bluuebunny/crossref_metadata_2025 huggingface dataset:
Vitreofoveal Traction Associated With Pilocarpine for Presbyopia
Authors: Amarikwa Linus , Michalak Suzanne M. , Caul Susan , Mruthyunjaya Prithvi , Rahimy Ehsan
Published: July 2022

Vuity (pilocarpine HCL ophthalmic 1.25%) was approved for the treatment of presbyopia in October 2021. Previous case series have reported the presence of vitreofoveal traction and retinal detachment following pilocarpine administration, but this was not reported in the recent randomized control trials assessing the efficacy of Vuity. The authors report a case of a woman of 65 years who developed vitreomacular traction immediately following the first administration of Vuity, review the literature, and present considerations regarding screening and management of patients starting Vuity.

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Ophthalmic Surg Lasers Imaging Retina
2022; 53:410–411.]
Retinal Detachment Present at Birth in an Infant With a Novel CTNNB1 Mutation
Authors: Mellen Phoebe , Baumal Caroline
Published: July 2022

A full-term neonate was diagnosed on birth with a unilateral total retinal detachment. The contralateral eye had extensive fibrovascular proliferation, temporal dragging, and peripheral nonvascularized retina. Genetic testing confirmed a mutation in the CTNNB1 gene, which has been associated with familiar exudative vitreoretinopathy and phenotypic features including intellectual disability and spastic diplegia. This novel mutation and its associated syndrome should be considered as a cause of retinal detachment presenting in the neonatal period.

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Ophthalmic Surg Lasers Imaging Retina
2022; 53:403–405.]
Asymptotics of the Poisson kernel and Green's functions of the fractional conformal Laplacian
Authors: Mayer Martin , Ndiaye Cheikh Birahim
Published: July 2022

We study the asymptotics of the Poisson kernel and Green's functions of the fractional conformal Laplacian for conformal infinities of asymptotically hyperbolic manifolds. We derive sharp expansions of the Poisson kernel and Green's functions of the conformal Laplacian near their singularities. Our expansions of the Green's functions answer the first part of the conjecture of Kim-Musso-Wei[21] in the case of locally flat conformal infinities of Poincare-Einstein manifolds and together with the Poisson kernel asymptotic is used also in our paper [25] to show solvability of the fractional Yamabe problem in that case. Our asymptotics of the Green's functions on the general case of conformal infinities of asymptotically hyperbolic space is used also in [29] to show solvability of the fractional Yamabe problem for conformal infinities of dimension \begin{document}$ 3 $\end{document} and fractional parameter in \begin{document}$ (\frac{1}{2}, 1) $\end{document} corresponding to a global case left by previous works.
Ground states for a system of nonlinear Schrödinger equations with singular potentials
Authors: Chen Peng , Tang Xianhua
Published: July 2022

In this paper, we consider the existence and asymptotic behavior of ground state solutions for a class of Hamiltonian elliptic system with Hardy potential. The resulting problem engages three major difficulties: one is that the associated functional is strongly indefinite, the second difficulty we must overcome lies in verifying the link geometry and showing the boundedness of Cerami sequences when the nonlinearity is different from the usual global super-quadratic condition. The third difficulty is singular potential, which does not belong to the Kato's class. These enable us to develop a direct approach and new tricks to overcome the difficulties caused by singularity of potential and the dropping of classical super-quadratic assumption on the nonlinearity. Our approach is based on non-Nehari method which developed recently, we establish some new existence results of ground state solutions of Nehari-Pankov type under some mild conditions, and analyze asymptotical behavior of ground state solutions.
Some sharp Sobolev inequalities on $ BV({\mathbb{R}}^n) $
Authors: Dai Jin , Mou Shuang
Published: July 2022

In this paper, some sharp Sobolev inequalities on $ BV({\mathbb{R}}^n) $, the space of functions of bounded variation on $ {\mathbb{R}}^n $, $ n\geq 2 $, are deduced through the $ L_p $ Brunn-Minkowski theory. We will prove that these inequalities can all imply the sharp Sobolev inequality on $ BV({\mathbb{R}}^n) $.
Batouala de René Maran, prix Goncourt 1921 : l’accueil de l’Île Maurice
Authors: Furlong Robert
Published: July 2022

L’attribution du prix Goncourt 1921 à un noir – en l’occurrence René Maran – a été reçue comme une onde de choc par l’intelligentsia mauricienne. En effet, la littérature mauricienne était alors européano-centrée et, à part l’écrivain-chroniqueur Léoville L’Homme (alias Léon Lauret), les commentateurs de la presse locale n’ont pas été tendres envers ce Goncourt sombre et son lauréat.
L’émancipation et les contours du rôle genré de l’auteur dans les écrits autobiographiques de Märta Tikkanen
Authors: Wulf Matilda
Published: July 2022

Selon Märta Tikkanen (née en 1935), elle et son mari, le célèbre auteur Henrik Tikkanen (1924-1984), auraient mené une vie heureuse si elle n’avait pas commencé à écrire. Ils avaient les meilleures intentions du monde. Pourtant, l’utopie d’un paradis amoureux de deux auteurs qui pourraient vivre ensemble dans un foyer rempli d’amour, de discussions intellectuelles et d’enfants qui jouent est devenue une lutte de toute une vie. Quand les conflits ont commencé à émerger, ils se sont tournés vers l’écriture. À travers leurs œuvres, un dialogue unique sur l’amour, la vie et les choix impossibles entre la réalisation de soi et la responsabilité envers les proches s’est construit. Dans cet article, j’étudierai les œuvres autobiographiques de Märta Tikkanen pour analyser comment elle dessine un rôle genré d’auteur en opposition avec le stéréotype traditionnel de génie créateur/artiste qui souffre. La description que Tikkanen offre d’une vie de mère-autrice de quatre enfants et d’épouse d’un mari alcoolique qui se dispute son attention avec les enfants, entre en conflit avec la déclaration de Virginia Woolf (1882-1941) selon laquelle « a woman must have money and a room of her own if she is to write fiction » (A Room of One’s Own, 1929). Au lieu d’une chambre à part où elle pourrait s’extraire de toutes les responsabilités et les distractions pour se consacrer à l’écriture, Tikkanen ancre son écriture dans les expériences chaotiques de la vie quotidienne familiale. Elle lutte pour trouver un équilibre entre le travail et la famille tout en refusant de choisir entre ses rôles de femme, épouse, mère et autrice. L’écriture devient son acte de révolte contre les structures hétéronormatives qui créent une inégalité entre les sexes. Mon objectif est de montrer comment Tikkanen appréhende et défie les conditions genrées de l’écriture.
Incarner les enjeux éthiques par la littérature : le dispositif autobiographique dans Min kamp de Karl Ove Knausgård
Authors: Reymond Emmanuel
Published: July 2022

Cet article vise à trouver un cadrage critique satisfaisant permettant de faire sens de ce qui est en jeu dans la somme autobiographique controversée Min kamp (2009-2011) du Norvégien Karl Ove Knausgård. L’auteur lui-même a éclairé son entreprise littéraire de l’intérieur, de manière rétroactive, en insérant au cœur de son sixième et dernier volume un essai de plus de 400 pages qui réinscrit son dispositif autobiographique au sein d’une réflexion plus globale sur le langage et l’écriture dans leur relation à l’autre. En se concentrant sur la dynamique de pensée développée dans cet essai, on cherchera à proposer une lecture apte à articuler les différents niveaux mis en jeu par la publication de Min kamp, à la croisée du texte et des gestes qui l’ont fait naître.
Un islam non colonisé. Le champ textuel de la shariʿa et le système juridique colonial en Inde
Authors: Chatterjee Nandini
Published: July 2022

L’une des lignes d’analyse les plus communes de l’histoire de la production des savoirs coloniaux est celle de la « conquête » coloniale du droit islamique ou shariʿa. Les spécialistes de l’histoire de l’Asie du Sud ont montré comment, à travers le processus d’accommodement au système juridique colonial, le droit islamique a été transformé en un ensemble rigide de règles dérivées d’un petit nombre de sources reconnues comme telles et applicables uniquement aux questions familiales et religieuses. Cet article conteste cette interprétation et démontre qu’en réalité, la jurisprudence islamique, ou fiqh, est restée florissante dans l’Inde coloniale, indépendamment du champ d’action des tribunaux coloniaux. Les ouvrages classiques et modernes de jurisprudence islamique, produits dans le monde islamique, ont continué à être lus et discutés. Avec la généralisation des technologies de l’imprimé, ils ont été diffusés encore plus largement qu’auparavant. En outre, des théoriciens du droit novateurs, tels que l’avocat et juge musulman indien Sayyid Amir Ali, ont puisé dans ce registre de savoirs pour influencer le déploiement du droit islamique au sein même du système juridique colonial.
Actualiser le gouvernement du peuple. La Suisse comme modèle alternatif en France, aux États-Unis et en Espagne à la fin du xixe siècle
Authors: Robinet François
Published: July 2022

La fin du xixe siècle est marquée par un « moment suisse » qui traverse aussi bien les mondes intellectuel que politique. De nouveaux mouvements de masse, parfois qualifiés de populistes, le People’s Party aux États-Unis, le boulangisme en France et le blasquisme en Espagne, s’inspirent de la démocratie suisse et promeuvent notamment l’initiative et le référendum. Attachés aux questions institutionnelles, ces mouvements trouvent en Suisse un modèle républicain pour restaurer la souveraineté du peuple qu’ils estiment usurpée par les régimes en place. L’article étudie les ressorts qui expliquent cet attrait pour les institutions suisses au même moment dans divers contextes géographiques, et interroge les dispositifs de captation d’écrits théoriques sur la démocratie suisse, puis le processus de diffusion auprès de l’électorat.
Time Effective Cloud Resource Scheduling Method for Data-Intensive Smart Systems
Authors: Duan Jiguang , Li Yan , Duan Liying , Sharma Amit
Published: July 2022

The cloud computing platforms are being deployed nowadays for resource scheduling of real time data intensive applications. Cloud computing still deals with the challenge of time oriented effective scheduling for resource allocation, while striving to provide the efficient quality of service. This article proposes a time prioritization-based ensemble resource management and Ant Colony based optimization (ERM-ACO) algorithm in order to aid effective resource allocation and scheduling mechanism which specifically deals with the task group feasibility, assessing and selecting the computing and the storage resources required to perform specific tasks. The research outcomes are obtained in terms of time-effective demand fulfillment rate, average response time as well as resource utilization time considering various grouping mechanisms based on data arrival intensity consideration. The proposed framework when compared to the present state-of-the-art methods, optimal fitness percentage of 98% is observed signifying the feasible outcomes for real-time scenarios.
Comparative Study for Facilities Location Problem in Supply Chain Design
Authors: Mankour Ikram , Yachba Khadidja
Published: July 2022

The interest in supply chains has increased in the last few years. The supply chain optimization aims to reduce the delays and costs generated between suppliers and customers. The researchers focus primarily on the supply chain design to transport products to clients. This paper attempts to find an optimal warehouse location using a metaheuristic method. The goal is to select the optimum warehouse location. FLP-GA (Facility Location Problem - Genetic Algorithms) is the proposed approach based on genetic algorithms that reduce the number of warehouses to be opened, the overall costs, and the distances between them from a set of customers and candidate warehouses. The authors compared the approach with three other methods. This approach can select a reduced number of warehouses with minimal cost.
Research on the Coordination of Time and Space Coupling Between New Urbanization and Economic Development Based on Cloud Computing
Authors: Xu Xiangjun
Published: July 2022

Through in-depth analysis of the definition and connotation of new urbanization quality, a new urbanization indicator system with typical representativeness and quantification is established, and a spatio-temporal coupling coordination model is constructed based on this indicator system, and model input is obtained through urban statistical yearbooks and relevant government year reports Data, complete the temporal-spatial coupling coordination analysis of new urbanization and economic development. Taking a province as an example, it has been experimentally verified that the quality of new urbanization in the province has developed rapidly from 2010 to 2014, and the quality of new urbanization has stagnated from 2014 to 2015. In 2018, the quality of new urbanization in the province has rapidly increased its comprehensive value.
Impact of Risk Perceptions and User Trust on Intention to Re-Use E-Government
Authors: Rouibah Kamel , Qurban Hasan , Al-Qirim Nabeel
Published: July 2022

Despite the plethora of studies investigating different impacting factors on intention to re-use (IR) e-government services, they suffer from two limitations. First, initial studies provide mixed results on the effect of risk perception (PR) on IR. Second, although e-commerce studies have considered PR as a complex construct that encompasses several dimensions to date, none have considered exploring the effect of this complex construct on IR e-government websites. Thus, this study attempts to extend surrogates to such gaps by integrating PR and user trust (UT) in IR e-government using mixed-methods. It involved both a qualitative study (n = 81) to identify perceive risk antecedents and quantitative study (369 users) to build and test the proposed model. Results show that of eight PR factors, only privacy, time, psychological, and overall emerged as negative influencers and as such indirectly affect the IR government, through the mediating role of perceived value and user’s trust. System quality also has an indirect effect on IR through perceived value mediation.
The Circumplex Model for Structuring Career Anchors of the IT/IS Personnel
Authors: Chang Christina Ling-hsing , Wu Sheng
Published: July 2022

A quantitative study involving Mainland China (the PRC), Taiwan, India, the UAE, and the US, five areas with 852 responses of IT/IS personnel data towards building a more suitable Circumplex Career Anchor Model for IT/IS personnel, and to test a research model of a reorganized (quadrant) anchors. The bureaucratic, protean, careerist, and the social four quadrant anchors, have a significantly positive effect on career satisfaction of the IT/IS personnel. The bureaucratic, protean, and social three quadrant anchors have a significantly positive effect on job satisfaction of the IT/IS personnel, but not on the careerist quadrant anchor. Thus, the result of this study not only provided a reorganized (quadrant) anchors framework for suitable IT/IS personnel, but also combined job satisfaction, career satisfaction, and turnover intention to extend the Circumplex career anchor model to be a more complete research model.
Detection of PD-L1–Expressing Myeloid Cell Clusters in the Hyaluronan-Enriched Stroma in Tumor Tissue and Tumor-Draining Lymph Nodes
Authors: Dominguez-Gutierrez Paul R , Kwenda Elizabeth P , Donelan William , Miranda Mariza , Doty Andria , O’Malley Padraic , Crispen Paul L , Kusmartsev Sergei
Published: July 2022

Expression of the transmembrane protein PD-L1 is frequently upregulated in cancer. Because PD-L1–expressing cells can induce apoptosis or anergy of T lymphocytes through binding to the PD1 receptor, the PD-L1–mediated inhibition of activated PD1+ T cells is considered a major pathway for tumor immune escape. However, the mechanisms that regulate the expression of PD-L1 in the tumor microenvironment are not fully understood. Analysis of organotypic tumor tissue slice cultures, obtained from mice with implanted syngeneic tumors (MBT2 bladder tumors in C3H mice, Renca kidney, and CT26 colon tumors in BALB/c mice), as well as from patients with cancer, revealed that tumor-associated hyaluronan (HA) supports the development of immunosuppressive PD-L1+ macrophages. Using genetically modified tumor cells, we identified epithelial tumor cells and cancer-associated mesenchymal fibroblast-like cells as a major source of HA in the tumor microenvironment. These HA-producing tumor cells, and particularly the vimentin-positive fibroblast-like cells of bone marrow origin, directly interact with tumor-recruited myeloid cells to form large stromal congregates/clusters that are highly enriched for both HA and PD-L1. Furthermore, similar cell clusters composed of HA-producing fibroblast-like cells and PD-L1+ macrophages were detected in tumor-draining, but not in distant, lymph nodes. Collectively, our findings indicate that the formation of multiple large HA-enriched stromal clusters that support the development of PD-L1–expressing APCs in the tumor microenvironment and draining lymph nodes could contribute to the immune escape and resistance to immunotherapy in cancer.
Nfkbid Overexpression in Nonobese Diabetic Mice Elicits Complete Type 1 Diabetes Resistance in Part Associated with Enhanced Thymic Deletion of Pathogenic CD8 T Cells and Increased Numbers and Activity of Regulatory T Cells
Authors: Dwyer Jennifer R , Racine Jeremy J , Chapman Harold D , Quinlan Anna , Presa Maximiliano , Stafford Grace A , Schmitz Ingo , Serreze David V
Published: July 2022

Type 1 diabetes (T1D) in both humans and NOD mice is caused by T cell–mediated autoimmune destruction of pancreatic β cells. Increased frequency or activity of autoreactive T cells and failures of regulatory T cells (Tregs) to control these pathogenic effectors have both been implicated in T1D etiology. Due to the expression of MHC class I molecules on β cells, CD8 T cells represent the ultimate effector population mediating T1D. Developing autoreactive CD8 T cells normally undergo extensive thymic negative selection, but this process is impaired in NOD mice and also likely T1D patients. Previous studies identified an allelic variant of Nfkbid, a NF-κB signal modulator, as a gene strongly contributing to defective thymic deletion of autoreactive CD8 T cells in NOD mice. These previous studies found ablation of Nfkbid in NOD mice using the clustered regularly interspaced short palindromic repeats system resulted in greater thymic deletion of pathogenic CD8 AI4 and NY8.3 TCR transgenic T cells but an unexpected acceleration of T1D onset. This acceleration was associated with reductions in the frequency of peripheral Tregs. In this article, we report transgenic overexpression of Nfkbid in NOD mice also paradoxically results in enhanced thymic deletion of autoreactive CD8 AI4 T cells. However, transgenic elevation of Nfkbid expression also increased the frequency and functional capacity of peripheral Tregs, in part contributing to the induction of complete T1D resistance. Thus, future identification of a pharmaceutical means to enhance Nfkbid expression might ultimately provide an effective T1D intervention approach.
Analysis of Gene Expression and TCR/B Cell Receptor Profiling of Immune Cells in Primary Sjögren’s Syndrome by Single-Cell Sequencing
Authors: Hou Xianliang , Hong Xiaoping , Ou Minglin , Meng Shuhui , Wang Tingting , Liao Shengyou , He Jingquan , Yu Haiyan , Liu Lixiong , Yin Lianghong , Liu Dongzhou , Tang Donge , Dai Yong
Published: July 2022

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease that is estimated to affect 35 million people worldwide and is characterized by lymphocytic infiltration, elevated circulating autoantibodies, and proinflammatory cytokines. The key immune cell subset changes and the TCR/BCR repertoire alterations in pSS patients remain unclear. In this study, we sought to comprehensively characterize the transcriptional changes in PBMCs of pSS patients by single-cell RNA sequencing and single-cell V(D)J sequencing. Naive CD8+ T cells and mucosal-associated invariant T cells were markedly decreased but regulatory T cells were increased in pSS patients. There were a large number of differentially expressed genes shared by multiple subpopulations of T cells and B cells. Abnormal signaling pathways, including Ag processing and presentation, the BCR signaling pathway, the TCR signaling pathway, and Epstein–Barr virus infection, were highly enriched in pSS patients. Moreover, there were obvious differences in the CD30, FLT3, IFN-II, IL-1, IL-2, IL-6, IL-10, RESISTIN, TGF-β, TNF, and VEGF signaling networks between pSS patients and healthy controls. Single-cell TCR and BCR repertoire analysis showed that there was a lower diversity of T cells in pSS patients than in healthy controls; however, there was no significant difference in the degree of clonal expansion, CDR3 length distribution, or degree of sequence sharing. Notably, our results further emphasize the functional importance of αβ pairing in determining Ag specificity. In conclusion, our analysis provides a comprehensive single-cell map of gene expression and TCR/BCR profiles in pSS patients for a better understanding of the pathogenesis, diagnosis, and treatment of pSS.
CD11bhigh B Cells Increase after Stroke and Regulate Microglia
Authors: Korf Janelle M , Honarpisheh Pedram , Mohan Eric C , Banerjee Anik , Blasco-Conesa Maria P , Honarpisheh Parisa , Guzman Gary U , Khan Romeesa , Ganesh Bhanu P , Hazen Amy L , Lee Juneyoung , Kumar Aditya , McCullough Louise D , Chauhan Anjali
Published: July 2022

Recent studies have highlighted the deleterious contributions of B cells to post-stroke recovery and cognitive decline. Different B cell subsets have been proposed on the basis of expression levels of transcription factors (e.g., T-bet) as well as specific surface proteins. CD11b (α-chain of integrin) is expressed by several immune cell types and is involved in regulation of cell motility, phagocytosis, and other essential functions of host immunity. Although B cells express CD11b, the CD11bhigh subset of B cells has not been well characterized, especially in immune dysregulation seen with aging and after stroke. Here, we investigate the role of CD11bhigh B cells in immune responses after stroke in young and aged mice. We evaluated the ability of CD11bhigh B cells to influence pro- and anti-inflammatory phenotypes of young and aged microglia (MG). We hypothesized that CD11bhigh B cells accumulate in the brain and contribute to neuroinflammation in aging and after stroke. We found that CD11bhigh B cells are a heterogeneous subpopulation of B cells predominantly present in naive aged mice. Their frequency increases in the brain after stroke in young and aged mice. Importantly, CD11bhigh B cells regulate MG phenotype and increase MG phagocytosis in both ex vivo and in vivo settings, likely by production of regulatory cytokines (e.g., TNF-α). As both APCs and adaptive immune cells with long-term memory function, B cells are uniquely positioned to regulate acute and chronic phases of the post-stroke immune response, and their influence is subset specific.
CD47 Promotes Autoimmune Valvular Carditis by Impairing Macrophage Efferocytosis and Enhancing Cytokine Production
Authors: Meier Lee A , Faragher Jessica L , Osinski Victoria , Auger Jennifer L , Voeller Rochus , Marath Aubyn , Binstadt Bryce A
Published: July 2022

Systemic autoantibody-mediated diseases accelerate chronic cardiovascular disease in humans. In the K/B.g7 mouse model of spontaneous autoantibody-mediated inflammatory arthritis, valvular carditis arises in part because of Fc receptor–mediated activation of macrophages, leading to production of pathogenic TNF and IL-6. In this study, we explored whether impaired efferocytosis mediated by the interaction of CD47-expressing apoptotic cells with signal regulatory protein α (SIRPα) on macrophages contributes to disease progression in this model. CD47-expressing apoptotic cells and SIRPα+ macrophages were abundant in inflamed/rheumatic cardiac valves from both mice and humans. In vivo anti-CD47 blockade both prevented and treated valvular carditis in K/B.g7 mice. Blocking CD47 enhanced macrophage efferocytosis and reduced macrophage production of TNF and IL-6. These studies highlight the CD47:SIRPα interaction as a key driver of chronic cardiac valve inflammation and suggest these molecules as potential therapeutic targets to reduce cardiovascular disease risk in autoantibody-driven inflammatory diseases.
Ontogeny of the B Cell Receptor Repertoire and Microbiome in Mice
Authors: Gilboa Amit , Hope Ronen , Ben Simon Shira , Polak Pazit , Koren Omry , Yaari Gur
Published: July 2022

The immune system matures throughout childhood to achieve full functionality in protecting our bodies against threats. The immune system has a strong reciprocal symbiosis with the host bacterial population and the two systems co-develop, shaping each other. Despite their fundamental role in health physiology, the ontogeny of these systems is poorly characterized. In this study, we investigated the development of the BCR repertoire by analyzing high-throughput sequencing of their receptors in several time points of young C57BL/6J mice. In parallel, we explored the development of the gut microbiome. We discovered that the gut IgA repertoires change from birth to adolescence, including an increase in CDR3 lengths and somatic hypermutation levels. This contrasts with the spleen IgM repertoires that remain stable and distinct from the IgA repertoires in the gut. We also discovered that large clones that germinate in the gut are initially confined to a specific gut compartment, then expand to nearby compartments and later on expand also to the spleen and remain there. Finally, we explored the associations between diversity indices of the B cell repertoires and the microbiome, as well as associations between bacterial and BCR clusters. Our results shed light on the ontogeny of the adaptive immune system and the microbiome, providing a baseline for future research.
Thrombin Differentially Modulates the Acute Inflammatory Response to Escherichia coli and Staphylococcus aureus in Human Whole Blood
Authors: Johnson Christina , Quach Huy Quang , Lau Corinna , Ekholt Karin , Espevik Terje , Woodruff Trent M , Pischke Søren Erik , Mollnes Tom Eirik , Nilsson Per H
Published: July 2022

Thrombin plays a central role in thromboinflammatory responses, but its activity is blocked in the common ex vivo human whole blood models, making an ex vivo study of thrombin effects on thromboinflammatory responses unfeasible. In this study, we exploited the anticoagulant peptide Gly-Pro-Arg-Pro (GPRP) that blocks fibrin polymerization to study the effects of thrombin on acute inflammation in response to Escherichia coli and Staphylococcus aureus. Human blood was anticoagulated with either GPRP or the thrombin inhibitor lepirudin and incubated with either E. coli or S. aureus for up to 4 h at 37°C. In GPRP-anticoagulated blood, there were spontaneous elevations in thrombin levels and platelet activation, which further increased in the presence of bacteria. Complement activation and the expression of activation markers on monocytes and granulocytes increased to the same extent in both blood models in response to bacteria. Most cytokines were not elevated in response to thrombin alone, but thrombin presence substantially and heterogeneously modulated several cytokines that increased in response to bacterial incubations. Bacterial-induced releases of IL-8, MIP-1α, and MIP-1β were potentiated in the thrombin-active GPRP model, whereas the levels of IP-10, TNF, IL-6, and IL-1β were elevated in the thrombin-inactive lepirudin model. Complement C5-blockade, combined with CD14 inhibition, reduced the overall cytokine release significantly, both in thrombin-active and thrombin-inactive models. Our data support that thrombin itself marginally induces leukocyte-dependent cytokine release in this isolated human whole blood but is a significant modulator of bacteria-induced inflammation by a differential effect on cytokine patterns.
Interactions with Asialo-Glycoprotein Receptors and Platelets Are Dispensable for CD8+ T Cell Localization in the Murine Liver
Authors: O’Connor James H , McNamara Hayley A , Cai Yeping , Coupland Lucy A , Gardiner Elizabeth E , Parish Christopher R , McMorran Brendan J , Ganusov Vitaly V , Cockburn Ian A
Published: July 2022

Liver-resident CD8+ T cells can play critical roles in the control of pathogens, including Plasmodium and hepatitis B virus. Paradoxically, it has also been proposed that the liver may act as the main place for the elimination of CD8+ T cells at the resolution of immune responses. We hypothesized that different adhesion processes may drive residence versus elimination of T cells in the liver. Specifically, we investigated whether the expression of asialo-glycoproteins (ASGPs) drives the localization and elimination of effector CD8+ T cells in the liver, while interactions with platelets facilitate liver residence and protective function. Using murine CD8+ T cells activated in vitro, or in vivo by immunization with Plasmodium berghei sporozoites, we found that, unexpectedly, inhibition of ASGP receptors did not inhibit the accumulation of effector cells in the liver, but instead prevented these cells from accumulating in the spleen. In addition, enforced expression of ASGP on effector CD8+ T cells using St3GalI-deficient cells lead to their loss from the spleen. We also found, using different mouse models of thrombocytopenia, that severe reduction in platelet concentration in circulation did not strongly influence the residence and protective function of CD8+ T cells in the liver. These data suggest that platelets play a marginal role in CD8+ T cell function in the liver. Furthermore, ASGP-expressing effector CD8+ T cells accumulate in the spleen, not the liver, prior to their destruction.
The IL-33/ST2 Axis Promotes Primary Sjögren’s Syndrome by Enhancing Salivary Epithelial Cell Activation and Type 1 Immune Response
Authors: Dong Yuanji , Ming Bingxia , Gao Rongfen , Mo Qian , Wu Xuefen , Zheng Fang , Zhong Jixin , Dong Lingli
Published: July 2022

The molecular mechanisms of primary Sjögren’s syndrome (pSS) are poorly understood. In this study, we explored the role of the IL-33/ST2 axis in the development of pSS. In the mouse model of experimental Sjögren’s syndrome, we found that the saliva flow rate at weeks 4 and 30 was preserved in IL-33−/− and ST2−/− mice, compared with that of wild-type mice. At week 30 of experimental Sjögren’s syndrome induction, the histological score, anti-nuclear Ab levels, and numbers of Th1 and B cells in draining lymph nodes of the salivary gland were lower in the IL-33−/− and ST2−/− mice, whereas Th17 cells and regulatory T cells were not changed. Primary salivary gland epithelial cells expressed the IL-33 receptor ST2. After stimulation with rIL-33, salivary gland epithelial cells increased the transcriptional levels of CD86 and CCL2, accompanied by the activation of the NF-κB inflammatory pathway. There was a synergistic effect between rIL-33 and rIL-12 in augmenting the production of IFN-γ in CD4+ T cells. In the pSS patients, the expression of IL-33 was elevated in the labial salivary gland, with the number of IL-33+ cells positively correlated with the score of the EULAR (European Alliance of Associations for Rheumatology) Sjögren’s syndrome disease activity index (ESSDAI). ST2 was highly expressed in the cytoplasm of ductal epithelial cells, with low levels of expression in lymphatic infiltration sites. Our data suggest that the IL-33/ST2 axis may promote the development of pSS by enhancing salivary epithelial cell activation and the type 1 immune response.
T Cell Immunogenicity, Gene Expression Profile, and Safety of Four Heterologous Prime-Boost Combinations of HIV Vaccine Candidates in Healthy Volunteers: Results of the Randomized Multi-Arm Phase I/II ANRS VRI01 Trial
Authors: Richert Laura , Lelièvre Jean-Daniel , Lacabaratz Christine , Hardel Lucile , Hocini Hakim , Wiedemann Aurélie , Lucht Frédéric , Poizot-Martin Isabelle , Bauduin Claire , Diallo Alpha , Rieux Véronique , Rouch Elodie , Surenaud Mathieu , Lefebvre Cécile , Foucat Emile , Tisserand Pascaline , Guillaumat Lydia , Durand Mélany , Hejblum Boris , Launay Odile , Thiébaut Rodolphe , Lévy Yves
Published: July 2022

Heterologous prime-boost strategies are of interest for HIV vaccine development. The order of prime-boost components could be important for the induction of T cell responses. In this phase I/II multi-arm trial, three vaccine candidates were used as prime or boost: modified vaccinia Ankara (MVA) HIV-B (coding for Gag, Pol, Nef); HIV LIPO-5 (five lipopeptides from Gag, Pol, Nef); DNA GTU-MultiHIV B (coding for Rev, Nef, Tat, Gag, Env gp160 clade B). Healthy human volunteers (n = 92) were randomized to four groups: 1) MVA at weeks 0/8 + LIPO-5 at weeks 20/28 (M/L); 2) LIPO-5 at weeks 0/8 + MVA at weeks 20/28 (L/M); 3) DNA at weeks 0/4/12 + LIPO-5 at weeks 20/28 (G/L); 4) DNA at weeks 0/4/12 + MVA at weeks 20/28 (G/M). The frequency of IFN-γ–ELISPOT responders at week 30 was 33, 43, 0, and 74%, respectively. Only MVA-receiving groups were further analyzed (n = 62). Frequency of HIV-specific cytokine-positive (IFN-γ, IL-2, or TNF-α) CD4+ T cells increased significantly from week 0 to week 30 (median change of 0.06, 0.11, and 0.10% for M/L, L/M, and G/M, respectively), mainly after MVA vaccinations, and was sustained until week 52. HIV-specific CD8+ T cell responses increased significantly at week 30 in M/L and G/M (median change of 0.02 and 0.05%). Significant whole-blood gene expression changes were observed 2 wk after the first MVA injection, regardless of its use as prime or boost. An MVA gene signature was identified, including 86 genes mainly related to cell cycle pathways. Three prime-boost strategies led to CD4+ and CD8+ T cell responses and to a whole-blood gene expression signature primarily due to their MVA HIV-B component.
Sex-Based Differences in Human Neutrophil Chemorepulsion
Authors: Consalvo Kristen M , Kirolos Sara A , Sestak Chelsea E , Gomer Richard H
Published: July 2022

A considerable amount is known about how eukaryotic cells move toward an attractant, and the mechanisms are conserved from Dictyostelium discoideum to human neutrophils. Relatively little is known about chemorepulsion, where cells move away from a repellent signal. We previously identified pathways mediating chemorepulsion in Dictyostelium, and here we show that these pathways, including Ras, Rac, protein kinase C, PTEN, and ERK1 and 2, are required for human neutrophil chemorepulsion, and, as with Dictyostelium chemorepulsion, PI3K and phospholipase C are not necessary, suggesting that eukaryotic chemorepulsion mechanisms are conserved. Surprisingly, there were differences between male and female neutrophils. Inhibition of Rho-associated kinases or Cdc42 caused male neutrophils to be more repelled by a chemorepellent and female neutrophils to be attracted to the chemorepellent. In the presence of a chemorepellent, compared with male neutrophils, female neutrophils showed a reduced percentage of repelled neutrophils, greater persistence of movement, more adhesion, less accumulation of PI(3,4,5)P3, and less polymerization of actin. Five proteins associated with chemorepulsion pathways are differentially abundant, with three of the five showing sex dimorphism in protein localization in unstimulated male and female neutrophils. Together, this indicates a fundamental difference in a motility mechanism in the innate immune system in men and women.
The Developmental Transcription Factor p63 Is Redeployed to Drive Allergic Skin Inflammation through Phosphorylation by p38α
Authors: Jiménez-Andrade Yanek , Hillette Kathryn R , Yoshida Toshimi , Kashiwagi Mariko , Choo Min-Kyung , Liang Yinming , Georgopoulos Katia , Park Jin Mo
Published: July 2022

Keratinocytes, the epithelial cells of the skin, reprogram their gene expression and produce immune effector molecules when exposed to environmental and endogenous triggers of inflammation. It remains unclear how keratinocytes process physiological signals generated during skin irritation and switch from a homeostatic to an inflammatory state. In this article, we show that the stress-activated protein kinase p38α is crucial for keratinocytes to prompt changes in their transcriptome upon cytokine stimulation and drive inflammation in allergen-exposed skin. p38α serves this function by phosphorylating p63, a transcription factor essential for the lineage identity and stemness of the skin epithelium. Phosphorylation by p38α alters the activity of p63 and redeploys this developmental transcription factor to a gene expression program linked to inflammation. Genetic ablation and pharmacological inhibition of p38α or the p38α–p63 target gene product MMP13 attenuate atopic dermatitis–like disease in mice. Our study reveals an epithelial molecular pathway promoting skin inflammation and actionable through treatment with topical small-molecule therapeutics.
LIGHT (TNFSF14) Costimulation Enhances Myeloid Cell Activation and Antitumor Immunity in the Setting of PD-1/PD-L1 and TIGIT Checkpoint Blockade
Authors: Yoo Kyung Jin , Johannes Kellsey , González Louis E , Patel Arpita , Shuptrine Casey W , Opheim Zachary , Lenz Karen , Campbell Kristen , Nguyen Thuy-Ai , Miriyala Jayalakshmi , Smith Connor , McGuire Ashlyn , Tsai Yi-Hsuan , Rangwala Fatima , de Silva Suresh , Schreiber Taylor H , Fromm George
Published: July 2022

Coinhibition of TIGIT (T cell immunoreceptor with Ig and ITIM domains) and PD-1/PD-L1 (PD-1/L1) may improve response rates compared with monotherapy PD-1/L1 blockade in checkpoint naive non–small cell lung cancer with PD-L1 expression >50%. TIGIT mAbs with an effector-competent Fc can induce myeloid cell activation, and some have demonstrated effector T cell depletion, which carries a clinical liability of unknown significance. TIGIT Ab blockade translates to antitumor activity by enabling PVR signaling through CD226 (DNAM-1), which can be directly inhibited by PD-1. Furthermore, DNAM-1 is downregulated on tumor-infiltrating lymphocytes (TILs) in advanced and checkpoint inhibition–resistant cancers. Therefore, broadening clinical responses from TIGIT blockade into PD-L1low or checkpoint inhibition–resistant tumors, may be induced by immune costimulation that operates independently from PD-1/L1 inhibition. TNFSF14 (LIGHT) was identified through genomic screens, in vitro functional analysis, and immune profiling of TILs as a TNF ligand that could provide broad immune activation. Accordingly, murine and human bifunctional fusion proteins were engineered linking the extracellular domain of TIGIT to the extracellular domain of LIGHT, yielding TIGIT-Fc-LIGHT. TIGIT competitively inhibited binding to all PVR ligands. LIGHT directly activated myeloid cells through interactions with LTβR (lymphotoxin β receptor), without the requirement for a competent Fc domain to engage Fcγ receptors. LIGHT costimulated CD8+ T and NK cells through HVEM (herpes virus entry mediator A). Importantly, HVEM was more widely expressed than DNAM-1 on T memory stem cells and TILs across a range of tumor types. Taken together, the mechanisms of TIGIT-Fc-LIGHT promoted strong antitumor activity in preclinical tumor models of primary and acquired resistance to PD-1 blockade, suggesting that immune costimulation mediated by LIGHT may broaden the clinical utility of TIGIT blockade.
Th2-Biased Transcriptional Profile Predicts HIV Envelope-Specific Polyfunctional CD4+ T Cells That Correlated with Reduced Risk of Infection in RV144 Trial
Authors: Cohen Kristen W , Tian Yuan , Thayer Casey , Seese Aaron , Amezquita Robert , McElrath M Juliana , De Rosa Stephen C , Gottardo Raphael
Published: July 2022

Ag-specific T cells play a critical role in responding to viral infections. In the RV144 HIV vaccine clinical trial, a rare subset of HIV-specific polyfunctional CD4+ T cells correlated with reduced risk of HIV-1 infection. Polyfunctional T cells are a subset of Ag-specific T cells that are able to simultaneously produce multiple effector cytokines. Little is known about what differentiates polyfunctional T cells from other vaccine-elicited T cells in humans. Therefore, we developed a novel live-cell multiplexed cytokine capture assay to identify, isolate, and transcriptionally profile vaccine-specific polyfunctional CD4+ T cells. We applied these methods to samples from subjects who received the RV144 vaccine regimen, as part of the HVTN 097 clinical trial. We identified two surface receptors (CD44 and CD82) upregulated on polyfunctional T cells and a Th2-biased transcriptional signature (IL-4, IL-5, and IL-13) that predicted the envelope-specific polyfunctional CD4+ T cell profiles that had correlated with reduced risk of HIV infection in RV144. By linking single-cell transcriptional and functional profiles, we may be able to further define the potential contributions of polyfunctional T cells to effective vaccine-elicited immunity.
Comprehensive Update and Revision of Nomenclature on Complement C6 and C7 Variants
Authors: Massri Mariam , Foco Luisa , Würzner Reinhard
Published: July 2022

Complement genes encompass a wide array of variants, giving rise to numerous protein isoforms that have often been shown to exhibit clinical significance. Given that these variants have been discovered over a span of 50 y, one challenging consequence is the inconsistency in the terminology used to classify them. This issue is prominently evident in the nomenclature used for complement C6 and C7 variants, for which we observed a great discrepancy between previously published works and variants described in current genome browsers. This report discusses the causes for the discrepancies in C6 and C7 nomenclature and seeks to establish a classification system that would unify existing and future variants. The inconsistency in the methods used to annotate amino acids and the modifications pinpointed in the C6 and C7 primers are some of the factors that contribute greatly to the discrepancy in the nomenclature. Several variants that were classified incorrectly are highlighted in this report, and we showcase first-hand how a unified classification system is important to match previous with current genetic information. Ultimately, we hope that the proposed classification system of nomenclature becomes an incentive for studies on complement variants and their physiological and/or pathological effects.
A Deep Learning Model for Accurate Diagnosis of Infection Using Antibody Repertoires
Authors: Chen Yuan , Ye Zhiming , Zhang Yanfang , Xie Wenxi , Chen Qingyun , Lan Chunhong , Yang Xiujia , Zeng Huikun , Zhu Yan , Ma Cuiyu , Tang Haipei , Wang Qilong , Guan Junjie , Chen Sen , Li Fenxiang , Yang Wei , Yan Huacheng , Yu Xueqing , Zhang Zhenhai
Published: July 2022

The adaptive immune receptor repertoire consists of the entire set of an individual’s BCRs and TCRs and is believed to contain a record of prior immune responses and the potential for future immunity. Analyses of TCR repertoires via deep learning (DL) methods have successfully diagnosed cancers and infectious diseases, including coronavirus disease 2019. However, few studies have used DL to analyze BCR repertoires. In this study, we collected IgG H chain Ab repertoires from 276 healthy control subjects and 326 patients with various infections. We then extracted a comprehensive feature set consisting of 10 subsets of repertoire-level features and 160 sequence-level features and tested whether these features can distinguish between infected individuals and healthy control subjects. Finally, we developed an ensemble DL model, namely, DL method for infection diagnosis (https://github.com/chenyuan0510/DeepID), and used this model to differentiate between the infected and healthy individuals. Four subsets of repertoire-level features and four sequence-level features were selected because of their excellent predictive performance. The DL method for infection diagnosis outperformed traditional machine learning methods in distinguishing between healthy and infected samples (area under the curve = 0.9883) and achieved a multiclassification accuracy of 0.9104. We also observed differences between the healthy and infected groups in V genes usage, clonal expansion, the complexity of reads within clone, the physical properties in the α region, and the local flexibility of the CDR3 amino acid sequence. Our results suggest that the Ab repertoire is a promising biomarker for the diagnosis of various infections.
Genomic and Transcriptional Mechanisms Governing Innate-like T Lymphocyte Development
Authors: Morgan Roxroy C , Kee Barbara L
Published: July 2022

Innate-like lymphocytes are a subset of lymphoid cells that function as a first line of defense against microbial infection. These cells are activated by proinflammatory cytokines or broadly expressed receptors and are able to rapidly perform their effector functions owing to a uniquely primed chromatin state that is acquired as a part of their developmental program. These cells function in many organs to protect against disease, but they release cytokines and cytotoxic mediators that can also lead to severe tissue pathologies. Therefore, harnessing the capabilities of these cells for therapeutic interventions will require a deep understanding of how these cells develop and regulate their effector functions. In this review we discuss recent advances in the identification of the transcription factors and the genomic regions that guide the development and function of invariant NKT cells and we highlight related mechanisms in other innate-like lymphocytes.
Adenosine Alleviates Necrotizing Enterocolitis by Enhancing the Immunosuppressive Function of Myeloid-Derived Suppressor Cells in Newborns
Authors: Zhou Dongmei , Yao Meng , Zhang Lijuan , Chen Yingying , He Juan , Zhang Yuxin , Xu Haixu , Zhou Pan , Zhong Wei , Yao Zhi , Zhou Jie
Published: July 2022

Necrotizing enterocolitis (NEC) is a common disorder in premature infants that is characterized by hyperinflammation and severe necrosis in the intestine. The pathogenesis of NEC remains to be elucidated. In this study, we demonstrate that adenosine, a metabolite more abundant in infants than in adults, plays an important role in the prevention of NEC. Administration of adenosine or its analog, adenosine-5′-N-ethyluronamide (NECA), dramatically relieved the severity of NEC in neonatal mice. Meanwhile, adenosine treatment significantly enhanced the immunosuppressive function, antibacterial activity, and migration of myeloid-derived suppressor cells (MDSCs). However, depletion of MDSCs or inhibition of their migration using the CXCR2 inhibitor SB225002 almost completely abrogated the protective effect of adenosine on NEC. Mechanistic studies showed that MDSCs in newborns expressed abundant adenosine receptor A2B (A2BR) that elicits intracellular cAMP signaling and its downstream target NF-κB. Importantly, intestinal tissues from patients with NEC showed significantly lower infiltration of A2BR-positive MDSCs than those from healthy donors. These observations revealed that adenosine-induced MDSCs represent an essential immune axis for intestinal homeostasis in newborns.