Law and order were Rome’s vehicles for displaying its imperial authority and supremacy over non-Roman subjects. However, Rome did not fill a legal vacuum; rather, it competed with established legal practices among communities in the Greek East. These communities took pride in their legal traditions, as they were being absorbed into the Roman legal order. Consequently, the sphere of law served provincials as a major arena for negotiating Roman power and demarcating their own local identities: what customs to maintain and what trends to resist? Despite scholarly interest in the plurality of laws under Rome, this project proposes an innovative cross-disciplinary study of these local legal cultures as an expression of provincial agency and self-determination. While previous studies were limited to the scattered remains of legal activities in the Greek East on papyri or on inscriptions, it is the premise of this project that only by integrating the hitherto neglected body of Jewish jurisprudence we may gain access into provincial perceptions of their legal cultures. Early rabbinic literature (1st-3rd centuries CE), which has been marginalized as an isolated phenomenon, is in fact the only comprehensive source of local law-making under Rome and is therefore the most appropriate framework for studying provincial legalisms in all of their forms. By applying a multi-dimensional comparative analysis of key legal fields, Local Law under Rome provides a structured method including the following stages for proceeding towards a new understanding of subordinate legal discourse: First, the project contextualizes each system of local law separately against the background of Roman legal administration and local traditions. Next, it discerns patterns of integration across different legal traditions, and finally it characterizes the distinct nature of provincial legalism, as means for cultural and political distinction in circumstances of law without power.

From a technological viewpoint photoreceptor proteins, the light-sensitive proteins involved in the sensing and response to light in a variety of organisms, represent biological light converters. Hence they are successfully utilized in a number of technological applications, e.g. the green-fluorescent protein used to visualize spatial and temporal information in cells. However, despite the ground-breaking nature of this utilization in life science and other disciplines, the attempts to design a photoreceptor for a particular application by protein mutation remains an open challenge. This is exactly the scope of my research proposal: the application of multi-scale modelling for the systematic design of biological photoreceptor mutants. With this target in mind I will study representatives of two prominent photoreceptor proteins subfamilies which are of towering interest to experimentalists: proteorhodopsins and cyanobacteriochromes. Computer models of these proteins will be constructed using accurate multi-scale modeling. Their excitation energies and other properties (e.g. excited-state reactivity and efficiency) will be calculated using multireference methods that were shown to have an accuracy of <3 kcal/mol. The insights gained from simulations of the wild-type proteins will provide the basis for proposing mutations with altered photochemical properties: in essence to predict absorption and emission spectra, excited-state lifetime and quantum yields. This research requires interactions across the disciplines, as the best candidates will be synthesized and characterized experimentally by collaborators. The outcome of these experiments will provide feedback to improve both the properties of the mutants and the simulation methodology. Ultimately this high-risk/high gain project should derive a comprehensive understanding that would result in novel biotechnological applications, e.g. optogenetic tools, fluorescent probes and biosensors.

Background and rationale: Adult acute leukemias pose a great challenge to cancer therapy, with only few advances made in 50 years. As these malignancies are commonly associated with multiple epigenetic aberrations, epigenetic factors represent attractive leukemia drug targets. Nevertheless, most epigenetic-targeting drugs have displayed limited clinical benefit and key leukemia drivers like MYC, ERG and MYB remained mostly undruggable. We have developed a new class of small molecule kinase inhibitors, termed “oncodestroyers” (ODs), single molecules combining supreme p53 activation with selective disruption of multiple leukemia-specific super-enhancers (SEs) that drive oncogenes and dependency/vulnerability factors. These inhibitors demonstrate an unprecedented therapeutic potency in mouse models of human leukemia and are entering now leukemia clinical trials. With this project we wish to study the principles of “oncodestruction”, mechanisms of drug action, immune system interface, and preempt drug resistance. Relevant knowledge may be applied to other cancer diseases, sharing vulnerabilities with leukemia. Major Goal: To expand the therapeutic potential of ODs in leukemia and pre-leukemia by studying their vulnerability basis, mechanisms of drug action and indicators of therapeutic response in individual patients. Research plan: 1) Expand the collection of small molecule kinase inhibitor ODs and develop OD-based PROTACs to gain an optimal spectrum of kinase targets with good therapeutic window in AML; 2) Elucidate the mechanisms of action and what distinguishes an OD, with emphasis on SE disruption, p53 activation and OD-immune-cooperation; 3) Explore the translational aspects of OD treatment by: identifying OD resistance and relapse mechanisms; study clonal evolution in MDS and AML patients undergoing phase 1a/b clinical trial; predict a patient response to ODs and use ODs for ameliorating age-related clonal hematopoiesis, thus possibly averting leukemogenesis.