Mrpl35, A Mitospecific Component of Mitoribosomes, Plays A Key Role in Cytochrome \u3cem\u3eC\u3c/em\u3e Oxidase Assembly

Mitoribosomes perform the synthesis of the core components of the oxidative phosphorylation (OXPHOS) system encoded by the mitochondrial genome. We provide evidence that MrpL35 (mL38), a mitospecific component of the yeast mitoribosomal central protuberance, assembles into a subcomplex with MrpL7 (uL5), Mrp7 (bL27), and MrpL36 (bL31) and mitospecific proteins MrpL17 (mL46) and MrpL28 (mL40). We isolated respiratory defective mrpL35 mutant yeast strains, which do not display an overall inhibition in mitochondrial protein synthesis but rather have a problem in cytochrome coxidase complex (COX) assembly. Our findings indicate that MrpL35, with its partner Mrp7, play a key role in coordinating the synthesis of the Cox1 subunit with its assembly into the COX enzyme and in a manner that involves the Cox14 and Coa3 proteins. We propose that MrpL35 and Mrp7 are regulatory subunits of the mitoribosome acting to coordinate protein synthesis and OXPHOS assembly events and thus the bioenergetic capacity of the mitochondria

Minimal requirements for the cultural evolution of language

Human language is both a cognitive and a cultural phenomenon. Any evolutionary account of language, then, must address both biological and cultural evolution. In this thesis, I give a mainly cultural evolutionary answer to two main questions: firstly, how do working systems of learned communication arise in populations in the absence of external or internal guidance? Secondly, how do those communication systems take on the fundamental structural properties found in human languages, i.e. systematicity at both a meaningless and meaningful level? A large, multi-disciplinary literature exists for each question, full of apparently conflicting results and analyses. My aim in this thesis is to survey this work, so as to find any commonalities and bring this together in order to provide a minimal account of the cultural evolution of language. The first chapter of this thesis takes a number of well-established models of the emergence of signalling systems. These are taken from several different fields: evolutionary linguistics, evolutionary game theory, philosophy, artificial life, and cognitive science. By using a common framework to directly compare these models, I show that three underlying commonalities determine the ability of any population of agents to reliably develop optimal signalling. The three requirements are that i) agents can create and transfer referential information, ii) there is a systemic bias against ambiguity, and iii) some mechanism leading to information loss exists. Following this, I extend the model to determine the effects of including referential uncertainty. I show that, for the group of models to which this applies, this places certain extra restrictions on the three requirements stated above. In the next chapter, I use an information-theoretic framework to construct a novel analysis of signalling games in general, and rephrase the three requirements in more formal terms. I then show that we can use these 3 criteria as a diagnostic for determining whether any given signalling game will lead to optimal signalling, without the requirement for repeated simulations. In the final, much longer, chapter, I address the topic of duality of patterning. This involves a lengthy review of the literature on duality of patterning, combinatoriality, and compositionality. I then argue that both levels of systematicity can be seen as a functional adaptation which maintains communicative accuracy in the face of noisy processes at different levels of analysis. I support this with results from a new, minimally-specified model, which also clarifies and informs a number of long-fought debates within the field

Morphological word structure in English and Swedish : the evidence from prosody

Trubetzkoy's recognition of a delimitative function of phonology, serving to signal boundaries between morphological units, is expressed in terms of alignment constraints in Optimality Theory, where the relevant constraints require specific morphological boundaries to coincide with phonological structure (Trubetzkoy 1936, 1939, McCarthy & Prince 1993). The approach pursued in the present article is to investigate the distribution of phonological boundary signals to gain insight into the criteria underlying morphological analysis. The evidence from English and Swedish suggests that necessary and sufficient conditions for word-internal morphological analysis concern the recognizability of head constituents, which include the rightmost members of compounds and head affixes. The claim is that the stability of word-internal boundary effects in historical perspective cannot in general be sufficiently explained in terms of memorization and imitation of phonological word form. Rather, these effects indicate a morphological parsing mechanism based on the recognition of word-internal head constituents. Head affixes can be shown to contrast systematically with modifying affixes with respect to syntactic function, semantic content, and prosodic properties. That is, head affixes, which cannot be omitted, often lack inherent meaning and have relatively unmarked boundaries, which can be obscured entirely under specific phonological conditions. By contrast, modifying affixes, which can be omitted, consistently have inherent meaning and have stronger boundaries, which resist prosodic fusion in all phonological contexts. While these correlations are hardly specific to English and Swedish it remains to be investigated to which extent they hold cross-linguistically. The observation that some of the constituents identified on the basis of prosodic evidence lack inherent meaning raises the issue of compositionality. I will argue that certain systematic aspects of word meaning cannot be captured with reference to the syntagmatic level, but require reference to the paradigmatic level instead. The assumption is then that there are two dimensions of morphological analysis: syntagmatic analysis, which centers on the criteria for decomposing words in terms of labelled constituents, and paradigmatic analysis, which centers on the criteria for establishing relations among (whole) words in the mental lexicon. While meaning is intrinsically connected with paradigmatic analysis (e.g. base relations, oppositeness) it is not essential to syntagmatic analysis

Individuating Part-whole Relations in the Biological World

What are the conditions under which one biological object is a part of another biological object? This paper answers this question by developing a general, systematic account of biological parthood. I specify two criteria for biological parthood. Substantial Spatial Inclusionrequires biological parts to be spatially located inside or in the region that the natural boundary of t he biological whole occupies. Compositional Relevance captures the fact that a biological part engages in a biological process that must make a necessary contribution to a condition that is minimally sufficient to one or more of the characteristic behaviors of the biological whole. Instead of emphasizing the diversity of part-whole relations in the biological world, this paper asks what biological part-whole relations have in common and what constrains their existence, in general. After presenting the two criteria for biological parthood I discuss in how far my account can cope with hard cases (e.g., redundant parts) and I reveal the merits and limits of monism

Influence of the 3D microenvironment on glioblastoma migration and drug response

Glioblastoma (GBM) is a highly invasive brain cancer characterized by poor prognosis. Despite significant efforts by the basic and clinical research community our understanding of GBM progression and recurrence has been incremental. Improvements in therapeutic response have been dismal, and GBM continues to be the deadliest tumor of the central nervous system, with patient average survival rate of 12 months. Synergistic relationships that the tumor cells establish with the brain microenvironment have been proven fundamental for successful tumor progression and maintenance. Yet, many in vitro GBM studies are performed in formats that fail to recapitulate the most essential component of the tumor microenvironment. In this work we aim to describe the influence of multiple features of the tumor microenvironment on GBM migration characteristics and response to drug treatment. Our approach involved the development of a 3D in vitro tissue model that recapitulates the cellular, chemical and mechanical features of brain microenvironment. To assess the influence of the physical properties of the extracellular matrix (ECM) on GBM migration we developed a matrix of hyaluronan supported by collagen with embedded microfibers to simulate the composition of brain ECM and the topographical cues of vasculature. Comparison of this model with Matrigel and collagen type-I showed that GBM exhibits different migration modes such as collective expansion, multicellular strands, and single cell migration as a response to the ECM composition and stiffness. Further incorporation of brain stromal cells as astrocytes and endothelial cells into the model showed that presence of astrocytes increased the migration of all GBM cell lines studied, however presence of endothelial cells only increased the migration of glioblastoma stem-like cells. Evaluation of the cytotoxic effect of multiple drugs on GBM was performed using our 3D model. Presence of extracellular matrix and stromal cells reduced the sensitivity of stem-like GBM cells to drug treatments. Our specific focus was on anti-STAT3 therapy and data obtained in the 3D model showed that the microenvironment regulates STAT3 activation as well as response to STAT3 drug targeting. This work supports the fundamental role of the 3D-microenvironment as a modulator of GBM behavior and provides a consistent and tunable in vitro platform to be used in GBM studies for a more realistic understanding of in vivo cancer progression and response to therapy

The Evolution of Cholesterol-Rich Membrane in Oxygen Adaption: The Respiratory System as a Model.

The increase in atmospheric oxygen levels imposed significant environmental pressure on primitive organisms concerning intracellular oxygen concentration management. Evidence suggests the rise of cholesterol, a key molecule for cellular membrane organization, as a cellular strategy to restrain free oxygen diffusion under the new environmental conditions. During evolution and the increase in organismal complexity, cholesterol played a pivotal role in the establishment of novel and more complex functions associated with lipid membranes. Of these, caveolae, cholesterol-rich membrane domains, are signaling hubs that regulate important in situ functions. Evolution resulted in complex respiratory systems and molecular response mechanisms that ensure responses to critical events such as hypoxia facilitated oxygen diffusion and transport in complex organisms. Caveolae have been structurally and functionally associated with respiratory systems and oxygen diffusion control through their relationship with molecular response systems like hypoxia-inducible factors (HIF), and particularly as a membrane-localized oxygen sensor, controlling oxygen diffusion balanced with cellular physiological requirements. This review will focus on membrane adaptations that contribute to regulating oxygen in living systems