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"Rosenberg, Eric M"
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Trauma and documentary photography of the FSA
\"Coauthored by the literary scholar Sara Blair and the art historian Eric Rosenberg, this volume of the Defining Moments in American Photography series offers new ways to understand the work of the famous Farm Security Administration photographers by exploring an expanded and much more variable idea of the documentary than what New Dealers proposed. The coauthors follow in the line of scholars who have, on the one hand, looked critically at the FSA photography project and identified its goals, biases, contradictions, and ambivalences and, on the other hand, discerned strikingly independent directions among its photographers. But what distinguishes their work from that of others is their wrestling with a specific term often applied to the Depression era: trauma. If it was the case that documentary, as a genre, and FSA photographs, as an umbrella project, came to prominence during a time of trauma and in the hands of socially minded photographers was meant to address and publicize trauma, the coauthors of this volume seek to understand how trauma and photography mixed and how, in the volatility of that mixture, the competing ideas for documentary took shape. Among the key figures they study are some of the most beloved in American photography, including Walker Evans, Ben Shahn, and Aaron Siskind\"-- Provided by publisher.
Book
An active allosteric mechanism in ASAP1-mediated Arf1 GTP hydrolysis redefines PH domain function
GTPase-activating proteins are important regulators of small GTPases; among these, ASAP1 stimulates GTP hydrolysis on Arf1 and is implicated in cancer progression. ASAP1 contains a Pleckstrin Homology (PH) domain essential for maximum Arf·GTP hydrolysis. The prevailing view of PH domains is that they regulate proteins through passive mechanisms like membrane recruitment. In sharp contrast, we show that the PH domain of ASAP1 actively contributes to Arf1 GTP hydrolysis. By combining NMR, molecular dynamics simulations, kinetic assays, and mutational analysis, we find that the PH domain binds Arf·GTP at the membrane, to establish an active state primed for GTP hydrolysis. We identify key residues on the PH domain and Arf that drive this allosteric mechanism, which mathematical modeling shows contributes as much to GTPase activation as membrane recruitment. The finding that PH domains directly modulate small GTPases has broad implications for the Ras and Rho oncoprotein families.
GTPase-activating proteins (GAPs) often contain regulatory PH domains. In this work, Soubias et al, using an integrated structure-function approach, discovered a mechanism where a GAP PH domain binds directly to a GTPase to induce allosteric changes facilitating GTP hydrolysis.
Journal Article
Point mutations in Arf1 reveal cooperative effects of the N-terminal extension and myristate for GTPase-activating protein catalytic activity
The ADP-ribosylation factors (Arfs) constitute a family of small GTPases within the Ras superfamily, with a distinguishing structural feature of a hypervariable N-terminal extension of the G domain modified with myristate. Arf proteins, including Arf1, have roles in membrane trafficking and cytoskeletal dynamics. While screening for Arf1:small molecule co-crystals, we serendipitously solved the crystal structure of the non-myristoylated engineered mutation [L8K]Arf1 in complex with a GDP analogue. Like wild-type (WT) non-myristoylated Arf1•GDP, we observed that [L8K]Arf1 exhibited an N-terminal helix that occludes the hydrophobic cavity that is occupied by the myristoyl group in the GDP-bound state of the native protein. However, the helices were offset from one another due to the L8K mutation, with a significant change in position of the hinge region connecting the N-terminus to the G domain. Hypothesizing that the observed effects on behavior of the N-terminus affects interaction with regulatory proteins, we mutated two hydrophobic residues to examine the role of the N-terminal extension for interaction with guanine nucleotide exchange factors (GEFs) and GTPase Activating Proteins (GAPs. Different than previous studies, all mutations were examined in the context of myristoylated Arf. Mutations had little or no effect on spontaneous or GEF-catalyzed guanine nucleotide exchange but did affect interaction with GAPs. [F13A]myrArf1 was less than 1/2500, 1/1500, and 1/200 efficient as substrate for the GAPs ASAP1, ARAP1 and AGAP1; however, [L8A/F13A]myrArf1 was similar to WT myrArf1. Using molecular dynamics simulations, the effect of the mutations on forming alpha helices adjacent to a membrane surface was examined, yet no differences were detected. The results indicate that lipid modifications of GTPases and consequent anchoring to a membrane influences protein function beyond simple membrane localization. Hypothetical mechanisms are discussed.
Journal Article
The Impact of Health Benefit Design on Patients With Infertility
Assisted reproductive technology (ART) is a treatment option available to patients diagnosed with infertility. This study evaluated the impact of infertility benefit coverage on ART utilization and pregnancy-related outcomes, addressing a gap in previous research.
Retrospective analysis.
This study utilized the Workpartners Research Reference Database containing claims from self-insured employers in the US from 2010 to 2022. Women aged 18 to 42 years with at least 1 infertility diagnosis and at least 2 years of continuous enrollment after the initial infertility diagnosis were classified into 1 of 2 cohorts: high cohort (those with both infertility diagnostic and treatment coverage) or low cohort (those with only diagnostic coverage or no diagnostic nor treatment coverage). Binary outcomes were analyzed using logistic regression and continuous outcomes were analyzed using 2-stage stepwise regressions. Models controlled for differences in employee demographics, job-related variables (exempt status, full-time status, hourly vs salary, annual salary), and number of insured dependents.
Of the 10,820 women who met the inclusion criteria, 7589 (70.1%) were in the high cohort and 3231 (29.9%) were in the low cohort, with mean (SE) ages of 34.4 (0.06) vs 33.5 (0.11) years, respectively (P < .0001). The high cohort had a higher adjusted likelihood than the low cohort of using ART medications (P < .0001) and having ART procedures performed (P < .0001). The high cohort also used a higher number of unique ART medications and procedures. The likelihood of becoming pregnant with any ART utilization was 69.6% for the high cohort and 65.3% for the low cohort (P = .0089). The only significant difference in pregnancy-related complications was claims for oligohydramnios (9.3% vs 7.2%, respectively; P = .0294).
Health benefit design that includes infertility treatment coverage resulted in significantly higher use of unique ART medications, number of ART procedures performed, and successful pregnancy outcomes.
Journal Article
The PH domain in the ArfGAP ASAP1 drives catalytic activation through an unprecedented allosteric mechanism
ASAP1 is a multidomain Arf GTPase-activating protein (ArfGAP) that catalyzes GTP hydrolysis on the small GTPase Arf1 and is implicated in cancer progression. The PH domain of ASAP1 enhances its activity greater than 7 orders of magnitude but the underlying mechanisms remain poorly understood. Here, we combined Nuclear Magnetic Resonance (NMR), Molecular Dynamic (MD) simulations and mathematical modeling of functional data to build a comprehensive structural-mechanistic model of the complex of Arf1 and the ASAP1 PH domain on a membrane surface. Our results support a new conceptual model in which the PH domain contributes to efficient catalysis not only by membrane recruitment but by acting as a critical component of the catalytic interface, binding Arf·GTP and allosterically driving it towards the catalytic transition state. We discuss the biological implications of these results and how they may apply more broadly to poorly understood membrane-dependent regulatory mechanisms controlling catalysis of the ArfGAP superfamily as well as other peripheral membrane enzymes.
Journal Article
Point mutations in Arf1 reveal cooperative effects of the N-terminal region and myristate for GTPase-activating protein catalytic activity
The ADP-ribosylation factors (Arfs) constitute a family of small GTPases within the Ras superfamily, with a distinguishing structural feature of a hypervariable N-terminal extension of the G domain modified with myristate. Arf proteins, including Arf1, have roles in membrane trafficking and cytoskeletal dynamics. While screening for Arf1:small molecule co-crystals, we serendipitously solved the crystal structure of the non-myristoylated engineered mutation [L8K]Arf1 in complex with a GDP analogue. Like wild-type (WT) non-myristoylated Arf1bulletGDP, we observed that [L8K]Arf1 exhibited an N-terminal helix that occludes the hydrophobic cavity that is occupied by the myristoyl group in the GDP-bound state of the native protein. However, the helices were offset from one another due to the L8K mutation, with a significant change in position of the hinge region connecting the N-terminus to the G domain. Hypothesizing that the observed effects on behavior of the N-terminus affects interaction with regulatory proteins, we mutated two hydrophobic residues to examine the role of the N-terminal extension for interaction with guanine nucleotide exchange factors (GEFs) and GTPase Activating Proteins (GAPs). Different than previous studies, all mutations were examined in the context of myristoylated Arf. Mutations had little or no effect on spontaneous or GEF-catalyzed guanine nucleotide exchange but did affect interaction with GAPs.[F13A]myrArf1 was less than 1/2500, 1/1500, and 1/200 efficient as substrate for the GAPs ASAP1, ARAP1 and AGAP1; however, [L8A/F13A]myrArf1 was similar to WT myrArf1. We hypothesized that the myristate moiety associates with the N-terminal extension to alter its structure, thereby affecting its function. Using molecular dynamics simulations, the effect of the mutations on forming alpha helices was examined, yet no differences were detected. The results indicate that lipid modifications of GTPases and consequent anchoring to a membrane influences protein function beyond simple membrane localization. Hypothetical mechanisms are discussed.Competing Interest StatementThe authors have declared no competing interest.
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