לוח שנה משולב

: Neuronal plasticity is a unique property that describes the ability of the system to undergo long-lasting changes, typically as a result of experience. This paradigm, initially discovery by Bliss and Lomo and dubbed long term potentiation (LTP), describes a scenario where the post-synaptic responses increase in strength for long durations, following a particular pre-synaptic stimulus. Conversely, LT-Depression, describes the long lasting depression of synaptic responses. Today, these phenomena are commonly used to describe the molecular model for learning and memory. A large body of work has implicated more than a hundred proteins and factors in modulating LTP and LTD, and thereby memory. Unfortunately, there is still a lively debate regarding the true necessity and exact role of each player. The need for new techniques and approaches to further explore synaptic function and dysfunction has never been more pressing, as the number of people developing neurodegenerative diseases rises exponentially to epidemic scales, with the aging population. These diseases are characterized by a strong decline in the number of synapses and in the ability of synapses to undergo plasticity, ultimately resulting in the severe decline of cognitive function- such as learning and memory. To better scrutinize synaptic plasticity and probe the function and role of its initiators (i.e. NMDA receptors and calcium ions), I have developed novel light-gated NMDA receptors and photoactivatable fluorescent Ca2+-probes to monitor synaptic activity with unmet spatio-temporal resolution and reversibility. I use the latter to examine the roles of specific NMDA-receptor subunits in plasticity.

Protein homeostasis in the cell is regulated by two highly conserved pathways, the UPS and the autophagy. So far the link between these pathways was mainly evaluated by blocking the degradation flux through either pathway, thus limiting the ability to accurately assess the cross talk between the two systems. Here we demonstrate that knockdown of the proteasome integral ubiquitin receptors S5a and ADRM1, impairs polyubiquitinated substrate degradation by the 26S proteasome, while avoiding the global deleterious outcomes associated with proteasome inhibitors. We demonstrate that p62-mediated autophagy effectively balances the reduced proteasome capacity. Finally, we provide evidence for the mechanism linking the regulation of p62 expression with proteasome activity. We propose that upon impairment of the proteasomal flux short-lived transcription factors constitute an inherent feedback loop that upregulate p62 dependent autophagy, thereby maintaining cellular proteostasis and prevent the formation of protein aggregates.

Karl Skorecki and his colleagues used a combination of population genetics and evolutionary medicine approaches to identify two sets of genetic sequence variants in the APOL1 innate immunity gene which account for 70% of the 4-fold disparity in chronic kidney disease in populations of Sub-Saharan African ancestry.

These variants rose to high allele frequency in the at-risk population due to past adaptive selection, which also facilitated population based disease risk gene discovery using admixture mapping. Odds ratios conferred by these variants range from 7 to 90 depending on epistatic and environmental interactions. Pathobiology, target identification, and drug discovery studies are now proceeding using a variety of experimental platforms and scientific collaborations which will be highlighted.

Dark matter (DM) is one of the most intriguing open problems in modern particle- and astrophysics. Direct, indirect, and collider searches have not yet conclusively established the particle nature of dark matter. After a short overview of dark-matter physics, I will focus on recent theoretical efforts to increase the discovery potential of dark-matter searches. If dark matter indeed has particle nature, then direct detection via scattering on atomic nuclei is one of the most promising discovery channels. Effective field theories (EFT) are the appropriate framework to describe the scattering process, involving physics at very different energy scales. I will show that radiative corrections can have a large impact on the interpretation of data, and stress the importance of a consistent EFT framework.
DM searches at particle colliders provide complementary information. If the relic abundance of dark matter is determined by co-annihilation processes in the early universe, this can lead to to characteristic signatures at the LHC. I will discuss these signatures in general terms and point out that not all of them are covered by current serches. Finally, I will illustrate the general strategy with a specific case study, where the coannihilation process is mediated by a scalar leptoquark. I will briefly discuss cosmological probes, collider searches, and constraints from precision physics.

TBA