The proposed research program explores different strategies developed in the digital age within and outside international human rights law to respond to new needs, interests, risks and challenges brought about by transition of inter-personal interactions, social activities and regulatory schemes from offline to online environments. It investigates the development in recent years of three generations of digital human rights: adaptation of existing rights and their manner of application to online environments (e.g., online privacy), the creation of new digital rights (e.g., right to access the Internet) and the introduction of new rights and duty holders (e.g., virtual persons and online platforms exercising quasi-sovereign power), as well as the development of alternative protection avenues based on private ordering, including rights by design and community standards, Internet governance and multi-stakeholder arrangements. The ERC project will examine these paradigmatic normative, institutional and theoretical developments, and the policy choices behind them from five methodological perspectives: (1) historical study of the evolution of digital human rights and of choices made by norm-entrepreneurs and law-makers between different protection frameworks; (2) analytical study of protection gaps, overlaps and conflicts across traditional and digital human rights and alternative arrangements; (3) comparative study juxtaposing developments in the field of digital human rights against analogous development in international human rights law, with a view to identifying paradigms of normative and institutional change; (4) empirical analysis through interviews of the perceived effectiveness and legitimacy in the eyes of stakeholders of the said developments ; (5) Evaluation of the developments under theories of rights, global governance, business ethics and corporate responsibility and rational choice.

Astrocytes are currently investigated in a range of questions extending far beyond their traditional 'housekeeping' functions. We have contributed to expanding the horizon of functions attributable to astrocytes, and have recently identified a novel and unexpected role for hippocampal astrocytes in signaling the location of reward. This pioneering ERC project, will drive considerable progress in an important and completely unknown facet of reward-related information processing: the roles of hippocampal astrocytes in signaling reward, and their interaction with dopamine, the main player in the reward system. In Aim 1 we will define the role of hippocampal astrocytes in the perception of reward. We will test whether astrocytes can encode the presences of reward irrespective of its location, based on non-spatial (auditory) cues. By simultaneously imaging both astrocytes and neurons, we will delineate the spatio-temporal interplay between them in reward representation, and examine the projection-specific effect of astrocytes in rewarded behavior. Work on Aim 2 will delineate the effects of the dopaminergic system on astrocytes. We will comprehensively analyse the distribution of dopamine receptors on astrocytes and the astrocytic response to tonic vs. phasic dopaminergic signals. We will also perform simultaneous imaging of dopamine levels and astrocyte Ca2+ dynamics in different behavioral states. Aim 3 will determine how astrocytes mediate the effects of the dopaminergic system. We will do that by manipulating astrocytic activity measure pre-synaptic dopamine axonal release in the hippocampus and its influence on the poorly understood phenomenon of over-representation of reward locations by neuronal place cells. Our published work and our new (unpublished) results generate the conceptual basis for this proposal and demonstrate its technical feasibility. Achieving our goals will provide fundamental insights into the roles of astrocytes in information processing.

Intra-tumor genetic heterogeneity imposes a great challenge on cancer therapy. Resistance to molecularly targeted therapies and chemotherapy can arise from selective growth of pre-existing sub-clones that carries drug-resistance mutations, altered metabolic and/or epigenomic states, providing a survival advantages. Early detection of these subclonal states can thus significantly aid cancer therapy. However, attempts to profile various types of primary cancer cells using single-cell techniques are relatively poor. One of the major limitations is the significant dropout rate (i.e., loss of alleles) observed in single-cell RNA-seq. It severely affects our ability to leverage single cell RNA-seq to accurately profile somatic mutation, to reveal cancer driver mutation and even extract low/mid-level expressed genes and splicing. For that reason, most of the efforts to expose mutations that are critical for cancer growth and can subsequently lead to more effective treatment are based on the sequencing of bulk populations. However, due to the noise introduced by PCR, sequencing and alignment processes, bulk sequencing is limited to identify mutations with a frequency higher than 5%. Here we propose to develop a novel 3D clone-based full-length RNA-seq profiling technology. A preliminary version of this technology for digital profiling of mRNA, already allowed us to significantly improve sensitivity comparing to gold-standard single-cell RNA-seq methods. Using this preliminary version on clones of lung adenocarcinoma, we revealed novel cancer stem like subpopulation that could not be detected using regular single cell RNA-seq maps. Altogether, improving the ability to detect rare mutations (<5%), splicing events and transcriptional variation between cancer cells, will be an extremely powerful tool for early diagnosis of cancer and effective means to improve personalized based drug treatment decision making.

We have recently shown that application of EGFR targeted synthetic dsRNA: Poly Iosine/Poly Cytosine (pIC) is highly efficient and selective against deadly cancers overexpressing EGFR, like glioblastoma (U87MGwtEGFR), breast cancer (MDA-MB-468) and adenocarcinoma (A431). Double-stranded RNA, frequently expressed in cells infected with viruses, activates a number of pro-apoptotic processes simultaneously. These dsRNA-induced mechanisms efficiently kill infected cells and induce expression of anti-proliferative cytokines from the interferon (IFN) family, thereby preventing spread of the virus. pIC delivered with Melittin-polyethylenimine-polyethyleneglycol-EGF (MPPE) eliminated orthotropic and subcutaneous tumors of the above cancers. Heterogeneous glioblastoma models where only half of the cells overexpress wtEGFR are also eliminated by local application, most likely due to a bystander antiproliferative effects, at least partially mediated by interferons (Shir et al., 2006). Systemic application of EGFR targeted pIC is also highly effective against breast and adenocarcinoma disseminated cancer models resembling metastatic cancers (Shir et al., 2011). During the last two years we have improved the vectors homing to EGFR to entities that can now be translated into clinical agents (Shaffert, 2011; Shir 2011, Abourbeh 2012). The impressive results with these more simplified vectors, make this project ready for clinical development, which requires fund raising from a Company/Venture capitalist. Commercialization of the therapy will be detailed in the proposal.