Showing papers by "University of Massachusetts Boston published in 2023"

Nutritional compensation of the circadian clock is a conserved process influenced by gene expression regulation and mRNA stability

Abstract: Compensation is a defining principle of a true circadian clock, where its approximately 24-hour period length is relatively unchanged across environmental conditions. Known compensation effectors directly regulate core clock factors to buffer the oscillator's period length from variables in the environment. Temperature Compensation mechanisms have been experimentally addressed across circadian model systems, but much less is known about the related process of Nutritional Compensation, where circadian period length is maintained across physiologically relevant nutrient levels. Using the filamentous fungus Neurospora crassa, we performed a genetic screen under glucose and amino acid starvation conditions to identify new regulators of Nutritional Compensation. Our screen uncovered 16 novel mutants, and together with 4 mutants characterized in prior work, a model emerges where Nutritional Compensation of the fungal clock is achieved at the levels of transcription, chromatin regulation, and mRNA stability. However, eukaryotic circadian Nutritional Compensation is completely unstudied outside of Neurospora. To test for conservation in cultured human cells, we selected top hits from our fungal genetic screen, performed siRNA knockdown experiments of the mammalian orthologs, and characterized the cell lines with respect to compensation. We find that the wild-type mammalian clock is also compensated across a large range of external glucose concentrations, as observed in Neurospora, and that knocking down the mammalian orthologs of the Neurospora compensation-associated genes CPSF6 or SETD2 in human cells also results in nutrient-dependent period length changes. We conclude that, like Temperature Compensation, Nutritional Compensation is a conserved circadian process in fungal and mammalian clocks and that it may share common molecular determinants.

Variation and Correlation of Potential Unintended Consequences of Antipsychotic Reduction in Ontario Nursing Homes Over Time

Abstract: Potentially inappropriate antipsychotic use has declined in nursing homes over the past decade; however, increases in the documentation of relevant clinical indications (eg, delusions) and the use of other psychotropic medications have raised concerns about diagnosis upcoding and medication substitution. Few studies have examined how these trends over time vary across and within nursing homes, information that may help to support antipsychotic reduction efforts.To jointly model facility-level time trends in potentially inappropriate antipsychotic use, antidepressant use, and the indications used to define appropriate antipsychotic use.We conducted a repeated cross-sectional study of all nursing homes in Ontario, Canada between April 1, 2010 and December 31, 2019 using linked health administrative data (N=649). Each nursing home's quarterly prevalence of potentially inappropriate antipsychotic use, antidepressant use, and relevant indications were measured as outcome variables. With time as the independent variable, multivariate random effects models jointly estimated time trends for each outcome across nursing homes and the correlations between time trends within nursing homes.We observed notable variations in the time trends for each outcome across nursing homes, especially for the relevant indications. Within facilities, we found no correlation between time trends for potentially inappropriate antipsychotic and antidepressant use ( r =-0.0160), but a strong negative correlation between time trends for potentially inappropriate antipsychotic use and relevant indications ( r =-0.5036).Nursing homes with greater reductions in potentially inappropriate antipsychotics tended to show greater increases in the indications used to define appropriate antipsychotic use-possibly leading to unmonitored use of antipsychotics.

LSD1 Inhibition Disrupts Super-Enhancer–Driven Oncogenic Transcriptional Programs in Castration-Resistant Prostate Cancer

Abstract: Abstract The lysine demethylase LSD1 (also called KDM1A) plays important roles in promoting multiple malignancies including both hematologic cancers and solid tumors. LSD1 targets histone and nonhistone proteins and can function as a transcriptional corepressor or coactivator. LSD1 has been reported to act as a coactivator of androgen receptor (AR) in prostate cancer and to regulate the AR cistrome via demethylation of its pioneer factor FOXA1. A deeper understanding of the key oncogenic programs targeted by LSD1 could help stratify prostate cancer patients for treatment with LSD1 inhibitors, which are currently under clinical investigation. In this study, we performed transcriptomic profiling in an array of castration-resistant prostate cancer (CRPC) xenograft models that are sensitive to LSD1 inhibitor treatment. Impaired tumor growth by LSD1 inhibition was attributed to significantly decreased MYC signaling, and MYC was found to be a consistent target of LSD1. Moreover, LSD1 formed a network with BRD4 and FOXA1 and was enriched at super-enhancer regions exhibiting liquid–liquid phase separation. Combining LSD1 inhibitors with BET inhibitors exhibited strong synergy in disrupting the activities of multiple drivers in CRPC, thereby inducing significant growth repression of tumors. Importantly, the combination treatment showed superior effects than either inhibitor alone in disrupting a subset of newly identified CRPC-specific super-enhancers. These results provide mechanistic and therapeutic insights for cotargeting two key epigenetic factors and could be rapidly translated in the clinic for CRPC patients. Significance: LSD1 drives prostate cancer progression by activating super-enhancer–mediated oncogenic programs, which can be targeted with the combination of LSD1 and BRD4 inhibitors to suppress the growth of CRPC.

Social justice and advocacy in the mental health field

Abstract: Health inequities influence the risk of behavioral disorders emerging in non-privileged communities, including access to health care, providers’ ability to offer services suited to the community's needs, and the overall outcomes of the care. Structural factors that result in inequities in mental health are most evident with one of our most vulnerable populations—children. Access to supportive environments, systemic alignment of initiatives, and mental health services are critical platforms for social justice and advocacy. As such, mental health practices require expansion into the systems that individual clients are embedded within, thus shifting the role of professionals and the potential impact of the field.

Context: Men and Women Writers in Late-Renaissance Italy

Abstract: A variety of sociopolitical, domestic, and cultural factors enabled early modern Italy’s uniquely cooperative culture, by which male and female poets were able to share the literary arena. Synthesizing the most important historical and literary studies of early modern gender from the last three decades, this chapter describes how social changes dovetailed with the rise of print culture in Italy, creating a situation in which women could enter into dialogue with men in manuscript and print. The focus here is on the late Cinquecento and early Seicento (about which significantly less has been written than earlier periods), an examination of a generation of writers who had only ever known a world in which women published in significant numbers alongside men.

Cytoplasmic polyadenylation is an ancestral hallmark of early development in animals

Abstract: ABSTRACT Differential regulation of gene expression has produced the astonishing diversity of life on Earth. Understanding the origin and evolution of mechanistic innovations for control of gene expression is therefore integral to evolutionary and developmental biology. Cytoplasmic polyadenylation is the biochemical extension of polyadenosine at the 3’-end of cytoplasmic mRNAs. This process regulates the translation of specific maternal transcripts and is mediated by the Cytoplasmic Polyadenylation Element Binding Protein family (CPEBs). Genes that code for CPEBs are amongst a very few that are present in animals but missing in non-animal lineages. Whether cytoplasmic polyadenylation is present in non bilaterian animals ( i.e. , sponges, ctenophores, placozoans, cnidarians) remains unknown. We have conducted phylogenetic analyses of CPEBs and our results show that CPEB1 and CPEB2 subfamilies originated in the animal stem lineage. Our assessment of expression in the sea anemone, Nematostella vectensis (Cnidaria), and the comb jelly, Mnemiopsis leidyi (Ctenophora), demonstrates that maternal expression of CPEB1 and the catalytic subunit of the cytoplasmic polyadenylation machinery (GLD2) is an ancient feature that is conserved across animals. Furthermore, our measurements of poly(A)-tail elongation reveal that key targets of cytoplasmic polyadenylation are shared between vertebrates, cnidarians, and ctenophores, indicating that this mechanism orchestrates a regulatory network that is conserved throughout animal evolution. We postulate that cytoplasmic polyadenylation through CPEBs was a fundamental innovation that contributed to animal evolution from unicellular life.

Creating Welfare States?: A Comparative History of Early Child Labor Legislation - Elisabeth Anderson. Agents of Reform: Child Labor and the Origins of the Welfare State. Princeton, NJ: Princeton University Press, 2021. xvi + 362 pp. $95.00 (cloth), ISBN 978-0-691-22090-1; $29.95 (paper), ISBN 978-0-691-22089-5.

Abstract: Creating Welfare States?: A Comparative History of Early Child Labor Legislation - Elisabeth Anderson. Agents of Reform: Child Labor and the Origins of the Welfare State. Princeton, NJ: Princeton University Press, 2021. xvi + 362 pp. 29.95 (paper), ISBN 978-0-691-22089-5. - Volume 22 Issue 3

ABCs: Differentiating Algorithmic Bias, Automation Bias, and Automation Complacency

Abstract: Algorithmic bias, automation bias, and automation complacency have been identified as culprits of a variety of human-computer interaction missteps, ethical offenses, and societal harms. However, these three terms are often mistaken and conflated. Students and professionals alike may have difficulty differentiating between the terms and fully understanding the impact of such psychological phenomena on their work and research. A review of relevant literature is conducted in order to establish an overview of historical documentation and analysis of the underlying themes; definitions and examples of each concept are then synthesized in order to provide a holistic understanding of the meaning behind this set of terminology.

Correspondence Lyric

Abstract: Correspondence verse was part of a broader vogue in Renaissance Italian literature of using contemporary, identifiable speakers. In contrast to the standard vagueness surrounding the identity of the beloved in amorous lyric, correspondence verse was often printed with the full names of both poetic participants. These poems are artistically mediated portrayals of speech, to be sure. Even so, these publicly circulated documents tell us how actual men and women imagined speaking in a variety of relationships— courtships, friendships, mentorships—highlighting Petrarchism’s capacity as a socially embedded practice. This chapter also demonstrates how attention to book history suggests an alternate gendered genealogy for the subgenre of correspondence verse, where women played a more significant role than has been previously recognized.

Susan North. <i>Sweet and Clean? Bodies and Clothes in Early Modern England</i>.

Abstract: Susan North’s Sweet and Clean? Bodies and Clothes in Early Modern England offers a trove of information about clothing in early modern England: how it was made, washed, worn, recycled, repaired, and more. There is also a significant long-overdue discussion of underwear. What are the differences between flax and hemp? A man’s smock versus a woman’s shift? Sweet and Clean is an invaluable resource for anyone interested in the practical household work of making, sewing, and washing clothes, as well as the history of bodies, health, and hygiene. The book is framed around a clear key finding: early modern men and women bathed. This argument may seem commonplace, but in actuality it is a significant historiographical revision. The prevailing belief, until now, has been that Europeans did not wash themselves frequently. They cleaned only their visible outer layers of clothing, which came to represent propriety, leaving their bodies and innermost layers of linen untouched. North revises this long-held misconception by showing that Englishmen and women did indeed wash their bodies and their clothes, and she provides a multitude of details demonstrating how and why they did so.

Data from LSD1 Inhibition Disrupts Super-Enhancer–Driven Oncogenic Transcriptional Programs in Castration-Resistant Prostate Cancer

Abstract: <div>Abstract<p>The lysine demethylase LSD1 (also called KDM1A) plays important roles in promoting multiple malignancies including both hematologic cancers and solid tumors. LSD1 targets histone and nonhistone proteins and can function as a transcriptional corepressor or coactivator. LSD1 has been reported to act as a coactivator of androgen receptor (AR) in prostate cancer and to regulate the AR cistrome via demethylation of its pioneer factor FOXA1. A deeper understanding of the key oncogenic programs targeted by LSD1 could help stratify prostate cancer patients for treatment with LSD1 inhibitors, which are currently under clinical investigation. In this study, we performed transcriptomic profiling in an array of castration-resistant prostate cancer (CRPC) xenograft models that are sensitive to LSD1 inhibitor treatment. Impaired tumor growth by LSD1 inhibition was attributed to significantly decreased MYC signaling, and MYC was found to be a consistent target of LSD1. Moreover, LSD1 formed a network with BRD4 and FOXA1 and was enriched at super-enhancer regions exhibiting liquid–liquid phase separation. Combining LSD1 inhibitors with BET inhibitors exhibited strong synergy in disrupting the activities of multiple drivers in CRPC, thereby inducing significant growth repression of tumors. Importantly, the combination treatment showed superior effects than either inhibitor alone in disrupting a subset of newly identified CRPC-specific super-enhancers. These results provide mechanistic and therapeutic insights for cotargeting two key epigenetic factors and could be rapidly translated in the clinic for CRPC patients.</p>Significance:<p>LSD1 drives prostate cancer progression by activating super-enhancer–mediated oncogenic programs, which can be targeted with the combination of LSD1 and BRD4 inhibitors to suppress the growth of CRPC.</p></div>

Meathead materialisms: César Aira’s ANTsy fictions of a world without conviction

Abstract: This essay considers several tendencies that have come to define the renewed concern with matter, assemblages, and objects associated with the new materialisms. Drawing on Bruno Latour’s Actor-Network Theory (ANT), postcritics and new formalists link the effort to revitalise and rethink the methods and aims of literary criticism to these concerns, while alerting us to the unique agency of artworks. The result is not just an idiosyncratic view of literature or of its relationship to society, but rather a peculiar vision of the world in which the notion that we can convince others or that we ourselves can be convinced holds no water. Perhaps no living writer provides a clearer picture of what it might mean to fully embrace this postcritical view of the world than César Aira. This is especially true for his novella La villa (Shantytown), which, in telling the story of how Maxi – a ‘meathead’ and ‘brainless hulk’ – becomes a ‘legend’ among the poor, presents a world saturated with the networked agency of human and nonhuman actors alike. Drawing our attention to the aesthetic and political limits of such a worldview, Aira’s ANTsy fictions illustrate how the new materialist emphasis on description, immediacy, and the spontaneous not only alters literary criticism’s more foundational concepts – text, reading, interpretation, and critique – but also, and more crucially, entails a disavowal of conviction. This essay explores what this disavowal means for Aira’s entire approach to fiction, and what, in turn, it ought to mean for the future of literary studies itself..

Empowerment Through Self-Advocacy

Abstract: Although mental healthcare has been gaining more social acceptance since the onset of the COVID-19 pandemic, several barriers still exist for new service users in the US. Prospective consumers and recently diagnosed individuals are often left to navigate this complex system with minimal support, which can lead to delays in achieving a higher quality of life. The author attempts to promote equitable care outcomes by encouraging consumers to engage in self-advocacy via education, community resources, and opportunities to lobby for client autonomy, universal accessibility, and disability inclusion. As a rehabilitation counselor trainee and a long-time recipient of psychiatric care, the author provides a unique perspective from both sides of the traditional mental health hierarchy and suggests future directions for collaborative approaches. Her professional insights inform a discussion of the standards to which clinicians should be held, while her lived experiences are woven throughout the text to underscore the shortcomings of the current system and offer examples of resilience.

Rethinking Religion and Political Participation: The Case of Voting Among Religiously Unaffiliated Americans

Abstract: Abstract Is civic disengagement correlated across institutions? One case of this question is a long-observed “secular voting gap” where religiously unaffiliated Americans are less likely to vote than their affiliated counterparts. This work often uses self-reports or exit polls that cannot measure variation within the unaffiliated. Using an improved measure of validated voter turnout in four presidential election years (2008, 2012, 2016, and 2020), I find estimates of the secular voting gap are attenuated by demographic controls. More importantly, the mechanism that explains this finding is that more frequent church attendance associates with a lower probability of turnout among respondents who are unaffiliated, and results vary by voting method. These results support a theory of civic disengagement as a domain-specific process and demonstrate the substantive value of revisiting classic findings about religion and political behavior amid social change.

Response to Richard Ned Lebow’s Review of <i>International Relations’ Last Synthesis? Decoupling Constructivist and Critical Approaches</i>

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Nature of the Shyok (Northern) Suture Zone between India and Asia: petrology, geochemistry and origin of the Tirit granitoids and associated dykes (Nubra Valley Ladakh Himalaya, NW India)

Abstract: Abstract The Shyok Suture Zone is an oceanic remnant of the Neo-Tethyan ocean sandwiched between the Ladakh Batholiths to the south and Karakoram Batholith to the north. The Tirit granitoids in this suture are dark-coloured, relatively rich in ferromagnesian minerals and range from granodiorite–tonalite to gabbro–diorite in composition. Mafic igneous enclaves are quite common and they are intruded by NW–SE parallel doleritic and aplitic dykes. The Tirit granitoids have a wide range of major oxide compositions (SiO 2 = 52.1–72.11 wt %, TiO 2 = 0.21–1.23 wt %, Al 2 O 3 = 11.42–13.52 wt %, MgO = 1.69–10.69 wt % and CaO = 3.24–9.31 wt %) and show calc-alkaline, metaluminous, I-type characteristics, transitional between primitive and mature arc continental plutons. Rare earth elements (REE) show considerable enrichment in light REE (LREE) as compared to the heavy REE (HREE). Late Cretaceous U/Pb dates (74–68 Ma) show that they formed during the pre-collision northward movement of India. The Tirit dykes are only slightly younger and probably part of the same episode.

The People’s Petrarch : Early Modern Italian Readers and the Gender of Celebrity

Abstract: This chapter explores Petrarch’s gendered portrayal in early modern printings of his lyric, with particular attention to Alessandro Vellutello’s edition of 1525. Vellutello rejected Petrarch’s own ordering, rearranging the poems into a linear, amorous plotline, and adding such paratexts as a “biography” of Laura and a map of the lovers’ environs. Often dismissed by sixteenth-century humanists and modern-day scholars alike, Vellutello’s Petrarch was the most popular of the period, embraced by readers who were enamored of its hybridity between critical edition and fan fiction. Theorizing a gendered contrast between Petrarchan fame and celebrity, I explore the evolution of Petrarch in the early modern imagination, an investigation that underpins subsequent chapters’ examinations of how Petrarchan imitators used literature to remake gender.

Religious Lyric*

Abstract: This chapter examines religious lyric from approximately 1530 to 1630, from the birth of the spiritual canzoniere with Vittoria Colonna to the definitive edition of Angelo Grillo’s landmark Pietosi affetti. Mixing devotion with desire, spiritual Petrarchists looked to incite readers to religious fervour using imagery that could be sensuous, erotic, or even perverse. In the Counter-Reformation in particular, this verse became increasingly corporeal and gender-ambiguous: sensual blazons of the body of Mary Magdalene; male-authored impersonations of saintly women; fantasies of touching, kissing, or penetrating Christ’s wounds. Such verse is evidence of writers’ exploration of the surprising space between gender norms that was opened up by the Counter-Reformation.