TARDIS: A Foundation of Time-Lock Puzzles in UC

Time-based primitives like time-lock puzzles (TLP) are finding widespread use in practical protocols, partially due to the surge of interest in the blockchain space where TLPs and related primitives are perceived to solve many problems. Unfortunately, the security claims are often shaky or plainly wrong since these primitives are used under composition. One reason is that TLPs are inherently not UC secure and time is tricky to model and use in the UC model. On the other hand, just specifying standalone notions of the intended task, left alone correctly using standalone notions like non-malleable TLPs only, might be hard or impossible for the given task. And even when possible a standalone secure primitive is harder to apply securely in practice afterwards as its behavior under composition is unclear. The ideal solution would be a model of TLPs in the UC framework to allow simple modular proofs. In this paper we provide a foundation for proving composable security of practical protocols using time-lock puzzles and related timed primitives in the UC model. We construct UC-secure TLPs based on random oracles and show that using random oracles is necessary. In order to prove security, we provide a simple and abstract way to reason about time in UC protocols. Finally, we demonstrate the usefulness of this foundation by constructing applications that are interesting in their own right, such as UC-secure two-party computation with output-independent abort

Three distinct developmental pathways for adaptive and two IFN-γ-producing γδ T subsets in adult thymus

Mouse γδ T cells have diverse functional subsets, but how these subsets are programmed during their development is still unclear. Here the authors show that three surface markers, CD117, CD200 and CD371, refine the development of γδ T cells in the thymus into three pathways programming distinct γδ T cell subsets

CRAFT: Composable Randomness Beacons and Output-Independent Abort MPC From Time

Recently, time-based primitives such as time-lock puzzles (TLPs) and verifiable delay functions (VDFs) have received a lot of attention due to their power as building blocks for cryptographic protocols. However, even though exciting improvements on their efficiency and security (e.g. achieving non-malleability) have been made, most of the existing constructions do not offer general composability guarantees and thus have limited applicability. Baum et al. (EUROCRYPT 2021) presented in TARDIS the first (im)possibility results on constructing TLPs with Universally Composable (UC) security and an application to secure two-party computation with output-independent abort (OIA-2PC), where an adversary has to decide to abort before learning the output. While these results establish the feasibility of UC-secure TLPs and applications, they are limited to the two-party scenario and suffer from complexity overheads. In this paper, we introduce the first UC constructions of VDFs and of the related notion of publicly verifiable TLPs (PV-TLPs). We use our new UC VDF to prove a folklore result on VDF-based randomness beacons used in industry and build an improved randomness beacon from our new UC PV-TLPs. We moreover construct the first multiparty computation protocol with punishable output-independent aborts (POIA-MPC), i.e. MPC with OIA and financial punishment for cheating. Our novel POIA-MPC both establishes the feasibility of (non-punishable) OIA-MPC and significantly improves on the efficiency of state-of-the-art OIA-2PC and (non-OIA) MPC with punishable aborts

CRAFT: Composable Randomness Beacons and Output-Independent Abort MPC From Time

Recently, time-based primitives such as time-lock puzzles (TLPs) and verifiable delay functions (VDFs) have received a lot of attention due to their power as building blocks for cryptographic protocols. However, even though exciting improvements on their efficiency and security (e.g. achieving non-malleability) have been made, most of the existing constructions do not offer general composability guarantees and thus have limited applicability. Baum et al. (EUROCRYPT 2021) presented in TARDIS the first (im)possibility results on constructing TLPs with Universally Composable (UC) security and an application to secure two party computation with output-independent abort (OIA-2PC), where an adversary has to decide to abort before learning the output. While these results establish the feasibility of UC-secure TLPs and applications, they are limited to the two-party scenario and suffer from complexity overheads. In this paper, we introduce the first UC constructions of VDFs and of the related notion of publicly verifiable TLPs (PV-TLPs). We use our new UC VDF to prove a folklore result on VDF-based randomness beacons used in industry and build an improved randomness beacon from our new UC PV-TLPs. We moreover construct the first multiparty computation protocol with punishable output-independent aborts (POIA MPC), i.e. MPC with OIA and financial punishment for cheating. Our novel POIA-MPC both establishes the feasibility of (non-punishable) OIA-MPC and significantly improves on the efficiency of state-of-the-art OIA-2PC and (non-OIA) MPC with punishable aborts

IgG and IgM cooperate in coating of intestinal bacteria in IgA deficiency

Immunoglobulin A (IgA) is acknowledged to play a role in the defence of the mucosal barrier by coating microorganisms. Surprisingly, IgA-deficient humans exhibit few infection-related complications, raising the question if the more specific IgG may help IgM in compensating for the lack of IgA. Here we employ a cohort of IgA-deficient humans, each paired with IgA-sufficient household members, to investigate multi-Ig bacterial coating. In IgA-deficient humans, IgM alone, and together with IgG, recapitulate coating of most bacterial families, despite an overall 3.6-fold lower Ig-coating. Bacterial IgG coating is dominated by IgG1 and IgG4. Single-IgG2 bacterial coating is sparse and linked to enhanced Escherichia coli load and TNF-α. Although single-IgG2 coating is 1.6-fold more prevalent in IgA deficiency than in healthy controls, it is 2-fold less prevalent than in inflammatory bowel disease. Altogether we demonstrate that IgG assists IgM in coating of most bacterial families in the absence of IgA and identify single-IgG2 bacterial coating as an inflammatory marker.</p

MicroRNAs in the pathogenesis, diagnosis, prognosis and targeted treatment of cutaneous T-cell lymphomas

Cutaneous T-cell lymphoma (CTCL) represents a heterogeneous group of potentially devastating primary skin malignancies. Despite decades of intense research efforts, the pathogenesis is still not fully understood. In the early stages, both clinical and histopathological diagnosis is often difficult due to the ability of CTCL to masquerade as benign skin inflammatory dermatoses. Due to a lack of reliable biomarkers, it is also difficult to predict which patients will respond to therapy or progress towards severe recalcitrant disease. In this review, we discuss recent discoveries concerning dysregulated microRNA (miR) expression and putative pathological roles of oncogenic and tumor suppressive miRs in CTCL. We also focus on the interplay between miRs, histone deacetylase inhibitors, and oncogenic signaling pathways in malignant T cells as well as the impact of miRs in shaping the inflammatory tumor microenvironment. We highlight the potential use of miRs as diagnostic and prognostic markers, as well as their potential as therapeutic targets. Finally, we propose that the combined use of miR-modulating compounds with epigenetic drugs may provide a novel avenue for boosting the clinical efficacy of existing anti-cancer therapies in CTCL

<i>Staphylococcus aureus</i> enterotoxins induce FOXP3 in neoplastic T cells in Sézary syndrome

Sezary syndrome (SS) is a heterogeneous leukemic subtype of cutaneous T-cell lymphoma (CTCL) with generalized erythroderma, lymphadenopathy, and a poor prognosis. Advanced disease is invariably associated with severe immune dysregulation and the majority of patients die from infectious complications caused by microorganisms such as, Staphylococcus aureus, rather than from the lymphoma per se. Here, we examined if staphylococcal enterotoxins (SE) may shape the phenotype of malignant SS cells, including expression of the regulatory T-cell-associated marker FOXP3. Our studies with primary and cultured malignant cells show that SE induce expression of FOXP3 in malignant cells when exposed to nonmalignant cells. Mutations in the MHC class II binding domain of SE-A (SEA) largely block the effect indicating that the response relies at least in part on the MHC class II-mediated antigen presentation. Transwell experiments show that the effect is induced by soluble factors, partly blocked by anti-IL-2 antibody, and depends on STAT5 activation in malignant cells. Collectively, these findings show that SE stimulate nonmalignant cells to induce FOXP3 expression in malignant cells. Thus, differences in exposure to environmental factors, such as bacterial toxins may explain the heterogeneous FOXP3 expression in malignant cells in SS.Dermatology-oncolog

Increased Production of IL-17A-Producing γδ T Cells in the Thymus of Filaggrin-Deficient Mice

Mutations in the filaggrin gene (Flg) are associated with increased systemic levels of Th17 cells and increased IL-17A production following antigen exposure in both humans and mice. In addition to Th17 cells, γδ T cells can produce IL-17A. The differentiation of γδ T cells to either IFNγ or IL-17A-producing (γδT17) cells is mainly determined in the thymus. Interestingly, it has been reported that filaggrin is expressed in the Hassall bodies in the human thymic medulla. However, whether filaggrin affects γδ T cell development is not known. Here, we show that filaggrin-deficient flaky tail (ft/ft) mice have an increased number of γδT17 cells in the spleen, epidermis, and thymus compared to wild-type (WT) mice. We demonstrate that filaggrin is expressed in the mouse thymic medulla and that blocking the egress of cells from the thymus results in accumulation of Vγ2+ γδT17 cells in the thymus of adult ft/ft mice. Finally, we find increased T cell receptor expression levels on γδ T cells and increased levels of IL-6 and IL-23 in the thymus of ft/ft mice. These findings demonstrate that filaggrin is expressed in the mouse thymic medulla and that production of Vγ2+ γδT17 cells is dysregulated in filaggrin-deficient ft/ft mice