Lithic Technological Organization at the Aztalan Site (47-je-0001)

Chipped stone artifacts represent just one aspect of a complex framework of behavioral adaptations to social and environmental forces, each requiring significant investments of both time and energy. This project consists of a complete lithic analysis of all chipped stone materials recovered by University of Wisconsin-Milwaukee field schools during 1984, 2011, and 2013 from the Aztalan site (47JE01), located in Southeastern Wisconsin. This assemblage includes 1,202 pieces of lithic debitage and 200 chipped stone tools. Through employing individual flake analysis of all debitage, this thesis has produced a large database of information that can provide valuable insight into the technological choices made by the people who lived at Aztalan. While Aztalan is a multi-component site, radiocarbon dating has placed the major prehistoric occupation of the Aztalan site between A.D. 1000-1200 (Richards and Jeske 2002) therefore, this thesis focuses on the overlapping Late Woodland and Middle-Mississippian components. The major goal of this thesis is to characterize the chipped stone artifacts from Aztalan through an assemblage-based approach, with the intention of answering questions relating to the lithic economy at the site. The UWM lithic assemblage suggests that lithic technological organization at Aztalan changed over time. Statistical analysis of the data from this project shows that with increased Middle Mississippian interaction came increased access to non-local raw materials. Not only was there an increase in access to non-local raw materials, but raw materials were also heat treated significantly less over time. Additionally, the results of this project suggest that the Late Woodland occupation at Aztalan may have already had access to a wider variety of raw materials than other Late Woodland groups in southeastern Wisconsin

Lithic Technological Organization at the Aztalan Site (47-je-0001)

Chipped stone artifacts represent just one aspect of a complex framework of behavioral adaptations to social and environmental forces, each requiring significant investments of both time and energy. This project consists of a complete lithic analysis of all chipped stone materials recovered by University of Wisconsin-Milwaukee field schools during 1984, 2011, and 2013 from the Aztalan site (47JE01), located in Southeastern Wisconsin. This assemblage includes 1,202 pieces of lithic debitage and 200 chipped stone tools. Through employing individual flake analysis of all debitage, this thesis has produced a large database of information that can provide valuable insight into the technological choices made by the people who lived at Aztalan. While Aztalan is a multi-component site, radiocarbon dating has placed the major prehistoric occupation of the Aztalan site between A.D. 1000-1200 (Richards and Jeske 2002) therefore, this thesis focuses on the overlapping Late Woodland and Middle-Mississippian components. The major goal of this thesis is to characterize the chipped stone artifacts from Aztalan through an assemblage-based approach, with the intention of answering questions relating to the lithic economy at the site. The UWM lithic assemblage suggests that lithic technological organization at Aztalan changed over time. Statistical analysis of the data from this project shows that with increased Middle Mississippian interaction came increased access to non-local raw materials. Not only was there an increase in access to non-local raw materials, but raw materials were also heat treated significantly less over time. Additionally, the results of this project suggest that the Late Woodland occupation at Aztalan may have already had access to a wider variety of raw materials than other Late Woodland groups in southeastern Wisconsin

Lithic Technological Organization at the Aztalan Site (47-je-0001)

Chipped stone artifacts represent just one aspect of a complex framework of behavioral adaptations to social and environmental forces, each requiring significant investments of both time and energy. This project consists of a complete lithic analysis of all chipped stone materials recovered by University of Wisconsin-Milwaukee field schools during 1984, 2011, and 2013 from the Aztalan site (47JE01), located in Southeastern Wisconsin. This assemblage includes 1,202 pieces of lithic debitage and 200 chipped stone tools. Through employing individual flake analysis of all debitage, this thesis has produced a large database of information that can provide valuable insight into the technological choices made by the people who lived at Aztalan. While Aztalan is a multi-component site, radiocarbon dating has placed the major prehistoric occupation of the Aztalan site between A.D. 1000-1200 (Richards and Jeske 2002) therefore, this thesis focuses on the overlapping Late Woodland and Middle-Mississippian components. The major goal of this thesis is to characterize the chipped stone artifacts from Aztalan through an assemblage-based approach, with the intention of answering questions relating to the lithic economy at the site. The UWM lithic assemblage suggests that lithic technological organization at Aztalan changed over time. Statistical analysis of the data from this project shows that with increased Middle Mississippian interaction came increased access to non-local raw materials. Not only was there an increase in access to non-local raw materials, but raw materials were also heat treated significantly less over time. Additionally, the results of this project suggest that the Late Woodland occupation at Aztalan may have already had access to a wider variety of raw materials than other Late Woodland groups in southeastern Wisconsin

Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction

Diabetic nephropathy (DN) is a major cause of end-stage renal disease, and therapeutic options for preventing its progression are limited. To identify novel therapeutic strategies, we studied protective factors for DN using proteomics on glomeruli from individuals with extreme duration of diabetes (≥ 50 years) without DN and those with histologic signs of DN. Enzymes in the glycolytic, sorbitol, methylglyoxal and mitochondrial pathways were elevated in individuals without DN. In particular, pyruvate kinase M2 (PKM2) expression and activity were upregulated. Mechanistically, we showed that hyperglycemia and diabetes decreased PKM2 tetramer formation and activity by sulfenylation in mouse glomeruli and cultured podocytes. Pkm-knockdown immortalized mouse podocytes had higher levels of toxic glucose metabolites, mitochondrial dysfunction and apoptosis. Podocyte-specific Pkm2-knockout (KO) mice with diabetes developed worse albuminuria and glomerular pathology. Conversely, we found that pharmacological activation of PKM2 by a small-molecule PKM2 activator, TEPP-46, reversed hyperglycemia-induced elevation in toxic glucose metabolites and mitochondrial dysfunction, partially by increasing glycolytic flux and PGC-1α mRNA in cultured podocytes. In intervention studies using DBA2/J and Nos3 (eNos) KO mouse models of diabetes, TEPP-46 treatment reversed metabolic abnormalities, mitochondrial dysfunction and kidney pathology. Thus, PKM2 activation may protect against DN by increasing glucose metabolic flux, inhibiting the production of toxic glucose metabolites and inducing mitochondrial biogenesis to restore mitochondrial function

Identification of Pyruvate Kinase in Methicillin-Resistant Staphylococcus aureus as a Novel Antimicrobial Drug Target▿

Novel classes of antimicrobials are needed to address the challenge of multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). Using the architecture of the MRSA interactome, we identified pyruvate kinase (PK) as a potential novel drug target based upon it being a highly connected, essential hub in the MRSA interactome. Structural modeling, including X-ray crystallography, revealed discrete features of PK in MRSA, which appeared suitable for the selective targeting of the bacterial enzyme. In silico library screening combined with functional enzymatic assays identified an acyl hydrazone-based compound (IS-130) as a potent MRSA PK inhibitor (50% inhibitory concentration [IC50] of 0.1 μM) with >1,000-fold selectivity over human PK isoforms. Medicinal chemistry around the IS-130 scaffold identified analogs that more potently and selectively inhibited MRSA PK enzymatic activity and S. aureus growth in vitro (MIC of 1 to 5 μg/ml). These novel anti-PK compounds were found to possess antistaphylococcal activity, including both MRSA and multidrug-resistant S. aureus (MDRSA) strains. These compounds also exhibited exceptional antibacterial activities against other Gram-positive genera, including enterococci and streptococci. PK lead compounds were found to be noncompetitive inhibitors and were bactericidal. In addition, mutants with significant increases in MICs were not isolated after 25 bacterial passages in culture, indicating that resistance may be slow to emerge. These findings validate the principles of network science as a powerful approach to identify novel antibacterial drug targets. They also provide a proof of principle, based upon PK in MRSA, for a research platform aimed at discovering and optimizing selective inhibitors of novel bacterial targets where human orthologs exist, as leads for anti-infective drug development

Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models

Continuous de novo fatty acid synthesis is a common feature of cancer required to meet the biosynthetic demands of a growing tumor. This process is controlled by the rate-limiting enzyme acetyl-CoA carboxylase (ACC), an attractive but traditionally intractable drug target. Here, we provide genetic and pharmacological evidence that in preclinical models ACC is required to maintain de novo fatty acid synthesis needed for growth and viability of non-small cell lung cancer (NSCLC). We describe the ability of ND-646—an allosteric inhibitor of the ACC enzymes ACC1 and ACC2 that prevents ACC subunit dimerization—to suppress fatty acid synthesis in vitro and in vivo. Chronic ND-646 treatment of xenograft and genetically engineered mouse models of NSCLC inhibited tumor growth. When administered as a single agent or in combination with the standard-of-care drug carboplatin, ND-646 markedly suppressed lung tumor growth in the Kras;Trp53(−/−) (also known as KRAS p53) and Kras;Stk11(−/−) (also known as KRAS Lkb1) mouse models of NSCLC. These findings demonstrate that ACC mediates a metabolic liability of NSCLC and that ACC inhibition by ND-646 is detrimental to NSCLC growth, supporting further examination of the use of ACC inhibitors in oncology