לוח שנה משולב

Multiple lines of evidence link numerous diseases to inherited errors in alternative splicing, the process connecting different exon and intron sequences to diversify gene expression. We explore potential involvement of acquired alternative splicing changes in non-familial Alzheimer's and Parkinson's diseases (AD, PD), where synaptic functioning fails and cholinergic or dopaminergic neurons die prematurely. Using whole genome microarrays, we found massive decline in exon exclusion events in the AD entorhinal cortex. In brain-injected mice, blocking exon exclusion caused learning and memory impairments and destruction of cholinergic neurons caused AD-like changes in exon exclusion. Suggesting physiological relevance, blocking exon exclusion in primary neuronal cells was preventable by cholinergic stimulation and caused dendritic and synapse loss. In comparison, blood leukocytes from advanced PD patients showed different alternative splicing changes. These were largely reversed by deep brain stimulation (DBS), which reduces motor symptoms, and were reversed again after disconnecting the stimulus. Measured modifications correlated with neurological treatment efficacy and classified controls from advanced PD patients and pre- from post-surgery patients. In an independent patient cohort, a "molecular signature" (6 out of the modified transcripts) further classified controls from patients with early PD or other neurological diseases. Our findings demonstrate functionally relevant disease-specific alternative splicing changes in the AD brain and PD leukocytes; highlight acquired alternative splicing changes as causally involved in different neurodegenerative diseases and identify new targets for intervention in DBS-treatable neurological diseases.

At BARC, we have been making efforts to fabricate hybrid electronic components, such as, a dielectric, rectifier, resonant tunnel diode, FET and memory, using self-asssembled mono/multilayers on Si. In this talk we shall touch upon some aspects related to our recent studies, viz. the electrografting of organic molecules on Si; design of new porphyrin-based sigma-pi molecules and the observation of memory effect and diode action in them; observation of NDR effect for LbL-grown APTMS films as well as electrografted DFTT films; and transport effects in O-MBE grown TM-phthalocyanine films.Very recently, we have embarked on the development of photoelectrochemical cells (PEC), too. Preliminary results on two different PEC systems will be described.

All organisms rely on noisy molecular recognition to convey, process and store information. This stochastic biophysical setting poses a tough challenge: how to construct information processing systems that are efficient and economical yet error-resilient? I will review recent results that reveal generic design principles of molecular information systems. This biological design problem turns out to be equivalent to the statistical physics of stochastic maps and optimization processes. The examples considered range from molecular codes [1] through molecular recognition and homologous recombination (a crucial mechanism of sexual reproduction that yields genetic diversity) [2] to the spatial organization of chromosomes in the cell nucleus.

[1] Tlusty, PRL 100, 048101 (2008); PNAS 105, 8238-8243 (2008); Phys Life Rev 7, 362-376 (2010).

[2] Savir et al., PNAS 107, 3475-80 (2010); Mol Cell 40(3), 388-396 (2010).