We observe a net anterograde bias in the ratio of anterograde to retrograde mitochondrial flux in the neuronal processes of unc-16 and unc-76, likely due to both increased Kinesin-1 and decreased Dynein in the neuronal processes. Our study shows that UNC-16 and UNC-76 indirectly limit mitochondrial density in the neuronal process by maintaining a balance in anterograde and retrograde mitochondrial axonal transport.

/pdf/unc-16-jip3-and-unc-76-fez1-limit-the-density-of-52h4653jm2.pdf

UNC-16/JIP3 and UNC-76/FEZ1 limit the density of mitochondria in C. elegans neurons by maintaining the balance of anterograde and retrograde mitochondrial transport.

We investigate the role of axonal transport in regulating neuronal mitochondrial density. We show that the density of mitochondria in the touch receptor neuron (TRN) of adult Caenorhabditis elegans is constant. Mitochondrial density and transport are controlled both by the Kinesin heavy chain and the Dynein-Dynactin complex. However, unlike in other models, the presence of mitochondria in C. elegans TRNs depends on Kinesin light chain as well. Mutants in the three C. elegans miro genes do not alter mitochondrial density in the TRNs. Mutants in the Kinesin-1 associated proteins, UNC-16/JIP3 and UNC-76/FEZ1, show increased mitochondrial density and also have elevated levels of both the Kinesin Heavy and Light Chains in neurons. Genetic analyses suggest that, the increased mitochondrial density at the distal end of the neuronal process in unc-16 and unc-76 depends partly on Dynein. We observe a net anterograde bias in the ratio of anterograde to retrograde mitochondrial flux in the neuronal processes of unc-16 and unc-76, likely due to both increased Kinesin-1 and decreased Dynein in the neuronal processes. Our study shows that UNC-16 and UNC-76 indirectly limit mitochondrial density in the neuronal process maintaining a balance in anterograde and retrograde mitochondrial axonal transport.

/pdf/unc-16-jip3-and-unc-76-fez1-limit-the-density-of-oflhzx3qbp.pdf

UNC-16/JIP3 and UNC-76/FEZ1 limit the density of mitochondria in C. elegans neurons by maintaining the balance of anterograde and retrograde mitochondrial transport

Swathi Devireddy

Papers

UNC-16/JIP3 and UNC-76/FEZ1 limit the density of mitochondria in C. elegans neurons by maintaining the balance of anterograde and retrograde mitochondrial transport.

UNC-16/JIP3 and UNC-76/FEZ1 limit the density of mitochondria in C. elegans neurons by maintaining the balance of anterograde and retrograde mitochondrial transport