לוח שנה משולב

What does it feel like to be a bat? Is conscious experience of echolocation closer to that of vision or audition? Or, echolocation is non-conscious processing and it doesn't feel anything? This famous question of bats' experience, posed by a philosopher Thomas Nagel in 1974, clarifies the difficult nature of the mind-body problem. Why a particular sense, such as vision, has to feel like vision, but not like audition, is puzzling. This is especially so given that any conscious experience is supported by neuronal activity. Activity of a single neuron appears fairly uniform across modalities, and even similar to those for non-conscious processing. Without any explanation on why a particular sense has to feel as the way it does, researchers even cannot approach the question of the bats' experience. Is there any theory that gives us a hope for such explanation? Currently, probably none, except for one. Integrated Information Theory (IIT), proposed by Tononi in 2004 has a potential to offer a plausible explanation. IIT essentially claims that any system that is composed of causally interacting mechanisms can have conscious experience. And precisely how the system feels like is determined by the way the mechanisms influence each other in a holistic way. In this talk, I will give a brief explanation of the essence of IIT and provide initial empirical partial tests of the theory, proposing a potential scientific pathway to approach bats' conscious experience. If IIT, or its improved or related versions, is validated enough, it will gain credibility to accept its prediction on rough nature of bats' experience. If we can gain a sophisticated insight as to whether bats' experience is closer to vision or audition, it is already a tremendously big step in consciousness science, which is just a first yet critical one, possibly a similar level of the breakthrough in cosmology in precisely estimating the age of the universe.
References:
0) talk slide: https://www.slideshare.net/NaoNaotsuguTsuchiya/17-june-20-empirical-test-of-iit-dresden
1) Andrew M. Haun, Masafumi Oizumi, Christopher K. Kovach, Hiroto Kawasaki, Hiroyuki Oya, Matthew A. Howard, Ralph Adolphs, Naotsugu Tsuchiya, (2017, accepted) “Conscious perception as integrated information patterns in human electrocorticography” eNeuro link
2) Tsuchiya “"What is it like to be a bat?" - a pathway to the answer from the Integrated Information Theory ” Philosophy Compass (2017) link
3) Oizumi M, Tsuchiya N, Amari S, “Unified framework for quantifying causality and integrated information in a dynamical system” (2016) PNAS link

Expeditious Synthesis of Bacterial Glycoconjugates
Suvarn S. Kulkarni
Department of Chemistry, IIT Bombay, Powai, Mumbai-400076
Bacterial glycoconjugates are comprised of rare D and L deoxy amino sugars, which are not present on the human cell surface. This peculiar structural difference allows discrimination between the pathogen and the host cell and offers avenues for target-specific drug discovery and carbohydrate-based vaccine development. However, they cannot be isolated with sufficient purity in acceptable amounts, and therefore chemical synthesis is a crucial step toward the development of these products.1 We recently established short and convenient methodologies for the synthesis of orthogonally protected bacterial D and L-deoxy amino hexopyranoside and glycosamine building blocks starting from cheaply available D-mannose and L-rhamnose.2-4 The one-pot protocols rely on highly regioselective nucleophilic displacements of triflates. These procedures have been applied to the synthesis of various bacterial glycoconjugates2-8 (Figure 1) as well as metabolic oligosaccharide engineering.7


1) Emmadi, M.; Kulkarni, S. S. Nat. Prod. Rep. 2014, 31, 870-879. 2) Emmadi, M.; Kulkarni, S. S. Nature Protocols 2013, 8, 1870-1889. 3) Sanapala, S. R.; Kulkarni S. S. J. Am. Chem. Soc. 2016, 138, 4938−4947. 4) Sanapala, S. R.; Kulkarni S. S. Org. Lett. 2016, 18, 3790–3793. 5) Podilapu, A. R.; Kulkarni, S. S. Org. Lett. 2014, 16, 4336-4339. 6) Sanapala, S. R.; Kulkarni, S. S., Chem. Eur. J. 2014, 20, 3578-3583. 7) Clark, E.; I.; Emmadi, M.; Krupp, K. L.; Podilapu, A. R.; Helble, J. D.; Kulkarni, S. S.; Dube, D. H. ACS Chem Biol 2016, 11, 3365-3373. 8) Podilapu, A. R.; Kulkarni, S. S. Org. Lett. 2017, 19, 5466-5469.

A hallmark of MAPK signaling is their nuclear translocation upon stimulation, which is necessary for their physiological/pathological functions. We have identified two novel, distinct, regulated nuclear translocation mechanisms for ERK1/2 and JNK/p38, of which we made use of as a promising therapeutic approach. We developed a myristoylated, NTS-derived phosphomimetic peptide (EPE peptide), which blocked ERK1/2 nuclear translocation. In culture, the EPE peptide induced apoptosis of melanoma cells, inhibited the proliferation of other cancer cells but had no effect on immortalized cells. Combination of the EPE peptide and the MEK inhibitor had synergistic antitumor activity in mutated NRAS, BRAF and NF1 melanoma and Kras pancreatic cells. In xenograft models, the peptide was significantly more effective than BRAF inhibitors in preventing tumor recurrence of treatment-eradicated melanoma xenografts. We also developed p38-derived myristoylated peptide, termed PERY peptide, which inhibited the importin interaction with JNK1/2 and p38α/β and prevented their nuclear translocation. This peptide affected viability of several breast cancer-derived cell lines, and significantly reduced inflammation and intestinal damage in a mouse model of colitis. Moreover, the peptide inhibited inflammation-induced colorectal cancer in a AOM/DSS mouse model. Taken together, both the cancer and inflammatory models support the use of nuclear translocation of MAPKs as a novel drug target for signaling-related diseases.