A subpopulation (60–70%) of Foxp3+ T regulatory (Treg) cells in both mouse and man express the transcription factor, Helios, but the role of Helios in Treg function is still unknown. In order to examine the function of Helios in Treg cells, we have generated Treg-specific Helios deficient mice. We show here that this selective deletion of Helios in Tregs leads to slow, progressive systemic immune activation, hypergammaglobulinemia, and enhanced germinal center formation in the absence of organ specific autoimmunity. Helios deficient Treg suppressor function was normal in vitro as well as in an in vivo inflammatory bowel disease model. However, Helios deficient Treg cells failed to control the expansion of pathogenic T cells derived from scurfy mice and failed to mediate T follicular regulatory cell function and control both TFH and Th1 effector cell responses. In competitive settings, Helios deficient Tregs, particularly effector Tregs, were at a disadvantage, indicating that Helios regulates effector Treg fitness. Thus, we have demonstrated, for the first time, that Helios controls certain aspects of Treg suppressive function, differentiation and survival.

JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact support@jstor.org.. abstract: Parasite prevalence shows tremendous spatiotemporal variation. Theory indicates that this variation might stem from lifehistory characteristics of parasites and key ecological factors. Here, we illustrate how the interaction of an important predator and the schedule of transmission potential of two parasites can explain parasite abundance. A field survey showed that a noncastrating fungus (Metschnikowia bicuspidata) commonly infected a dominant zooplankton host (Daphnia dentifera), while a castrating bacterial parasite (Pasteuria ramosa) was rare. This result seemed surprising given that the bacterium produces many more infectious propagules (spores) than the fungus upon host death. The fungus's dominance can be explained by the schedule of within-host growth of parasites (i.e., how transmission potential changes over the course of infection) and the release of spores from "sloppy" predators (Chaoborus spp., who consume Daphnia prey whole and then later regurgitate the carapace and parasite spores). In essence, sloppy predators create a niche that the faster-schedule fungus currently occupies. However, a selection experiment showed that the slower-schedule bacterium can evolve into this faster-schedule, predator-mediated niche (but pays a cost in maximal spore yield to do so). Hence, our study shows how parasite life history can interact with predation to strongly influence the ecology, epidemiology, and evolution of infectious disease.

and the Inovitro system from Novocure to support parts of the work reported here. The conceptualization, design, data collection, analysis, interpretation, decision to publish and manuscript preparation were performed by the authors independent of Novocure. D.C. and D.D.T. are inventors of 2 patent applications (63172862 and 63015093) based on the data. All rights were 2 transferred to Novocure. D.D.T. has received research funding in the last 12 months from Merck, Sarepta, and Lacerta for unrelated works. Other co-authors have declared no conflict of interest.

Cancer vaccines initiate antitumor responses in a subset of patients, but the lack of clinically meaningful biomarkers to predict treatment response limits their development. Here, we design multifunctional RNA-loaded magnetic liposomes to initiate potent antitumor immunity and function as an early biomarker of treatment response. These particles activate dendritic cells (DCs) more effectively than electroporation, leading to superior inhibition of tumor growth in treatment models. Inclusion of iron oxide enhances DC transfection and enables tracking of DC migration with magnetic resonance imaging (MRI). We show that T 2*-weighted MRI intensity in lymph nodes is a strong correlation of DC trafficking and is an early predictor of antitumor response. In preclinical tumor models, MRI-predicted “responders” identified 2 days after vaccination had significantly smaller tumors 2–5 weeks after treatment and lived 73% longer than MRI-predicted “nonresponders”. These studies therefore provide a simple, scalable nanoparticle formulation to generate robust antitumor immune responses and predict individual treatment outcome with MRI.

With improving biofabrication technology, 3D bioprinted constructs increasingly resemble real tissues. However, the fundamental principles describing how cell-generated forces within these constructs drive deformations, mechanical instabilities, and structural failures have not been established, even for basic biofabricated building blocks. Here we investigate mechanical behaviours of 3D printed microbeams made from living cells and extracellular matrix, bioprinting these simple structural elements into a 3D culture medium made from packed microgels, creating a mechanically controlled environment that allows the beams to evolve under cell-generated forces. By varying the properties of the beams and the surrounding microgel medium, we explore the mechanical behaviours exhibited by these structures. We observe buckling, axial contraction, failure, and total static stability, and we develop mechanical models of cell-ECM microbeam mechanics. We envision these models and their generalizations to other fundamental 3D shapes to facilitate the predictable design of biofabricated structures using simple building blocks in the future.

We synthesized an efficient dual-directional multivalent pyrenebearing azaphthalocyanine conjugate (AzaPc−pyrene) and alkyne-terminated azaphthalocyanine (AzaPc1). The ultrafast nonlinear optical characteristics of these macrocycles were studied using a near-infrared femtosecond (fs) Z-scan experiment. The results for these Pc solutions showed good nonlinear optical coefficients, low optical limiting threshold (38 mJ/cm 2 ), and a good set of figures of merit that satisfied the criteria for optical switching materials, thus proving their usefulness in photonic applications. Comparison with other phthalocyanines showed that both AzaPc−pyrene and AzaPc1 are strong nonlinear optical materials. The most important outcome of our study was a huge enhancement in the nonlinear absorption value of AzaPc−pyrene in the film phase that was up to 10 5 times greater than the corresponding values for AzaPc1 solutions; this enhancement was established using ultrafast laser irradiation-induced deformations in AzaPc−pyrene-embedded PMMA films, whereas the AzaPc1 film showed saturable absorption behavior. A promising limiting threshold of 1.5 mJ/cm 2 with very low linear absorption was achieved in the deformed pyrene-incorporated AzaPc films; this is lower than the previously reported values for highly nonlinear materials, making these materials as potential nonlinear optical materials in the near-infrared wavelength range.

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METHODS. Nonobese (BMI 22-25 kg/m 2) and obese participants (BMI ≥30 kg/m 2) were given a single dose of PPSV23. Blood was drawn immediately prior to and 4-6 weeks after vaccination. Serum samples were used to assess PPSV23-specific antibodies. STING1 genotypes were identified using PCR on DNA extracted from peripheral blood samples. RESULTS. Forty-six participants were categorized as nonobese (n = 23; 56.5% women; mean BMI 23.3 kg/m 2) or obese (n = 23; 65.2% women; mean BMI 36.3 kg/m 2). Obese participants had an elevated fold change in vaccine-specific responses compared with nonobese participants (P < 0.0001). The WT STING1 group (R232/R232) had a significantly higher PPSV23 response than individuals with a single copy of HAQ-STING1 regardless of BMI (P = 0.0025). When WT was assessed alone, obese participants had a higher fold serotype-specific response compared with nonobese participants (P < 0.0001), but no difference was observed between obese and nonobese individuals with 1 HAQ allele (P = 0.693). CONCLUSIONS. These observations demonstrate a positive association between obesity and PPSV23 efficacy specifically in participants with the WT STING1 genotype. TRIAL REGISTRATION. ClinicalTrials.gov NCT02471014.