Natural Killer Cell Killing of Acute Myelogenous Leukemia and Acute Lymphoblastic Leukemia Blasts by Killer Cell Immunoglobulin-Like Receptor–Negative Natural Killer Cells after NKG2A and LIR-1 Blockade

Although the study of natural killer (NK) cell alloreactivity has been dominated by studies of killer cell immunoglobulin-like receptors (KIRs), we hypothesized that NKG2A and LIR-1, present on 53% ± 13% and 36% ± 18% of normal NK cells, respectively, play roles in the NK cell killing of primary leukemia targets. KIR- cells, which compose nearly half of the circulating NK cell population, exhibit tolerance to primary leukemia targets, suggesting signaling through other inhibitory receptors. Both acute myelogenous leukemia and acute lymphoblastic leukemia targets were rendered susceptible to lysis by fresh resting KIR- NK cells when inhibitory receptor–major histocompatibility class I interactions were blocked by pan-HLA antibodies, demonstrating that these cells are functionally competent. Blockade of a single inhibitory receptor resulted in slightly increased killing, whereas combined LIR-1 and NKG2A blockade consistently resulted in increased NK cell cytotoxicity. Dual blockade of NKG2A and LIR-1 led to significant killing of targets by resting KIR- NK cells, demonstrating that this population is not hyporesponsive. Together these results suggest that alloreactivity of a significant fraction of KIR- NK cells is mediated by NKG2A and LIR-1. Thus strategies to interrupt NKG2A and LIR-1 in combination with anti-KIR blockade hold promise for exploiting NK cell therapy in acute leukemias

Swimming in circles: Motion of bacteria near solid boundaries

Near a solid boundary, E. coli swims in clockwise circular motion. We provide a hydrodynamic model for this behavior. We show that circular trajectories are natural consequences of force-free and torque-free swimming, and the hydrodynamic interactions with the boundary, which also leads to a hydrodynamic trapping of the cells close to the surface. We compare the results of the model with experimental data and obtain reasonable agreement. In particular, we show that the radius of curvature of the trajectory increases with the length of the bacterium body.Comment: Also available at http://people.deas.harvard.edu/~lauga

Donor KIR B Genotype Improves Progression-Free Survival of Non-Hodgkin Lymphoma Patients Receiving Unrelated Donor Transplantation

Donor killer immunoglobulin-like receptor (KIR) genotypes are associated with relapse protection and survival after allotransplantation for acute myelogenous leukemia. We examined the possibility of a similar effect in a cohort of 614 non-Hodgkin lymphoma (NHL) patients receiving unrelated donor (URD) T cell-replete marrow or peripheral blood grafts. Sixty-four percent (n = 396) of donor-recipient pairs were 10/10 allele HLA matched and 26% were 9/10 allele matched. Seventy percent of donors had KIR B/x genotype; the others had KIR A/A genotype. NHL patients receiving 10/10 HLA-matched URD grafts with KIR B/x donors experienced significantly lower relapse at 5 years (26%; 95% confidence interval [CI], 21% to 32% versus 37%; 95% CI, 27% to 46%; P = .05) compared with KIR A/A donors, resulting in improved 5-year progression-free survival (PFS) (35%; 95% CI, 26% to 44% versus 22%; 95% CI, 11% to 35%; P = .007). In multivariate analysis, use of KIR B/x donors was associated with significantly reduced relapse risk (relative risk [RR], .63, P = .02) and improved PFS (RR, .71, P = .008). The relapse protection afforded by KIR B/x donors was not observed in HLA-mismatched transplantations and was not specific to any particular KIR-B gene. Selecting 10/10 HLA-matched and KIR B/x donors should benefit patients with NHL receiving URD allogeneic transplantation

The Role of Focal Adhesion Kinase Binding in the Regulation of Tyrosine Phosphorylation of Paxillin

Focal adhesion kinase (FAK) and paxillin are focal adhesion-associated, phosphotyrosine-containing proteins that physically interact. A previous study has demonstrated that paxillin contains two binding sites for FAK. We have further characterized these two binding sites and have demonstrated that the binding affinity of the carboxyl-terminal domain of FAK is the same for each of the two binding sites. The presence of both binding sites increases the affinity for FAK by 5-10-fold. A conserved paxillin sequence called the LD motif has been implicated in FAK binding. We show that mutations in the LD motifs in both FAK-binding sites are required to dramatically impair FAK binding in vitro. A paxillin mutant containing point mutations in both FAK-binding sites was characterized. The mutant exhibited reduced levels of phosphotyrosine relative to wild type paxillin in subconfluent cells growing in culture, following cell adhesion to fibronectin and in src-transformed fibroblasts. These results suggest that paxillin must bind FAK for maximal phosphorylation in response to cell adhesion and that FAK may function to direct tyrosine phosphorylation of paxillin in the process of transformation by the src oncogene

The case for the continued use of the genus name Mimulus for all monkeyflowers

The genus Mimulus is a well-studied group of plant species, which has for decades allowed researchers to address a wide array of fundamental questions in biology (Wu & al. 2008; Twyford & al. 2015). Linnaeus named the type species of Mimulus (ringens L.), while Darwin (1876) used Mimulus (luteus L.) to answer key research questions. The incredible phenotypic diversity of this group has made it the focus of ecological and evolutionary study since the mid-20th century, initiated by the influential work of Clausen, Keck, and Hiesey as well as their students and collaborators (Clausen & Hiesey 1958; Hiesey & al. 1971, Vickery 1952, 1978). Research has continued on this group of diverse taxa throughout the 20th and into the 21st century (Bradshaw & al. 1995; Schemske & Bradshaw 1999; Wu & al. 2008; Twyford & al. 2015; Yuan 2019), and Mimulus guttatus was one of the first non-model plants to be selected for full genome sequencing (Hellsten & al. 2013). Mimulus has played a key role in advancing our general understanding of the evolution of pollinator shifts (Bradshaw & Schemske 2003; Cooley & al. 2011; Byers & al. 2014), adaptation (Lowry & Willis 2010; Kooyers & al. 2015; Peterson & al. 2016; Ferris & Willis 2018; Troth & al. 2018), speciation (Ramsey & al. 2003; Wright & al. 2013; Sobel & Streisfeld 2015; Zuellig & Sweigart 2018), meiotic drive (Fishman & Saunders 2008), polyploidy (Vallejo-Marín 2012; Vallejo-Marín & al. 2015), range limits (Angert 2009; Sexton et al. 2011; Grossenbacher & al. 2014; Sheth & Angert 2014), circadian rhythms (Greenham & al. 2017), genetic recombination (Hellsten & al. 2013), mating systems (Fenster & Ritland 1994; Dudash & Carr 1998; Brandvain & al. 2014) and developmental biology (Moody & al. 1999; Baker & al. 2011, 2012; Yuan 2019). This combination of a rich history of study coupled with sustained modern research activity is unparalleled among angiosperms. Across many interested parties, the name Mimulus therefore takes on tremendous biological significance and is recognizable not only by botanists, but also by zoologists, horticulturalists, naturalists, and members of the biomedical community. Names associated with a taxonomic group of this prominence should have substantial inertia, and disruptive name changes should be avoided. As members of the Mimulus community, we advocate retaining the genus name Mimulus to describe all monkeyflowers. This is despite recent nomenclature changes that have led to a renaming of most monkeyflower species to other genera.Additional co-authors: Jannice Friedman, Dena L Grossenbacher, Liza M Holeski, Christopher T Ivey, Kathleen M Kay, Vanessa A Koelling, Nicholas J Kooyers, Courtney J Murren, Christopher D Muir, Thomas C Nelson, Megan L Peterson, Joshua R Puzey, Michael C Rotter, Jeffrey R Seemann, Jason P Sexton, Seema N Sheth, Matthew A Streisfeld, Andrea L Sweigart, Alex D Twyford, John H Willis, Kevin M Wright, Carrie A Wu, Yao-Wu Yua

The Liquidity Trap, the Real Balance Effect, and the Friedman Rule

This paper studies the behavior of the economy and the efficacy of monetary policy under zero nominal interest rates, using a model with population growth that nests, as a special case, a more conventional specification in which there is a single infinitely lived representative agent. The paper shows that with a growing population, monetary policy has distributional effects that give rise to a real balance effect, thereby eliminating the liquidity trap. These same distributional effects, however, can also work to make many agents much worse off under zero nominal interest rates than they are when the nominal interest rate is positive

Measuring Anxiety in Youth with Learning Disabilities: Reliability and Validity of the Multidimensional Anxiety Scale for Children (MASC)

Youth with learning disabilities (LD) are at an increased risk for anxiety disorders and valid measures of anxiety are necessary for assessing this population. We investigated the psychometric properties of the Multidimensional Anxiety Scale for Children (MASC; March in Multidimensional anxiety scale for children. Multi-Health Systems, North Tonawanda, 1998) in 41 adolescents (ages 11– 17 years) with LD. Youth and parents completed the MASC and were administered the semi-structured Anxiety Disorders Interview Schedule: Child and Parent Versions (ADIS: C/P; Silverman and Albano in The Anxiety Disorders Interview Schedule for DSM-IV-Child and Parent Versions. Psychological Corporation, San Antonio, 1996). Results found that child and parent reports of Social Anxiety on the MASC closely corresponded with ADIS-generated social phobia diagnoses, and parent total scores discriminated well among youth with and without any anxiety disorder. A multi-method multi-trait matrix provided evidence of the construct validity of the MASC total score for both parent and child reports. Our findings provide empirical evidence that parent and child versions of the MASC are useful for assessing anxiety in youth with LD

Demonstration of surface electron rejection with interleaved germanium detectors for dark matter searches

The following article appeared in Applied Physics Letters 103.16 (2013): 164105 and may be found at http://scitation.aip.org/content/aip/journal/apl/100/26/10.1063/1.4729825The SuperCDMS experiment in the Soudan Underground Laboratory searches for dark matter with a 9-kg array of cryogenic germanium detectors. Symmetric sensors on opposite sides measure both charge and phonons from each particle interaction, providing excellent discrimination between electron and nuclear recoils, and between surface and interior events. Surface event rejection capabilities were tested with two 210 Pb sources producing ∼130 beta decays/hr. In ∼800 live hours, no events leaked into the 8–115 keV signal region, giving upper limit leakage fraction 1.7 × 10−5 at 90% C.L., corresponding to < 0.6 surface event background in the future 200-kg SuperCDMS SNOLAB experiment.This work is supported in part by the National Science Foundation (Grant Nos. AST-9978911, NSF-0847342, PHY-1102795,NSF-1151869, PHY-0542066, PHY-0503729, PHY-0503629, PHY-0503641, PHY-0504224, PHY-0705052,PHY-0801708, PHY-0801712, PHY-0802575, PHY-0847342, PHY-0855299, PHY-0855525, and PHY-1205898), by the Department of Energy (Contract Nos. DE-AC03-76SF00098, DE-FG02-92ER40701, DE-FG02-94ER40823,DE-FG03-90ER40569, DE-FG03-91ER40618, and DESC0004022),by NSERC Canada (Grant Nos. SAPIN 341314 and SAPPJ 386399), and by MULTIDARK CSD2009-00064 and FPA2012-34694. Fermilab is operated by Fermi Research Alliance, LLC under Contract No. De-AC02-07CH11359, while SLAC is operated under Contract No. DE-AC02-76SF00515 with the United States Department of Energy

Why Do Borrowers Pledge Collateral? New Empirical Evidence on the Role of Asymmetric Information

An important theoretical literature motivates collateral as a mechanism that mitigates adverse selection, credit rationing, and other inefficiencies that arise when borrowers hold ex ante private information. There is no clear empirical evidence regarding the central implication of this literature - that a reduction in asymmetric information reduces the incidence of collateral. We exploit exogenous variation in lender information related to the adoption of an information technology that reduces ex ante private information, and compare collateral outcomes before and after adoption. Our results are consistent with this central implication of the private-information models and support the empirical importance of this theory

Revised Lithostratigraphy of the Sonsela Member (Chinle Formation, Upper Triassic) in the Southern Part of Petrified Forest National Park, Arizona

BACKGROUND: Recent revisions to the Sonsela Member of the Chinle Formation in Petrified Forest National Park have presented a three-part lithostratigraphic model based on unconventional correlations of sandstone beds. As a vertebrate faunal transition is recorded within this stratigraphic interval, these correlations, and the purported existence of a depositional hiatus (the Tr-4 unconformity) at about the same level, must be carefully re-examined. METHODOLOGY/PRINCIPAL FINDINGS: Our investigations demonstrate the neglected necessity of walking out contacts and mapping when constructing lithostratigraphic models, and providing UTM coordinates and labeled photographs for all measured sections. We correct correlation errors within the Sonsela Member, demonstrate that there are multiple Flattops One sandstones, all of which are higher than the traditional Sonsela sandstone bed, that the Sonsela sandstone bed and Rainbow Forest Bed are equivalent, that the Rainbow Forest Bed is higher than the sandstones at the base of Blue Mesa and Agate Mesa, that strata formerly assigned to the Jim Camp Wash beds occur at two stratigraphic levels, and that there are multiple persistent silcrete horizons within the Sonsela Member. CONCLUSIONS/SIGNIFICANCE: We present a revised five-part model for the Sonsela Member. The units from lowest to highest are: the Camp Butte beds, Lot's Wife beds, Jasper Forest bed (the Sonsela sandstone)/Rainbow Forest Bed, Jim Camp Wash beds, and Martha's Butte beds (including the Flattops One sandstones). Although there are numerous degradational/aggradational cycles within the Chinle Formation, a single unconformable horizon within or at the base of the Sonsela Member that can be traced across the entire western United States (the "Tr-4 unconformity") probably does not exist. The shift from relatively humid and poorly-drained to arid and well-drained climatic conditions began during deposition of the Sonsela Member (low in the Jim Camp Wash beds), well after the Carnian-Norian transition