לוח שנה משולב

In this talk, I will present our novel synthetic approaches for peptide and protein ubiquitination to shed light on the various unknown aspects of the ubiquitin signal. The attachment of ubiquitin to a protein target is a widely utilized posttranslational modification in eukaryotes, which is involved in various aspects of cellular functions e.g. protein degradation and DNA repair. Notably, ubiquitination has been implicated in several diseases including cancer and neurodegenerative diseases. In this process, three distinct enzymes, known as the E1-E3 system, collaborate to achieve a site-specific tagging of the lysine residue(s) in the target protein. The overwhelming majority of studies in the field rely on the in vitro enzymatic reconstitution of this complex posttranslational modification for the protein of interest. However, this process is often challenged by the heterogeneity of the modified protein, the isolation of the specific ligase (E3) and obtaining reasonable quantities of the ubiquitinated protein. Our group reported the developments of highly efficient and site-specific peptide and protein ubiquitination utilizing thiolysine residue, which mimic the action of the enzymatic machinery. This battery of chemical tools allowed for the first semi-synthesis of homogeneous ubiquitinated alpha-synuclein to support the ongoing efforts aiming at studying the effect of ubiquitination in health and disease. In addition, the total chemical synthesis of all di-ubiquitin chains as well as the K48-linked tetra-ubiquitin, composed of 304 amino acids, was also achieved. More recently, the synthesis of ubiquitinated peptides linked to mono-, di-, tri-, and tetra-ubiquitin (K48 and K63) was also made possible, which enabled us to examine the behavior of these novel bioconjugates with several deubiquitinases. We have also expanded these approaches to target different deubiquitinases in the ubiquitin system to shed light on their role in health and disease, and ultimately, for drug development

In this talk, I will present our novel synthetic approaches for peptide and protein ubiquitination to shed light on the various unknown aspects of the ubiquitin signal. The attachment of ubiquitin to a protein target is a widely utilized posttranslational modification in eukaryotes, which is involved in various aspects of cellular functions e.g. protein degradation and DNA repair. Notably, ubiquitination has been implicated in several diseases including cancer and neurodegenerative diseases. In this process, three distinct enzymes, known as the E1-E3 system, collaborate to achieve a site-specific tagging of the lysine residue(s) in the target protein. The overwhelming majority of studies in the field rely on the in vitro enzymatic reconstitution of this complex posttranslational modification for the protein of interest. However, this process is often challenged by the heterogeneity of the modified protein, the isolation of the specific ligase (E3) and obtaining reasonable quantities of the ubiquitinated protein. Our group reported the developments of highly efficient and site-specific peptide and protein ubiquitination utilizing thiolysine residue, which mimic the action of the enzymatic machinery. This battery of chemical tools allowed for the first semi-synthesis of homogeneous ubiquitinated alpha-synuclein to support the ongoing efforts aiming at studying the effect of ubiquitination in health and disease. In addition, the total chemical synthesis of all di-ubiquitin chains as well as the K48-linked tetra-ubiquitin, composed of 304 amino acids, was also achieved. More recently, the synthesis of ubiquitinated peptides linked to mono-, di-, tri-, and tetra-ubiquitin (K48 and K63) was also made possible, which enabled us to examine the behavior of these novel bioconjugates with several deubiquitinases. We have also expanded these approaches to target different deubiquitinases in the ubiquitin system to shed light on their role in health and disease, and ultimately, for drug development

Our approach is based on extension of the QCD (Quantum Chromodynamics) sum rules (SR) method to systems with finite density of the baryon quantum number. It is based on the dispersion relations for the function, describing the system which carries the quantum numbers of the hadron. Exchange by the strongly correlated quark systems (mesons) is expressed in terms of exchange by the system of weakly interacting quarks with the same quantum numbers. The nucleon self-energies are obtained without employing a controversial conception of interaction between point-like nucleons. The calculation does not involve phenomenological parameters.
Application of the approach enables to express such characteristics of nucleon in nuclear matter as the Dirac effective mass m* and the vector self energy Sigma in terms of the density dependent QCD condensates. The condensates of the lowest dimension d=3 are the most important ones. These are the vector and the scalar quark condensate. The vector condensate is exactly proportional to the density due to conservation of the vector current. The linear part of the scalar condensate is presented in terms of the pion-nucleon sigma term, which can be expressed through the amplitude of the pion-nucleon elastic scattering. The most important next-to-leading condensates of dimension d=4 are expressed through the moments of the proton deep inelastic structure functions. Thus the most important density-dependent condensates are either calculated or related to observables. As a result, we find m* ~ -600 MeV, Sigma ~ 300 MeV at the phenomenological saturation value of density, in agreement with the results of the standard nuclear physics. We obtain also the density dependence of these characteristics.

Organic-based materials exhibiting the technologically important property of bulk magnetism have been prepared and studied in collaboration with many research groups worldwide frequently exhibit supramolecular extended 3-D structures. These magnets are prepared via conventional organic synthetic chemistry methodologies, but unlike classical inorganic-based magnets do not require high-temperature metallurgical processing. Furthermore, these magnets are frequently soluble in conventional solvents (e. g., toluene, dichloromethane, acetonitrile, THF) and have saturation magnetizations more than twice that of iron metal on a mole basis, as well as in some cases coercive fields exceeding that of all commercial magnets (e.g., Co5Sm). Also several magnets with critical temperatures (Tc) exceeding room temperature have been prepared. In addition to an overview of magnetic behavior, numerous examples of structurally characterized magnets made from molecules will be presented. Our groups has discovered 8 families of molecule-based magnets, mostly organic-based, and have significantly contributed to an eight family based upon the Prussian blue structure. Four examples magnetically order above room temperature and as high at 127 oC. These will include [MIII(C5Me5)2][A], [MnIII(porphyrin)][A] (A = cyanocarbon etc. electron acceptors) as well as M[TCNE]x, which for M = V is a room temperature magnet that can be fabricated as a thin film magnet via Chemical Vapor Deposition (CVD) techniques. A newer class of magnets of [Ru2(O2CR)4]3[M(CN)6] (M = Cr, Fe; R = Me, t-Bu) composition will also discussed. For R = Me an interpenetrating, cubic (3-D) lattice forms and the magnet exhibits anomalous hysteresis, saturation magnetization, out-of-phase, "(T), AC susceptibility, and zero field cooled-field cooled temperature-dependent magnetization data. This is in contrast to R = t-Bu, which forms a layered (2-D) lattice. Additionally, new magnets possessing the nominal Prussian blue composition, M'[M(CN)6]x and (Cation)yM'[M(CN)6], but not their structure, will be described. The organic chemistry crucial to designing and preparing organic-based magnets will be discussed.

Much like humans, animals may choose to initiate behavior based on their "internal state" rather than as a response to external stimuli alone. The neuronal underpinnings responsible for generating this ‘internal state’, however, remain elusive. The parasitoid jewel wasp hunts cockroaches to serve as a live food supply for its offspring. The wasp stings the cockroach in the head and delivers a neurotoxic venom cocktail directly inside the prey’s cerebral ganglia to apparently ‘hijack its free will’. Although not paralyzed, the stung cockroach becomes a living yet docile ‘zombie’ incapable of self-initiating walking or escape running.
We demonstrate that the venom selectively depresses the cockroach’s motivation or ‘drive’ to initiate and maintain walking-related behaviors, rather than inducing an overall decrease in arousal or a ‘sleep-like’ state. Such a decrease in the drive for walking can be attributed to a decrease in neuronal activity in a small region of the cockroach cerebral nervous system, the sub-esophageal ganglion (SEG). Specifically, we have used behavioral, neuro-pharmacological and electrophysiological methods to show that artificial focal injection of crude milked venom or procaine into the SEG of non-stung cockroaches decreases spontaneous and evoked walking, as seen with naturally-stung cockroaches. Moreover, spontaneous and evoked neuronal spiking activity in the SEG, recorded with an extracellular bipolar microelectrode, is markedly decreased in stung cockroaches as compared with non-stung controls. By injecting a venom cocktail directly into the SEG, the parasitoid Jewel Wasp selectively manipulates the cockroach’s motivation to initiate walking without interfering with other non-related behaviors.