AP3M2, NEW MOLECULAR TARGET IN COLORECTAL CANCER THERAPY

Annually, around 1 million cases of CRC are diagnosed, with 50% death rate, representing 8% of cancer-related deaths worldwide. The implementation of early diagnosis screening programs contributed to the reduction of the incidence and the mortality rates. The combination of chemotherapeutic regimens (5-FU, oxaliplatin and irinotecan) and targeted drugs (EGFR and VEGF inhibitors) have improved patients' prognosis. However, the combination of some types of chemical and biological therapies failed in the fourth line treatment and resistance to targeted therapies is the major limit in CRC. Under these circumstances, we have conducted an RNAi screening aiming to identify new targetable oncogenes. Starting from the studies conducted by the Cancer Genome Atlas that identified a list of amplified genes in CRC, we analyzed putative genes that their Knockdown could negatively influence cell viability in different CRC cell lines, indicating the possible involvement in CRC. After a careful bioinformatic analysis I found that one gene called AP3M2 could be a successful candidate. AP3M2 (adaptor related protein complex 3 subunit mu 2) encodes for the neuronal Mu subunit of the heterotetrameric adaptor-related protein complex 3 (AP-3), which recognizes tyrosine-based sorting signals within the cytoplasmic domains of transmembrane cargo proteins and is involved in the biogenesis of lysosome-related organelles. Deletion of this gene in mice was associated with susceptibility to drug-induced seizures and fewer synaptic vesicles. In the other hand, AP3M2 amplicons were observed in the primary tumor and maintained in at least two passages of breast cancer xenograft. AP3M2 is also in the list of genes in recurrent amplicons associated with reduced survival in breast cancer. The new "druggable" gene was found to be altered in 6% of CRC patients and was associated with reduced survival rate according to the TGCA data. Our experiments confirmed it to be overexpressed in colon cancer patient tissues and cancer cell lines and proved to be a potent oncogene by promoting the colorectal cancer cell lines viability, adhesion and colony formation. Interestingly, AP3M2 levels affects the expression of other CRC associated protein such as P62, ATG7and ARF6 involved in autophagy and influenced ROS levels in colorectal cancer cell lines

Response-dependent dynamics of cell-specific inhibition in cortical networks in vivo

In the visual cortex, inhibitory neurons alter the computations performed by target cells via combination of two fundamental operations, division and subtraction. The origins of these operations have been variously ascribed to differences in neuron classes, synapse location or receptor conductances. Here, by utilizing specific visual stimuli and single optogenetic probe pulses, we show that the function of ​parvalbumin-expressing and ​somatostatin-expressing neurons in mice in vivo is governed by the overlap of response timing between these neurons and their targets. In particular, ​somatostatin-expressing neurons respond at longer latencies to small visual stimuli compared with their target neurons and provide subtractive inhibition. With large visual stimuli, however, they respond at short latencies coincident with their target cells and switch to provide divisive inhibition. These results indicate that inhibition mediated by these neurons is a dynamic property of cortical circuits rather than an immutable property of neuronal classes.Marie Curie International Fellowship (Postdoctoral Fellowship FP7-PEOPLE-2010-IOF))National Institutes of Health (U.S.) (Grant EY007023)National Institutes of Health (U.S.) (Grant NS090473)Simons Foundatio

Incitement And Defamation In Saudi Arabia: The Case Of Human Rights Lawyer Waleed Abu Al-Khair

Saudi human rights lawyer and pro-democracy activist Waleed Abu Al-Khair was convicted for “inciting public opinion” and “harming the reputation of the King.” As a result, he is currently serving a fifteen-year prison sentence in the Kingdom of Saudi Arabia. This Article analyzes Abu Al-Khair’s criminal conviction under international law, with a focus on the universal standard for the protection of freedom of expression. Specifically, this article explores international law rules that call for narrow constructions of the offenses of “incitement” and “defamation” under domestic law when dealing with public figures and public affairs. Portions of this paper have been reproduced with updates from a prior 2016 Human Rights Foundation Report, written by the same authors of this article. This Article is intended to replace the 2016 Report previously publishe

Innovation in organizations having founder's syndrome

The founder’s syndrome is considered a management weakness and leadership disorder affecting every entrepreneur envisioning and planning a long-term journey for his/her established business. The challenge, with expanding companies, is that the bigger they become, the more re-organization they require through re-design, processes re-engineering, restructuring, reforming corporate governance structure and more innovation plans and strategies they would need to withhold the complexities and uncertainties of their external environments they are exposed to. Therefore, re-organizing growing businesses can become very difficult if the decision-making process remains caught at the upper level of hierarchy. The major risk factor in a business-growing journey is to be confronted with the founder’s syndrome. A growing company led by an entrepreneur suffering from the founder’s syndrome who is afraid to let go and resist organizational re-alignment, development of strategies and introduction of advanced management systems, can never survive the complex external environmental challenges due to the excessive lack of innovation. Business innovation in complex and uncertain environments requires innovative strategy setting which, if applied, should be complemented by a re-organizational structure and design compatible with the roadmap of strategy innovation. In fact, to support and stand for innovation, the business corporate leadership culture should not be contaminated with the effect of founder’s syndrome. On the contrary, the founder should have enough creativity and empowerment skills to accept the compromise of power and control with more open communication and information sharing combined with lean organizational design, to facilitate and encourage innovation for an extended long term organizational survival

Brain Tumor Vascular Network Segmentation from Micro-Tomography

Micro-tomography produces high resolution images of bio- logical structures such as vascular networks. In this paper, we present a new approach for segmenting vascular network into pathological and normal regions from considering their micro-vessel 3D structure only. We define and use a condi- tional random field for segmenting the output of a watershed algorithm. The tumoral and normal classes are thus character- ized by their respective distribution of watershed region size interpreted as local vascular territories

Vascular network segmentation: an unsupervised approach

Micro-tomography produces high resolution images of biological structures such as vascular networks. In this paper, we present a new approach for segmenting vascular network into pathological and normal regions from considering their micro-vessel 3D structure only. We consider a partition of the volume obtained by a watershed algorithm based on the distance from the nearest vessel. Each territory is characterized by its volume and the local vascular density. The volume and density maps are first regularized by minimizing the total variation. Then, a new approach is proposed to segment the volume from the two previous restored images based on hypothesis testing. Results are presented on 3D micro-tomographic images of the brain micro-vascular network

An efficient and reliable steel assembly modelling scheme using second-order cone programming and dual error estimator.

International audienceThe modelling of steel assemblies under static loading using elastic, elasto-plastic or rigid perfectly plastic material coupled with frictional unilateral contact is discussed within the framework of the second-order cone programming (SOCP). In this article, using a combination of the hard-contact conditions coupled with an associated Coulomb frictional behaviour, the contact conditions are written as second-order cones using a pair of dual kinematic and static variables. The minimizations are then formulated as a pair of dual SOCP problems which are then solved using a state-of-the art primal-dual interior point method (IPM). In comparison with a Newton-Raphson algorithm generally used to solve nonlinear problems, the IPM shows better robustness and efficiency and specially for limit analysis where the Newton-Raphson algorithm cannot be used and allows us to formulate the problem using a dual approach. This yields an optimal pair of dual kinematically and statically admissible fields which allows the user to assess the quality of convergence and to efficiently calculate a discretization error estimator which includes a contact surface error term and plasticity error terms. An efficient remesh scheme, based on the local contributions of the elements to the global error, can then be used to limit the number of elements in the 3D analysis. This article illustrates the whole process in some examples of typical steel assemblies. This will allow structural engineers to evaluate the quality of their results and to produce better and more economical designs

The Casimir force at high temperature

The standard expression of the high-temperature Casimir force between perfect conductors is obtained by imposing macroscopic boundary conditions on the electromagnetic field at metallic interfaces. This force is twice larger than that computed in microscopic classical models allowing for charge fluctuations inside the conductors. We present a direct computation of the force between two quantum plasma slabs in the framework of non relativistic quantum electrodynamics including quantum and thermal fluctuations of both matter and field. In the semi-classical regime, the asymptotic force at large slab separation is identical to that found in the above purely classical models, which is therefore the right result. We conclude that when calculating the Casimir force at non-zero temperature, fluctuations inside the conductors can not be ignored.Comment: 7 pages, 0 figure