bluuebunny/crossref_metadata_2025 huggingface dataset:
The Foundations of American Constitutionalism
Authors: Redish Martin H.
Published: May 2023

This chapter contrasts the American form of written, mandatory constitutionalism with unwritten systems grounded in legislative supremacy. It explains the careful balances struck by the Constitution’s Framers between the needs for popular sovereignty and the avoidance of tyranny. It argues that given the explicitly counter-majoritarian form of constitutionalism adopted by the nation, an independent judiciary insulated from external political and popular controls as the final interpreter and enforcer of the Constitution is essential to the viability of American constitutionalism. The chapter argues that modern scholarly theories of departmentalism, to the extent they challenge or undermine final judicial authority to interpret the Constitution, are seriously misguided and represent a perversion of the constitutional system’s delicate balance of power among the branches.
A Taxonomy of Judicial Independence
Authors: Redish Martin H.
Published: May 2023

This chapter provides a taxonomy of judicial independence, dividing it into five conceivable subcategories: institutional independence; decisional independence; countermajoritarian independence; lawmaking independence; and judgmental independence. It argues that while institutional, decisional, and countermajoritarian independence are appropriately viewed as foundational elements of American constitutionalism, lawmaking independence is a spurious category; while our constitutional system vests the judiciary with final power to interpret the Constitution, to enable them to fashion sub-constitutional law freely would undermine fundamental precepts of democratic government because it would vest in the one branch of government insulated from popular accountability the final authority on basic social policy choices. Judgmental independence, while explicitly recognized by the Supreme Court, is only of limited importance to the maintenance of American constitutionalism. Though direct review of judicial decisions by representatives of the political branches would most certainly violate decisional independence, this need can be satisfied without recognition of this additional category.
State Courts, Due Process, and the Dangers of Popular Constitutionalism
Authors: Redish Martin H.
Published: May 2023

This chapter argues that the true constitutional problem is not how state judges are selected in the first place, but rather how they are retained. Judges subject to political control—either through the electorate or political office holders—are not appropriately deemed truly “neutral” adjudicators in any case in which the state is a party because they are always subject to the fear—if only subconscious—that an unpopular decision will prevent their retention. For this reason, the chapter argues, state court systems lacking life tenure or at least an extended term without possibility of retention are properly viewed to violate the Fourteenth Amendment’s Due Process Clause. To be sure, this is a view radically different from current understanding. It is, however, a view that is logically dictated by the foundations of American constitutionalism and the precepts of judicial independence that grown out of it.
Introduction
Authors: Mintz Alan
Published: May 2023

The origins of the project of writing a cycle of stories about Buczacz are presented in the story “The Sign,” in which an Agnon-like narrator experiences a mystical visitation by a Jewish medieval poet who models literary creation as a way to memorialize the destroyed city. Although many of the stories were published in the author’s lifetime, scant attention was paid to them then or when they were published in book form. Israeli culture had a conflicted relationship to the Holocaust, and there was little interest in literature devoted to the Old World life that Zionism had sought to replace. There has been a significant change in attitude since that time, and A City in Its Fullness has recently become the object of increasing critical attention.
Inventing a Narrator
Authors: Mintz Alan
Published: May 2023

Writing stories set in a period beyond modern memory presented Agnon with the challenge of a workable narrative premise. For this task Agnon gave up the autobiographical narrator that had been the mainstay of his earlier fiction and developed a unique narrator—actually, a set of variations on a single premise—who speaks as a believing Jew within the historical milieu of the stories. The narrator’s views are aligned with the contemporary rabbinic elite and, like the leaders of Buczacz, skeptical of mysticism and Hasidism. His tone assumes the authority of the communal minute book, the pinkas; yet although impersonal, and without a recognizable identity, he uses the “I” in a garrulous and compunctious manner. This chapter describes how the stories communicate simultaneously with the implied traditional audience contemporary to the events and the modern audience reading the stories as they appeared in Haaretz and similar news journals.
Rabbis and Scholars
Authors: Mintz Alan
Published: May 2023

The major novella at the heart of A City in Its Fullness asks whether it is possible to combine two kinds of rabbinic leadership: the pure scholar and the community rabbi. Whether the source is the Polish magnate or the Austrian government official, government interference in appointments to rabbinic seats is a factor that few Jewish communities can elude. The novella concerns Buczacz’s failed quest to find a rabbi who is equal in all respects to the community’s high regard for its own learning and piety. Because of the ineluctability of gentile interference, the story concludes that true Torah scholarship can almost never be realized by a rabbi beholden to the community.
Jews and Poles
Authors: Mintz Alan
Published: May 2023

Until 1772, Buczacz, like many Polish towns, was owned outright by a Polish noble, who was the source of all law. In the social space between the Catholic land-owning Poles and the Orthodox Ruthenian/Ukrainian serfs, the Jews operated as merchants, shopkeepers, and craftsmen. Although the services provided by the Jews were economically critical to the Poles, the latter despised the former and knew little of their inner religious life. Two major stories imagine a set of circumstances in which these roles are reversed and two great magnates become dependent for their lives on Jews, one a great communal leader and the other a humble charcoal maker. The chapter examines how Agnon uses established historical information to create alternative history and reimagine a “corrected” relationship between the two communities.
Moments of Redemption
Authors: Mintz Alan
Published: May 2023

The depiction of the Buczacz Jewish community under Austrian rule is so negative that it threatens the very enterprise of A City in Its Fullness as a memorial project. To counterbalance this, at the end of the volume, Agnon explores redemption as both a theological and social construct. He locates the potential for redemption not within the rabbinic elite or communal leadership, but within the love of learning on the part of ordinary householders. In a story called “In a Single Moment,” the unmarried status of an outstanding fifteen-year-old scholar is of great concern to his parents. During the climactic conclusion of the events of a single day, the boy weds a young woman who has been left under the ḥuppah by an unscrupulously materialistic bridegroom. The joy that suddenly floods the community provides a moment of redemption, a brief but significant recoupment of the community’s spiritual glory.
Epilogue
Authors: Mintz Alan
Published: May 2023

A City in Its Fullness represents an extraordinary instance of a major writer returning to the golden age of East European Jewry and reimagining it through the medium of modernist fiction. Although the stories are carefully set within the facts of their historical periods, Agnon sometimes arrogates to himself the freedom to “correct” the historical record by fashioning stories that accord to their Jewish subjects the dignity they deserved in their own time but did not receive.
Scriptorium 2.0
Authors: Whearty Bridget
Published: May 2023

Chapter 1 demystifies the processes of creating digital manuscripts by tracing the creation of a single digital book: Stanford, Stanford University Libraries, Department of Special Collections, Manuscript Collection, MSS Codex M0379, a largely unstudied fifteenth-century book of hours, which was digitized in November 2014. Pushing against scholarly generalizations about digitization, this chapter foregrounds the specifics of library-authored standard digitization workflows. I also foreground the intellectual and bodily labor that goes into making a digital book, connecting modern digitization to a long history of scribal labor, preserved in medieval scribal complaints. This chapter concludes by showing how embracing a more self-consciously medieval and global perspective on modern digitization reveals that the erasure of modern copyists is a particular, limited regional choice and not a transhistorical, transnational norm.
Value and Visibility
Authors: Whearty Bridget
Published: May 2023

Chapter 2 traces the media history of an autograph manuscript by the poet Thomas Hoccleve. It begins with the manuscript’s digitization in 2014, and then follows HM 111 through its six-hundred-year copying history: from the early 1420s to 1796 as Poems by Thomas Hoccleve, Never Before Printed, edited by George Mason, to 1892 as Hoccleve’s Works, Vol. 1: The Minor Poems, edited by Frederick J. Furnivall, to 2002 as Thomas Hoccleve: A Facsimile of the Autograph Verse Manuscripts, edited by J. A. Burrow and A. I. Doyle--both for the Early English Text Society. Much of this media history demonstrates that HM 111 was not being copied into emerging reprographic media; this chapter challenges long-standing commonplaces about new copying technologies opening up access to inaccessible works. Instead it shows how perceptions and critiques of digitization are deeply rooted in predigital copies and technologies.
The Transported Word
Authors: Wolff Tristram
Published: May 2023

Chapter 2 proposes that what Phillis Wheatley calls a “softer language,” linking images of poetry, freedom, and the afterlife, offers a vision of language in motion through “scenes of transport.” In emphasizing the texture of language softened by free movement, Wheatley intervenes in the monolithic chronology of language that emerged through the enlightenment’s stadial theories of civilization. In her conscious role as exceptional, representative, lettered Black lyric subject, Wheatley’s management of her own audibility instructively differentiates her balance of license and constraint from the compromised agency celebrated in later romantic formulas (whose prototype for my purposes is Wordsworthian “wise passiveness”). Against a backdrop of influential theories of language, stadial civilization, and organicism (in the work of Adam Smith and Wilhelm von Humboldt), I show how Wheatley, described as previously an “uncultivated Barbarian,” uses her poetry to unravel the primitivist timeline of linguistic modernity.
Radical Diversions
Authors: Wolff Tristram
Published: May 2023

Chapter 4 places the much debated desire for the vernacular in Wordsworth’s early poetics—or the infamous “real language of men”—in the context of a dissolution of linguistic categories under way in British radicalism of the 1790s. It recounts the stir caused by John Horne Tooke’s immensely influential etymologies in The Diversions of Purley (1786/1812), which grafted political radicalism onto linguistic roots. This philological lens leads to new insights into the grayer undertones of Wordsworth’s so-called “green language.” The chapter culminates in a reading of “Hart-Leap Well,” building on scholarship that shows how native antiquarianism drew on a broader colonial imaginary. The chapter closes by suggesting that the idea of freedom grounding Wordsworth’s ambivalent radicalism is clarified by contrasting approaches to Haiti and history in the sonnet “To Toussaint L’Ouverture” and in a contemporaneous ode to liberty by the Haitian poet Antoine Dupré.
The Primitive Today
Authors: Wolff Tristram
Published: May 2023

Chapter 5 accounts for the complex primitivism of Henry David Thoreau’s writings, under the phenomenological influence of figures like Emerson and Goethe, but also of a wide range of contributors to the linguistic study of Indigenous American languages, such as Heckewelder, Du Ponceau, and Schoolcraft. The chapter examines Thoreau’s desire for proximity to Wabanaki languages of the Northeast, like Penobscot, alongside his inability to understand them as contemporary with his own utterance. It locates the contradictions that stem from the persistence of Thoreau’s racialized primitivism with respect to Indigenous life, in the face of his meticulous work with etymological tropes against origins-thinking and his regard for variation, mixed durations, and regeneration in the natural world. Among other texts, the chapter examines The Maine Woods, Walden, the Journal, and the unpublished Indian Notebooks.
Introduction
Authors: Bailey Christian
Published: May 2023

The Introduction lays out how experiences of love informed and transformed German Jews’ sense of self across a turbulent hundred-year epoch. Explaining the terminal dates of 1871 and 1979, this introduction discusses the social transformation and political upheaval of the era, including Germany’s experience of urbanization and its multiple, often violent, regime changes. These shifts affected many Jewish citizens sharply; for this reason a loving private sphere became an especially important refuge for them. But the veneration of romantic love in Jewish communities was also the product of a broader love myth in German culture: that the most authentic Germany existed in the loving private realm. The Introduction moves on to discuss the wide range of first-person accounts and diverse normative sources used in the study. These private and public sources illustrate how emotional scripts were formulated and, in turn, reproduced and reworked by Jewish women and men.
The FAO
Authors: Margulis Matias E.
Published: May 2023

The first chapter shows evidence of intervention by the Food and Agriculture Organization (FAO) in the GATT Uruguay Round (1986–94) and the WTO Doha Round (2001–8). I demonstrate that FAO officials sought to insert themselves into the politics of the agriculture negotiations by using the strategy of mobilizing GATT/WTO member states. In the Uruguay Round, the FAO chose to intervene out of concern that proposed global trade rules would increase global food prices and thus make food less affordable and less accessible for the world’s poorest people. The FAO exerted influence over the outcome of the Uruguay Round, as the chief architect of an agreement to safeguard food security.
Sensitivity Analysis of SWAT Model in a Tropical Watershed, East Java
Authors: Sujarwo Mohamad Wawan , Indarto Indarto , Mandala Marga
Published: May 2023

Brantas watershed has approximately 14,103 km2 and play an essential role in supplying water for about 30% of the East Java population. Management of water resources in this watershed has become a challenging issue. Conformity of modeling processes and result to mimic the existing hydrological processes is still in question. This study aims to analyze the sensitive parameters of the Soil Water Assessment Tool (SWAT) model on the watershed. Hydrological processes are observed both monthly and annually. Sensitivity analysis using the SWAT-CUP tool show 18 sensitive parameters. 9 parameters have more than a 50% sensitivity level. 4 are correlated to the soil layer’s runoff generation and water movement. Then, 8 parameters correlated to baseflow calculation. Simulation results illustrate the strong effect of climate change (especially rainfall) on water yield and sedimentation.
Vacuum system of the Space Plasma Environment Research Facility
Authors: Jin Chenggang , Zhang Yongqi , Ling Wenbin , Chen Chunxi , Wang Huan , Hao Huiping , Dong Yunning , Lu Yaowen , Li Liyi , E Peng
Published: May 2023

The Space Plasma Environment Research Facility (SPERF) being built in Harbin provides a laboratory platform for research on space plasma. The vacuum system, as an essential subsystem, is designed to set up an experimental vacuum environment for plasma experiments. However, the SPERF with a large volume of 2.315×105 l contains a lot of outgassing loads and hundreds of interfaces, which poses a big challenge for high vacuum acquisition. In addition, the plasma experiments on the SPERF require a pure background vacuum environment. In this study, the vacuum system is designed to meet the experimental requirements for the vacuum environment, with emphasis on the pumping system configuration and the vacuum acquisition process. Benefiting from the great construction techniques and advanced configuration of the pumping system, the target ultimate pressure of 1.0×10−4 Pa in the chamber can be obtained within 24 h and the leakage rate of the vacuum chamber is 30% smaller than the target value. It is significant that the high vacuum environment is efficiently achieved in such a big chamber, and the design may throw some new light on constructing other similar large-scale vacuum systems.
Pathways for diversifying and enhancing science advocacy
Authors: Tormos-Aponte Fernando , Brown Phil , Dosemagen Shannon , Fisher Dana R. , Frickel Scott , MacKendrick Norah , Meyer David S. , Parker John N.
Published: May 2023

Science is under attack and scientists are becoming more involved in efforts to defend it. The rise in science advocacy raises important questions regarding how science mobilization can both defend science and promote its use for the public good while also including the communities that benefit from science. This article begins with a discussion of the relevance of science advocacy. It then reviews research pointing to how scientists can sustain, diversify, and increase the political impact of their mobilization. Scientists, we argue, can build and maintain politically impactful coalitions by engaging with and addressing social group differences and diversity instead of suppressing them. The article concludes with a reflection on how the study of science-related mobilization would benefit from further research.
Tumor-derived semaphorin 4A improves PD-1–blocking antibody efficacy by enhancing CD8
+
T cell cytotoxicity and proliferation
Authors: Naito Yujiro , Koyama Shohei , Masuhiro Kentaro , Hirai Takashi , Uenami Takeshi , Inoue Takako , Osa Akio , Machiyama Hirotomo , Watanabe Go , Sax Nicolas , Villa Jordan , Kinugasa-Katayama Yumi , Nojima Satoshi , Yaga Moto , Hosono Yuki , Okuzaki Daisuke , Satoh Shingo , Tsuda Takeshi , Nakanishi Yoshimitsu , Suga Yasuhiko , Morita Takayoshi , Fukushima Kiyoharu , Nishide Masayuki , Shiroyama Takayuki , Miyake Kotaro , Iwahori Kota , Hirata Haruhiko , Nagatomo Izumi , Yano Yukihiro , Tamiya Motohiro , Kumagai Toru , Takemoto Norihiko , Inohara Hidenori , Yamasaki Sho , Yamashita Kazuo , Aoshi Taiki , Akbay Esra A. , Hosen Naoki , Shintani Yasushi , Takamatsu Hyota , Mori Masahide , Takeda Yoshito , Kumanogoh Atsushi
Published: May 2023

Immune checkpoint inhibitors (ICIs) have caused revolutionary changes in cancer treatment, but low response rates remain a challenge. Semaphorin 4A (Sema4A) modulates the immune system through multiple mechanisms in mice, although the role of human Sema4A in the tumor microenvironment remains unclear. This study demonstrates that histologically Sema4A-positive non–small cell lung cancer (NSCLC) responded significantly better to anti–programmed cell death 1 (PD-1) antibody than Sema4A-negative NSCLC. Intriguingly, SEMA4A expression in human NSCLC was mainly derived from tumor cells and was associated with T cell activation. Sema4A promoted cytotoxicity and proliferation of tumor-specific CD8
+
T cells without terminal exhaustion by enhancing mammalian target of rapamycin complex 1 and polyamine synthesis, which led to improved efficacy of PD-1 inhibitors in murine models. Improved T cell activation by recombinant Sema4A was also confirmed using isolated tumor-infiltrating T cells from patients with cancer. Thus, Sema4A might be a promising therapeutic target and biomarker for predicting and promoting ICI efficacy.
Multiscale stiffness of human emphysematous precision cut lung slices
Authors: Kim Jae Hun , Schaible Niccole , Hall Joseph K. , Bartolák-Suki Erzsébet , Deng Yuqing , Herrmann Jacob , Sonnenberg Adam , Behrsing Holger P. , Lutchen Kenneth R. , Krishnan Ramaswamy , Suki Béla
Published: May 2023

Emphysema is a debilitating disease that remodels the lung leading to reduced tissue stiffness. Thus, understanding emphysema progression requires assessing lung stiffness at both the tissue and alveolar scales. Here, we introduce an approach to determine multiscale tissue stiffness and apply it to precision-cut lung slices (PCLS). First, we established a framework for measuring stiffness of thin, disk-like samples. We then designed a device to verify this concept and validated its measuring capabilities using known samples. Next, we compared healthy and emphysematous human PCLS and found that the latter was 50% softer. Through computational network modeling, we discovered that this reduced macroscopic tissue stiffness was due to both microscopic septal wall remodeling and structural deterioration. Lastly, through protein expression profiling, we identified a wide spectrum of enzymes that can drive septal wall remodeling, which, together with mechanical forces, lead to rupture and structural deterioration of the emphysematous lung parenchyma.
Structure of the immunoregulatory sialidase NEU1
Authors: Gorelik Alexei , Illes Katalin , Mazhab-Jafari Mohammad T. , Nagar Bhushan
Published: May 2023

Sialic acids linked to glycoproteins and glycolipids are important mediators of cell and protein recognition events. These sugar residues are removed by neuraminidases (sialidases). Neuraminidase-1 (sialidase-1 or NEU1) is a ubiquitously expressed mammalian sialidase located in lysosomes and on the cell membrane. Because of its modulation of multiple signaling processes, it is a potential therapeutic target for cancers and immune disorders. Genetic defects in NEU1 or in its protective protein cathepsin A (PPCA, CTSA) cause the lysosomal storage diseases sialidosis and galactosialidosis. To further our understanding of this enzyme’s function at the molecular level, we determined the three-dimensional structure of murine NEU1. The enzyme oligomerizes through two self-association interfaces and displays a wide substrate-binding cavity. A catalytic loop adopts an inactive conformation. We propose a mechanism of activation involving a conformational change in this loop upon binding to its protective protein. These findings may facilitate the development of selective inhibitor and agonist therapies.
CDK12 and Integrator-PP2A complex modulates LEO1 phosphorylation for processive transcription elongation
Authors: Qiu Min , Yin Zhinang , Wang Honghong , Lei Lingyu , Li Conghui , Cui Yali , Dai Rong , Yang Peiyuan , Xiang Ying , Li Qiuzi , Lv Junhui , Hu Zhuang , Chen Min , Zhou Hai-Bing , Fang Pingping , Xiao Ruijing , Liang Kaiwei
Published: May 2023

Cyclin-dependent kinase 12 (CDK12) interacts with cyclin K to form a functional nuclear kinase that promotes processive transcription elongation through phosphorylation of the C-terminal domain of RNA polymerase II (Pol II). To gain a comprehensive understanding of CDK12's cellular function, we used chemical genetic and phosphoproteomic screening to identify a landscape of nuclear human CDK12 substrates, including regulators of transcription, chromatin organization, and RNA splicing. We further validated LEO1, a subunit of the polymerase-associated factor 1 complex (PAF1C), as a bona fide cellular substrate of CDK12. Acute depletion of LEO1, or substituting LEO1 phosphorylation sites with alanine, attenuated PAF1C association with elongating Pol II and impaired processive transcription elongation. Moreover, we discovered that LEO1 interacts with and is dephosphorylated by the Integrator-PP2A complex (INTAC) and that INTAC depletion promotes the association of PAF1C with Pol II. Together, this study reveals an uncharacterized role for CDK12 and INTAC in regulating LEO1 phosphorylation, providing important insights into gene transcription and its regulation.
A revised perspective on the evolution of the lateral frontal cortex in primates
Authors: Amiez Céline , Sallet Jérôme , Giacometti Camille , Verstraete Charles , Gandaux Clémence , Morel-Latour Valentine , Meguerditchian Adrien , Hadj-Bouziane Fadila , Ben Hamed Suliann , Hopkins William D. , Procyk Emmanuel , Wilson Charles R. E. , Petrides Michael
Published: May 2023

Detailed neuroscientific data from macaque monkeys have been essential in advancing understanding of human frontal cortex function, particularly for regions of frontal cortex without homologs in other model species. However, precise transfer of this knowledge for direct use in human applications requires an understanding of monkey to hominid homologies, particularly whether and how sulci and cytoarchitectonic regions in the frontal cortex of macaques relate to those in hominids. We combine sulcal pattern analysis with resting-state functional magnetic resonance imaging and cytoarchitectonic analysis to show that old-world monkey brains have the same principles of organization as hominid brains, with the notable exception of sulci in the frontopolar cortex. This essential comparative framework provides insights into primate brain evolution and a key tool to drive translation from invasive research in monkeys to human applications.
Nanoscale clustering of mycobacterial ligands and DC-SIGN host receptors are key determinants for pathogen recognition
Authors: Viljoen Albertus , Vercellone Alain , Chimen Myriam , Gaibelet Gérald , Mazères Serge , Nigou Jérôme , Dufrêne Yves F.
Published: May 2023

The bacterial pathogen
Mycobacterium tuberculosis
binds to the C-type lectin DC-SIGN (dendritic cell–specific intercellular adhesion molecule 3-grabbing nonintegrin) on dendritic cells to evade the immune system. While DC-SIGN glycoconjugate ligands are ubiquitous among mycobacterial species, the receptor selectively binds pathogenic species from the
M. tuberculosis
complex (
MTBC
). Here, we unravel the molecular mechanism behind this intriguing selective recognition by means of a multidisciplinary approach combining single-molecule atomic force microscopy with Förster resonance energy transfer and bioassays. Molecular recognition imaging of mycobacteria demonstrates that the distribution of DC-SIGN ligands markedly differs between
Mycobacterium bovis
Bacille Calmette-Guérin (BCG) (model
MTBC
species) and
Mycobacterium smegmatis
(non-
MTBC
species), the ligands being concentrated into dense nanodomains on
M. bovis
BCG. Upon bacteria-host cell adhesion, ligand nanodomains induce the recruitment and clustering of DC-SIGN. Our study highlights the key role of clustering of both ligands on
MTBC
species and DC-SIGN host receptors in pathogen recognition, a mechanism that might be widespread in host-pathogen interactions.
Desensitization and belatacept-based maintenance therapy in pregnancy-sensitized monkeys receiving a kidney transplant
Authors: Manook Miriam , Olaso Danae , Anwar Imran J. , Yoon Janghoon , Delaura Isabel , Bae Yeeun , Moris Dimitrios , Shaw Brian , Song Mingqing , Farris Alton B. , Jackson Annette , Kwun Jean , Knechtle Stuart
Published: May 2023

Among sensitized patients awaiting a transplant, females are disproportionately represented, partly because of pregnancy-induced sensitization. Using female NHPs sensitized by pregnancy alone, we examined the efficacy of costimulation blockade and proteasome inhibition for desensitization. Three animals received no desensitization (control), and seven animals received weekly carfilzomib (27 mg/m
2
) and belatacept (20 mg/kg) before kidney transplantation. All animals received renal allografts from crossmatch-positive/maximally MHC-mismatched donors. Controls and three desensitized animals received tacrolimus-based immunosuppression. Four desensitized animals received additional belatacept with tacrolimus-based immunosuppression. Multiparous females had less circulating donor-specific antibody when compared to skin-sensitized males before transplantation. While females receiving desensitization showed only a marginal survival benefit over control females (MST = 11 days versus 63 days), additional belatacept to posttransplant maintenance significantly prolonged graft survival (MST > 164 days) and suppressed posttransplant DSA and circulating follicular helper T-like cells. This combination of therapies demonstrates great potential to reduce antibody-mediated rejection in sensitized recipients.
Molecular evolution of Keap1 was essential for adaptation of vertebrates to terrestrial life
Authors: Yumimoto Kanae , Sugiyama Shigeaki , Motomura Saori , Takahashi Daisuke , Nakayama Keiichi I.
Published: May 2023

Reactive oxygen species (ROS) posed a risk for the transition of vertebrates from aquatic to terrestrial life. How ancestral organisms adapted to such ROS exposure has remained a mystery. Here, we show that attenuation of the activity of the ubiquitin ligase CRL3Keap1 for the transcription factor Nrf2 during evolution was key to development of an efficient response to ROS exposure. The Keap1 gene was duplicated in fish to give rise to Keap1A and the only remaining mammalian paralog Keap1B, the latter of which shows a lower affinity for Cul3 and contributes to robust Nrf2 induction in response to ROS exposure. Mutation of mammalian Keap1 to resemble zebrafish Keap1A resulted in an attenuated Nrf2 response, and most knock-in mice expressing such a Keap1 mutant died on exposure as neonates to sunlight-level ultraviolet radiation. Our results suggest that molecular evolution of Keap1 was essential for adaptation to terrestrial life.
Imaging of the electronic bonding of diamond at pressures up to 2 million atmospheres
Authors: Lee Sung Keun , Yi Yoosoo , Kim Yong-Hyun , Kim Hyo-im , Chow Paul , Xiao Yuming , Eng Peter , Shen Guoyin
Published: May 2023

Diamond shows unprecedented hardness. Because hardness is a measure of resistance of chemical bonds in a material to external indentation, the electronic bonding nature of diamond beyond several million atmospheres is key to understanding the origin of hardness. However, probing the electronic structures of diamond at such extreme pressure has not been experimentally possible. The measurements on the inelastic x-ray scattering spectra for diamond up to 2 million atmospheres provide data on the evolution of its electronic structures under compression. The mapping of the observed electronic density of states allows us to obtain a two-dimensional image of the bonding transitions of diamond undergoing deformation. The spectral change near edge onset is minor beyond a million atmospheres, while its electronic structure displays marked pressure-induced electron delocalization. Such electronic responses indicate that diamond’s external rigidity is supported by its ability to reconcile internal stress, providing insights into the origins of hardness in materials.
Tracing black shales in the source of a porphyry Mo deposit using molybdenum isotopes
Authors: Xue Qiqi , Zhang Lipeng , Chen Shuo , Guo Kun , Li Tao , Han Zhong , Sun Weidong
Published: May 2023

Porphyry Mo deposits are important suppliers of molybdenum for industrial applications, but the origin and source of metals in these deposits remain debated. Here, we present Mo isotope data for Miocene mineralized porphyritic monzogranites (MPMs) and Paleocene barren biotite monzogranites and tuffs (BMTs) from the Bangpu porphyry Mo (Cu) deposit in the Gangdese metallogenic belt. The results show that the MPMs display radiogenic Sr and Pb isotopes and elevated δ98/95Mo (relative to NIST SRM 3134; +0.07‰–1.2‰) and Mo contents, which exceed the range of the depleted mantle. These characteristics cannot be attributed to surface weathering, hydrothermal alteration, magmatic differentiation, or partial melting but rather reflect the incorporation of Mo from black shales into their magma sources, as evidenced by the significant correlations between δ98/95Mo and εNd(t) and aluminum saturation index (ASI) values. In contrast, the BMTs display lower Mo and δ98/95Mo values than the mineralized samples, and their δ98/95Mo values display no correlations with radiogenic isotopes or ASI values. The contrasting characteristics of mineralized and barren samples provide strong evidence that the addition of black shales played an important role in the formation of the Bangpu porphyry Mo deposit. Our study thus establishes a possible link between porphyry Mo deposits and organic-rich sediments and highlights the great potential of Mo isotopes in studying porphyry Mo deposits.
Detrital zircon U-Pb and Hf isotope signature of Carboniferous and older strata of the Yukon-Tanana terrane in Yukon, Canadian Cordillera: Implications for terrane correlations and the onset of Late Devonian arc magmatism
Authors: Kroeger Emma D.L. , McClelland William C. , Colpron Maurice , Piercey Stephen J. , Gehrels George E.
Published: May 2023

The Yukon-Tanana terrane in Yukon, Canada, records Late Devonian (ca. 366–360 Ma) rifting and the onset of latest Devonian–Carboniferous arc and back-arc magmatism (ca. 360–325 Ma) in the Northern Cordillera. Detrital zircon U-Pb and Hf isotope analyses indicate that the metasedimentary basement of the Yukon-Tanana terrane was sourced in northwestern Laurentia. Sandstones in Late Devonian–Carboniferous successions generally have robust Late Devonian–Mississippian age peaks, and their Hf isotope signatures are characterized by strongly negative εHft values in Late Devonian zircons followed by progressively more juvenile εHft values in Carboniferous zircons. This Hf isotopic “pull-up” reflects the melting of Precambrian crust related to regional extension in the Late Devonian, followed by progressively more juvenile magmatism as the arc matured through the Carboniferous.

Paleozoic rocks of the Tracy Arm terrane in southeastern Alaska, USA (formerly Yukon-Tanana south), have been compared with the Yukon-Tanana terrane in Yukon. Detrital zircons from the metasedimentary basement to the Tracy Arm terrane have distinct Precambrian populations that indicate sources along a different segment of the Laurentian margin compared to basement of the Yukon-Tanana terrane. Magmatism in the Tracy Arm terrane ranges from 440 Ma to 360 Ma and is characterized by an Hf isotopic “pull-down” in the Silurian to Early Devonian, followed by a “pull-up” in the Middle to Late Devonian and a second “pull-down” in the Late Devonian to early Mississippian. Thus, the Yukon-Tanana and Tracy Arm terranes record distinct pre-Carboniferous histories. Interactions between these two terranes are suggested by the influx of exotic early Mississippian clasts and detrital zircons on the Tracy Arm terrane that match sources in the Yukon-Tanana terrane.
Metastatic recurrence of lung adenocarcinoma in thyroid clinically masquerading as primary thyroid cancer and immunohistochemically positive for thyroglobulin
Authors: Yorita Kenji , Hokimoto Norihiro , Tanida Nobuyuki , Matsuoka Hisashi
Published: May 2023

We report a case of a man in his 60s with metastatic lung adenocarcinoma in the thyroid and cervical lymph nodes. The lung cancer was resected 5 years prior to presentation. The metastasis mimicked primary thyroid cancer by clinical examination and CT. However, fine-needle aspiration cytology of the thyroid and the lymph node lesions favoured lung cancer metastasis rather than thyroid cancer. Left thyroid lobectomy and lymphadenectomy were performed. Pathology confirmed the presence of an adenocarcinoma in the thyroid and two lymph nodes, which was similar to the previous lung cancer. The tumour cells in the thyroid were immunohistochemically positive for TTF1 and thyroglobulin and negative for PAX8. This is the second reported case of metastatic lung cancer in the thyroid that was focally positive for thyroglobulin. This can be a pitfall in differentiating between primary thyroid tumour and metastatic lung adenocarcinoma by pathological and cytological examination.
Breaking the silence on gendered harassment and assault of community health workers: an analysis of ethnographic studies
Authors: Closser Svea , Sultan Marium , Tikkanen Roosa , Singh Shalini , Majidulla Arman , Maes Kenneth , Gerber Sue , Rosenthal Anat , Palazuelos Daniel , Tesfaye Yihenew , Finley Erin , Abesha Roza , Keeling Ann , Justice Judith
Published: May 2023

Introduction

Across a variety of settings, women in tenuous financial circumstances are drawn to community health work as a way to advance themselves in the context of limited employment options. Female Community Health Workers (CHWs) are often preferred because they can more easily access mothers and children; at the same time, gender norms are at the heart of many of the challenges and inequities that these workers encounter. Here, we explore how these gender roles and a lack of formal worker protections leave CHWs vulnerable to violence and sexual harassment, common occurrences that are frequently downplayed or silenced.

Methods

We are a group of researchers who work on CHW programmes in a variety of contexts globally. The examples here are drawn from our ethnographic research (participant observation and in-depth interviews).

Results

CHW work creates job opportunities for women in contexts where such opportunities are extremely rare. These jobs can be a lifeline for women with few other options. Yet the threat of violence can be very real: women may face violence from the community, and some experience harassment from supervisors within health programmes.

Conclusion

Taking gendered harassment and violence seriously in CHW programmes is critical for research and practice. Fulfilling CHWs’ vision of health programmes that value them, support them and give them opportunities may be a way for CHW programmes to lead the way in gender-transformative labour practices.
Differences in minimal disease knowledge of keratoconus patients: results from an international survey
Authors: Baenninger Philipp B , Romano Vito , Figueiredo Francisco C , Pradhan Sayali P , Vohra Vishal , Jeng Bennie H , Iselin Katja C , Murphy Conor C , Kaufmann Claude , Thiel Michael A , Bachmann Lucas M
Published: May 2023

Background/aims

The objective of this multicentre, multinational, prospective study was to assess the level of basic understanding that individuals with keratoconus possessed about their condition.

Methods

We recruited 200 active keratoconus patients who were under regular review, and cornea specialists established a standard of ‘minimal keratoconus knowledge’ (MKK) that included an understanding of the definition, risk factors, symptoms and treatment options for the condition. We collected data from each participant regarding their clinical characteristics, highest level of education, (para)medical background and experiences with keratoconus within their social circle, and calculated the percentage of MKK attained by each patient.

Results

Our findings revealed that none of the participants met the MKK standard, with the average MKK score being 34.6% and ranging from 0.0% to 94.4%. Furthermore, our study showed that patients with a university degree, previous surgical intervention for keratoconus or affected parents had a higher MKK. However, age, gender, disease severity, paramedical knowledge, disease duration and best-corrected visual acuity did not significantly affect the MKK score.

Conclusions

Our study demonstrates a concerning lack of basic disease knowledge among keratoconus patients in three different countries. The level of knowledge exhibited by our sample was only one-third of what cornea specialists would typically anticipate from patients. This highlights the need for greater education and awareness campaigns surrounding keratoconus. Further research is needed to determine the most efficient approaches for enhancing MKK and subsequently improving the management and treatment of keratoconus.
Prescribing for pregnancy: inflammatory rheumatic disease
Authors: Steele Samantha , Thorne Iona
Published: May 2023

Inflammatory rheumatic disease during pregnancy requires careful management. Key factors for successful pregnancy outcome are disease remission at the time of conception and optimal disease control during pregnancy. This article forms part of a series on prescribing for pregnancy and discusses the impact of inflammatory arthritis on pregnancy and the influence pregnancy may have on inflammatory arthritis. It highlights the importance of prepregnancy care and collaborative working between obstetric and rheumatology specialties as well as focusing on prescribing before, during and after pregnancy.
Dual TLR9 and PD-L1 targeting unleashes dendritic cells to induce durable antitumor immunity
Authors: Fernandez-Rodriguez Laura , Cianciaruso Chiara , Bill Ruben , Trefny Marcel P , Klar Richard , Kirchhammer Nicole , Buchi Mélanie , Festag Julia , Michel Sven , Kohler Rainer H , Jones Elham , Maaske Andre , vom Berg Johannes , Kobold Sebastian , Kashyap Abhishek S , Jaschinski Frank , Dixon Karen O , Pittet Mikael J , Zippelius Alfred
Published: May 2023

Background

Although immune checkpoint inhibitors have been a breakthrough in clinical oncology, these therapies fail to produce durable responses in a significant fraction of patients. This lack of long-term efficacy may be due to a poor pre-existing network linking innate and adaptive immunity. Here, we present an antisense oligonucleotide (ASO)-based strategy that dually targets toll-like receptor 9 (TLR9) and programmed cell death ligand 1 (PD-L1), aiming to overcome resistance to anti-PD-L1 monoclonal therapy.

Methods

We designed a high-affinity immunomodulatory IM-TLR9:PD-L1-ASO antisense oligonucleotide (hereafter, IM-T9P1-ASO) targeting mouse PD-L1 messenger RNA and activating TLR9. Then, we performedin vitroandin vivostudies to validate the IM-T9P1-ASO activity, efficacy, and biological effects in tumors and draining lymph nodes. We also performed intravital imaging to study IM-T9P1-ASO pharmacokinetics in the tumor.

Results

IM-T9P1-ASO therapy, unlike PD-L1 antibody therapy, results in durable antitumor responses in multiple mouse cancer models. Mechanistically, IM-T9P1-ASO activates a state of tumor-associated dendritic cells (DCs), referred to here as DC3s, which have potent antitumor potential but express the PD-L1 checkpoint. IM-T9P1-ASO has two roles: it triggers the expansion of DC3s by engaging with TLR9 and downregulates PD-L1, thereby unleashing the antitumor functions of DC3s. This dual action leads to tumor rejection by T cells. The antitumor efficacy of IM-T9P1-ASO depends on the antitumor cytokine interleukin-12 (IL-12), produced by DC3s, andBatf3, a transcription factor required for DC development.

Conclusions

By simultaneously targeting TLR9 and PD-L1, IM-T9P1-ASO amplifies antitumor responses via DC activation, leading to sustained therapeutic efficacy in mice. By highlighting differences and similarities between mouse and human DCs, this study could serve to develop similar therapeutic strategies for patients with cancer.
Is it time for a paradigmatic shift in relation to healthcare in the UK? A reflection
Authors: Saunders Karen , Sakel Mohamed , Cooper Cary L
Published: May 2023

Context

Conflict is a driver of change and unions representing professional groups across the National Health Service (NHS) are currently engaged in direct conflict with the government. For the first time in the history of the NHS, healthcare professionals have taken industrial strike action. Junior doctors and consultant physicians are currently engaged in their respective union ballots and indicative poll surveys regarding potential strike action in the future. In the wake of such widespread industrial action, we have taken time to think deeply about the confronting challenges and issues and offer this reflection as an opportunity to redefine and re-frame an unsustainable healthcare system into one that is the best it can be in terms of fit for purpose.

Insights and resource signposting

We present the current context with a reflective framework table focused on ‘What do we do well? What is not done so well? What could some possible ideas and solutions be? and How could this change be supported?’

We outline how a culture of well-being could be strategically and operationally introduced into the NHS workplace using research-based evidence and practical tools supported by expert guidance.
Surveillance of Mpox Cases Attending Sexual Health Services in England (SOMASS): design, implementation and initial findings from the SOMASS data collection tool, 2022
Authors: Charles Hannah , Prochazka Mateo , Murray Judith , Sexual Health Liaison Group UKHSA , Soni Suneeta , Haddow Lewis , Beets Katie , Pilkington Victoria , Low Nicola , Candfield Sophie , Jones Rachael , Bleiker Tanya , Dewsnap Claire , Phillips Matt , Phillips David
Published: May 2023

Objectives

We aimed to design and implement a data collection tool to support the 2022 mpox (monkeypox) outbreak, and to describe clinical and epidemiological data from individuals with mpox attending sexual health services (SHSs) in England.

Methods

The UK Health Security Agency and the British Association for Sexual Health and HIV established the Surveillance of Mpox Cases Attending Sexual Health Services in England (SOMASS) system.

Descriptive data were collected via a secure web-based data collection tool, completed by SHS clinicians following consultation with individuals with suspected mpox. Data were collected on patient demographics, clinical presentation and severity, exposures and behavioural characteristics.

Results

As of 17 November 2022, 276 SOMASS responses were submitted from 31 SHSs in England.

Where recorded, most (245 of 261; 94%) individuals identified as gay, bisexual or men who have sex with men (GBMSM), of whom two-thirds were HIV negative (170 of 257; 66%) and taking HIV pre-exposure prophylaxis (87 of 140; 62%), with a median age of 37 years (IQR: 30–43). Where known, thirty-nine per cent (63 of 161) had a concurrent sexually transmitted infection (STI) at the time of their mpox diagnosis.

For 46% of individuals (127 of 276), dermatological lesions were the initial symptom. Lesions were mostly asymmetrical and polymorphic, predominately affecting the genital area and perianal areas.

Nine per cent (24 of 276) of individuals were hospitalised. We report an association between receptive anal intercourse among GBMSM and proctitis (27 of 115; 24% vs 7 of 130; 5%; p<0.0001), and the presence of perianal lesions as the primary lesion site (46 of 115; 40% vs 25 of 130; 19%; p=0.0003).

Conclusions

We demonstrate multidisciplinary and responsive working to develop a robust data collection tool, which improved surveillance and strengthened the knowledge base. The SOMASS tool will allow data collection if mpox resurges in England. The model for developing the tool can be adapted to facilitate the preparedness and response to future STI outbreaks.