Regulatory T cell-derived IL-1Ra suppresses the innate response to respiratory viral infection.

Regulatory T (Treg) cell modulation of adaptive immunity and tissue homeostasis is well described; however, less is known about Treg cell-mediated regulation of the innate immune response. Here we show that deletion of ST2, the receptor for interleukin (IL)-33, on Treg cells increased granulocyte influx into the lung and increased cytokine production by innate lymphoid and γδ T cells without alteration of adaptive immunity to influenza. IL-33 induced high levels of the interleukin-1 receptor antagonist (IL-1Ra) in ST2+ Treg cells and deletion of IL-1Ra in Treg cells increased granulocyte influx into the lung. Treg cell-specific deletion of ST2 or IL-1Ra improved survival to influenza, which was dependent on IL-1. Adventitial fibroblasts in the lung expressed high levels of the IL-1 receptor and their chemokine production was suppressed by Treg cell-produced IL-1Ra. Thus, we define a new pathway where IL-33-induced IL-1Ra production by tissue Treg cells suppresses IL-1-mediated innate immune responses to respiratory viral infection.

CD4 Effector TCR Avidity for Peptide on APC Determines the Level of Memory Generated.

Initial TCR affinity for peptide Ag is known to impact the generation of memory; however, its contributions later, when effectors must again recognize Ag at 5-8 d postinfection to become memory, is unclear. We examined whether the effector TCR affinity for peptide at this "effector checkpoint" dictates the extent of memory and degree of protection against rechallenge. We made an influenza A virus nucleoprotein (NP)-specific TCR transgenic mouse strain, FluNP, and generated NP-peptide variants that are presented by MHC class II to bind to the FluNP TCR over a broad range of avidity. To evaluate the impact of avidity in vivo, we primed naive donor FluNP in influenza A virus-infected host mice, purified donor effectors at the checkpoint, and cotransferred them with the range of peptides pulsed on activated APCs into second uninfected hosts. Higher-avidity peptides yielded higher numbers of FluNP memory cells in spleen and most dramatically in lung and draining lymph nodes and induced better protection against lethal influenza infection. Avidity determined memory cell number, not cytokine profile, and already impacted donor cell number within several days of transfer. We previously found that autocrine IL-2 production at the checkpoint prevents default effector apoptosis and supports memory formation. Here, we find that peptide avidity determines the level of IL-2 produced by these effectors and that IL-2Rα expression by the APCs enhances memory formation, suggesting that transpresentation of IL-2 by APCs further amplifies IL-2 availability. Secondary memory generation was also avidity dependent. We propose that this regulatory pathway selects CD4 effectors of highest affinity to progress to memory.

Strong influenza-induced TFH generation requires CD4 effectors to recognize antigen locally and receive signals from continuing infection.

While influenza infection induces robust, long-lasting, antibody responses and protection, including the T follicular helper cells (TFH) required to drive B cell germinal center (GC) responses, most influenza vaccines do not. We investigated the mechanisms that drive strong TFH responses during infection. Infection induces viral replication and antigen (Ag) presentation lasting through the CD4 effector phase, but Ag and pathogen recognition receptor signals are short-lived after vaccination. We analyzed the need for both infection and Ag presentation at the effector phase, using an in vivo sequential transfer model to time their availability. Differentiation of CD4 effectors into TFH and GC-TFH required that they recognize Ag locally in the site of TFH development, at the effector phase, but did not depend on specific Ag-presenting cells (APCs). In addition, concurrent signals from infection were necessary even when sufficient Ag was presented. Providing these signals with a second dose of live attenuated influenza vaccine at the effector phase drove TFH and GC-TFH development equivalent to live infection. The results suggest that vaccine approaches can induce strong TFH development that supports GC responses akin to infection, if they supply these effector phase signals at the right time and site. We suggest that these requirements create a checkpoint that ensures TFH only develop fully when infection is still ongoing, thereby avoiding unnecessary, potentially autoimmune, responses.

Durable CD4 T-Cell Memory Generation Depends on Persistence of High Levels of Infection at an Effector Checkpoint that Determines Multiple Fates.

We have discovered that the determination of CD4 effector and memory fates after infection is regulated not only by initial signals from antigen and pathogen recognition, but also by a second round of such signals at a checkpoint during the effector response. Signals to effectors determine their subsequent fate, inducing further progression to tissue-restricted follicular helpers, cytotoxic CD4 effectors, and long-lived memory cells. The follicular helpers help the germinal center B-cell responses that give rise to high-affinity long-lived antibody responses and memory B cells that synergize with T-cell memory to provide robust long-lived protection. We postulate that inactivated vaccines do not provide extended signals from antigen and pathogen beyond a few days, and thus elicit ineffective CD4 T- and B-cell effector responses and memory. Defining the mechanisms that underlie effective responses should provide insights necessary to develop vaccine strategies that induce more effective and durable immunity.

Introducing the 21st Century's New Four Horsemen of the Coronapocalypse.

As the world struggles through the COVID-19 pandemic, we should also be asking what systems-level measures will be needed to prevent this or even worse disasters from happening in the future. We argue that the pandemic is merely one of potentially myriad and pleiomorphic future global disasters generated by the same underlying dynamical system. We explain that there are four broad but easily identifiable systemic, pathologically networked conditions that are hurtling civilization toward potential self-destruction. As long as these conditions are not resolved, we should consider catastrophe as an inevitable emergent endpoint from the dynamics. All four conditions can be reversed with collective action to begin creating an enduring and thriving post- COVID-19 world. This will require maximal application of the precautionary principle.

Synaptic Pruning in Schizophrenia: Does Minocycline Modulate Psychosocial Brain Development?

Recent studies suggest that the tetracycline antibiotic minocycline, or its cousins, hold therapeutic potential for affective and psychotic disorders. This is proposed on the basis of a direct effect on microglia-mediated frontocortical synaptic pruning (FSP) during adolescence, perhaps in genetically susceptible individuals harboring risk alleles in the complement component cascade that is involved in this normal process of CNS circuit refinement. In reviewing this field, it is argued that minocycline is actually probing and modulating a deeply evolved and intricate system wherein psychosocial stimuli sculpt the circuitry of the "social brain" underlying adult behavior and personality. Furthermore, this system can generate psychiatric morbidity that is not dependent on genetic variation. This view has important ramifications for understanding "pathologies" of human social behavior and cognition as well as providing long-sought potential mechanistic links between social experience and susceptibility to mental and physical disease.

Paradoxical Survival: Examining the Parrondo Effect across Biology.

Parrondo's paradox, in which losing strategies can be combined to produce winning outcomes, has received much attention in mathematics and the physical sciences; a plethora of exciting applications has also been found in biology at an astounding pace. In this review paper, the authors examine a large range of recent developments of Parrondo's paradox in biology, across ecology and evolution, genetics, social and behavioral systems, cellular processes, and disease. Intriguing connections between numerous works are identified and analyzed, culminating in an emergent pattern of nested recurrent mechanics that appear to span the entire biological gamut, from the smallest of spatial and temporal scales to the largest-from the subcellular to the complete biosphere. In analyzing the macro perspective, the pivotal role that the paradox plays in the shaping of biological life becomes apparent, and its identity as a potential universal principle underlying biological diversity and persistence is uncovered. Directions for future research are also discussed in light of this new perspective.

Black Swans of CRISPR: Stochasticity and Complexity of Genetic Regulation.

Recent waves of controversies surrounding genetic engineering have spilled into popular science in Twitter battles between reputable scientists and their followers. Here, a cautionary perspective on the possible blind spots and risks of CRISPR and related biotechnologies is presented, focusing in particular on the stochastic nature of cellular control processes.

The acute medical unit model: A characterisation based upon the National Health Service in Scotland.

BACKGROUND: Acute medical units (AMUs) receive the majority of acute medical patients presenting to hospital as an emergency in the United Kingdom (UK) and in other international settings. They have emerged as a result of local service innovation in the context of a limited evidence base. As such, the AMU model is not well characterised in terms of its boundaries, patient populations and components of care. This makes service optimisation and development through strategic resource planning, quality improvement and research challenging. AIM: This study aims to evaluate a national set of AMUs with the intent of characterising the AMU model. METHODS: Twenty-nine AMUs in Scotland were identified. Data were collected by semi-structured interviews with multidisciplinary healthcare professionals working in each AMU. A draft report was produced for each unit and verified by a unit representative. The unit reports were then analysed to develop a conceptual framework of key components of AMUs and a service definition of the boundaries of acute medical care. RESULTS: Acute medical care in Scotland can be described as being delivered in "acute medical services" rather than geographically distinct AMUs. Twelve key components of AMU care were identified: care areas, functions, populations, patient flow, support services, communication, nurse care, allied healthcare professional care, non-consultant medical care, consultant care, patient assessment and specialty care. DISCUSSION: This empirically derived characterisation of the AMU model is likely to be of utility to practitioners, managers, policy makers and researchers: it is relevant on an operational level, will aid quality improvement and is a foundation to needed further research into how best to deliver care in AMUs. This is important given the central role AMUs play in the journey of the majority of patients presenting to hospital acutely in Scotland, the UK and internationally.

The Chemokine Receptor CCR8 Promotes the Migration of Dendritic Cells into the Lymph Node Parenchyma to Initiate the Allergic Immune Response.

The migration of mature dendritic cells (DCs) into the draining lymph node (dLN) is thought to depend solely on the chemokine receptor CCR7. CD301b+ DCs migrate into the dLN after cutaneous allergen exposure and are required for T helper 2 (Th2) differentiation. We found that CD301b+ DCs poorly upregulated CCR7 expression after allergen exposure and required a second chemokine signal, mediated by CCR8 on CD301b+ DCs and its ligand CCL8, to exit the subcapsular sinus (SCS) and enter the lymph node (LN) parenchyma. After allergen exposure, CD169+SIGN-R1+ macrophages in interfollicular regions produced CCL8, which synergized with CCL21 in a Src-kinase-dependent manner to promote CD301b+ DC migration. In CCR8-deficient mice, CD301b+ DCs remained in the SCS and were unable to enter the LN parenchyma, resulting in defective Th2 differentiation. We have defined a CCR8-dependent stepwise mechanism of DC-subset-specific migration through which LN CD169+SIGN-R1+ macrophages control the polarization of the adaptive immune response.

Pathogen Recognition by CD4 Effectors Drives Key Effector and Most Memory Cell Generation Against Respiratory Virus.

Although much is known about the mechanisms by which pathogen recognition drives the initiation of T cell responses, including those to respiratory viruses, the role of pathogen recognition in fate decisions of T cells once they have become effectors remains poorly defined. Here, we review our recent studies that suggest that the generation of CD4 T cell memory is determined by recognition of virus at an effector "checkpoint." We propose this is also true of more highly differentiated tissue-restricted effector cells, including cytotoxic "ThCTL" in the site of infection and TFH in secondary lymphoid organs. We point out that ThCTL are key contributors to direct viral clearance and TFH to effective Ab response, suggesting that the most protective immunity to influenza, and by analogy to other respiratory viruses, requires prolonged exposure to antigen and to infection-associated signals. We point out that many vaccines used today do not provide such prolonged signals and suggest this contributes to their limited effectiveness. We also discuss how aging impacts effective CD4 T cell responses and how new insights about the response of aged naive CD4 T cells and B cells might hold implications for effective vaccine design for both the young and aged against respiratory viruses.

Short-Lived Antigen Recognition but Not Viral Infection at a Defined Checkpoint Programs Effector CD4 T Cells To Become Protective Memory.

Although memory CD4 T cells are critical for effective immunity to pathogens, the mechanisms underlying their generation are still poorly defined. We find that following murine influenza infection, most effector CD4 T cells undergo apoptosis unless they encounter cognate Ag at a defined stage near the peak of effector generation. Ag recognition at this memory checkpoint blocks default apoptosis and programs their transition to long-lived memory. Strikingly, we find that viral infection is not required, because memory formation can be restored by the addition of short-lived, Ag-pulsed APC at this checkpoint. The resulting memory CD4 T cells express an enhanced memory phenotype, have increased cytokine production, and provide protection against lethal influenza infection. Finally, we find that memory CD4 T cell formation following cold-adapted influenza vaccination is boosted when Ag is administered during this checkpoint. These findings imply that persistence of viral Ag presentation into the effector phase is the key factor that determines the efficiency of memory generation. We also suggest that administering Ag at this checkpoint may improve vaccine efficacy.

A Paradoxical Evolutionary Mechanism in Stochastically Switching Environments.

Organisms with environmental sensors that guide survival are considered more likely to be favored by natural selection if they possess more accurate sensors. In this paper, we develop a theoretical model which shows that under certain conditions of environmental stochasticity, selection actually favors sensors of lower accuracy. An analogy between this counter-intuitive phenomenon and the well-known Parrondo's paradox is suggested.

The effectiveness and variation of acute medical units: a systematic review.

PURPOSE: To evaluate the evidence for the effectiveness of acute medical units (AMUs) compared with other models of care and compare the components of AMU models. DATA SOURCES: Six electronic databases and grey literature sources searched between 1990 and 2014. STUDY SELECTION: Studies reporting on AMUs as an intervention for unplanned medical presentations to hospital with the inclusion of all outcome measures/study designs/comparators. DATA EXTRACTION: Data on study characteristics/outcomes/AMU components were extracted by one author and confirmed by a second. DATA SYNTHESIS: Seventeen studies of 12 AMUs across five countries were included. The AMU model was associated with a reduction in-hospital length of stay (LOS) in all analyses ranging from 0.3 to 2.6 days; and a reduction in mortality in 12 of the 14 analyses with the change ranging from a 0.1% increase to a 8.8% reduction. Evidence relating to readmissions and patient/staff satisfaction was less conclusive. There was variation in the following components of AMUs: admission criteria, entry sources, functions and consultant work patterns. CONCLUSION: This review provides evidence that AMUs are associated with reductions in-hospital LOS and, less convincingly, mortality compared with other models of care when implemented in European and Australasian settings. Reported estimates may be affected by residual confounding. This review reports heterogeneity in components of the AMU model. Further work to identify what constitutes the key components of an AMU is needed to improve the quality and effectiveness of acute medical care. This is of particular importance given the escalating demand on acute services.

Blast wave energy diagnostic.

The distance radiation waves that supersonically propagate in optically thick, diffusive media are energy sensitive. A blast wave can form in a material when the initially diffusive, supersonic radiation wave becomes transonic. Under specific conditions, the blast wave is visible with radiography as a density perturbation. [Peterson et al., Phys. Plasmas 13, 056901 (2006)] showed that the time-integrated drive energy can be measured using blast wave positions with uncertainties less than 10% at the Z Facility. In some cases, direct measurements of energy loss through diagnostic holes are not possible with bolometric and x-ray radiometric diagnostics. Thus, radiography of high compression blast waves can serve as a complementary technique that provides time-integrated energy loss through apertures. In this paper, we use blast waves to characterize the energy emerging through a 2.4 mm aperture and show experimental results in comparison to simulations.