Theory of Evolution and Faith in Creation On the History of a Tense Relationship

This overview of the history of the idea of evolution includes the work of many European scholars often omitted from such accounts, particularly in the United States. It provides a case study in the origin of cultural tensions, owing to the attempts of some scientists and theologians, without sufficient interdisciplinary understanding, to undermine public confidence in each other\'s proper authority

Antibodies Directed against the Extracellular Region of the Epidermal Growth Factor Receptor Adopt Distinct Modes of Binding and Inhibition

The work described in this dissertation comprises two distinct projects. In the first, we describe the structural and functional characterization of a family of Golgi associated cytosolic proteins, represented by Vps74 in fungi and GOLPH3 in animals, by X-ray crystallography, biophysical assays, and cellular techniques. We find that Vps74 is required for the proper steady state localization of a subset of Golgi enzymes in yeast, and that disruption of vps74 results in incomplete protein glycosylation. We further describe the crystal structures of Vps74 and GOLPH3, identifying structural motifs required both for oligomer formation and protein function. Finally, we find that both Vps74 and GOLPH3 specifically bind the Golgi enriched phospholipid, PtdIns4P. These results suggest a role for Vps74 and GOLPH3 in retrograde trafficking of components to the Golgi apparatus. In a separate and unrelated project, we characterize several inhibitory antibodies directed against the extracellular region of the epidermal growth factor receptor (EGFR). Aberrant activation of EGFR occurs in large proportion of epithelial cancers. Consequently, this receptor is a target for anti-cancer therapeutics that inhibit its activation, including antibodies and antibody-derived molecules. We have biochemically characterized a panel of conventional inhibitory antibodies with unique properties, and have identified approximate epitopes for these antibodies on domain 3 of EGFR. Additionally, we describe the crystal structures of three unconventional single chain antibody fragments in complex with the EGFR extracellular region. These single chain antibodies bind to novel epitopes on the receptor but share key characteristics with conventional inhibitory antibodies. Our findings highlight the diversity of binding modes among anti-EGFR antibodies, and suggest opportunities for novel therapeutics

Bioinformatic identification of ClpI, a distinct class of Clp unfoldases in Actinomycetota

All clades of bacteria possess Hsp100/Clp family unfoldase enzymes that contribute to aspects of protein quality control. In Actinomycetota, these include ClpB, which functions as an independent chaperone and disaggregase, and ClpC, which cooperates with the ClpP1P2 peptidase to carry out regulated proteolysis of client proteins. We initially sought to algorithmically catalog Clp unfoldase orthologs from Actinomycetota into ClpB and ClpC categories. In the process, we uncovered a phylogenetically distinct third group of double-ringed Clp enzymes, which we term ClpI. ClpI enzymes are architecturally similar to ClpB and ClpC, with intact ATPase modules and motifs associated with substrate unfolding and translation. While ClpI possess an M-domain similar in length to that of ClpC, its N-terminal domain is more variable than the strongly conserved N-terminal domain of ClpC. Surprisingly, ClpI sequences are divisible into sub-classes that either possess or lack the LGF-motifs required for stable assembly with ClpP1P2, suggesting distinct cellular roles. The presence of ClpI enzymes likely provides bacteria with expanded complexity and regulatory control over protein quality control programs, supplementing the conserved roles of ClpB and ClpC

Behavioral Theory for Stochastic Systems? A Data-driven Journey from Willems to Wiener and Back Again

The fundamental lemma by Jan C. Willems and co-workers, which is deeply rooted in behavioral systems theory, has become one of the supporting pillars of the recent progress on data-driven control and system analysis. This tutorial-style paper combines recent insights into stochastic and descriptor-system formulations of the lemma to further extend and broaden the formal basis for behavioral theory of stochastic linear systems. We show that series expansions -- in particular Polynomial Chaos Expansions (PCE) of $L^2$-random variables, which date back to Norbert Wiener's seminal work -- enable equivalent behavioral characterizations of linear stochastic systems. Specifically, we prove that under mild assumptions the behavior of the dynamics of the $L^2$-random variables is equivalent to the behavior of the dynamics of the series expansion coefficients and that it entails the behavior composed of sampled realization trajectories. We also illustrate the short-comings of the behavior associated to the time-evolution of the statistical moments. The paper culminates in the formulation of the stochastic fundamental lemma for linear (descriptor) systems, which in turn enables numerically tractable formulations of data-driven stochastic optimal control combining Hankel matrices in realization data (i.e. in measurements) with PCE concepts.Comment: 30 pages, 8 figure

Cerebrospinal fluid outflow along lumbar nerves and possible relevance for pain research: case report and review

CSF outflow through the cribriform plate near the olfactory nerves and the outflow along brain and spinal nerves are together known as peripheral CSF outflow pathway (PCOP). It is still not clear whether the PCOP has pathogenetic relevance. Our previous clinical observations have indicated that CSF may interact with nerves along the PCOP and in this article we present our finding of CSF outflow demonstrated by myelography in a single patient. We also discuss unexplained experimental pain pathomechanisms against the background of the PCOP hypothesis. We observed that CSF flowed along lumbar nerves in distal direction at a speed of about 10 cm per hour on its way through the tissues, mainly muscles. Total CSF outflow volume at the lumbar site was remarkable. CSF outflow at lumbar nerves was also documented by neuroradiology. It is plausible that CSF signaling serves for interaction with nerves along the PCOP, which could explain previously unknown pathomechanisms in pain generation. Experimental findings of tactile pain hypersensitivity within lumbosacral pain pathways could be explained by releasing of molecules, microparticles, or exosomes into the CSF by mast cells, which then move with CSF outflow along the PCOP and interact with nerves, initiating even retrograde synaptic stripping