scholarly journals A multivariate modeling framework to quantify immune checkpoint context-dependent stimulation on T cells

2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Léa Karpf ◽  
Coline Trichot ◽  
Lilith Faucheux ◽  
Iris Legbre ◽  
Maximilien Grandclaudon ◽  
...  
Keyword(s):  
Cellular Response ◽  
Immune Cell ◽  
Experimental System ◽  
Context Dependency ◽  
Modeling Framework ◽  
Th Cell ◽  
Ox40 Ligand ◽  
Context Dependent ◽  
Unique Framework ◽  
Modeling Strategy

AbstractCells receive, and adjust to, various stimuli, which function as part of complex microenvironments forming their “context”. The possibility that a given context impacts the response to a given stimulus defines “context-dependency” and it explains large parts of the functional variability of physiopathological and pharmacological stimuli. Currently, there is no framework to analyze and quantify context-dependency over multiple contexts and cellular response outputs. We established an experimental system including a stimulus of interest, applied to an immune cell type in several contexts. We studied the function of OX40 ligand (OX40L) on T helper (Th) cell differentiation, in 4 molecular (Th0, Th1, Th2, and Th17) and 11 dendritic cell (DC) contexts (monocyte-derived DC and cDC2 conditions). We measured 17 Th output cytokines in 302 observations, and developed a statistical modeling strategy to quantify OX40L context-dependency. This revealed highly variable context-dependency, depending on the output cytokine and context type itself. Among molecular contexts, Th2 was the most influential on OX40L function. Among DC contexts, the DC type rather than the activating stimuli was dominant in controlling OX40L context-dependency. This work mathematically formalizes the complex determinants of OX40L functionality, and provides a unique framework to decipher and quantify the context-dependent variability of any biomolecule or drug function.

Algorithmenkompatibles Verwaltungsrecht?

2021 ◽  
Vol 54 (2) ◽  
pp. 251-272
Author(s):  
Margrit Seckelmann
Keyword(s):  
Computer Code ◽  
Administrative Law ◽  
Context Dependency ◽  
New Paradigm ◽  
Starting Point ◽  
Context Dependent ◽  
Legal Meaning ◽  
Automatic Decisions

Die Übersetzung von Recht in (Computer–)‌Code ist derzeit in aller Munde. Lawrence Lessigs berühmtes Diktum, „Code is Law“ wird neuerdings dahingehend reformuliert, dass „Law“ auch „Code“ sei, dass man bei der Rechtsetzung also zugleich seine rechentechnische Umsetzbarkeit mitzudenken habe. Einen Ansatzpunkt für eine derartige „Algorithmisierbarkeit“ von Recht bietet § 35a des Verwaltungsverfahrensgesetzes des Bundes, wonach „automatisierte“ Entscheidungen in bestimmten Fällen zugelassen werden. Ein aktuelles Papier des Fraunhofer FOKUS-Instituts unter dem Titel „Recht Digital“ denkt dieses weiter und suggeriert, man müsse nur die passenden, eindeutigen Ausdrücke finden, dann sei Recht gleichsam „programmierbar“. Aber genau hier stellt sich das Problem: Rechtssprache ist eine Multi-Adressaten-Sprache, also eine Sprache, die sich ebenso sehr an ein Fachpublikum wie an Laien (Bürgerinnen und Bürger) wendet. Sie ist zudem kontextabhängig. Der aktuelle Hype um den Begriff der „Algorithmisierung“ von Gesetzen verbirgt zudem, dass es sich hierbei um ein Grundproblem von Rechtssprache handelt, das in den 1960er bis 1980er Jahren unter den Paradigmata „Rechts-/Verwaltungsautomation“ oder Rechtskybernetik verhandelt wurde. Wie kann man sich also dem Problem der Kontextabhängigkeit von Recht unter dem neuen Paradigma der Algorithmisierung nähern? Im Beitrag über „Algorithmenkompatibles Verwaltungsrecht? Juristische und sprachwissenschaftliche Überlegungen zu einer ‚Standardisierung von Rechtsbegriffen‘“ werden verschiedene Zugänge zur Schaffung einer „algorithmenkonformen“ Rechtssprache vorgestellt. Letztlich aber vermögen es noch so ausgefeilte technische Methoden nicht, das Problem demokratischer Deliberation zu verdrängen – über die fundamentalen Fragen einer Algorithmisierung der Rechtssprache muss der unmittelbar demokratisch legitimierte Gesetzgeber entscheiden. „Kontext“ und „Text“ geraten insoweit in ein wechselseitiges Abhängigkeitsverhältnis. The translation of law into (computer) code seems to be currently on everyone’s lips. Lawrence Lessigs’ famous dictum “Code is Law” has recently been rephrased saying that “Law” was also “Code”. This means that the wording of laws should directly take their “computer implementability” into consideration. A starting point for those postulations can be seen in the (relatively) new section 35a of the (Federal) Administrative Prodecure Act (Verwaltungsverfahrensgesetz), which allows “automatic” decisions in specific cases. A new paper of the Fraunhofer FOKUS institute takes this up and suggests that we have only to look for the appropriate, unambiguous term that corresponds with an unequivocal legal meaning. In doing so, law could be programmable. But this is exactly the point where the problem arises: laws have more than one addressee; they address lawyers as well as citizens (mostly laypeople). Furthermore, legal terminology is context dependent. The current hype regarding the “algorithmization” of legal terminology also hides the fact that this issue was – more or less – discussed once before under the paradigm “legal cybernetics” between 1960 and 1985. So how can we approach the problem of context-dependency of law under the new paradigm of algorithmization? In our contribution on “Algorithm-compatible administrative law? Legal and linguistic considerations concerning the ‘standardization’ of legal terminology”, we will introduce different approaches to safeguard the compatibility of law with computer technics. But how sophisticated a technical method can be: It is the democratically legitimised parliament that must make the fundamental decisions when it comes to an “algorithmization” of legal terminology, because there is no text without context.

Context-Dependent Modulation of Early Visual Cortical Responses to Numerical and Nonnumerical Magnitudes

2021 ◽  
pp. 1-12
Author(s):  
Joonkoo Park ◽  
Sonia Godbole ◽  
Marty G. Woldorff ◽  
Elizabeth M. Brannon
Keyword(s):  
Visual Processing ◽  
Context Dependency ◽  
Numerical Magnitude ◽  
Continuous Variables ◽  
Processing Stream ◽  
Cortical Responses ◽  
Early Visual Cortex ◽  
Context Dependent ◽  
Visual Cortical ◽  
The Brain

Abstract Whether and how the brain encodes discrete numerical magnitude differently from continuous nonnumerical magnitude is hotly debated. In a previous set of studies, we orthogonally varied numerical (numerosity) and nonnumerical (size and spacing) dimensions of dot arrays and demonstrated a strong modulation of early visual evoked potentials (VEPs) by numerosity and not by nonnumerical dimensions. Although very little is known about the brain's response to systematic changes in continuous dimensions of a dot array, some authors intuit that the visual processing stream must be more sensitive to continuous magnitude information than to numerosity. To address this possibility, we measured VEPs of participants viewing dot arrays that changed exclusively in one nonnumerical magnitude dimension at a time (size or spacing) while holding numerosity constant and compared this to a condition where numerosity was changed while holding size and spacing constant. We found reliable but small neural sensitivity to exclusive changes in size and spacing; however, changing numerosity elicited a much more robust modulation of the VEPs. Together with previous work, these findings suggest that sensitivity to magnitude dimensions in early visual cortex is context dependent: The brain is moderately sensitive to changes in size and spacing when numerosity is held constant, but sensitivity to these continuous variables diminishes to a negligible level when numerosity is allowed to vary at the same time. Neurophysiological explanations for the encoding and context dependency of numerical and nonnumerical magnitudes are proposed within the framework of neuronal normalization.

scholarly journals Chronic Occupational Mold Exposure Drives Expansion of Aspergillus-Reactive Type 1 and Type 2 T-Helper Cell Responses

2021 ◽  
Vol 7 (9) ◽  
pp. 698
Author(s):  
Chris D. Lauruschkat ◽  
Sonja Etter ◽  
Elisabeth Schnack ◽  
Frank Ebel ◽  
Sascha Schäuble ◽  
...  
Keyword(s):  
Immune Cell ◽  
Allergic Diseases ◽  
T Helper ◽  
Cell Repertoire ◽  
Cell Responses ◽  
Th Cell ◽  
Organic Farmers ◽  
Occupationally Exposed ◽  
Mold Exposure ◽  
Th1 And Th2

Occupational mold exposure can lead to Aspergillus-associated allergic diseases including asthma and hypersensitivity pneumonitis. Elevated IL-17 levels or disbalanced T-helper (Th) cell expansion were previously linked to Aspergillus-associated allergic diseases, whereas alterations to the Th cell repertoire in healthy occupationally exposed subjects are scarcely studied. Therefore, we employed functional immunoassays to compare Th cell responses to A. fumigatus antigens in organic farmers, a cohort frequently exposed to environmental molds, and non-occupationally exposed controls. Organic farmers harbored significantly higher A. fumigatus-specific Th-cell frequencies than controls, with comparable expansion of Th1- and Th2-cell frequencies but only slightly elevated Th17-cell frequencies. Accordingly, Aspergillus antigen-induced Th1 and Th2 cytokine levels were strongly elevated, whereas induction of IL-17A was minimal. Additionally, increased levels of some innate immune cell-derived cytokines were found in samples from organic farmers. Antigen-induced cytokine release combined with Aspergillus-specific Th-cell frequencies resulted in high classification accuracy between organic farmers and controls. Aspf22, CatB, and CipC elicited the strongest differences in Th1 and Th2 responses between the two cohorts, suggesting these antigens as potential candidates for future bio-effect monitoring approaches. Overall, we found that occupationally exposed agricultural workers display a largely balanced co-expansion of Th1 and Th2 immunity with only minor changes in Th17 responses.

scholarly journals The role of sublexical variables in reading fluency development among Spanish children

2018 ◽  
Vol 45 (4) ◽  
pp. 858-877 ◽  
Author(s):  
Marta ÁLVAREZ-CAÑIZO ◽  
Paz SUÁREZ-COALLA ◽  
Fernando CUETOS
Keyword(s):  
Reading Fluency ◽  
Repeated Exposure ◽  
Context Dependency ◽  
Orthographic Representation ◽  
New Words ◽  
Orthographic Representations ◽  
Syllabic Structure ◽  
Context Dependent

AbstractSeveral studies have found that, after repeated exposure to new words, children form orthographic representations that allow them to read those words faster and more fluently. However, these studies did not take into account variables related to the words. The aim of this study was to investigate the influence of sublexical variables on the formation of orthographic representations of words by Spanish children. The first experiment used pseudo-words of varying syllabic structure and syllabic frequency. The stimuli for the second experiment were formed with or without context-dependent graphemes. We found that formation of orthographic representations was influenced by syllabic structure (easier for words with simple syllabic structure) and the context-dependency of graphemes (easier in the absence of context-dependent graphemes), but not syllabic frequency. These results indicate that the easier it is to read a word, the easier it is to form an orthographic representation of it.

scholarly journals Human cells enter mitosis with damaged DNA after treatment with pharmacological concentrations of genotoxic agents

2012 ◽  
Vol 446 (3) ◽  
pp. 373-381 ◽  
Author(s):  
Philip M. Kubara ◽  
Sophie Kernéis-Golsteyn ◽  
Aurélie Studény ◽  
Brittany B. Lanser ◽  
Laurent Meijer ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cellular Response ◽  
Experimental System ◽  
Human Cells ◽  
Cyclin Dependent Kinase ◽  
Histone H2ax ◽  
Checkpoint Adaptation ◽  
Genotoxic Agents ◽  
G2 Phase ◽  
Damaged Dna

In the present paper, we report that mitosis is a key step in the cellular response to genotoxic agents in human cells. Cells with damaged DNA recruit γH2AX (phosphorylated histone H2AX), phosphorylate Chk1 (checkpoint kinase 1) and arrest in the G2-phase of the cell cycle. Strikingly, nearly all cells escape the DNA damage checkpoint and become rounded, by a mechanism that correlates with Chk1 dephosphorylation. The rounded cells are alive and in mitosis as measured by low phospho-Tyr15 Cdk1 (cyclin-dependent kinase 1), high Cdk activity, active Plk1 (Polo-like kinase 1) and high phospho-histone H3 signals. This phenomenon is independent of the type of DNA damage, but is dependent on pharmacologically relevant doses of genotoxicity. Entry into mitosis is likely to be caused by checkpoint adaptation, and the HT-29 cell-based model provides a powerful experimental system in which to explore its molecular basis. We propose that mitosis with damaged DNA is a biologically significant event because it may cause genomic rearrangement in cells that survive genotoxic damage.

scholarly journals Roles of activating functions 1 and 2 of estrogen receptor α in lymphopoiesis

2018 ◽  
Vol 236 (2) ◽  
pp. 99-109 ◽  
Author(s):  
Annica Andersson ◽  
Anna E Törnqvist ◽  
Sofia Moverare-Skrtic ◽  
Angelina I Bernardi ◽  
Helen H Farman ◽  
...  
Keyword(s):  
Immune System ◽  
B Cells ◽  
Estrogen Receptors ◽  
B Cell ◽  
Sex Steroids ◽  
Cellular Response ◽  
Immune Cell ◽  
Cell Development ◽  
B Lymphopoiesis ◽  
The Impact

Apart from the role of sex steroids in reproduction, sex steroids are also important regulators of the immune system. 17β-estradiol (E2) represses T and B cell development, but augments B cell function, possibly explaining the different nature of immune responses in men and women. Both E2 and selective estrogen receptors modulators (SERM) act via estrogen receptors (ER). Activating functions (AF)-1 and 2 of the ER bind to coregulators and thus influence target gene transcription and subsequent cellular response to ER activation. The importance of ERαAF-1 and AF-2 in the immunomodulatory effects of E2/SERM has previously not been reported. Thus, detailed studies of T and B lymphopoiesis were performed in ovariectomized E2-, lasofoxifene- or raloxifene-treated mice lacking either AF-1 or AF-2 domains of ERα, and their wild-type littermate controls. Immune cell phenotypes were analyzed with flow cytometry. All E2 and SERM-mediated inhibitory effects on thymus cellularity and thymic T cell development were clearly dependent on both ERαAFs. Interestingly, divergent roles of ERαAF-1 and ERαAF-2 in E2 and SERM-mediated modulation of bone marrow B lymphopoiesis were found. In contrast to E2, effects of lasofoxifene on early B cells did not require functional ERαAF-2, while ERαAF-1 was indispensable. Raloxifene reduced early B cells partly independent of both ERαAF-1 and ERαAF-2. Results from this study increase the understanding of the impact of ER modulation on the immune system, which can be useful in the clarification of the molecular actions of SERMs and in the development of new SERM.

scholarly journals Cellular Immune Response against Nontypeable Haemophilus influenzae Infecting the Preinflamed Middle Ear of the Junbo Mouse

2019 ◽  
Vol 87 (12) ◽  
Author(s):  
Pratik P. Vikhe ◽  
Tom Purnell ◽  
Steve D. M. Brown ◽  
Derek W. Hood
Keyword(s):  
Immune Response ◽  
Haemophilus Influenzae ◽  
Cell Population ◽  
Middle Ear ◽  
Cellular Immune Response ◽  
Cellular Response ◽  
Transforming Growth Factor ◽  
Immune Cell ◽  
Acute Otitis Media ◽  
Cellular Immune

ABSTRACT Nontypeable Haemophilus influenzae (NTHi) is a major pathogen causing acute otitis media (AOM). The pathology of AOM increases during long-term infection in the middle ear (ME), but the host cellular immune response to bacterial infection in this inflamed environment is poorly understood. Using the Junbo mouse, a characterized NTHi infection model, we analyzed the cellular response to NTHi infection in the Junbo mouse middle ear fluid (MEF). NTHi infection increased the total cell number and significantly decreased the proportion of live cells in the MEF at day 1, and this further decreased gradually on each day up to day 7. Flow cytometry analysis showed that neutrophils were the dominant immune cell population in the MEF and that NTHi infection significantly increased their proportion whereas it decreased the monocyte, macrophage, and dendritic cell proportions. Neutrophil and macrophage numbers increased in blood and spleen after NTHi infection. The T-cell population was dominated by T-helper (Th) cells in noninoculated MEF, and the effector Th (CD44+) cell population increased at day 2 of NTHi infection with an increase in IL-12p40 levels. Sustained NTHi infection up to 3 days increased the transforming growth factor β levels, decreasing the effector cell population and increasing the T-regulatory (T-reg) cell population. In the preinflamed ME environment of the Junbo mouse, neutrophils are the first responder to NTHi infection followed by T-reg immune suppressive cells. These data indicate that sustained NTHi infection in the ME induces the immune suppressive response by inducing the T-reg cell population and reducing immune cell infiltration, thus promoting longer-term infection.

scholarly journals Distinguishing neural correlates of context-dependent advantageous- and disadvantageous-inequity aversion

2018 ◽  
Vol 115 (33) ◽  
pp. E7680-E7689 ◽  
Author(s):  
Xiaoxue Gao ◽  
Hongbo Yu ◽  
Ignacio Sáez ◽  
Philip R. Blue ◽  
Lusha Zhu ◽  
...  
Keyword(s):  
Decision Making ◽  
Prefrontal Cortex ◽  
Computational Models ◽  
Social Contexts ◽  
Inequity Aversion ◽  
Context Dependency ◽  
Anterior Cingulate ◽  
Dorsal Anterior Cingulate Cortex ◽  
Decision Making Processes ◽  
Context Dependent

Humans can integrate social contextual information into decision-making processes to adjust their responses toward inequity. This context dependency emerges when individuals receive more (i.e., advantageous inequity) or less (i.e., disadvantageous inequity) than others. However, it is not clear whether context-dependent processing of advantageous and disadvantageous inequity involves differential neurocognitive mechanisms. Here, we used fMRI to address this question by combining an interactive game that modulates social contexts (e.g., interpersonal guilt) with computational models that enable us to characterize individual weights on inequity aversion. In each round, the participant played a dot estimation task with an anonymous coplayer. The coplayer would receive pain stimulation with 50% probability when either of them responded incorrectly. At the end of each round, the participant completed a variant of dictator game, which determined payoffs for him/herself and the coplayer. Computational modeling demonstrated the context dependency of inequity aversion: when causing pain to the coplayer (i.e., guilt context), participants cared more about the advantageous inequity and became more tolerant of the disadvantageous inequity, compared with other conditions. Consistently, neuroimaging results suggested the two types of inequity were associated with differential neurocognitive substrates. While the context-dependent processing of advantageous inequity was associated with social- and mentalizing-related processes, involving left anterior insula, right dorsolateral prefrontal cortex, and dorsomedial prefrontal cortex, the context-dependent processing of disadvantageous inequity was primarily associated with emotion- and conflict-related processes, involving left posterior insula, right amygdala, and dorsal anterior cingulate cortex. These results extend our understanding of decision-making processes related to inequity aversion.

scholarly journals OX40 ligand expressed by DCs costimulates NKT and CD4+ Th cell antitumor immunity in mice

2007 ◽  
Vol 117 (11) ◽  
pp. 3330-3338 ◽  
Author(s):  
Jamal Zaini ◽  
Sita Andarini ◽  
Minoru Tahara ◽  
Yasuo Saijo ◽  
Naoto Ishii ◽  
...  
Keyword(s):  
Antitumor Immunity ◽  
Th Cell ◽  
Ox40 Ligand

scholarly journals COVID-19 Lung Pathogenesis in SARS-CoV-2 Autopsy Cases

2021 ◽  
Vol 12 ◽  
Author(s):  
Silvana Valdebenito ◽  
Simon Bessis ◽  
Djillali Annane ◽  
Geoffroy Lorin de la Grandmaison ◽  
Elisabeth Cramer–Bordé ◽  
...  
Keyword(s):  
Immune Response ◽  
Cellular Response ◽  
Immune Cell ◽  
Systemic Disease ◽  
Lung Damage ◽  
Public Health Issue ◽  
Alveolar Wall ◽  
Lung Pathology ◽  
Strong Immune Response ◽  
Immune Infiltration

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major public health issue. COVID-19 is considered an airway/multi-systemic disease, and demise has been associated with an uncontrolled immune response and a cytokine storm in response to the virus. However, the lung pathology, immune response, and tissue damage associated with COVID-19 demise are poorly described and understood due to safety concerns. Using post-mortem lung tissues from uninfected and COVID-19 deadly cases as well as an unbiased combined analysis of histology, multi-viral and host markers staining, correlative microscopy, confocal, and image analysis, we identified three distinct phenotypes of COVID-19-induced lung damage. First, a COVID-19-induced hemorrhage characterized by minimal immune infiltration and large thrombus; Second, a COVID-19-induced immune infiltration with excessive immune cell infiltration but no hemorrhagic events. The third phenotype correspond to the combination of the two previous ones. We observed the loss of alveolar wall integrity, detachment of lung tissue pieces, fibroblast proliferation, and extensive fibrosis in all three phenotypes. Although lung tissues studied were from lethal COVID-19, a strong immune response was observed in all cases analyzed with significant B cell and poor T cell infiltrations, suggesting an exhausted or compromised immune cellular response in these patients. Overall, our data show that SARS-CoV-2-induced lung damage is highly heterogeneous. These individual differences need to be considered to understand the acute and long-term COVID-19 consequences.

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