Publications

    Francesca C. Fortenbaugh, Alexander Sugarman, Lynn C. Robertson, and Michael Esterman. 2019. “The attentional repulsion effect and relative size judgments.” Attention, Perception, & Psychophysics, 81, Pp. 442-461. Publisher's VersionAbstract
    fortenbaugh_etal_2019_app.pdf
    Rapid shifts of involuntary attention have been shown to induce mislocalizations of nearby objects. One pattern of mislocalization, termed the Attentional Repulsion Effect (ARE), occurs when the onset of peripheral pre-cues lead to perceived shifts of subsequently presented stimuli away from the cued location. While the standard ARE configuration utilizes vernier lines, to date, all previous ARE studies have only assessed distortions along one direction and tested one spatial dimension (i.e., position or shape). The present study assessed the magnitude of the ARE using a novel stimulus configuration. Across three experiments participants judged which of two rectangles on the left or right side of the display appeared wider or taller. Pre-cues were used in Experiments 1 and 2. Results show equivalent perceived expansions in the width and height of the pre-cued rectangle in addition to baseline asymmetries in left/right relative size under no-cue conditions. Altering cue locations led to shifts in the perceived location of the same rectangles, demonstrating distortions in perceived shape and location using the same stimuli and cues. Experiment 3 demonstrates that rectangles are perceived as larger in the periphery compared to fixation, suggesting that eye movements cannot account for results from Experiments 1 and 2. The results support the hypothesis that the ARE reflects a localized, symmetrical warping of visual space that impacts multiple aspects of spatial and object perception.
    Michael Esterman, Francesca C. Fortenbaugh, Meghan E. Pierce, Jennifer R. Fonda, Joseph DeGutis, William Milberg, and Regina McGlinchey. 2019. “Trauma-Related Psychiatric and Behavioral Conditions Are Uniquely Associated With Sustained Attention Dysfunction.” Neuropsychology, 33, 5, Pp. 711-724. Publisher's VersionAbstract
    esterman_etal_2019_neuropsychology.pdf
    Objective: It is increasingly recognized that trauma victims, particularly Veterans, have co-occurring psychological and physical conditions that impact cognition, especially the domains of sustained attention and executive functioning. Although previous work has generally attempted to isolate the unique cognitive effects of common combat-related comorbidities, less work has been done to examine how these conditions co-occur, and whether unique cognitive signatures accompany certain clinical combinations. Method: To address this gap, we examined how several deployment-related conditions were associated with performance on a well-validated measure of sustained attention (i.e., gradual onset continuous performance task [gradCPT]) and a battery of standard neuropsychological measures in 123 Veterans from the Translational Research Center for TBI and Stress Disorders. Initially, a Principal component analysis was conducted to investigate how comorbid conditions grouped together. Results: Several sustained attention measures from the gradCPT were differentially associated with four unique combinations of trauma-related pathology. Specifically, a somatic component representing the combination of current pain, sleep disturbance, and mild traumatic brain injury was associated with a higher rate of failures of attentional engagement. On the other hand, a comorbid posttraumatic stress disorder (PTSD) and mood disorder component (moodPTSD), as well as a substance use disorder component, were associated with higher rates of inhibitory control failures. Increased attentional instability was associated with moodPTSD as well as an anxiety disorder component. In contrast, the cognitive effects of deployment-related trauma were not observed on standard neuropsychological measures. Conclusion: These findings suggest that unique combinations of trauma-related pathology have dissociable effects on sustained attentional control.
    C. S. Hemmingsen, S. L. Glimberg, N. Quadrio, C. Völcker, K. K. Nielsen, J. H. Walther, M. Byrne, and A. P. Engsig-Karup. 2019. “Multiphase coupling of a reservoir simulator and computational fluid dynamics for accurate near-well flow.” Journal of Petroleum Science and Engineering, 178, Pp. 517–527. Publisher's VersionAbstract

    Near-well flow analysis is an important tool for gaining detailed insight of the flow behaviour and for improving well design and production optimization of real reservoirs. One challenge of accurate numerical modelling of the flow field in the vicinity of the well is related to the scale disparity factor in space and time. The numerical scale gap between the reservoir and the wellbore justifies the representation of a well as a point or line sink/source term in traditional reservoir models. However, standard numerical techniques for reservoir simulation are incapable of resolving the near-singular character of the pressure field in the vicinity of the well. Under the assumption that all length scales have impact on flow patterns, we present a proof-of-concept study aimed at improving the quality of the numerical simulation by considering the geometry and fluid flow near the wellbore in a fully connected system, thus accounting for the fine scale phenomena by means of a hybrid Navier-Stokes/Darcy wellbore model coupled with a full scale reservoir model. A weak coupling method based on fixed-point iterations, that preserves the mass flux transport across the coupled interface, while adjusting productivity indices, is demonstrated via numerical experiments. Several different numerical experiments are performed to demonstrate the versatility and the improved well performance insight that the coupled method offers, including horizontal well inflow profile, influence of formation damage and optimal well configuration.

    Patricia M Greenfield, Oshrat Sulika Rotem, and Michael Weinstock. 2019. “Ethiopian immigrants to Israel: The persistence and transformation of African values and practices in art and life.” Journal of psychology in Africa, 29, 6, Pp. 613–624.Abstract
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    We present a qualitative interdisciplinary study of seven Ethiopian potters who immigrated to Israel as adults. Data sources include cultural products (their clay sculptures), interviews, and archival photos at the time of immigration. Together these data sources show how these women carried African values (procreation, family closeness, sharing, and respect for elders) and memories of subsistence activities to Israel. They also show how the women expressed these values and practices in their sculptures. Additionally, findings reveal the contrasting, often conflicting, cultural values and practices that the women met in the broader Israeli society. Furthermore, we document spontaneous stylistic changes in the pottery in adaptation to the new environment. In Ethiopia, potters learned to work in clay by observing their mothers in an apprenticeship process. A new project will give Ethiopian immigrant potters an opportunity to use apprenticeship methods to transmit their techniques to a new generation of Israelis.
    Turky Abu Aleon, Michael Weinstock, Adriana M Manago, and Patricia M Greenfield. 2019. “Social Change and Intergenerational Value Differences in a Bedouin Community in Israel.” Journal of cross-cultural psychology, 50, 5, Pp. 708–727.Abstract
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    The current study tests the application of Greenfield’s theory of social change and human development to an Arab Bedouin community transitioning from a nomadic to a sedentary way of life. We predicted that sociodemographic change across three generations away from a rural subsistence way of life (a Gemeinschaft ecology) toward an urban, educated, and technological way of life in a commercial economy (a Gesellschaft ecology) would correspond to generational differences in individualistic values related to gender, focusing on equality and chosen roles. We also examined the hypothesis that the pattern of intergenerational differences would suggest a more rapid pace of value change for women than for men. We presented 20 adolescent girls, their mothers, and their grandmothers, and 20 adolescent boys, their fathers, and their grandfathers with a series of vignettes to measure their values. Results showed increasing Gesellschaft-adapted values across generations of both women and men; however, the pattern of generational differences suggested that the most dramatic change for women was in the parent generation, whereas the most dramatic change for men was in the adolescent generation. This pattern suggested a more rapid pace of value change for women than for men. Mediation analyses showed that education, TV watching, and Internet use explained differences in values across the generations. Qualitative examples illustrate how beliefs about ideal gender behaviors and male–female relations shift across generations in correspondence with sociodemographic changes.
    123 -, Chantre CO, Hoerstrup SP, and Parker KK. 2019. “Engineering biomimetic and instructive materials for wound healing and regeneration.” Current Opinion in Biomedical Engineering, 10, Pp. 97-106. Publisher's VersionAbstract
    Engineering biomimetic and instructive materials for wound healing and regeneration.
    Development of biomimetic and instructive materials is emerging as a promising approach for redirecting fibrotic wound healing into a regenerative process. In nature, complete tissue regeneration can transpire in certain organ substructures, during embryogenesis and, remarkably, in some organisms in which whole limbs can regrow. These regenerative phenomena were observed to possess specific extracellular matrices, as well as stem cell niches and regulatory signaling pathways, that likely act as spatiotemporal organizers of these preferred outcomes. Biomimetic materials are now improving on the limitations of existing wound care treatments because they are being designed to stimulate these spatiotemporal cues, thus supporting regeneration within host tissues. A variety of novel materials have already emerged and demonstrated promise both in preclinical studies and in patients. This review discusses the recent advances in understanding these biomimetic and instructive properties and their integration into wound care scaffolds.
    116 -, Glieberman AL, Pope BD, Zimmerman JF, Liu Q, Ferrier JP, Kenty JHR, Schrell AM, Mukhitov N, Shores KL, Tepole AB, Melton DA, Roper MG, and Parker KK. 2019. “Synchronized Stimulation and Continuous Insulin Sensing in a Microfluidic Human Islet on a Chip Designed for Scalable Manufacturing.” Lab on a Chip, 19, 18, Pp. 2993-3010. Publisher's VersionAbstract
    Synchronized Stimulation and Continuous Insulin Sensing in a Microfluidic Human Islet on a Chip Designed for Scalable Manufacturing
    Pancreatic β cell function is compromised in diabetes and is typically assessed by measuring insulin secretion during glucose stimulation. Traditionally, measurement of glucose-stimulated insulin secretion involves manual liquid handling, heterogeneous stimulus delivery, and enzyme-linked immunosorbent assays that require large numbers of islets and processing time. Though microfluidic devices have been developed to address some of these limitations, traditional methods for islet testing remain the most common due to the learning curve for adopting microfluidic devices and the incompatibility of most device materials with large-scale manufacturing. We designed and built a thermoplastic, microfluidic-based Islet on a Chip compatible with commercial fabrication methods, that automates islet loading, stimulation, and insulin sensing. Inspired by the perfusion of native islets by designated arterioles and capillaries, the chip delivers synchronized glucose pulses to islets positioned in parallel channels. By flowing suspensions of human cadaveric islets onto the chip, we confirmed automatic capture of islets. Fluorescent glucose tracking demonstrated that stimulus delivery was synchronized within a two-minute window independent of the presence or size of captured islets. Insulin secretion was continuously sensed by an automated, on-chip immunoassay and quantified by fluorescence anisotropy. By integrating scalable manufacturing materials, on-line, continuous insulin measurement, and precise spatiotemporal stimulation into an easy-to-use design, the Islet on a Chip should accelerate efforts to study and develop effective treatments for diabetes.
    Xin Hu, Dongxi Xiang, Ying Xie, Luwei Tao, Yu Zhang, Yue Jin, Luca Pinello, Youzhong Wan, Guo-Cheng Yuan, and Zhe Li. 2019. “LSD1 suppresses invasion, migration and metastasis of luminal breast cancer cells via activation of GATA3 and repression of TRIM37 expression.” Oncogene, 38, 44, Pp. 7017-7034.Abstract
    LSD1 (KDM1A) is a histone demethylase that plays both oncogenic and tumor suppressor roles in breast cancer. However, the exact contexts under which it plays these opposite functions remain largely elusive. By characterizing its role in luminal breast epithelial cells, here we show that inhibition of LSD1 by both genetic and pharmacological approaches increases their invasion and migration, whereas its inhibition by genetic approach, but not by pharmacological approach, impairs their proliferation/survival. Induced loss of LSD1 in luminal cells in a mouse model of luminal breast cancer, MMTV-PyMT, leads to a profound increase in lung metastasis. Mechanistically, LSD1 interacts with GATA3, a key luminal-specific transcription factor (TF), and their common target genes are highly related to breast cancer. LSD1 positively regulates GATA3 expression. It also represses expression of TRIM37, a breast epithelial oncogene encoding a histone H2A ubiquitin ligase, and ELF5, a key TF gene for luminal progenitors and alveolar luminal cells. LSD1-loss also leads to reduced expression of several cell-cell adhesion genes (e.g., CDH1, VCL, CTNNA1), possibly via TRIM37-upregulation and subsequently TRIM37-mediated repression. Collectively, our data suggest LSD1 largely plays a tumor suppressor role in luminal breast cancer and the oncogenic program associated with LSD1-inhibition may be suppressed via TRIM37-inhibition.
    Claudia Corrò, Marc E Healy, Stefanie Engler, Bernd Bodenmiller, Zhe Li, Peter Schraml, Achim Weber, Ian J Frew, Markus Rechsteiner, and Holger Moch. 2019. “IL-8 and CXCR1 expression is associated with cancer stem cell-like properties of clear cell renal cancer.” J Pathol, 248, 3, Pp. 377-389.Abstract
    Recent studies suggest that clear cell renal cell carcinoma (ccRCC) possesses a rare population of cancer stem cells (CSCs) that might contribute to tumor heterogeneity, metastasis and therapeutic resistance. Nevertheless, their relevance for renal cancer is still unclear. In this study, we successfully isolated CSCs from established human ccRCC cell lines. CSCs displayed high expression of the chemokine IL-8 and its receptor CXCR1. While recombinant IL-8 significantly increased CSC number and properties in vitro, CXCR1 inhibition using an anti-CXCR1 antibody or repertaxin significantly reduced these features. After injection into immune-deficient mice, CSCs formed primary tumors that metastasized to the lung and liver. All xenografted tumors in mice expressed high levels of IL-8 and CXCR1. Furthermore, IL-8/CXCR1 expression significantly correlated with decreased overall survival in ccRCC patients. These results suggest that the IL-8/CXCR1 phenotype is associated with CSC-like properties in renal cancer. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
    Rui Qing, Qiuyi Han, Michael Skuhersky, Haeyoon Chung, Myriam Badr, Thomas Schubert, and Shuguang Zhang. 2019. “QTY code designed thermostable and water-soluble chimeric chemokine receptors with tunable ligand affinity.” Proc Natl Acad Sci U S A, 116, 51, Pp. 25668-25676.Abstract
    Chemokine receptors are of great interest as they play a critical role in many immunological and pathological processes. The ability to study chemokine receptors in aqueous solution without detergent would be significant because natural receptors require detergents to become soluble. We previously reported using the QTY code to design detergent-free chemokine receptors. We here report the design of 2 detergent-free chimeric chemokine receptors that were experimentally unattainable in detergent solution. We designed chimeric receptors by switching the N terminus and 3 extracellular (EC) loops between different receptors. Specifically, we replaced the N terminus and 3 EC loops of CCR5QTY with the N terminus and 3 EC loops of CXCR4. The ligand for CXCR4; namely CXCL12, binds to the chimeric receptor CCR5QTY (7TM)-CXCR4 (N terminus+3 EC loops), but with lower affinity compared to CXCR4; the CCL5 ligand of CCR5 binds the chimeric receptor with ∼20× lower affinity. The chimeric design helps to elucidate the mechanism of native receptor-ligand interaction. We also show that all detergent-free QTY-designed chemokine receptors, expressed in Escherichia coli, bind to their respective chemokines with affinities in the nanomolar (nM) range, similar to the affinities of native receptors and SF9-produced QTY variants. These QTY-designed receptors exhibit remarkable thermostability in the presence of arginine and retain ligand-binding activity after heat treatment at 60 °C for 4 h and 24 h, and at 100 °C for 10 min. Our design approach enables affordable scale-up production of detergent-free QTY variant chemokine receptors with tunable functionality for various uses.
    Hayden Riley Schmidt. 2019. “Structural and Biochemical Investigations of Sigma Receptors.” Harvard University Division of Medical Sciences.Abstract
    The sigma-1 and sigma-2 receptors are a pair of enigmatic membrane proteins that are promising drug targets for the treatment of several conditions. Ligands targeting the sigma-1 receptor may be useful for the treatment of neuropathic pain, ischemic stroke, Alzheimer’s disease, and other neurodegenerative diseases. Ligands targeting the sigma-2 receptor hold promise for the treatment and imaging of cancer, and for the treatment of the negative symptoms of schizophrenia. Since the discovery of these receptors, myriad small molecules have been identified that bind to these receptors with high affinity. However, despite their pharmacological tractability and therapeutic potential, the basic molecular functions of the sigma receptors remain ambiguous. The work presented in this dissertation makes key advances towards understanding the molecular biology of both sigma-1 and sigma-2 receptors. In this dissertation, I describe the first crystal structures of the human sigma-1 receptor bound to five different small molecule ligands, including classical antagonist and an agonist. These structures provide a model of the sigma-1 receptor’s structure, reveal how it binds a multitude of small ligands with high (<100 nM) affinity, and suggests a structural mechanism by which agonists may differ from antagonists. Additionally, a detailed analysis of sigma-1 receptor ligand-binding kinetics provides key insights into receptor-ligand interactions. Notably, this work reveals that the association between the sigma-1 receptor and its ligands is a multi-step process that is rate limited by a conformational change in the receptor prior to ligand binding. Finally, we identified the gene that codes for the sigma-2 receptor as Tmem97, resolving a nearly 40-year old pharmacological mystery. The identification of the sigma-2 receptor as TMEM97 unities two previously independent fields of study, simultaneously providing the sigma-2 receptor field with access to modern molecular biological techniques and the TMEM97 field with a diverse collection of pharmacological tools. Collectively, the work described here represents progress towards a molecular understanding of sigma receptor function, which will be crucial to realizing the full therapeutic potential of these enigmatic receptors.
    Peter Cram, Bruce E. Landon, John Matelski, Vicki Ling, Anthony V. Perruccio, J. Michael Paterson, and Y. Raja Rampersaud. 2019. “Utilization and Outcomes for Spine Surgery in the United States and Canada.” Spine, 44, 19, Pp. 1371-1380.Abstract
    STUDY DESIGN: A retrospective cohort study. OBJECTIVE: The aim of this study was to examine variation in spine surgery utilization between the province of Ontario and state of New York among all patients and pre-specified patient subgroups. SUMMARY OF BACKGROUND DATA: Spine surgery is common and costly. Within-country variation in utilization is well studied, but there has been little exploration of variation in spine surgery utilization between countries. METHODS: We used population-level administrative data from Ontario (years 2011-2015) and New York (2011-2014) to identify all adults who underwent inpatient spinal decompression or fusion surgery using relevant procedure codes. Patients were stratified according to age and surgical urgency (elective vs. emergent). We calculated standardized utilization rates (procedures per-10,000 population per year) for each jurisdiction. We compared Ontario and New York with respect to patient demographics and the percentage of hospitals performing spine surgery. We compared utilization rates of spinal decompression and fusion surgery in Ontario and New York among all patients and after stratifying by surgical urgency and patient age. RESULTS: Patients in Ontario were older than patients in New York for both decompression (mean age 58.8 vs. 51.3 years; P < 0.001) and fusion (58.1 vs. 54.9; P < 0.001). A smaller percentage of hospitals in Ontario than New York performed decompression (26.1% vs. 54.9%; P < 0.001) or fusion (15.2% vs. 56.7%; P < 0.001). Overall, utilization of spine surgery (decompression plus fusion) in Ontario was 6.6 procedures per-10,000 population per-year and in New York was 16.5 per-10,000 per-year (P < 0.001). Ontario-New York differences in utilization were smaller for emergent cases (2.0 per 10,000 in Ontario vs. 2.5 in New York; P < 0.001), but larger for elective cases (4.6 vs. 13.9; P < 0.001). The lower utilization in Ontario was particularly large among younger patients (age <60 years). CONCLUSION: We found significantly lower utilization of spine surgery in Ontario than in New York. These differences should inform policy reforms in both jurisdictions. LEVEL OF EVIDENCE: 3.

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