bluuebunny/crossref_metadata_2025 huggingface dataset:
Quijote-PNG: The Information Content of the Halo Power Spectrum and Bispectrum
Authors: Coulton William R , Villaescusa-Navarro Francisco , Jamieson Drew , Baldi Marco , Jung Gabriel , Karagiannis Dionysios , Liguori Michele , Verde Licia , Wandelt Benjamin D.
Published: February 2023

We investigate how much can be learnt about four types of primordial non-Gaussianity (PNG) from small-scale measurements of the halo field. Using the quijote-png simulations, we quantify the information content accessible with measurements of the halo power spectrum monopole and quadrupole, the matter power spectrum, the halo–matter cross spectrum, and the halo bispectrum monopole. This analysis is the first to include small, nonlinear scales, up to

k

max

=
0.5

h

Mpc

−
1

, and to explore whether these scales can break degeneracies with cosmological and nuisance parameters making use of thousands of N-body simulations. We perform all the halo measurements in redshift space with a single sample comprised of all halos with mass >3.2 × 1013
h
−1
M
⊙. For local PNG, measurements of the scale-dependent bias effect from the power spectrum using sample variance cancellation provide significantly tighter constraints than measurements of the halo bispectrum. In this case measurements of the small scales add minimal additional constraining power. In contrast, the information on equilateral and orthogonal PNG is primarily accessible through the bispectrum. For these shapes, small-scale measurements increase the constraining power of the halo bispectrum by up to 4×, though the addition of scales beyond k ≈ 0.3 h Mpc−1 improves constraints largely through reducing degeneracies between PNG and the other parameters. These degeneracies are even more powerfully mitigated through combining power spectrum and bispectrum measurements. However, even with combined measurements and small-scale information, equilateral non-Gaussianity remains highly degenerate with σ
8 and our bias model.
The Small-scale Dynamo in a Multiphase Supernova-driven Medium
Authors: Gent Frederick A. , Mac Low Mordecai-Mark , Korpi-Lagg Maarit J. , Singh Nishant K.
Published: February 2023

Magnetic fields grow quickly, even at early cosmological times, suggesting the action of a small-scale dynamo (SSD) in the interstellar medium (ISM) of galaxies. Many studies have focused on idealized, isotropic, homogeneous, turbulent driving of the SSD. Here we analyze more realistic simulations of supernova-driven turbulence to understand how it drives an SSD. We find that SSD growth rates are intermittently variable as a result of the evolving multiphase ISM structure. Rapid growth in the magnetic field typically occurs in hot gas, with the highest overall growth rates occurring when the fractional volume of hot gas is large. SSD growth rates correlate most strongly with vorticity and fluid Reynolds number, which also both correlate strongly with gas temperature. Rotational energy exceeds irrotational energy in all phases, but particularly in the hot phase while SSD growth is most rapid. Supernova rate does not significantly affect the ISM average kinetic energy density. Rather, higher temperatures associated with high supernova rates tend to increase SSD growth rates. SSD saturates with total magnetic energy density around 5% of equipartition to kinetic energy density, increasing slightly with magnetic Prandtl number. While magnetic energy density in the hot gas can exceed that of the other phases when SSD grows most rapidly, it saturates below 5% of equipartition with kinetic energy in the hot gas, while in the cold gas it attains 100%. Fast, intermittent growth of the magnetic field appears to be a characteristic behavior of supernova-driven, multiphase turbulence.
On the Role of Dynamical Cooling in the Dynamics of Circumbinary Disks
Authors: Wang Hai-Yang , Bai Xue-Ning , Lai Dong
Published: February 2023

Hydrodynamical interactions between binaries and circumbinary disks (CBDs) play an important role in a variety of astrophysical systems, from young stellar binaries to supermassive black hole binaries. Previous simulations of CBDs have mostly employed locally isothermal equations of state. We carry out 2D viscous hydrodynamic simulations of CBDs around equal-mass, circular binaries, treating the gas thermodynamics by thermal relaxation toward equilibrium temperature (the constant-β cooling ansatz, where β is the cooling time in units of the local Keplerian time). As an initial study, we use the grid-based code Athena++ on a polar grid, covering an extended disk outside the binary co-orbital region. We find that with a longer cooling time, the accretion variability is gradually suppressed, and the morphology of the CBD becomes more symmetric. The disk also shows evidence of hysteresis behavior depending on the initial conditions. Gas cooling also affects the rate of angular momentum transfer between the binary and the CBD, where given our adopted disk thickness and viscosity (H/r ∼ 0.1 and α ∼ 0.1), the binary orbit expands while undergoing accretion for most β values between 0 and 4.0 except over a narrow range of intermediate β values. The validity of using a polar grid excising the central domain is also discussed.
Quasi-parallel Whistler Waves and Their Interaction with Resonant Electrons during High-velocity Bulk Flows in the Earth’s Magnetotail
Authors: Grigorenko Elena E. , Malykhin Andrey Y. , Kronberg Elena A. , Panov Evgeny V.
Published: February 2023

In collisionless space, plasma waves are important channels of energy conversion, affecting the local particle velocity distribution functions through wave–particle interactions. In this paper we present a comparative statistical analysis of the characteristics of quasi-parallel narrowband whistler waves and the properties of resonant electrons interacting with these waves during the intervals of earthward and tailward high-velocity bulk flows produced by the near-Earth X-line and observed by Magnetospheric Multiscale Mission spacecraft. We found that on both sides of the X-line, the suprathermal electrons (≥1 keV) having large pitch angles make the major contribution to the maximal growth rate (γ) of these waves. The whistler waves were observed almost simultaneously with strong enhancements of perpendicular magnetic gradients localized at electron scales near dipolarization fronts associated with the earthward bulk flows, and near flux ropes/magnetic islands embedded into the tailward bulk flows. Betatron energization of electrons due to the appearance of such gradients increases the perpendicular anisotropy of electron distribution, which could be responsible for the whistler wave generation. We found that in the course of electron interactions with the whistler waves the lower-energy resonant electrons can transfer a part of their kinetic energy to the higher-energy electrons, especially in the Central Plasma Sheet. This results in formation/enhancement of energy-dependent perpendicular anisotropy and power-law tails in the high-energy range of electron velocity distribution. We conclude that despite the differences in the magnetic structure of the earthward and tailward bulk flows, the mechanisms of the quasi-parallel whistler wave generation and the properties of resonant electrons are quite similar.
Gamma-Ray Emission from Galaxies Hosting Molecular Outflows
Authors: McDaniel Alex , Ajello Marco , Karwin Chris
Published: February 2023

Many star-forming galaxies and those hosting active galactic nuclei show evidence of massive outflows of material in a variety of phases including ionized, neutral atomic, and molecular. Molecular outflows in particular have been the focus of recent interest as they may be responsible for removing gas from the galaxy, thereby suppressing star formation. As material is ejected from the cores of galaxies, interactions of the outflowing material with the interstellar medium can accelerate cosmic rays and produce high-energy gamma rays. In this work, we search for gamma-ray emission from a sample of local galaxies known to host molecular outflows using data collected by the Fermi Large Area Telescope. We employ a stacking technique in order to search for and characterize the average gamma-ray emission properties of the sample. Gamma-ray emission is detected from the galaxies in our sample at the 4.4σ level with a power-law photon index of Γ ≈ 2 in the 1–800 GeV energy range. The emission is found to correlate with tracers of star formation activity, namely the 8–1000 μm infrared luminosity. We also find that the observed signal can be predominantly attributed to H ii galaxies hosting energy-driven outflows. While we do not find evidence suggesting that the outflows are accelerating charged particles directly, galaxies with molecular outflows may produce more gamma rays than galaxies without outflows. In particular, the set consisting of gamma-ray-detected galaxies with molecular outflows are nearly perfect calorimeters and may be future targets for searches of high-energy neutrinos.
Ammonia Abundance Derived from Juno MWR and VLA Observations of Jupiter
Authors: Moeckel Chris , de Pater Imke , DeBoer David
Published: February 2023

The vertical distribution of trace gases in planetary atmospheres can be obtained with observations of the atmosphere’s thermal emission. Inverting radio observations to recover the atmospheric structure, however, is nontrivial, and the solutions are degenerate. We propose a modeling framework to prescribe a vertical distribution of trace gases that combines a thermochemical equilibrium model with a vertical temperature structure and compare these results to models where ammonia can vary between predefined pressure nodes.  We compare these model to nadir brightness temperatures and limb-darkening parameters, together with their uncertainties, which we reduced from the raw Juno Microwave Radiometer (MWR) data set. We then apply this framework to MWR observations during Juno’s first years of operation (perijove passes 1–12) and to longitudinally averaged latitude scans taken with the upgraded Very Large Array. We use the model to constrain the distribution of ammonia between −60° and 60° latitude and down to 100 bars. We constrain the ammonia abundance to be

340.5

−
21.2

+
34.8

ppm (

2.66

−
0.17

+
0.27

×

solar abundance) and find a depletion of ammonia down to a depth of ∼20 bars, which supports the existence of processes that deplete the atmosphere below the ammonia and water cloud layers. At the equator we find an increase of ammonia with altitude, while the zones and belts in the midlatitudes can be traced down to levels where the atmosphere is well mixed. The latitudinal variation in the ammonia abundance appears to be opposite to that shown at higher altitudes, which supports the existence of a stacked-cell circulation model.
Identification and reproductive isolation of Euborellia species (Insecta, Dermaptera, Anisolabididae) from East and Southeast Asia
Authors: Kamimura Yoshitaka , Lee Chow-Yang , Yamasako Junsuke , Nishikawa Masaru
Published: February 2023

Euborellia(Anisolabididae: Anisolabidinae) is one of the most speciose genera of earwigs (Dermaptera), and its species-level classification is difficult. To settle the classification of brachypterous species with abbreviated tegmina recorded from East and Southeast Asia, we examined the morphology and reproductive isolation of three tentativeEuborelliaspecies, and analyzed the DNA barcoding region of the mitochondrial cytochrome oxidase subunit I (COI) gene. The observed complete reproductive isolation among the threeEuborelliataxa and considerable differentiation in the COI sequences clearly show that each should be treated as a separate species. Based on morphology, distribution and the DNA sequence, we identifyEuborelliasp. 1 of Malaysia asE. annulata(Fabricius), a circumtropical cosmopolitan with no records of a fully winged form. Samples from Ioto Island (= Iwo-jima Island: Ogasawara Islands, southern Japan) were also identified as this species.Euborelliasp. 3, from the main islands of Japan, was generally larger and lacked a Y-shaped pigmented area on the penis lobe, which is characteristic ofEuborelliasp. 1. We propose reinstatingE. pallipes(Shiraki) as the oldest name for this taxon.Euborelliasp. 2, even the brachypterous form, can be distinguished from these two species by its paler coloration (particularly the femora), ecarinate post-abdomen, and the shape of the male genitalia (parameres). We tentatively identify this species asE. philippinensisSrivastava based on the morphology of the brachypterous form, although the macropterous form cannot be distinguished fromE. femoralis(Dohrn).
Literarische Netzwerk- und Feldanalyse. Methodische Unterschiede und Gemeinsamkeiten mit einem Einordnungsversuch sprachexperimenteller Lyrik um 1990 (Kling, Grünbein, Papenfuß)
Authors: Tommek Heribert
Published: February 2023

Le paradigme du réseau est au cœur du « nouvel esprit du capitalisme » et il est donc directement pertinent pour la production culturelle contemporaine. Les études littéraires qui ont développé des approches d’analyse de réseaux au cours des dernières années se sont concentrées jusqu’à présent sur la littérature du xviii e  siècle, sur les réseaux d’auteurs, d’œuvres et de lecteurs et en particulier sur l’analyse des personnages et des intrigues dans le drame. En raison d’autres caractéristiques génériques, la poésie ne semble pas se prêter à une analyse de réseau intra-littéraire. L’article esquisse les grandes lignes des approches de l’analyse de réseau dans les études littéraires et montre les points communs et les différences avec l’analyse de champ littéraire. Enfin, il présente les différentes classifications des positions d’expérimentation linguistique en poésie depuis la Wende dans une ligne ascendante allant de l’analyse de réseau à l’analyse de champ en passant par l’analyse de discours.
Hegel, Weber et les Quakers : la tolérance comme expérience de la séparation
Authors: Slama Paul
Published: February 2023

Dans cet article, on articule les pensées de Hegel et de Weber à partir de la figure du Quaker et de la tolérance étatique qu’elle implique. L’on montre que Hegel pense la tolérance comme l’épreuve par l’État du négatif préservé dans sa négativité, insoluble dans l’unité rationnelle étatique, et que Weber renverse la perspective pour penser la tolérance à partir des intérêts communautaires de la secte. Une telle comparaison autorise une étude phénoménologique de la communauté sectaire comme espace normatif normé par les regards, où chacun est sous le regard de chacun et fond sa subjectivité dans la communauté tout entière, sans qu’il soit besoin d’une transcendance normative autre que la secte elle-même. Nous montrons qu’un tel mode d’existence, caractéristique de la modernité, est expérience de la séparation, et in fine de la mort de dieu.
Activité historienne et appartenance urbaine
Authors: Lévy Fabien
Published: February 2023

Du xi e au xiv e siècles Gênes bâtit au gré de ses chroniques un discours historique fondé sur son identité républicaine et maritime. La crise politique et économique que traverse la cité à la fin du Moyen Âge semble cependant se répercuter dans le domaine culturel, où elle perd la maîtrise de son récit. Pire, au début du xvi e siècle, ses nouveaux maîtres français vont appuyer leur domination en créant un discours concurrent, centré autour de l’idéal monarchique, s’appuyant pour cela sur des chroniqueurs français mais aussi italiens et génois. Loin de ces œuvres de commande, l’esprit civique des Génois se manifestera pourtant au sein de nombreuses productions littéraires aux ambitions historiques, permettant de renouer avec l’idéal républicain de ses origines, triomphant lors de la réforme et de l’indépendance retrouvée de 1528.
Le son, l’espace et la cohérence de la notion kantienne de sens externe
Authors: Fournier Jean-Baptiste
Published: February 2023

Les mathématiciens et philosophes du xix e  siècle ont souligné l’incapacité de la doctrine kantienne de l’espace à prendre en charge la fondation des géométries non euclidiennes, et cette difficulté semble pouvoir être rapportée à une tension interne à la notion kantienne d’extériorité : en cherchant à « exposer » l’espace comme condition de possibilité de la géométrie comme science a priori , Kant s’interdirait en réalité de rendre compte de sa fonction de possibilisation de l’expérience externe en général. Le même problème se manifeste lorsqu’on cherche à rendre compte, comme nous le faisons ici, de l’extériorité des phénomènes sonores. À travers la description du rapport du son au temps, mais aussi à l’espace, et à la lumière de la musique savante contemporaine et en particulier d’une œuvre de Pierre Boulez dans laquelle la spatialisation du son joue un rôle majeur, nous montrons qu’il est nécessaire, pour sauver le transcendantal, de lui imposer un reformatage – et plus précisément un déplacement. Car dans la tension entre fondation des axiomes géométriques et ouverture du sujet à l’extériorité, ce qui se joue n’est pas autre chose que le sens même de la question transcendantale.
Kant et la renaissance de la métaphysique
Authors: Römer Inga
Published: February 2023

Après des décennies durant lesquelles la thèse de la « fin de la métaphysique » semblait aller de soi, on assiste actuellement à une certaine renaissance de la métaphysique dans différents courants de la philosophie contemporaine. Ce regain d’intérêt pour le problème de la métaphysique est également présent dans les interprétations de l’œuvre de Kant. L’article résume les recherches dans ce domaine avant de développer une perspective spécifique basée sur le Preisschrift de Kant sur les progrès de la métaphysique en Allemagne depuis Leibniz et Wolff. Une première section montre comment Kant esquisse une métaphysique spéciale critique qui opère avec des objets posés par l’homme et lui permet de repenser ainsi que de transformer le monde. Une deuxième section traite de la question de savoir si cette conception kantienne peut être comprise comme une « onto-théo-logie » au sens heideggerien du terme. Une conclusion affirme que l’approche de Kant peut difficilement être qualifiée d’« onto-théo-logique », mais qu’elle introduit plutôt un type particulier de métaphysique, inscrit dans l’histoire de la métaphysique spéciale, mais fondé sur la philosophie morale – un type de métaphysique qui pourrait être intéressant dans le cadre des débats contemporains sur le problème de la métaphysique.
Concept difficulty in secondary school chemistry: An intra-play of gender, school location and school type
Authors: Oladejo Adekunle Ibrahim , Ademola Ibukunolu A. , Ayanwale Musa Adekunle , O. Tobih Deborah
Published: February 2023

This study focused on addressing underperformance in chemistry in Anglophone West African countries. The main purpose of the study was to determine if factors such as gender, school location and ownership impact students’ perception of the difficulty of chemistry concepts and to suggest how these difficult concepts can be made easy to learn from the perspectives of the students. A mixed-methods approach was adopted. Participants were 1,292 chemistry students from nine public and 12 private secondary schools in Nigeria and Ghana with about three-quarters of the schools from urban areas. About 51% of the participants were females. Twenty-four students were interviewed to gather qualitative data. The Difficult Concept in Chemistry Questionnaire (DCCQ) and the Difficult Concepts in Chemistry Interview Guide (DCCIG) were used for data collection. The test-retest reliability coefficient of the DCCQ was 0.88. We found a slight difference in the perception of male and female students while school type came as a major determinant factor on students’ perception of difficult concepts in chemistry, just as school location. Phobia for calculations came out as a major cause of difficulty in the top five perceived difficult concepts. Findings on causes of learning difficulties were reported as well as suggestions for improvement as viewed by the students. Recommendations were made for improving the teaching and learning of chemistry in Anglophone West African schools.
From basic approaches to novel challenges and applications in Sequential Pattern Mining
Authors: Bechini Alessio , Bondielli Alessandro , Dell'Oglio Pietro , Marcelloni Francesco
Published: February 2023

Sequential Pattern Mining (SPM) is a branch of data mining that deals with finding statistically relevant regularities of patterns in sequentially ordered data. It has been an active area of research since mid 1990s. Even if many prime algorithms for SPM have a long history, the field is nevertheless very active. The literature is focused on novel challenges and applications, and on the development of more efficient and effective algorithms. In this paper, we present a brief overview on the landscape of algorithms for SPM, including an evaluation on performances for some of them. Further, we explore additional problems that have spanned from SPM. Finally, we evaluate available resources for SPM, and hypothesize on future directions for the field.
On the fourth power mean of one special two-term exponential sums
Authors: Zhang Wenpeng , Meng Yuanyuan
Published: February 2023

The main purpose of this paper is using the elementary methods and the number of the solutions of some congruence equations to study the calculating problem of the fourth power mean of one special two-term exponential sums, and give an exact calculating formula for it.
The correlation between physical inactivity and students' health based on data mining and related influencing factors
Authors: Zhang Hanying , Xu Zhongqiu
Published: February 2023

The sedentary behavior among college students has become one of the most important factors affecting the development of physical and mental health. Chronic lack of physical activity may lead to health problems such as decreased physical fitness, and increased psychological disorders. In the post-epidemic era, it is necessary for college students to have a strong immune system, and a strong body cannot be achieved without regular leisure physical activity. Therefore, it is necessary to explore the relationship between relevant health factors and physical activity. This paper presents an optimized COM-B model. And the experimental results show that the optimized model is well applied in describing the current situation of physical activity participation among college students, analyzing the distribution characteristics of socio-demographic variables related to physical activity, and exploring the correlation between physical activity and the subhealth status of college students.
Sliding dynamics and bifurcations of a human influenza system under logistic source and broken line control strategy
Authors: Li Guodong , Li Wenjie , Zhang Ying , Guan Yajuan
Published: February 2023

This paper proposes a non-smooth human influenza model with logistic source to describe the impact on media coverage and quarantine of susceptible populations of the human influenza transmission process. First, we choose two thresholds $ I_{T} $ and $ S_{T} $ as a broken line control strategy: Once the number of infected people exceeds $ I_{T} $, the media influence comes into play, and when the number of susceptible individuals is greater than $ S_{T} $, the control by quarantine of susceptible individuals is open. Furthermore, by choosing different thresholds $ I_{T} $ and $ S_{T} $ and using Filippov theory, we study the dynamic behavior of the Filippov model with respect to all possible equilibria. It is shown that the Filippov system tends to the pseudo-equilibrium on sliding mode domain or one endemic equilibrium or bistability endemic equilibria under some conditions. The regular/virtulal equilibrium bifurcations are also given. Lastly, numerical simulation results show that choosing appropriate threshold values can prevent the outbreak of influenza, which implies media coverage and quarantine of susceptible individuals can effectively restrain the transmission of influenza. The non-smooth system with logistic source can provide some new insights for the prevention and control of human influenza.
Condamnation en demi-teinte de la France par la Cour européenne des droits de l’Homme au titre de la violation du droit d’entrer dans son pays commise à l’encontre de ses ressortissants présents en Syrie
Authors: GENONCEAU Cassandre
Published: February 2023

À l’occasion d’un refus tacite de rapatriement opposé à deux de ses ressortissantes et à leurs enfants présents en Syrie, la France a été condamnée par la Grande chambre de la Cour européenne des droits de l’Homme le 14 septembre dernier au titre de la violation du droit d’entrer dans son pays. En considération de circonstances propres à l’espèce, la Cour a étendu les obligations positives attachées à ce droit fondamental, y compris dans un domaine purement régalien tel que la protection diplomatique1. Pour autant, en limitant la responsabilité de l’État au souci d’offrir une protection effective contre l’arbitraire, cet arrêt est révélateur des réticences de la Cour à étendre la portée de la Convention européenne des droits de l’Homme et de ses Protocoles en présence d’un fait extraterritorial, y compris s’il produit des effets gravement préjudiciables à la dignité humaine.
Enfermer en « salle détente ».
Authors: Primerano Adrien
Published: February 2023

Depuis le début des années 2000, évolutions juridiques et recommandations de bonnes pratiques ont produit un ensemble de nouvelles normes visant la « bientraitance » en établissements médico-sociaux. Pour autant, l’usage de la contrainte n’a pas disparu des pratiques professionnelles en institution. Cet article interroge ce paradoxe apparent en cherchant à saisir les discours et usages qui entourent les espaces d’enfermement au sein d’Instituts Médico-Éducatifs (IME) accueillant des adolescent·e·s désigné·e·s autistes. L’« espace d’enfermement » désigne des pièces dont l’un des usages est d’enfermer à clef, seul, un individu. Cet usage est structuré autour de l’idée d’un bénéfice pour la personne enfermée, d’une dimension d’apprentissage et de progrès à travers un cadrage éducatif. Ces dimensions sont regroupées ici sous le vocable d’« objectif éducatif ». Pour autant, le recours à l’enfermement prend également la forme d’une épreuve de professionnalité, mettant en jeu les dimensions éthiques et morales du travail des éducateur·rice·s. Ils et elles cherchent à légitimer leurs pratiques en s’appuyant sur les psychologues et psychiatres, en réclamant une plus grande protocolisation. L’idée de « soupape » émerge enfin, dans l’enfermement, comme un usage pour rendre durable le travail émotionnel des éducateur·rice·s, comme une pratique par défaut au vu du contexte organisationnel.
Le savant sans le politique : La conception hayékienne de l’action publique au Chili
Authors: Larrouqué Damien
Published: February 2023

Le Chili a toujours été présenté comme un laboratoire du néolibéralisme. Dans cet article, nous allons au-delà de cette appréciation généralement acquise et défendons la thèse selon laquelle il s’agit plutôt d’un modèle hayékien par essence. Relevant d’une réflexion de théorie politique informée par le terrain, notre argumentation se divise en deux parties. La première démontre que la Constitution de 1980 a été pétrie par la doctrine juridique, politique et économique de l’intellectuel austro-américain. La seconde étaye en quoi l’ombre portée de la philosophie hayékienne a obscurci la transition démocratique et s’illustre toujours empiriquement dans la survalorisation technocratique, dans l’incarcération de masse comme substitution à l’État social et dans une structure fiscale résolument régressive.
An Interpretative View on Innovation Acceptance for Bitcoin and Blockchain Phenomena
Authors: Rainero Christian , Modarelli Giuseppe
Published: February 2023

The research, in its general lines, tends to open an interpretative perspective on the fact that the bitcoin and blockchain (BTC-BC) phenomenon could be defined primarily through the social learning lens, and in that case would be considered a privileged way to investigate humans' behavior related to the emergent innovations, considering voluntariness in information seeking as antecedent of reduced reticence to acceptance. The approach inherent in the analysis proposed should be considered as exploratory and embryonic, but interesting and crucial for a seminal investigation of the field, due to the rapid emergence of the phenomenon object of the study. The main implication of the interpretative paradigm provided on the BTC-BC scene, considering the social learning view, could be found on the managerial side, thanks to the possible indirect knowledge-based strategy, able to shape an informed social context, promoting the future probable and potentially facilitated application of “disruptive” technologies in several work environments.
The development of peripheral intraepithelial lymphocytes in vivo is influenced by microbial metabolites
Authors: Soderholm Amelia T , Beresford-Jones Benjamin , Clare Simon , Pedicord Virginia Ahn
Published: February 2023

Peripheral CD4+CD8αα+TCRαβ+ intraepithelial lymphocytes (pIELs) are a specialised T cell population that require the presence of intestinal microbes for their development, however the microbes and factors involved are not well characterised. pIELs are closely associated with intestinal epithelial cells (IECs) that line the gastrointestinal tract, but the contribution of IECs in shaping pIEL development is also not well defined. We investigated a number of microbial metabolites for their ability to influence pIEL development, and whether this is mediated by microbe-IEC-pIEL interactions.

In this study we utilised flow cytometry to characterise pIEL frequencies in GF mice administered with different microbial metabolites, in SPF mice from different colonies and animal facilities, and in GF mice monocolonised with potential pIEL-inducing commensal species. qPCR of IEC RNA isolated from these mice was performed to identify candidate genes expressed by IECs that may influence pIEL development.

We identified a common bacterial metabolite that partially restores pIEL development in GF mice, and a novel pIEL-inducing bacterial species. pIEL frequency of SPF mice varied between different sources, and qPCR identified IECs expressed several T-cell-influencing cytokines that correlated with pIEL frequency in vivo.

Our results identify a common microbial metabolite that contributes to pIEL development that may mediate IEC expression of T-cell-influencing cytokines. Our work further elucidates the mechanisms of host tolerance triggered by commensal microbes, which will facilitate the development of better strategies to prevent and treat intestinal infections and inflammatory diseases.
Hedgehog signaling interfaces with the Hexoseamine Biosynthetic Pathway to promote M2 polarization of mammary tumor associated macrophages
Authors: Hinshaw Dominique C , Hanna Ann , Samant Rajeev , Shevde-Samant Lalita
Published: February 2023

The Hedgehog (Hh) signaling pathway is aberrantly activated in breast cancer, and contributes to tumor cell survival, proliferation, and migration. The success of these events is heavily influenced by the surrounding immune microenvironment. One such cell type, macrophages (MΦ) can make up to 50% of the tumor mass. MΦs can be polarized to M1 (tumor-eradicating) or M2 (tumor-promoting), and a high M2/M1 ratio within the tumor microenvironment (TME) is correlated with worse prognosis.

We have uncovered a novel role for Hh signaling in promoting M2 polarization. We propose that the mechanism underlying this phenomenon is due to changes in the Hexoseamine Biosynthetic Pathway and consequently cellular O-GlcNAcylation. M2 MΦs have considerably higher levels of UDP-GlcNAc, the substrate for O-GlcNAcylation, compared to M1s, but the consequences of this are unknown. We hypothesize that O-GlcNAc modifications on key M2-specific proteins contribute to enhanced M2 phenotype and function within the TME, and that this phenomenon can be reversed with Hh blockade.

Methodology: mouse model of mammary carcinoma, flow cytometry, RNA-seq, metabolomics, IP.

This study is the first to elucidate Hh signaling’s role in recalibrating the metabolism of tumor-supporting MΦs. Inhibition of Hh signaling reduces MΦ O-GlcNAcylation resulting in weakened suppressive properties of M2 MΦs through the reduced activity of STAT6. Moreover, mitigating O-GlcNAcylation through Hh blockade pivots M2 MΦs to resemble M1s.

Our work provides evidence for modulating Hh activity, and consequently MΦ metabolism, to sculpt the plasticity of MΦs. This knowledge will help us to better understand how to target and diminish the pro-tumorigenic phenotypes of MΦs in the TME.
Mature neutrophils acquire a T cell suppressor phenotype in the ovarian cancer microenvironment characterized by disruption of key T cell signaling and metabolic responses
Authors: Giridharan Thejaswini , Emmons Tiffany R , Khan ANM Nazmul , Suzuki Sora , Varghese Aaron , Sullivan Meagan , Odunsi Kunle , Zsiros Emese , Yaffe Michael B , Segal Brahm H
Published: February 2023

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. Despite being an immunogenic tumor, single-agent checkpoint inhibitor therapy in the recurrent setting has been disappointing, raising the notion of suppressive factors in the tumor microenvironment (TME) as obstacles to immunotherapy. We previously observed that neutrophils acquire a complement dependent T cell suppressor phenotype in the TME, characterized by inhibition of T cell proliferation and activation through mechanisms distinct from myeloid-derived suppressor cells. Using ascites fluid supernatants (ASC) from patients with EOC as an authentic component of the TME, we identified ASC-activated neutrophils require multiple neutrophil effector functions including NADPH oxidase activation, SNARE-mediated exocytosis and degranulation. ASC-activated neutrophils also adhered to T cells and caused trogocytosis of T cell membranes. These injury and signaling cues resulted in T cell immunoparalysis, characterized by impaired CD3/CD28 stimulated Zap70 phosphorylation, NFAT translocation, IL2 production, glucose uptake, mitochondrial function, and mTOR activation. We also observed that in anti-CD3/CD28 pre-activated T cells, addition of neutrophils + ASC resulted significant reduction in Zap70 phosphorylation. Our results demonstrate complement-dependent priming of neutrophils in the TME inducing a T cell non-responsiveness distinct from established checkpoint pathways and identify targets for immunotherapy. Further studies will focus on the effects of neutrophil suppressors on the TCR signaling cascade and cell stress response pathways that may enable T cell survival in response to neutrophil damage at the expense of activation.
Elucidating the role of CD91 on dendritic cells during immunosurveillance of emerging tumors
Authors: Nayak Devanshi A , Binder Robert J
Published: February 2023

The premise of immunosurveillance is that the immune system, particularly T cells, can detect and eliminate emerging tumor cells. However, the mechanisms that allow efficient T cell priming during nascent tumor immunosurveillance despite limited antigen availability remain unclear. Immunogenic heat shock proteins (HSPs) such as gp96 can efficiently chaperone minute levels of peptides available in nascent tumors to elicit antigen-specific immunity. In immune-competent hosts, the receptor CD91 which is expressed on antigen presenting cells (APCs) facilitates uptake and cross-presentation of these chaperoned tumor antigens. Further, engagement of CD91 on dendritic cells (DCs) initiates signals for co-stimulation and cytokine production to prime anti-tumor responses. Recent studies from our lab indicate that mice deficient in CD91 expression in DCs are more susceptible to chemically induced tumors compared to wild type mice. DCs are critical in CD91-mediated immune responses, yet the CD91+ DC subset(s) that prime robust anti-tumor T cell responses have not been elucidated. This study seeks to define the DC subset(s) necessary for CD91-mediated immune responses using mice with DC-specific CD91 deficiency. Given the dual role of CD91 on DCs in antigen transfer and co-stimulation, we examine the mechanism and consequences of CD91-mediated immunosurveillance during cancer induction. Advancing our understanding of this mechanism of immunosurveillance and the role of CD91+ DCs will have significant implications for predicting cancer incidence and therapy.
The responder/nonresponder phenomena: The immune system’s role in determining the outcome of radiation therapy in rectal cancer
Authors: Uccello Taylor Paige , Mills Bradley N. , Kintzel Sarah , Lord Edith M. , Linehan David C. , Gerber Scott A.
Published: February 2023

While surgical resection is a viable option to treat patients with rectal cancer (RC), it is not without significantly reducing patients’ quality of life. In an effort to delay or even prevent surgery, patients are often administered pre-operative radiation therapy (RT). Although RT can significantly reduce tumor burden in a subset of patients, there are many patients whose tumors do not respond to RT. To study this, we developed an orthotopic model of RC that recapitulates human disease in which administration of clinically relevant RT results in mice bearing tumors that demonstrate a reduction of tumor burden (responders), and a group of animals whose tumors respond poorly (nonresponders). RNA-sequencing of intratumoral immune populations identified a unique gene signature associated with each group. Tumor-associated macrophages (TAMs) from nonresponding tumors were more similar to TAMs from untreated tumors when compared to TAMs from responding tumors. Interestingly, TAMs in responding tumors upregulate pathways associated with pattern recognition receptor signaling and damage associated molecular patterns. These data suggest that TAMs from responding tumors may be polarized to respond to the immunostimulatory damage induced by RT. While TAM polarization plays a large role in promoting either an immunostimulatory or immunosuppressive microenvironment, CD8+ T cells are directly responsible for killing tumor cells. We sequenced intratumoral CD8+ T cells as well and determined that T cells from responding tumors induced pathways consistent with enhanced effector function. These data suggest that a targeted therapy aimed at the TAM:CD8+ T cell interaction may promote a stronger RT response in the nonresponding tumors.
CaMKK2 deletion increases antitumor potential through enhanced MHC-II expression in Macrophages
Authors: Perera Jonathan J , Tomaszewski William H , Polania Jessica Waibl , Racioppi Luigi , Sanchez-Perez Luis A , Gunn Michael D. , Sampson John H
Published: February 2023

Objective:

Glioblastoma is the most common and aggressive primary brain tumor with a 5 year prognosis of less than 5% survival. Efforts to extend this survival through therapeutic advancement have only led to modest improvements. Immunotherapy has shown promise in other cancers but only has limited effect in GBM, partially due to the dense infiltration of pro-tumor myeloid cells. Calmodulin-dependent Kinase Kinase 2 (CaMKK2) is highly expressed in myeloid cells and high expression is associated with a more severe tumor grade and worse survival in GBM. Preliminary studies show that CaMKK2 KO mice display extended median survival and tumor clearance. We hypothesize that CaMKK2 may drive myeloid cells’ pro-tumor function.

Methods:

To investigate this, immune cells were isolated from tumor-bearing CaMKK2 KO, LysMcre x CaMKK2fl/fl and CaMKK2-eGFP reporter mice. Multi-parameter flow was used to detect CaMKK2 and phenotype the tumor microenvironment (TME). The presence of CaMKK2 expressing myeloid cells in the TME was confirmed by confocal microscopy.

Results/Conclusions:

CaMKK2 is preferentially expressed in myeloid cells in naïve and tumorous mice. CaMKK2 deletion upregulated MHC-II in macrophages which is expected to promote an antitumor response. Upregulation was not seen in naive CaMKK2 KO mice suggesting it is a product of tumor-exposure. Conditional deletion of CaMKK2 in bone-marrow derived macrophages (BMDM) did not lead to this MHC-II upregulation suggesting that it is not a BMDM-intrinsic phenotype but results from CaMKK2 deletion in another cell-type. In summary, CaMKK2 deletion induced macrophages to a more immunostimulatory phenotype with expected anti-tumor effect, making CaMKK2 a promising therapeutic target for GBM.
Vaccine-elicited T cells adopt an early memory-like transcriptional phenotype distinct from infection-elicited T cells
Authors: Thompson Scott Beckett , Ivanova Daria Leonidovna , Klarquist Jared , Kedl Ross
Published: February 2023

Protection from pathogens relies on both humoral (antibody-mediated) and cellular (T cell-mediated) responses. While infections robustly elicit both of these types of immunity, currently approved vaccine adjuvants largely fail to induce significant T cell responses. However, recent work by our lab and others suggests that the mechanisms governing vaccine-elicited T cells (Tvac) may be substantially different than those governing infection-elicited T cells (Tinf). We have recently demonstrated that optimal subunit vaccine-elicited T cell responses rely on different cytokine signals (IL-27 and 15) and metabolic function (oxidative phosphorylation vs. aerobic glycolysis) leading to phenotypically and functionally different outcomes (memory vs. effector). Our goal was to investigate the transcriptional programming that drives Tvac formation and function from immunization to memory timepoints. Using a single-cell RNA-seq approach along with functional assays, we compared Tvac and Tinf at various time points post-immunization or infectious challenge. Our data indicate that the gene expression of Tvac markedly diverges from Tinf at early and peak time points. Remarkably, while capable of being highly proliferative, Tvac adopt a distinct transcriptional phenotype with similarities to recently identified self-renewing stem cell memory T cells, such as TCF1 expression. This transcriptional program likely enables the persistence of Tvac in substantially greater abundance at memory time points conferring overall greater protection. Taken together, our data have identified a novel transcriptional program that supports a robust vaccine-elicited T cell response with implications for future therapeutic vaccine design.
The transcription factor T cell factor 1 (TCF1) expression is elevated in vaccine-elicited CD8+ T cells and negatively regulated by T-bet
Authors: Ivanova Daria Leonidovna , Kilgore Augustus , Klarquist Jared , Kedl Ross
Published: February 2023

T cells that express high levels of TCF1 display stem cell-like properties and give rise to effector-like cells that protect during chronic infections and cancer. Due to their increased responsiveness to checkpoint blockade, TCF1hi T cells are now recognized as promising targets for immunotherapies. We found that adjuvanted subunit vaccine-elicited T cells (Tvac) express significantly higher levels of TCF1 than T cells responding to infections (Tinf). In exploring the underlying causes for such high expression of TCF1 in Tvac, we examined the role of sustained TCR and inflammatory mediators in Tvac TCF1 regulation. Using Nr4a3-Tocky reporter mice and pMHCI antibody blockade, we found that TCR mediated signals regulate Tvac TCF1 to a limited degree. In line with previous reports, TCF1 expression in Tvac inversely correlated with adjuvant-elicited pro-inflammatory signals, increasing concomitantly with the rapid decline of cytokines after adjuvant administration. Further, the addition of TLR9 ligand CpG increased inflammatory cytokine production as it reduced TCF1 expression. However, in contrast to previous work, anti-IL-12 or anti-IFNγ treatment failed to reverse the lower TCF1 expression induced by CpG. More surprisingly, we found that Tvac TCF1 is regulated independently of Foxo1 even while Foxo1 plays its canonical role in facilitating TCF1 expression under inflammatory conditions. Inflammation does however negatively regulate TCF1 in a T-bet dependent manner, such that T-bet KO Tvac maintained high TCF1 expression even when inflammation was increased. Our data highlight differences in the transcriptional regulation of vaccine- and infection-elicited T cells and provide insights into the mechanism of TCF1 regulation.
Co-delivery of antigens with TLR7/8 agonists leads to an improved Th1-mediated immune response to subunit vaccines.
Authors: Lathrop Stephanie K , Massena Casey J. , Davison Clara J. , Schoener Roman , Burkhart David J. , Evans Jay T.
Published: February 2023

When designing an effective and safe vaccine, the induction of a protective immune response to a pathogen without unacceptable levels of immunopathology is critical. The use of purified or recombinant antigens in combination with adjuvants that elicit a defined immune response is a promising strategy for eliciting a productive immune response while minimizing toxicity. Our group has developed libraries of novel toll-like receptor (TLR)7 and 8 ligands with a range of activity. Previous clinical trials have shown that the high potency of TLR7/8 adjuvants can lead to unacceptable toxicity. We hypothesized that direct conjugation of the adjuvant to the antigen will limit systemic distribution of the adjuvant, while boosting the immune response by ensuring co-delivery of antigen and adjuvant to antigen presenting cells. We demonstrate that covalent conjugation of TLR7/8 agonists to antigens results in greatly improved humoral and cell-mediated responses, without apparent systemic or local inflammation. This likely improves safety by preventing off-target immune responses from the engagement of PAMPs in the absence of appropriate antigens. When mice were immunized with an antigen/adjuvant conjugate we observed a switch towards IgG2a and away from IgG1 antigen-specific antibodies, plus greater Th1 cytokine production after restimulation of immune cells ex vivo. We hypothesize that co-delivery of a TLR7/8 agonist with antigen leads to activation of CD4+ T cells in the presence of Th1-skewing cytokines. The TLR7/8 agonist also appears to improve cross-presentation, inducing CD8+ T cells. We find this approach has great potential to enhance vaccine efficacy, while reducing potential immunopathology by TLR7/8 adjuvants.
Priming of Long-Lived Memory CD8+ T cell Responses in the Spleen During Influenza Virus Infection
Authors: Jenkins Meagan M , Bachus Holly , Botta Davide , Schultz Michael , Rosenberg Alexander , León Beatriz , Ballesteros-Tato André
Published: February 2023

CD8+ T cell responses to influenza virus infection are canonically known to be activated solely in the lung draining, mediastinal lymph node (mLN). Mechanistically, migratory dendritic cells (mDCs) are activated in the lungs and traffic to the mLN where they encounter cognate CD8+ T cells, initiating the heterogeneous response to influenza virus. As such, when mDCs are absent or when migration is inhibited, CD8+ T cell responses are compromised and the viral burden in the lungs increases. In contrast to the current paradigm, local priming of CD8+ T cells has been hypothesized to occur in the spleen, and mDCs are thought to die in the mLN shortly after trafficking. Therefore, how CD8+ T cells could be primed locally in the spleen has remained an unpopular hypothesis. Here we show using a mouse model of influenza infection, that mDCs not only prime CD8+ T cells in the mLN, but can also prime CD8+ T cell responses locally in the spleen. Mechanistically, we show that a portion of the mDCs trafficking to the mLN can egress the mLN, enter the blood via an S1P/S1PR dependent mechanism, and enter the spleen. CD8+ T cell responses initiated in the spleen are longer lived than mLN primed responses. Collectively, our results demonstrate a novel DC trafficking pathway and support a new paradigm for how heterogeneous T cell responses to influenza are initiated.