Molecular analysis of the ZIC3 and TCF7L1 interaction and its implication in human Heterotaxy

Heterotaxy is a congenital disorder that occurs due to the defective establishment of the left-right (L-R) body axis during early embryo development. The disorder affects 1/10,000 live births, results in the abnormal alignment of internal organs with respect to the L-R axis, and is often accompanied by severe cardiac malformations. The most commonly mutated gene in human cases of Heterotaxy is the X-linked ZIC3, which was first associated with the condition in 1997. ZIC3 belongs to a family of multifunctional transcriptional regulator proteins (ZIC family) all characterised by a C2H2 type zinc finger domain (ZFD). This domain is implicated in the transactivation (DNA binding) and co-factor (protein binding) function of the proteins. However, despite both capabilities, it is still not known when during development the co-factor role of ZIC3 is necessary over the transcription factor role. Consequently, the exact cellular and molecular causes underlying ZIC3-associated Heterotaxy remain unknown. Mouse models of Zic3 loss-of-function reveal phenotypes that resemble human Heterotaxy and exhibit a defective node (the structure that confers the L-R axis during development). More recently, studies have shown murine Zic3 alleles lead to incompletely penetrant, partial (posterior) axis duplications and anterior truncation, phenotypes characteristic of elevated canonical Wnt signalling. The expression pattern of Zic3 during mammalian gastrulation overlaps with a known repressor of the canonical Wnt pathway, Tcf7l1 and it has also been shown that a related ZIC protein (ZIC2) can interact with TCF proteins to co-repress Wnt/b-catenin mediated transcription when overexpressed in cell lines. Overall, this leads to the novel hypothesis that ZIC3 controls the establishment of the L-R axis by interacting with TCF7L1 to repress Wnt signalling during mammalian gastrulation. In this thesis I examine the molecular role of ZIC3 in the Wnt pathway and investigate the functional consequences of ZIC3 Heterotaxy-associated protein variants. A physical interaction between ZIC3 and TCF7L1 was demonstrated by several molecular assays. Additionally, 17 Heterotaxy-associated human ZIC3 variants were functionally assessed in well-established cell-based assays. Four of the human protein variants exhibit non-pathogenic properties as they retain wildtype ZIC3 function in these assays. The remaining variants, which affect key residues within the ZFD or contain a premature termination codon, display impaired transcription factor and co-factor functions: they can no longer activate transcription at a ZIC responsive element and have reduced ability to inhibit b-catenin-mediated Wnt transcription. Loss of Wnt inhibition did not always correlate with loss of TCF7L1 interaction, suggesting ZIC3 and/or TCF7L1 must interact with additional co-repressors or repressive chromatin complexes to mediate transcriptional repression in the Wnt pathway. Additionally, in this thesis I identified several evolutionary conserved domains implicated in transactivation, including the newly annotated SANC and SACC domains, enhancing our understanding of the structural domains required for ZIC3 molecular function. Overall, this thesis supports a new model of ZIC3 molecular function: ZIC3 interacts with TCF7L1 to inhibit canonical Wnt signalling during mammalian gastrulation and correctly establish the L-R axis. Ultimately, ZIC3-associated Heterotaxy arises when ZIC3 is unable to function as a Wnt co-repressor

An unsupervised neuromorphic clustering algorithm

Brains perform complex tasks using a fraction of the power that would be required to do the same on a conventional computer. New neuromorphic hardware systems are now becoming widely available that are intended to emulate the more power efficient, highly parallel operation of brains. However, to use these systems in applications, we need “neuromorphic algorithms” that can run on them. Here we develop a spiking neural network model for neuromorphic hardware that uses spike timing-dependent plasticity and lateral inhibition to perform unsupervised clustering. With this model, time-invariant, rate-coded datasets can be mapped into a feature space with a specified resolution, i.e., number of clusters, using exclusively neuromorphic hardware. We developed and tested implementations on the SpiNNaker neuromorphic system and on GPUs using the GeNN framework. We show that our neuromorphic clustering algorithm achieves results comparable to those of conventional clustering algorithms such as self-organizing maps, neural gas or k-means clustering. We then combine it with a previously reported supervised neuromorphic classifier network to demonstrate its practical use as a neuromorphic preprocessing module

Guest Editorial Circuits and Systems for Smart Agriculture and Healthy Foods

This Special Issue of the IEEE JOURNAL ON EMERGING AND SELECTED TOPICS IN CIRCUITS AND SYSTEMS (JETCAS) is dedicated to Circuits and Systems applied to innovative products for the Agriculture and Food value chain

Modeling the Dietary Pesticide Exposures of Young Children

A stepped approach was used to assess the exposures of 1 1/2 – 4 1/2-year-old children in the United Kingdom to residues of pesticides (dithiocarbamates; phosmet; carbendazim) found in apples and pears. The theoretical possibility that the acute reference dose (ARD) was being exceeded for a particular pesticide/fruit was tested by applying a combination of maximal variability and maximum measured residue relative to an average-body-weight consumer. The actual risk was then quantified by stochastically modeling consumption, from dietary survey data, with individual body weights, against published residue results for 2000–2002 and the variability of residue distribution within batches. The results, expressed as numbers of children per day likely to ingest more than the ARD, were in the range of 10–226.6 children per day, depending upon the pesticide and year of sampling. The implications for regulatory action are discussed

Local crystallographic texture and voiding in passivated copper interconnects

A correlation between local crystallographic texture and stress‐induced void formation in tantalum‐encapsulated, copper interconnects was revealed by electron backscattering diffraction studies in a scanning electron microscope. Lines exhibiting an overall stronger 〈111〉 texture showed better resistance to void formation. Furthermore, grains adjacent to voids exhibited weaker 〈111〉 texture than grains in unvoided regions of the same line. The locally weaker 〈111〉 texture at voided locations suggests the presence of higher diffusivity, twist boundaries. This work, which represents the first characterization of local texture in stress voided, copper lines, helps to elucidate the relative importance of the thermodynamic and kinetic factors which govern void formation and growth. © 1996 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/70319/2/APPLAB-69-26-4017-1.pd

In-vivo monitoring for electrical expression of plant living parameters by an impedance lab system

We present a complete in-lab system to monitor the plant and its surrounding environment. The plant impedance is directly measured in a continuous manner, while, simultaneously surrounding environment parameters known to affect plant status, are monitored. This is done combining a new in-vivo direct measurement of the plant together with an embedded system using available sensor technology and a designated interface for continuous data acquisition. Furthermore, the next versions this system can be deployed as a field monitoring device, with simple adaptations

Treatment of Low-flow Vascular Malformations by Ultrasound-guided Sclerotherapy with Polidocanol Foam: 24 Cases and Literature Review

AbstractObjectivesTreatment by sclerotherapy has been suggested as a first-line treatment of low-flow vascular malformations. This study reports our experience in treating low-flow vascular malformations by ultrasound-guided sclerosis with polidocanol foam at the Vascular Medicine Department in Grenoble, France.DesignRetrospective single-centre consecutive series.Materials and methodsBetween January 2006 and December 2009, we analysed the complete records of patients with symptomatic low-flow vascular malformations of venous, lymphatic or complex type (Klippel–Trenaunay syndrome, KTS) treated by ultrasound-guided sclerosis. The therapeutic indication was always validated by the Consultative Committee for vascular malformations of the University Hospital of Grenoble. All vascular malformations were classified according to the Hamburg Classification. The sclerosing agent was polidocanol used as foam.ResultsA total of 24 patients between 7 and 78 years were treated (19 venous malformations, three KTSs and two venous-lymphatic malformations). The concentrations of polidocanol used ranged from 0.25% to 3%. The average number of sessions was 2.3 (1–16). After a median follow-up at 5 months after the last session, 23 out of 24 patients reported a decrease in pain; in nine cases (37.5%), over 50% reduction in size was observed, and in 14 cases (58.3%), a reduction of less than 50% of the original size was obtained. Two minor side effects were reported.ConclusionsTreatment by ultrasound-guided sclerosis using polidocanol foam seems to be well tolerated and can improve the symptoms of low-flow malformations without the risks of more aggressive sclerosing agents, such as ethanol