לוח שנה משולב

Over the past few decades, there has been steady progress in both our ability to produce biological material and in our ability to manipute matter at small length scales. These two developments merge in a fascinating area of confluence called single-molecule biophysics in which an understanding of biological matter from physical principles becomes possible. I will illustrate the development of this interdisciplinary field and show how several newly-developed techniques allow us to shed light on genomic processes such as DNA compaction, replication, and transcription.
For example, by measuring the twist and length of single DNA molecules, we are able to learn about DNA compaction into chromatin. We monitor the real-time loading of tetramers or complete histone octamers onto DNA and find, remarkably, that tetrasomes exhibit spontaneous flipping between a preferentially occupied left-handed state and a right-handed state, separated by free energy difference of 2.3 kBT (1.5 kcal/mol). The application of weak positive torque converts left-handed tetrasomes into right-handed tetrasomes, whereas nucleosomes display more gradual conformational changes. These findings reveal unexpected dynamical rearrangements of the nucleosomal structure, suggesting that chromatin can serve as a ‘‘twist reservoir,’’ offering a mechanistic explanation for the regulation of DNA supercoiling in chromatin.
By making use of high-throughput single-molecule techniques, we are able to gain new insights into the termination of DNA replication. In Escherichia coli, replisome progression beyond the termination site is prevented by Tus proteins bound to asymmetric Ter sites. Structural evidence indicates that strand separation on the blocking (non-permissive) side of Tus–Ter triggers roadblock formation, but biochemical evidence also suggests roles for protein- protein interactions. We perform DNA unzipping experiments which demonstrate that nonpermissively oriented Tus–Ter forms a tight lock in the absence of replicative proteins, whereas permissively oriented Tus–Ter allows nearly unhindered strand separation. Quantifying the lock strength reveals the existence of several intermediate lock states that are impacted by mutations in the lock domain but not by mutations in the DNA-binding domain. Lock formation is highly specific and exceeds reported in vivo efficiencies. We therefore postulate that protein-protein interactions may actually hinder, rather than promote, proper lock formation.
I will conclude by describing how such types of biophysical measurements should complement biochemical investigations in the coming few years

The proteins that mediate the three pillars of energy metabolism – synthesis of acetyl CoA, oxidation of acetyl CoA via the TCA cycle to generate NADH, and utilization of NADH by the electron transport chain to generate ATP – have long been the focus of investigation. In contrast, much less is known about the role of lipids in the production of energy. Recent studies show that cardiolipin, the signature lipid of the mitochondrial membrane, plays a key role in all three pathways of energy metabolism. This knowledge is expected to provide insight into the mechanisms underlying cardiomyopathy in Barth syndrome, a life-threatening genetic disorder of cardiolipin metabolism.

Presence of the hot (kTe ~ 3 - 10 KeV) rarefied gas in the clusters of galaxies (most massive gravitationally bound objects in the Universe) leads to the appearance of "shadows" in the angular distribution of the Cosmic Microwave Background (CMB) Radiation and permits to measure the peculiar velocities of these clusters relative to the unique coordinate frame where CMB is isotropic. I plan to describe the physics leading to these observational effects. Planck spacecraft, ground based South Pole and Atacama Cosmology Telescopes discovered recently more than thousand of unknown before Clusters of Galaxies at high redshifts detecting these "shadows" and traces of kinematic effect, demonstrating the correlation of the hot gas velocities with mass concentrations on large scales. Giant ALMA submillimeter interferometer in Atacama desert resolved recently strong shocks between merging clusters of galaxies.
Newly discovered clusters of galaxies permit to study the rate of growth of the large scale structure of the Universe and open an independent way to measure key cosmological parameters of our Universe.
I plan to mention Russian - German Spectrum-X/eRosita space mission under preparation for the launch in the March of 2018. This mission will be able to detect all (hundred thousand !) rich clusters of galaxies in the observable Universe and up to 3 millions of accreting supermassive black holes (in Active Galactic Nuclei) during 4 year long X-Ray sky survey. S3 and S4 ground based CMB research programs promise to reach similar or even higher sensitivities and detect up to a million of clusters and groups of galaxies containing hot gas.