Proof systems allow a weak verifier to ascertain the correctness of complex computational statements. Efficiently-verifiable proof systems are fundamental objects in the study of computation, and have led to some of the deepest and most celebrated insights in cryptography and in complexity theory. The vast and rich literature on proof systems focuses primarily on proving the correctness of intractable statements, e.g. ones that are NP-complete. While the verification can be efficient, the proofs themselves cannot be generated in polynomial time. This limits the applicability of such proof systems, both from a theoretical perspective and in their real-world impact. This proposal aims to obtain a comprehensive understanding of proof systems with polynomial-time proof generation, to explore their practical applicability, and to investigate their connections with foundational questions in cryptography and in complexity theory. Our study will focus primarily on interactive proof systems for tractable computations. The proposed research aims to revolutionize our understanding of these foundational objects by providing a complete and tight characterization of the complexity or proving and verifying general statements, by achieving breakthroughs in the study of related proof system notions, such as cryptographic arguments, and by building a fine-grained “algorithmic” theory of proof systems for central polynomial-time computational problems. Our research will leverage these advances towards diverse applications: from real-world security challenges, such as verifying the correctness of computations performed by the cloud and cryptographic “proofs of work”, to a complexity-theoretic understanding of the complexity of approximating problems in P and of solving them on random instances.

The rapid emergence and spread of Multi-drug Antimicrobial Resistance (AMR), alongside the negligible efforts of the major pharmaceuticals companies in the development of new antibiotics, result in a major global concern of modern medicine. Moreover, the currently clinically used antibiotics contaminate the environment and may harm the human microbiome, causing unpredictable health concerns. We discovered that by targeting species-specific ribosome unique structural motifs, identified by us, using our designed degradable novel synthetic lead compounds, it is possible to inhibit protein biosynthesis in bacteria. Our approach should enable distinction between pathogenic and non-pathogenic bacteria and between bacterial and human ribosome. This drug selectivity should decrease resistance, preserve the beneficial microbiome and allow usage of lower antibiotics dozes. Furthermore, the designed degradable lead compounds should prevent additional environmental contamination. Hence, our approach allows designing innovative powerful selective antibiotics that escape the existing resistance mechanisms. Several of the primary designed compounds shown to stop the growth of the multi-resistant S. aureus human pathogen were delivered into the bacterial cells by attaching specific chemical moieties to them. In this PoC we plan to design similar compounds for other human pathogens, such as Enterococcus and Pseudomonas species, where revolutionary effective antibiotic drugs against their resistant strains is desperately needed. In addition to the technological PoC in this project, we will attempt pre-commercialization studies aiming at perfecting the commercialization strategy, protecting the IP and strengthen the network for best possible commercialization outcome. The general objective is to establish at least one strategic partnership with a pharma company which has the capacity to further test, develop and commercialize antibiotics that exploit ribosomal novel unique targets.

In multicellular orIn multicellular organisms, how variation is achieved while cells comprise identical genetic information represents a fundamental open challenge my group strives to engage in the coming years. The development of a single fertilized egg into a complete embryo represents an especially beautiful embodiment of this problem. The process of differentiation is defined by the capacity of the cell ensemble to acquire increasingly more specialized internal states in a coordinated fashion. We are therefore excited by recent breakthroughs in single-cell transcriptomics and epigenomics since these can capture the emergence of embryonic cellular diversification at incredible resolution. But, we believe there is an urgent need in the field to match descriptive single cell atlases with models and experimental frameworks to derive novel understanding of function and regulation in this process. To this end, we will undertake three complementary approaches – all implemented during specification of the basic mammalian body plan (gastrulation) in vivo. (i) We will scrutinize parallel and converged differentiation in embryonic and extraembryonic lineages at absolute time. This will be achieved in both mouse and rabbit, providing unprecedented molecular insight into the evolutionary hourglass theory. (ii) Building on our recently developed capabilities, we will systematically dissect epigenetic mechanisms shaping and memorizing intracellular states. Importantly, we will do so by controlling for cell type and effects that propagate in and between tissues over time. (iii) Finally, we will chart and manipulate extracellular signaling affecting cell specification in the 3D embryonic space. Our study will provide mechanistic understanding and much-needed quantitative models that truly represent embryonic development as a concurrent interacting ensemble with far-reaching implications for other fields, such as regenerative medicine, cancer, aging, and synthetic embryogenesis.

Understanding, and ultimately treating Alzheimer’s disease (AD) is a major need in Western countries. Currently, there is no available treatment to modify the disease. Several pioneering discoveries made by my team, attributing a key role to systemic immunity in brain maintenance and repair, and identifying unique interface between the brain’s borders through which the immune system assists the brain, led us to our recent discovery that transient reduction of systemic immune suppression could modify disease pathology, and reverse cognitive loss in mouse models of AD (Nature Communications, 2015; Nature Medicine, 2016; Science, 2014). This discovery emphasizes that AD is not restricted to the brain, but is associated with systemic immune dysfunction. Thus, the goal of addressing numerous risk factors that go awry in the AD brain, many of which are -as yet- unknown, could be accomplished by immunotherapy, using immune checkpoint blockade directed at the Programmed-death (PD)-1 pathway, to empower the immune system. In this proposal, we will adopt our new experimental paradigm to discover mechanisms through which the immune system supports the brain, and to identify key/novel molecular and cellular processes at various stages of the disease that are responsible for cognitive decline long before neurons are lost, and whose reversal or modification is needed to mitigate AD pathology, and prevent cognitive loss. Achieving our goals requires the multidisciplinary approaches and expertise at our disposal, including state-of-the art immunological, cellular, molecular, and genomic tools. The results will pave the way for developing a novel next-generation immunotherapy, by targeting additional selective immune checkpoint pathways, or identifying a specific immune-based therapeutic target, for prevention and treatment of AD. We expect that our results will help attain the ultimate goal of converting an escalating untreatable disease into a chronic treatable one.

In condensed matter physics there are several iconic predictions that have evaded experimental discovery for many decades. Well-known examples include the proposed fractionally-charged quasiparticles in one-dimension, the theorized quantum crystal of electrons, and the elusive Kondo cloud. These sought-after many-body states all share two key aspects underscoring why they are so hard to discover: They each involve a fragile quantum state of matter that is destroyed easily by disorder or elevated temperatures, and in each case the distinguishing fingerprint is encoded in their real-space structure, which is often difficult to probe directly. The discovery of such phases therefore requires two challenging experimental components: A superb material system in which these phases can be generated, and a novel real-space probe that can image their spatial structure, yet is minimally invasive as not to destroy them. Recently, we have developed a radically new approach for creating the state-of-the-art in both material systems and scanning probes, based on carbon nanotube devices of unprecedented complexity and cleanliness. With these components in place, we are poised to make the next quantum leap in technology by building a conceptually new experimental platform in which fragile quantum states of matter can be realized and studied microscopically: We will use a nanotube single-electron-transistor as a high-resolution, ultrasensitive scanning charge detector to non-invasively image an exotic quantum state within a second pristine nanotube. With this new platform we will thus be able to address several foundational questions in condensed matter physics (including those mentioned above) and unravel their underlying physics.