Deep Archetypal Analysis

"Deep Archetypal Analysis" generates latent representations of high-dimensional datasets in terms of fractions of intuitively understandable basic entities called archetypes. The proposed method is an extension of linear "Archetypal Analysis" (AA), an unsupervised method to represent multivariate data points as sparse convex combinations of extremal elements of the dataset. Unlike the original formulation of AA, "Deep AA" can also handle side information and provides the ability for data-driven representation learning which reduces the dependence on expert knowledge. Our method is motivated by studies of evolutionary trade-offs in biology where archetypes are species highly adapted to a single task. Along these lines, we demonstrate that "Deep AA" also lends itself to the supervised exploration of chemical space, marking a distinct starting point for de novo molecular design. In the unsupervised setting we show how "Deep AA" is used on CelebA to identify archetypal faces. These can then be superimposed in order to generate new faces which inherit dominant traits of the archetypes they are based on.Comment: Published at the German Conference on Pattern Recognition 2019 (GCPR

Understanding constraint expressions in large conceptual schemas by automatic filtering

Human understanding of constraint expressions (also called schema rules) in large conceptual schemas is very di cult. This is due to the fact that the elements (entity types, attributes, relationship types) involved in an expression are de ned in di fferent places in the schema, which may be very distant from each other and embedded in an intricate web of irrelevant elements. The problem is insignifi cant when the conceptual schema is small, but very signi cant when it is large. In this paper we describe a novel method that, given a set of constraint expressions and a large conceptual schema, automatically filters the conceptual schema, obtaining a smaller one that contains the elements of interest for the understanding of the expressions. We also show the application of the method to the important case of understanding the specication of event types, whose constraint expressions consists of a set of pre and postconditions. We have evaluated the method by means of its application to a set of large conceptual schemas. The results show that the method is eff ective and e cient. We deal with conceptual schemas in UML/OCL, but the method can be adapted to other languages.Peer ReviewedPreprin

Head-mounted Sensory Augmentation Device: Comparing Haptic and Audio Modality

This paper investigates and compares the effectiveness of haptic and audio modality for navigation in low visibility environment using a sensory augmentation device. A second generation head-mounted vibrotactile interface as a sensory augmentation prototype was developed to help users to navigate in such environments. In our experiment, a subject navigates along a wall relying on the haptic or audio feedbacks as navigation commands. Haptic/audio feedback is presented to the subjects according to the information measured from the walls to a set of 12 ultrasound sensors placed around a helmet and a classification algorithm by using multilayer perceptron neural network. Results showed the haptic modality leads to significantly lower route deviation in navigation compared to auditory feedback. Furthermore, the NASA TLX questionnaire showed that subjects reported lower cognitive workload with haptic modality although both modalities were able to navigate the users along the wall

Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy

Leukoencephalopathies are a group of white matter disorders related to abnormal formation, maintenance, and turnover of myelin in the central nervous system. These disorders of the brain are categorized according to neuroradiological and pathophysiological criteria. Herein, we have identified a unique form of leukoencephalopathy in seven patients presenting at ages 2 to 4 months with progressive microcephaly, spastic quadriparesis, and global developmental delay. Clinical, metabolic, and imaging characterization of seven patients followed by homozygosity mapping and linkage analysis were performed. Next generation sequencing, bioinformatics, and segregation analyses followed, to determine a loss of function sequence variation in the phospholipase A2-activating protein encoding gene (PLAA). Expression and functional studies of the encoded protein were performed and included measurement of prostaglandin E2 and cytosolic phospholipase A2 activity in membrane fractions of fibroblasts derived from patients and healthy controls. Plaa-null mice were generated and prostaglandin E2 levels were measured in different tissues. The novel phenotype of our patients segregated with a homozygous loss-of-function sequence variant, causing the substitution of leucine at position 752 to phenylalanine, in PLAA, which causes disruption of the protein's ability to induce prostaglandin E2 and cytosolic phospholipase A2 synthesis in patients' fibroblasts. Plaa-null mice were perinatal lethal with reduced brain levels of prostaglandin E2 The non-functional phospholipase A2-activating protein and the associated neurological phenotype, reported herein for the first time, join other complex phospholipid defects that cause leukoencephalopathies in humans, emphasizing the importance of this axis in white matter development and maintenance

Study of cosolvent-induced α-chymotrypsin fibrillogenesis: Does protein surface hydrophobicity trigger early stages of aggregation reaction?

The misfolding of specific proteins is often associated with their assembly into fibrillar aggregates, commonly termed amyloid fibrils. Despite the many efforts expended to characterize amyloid formation in vitro, there is no deep knowledge about the environment (in which aggregation occurs) as well as mechanism of this type of protein aggregation. Alpha-chymotrypsin was recently driven toward amyloid aggregation by the addition of intermediate concentrations of trifluoroethanol. In the present study, approaches such as turbidimetric, thermodynamic, intrinsic fluorescence and quenching studies as well as chemical modification have been successfully used to elucidate the underlying role of hydrophobic interactions (involved in early stages of amyloid formation) in α-chymotrypsin-based experimental system. © 2009 Springer Science+Business Media, LLC

Tourism Destination Management: A Collaborative Approach

Collaboration is a key factor of sustainable growth across territories and industrial sectors. Tourism, one of the largest industries in the world, has been subject to strongest innovation in the last years. Main reasons of this reside both in the availability of new ICTs - Information and Communication Technologies - and organizational models, which directly connect tourists among them and with service providers, and in the always more personalized supply of tourism experience. Tourism destinations can benefit of such innovations if they are able to reorganize the territorial tourism offer around different pattern of collaboration in order to give 2.0 tourists opportunities to live an augmented tourism experience. This paper deals with the possible forms of collaborative networks that can rise within a destination with a focus on relationships between services delivered by the Tourism Destination and the requests of services at the different phases of the tourist 2.0 lifecycle

New Modularity of DAP-Kinases: Alternative Splicing of the DRP-1 Gene Produces a ZIPk-Like Isoform

DRP-1 and ZIPk are two members of the Death Associated Protein Ser/Thr Kinase (DAP-kinase) family, which function in different settings of cell death including autophagy. DAP kinases are very similar in their catalytic domains but differ substantially in their extra-catalytic domains. This difference is crucial for the significantly different modes of regulation and function among DAP kinases. Here we report the identification of a novel alternatively spliced kinase isoform of the DRP-1 gene, termed DRP-1β. The alternative splicing event replaces the whole extra catalytic domain of DRP-1 with a single coding exon that is closely related to the sequence of the extra catalytic domain of ZIPk. As a consequence, DRP-1β lacks the calmodulin regulatory domain of DRP-1, and instead contains a leucine zipper-like motif similar to the protein binding region of ZIPk. Several functional assays proved that this new isoform retained the biochemical and cellular properties that are common to DRP-1 and ZIPk, including myosin light chain phosphorylation, and activation of membrane blebbing and autophagy. In addition, DRP-1β also acquired binding to the ATF4 transcription factor, a feature characteristic of ZIPk but not DRP-1. Thus, a splicing event of the DRP-1 produces a ZIPk like isoform. DRP-1β is highly conserved in evolution, present in all known vertebrate DRP-1 loci. We detected the corresponding mRNA and protein in embryonic mouse brains and in human embryonic stem cells thus confirming the in vivo utilization of this isoform. The discovery of module conservation within the DAPk family members illustrates a parsimonious way to increase the functional complexity within protein families. It also provides crucial data for modeling the expansion and evolution of DAP kinase proteins within vertebrates, suggesting that DRP-1 and ZIPk most likely evolved from their ancient ancestor gene DAPk by two gene duplication events that occurred close to the emergence of vertebrates

Oscillatory stimuli differentiate adapting circuit topologies

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this record.Biology emerges from interactions between molecules, which are challenging to elucidate with current techniques. An orthogonal approach is to probe for 'response signatures' that identify specific circuit motifs. For example, bistability, hysteresis, or irreversibility are used to detect positive feedback loops. For adapting systems, such signatures are not known. Only two circuit motifs generate adaptation: negative feedback loops (NFLs) and incoherent feed-forward loops (IFFLs). On the basis of computational testing and mathematical proofs, we propose differential signatures: in response to oscillatory stimulation, NFLs but not IFFLs show refractory-period stabilization (robustness to changes in stimulus duration) or period skipping. Applying this approach to yeast, we identified the circuit dominating cell cycle timing. In Caenorhabditis elegans AWA neurons, which are crucial for chemotaxis, we uncovered a Ca2+ NFL leading to adaptation that would be difficult to find by other means. These response signatures allow direct access to the outlines of the wiring diagrams of adapting systems.The work was supported by US National Institutes of Health grant 5RO1-GM078153-07 (F.R.C.), NRSA Training Grant CA009673-36A1 (S.J.R.), a Merck Postdoctoral Fellowship at The Rockefeller University (S.J.R.), and the Simons Foundation (S.J.R.). J.L. was supported by a fellowship from the Boehringer Ingelheim Fonds. E.D.S. was partially supported by the US Office of Naval Research (ONR N00014-13-1-0074) and the US Air Force Office of Scientific Research (AFOSR FA9550-14-1-0060)

Differential Gene Expression Regulated by Oscillatory Transcription Factors

Cells respond to changes in the internal and external environment by a complex regulatory system whose end-point is the activation of transcription factors controlling the expression of a pool of ad-hoc genes. Recent experiments have shown that certain stimuli may trigger oscillations in the concentration of transcription factors such as NF-B and p53 influencing the final outcome of the genetic response. In this study we investigate the role of oscillations in the case of three different well known gene regulatory mechanisms using mathematical models based on ordinary differential equations and numerical simulations. We considered the cases of direct regulation, two-step regulation and feed-forward loops, and characterized their response to oscillatory input signals both analytically and numerically. We show that in the case of indirect two-step regulation the expression of genes can be turned on or off in a frequency dependent manner, and that feed-forward loops are also able to selectively respond to the temporal profile of oscillating transcription factors