cis-Inhibition of Notch by Endogenous Delta Biases the Outcome of Lateral Inhibition

SummaryLateral inhibition mediated by Delta/Notch (Dl/N) signaling is used throughout development to limit the number of initially equivalent cells that adopt a particular fate [1–3]. Although adjacent cells express both Dl ligand and N receptor, signaling between them ultimately occurs in only one direction. Classically, this has been explained entirely by feedback: activated N can downregulate Dl, amplifying even slight asymmetries in the Dl or N activities of adjacent cells [1–5]. Here, however, we present an example of lateral inhibition in which unidirectional signaling depends instead on Dl's ability to inhibit N within the same cell, a phenomenon known as cis-inhibition [6–11]. By genetically manipulating individual R1/R6/R7 photoreceptor precursors in the Drosophila eye, we show that loss of Dl-mediated cis-inhibition reverses the direction of lateral signaling. Based on our finding that Dl in R1/R6s requires endocytosis to trans-activate but not to cis-inhibit N, we reexamine previously published data from other examples of lateral inhibition. We conclude that cis-inhibition generally influences the direction of Dl/N signaling and should therefore be included in standard models of lateral inhibition

Distinct Lysosomal Network Protein Profiles in Parkinsonian Syndrome Cerebrospinal Fluid.

BackgroundClinical diagnosis of parkinsonian syndromes like Parkinson's disease (PD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) is hampered by overlapping symptomatology and lack of diagnostic biomarkers, and definitive diagnosis is only possible post-mortem.ObjectiveSince impaired protein degradation plays an important role in many neurodegenerative disorders, we hypothesized that profiles of select lysosomal network proteins in cerebrospinal fluid could be differentially expressed in these parkinsonian syndromes.MethodsCerebrospinal fluid samples were collected from PD patients (n = 18), clinically diagnosed 4-repeat tauopathy patients; corticobasal syndrome (CBS) (n = 3) and PSP (n = 8); and pathologically diagnosed PSP (n = 8) and CBD patients (n = 7). Each patient set was compared to its appropriate control group consisting of age and gender matched individuals. Select lysosomal network protein levels were detected via Western blotting. Factor analysis was used to test the diagnostic sensitivity, specificity and accuracy of the select lysosomal network protein expression profiles.ResultsPD, CBD and PSP were markedly different in their cerebrospinal fluid lysosomal network protein profiles. Lysosomal-associated membrane proteins 1 and 2 were significantly decreased in PD; early endosomal antigen 1 was decreased and lysozyme increased in PSP; and lysosomal-associated membrane proteins 1 and 2, microtubule-associated protein 1 light chain 3 and lysozyme were increased in CBD. A panel of lysosomal-associated membrane protein 2, lysozyme and microtubule-associated protein 1 light chain discriminated between controls, PD and 4-repeat tauopathies.ConclusionsThis study offers proof of concept that select lysosomal network proteins are differentially expressed in cerebrospinal fluid of Parkinson's disease, corticobasal syndrome and progressive supranuclear palsy. Lysosomal network protein analysis could be further developed as a diagnostic fluid biomarker in parkinsonian syndromes

Peripheral Innate Immune Activation Correlates With Disease Severity in GRN Haploinsufficiency.

Objective: To investigate associations between peripheral innate immune activation and frontotemporal lobar degeneration (FTLD) in progranulin gene (GRN) haploinsufficiency. Methods: In this cross-sectional study, ELISA was used to measure six markers of innate immunity (sCD163, CCL18, LBP, sCD14, IL-18, and CRP) in plasma from 30 GRN mutation carriers (17 asymptomatic, 13 symptomatic) and 29 controls. Voxel based morphometry was used to model associations between marker levels and brain atrophy in mutation carriers relative to controls. Linear regression was used to model relationships between plasma marker levels with mean frontal white matter integrity [fractional anisotropy (FA)] and the FTLD modified Clinical Dementia Rating Scale sum of boxes score (FTLD-CDR SB). Results: Plasma sCD163 was higher in symptomatic GRN carriers [mean 321 ng/ml (SD 125)] compared to controls [mean 248 ng/ml (SD 58); p < 0.05]. Plasma CCL18 was higher in symptomatic GRN carriers [mean 56.9 pg/ml (SD 19)] compared to controls [mean 40.5 pg/ml (SD 14); p < 0.05]. Elevation of plasma LBP was associated with white matter atrophy in the right frontal pole and left inferior frontal gyrus (p FWE corrected <0.05) in all mutation carriers relative to controls. Plasma LBP levels inversely correlated with bilateral frontal white matter FA (R2 = 0.59, p = 0.009) in mutation carriers. Elevation in plasma was positively correlated with CDR-FTLD SB (b = 2.27 CDR units/μg LBP/ml plasma, R2 = 0.76, p = 0.003) in symptomatic carriers. Conclusion: FTLD-GRN is associated with elevations in peripheral biomarkers of macrophage-mediated innate immunity, including sCD163 and CCL18. Clinical disease severity and white matter integrity are correlated with blood LBP, suggesting a role for peripheral immune activation in FTLD-GRN

On the Progenitor System of the Type Iax Supernova 2014dt in M61

We present pre-explosion and post-explosion Hubble Space Telescope images of the Type Iax supernova (SN Iax) 2014dt in M61. After astrometrically aligning these images, we do not detect any stellar sources at the position of the SN in the pre-explosion images to relatively deep limits (3 sigma limits of M_F438W > -5.0 mag and M_F814W > -5.9 mag). These limits are similar to the luminosity of SN 2012Z's progenitor system (M_F435W = -5.43 +/- 0.15 and M_F814W = -5.24 +/- 0.16 mag), the only probable detected progenitor system in pre-explosion images of a SN Iax, and indeed, of any white dwarf supernova. SN 2014dt is consistent with having a C/O white-dwarf primary/helium-star companion progenitor system, as was suggested for SN 2012Z, although perhaps with a slightly smaller or hotter donor. The data are also consistent with SN 2014dt having a low-mass red giant or main-sequence star companion. The data rule out main-sequence stars with M_init > 16 M_sun and most evolved stars with M_init > 8 M_sun as being the progenitor of SN 2014dt. Hot Wolf-Rayet stars are also allowed, but the lack of nearby bright sources makes this scenario unlikely. Because of its proximity (D = 12 Mpc), SN 2014dt is ideal for long-term monitoring, where images in ~2 years may detect the companion star or the luminous bound remnant of the progenitor white dwarf.Comment: 5 pages, 3 figures, submitted to ApJ

Personalized human computation

Significant effort in machine learning and information retrieval has been devoted to identifying personalized content such as recommendations and search results. Personalized human computation has the potential to go beyond existing techniques like collaborative filtering to provide personalized results on demand, over personal data, and for complex tasks. This work-in-progress compares two approaches to personalized human computation. In both, users annotate a small set of training examples which are then used by the crowd to annotate unseen items. In the first approach, which we call taste-matching, crowd members are asked to annotate the same set of training examples, and the ratings of similar users on other items are then used to infer personalized ratings. In the second approach, taste-grokking, the crowd is presented with the training examples and asked to use them predict the ratings of the target user on other items

Matching and Grokking: Approaches to Personalized Crowdsourcing

Personalization in computing helps tailor content to a person’s individual tastes. As a result, the tasks that benefit from personalization are inherently subjective. Many of the most robust approaches to personalization rely on large sets of other people’s preferences. However, existing preference data is not always available. In these cases we propose leveraging online crowds to provide on-demand personalization. We introduce and evaluate two methods for personalized crowdsourcing: taste-matching for finding crowd workers that are similar to a personalization target, and taste-grokking, where crowd workers explicitly predict the requester’s tastes. Both approaches show improvement over a non-personalized baseline, and have various benefits and drawbacks that are discussed

Demonstration of Qurk: A Query Processor for Human Operators

Crowdsourcing technologies such as Amazon's Mechanical Turk ("MTurk") service have exploded in popularity in recent years. These services are increasingly used for complex human-reliant data processing tasks, such as labelling a collection of images, combining two sets of images to identify people that appear in both, or extracting sentiment from a corpus of text snippets. There are several challenges in designing a workflow that filters, aggregates, sorts and joins human-generated data sources. Currently, crowdsourcing-based workflows are hand-built, resulting in increasingly complex programs. Additionally, developers must hand-optimize tradeoffs among monetary cost, accuracy, and time to completion of results. These challenges are well-suited to a declarative query interface that allows developers to describe their worflow at a high level and automatically optimizes workflow and tuning parameters. In this demonstration, we will present Qurk, a novel query system that allows human-based processing for relational databases. The audience will interact with the system to build queries and monitor their progress. The audience will also see Qurk from an MTurk user's perspective, and complete several tasks to better understand how a query is processed

Cues, context, and long-term memory: the role of the retrosplenial cortex in spatial cognition

Spatial navigation requires representations of landmarks and other navigation cues. The retrosplenial cortex (RSC) is anatomically positioned between limbic areas important for memory formation, such as the hippocampus and the anterior thalamus, and cortical regions along the dorsal stream known to contribute importantly to long-term spatial representation, such as the posterior parietal cortex. Damage to the RSC severely impairs allocentric representations of the environment, including the ability to derive navigational information from landmarks. The specific deficits seen in tests of human and rodent navigation suggest that the RSC supports allocentric representation by processing the stable features of the environment and the spatial relationships among them. In addition to spatial cognition, the RSC plays a key role in contextual and episodic memory. The RSC also contributes importantly to the acquisition and consolidation of long-term spatial and contextual memory through its interactions with the hippocampus. Within this framework, the RSC plays a dual role as part of the feedforward network providing sensory and mnemonic input to the hippocampus and as a target of the hippocampal-dependent systems consolidation of long-term memory