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Background: The experimental fusion protein rFlaA:Betv1 was shown to efficiently suppress allergen‐specific sensitization in mice. However, the detailed mechanism of rFlaA:Betv1‐mediated immune modulation is not fully understood. In this study, we investigated the effect of rFlaA:Betv1 on naïve murine B cells. Methods: Immune modulating capacity of rFlaA:Betv1 was screened in IL‐10 reporter mice. B cells were isolated from spleens of naïve C57Bl/6, TLR5−/−, or MyD88−/− mice, stimulated with rFlaA:Betv1 and controls, and monitored for the expression of the regulatory B cell markers CD1d, CD24, CD38, and surface IgM by flow cytometry. Secreted cytokines, antibodies, and reactivity of the induced antibodies were investigated by ELISA and intracellular flow cytometry. Suppressive capacity of rFlaA:Betv1‐stimulated B cells was tested in mDC:CD4+ T cell:B cell triple cultures. Results: Upon in vivo application of rFlaA:Betv1 into IL‐10‐GFP reporter mice, CD19+ B cells were shown to produce anti‐inflammatory IL‐10, suggesting B cells to contribute to the immune‐modulatory properties of rFlaA:Betv1. rFlaA:Betv1‐induced IL‐10 secretion was confirmed in human B cells isolated from buffy coats. In vitro stimulation of naïve murine B cells with rFlaA:Betv1 resulted in an mTOR‐ and MyD88‐dependent production of IL‐10 and rFlaA:Betv1 induced Bet v 1‐reactive IgG production, which was not observed for IgA. rFlaA:Betv1‐stimulated B cells formed a CD19+CD24+CD1d+IgM+CD38+ Breg subpopulation capable of suppressing Bet v 1‐induced TH2 cytokine secretion in vitro. Conclusion: rFlaA:Betv1 can act as a thymus‐independent B cell antigen, stimulating the mTOR‐ and MyD88‐dependent differentiation of B cells displaying a regulatory phenotype, IL‐10 secretion, antigen‐binding antibody production, and a suppressive capacity in vitro. [ABSTRACT FROM AUTHOR]

Abstract Background We consider the following problem: Given an undirected network and a set of sender-receiver pairs, direct all edges such that the maximum number of "signal flows" defined by the pairs can be routed respecting edge directions. This problem has applications in understanding protein interaction based cell regulation mechanisms. Since this problem is NP-hard, research so far concentrated on polynomial-time approximation algorithms and tractable special cases. Results We take the viewpoint of parameterized algorithmics and examine several parameters related to the maximum signal flow over vertices or edges. We provide several fixed-parameter tractability results, and in one case a sharp complexity dichotomy between a linear-time solvable case and a slightly more general NP-hard case. We examine the value of these parameters for several real-world network instances. Conclusions Several biologically relevant special cases of the NP-hard problem can be solved to optimality. In this way, parameterized analysis yields both deeper insight into the computational complexity and practical solving strategies.

The complexity of variants of 3 -SAT and Not-All-Equal 3 -SAT is well studied. However, in contrast, very little is known about the complexity of the problems' quantified counterparts. In the first part of this paper, we show that ∀∃ 3 -SAT is Π 2 P -complete even if (1) each variable appears exactly twice unnegated and exactly twice negated, (2) each clause is a disjunction of exactly three distinct variables, and (3) the number of universal variables is equal to the number of existential variables. Furthermore, we show that the problem remains Π 2 P -complete if (1a) each universal variable appears exactly once unnegated and exactly once negated, (1b) each existential variable appears exactly twice unnegated and exactly twice negated, and (2) and (3) remain unchanged. On the other hand, the problem becomes NP-complete for certain variants in which each universal variable appears exactly once. In the second part of the paper, we establish Π 2 P -completeness for ∀∃ Not-All-Equal 3 -SAT even if (1′) the Boolean formula is linear and monotone, (2′) each universal variable appears exactly once and each existential variable appears exactly three times, and (3′) each clause is a disjunction of exactly three distinct variables that contains at most one universal variable. On the positive side, we uncover variants of ∀∃ Not-All-Equal 3 -SAT that are co-NP-complete or solvable in polynomial time. [ABSTRACT FROM AUTHOR]

Allergen specific tolerance induction efficiently ameliorates subsequent allergen induced inflammatory responses. The underlying regulatory mechanisms have been attributed mainly to interleukin (IL)‐10 produced by diverse hematopoietic cells, while targets of IL‐10 in allergen specific tolerance induction have not yet been well defined. Here, we investigate potential cellular targets of IL‐10 in allergen specific tolerance induction using mice with a cell type specific inactivation of the IL‐10 receptor gene. Allergic airway inflammation was effectively prevented by tolerance induction in mice with IL‐10 receptor (IL‐10R) deficiency in T or B cells. Similarly, IL‐10R on monocytes/macrophages and/or neutrophils was not required for tolerance induction. In contrast, tolerance induction was impaired in mice that lack IL‐10R on dendritic cells: those mice developed an allergic response characterized by a pronounced neutrophilic lung infiltration, which was not ameliorated by tolerogenic treatment. In conclusion, our results show that allergen specific tolerance can be effectively induced without a direct impact of IL‐10 on cells of the adaptive immune system, and highlight dendritic cells, but not macrophages nor neutrophils, as the main target of IL‐10 during tolerance induction. IL‐10 signaling is crucial for tolerance induction in a murine model of allergic airway inflammation. Here we examined the targets of IL‐10 by using cell type specific IL‐10 receptor depleted mice. An amelioration of allergic airway inflammation after tolerance induction was observed when IL‐10R was depleted on T cells, B cells, monocytes/ macrophage, and neutrophils, but no tolerance induction could be observed in mice that lack IL‐10R on dendritic cells. These results reveal a fundamental role of IL‐10 signaling in dendritic cells during tolerance induction in allergic airway inflammation. [ABSTRACT FROM AUTHOR]

The prominent Boolean formula satisfiability problem SAT is known to be 𝒩 𝒫 -complete even for very restricted variants such as 3-SAT, Monotone 3-SAT, or Planar 3-SAT, or instances with bounded variable appearance. We settle the computational complexity status for two variants with bounded variable appearance: We show that Planar Monotone Sat — the variant of Monotone Sat in which the incidence graph is required to be planar — is 𝒩 𝒫 -complete even if each clause consists of at most three distinct literals and each variable appears exactly three times, and that Monotone Sat is 𝒩 𝒫 -complete even if each clause consists of three distinct literals and each variable appears exactly four times in the formula. The latter confirms a conjecture stated in scribe notes [7] of an MIT lecture by Eric Demaine. In addition, we provide hardness results with respect to bounded variable appearances for two variants of Planar Monotone Sat. [ABSTRACT FROM AUTHOR]

Regulatory mechanisms initiated by allergen-specific immunotherapy are mainly attributed to T cell derived IL-10. However, it has not been shown that T cell derived IL-10 is required for successful tolerance induction (TI). Here, we analyze cellular sources and the functional relevance of cell type specific IL-10 during TI in a murine model of allergic airway inflammation. While TI was effective in IL-10 competent mice, neutralizing IL-10 prior to tolerogenic treatment completely abrogated the beneficial effects. Cellular sources of IL-10 during TI were identified by using transcriptional reporter mice as T cells, B cells, and to a lesser extent DCs. Interestingly, TI was still effective in mice with T cell, B cell, B and T cell, or DC-specific IL-10 deficiency. In contrast, TI was not possible in mice lacking IL-10 in all hematopoetic cells, while it was effective in bone marrow (BM) chimera that lacked IL-10 only in nonhematopoetic cells. Taken together, allergen-specific tolerance depends on IL-10 from hematopoetic sources. The beneficial effects of allergen-specific immunotherapy cannot solely be attributed to IL-10 from T cells, B cells, or even DCs, suggesting a high degree of cellular redundancy in IL-10-mediated tolerance. [ABSTRACT FROM AUTHOR]

Interleukin 10 ( IL-10) has been implied in the regulation of allergic contact dermatitis. Using transcriptional reporter mice we analyzed cellular sources of IL-10 during contact hypersensitivity ( CHS) and identified IL-10 expressing CD8+ T cells in the skin that are antigen-specific, display PD-1, an effector memory phenotype, and IL-10 expression comparable to that of CD4+ T cells. However, in mice with a selective IL-10 deficiency in CD8+ T cells CHS responses were comparable to that of controls, even in the absence of CD4+ cells, suggesting that CD8+ T cell-derived IL-10 does not contribute significantly to the resolution of CHS responses. [ABSTRACT FROM AUTHOR]

We consider a linear transport equation on the edges of a network with time-varying coefficients. Using methods for non-autonomous abstract Cauchy problems, we obtain well-posedness of the problem and describe the asymptotic profile of the solutions under certain natural conditions on the network. We further apply our theory to a model used for air traffic flow management. [ABSTRACT FROM AUTHOR]

Abstract: To make a joint decision, agents (or voters) are often required to provide their preferences as linear orders. To determine a winner, the given linear orders can be aggregated according to a voting protocol. However, in realistic settings, the voters may often only provide partial orders. This directly leads to the Possible Winner problem that asks, given a set of partial votes, whether a distinguished candidate can still become a winner. In this work, we consider the computational complexity of Possible Winner for the broad class of voting protocols defined by scoring rules. A scoring rule provides a score value for every position which a candidate can have in a linear order. Prominent examples include plurality, k-approval, and Borda. Generalizing previous NP-hardness results for some special cases, we settle the computational complexity for all but one scoring rule. More precisely, for an unbounded number of candidates and unweighted voters, we show that Possible Winner is NP-complete for all pure scoring rules except plurality, veto, and the scoring rule defined by the scoring vector , while it is solvable in polynomial time for plurality and veto. [ABSTRACT FROM AUTHOR]

The expression of E-cadherin on Langerhans cells (LC) is required for adequate dendrite intercalation between epidermal keratinocytes. Upon disruption of epidermal homeostasis by tape stripping, E-cadherin competent LC extend dendrites reaching up to the epidermal surface, while E-cad deficient LC lack this ability., (© 2024 The Authors. European Journal of Immunology published by Wiley‐VCH GmbH.)

Proteins are dynamic entities that intermittently depart from their ground-state structures and undergo conformational transitions as a critical part of their functions. Central to understanding such transitions are the structural rearrangements along the connecting pathway, where the transition state plays a special role. Using NMR relaxation at variable temperature and pressure to measure aromatic ring flips inside a protein core, we obtain information on the structure and thermodynamics of the transition state. We show that the isothermal compressibility coefficient of the transition state is similar to that of short-chain hydrocarbon liquids, implying extensive local unfolding of the protein. Our results further indicate that the required local volume expansions of the protein can occur not only with a net positive activation volume of the protein, as expected from previous studies, but also with zero activation volume by compaction of remote void volume, when averaged over the ensemble of states., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Background: We consider the following problem: Given an undirected network and a set of sender-receiver pairs, direct all edges such that the maximum number of "signal flows" defined by the pairs can be routed respecting edge directions. This problem has applications in understanding protein interaction based cell regulation mechanisms. Since this problem is NP-hard, research so far concentrated on polynomial-time approximation algorithms and tractable special cases., Results: We take the viewpoint of parameterized algorithmics and examine several parameters related to the maximum signal flow over vertices or edges. We provide several fixed-parameter tractability results, and in one case a sharp complexity dichotomy between a linear-time solvable case and a slightly more general NP-hard case. We examine the value of these parameters for several real-world network instances., Conclusions: Several biologically relevant special cases of the NP-hard problem can be solved to optimality. In this way, parameterized analysis yields both deeper insight into the computational complexity and practical solving strategies.