Depth and morphology of reflectors from the 2-D non-linear inversion of arrival-time and waveform semblance data: method and applications to synthetic data

We propose a two-dimensional, non-linear method for the inversion of reflected/converted traveltimes and waveform semblance designed to obtain the location and morphology of seismic reflectors in a lateral heterogeneous medium and in any source-to-receiver acquisition lay-out. This method uses a scheme of non-linear optimisation for the determination of the interface parameters where the calculation of the traveltimes is carried out using a finite- difference solver of the Eikonal equation, assuming an a priori known back- ground velocity model. For the search of the optimal interface model, we have used a multiscale approach and the Genetic Algorithm global optimization technique. During the initial stages of inversion, we used the arrival times of the reflection phase to retrieve the interface model that is defined by a small num- ber of parameters. In the successive steps, the inversion is based on the opti- mization of the semblance value determined along the calculated traveltime curves. Errors in the final model parameters and the criteria for the choice of the bestfit model are also estimated from the shape of the semblance function in the model parameter space. The method is tested and validated on a synthe- tic dataset that simulates the acquisition of reflection data in a complex volca- nic structure

Investigating h-Prune activation of Wnt signalling in breast cancer

We have been investigating a novel link between two independent processes linked to breast cancer: Wnt signalling and h-Prune overexpression. The canonical Wnt signalling pathway was activated in 40% to 60% of human breast cancers through mechanisms that are not understood. Similarly, the phosphodiesterase h-Prune was overexpressed or amplified in 54% of breast cancers and was linked to breast tumour progression through unknown mechanisms. We have shown that overexpression of xenopus Prune induced formation of a secondary axis in a standard assay to identify activators of the Wnt signalling pathway. In HEK293 cells, xenopus Prune overexpression induced a 300-fold increase in Wnt/TCF-dependent transcription. Whilst human prune does not appear to be able to activate Wnt signalling as potently as its xenopus homologue, it does synergise with other activators of the pathway to increase TCF-dependent transcription. Here we show whether there is a correlation between overexpression of h-Prune and active Wnt signalling in breast cancer, and whether the synergistic responses described are mediated through the enzymatic activity of prune, or through binding to GSK-3

In vivo bioluminescence imaging using orthotopic xenografts towards patient's derived-xenograft Medulloblastoma models

BACKGROUND: Medulloblastoma is a cerebellar neoplasia of the central nervous system. Four molecular subgrups have been identified (MBWNT, MBSHH, MBgroup3 and MBgroup4) with distinct genetics and clinical outcome. Among these, MBgroup3-4 are highly metastatic with the worst prognosis. The current standard therapy includes surgery, radiation and chemotherapy. Thus, specific treatments adapted to cure those different molecular subgroups are needed. The use of orthotopic xenograft models, together with the non-invasive in vivo biolumiscence imaging (BLI) technology, is emerging during preclinical studies to test novel therapeutics for medulloblastoma treatment. METHODS: Orthotopic MB xenografts were performed by injection of Daoy-luc cells, that had been previously infected with lentiviral particles to stably express luciferase gene, into the fourth right ventricle of the cerebellum of ten nude mice. For the implantation, specific stereotactic coordinates were used. Seven days after the implantation the mice were imaged by acquisitions of bioluminescence imaging (BLI) using IVIS 3D Illumina Imaging System (Xenogen). Tumor growth was evaluated by quantifying the bioluminescence signals using the integrated fluxes of photons within each area of interest using the Living Images Software Package 3.2 (Xenogen-Perkin Elmer). Finally, histological analysis using hematoxylin-eosin staining was performed to confirm the presence of tumorigenic cells into the cerebellum of the mice. RESULTS: We describe a method to use the in vivo bioluminescent imaging (BLI) showing the potential to be used to investigate the potential antitumorigenic effects of a drug for in vivo medulloblastoma treatment. We also discuss other studies in which this technology has been applied to obtain a more comprehensive knowledge of medulloblastoma using orthotopic xenograft mouse models. CONCLUSIONS: There is a need to develop patient's derived-xenograft (PDX) model systems to test novel drugs for medulloblastoma treatment within each molecular sub-groups with a higher predictive value. Here we show how this technology should be applied with hopes on generations of new treatments to be applied then in human

What sparks ethical decision making? The interplay between moral intuition and moral reasoning: lessons from the scholastic doctrine

Recent theories on cognitive science have stressed the significance of moral intuition as a counter to and complementary part of moral reasoning in decision making. Thus, the aim of this paper is to create an integrated framework that can account for both intuitive and reflective cognitive processes, in order to explore the antecedents of ethical decision making. To do that, we build on Scholasticism, an important medieval school of thought from which descends the main pillars of the modern Catholic social doctrine. Particularly, the focus will be on the scholastic concept of synderesis, which is an innate human faculty that constantly inclines decision makers toward universal moral principles. Managerial implications are discussed, stressing how a rediscovery of decision makers’ intuitive moral judgments could be relevant in the reflective thinking practice of managers’ ethical reasoning, thus saving them from rational insensitivity to ethical dilemmas

PRUNE (prune exopolyphosphatase)

Short communication on PRUNE, with data on DNA/RNA, on the protein encoded and where the gene is implicated

PRUNE1: a disease-causing gene for secondary microcephaly

In their Letter to the Editor, Karakaya et al. (2017) present an interesting case report describing the clinical course involving secondary microcephaly of a 3-year-old Turkish boy found to be homozygous for a frameshift mutation in PRUNE1 identified through whole exome sequencing. The child presented with congenital hypotonia, contractures and global developmental delay with respiratory insufficiency and seizures developing in the first year of life. The authors note that the affected child’s head circumference plotted on the 75th centile at birth, and that by 38 months of age he had developed microcephaly. Neuroimaging at 14 months revealed cerebral and cerebellar atrophy consistent with other patients described with Prune syndrome (Karaca et al., 2015; Costain et al., 2017; Zollo et al., 2017). Although the child had abnormal neurology from birth, there was a period of early developmental regression. Peripheral spasticity in the lower extremities and optic atrophy were not documented until 38 months. In addition to the PRUNE1 variant, Karakaya et al. also identified a second homozygous variant in the CCDC14 gene in the Turkish child’s whole exome sequencing data that, while listed to have an allele count of 108 in the current Genome Aggregation Database (gnomAD) release, is notably absent in homozygous fashion (Lek et al., 2016). CCDC14 is known to be expressed in human brain, reported to negatively regulate centriole duplication and interact with proteins previously associated with primary microcephaly (Firat-Karalar et al., 2014). Thus, while it seems likely that the homozygous PRUNE1 variant is primarily responsible for the clinical presentation in the Turkish child, it is impossible to determine whether there may be any phenotypical contribution from this additional homozygous sequence variant. Recently, Costain et al. (2017) described a homozygous consensus splice site variant in PRUNE1 (c.521-2A4G; NM_021222.1) in a 2-year-old Oji-Cre male who presented with congenital hypotonia and talipes, whose head circumference was large at birth ( +3 standard deviations), but by 2 years and 2 months plotted on the 50th centile, with a weight and height on the 95th and 75th centiles, respectively. However, it should be noted that the child’s father is macrocephalic ( +4 standard deviations), the published clinical photographs at 2 years 5 months of age illustrate bitemporal narrowing, a sloping forehead and large ears, consistent with a developing microcephaly, and neuroimaging revealed cortical and cerebellar atrophy. He developed respiratory insufficiency shortly after birth, and infantile spasms in the first year of life (Costain et al., 2017). It remains to be determined how the phenotypical outcomes stemming from proposed loss-of-function mutations defined by Karakaya et al. and Costain et al., relate to missense mutations published by Karaca et al. and also Zollo et al., which are likely to involve at least partial gain-of-function outcomes in PRUNE1 activity. However, as more cases are investigated and published, the phenotype associated with autosomal recessive Prune neurodevelopmental disorder, and the functional outcomes of PRUNE1 mutation, are becoming clearer. It is now apparent that while some patients have a small head at birth and others a head circumference in the normal range, the key component of the microcephaly is that it is progressive, and associated with characteristic neuroimaging findings with a thin or hypoplastic corpus callosum and cortical and cerebellar atrophy developing in early childhood. Although all patients with Prune syndrome described to date are neurologically impaired from birth, there also appears to be a neurodegenerative component with progression of the disorder. In our manuscript, we described clinical overlap of Prune syndrome with the neurodegenerative condition associated with homozygous mutations in TBCD (Zollo et al., 2017). TBCD encodes one of the five tubulin-specific chaperones that are required for a/b-tubulin de novo heterodimer formation and the disorder is characterized by developmental regression, seizures, optic atrophy and secondary microcephaly, cortical atrophy with delayed myelination, cerebellar atrophy and thinned corpus callosum (Edvardson et al., 2016; Flex et al., 2016; Miyake et al., 2016; Pode-Shakked et al., 2017). The neurodegenerative phenotype documented in the Turkish child by Karakaya et al. further demonstrates the similarities with the TBCD disorder and Prune syndrome, and confirms optic atrophy to be a feature of Prune syndrome. Interestingly, it is also becoming clear that respiratory insufficiency is a common feature of Prune syndrome, having been documented by Karakaya et al. and in the Oji-Cre child, as well as the youngest affected Omani child described in our manuscript

Underwater acoustic channel properties in the Gulf of Naples and their effects on digital data transmission

In this paper we studied the physical properties of the Gulf of Naples (Southern Italy) for its use as a commu- nication channel for the acoustic transmission of digital data acquired by seismic instruments on the seafloor to a moored buoy. The acoustic link will be assured by high frequency acoustic modems operating with a central frequency of 100 kHz and a band pass of 10 kHz. The main operational requirements of data transmission con- cern the near horizontal acoustic link, the maximum depth of the sea being about 300 m and the planned hori- zontal distance between seismic instruments and buoy 2 km. This study constructs the signal-to-noise ratio maps to understand the limits beyond which the clarity of the transmission is no longer considered reliable. Using ray- theory, we compute the amplitudes of a transmitted signal at a grid of 21×12 receivers to calculate the transmis- sion loss at each receiver. The signal-to-noise ratio is finally computed for each receiver knowing also the trans- mitter source level and the acoustic noise level in the Gulf of Naples. The results show that the multipath effects predominate over the effects produced by the sound velocity gradient in the sea in the summer period. In the case of omnidirectional transmitters with a Source Level (SL) of 165 dB and a baud rate of 2.4 kbit/s, the results al- so show that distances of 1400-1600 m can be reached throughout the year for transmitter-receiver connections below 50 m depth in the underwater acoustic channel