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Loss of Neu5Gc during Human Evolution: Impact on Macrophage Inflammation and Muscle Metabolism
Full text linkAround 2-3 million years ago, Alu-mediated deletion of a critical exon in the CMAH gene became fixed in the hominin lineage ancestral to humans and may have contributed to the speciation of Homo. Although CMAH loss has occurred independently in some other animal lineages, it is functionally intact in Old World primates, including our closest relatives, the chimpanzees. Chapter 1 is a thorough but concise review of the known consequences of Neu5Gc loss. We have speculated that hominin CMAH loss contributes to human evolution, at a time where our ancestors were using stone tools, increasing their consumption of meat, and possibly hunting. In Chapter 2, we show that when modeling Cmah loss in mice, they manifest a decreased survival in endotoxemia following bacterial lipopolysaccharide (LPS)injection. Macrophages and whole blood from Cmah-/- mice also killed E. coli K12 bacteria more effectively and this appears to be a conserved difference between humans and chimpanzees. While multiple mechanisms are likely involved, one causeis altered expression of C/EBPβ, a transcription factor affecting macrophage function that can be differentially expressed by simply feeding Neu5Gc to Cmah-/- macrophages. In Chapter 3, we show that Cmah-/- mice have a greater exercise capacity. Remarkably, the gastrocnemius complex time to fatigue measured in situ was more than 2-fold higher in non-exercise trained Cmah-/- mice when compared to WT controls. Mechanistically, the capillary to muscle fiber ratio is higher in Cmah-/- soleus, which could be contributing to a greater oxygen delivery during fatigue testing. After exercise training, metabolites in the pentose phosphate pathway and amino acid metabolism are also enriched in exercise-trained Cmah-/- soleus compared to WT, indicating a greater anabolic response. C/EBPδ, a transcription factor involved in regulation of metabolic and inflammatory pathways is also differentially expressed in Cmah-/- muscle. Therefore, we propose that the loss of CMAH in Homo likely allowed for greater bacterial killing and a greater maximum aerobic capacity. We speculate that this could have been a selective advantage when Homo transitioned towards persistence hunting and greater consumption of meat, but is likely coupled with a greater susceptibility to inflammatory pathologies and endotoxic shock
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Studies of highly conserved amino acid residues with fixed mutations unique to the human lineage.
Full text linkAnthropogeny asks the deepest questions of human curiosity: “Where did we come from? How did we get here?” This dissertation of biomedical sciences takes advantage of molecular and cellular methods to investigate these questions. The human genome is highly similar to the genome of our closest living evolutionary relative, the chimpanzee. Parsing the molecular mechanisms responsible for distinctly-human phenotypes is a daunting challenge. Over recent decades, it has become apparent that the biology of sialic acids, monosaccharides that coat the surface of all cells, is rapidly evolving in the human species. SIGLEC12 and ST8SIA2 are two specific genes involved in sialic acid biology which each contain such human-specific amino acid changes. SIGLEC12 is a cell-surface sialic acid receptor which, in addition to a fixed amino acid change in the human lineage, is experience selection throughout human populations. We discover implications of these evolutionary changes in human cancer risk and progression. ST8SIA2 is a sialyltransferase that is involved in neuroplasticity, neurodevelopment, and in psychiatric and neurodegenerative disease. We identify a single amino acid change in ST8SIA2 that has functional consequences and may contribute to many distinctly human properties of the brain
I-Type Lectins
Full text linkI-type lectins are defined as glycan-binding proteins (excluding antibodies and T-cell receptors) in which the binding domain is homologous to the large and varied immunoglobulin superfamily (IgSF) of proteins. Among I-type lectins, the Siglec family of sialic acid–recognizing lectins is the best characterized subgroup, both structurally and functionally, and is therefore the major focus of this chapter. Details of their discovery, characterization, binding properties, and biology are provided, along with discussions of their functional roles in vertebrate biology, with most currently available information being in mammals, and multiple unusual changes during human evolution
Molecular Mimicry of Host Sialome by Human Pathogens to exploit Immunoregulatory Siglecs
No full textGoing Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Nothing in Glycobiology Makes Sense, except in the Light of Evolution
No full textThe remarkable structural diversity of glycans in nature, and their roles in cellular processes, host-pathogen interactions, biological diversity and speciation can be explained by evolutionary processes
Exploring the Impact of Ketodeoxynonulosonic Acid in Host-Pathogen Interactions Using Uptake and Surface Display by Nontypeable Haemophilus influenzae
Full text linkThis work is supported by grant R01GM32373 to A.V. from the U.S. National Institutes of Health
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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