Cognitive computing: algorithm design in the intersection of cognitive science and emerging computer architectures

For the first time in decades computers are evolving into a fundamentally new class of machine. Transistors are still getting smaller, more economical, and more power-efficient, but operating frequencies leveled off in the mid-2000's. Today, improving performance requires placing a larger number of slower processing cores on each of many chips. Software written for such machines must scale out over many cores rather than scaling up with a faster single core. Biological computation is an extreme manifestation of such a many-slow-core architecture and therefore offers a potential source of ideas for leveraging new hardware. This dissertation addresses several problems in the intersection of emerging computer architectures and biological computation, termed Cognitive Computing: What mechanisms are necessary to maintain stable representations in a large distributed learning system? How should complex biologically-inspired algorithms be tested? How do visual sensing limitations like occlusion influence performance of classification algorithms? Neurons have a limited dynamic output range, but must process real-world signals over a wide dynamic range without saturating or succumbing to endogenous noise. Many existing neural network models leverage spatial competition to address this issue, but require hand-tuning of several parameters for a specific, fixed distribution of inputs. Integrating spatial competition with a stabilizing learning process produces a neural network model capable of autonomously adapting to a non-stationary distribution of inputs. Human-engineered complex systems typically include a number of architectural features to curtail complexity and simplify testing. Biological systems do not obey these constraints. Biologically-inspired algorithms are thus dramatically more difficult to engineer. Augmenting standard tools from the software engineering community with features targeted towards biologically-inspired systems is an effective mitigation. Natural visual environments contain objects that are occluded by other objects. Such occlusions are under-represented in the standard benchmark datasets for testing classification algorithms. This bias masks the negative effect of occlusion on performance. Correcting the bias with a new dataset demonstrates that occlusion is a dominant variable in classification performance. Modifying a state-of-the-art algorithm with mechanisms for occlusion resistance doubles classification performance in high-occlusion cases without penalty for unoccluded objects

Application of “annual” moraines to assess recent patterns and rates of ice-marginal retreat at Skálafellsjökull, SE Iceland

Iceland is situated in a climatically sensitive area close to both atmospheric and oceanic polar fronts, thus representing an important location for understanding North Atlantic climatic change. Icelandic glaciers are particularly sensitive to climatic fluctuations on annual to decadal timescales, and have exhibited accelerating rates of ice-marginal retreat and mass loss during the past decade. Understanding these current rapid glacier fluctuations is crucial to placing current atmospheric warming and associated glacier retreat in a broader context. This study uses the characteristics of recessional (“annual”) moraines and complementary climate data to examine patterns, rates and drivers of ice-marginal retreat that has occurred at Skálafellsjökull, SE Iceland since the 1930s. High-resolution glacial geomorphological mapping reveals suites of minor moraines across the glacier foreland, with the features displaying distinctive sawtooth planform geometries. Chronological investigations of the Skálafellsjökull moraines, which integrate remote sensing observations and lichenometry, indicate that minor moraines on the northern and central parts of the glacier foreland formed on an annual basis. Sedimentological investigations reveal that these annual moraines form through a range of ice-marginal processes, with push/squeeze mechanisms being dominate. The geomorphological, chronological and sedimentological data therefore indicate these moraines represent successive annual ice-frontal positions. Thus, these annual moraines provide a framework for exploring patterns, rates and drivers of ice-marginal retreat at Skálafellsjökull. Annual ice-margin retreat rates (IMRRs), equivalent to annual moraine spacing, indicate prominent periods of glacier recession at Skálafellsjökull are coincident with those at other Icelandic outlet glaciers, as well as those identified at Greenlandic outlet glaciers. Analysis of IMRRs and climate data suggests summer air temperature, sea surface temperature and North Atlantic Oscillation have an influence on IMRRs at Skálafellsjökull, with the glacier appearing to be most sensitive to summer air temperature. Based on this analysis, it is hypothesised that sea surface temperature may drive air temperature changes in the North Atlantic region, which in turn forces IMRRs. The increase in SST over recent decades may link to atmospheric-driven variations in North Atlantic subpolar gyre dynamics. Further research on glacier change in the North Atlantic region, and the controls thereon, is nonetheless required to test this hypothesis

Charge fluctuations in nano-scale capacitors

The fluctuations of the charge on an electrode contain information on the microscopic correlations within the adjacent fluid and their effect on the electronic properties of the interface. We investigate these fluctuations using molecular dynamics simulations in a constant-potential ensemble with histogram reweighting techniques. This approach offers in particular an efficient, accurate and physically insightful route to the differential capacitance that is broadly applicable. We demonstrate these methods with three different capacitors: pure water between platinum electrodes, and a pure as well as a solvent-based organic electrolyte each between graphite electrodes. The total charge distributions with the pure solvent and solvent-based electrolytes are remarkably Gaussian, while in the pure ionic liquid the total charge distribution displays distinct non-Gaussian features, suggesting significant potential-driven changes in the organization of the interfacial fluid

A spatially-restricted Younger Dryas plateau icefield in the Gaick, Scotland: reconstruction and palaeoclimatic implications

Considerable research has been conducted in Scotland to reconstruct Younger Dryas glaciers and palaeoclimatic conditions, but our understanding remains incomplete. In this contribution, we examine the Gaick, a dissected plateau that extends over ∼520 km 2 in the Central Grampians, Scotland. The extent and style of Younger Dryas glaciation in the Gaick has been repeatedly contested, although a model of extensive plateau icefield glaciation has become generally accepted. This is despite well-documented issues with key elements of the plateau icefield reconstruction. We synthesise the results of recent geomorphological mapping in the Gaick and recognise a distinct morphostratigraphic signature in the upper parts of the western catchments. This differs markedly from sediment-landform associations in other parts of the area, and we argue this provides a strong indication of spatially-restricted Younger Dryas (∼12.9–11.7 ka) glaciation in the Gaick. Our interpretation is independently supported by glacierisation threshold analysis, which implies that the eastern Gaick was unable to nourish Younger Dryas ice. We therefore contest the accepted paradigm of extensive Younger Dryas glaciation in this area. Based on the geomorphological evidence and glacier surface profile modelling, we reconstruct a ∼42 km 2 plateau icefield that yields an equilibrium line altitude of 751 ± 46 m. Using this value, a sea-level precipitation value of 826 ± 331 mm a −1 is inferred for the Younger Dryas, which suggests considerably drier conditions than at present. Using recalculated glacier-derived precipitation estimates from Scotland, we present regional climate analysis that corroborates arguments for a strong west-east precipitation gradient across Scotland

Multi-omics Characterization of the Breast Cancer Radiation Response Identifies Apoptosis and Cell Cycle Proteins as Mediators of Radiation Resistance

Breast cancer (BC) is the most commonly diagnosed cancer in women and the second most deadly. Trimodality therapy consisting of surgery, chemotherapy, and radiation therapy is used to treat the majority of BC patients. However, despite the use of RT, a significant portion of patients, specifically those with basal-like BC, develop recurrences within 5-years of treatment completion. In an effort to understand why patients with basal-like BC are more likely to recur than patients with luminal or Her2-enriched BC we undertook a series of studies to understand the biology underlying radioresistance in basal-like BC. We first performed transcriptomic and proteomic analysis in cell lines representing the spectrum of BC subtypes treated with radiation (RT). RT induced RNA and protein expression changes in cell cycle, DNA damage, and p53 signaling pathways, which may act as modulators of the RT response in basal-like BC and lead to resistance. RT was unable to induce genes and proteins related to apoptosis after RT in radioresistant, p53-mutant BC cell lines, indicating that an inability to activate this pathway may contribute to radioresistance. Activation of the apoptosis pathway, through inhibition of Bcl-2 family anti-apoptotic proteins, radiosensitized p53-mutant, PIK3CA/PTEN wild-type basal-like BC. Specific inhibition of Bcl-xL, but not Bcl-2, lead to radiosensitization of p53-mutant PIKCA/PTEN wild-type basal-like BC. Radiosensitization was mediated through RT induced Mcl-1 degradation, that in combination with Bcl-xL specific inhibition, increased the percentage of apoptotic cells. Overexpression of Mcl-1 in p53-mutant, PIK3CA/PTEN wild-type basal-like BC rescued this radioresistance. In vivo, pan inhibition of Bcl-2 family proteins or specific inhibition of Bcl-xL in combination with RT delayed tumor growth and increase time to tumor doubling and tripling. These data provide a rationale for using Bcl-xL inhibitors for the radiosensitization of p53-mutant, PIK3CA/PTEN wild-type basal-like BC. To expand upon these studies and further identify proteins related to recurrence we correlated gene expression to early recurrence (< 3 years) in four independent datasets with patient outcomes and found TTK, a cell cycle kinase, was most differentially expressed. Inhibition of TTK (both genetic and pharmacologic) radiosensitized basal-like BC. Reintroduction of wild-type TTK, after endogenous TTK knockdown, rescued radiosensitization, however reintroduction of kinase-dead TTK was unable to do so. TTK inhibition (both genetic and pharmacologic) led to unresolved double stranded DNA (dsDNA) damage over time after RT, indicating that TTK inhibition may compromise dsDNA repair efficiency. Using a homologous recombination (HR) specific reporter system, we found that TTK inhibition (both genetic and pharmacologic) decreased HR efficiency. Furthermore, TTK knockdown decreased Rad51 foci formation, a marker for active HR, after RT. Reintroduction of wild-type TTK, after endogenous TTK knockdown, rescued HR repair efficiency and Rad51 foci formation, however reintroduction of kinase-dead TTK was unable to do so. Using a specific non-homologous end joining (NHEJ) reporter system, we found that TTK inhibition (both genetic and pharmacologic) had no effect on NHEJ repair efficiency. In vivo, TTK inhibition (both genetic and pharmacologic) in combination with RT reduced tumor growth and increase time to tumor tripling in subcutaneous basal-like BC cell line models. In an orthotopic patient derived xenograft model, pharmacologic inhibition of TTK in combination with RT synergistically reduced tumor growth and increased time to tumor tripling. Together our results show that a multi-omics characterization of the RT response led to successful nomination of radiosensitization targets that may be clinically tractable.PHDCancer BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/155055/1/chandleb_1.pd