The three nucleon problem

Imperial Users onl

Quantitative assessment of cell fate decision between autophagy and apoptosis

Abstract Autophagy and apoptosis are cellular processes that regulate cell survival and death, the former by eliminating dysfunctional components in the cell, the latter by programmed cell death. Stress signals can induce either process, and it is unclear how cells ‘assess’ cellular damage and make a ‘life’ or ‘death’ decision upon activating autophagy or apoptosis. A computational model of coupled apoptosis and autophagy is built here to analyze the underlying signaling and regulatory network dynamics. The model explains the experimentally observed differential deployment of autophagy and apoptosis in response to various stress signals. Autophagic response dominates at low-to-moderate stress; whereas the response shifts from autophagy (graded activation) to apoptosis (switch-like activation) with increasing stress intensity. The model reveals that cytoplasmic Ca2+ acts as a rheostat that fine-tunes autophagic and apoptotic responses. A G-protein signaling-mediated feedback loop maintains cytoplasmic Ca2+ level, which in turn governs autophagic response through an AMP-activated protein kinase (AMPK)-mediated feedforward loop. Ca2+/calmodulin-dependent kinase kinase β (CaMKKβ) emerges as a determinant of the competing roles of cytoplasmic Ca2+ in autophagy regulation. The study demonstrates that the proposed model can be advantageously used for interrogating cell regulation events and developing pharmacological strategies for modulating cell decisions

Reducing Surface Clutter in Cloud Profiling Radar Data

An algorithm has been devised to reduce ground clutter in the data products of the CloudSat Cloud Profiling Radar (CPR), which is a nadir-looking radar instrument, in orbit around the Earth, that measures power backscattered by clouds as a function of distance from the instrument. Ground clutter contaminates the CPR data in the lowest 1 km of the atmospheric profile, heretofore making it impossible to use CPR data to satisfy the scientific interest in studying clouds and light rainfall at low altitude. The algorithm is based partly on the fact that the CloudSat orbit is such that the geodetic altitude of the CPR varies continuously over a range of approximately 25 km. As the geodetic altitude changes, the radar timing parameters are changed at intervals defined by flight software in order to keep the troposphere inside a data-collection time window. However, within each interval, the surface of the Earth continuously "scans through" (that is, it moves across) a few range bins of the data time window. For each radar profile, only few samples [one for every range-bin increment ((Delta)r = 240 m)] of the surface-clutter signature are available around the range bin in which the peak of surface return is observed, but samples in consecutive radar profiles are offset slightly (by amounts much less than (Delta)r) with respect to each other according to the relative change in geodetic altitude. As a consequence, in a case in which the surface area under examination is homogenous (e.g., an ocean surface), a sequence of consecutive radar profiles of the surface in that area contains samples of the surface response with range resolution (Delta)p much finer than the range-bin increment ((Delta)p 10 dB and a reduction of the contaminated altitude over ocean from about 1 km to about 0.5 km (over the ocean). The algorithm has been embedded in CloudSat L1B processing as of Release 04 (July 2007), and the estimated flat surface clutter is removed in L2B-GEOPROF product from the observed profile of reflectivity (see CloudSat product documentation for details and performance at http://www.cloudsat.cira.colostate.edu/ dataSpecs.php?prodid=1)

The Toll-Like receptor adaptor TRIF contributes to otitis media pathogenesis and recovery

<p>Abstract</p> <p>Background</p> <p>Toll-like receptor (TLR) signalling is crucial for innate immune responses to infection. The involvement of TLRs in otitis media (OM), the most prevalent childhood disease in developed countries, has been implicated by studies in middle ear cell lines, by association studies of TLR-related gene polymorphisms, and by altered OM in mice bearing mutations in TLR genes. Activated TLRs signal via two alternative intracellular signaling molecules with differing effects; MyD88 (Myeloid differentiation primary response gene 88) inducing primarily interleukin expression and TRIF (Tir-domain-containing adaptor inducing interferon β) mediating type I interferon (IFN) expression. We tested the hypothesis that TRIF and type I IFN signaling play a role in OM, using a murine model of OM induced by non-typeable <it>Haemophilus influenzae </it>(NTHi). The ME inflammatory response to NTHi was examined in wild-type (WT) and TRIF-/- mice by qPCR, gene microarray, histopathology and bacterial culture.</p> <p>Results</p> <p>Expression of TRIF mRNA was only modesty enhanced during OM, but both type I IFN signalling genes and type I IFN-inducible genes were significantly up-regulated in WT mice. TRIF-deficient mice showed reduced but more persistent mucosal hyperplasia and less leukocyte infiltration into the ME in response to NTHi infection than did WT animals. Viable bacteria could be cultured from MEs of TRIF-/- mice for much longer in the course of disease than was the case for middle ears of WT mice.</p> <p>Conclusion</p> <p>Our results demonstrate that activation of TRIF/type I IFN responses is important in both the pathogenesis and resolution of NTHi-induced OM.</p

Dissociating morphological and form priming with novel complex word primes: Evidence from masked priming, overt priming, and event-related potentials

Recent research suggests that visually-presented words are initially morphologically segmented whenever the letter-string can be exhaustively assigned to existing morphological representations, but not when an exhaustive parse is unavailable; e.g., priming is observed for both hunter→HUNT and brother →BROTH, but not for brothel→BROTH. Few studies have investigated whether this pattern extends to novel complex words, and the results to date (all from novel suffixed words) are mixed. In the current study, we examine whether novel compounds (drugrack→RACK) yield morphological priming which is dissociable from that in novel pseudoembedded words (slegrack→RACK). Using masked priming, we find significant and comparable priming in reaction times for word-final elements of both novel compounds and novel pseudoembedded words. Using overt priming, however, we find greater priming effects (in both reaction times and N400 amplitudes) for novel compounds compared to novel pseudoembedded words. These results are consistent with models assuming across-the-board activation of putative constituents, while also suggesting that morpheme activation may persevere despite the lack of an exhaustive morpheme-based parse when an exhaustive monomorphemic analysis is also unavailable. These findings highlight the critical role of the lexical status of the pseudoembedded prime in dissociating morphological and orthographic priming