לוח שנה משולב

The eIF4E Homolog Protein (4EHP, eIF4E2) is a mRNA cap-binding protein that in contrast to eIF4E cannot interact with eIF4G and acts as a translation repressor. The CCR4-NOT complex functions in miRNA-mediated mRNA silencing through its recruitment by the RISC (RNA-induced silencing complex). The CCR4-NOT complex recruits the helicase DDX6, which binds 4E-T (eIF4E-Transporter), which in turn binds 4EHP resulting in inhibition of cap-dependent translation (Proc. Natl. Acad. Sci. 2017). 4EHP suppresses IFN-production by promoting the miR-34a-induced translational silencing of Ifnb1 mRNA. (Mol. Cell, 2021). The SARS-CoV2 encoded Non-Structural Protein 2 (NSP2), directly interacts with the cellular GIGYF2 protein and enhances the binding of GIGYF2 to 4EHP and thereby enhances translational repression of Ifnb-1 mRNA. Depletion of 4EHP or GIGYF2 resulted in enhanced IFN-ß expression accompanied by a significant reduction of SARS-CoV-2 replication.

Small molecule inhibitors and drugs that are able to form a covalent bond with
their protein target have several advantages over traditional binders. While they were
avoided for a long time due to concerns of specificity, in recent years they are attracting
significant interest as underscored by FDA approvals of rationally designed covalent
drugs, such as Ibrutinib and Afatinib. In the past few years my research team has been
focused on technology development for the field of Covalent Ligand Discovery. These
include: covalent virtual screening, empirical covalent fragment screening, the first
reported reversible covalent targeted degraders (PROTACs), and most recently the
discovery of new chemistry that enables the design of superior covalent binders. These
technologies enabled the discovery of novel, potent inhibitors for several challenging
targets. These inhibitors, in turn, have shed new light on the target’s biological function
and represent potential therapeutic leads. I will describe our journey from the original goal
of mere ‘discovery’ of covalent binders to the current challenge of functionalizing covalent
binders for various applications.

Jodi Nunnari is a pioneer in the field of mitochondrial biology. She was the first to describe the organelle as a dynamic network in homeostatic balance and decipher the mechanisms of the machines responsible for mitochondrial division and fusion, which are critical determinants of overall mitochondrial shape and distribution. Nunnari’s laboratory at UC Davis is using system-based approaches to address how mitochondrial behavior is physiologically regulated within cells to shed light onto how mitochondrial dysfunction contributes to human disease.

Solid-state NMR has become an essential tool for structural characterisation of materials,
in particular systems with poor crystallinity and structural disorder. In recent years, a surge of
interest has been observed for the study of paramagnetic systems, in which the interaction between
nuclei and unpaired electrons allows to probe the electronic structure and properties of materials
more directly. However, simultaneously this interaction leads to very broad resonances, which are
dicult to acquire and interpret. While signicant advancements in both NMR instrumentation
and methodology have paved the way for the study of spin I = 1=2 nuclei in these systems, still
many issues remain to be resolved for routine investigation of quadrupolar nuclei I > 1=2. Here we
focus on improving both the excitation of the broad resonances and the resolution in the spectra
of spin I = 1 nuclei. The latter problem is addressed by developing methods for separation of the
shift and the quadrupolar interactions. We introduce two new methods under static conditions,
which have the advantage over previous experiments of both suppressing spectral artefacts and
exhibiting a broader excitation bandwidth. Furthermore, we demonstrate for the rst time an
approach for separation of the anisotropic parts of the shift and quadrupolar interaction under
magic-angle spinning. Secondly, to achieve broadband excitation we develop a new theoretical
formalism for phase-modulated pulse sequences in rotating solids, which are applicable to nuclear
spins with anisotropic interactions substantially larger than the spinning frequency, under conditions
where the radio-frequency amplitude is smaller than or comparable to the spinning frequency. We
apply the framework to the excitation of double-quantum spectra of 14N and design new pulse
schemes with
-encoded properties. Finally, we employ the new sequences together with density
functional theory calculations to elucidate the electron and hydride ion conduction mechanisms in
barium titanium oxyhydride.

Charge transfer and transport processes through molecular interfaces are ubiquitous and of a crucial role in determining functionality of biological systems and in enabling energy conversion applications. We study computationally such processes to understand structure-function relationships at the molecular level.

We will discuss studies in the following two primary fields: (1) Photovoltaic and charge transfer properties of organic semiconductors materials. (2) Charge transport through voltage-biased molecular scale bridges. Importantly we establish predictive computational scheme that addresses key challenges. Our studies are employed in conjunction with experimental efforts to design materials and applications that control and tune relevant physical properties