Junior Recital, Nathanael Clark, alto saxophone

The presentation of this junior recital will fulfill in part the requirements for the Bachelor of Music degree in Jazz Studies. Nathanael Clark studies alto saxophone with J.C. Kuhl

Senior Recital, Nathanael Clark, alto saxophone

The presentation of this senior recital will fulfill in part the requirements for the Bachelor of Music degree in Jazz Studies. Nathanael Clark studies alto saxophone with J.C. Kuhl

Vomocytosis of live pathogens from macrophages is regulated by the atypical MAP kinase ERK5

Vomocytosis, or non-lytic extrusion, is a poorly understood process through which macrophages release live pathogens that they have failed to kill back into the extracellular environment. Vomocytosis is conserved across vertebrates and occurs with a diverse range of pathogens, but to date the host signaling events that underpin expulsion remain entirely unknown. Here we use a targeted inhibitor screen to identify the MAP-kinase ERK5 as a critical suppressor of vomocytosis. Pharmacological inhibition or genetic manipulation of ERK5 activity significantly raises vomocytosis rates in human macrophages whilst stimulation of the ERK5 signaling pathway inhibits vomocytosis. Lastly, using a zebrafish model of cryptococcal disease, we show that reducing ERK5 activity in vivo stimulates vomocytosis and results in reduced dissemination of infection. ERK5 therefore represents the first host regulator of vomocytosis to be identified and a potential target for the future development of vomocytosis-modulating therapies

CDK7 Inhibition Suppresses Super-Enhancer-Linked Oncogenic Transcription in MYCN-Driven Cancer

The MYC oncoproteins are thought to stimulate tumor cell growth and proliferation through amplification of gene transcription, a mechanism that has thwarted most efforts to inhibit MYC function as potential cancer therapy. Using a covalent inhibitor of cyclin-dependent kinase 7 (CDK7) to disrupt the transcription of amplified MYCN in neuroblastoma cells, we demonstrate downregulation of the oncoprotein with consequent massive suppression of MYCN-driven global transcriptional amplification. This response translated to significant tumor regression in a mouse model of high-risk neuroblastoma, without the introduction of systemic toxicity. The striking treatment selectivity of MYCN-overexpressing cells correlated with preferential downregulation of super-enhancer-associated genes, including MYCN and other known oncogenic drivers in neuroblastoma. These results indicate that CDK7 inhibition, by selectively targeting the mechanisms that promote global transcriptional amplification in tumor cells, may be useful therapy for cancers that are driven by MYC family oncoproteins.United States. National Institutes of Health (R01CA148688)United States. National Institutes of Health (R01CA148688S1)United States. National Institutes of Health (R01CA179483-01)United States. National Institutes of Health (CA109901)United States. National Institutes of Health (HG002668)United States. National Institutes of Health (R21HG006778)American Cancer Society (RSG-12-247-TBG)United States. Department of Defense (PR120741A)Friends for Life Neuroblastoma Foundatio

Selective Oxidation of Pharmaceuticals and Suppression of Perchlorate Formation during Electrolysis of Fresh Human Urine

Many pharmaceutical compounds are excreted unchanged or as active metabolites via urine. They pass through conventional wastewater treatment processes and present a risk to aquatic ecosystems and humans. Point-source remediation of source-separated urine provides a promising alternative to destroy pharmaceuticals before dilution with wastewater. Electrochemical advanced oxidation processes are one possible option for degrading pharmaceuticals in urine, but they often lead to the formation of oxidation byproducts (OBPs) including chlorate, perchlorate, and halogenated organics at hazardous concentrations due to high background chloride concentrations. Here, we show that the high urea content of fresh human urine suppresses the formation of oxychlorides by inhibiting formation of HOCl/OCl‒ during electrolysis, while still enabling the oxidation of pharmaceuticals by •OH due to the slow rate of urea oxidation by •OH. This results in improved performance when compared to equivalent treatment of hydrolyzed aged urine. This (primarily indirect) electrochemical oxidation scheme is shown to degrade the model pharmaceuticals cyclophosphamide and sulfamethoxazole with surface-area-to-volume-normalized pseudo-first-order observed rate constants greater than 0.08 cm/min in authentic fresh human urine matrixes. It results in two orders-of-magnitude decrease in pharmaceutical concentrations in 2 hours while generating three orders-of-magnitude lower oxychloride byproduct concentrations in synthetic fresh urine as compared to synthetic hydrolyzed aged urine matrixes. Importantly, this proof-of-principle shows that simple and safe electrochemical methods can be used for point-source-remediation of pharmaceuticals in fresh human urine (before storage and hydrolysis), without formation of significant oxychloride byproducts. </p

Saxophone Studio

from the studio of Albert Regn

Transfer Learning for Mortality Prediction in Non-Small Cell Lung Cancer with Low-Resolution Histopathology Slide Snapshots

High-resolution whole slide image scans of histopathology slides have been widely used in recent years for prediction in cancer. However, in some cases, clinical informatics practitioners may only have access to low-resolution snapshots of histopathology slides, not high-resolution scans. We evaluated strategies for training neural network prognostic models in non-small cell lung cancer (NSCLC) based on low-resolution snapshots, using data from the Veterans Affairs Precision Oncology Data Repository. We compared strategies without transfer learning, with transfer learning from general domain images, and with transfer learning from publicly available high-resolution histopathology scans. We found transfer learning from high-resolution scans achieved significantly better performance than other strategies. Our contribution provides a foundation for future development of prognostic models in NSCLC that incorporate data from low-resolution pathology slide snapshots alongside known clinical predictors

Characterization of WZ4003 and HTH-01-015 as selective inhibitors of the LKB1-tumour-suppressor-activated NUAK kinases

The related NUAK1 and NUAK2 are members of the AMPK (AMP-activated protein kinase) family of protein kinases that are activated by the LKB1 (liver kinase B1) tumour suppressor kinase. Recent work suggests they play important roles in regulating key biological processes including Myc-driven tumorigenesis, senescence, cell adhesion and neuronal polarity. In the present paper we describe the first highly specific protein kinase inhibitors of NUAK kinases namely WZ4003 and HTH-01-015. WZ4003 inhibits both NUAK isoforms (IC50 for NUAK1 is 20 nM and for NUAK2 is 100 nM), whereas HTH-01-015 inhibits only NUAK1 (IC50 is 100 nM). These compounds display extreme selectivity and do not significantly inhibit the activity of 139 other kinases that were tested including ten AMPK family members. In all cell lines tested, WZ4003 and HTH-01-015 inhibit the phosphorylation of the only well-characterized substrate, MYPT1 (myosin phosphate-targeting subunit 1) that is phosphorylated by NUAK1 at Ser445. We also identify a mutation (A195T) that does not affect basal NUAK1 activity, but renders it ~50-fold resistant to both WZ4003 and HTH-01-015. Consistent with NUAK1 mediating the phosphorylation of MYPT1 we find that in cells overexpressing drug-resistant NUAK1[A195T], but not wild-type NUAK1, phosphorylation of MYPT1 at Ser445 is no longer suppressed by WZ4003 or HTH-01-015. We also demonstrate that administration of WZ4003 and HTH-01-015 to MEFs (mouse embryonic fibroblasts) significantly inhibits migration in a wound-healing assay to a similar extent as NUAK1-knockout. WZ4003 and HTH-01-015 also inhibit proliferation of MEFs to the same extent as NUAK1 knockout and U2OS cells to the same extent as NUAK1 shRNA knockdown. We find that WZ4003 and HTH-01-015 impaired the invasive potential of U2OS cells in a 3D cell invasion assay to the same extent as NUAK1 knockdown. The results of the present study indicate that WZ4003 and HTH-01-015 will serve as useful chemical probes to delineate the biological roles of the NUAK kinases