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Ig diversification occurs in peripheral lymphoid organs after establishment of central tolerance during B cell development. In germinal centers (GCs), somatic hypermutation of Ig genes occurs in dark zones, followed by selection of mutated clones in light zones (LZs). This generates high-affinity Ig receptors to pathogens but can also produce autoreactive Ig receptors, which are removed by selection mechanisms that are incompletely understood. The ubiquitin ligase Itch prevents the emergence of autoimmune disease and autoantibodies in humans and mice, and patients lacking Itch develop potentially fatal autoimmune diseases; yet, how Itch regulates GC B cells is not well understood. By studying Itch-deficient mice, we have recently shown that Itch directly limits the magnitude of GC responses. Proteomic profiling of GC B cells uncovered that Itch-deficient cells exhibit high mTORC1 and Myc activity, hallmarks of positive selection. Bone marrow chimera and adoptive transfer experiments revealed that B cell Itch restricts noncycling LZ cells. These results support, to our knowledge, a novel role for Itch in skewing selection of GC B cells to restrict LZ accumulation and shape GC-derived humoral immunity. Determining how B cells integrate cues within GCs to navigate through LZs and dark zones will aid in understanding how autoreactive clones emerge from GCs in people with autoimmune disease.

The thermal Sunyaev-Zel'dovich (tSZ) effect is a powerful tool with the potential for constraining directly the properties of the hot gas that dominates dark matter halos because it measures pressure and thus thermal energy density. Studying this hot component of the circumgalactic medium (CGM) is important because it is strongly impacted by star-formation and active galactic nuclei (AGN) activity in galaxies, participating in the feedback loop that regulates star and black hole mass growth in galaxies. We study the tSZ effect across a wide halo mass range using three cosmological hydrodynamical simulations: Illustris-TNG, EAGLE, and FIRE-2. Specifically, we present the scaling relation between tSZ signal and halo mass and radial profiles of gas density, temperature, and pressure for all three simulations. The analysis includes comparisons to Planck tSZ observations and to the thermal pressure profile inferred from the Atacama Cosmology Telescope (ACT) measurements. We compare these tSZ data to the simulations to interpret the measurements in terms of feedback and accretion processes in the CGM. We also identify as-yet unobserved potential signatures of these processes that may be visible in future measurements, which will have the capability of measuring tSZ signals to even lower masses. We also perform internal comparisons between runs with different physical assumptions. We conclude: (1) there is strong evidence for the impact of feedback at $R_{500}$ but that this impact decreases by $5R_{500}$, and (2) the thermodynamic profiles of the CGM are highly dependent on the implemented model, such as cosmic-ray or AGN feedback prescriptions., 21 pages, 10 figures, submitted to ApJ, comments welcome

As the signal-to-noise of Sunyaev-Zeldovich (SZ) cross-correlation measurements of galaxies improves our ability to infer properties about the circumgalactic medium (CGM), we will transition from being limited by statistical uncertainties to systematic uncertainties. Using thermodynamic profiles of the CGM created from the IllustrisTNG (The Next Generation) simulations we investigate the importance of specific choices in modeling the galaxy sample. These choices include different sample selections in the simulation (stellar versus halo mass, color selections) and different fitting models (matching by the shape of the mass distribution, inclusion of a two-halo term). We forward model a mock galaxy sample into projected SZ observable profiles and fit these profiles to a generalized Navarro-Frenk-White profile using forecasted errors of the upcoming Simons Observatory experiment. We test the number of free parameters in the fits and show that this is another modeling choice that yields different results. Finally, we show how different fitting models can reproduce parameters of a fiducial profile, and show that the addition of a two-halo term and matching by the mass distribution of the sample are extremely important modeling choices to consider., 23 pages, 9 figures, published in the Astrophysical Journal

We present $\sim10-40\,\mu$m SOFIA-FORCAST images of 14 intermediate-mass protostar candidates as part of the SOFIA Massive (SOMA) Star Formation Survey. We build spectral energy distributions (SEDs), also utilizing archival Spitzer, Herschel and IRAS data. We then fit the SEDs with radiative transfer (RT) models of Zhang & Tan (2018), based on Turbulent Core Accretion theory, to estimate key protostellar properties. With the addition of these intermediate-mass sources, SOMA protostars span luminosities from $\sim10^{2}-10^{6}\:L_{\odot}$, current protostellar masses from $\sim0.5-30\:M_{\odot}$ and ambient clump mass surface densities, $\Sigma_{\rm cl}$ from $0.1-3\:{\rm{g\:cm}^{-2}}$. A wide range of evolutionary states of the individual protostars and of the protocluster environments are also probed. We have also considered about 50 protostars identified in Infrared Dark Clouds and expected to be at the earliest stages of their evolution. With this global sample, most of the evolutionary stages of high- and intermediate-mass protostars are probed. From the best fitting models, there is no evidence of a threshold value of protocluster clump mass surface density being needed to form protostars up to $\sim25\:M_\odot$. However, to form more massive protostars, there is tentative evidence that $\Sigma_{\rm{cl}}$ needs to be $\gtrsim1\:{\rm{g\,cm}}^{-2}$. We discuss how this is consistent with expectations from core accretion models that include internal feedback from the forming massive star., Comment: 40 pages, 21 figures, 4 tables, accepted to ApJ

The thermal and kinematic Sunyaev-Zel'dovich effects (tSZ, kSZ) probe the thermodynamic properties of the circumgalactic and intracluster medium (CGM and ICM) of galaxies, groups, and clusters, since they are proportional, respectively, to the integrated electron pressure and momentum along the line-of-sight. We present constraints on the gas thermodynamics of CMASS galaxies in the Baryon Oscillation Spectroscopic Survey (BOSS) using new measurements of the kSZ and tSZ signals obtained in a companion paper. Combining kSZ and tSZ measurements, we measure within our model the amplitude of energy injection $\epsilon M_\star c^2$, where $M_\star$ is the stellar mass, to be $\epsilon=(40\pm9)\times10^{-6}$, and the amplitude of the non-thermal pressure profile to be $\alpha_{\rm Nth}, Comment: Corrected error in the algorithm that calculates the kSZ temperature profile for a given GNFW density model. The value of $\log_{\rm10} \rho_0$ changed by 0.75$\sigma$ in Tab.II and Fig.2, and affected the results in the left panels of Fig. 6. Conclusions are unchanged. Erratum published at https://link.aps.org/doi/10.1103/PhysRevD.107.049903

Pediatric marijuana poisonings are increasing in the United States. Signs and symptoms of marijuana exposure in pediatric patients differ throughout the pediatric age spectrum, and it is important for clinicians to be familiar with the profound lethargy or altered mental status that can occur in pediatrics, particularly in toddlers. This article reviews the clinical effects and treatment of pediatric marijuana exposure, as well as issues around legalization and prevention.

We conduct a census of the high-mass protostellar population of the $\sim70,000\:M_\odot$ Infrared Dark Cloud (IRDC) G028.37+00.07, identifying 35 sources based on their $70\:��$m emission, as reported in the {\it Herschel} Hi-GAL catalog of Molinari et al. (2016). We perform aperture photometry to construct spectral energy distributions (SEDs), which are then fit with the massive protostar models of Zhang & Tan (2018). We find that the sources span a range of isotropic luminosities from $\sim$20 to 4,500$\:L_\odot$. The most luminous sources are predicted to have current protostellar masses of $m_{*}\sim10\:M_\odot$ forming from cores of mass $M_{c}\sim40$ to $400\:M_\odot$. The least luminous sources in our sample are predicted to be protostars with masses as low as $\sim 0.5\:M_\odot$ forming from cores with $M_{c}\sim10\:M_\odot$, which are the minimum values explored in the protostellar model grid. The detected protostellar population has a total estimated protostellar mass of $M_{*}\sim 100\:M_\odot$. Allowing for completeness corrections, which are constrained by comparison with an ALMA study in part of the cloud, we estimate a star formation efficiency per free-fall time of $\sim3\%$ in the IRDC. Finally, analyzing the spatial distribution of the sources, we find relatively low degrees of central concentration of the protostars. The protostars, including the most massive ones, do not appear to be especially centrally concentrated in the protocluster as defined by the IRDC boundary., 18 pages, accepted to ApJ, comments welcome

Introduction Cardiac tamponade is an uncommon presentation to the pediatric emergency department and requires early recognition and emergent intervention. Methods We developed this patient simulation case to simulate a low-frequency, high-acuity scenario for pediatric emergency medicine fellows and resident physicians in emergency medicine, pediatrics, and family medicine. We ran the case in a pediatric emergency department using a high-fidelity pediatric mannequin and equipment found in the clinical environment, including a bedside ultrasound machine. The case involved a 10-year-old patient with Hodgkin lymphoma who presented with fever, neutropenia, and shock and was found to have a pericardial effusion with tamponade after evaluation. The providers were expected to identify signs and symptoms of shock, as well as cardiac tamponade, and demonstrate appropriate emergent evaluation and management. Required personnel included a simulation technician, instructors, and a nurse. Debriefing tools tailored specifically for this scenario were created to facilitate a formal debriefing and formative learner assessment at the end of the simulation. Results This case has been implemented with 10 pediatric emergency medicine fellows during two 3-year cycles of fellow education. Session feedback reflected a high level of satisfaction with the case and an increased awareness of bedside ultrasound in the identification of cardiac tamponade. Discussion This resource for teaching the critical components for diagnosing and managing unstable cardiac tamponade in the pediatric patient, including use of bedside ultrasound, was well received by pediatric emergency medicine fellows.

Background Washington State was one of the first states to legalize recreational marijuana. Increased availability of marijuana may result in more unintentional pediatric exposure, which often presents as altered mental status with unknown cause. Objectives To quantify unintentional pediatric marijuana exposures reported to the Washington Poison Center (WAPC) prior to and after legalization and commercial availability of recreational marijuana. Methods Data were obtained from the WAPC database, toxiCALL®. Patients ≤ 9 years old with a reported marijuana exposure between July 2010 and July 2016 were included in the analysis. Patient and exposure characteristics were summarized and median exposure frequencies were calculated for the periods prior to and after legalization. Results There were 161 cases meeting the inclusion criteria that occurred between July 2010 and July 2016. Of these, 130 (81%) occurred in the 2.5-year period after legalization of recreational marijuana in January 2013. The median age of exposed children was 2 years (range 0–9 years). Eighty-one percent of the exposures occurred in the child's own home. The number of exposures per month increased after recreational marijuana was legalized in November 2012, and increased further once recreational marijuana shops were legally allowed to open in July 2014. Conclusion Reported unintentional pediatric marijuana exposure has increased in the state of Washington since recreational marijuana was legalized. As marijuana becomes more available, clinicians should be aware of the risk of unintentional pediatric marijuana exposure, and this should inform lawmakers regarding regulations around childhood exposure to marijuana.

The melanocortin 2 receptor (MC2R) is unique in terms of ligand selectivity and in vitro expression in mammalian cell lines as compared to the other four mammalian MCRs. It is well established that ACTH is the only melanocortin ligand that can activate the ACTH receptor (i.e., melanocortin 2 receptor). Recent studies have provided new insights into the presence of a common binding site for the HFRW motif common to all melanocortin ligands. However, the activation of the melanocortin 2 receptor requires an additional amino acid motif that is only found in the sequence of ACTH. This mini-review will focus on these two topics and provide a phylogenetic perspective on the evolution of MC2R ligand selectivity.

Early detection of cancers, although essential for treatment effectiveness, can be difficult to achieve, and some tests introduce additional health risks. New, non-invasive detection methods with greater sensitivity and specificity are needed. Several authors have published research suggesting that dogs may be able to detect lung, breast, prostate, ovarian, and melanoma cancers by smelling skin lesions, urine, exhaled breath, and surgically extracted tumors. We conducted a systematic search using the PubMed and EMBASE databases to identify all known published data on canine scent detection of cancers. Of 531 potentially relevant publications, 11 full text articles were examined, and 5 were selected for inclusion in the review. Two studies involved dogs detecting breast cancer (sensitivity 88% using exhaled breath and 22% using urine; specificity was 98% and 20%, respectively), 1 involved bladder cancer (41% of urine samples detected), 1 involved melanoma (75–85.7% of in situ tumors detected), 1 involved lung cancer (sensitivity 99% and specificity 99% using exhaled breath), 1 involved ovarian cancer (sensitivity 100% and specificity 97.5% using thawed frozen tumor samples), and 1 involved prostate cancer (18% of urine samples detected). One study on ovarian cancer is in progress. Early successes with canine scent detection suggest chemical analysis of exhaled breath may be a valid method for cancer detection. Tests using exhaled breath showed better sensitivity and specificity than with urine. Future research should target other tumor types, and seek to identify what exhaled compounds may signal a cancer diagnosis.

MeCP2 duplication syndrome is a devastating neurodevelopmental disorder caused by duplication of the Xq28 region of the X chromosome, primarily affecting males. Methyl-CpG-binding protein 2 (MeCP2) ubiquitously binds methylated CpG sites in the genome, and regulates gene expression by recruitment of transcriptional mediators. MeCP2 is expressed highly in both neurons and immune cells, thus mutations or over-expression of MeCP2 are associated with neurologic pathology (including seizures, motor dysfunction, and cognitive impairment), and immunologic pathology. Many patients die by the age of 25, and recurrent respiratory infections are a common cause of death. We are studying the pathogenesis of influenza A virus in a mouse model of MeCP2 overexpression, the MeCP2Tg3 mouse, which expresses MeCP2 at ~3 fold normal levels. MeCP2Tg3 mice display significant mortality approximately one week post infection, with T and B cell deficiencies in both number and activation, further characterized by high viral titer and low virus-specific antibody levels in the infected lung. Preliminary evidence suggests that vascular and/or lymphatic impairment may underlie both immunologic defects and the increased mortality observed in MeCP2Tg3 mice during influenza A virus infection. In sum, these findings uncover MeCP2 as an important regulator of host response to respiratory virus infection and may inform treatment of human patients with MeCP2 duplication syndrome.

Influenza A virus (IAV) infection in the respiratory tract triggers a robust immune response, resulting in both virus clearance and lung inflammation and injury. After virus clearance, resolution of lung disease occurs during a distinct recovery period. The costimulatory molecule CD86 can modulate T cell activity during the initiation and effector stages of the host response to IAV infection, but the role of CD86 during recovery is unknown. We found that antibody-mediated CD86 blockade after virus clearance led to a delay in recovery, characterized by increased numbers of lung neutrophils and innate cytokines in the bronchial alveolar lavage fluid (BAL), but no change in conventional IAV-specific T cell responses. However, CD86 blockade led to decreased numbers of FoxP3+ regulatory T cells (Tregs), and adoptive transfer of Tregs into α-CD86 treated mice rescued the effect of the blockade, supporting a role for Tregs in promoting recovery after virus clearance. Direct depletion of Tregs late after infection using DEREG mice mimicked the CD86 blockade phenotype, confirming a role for Tregs during recovery after virus clearance. Finally, we identified neutrophils as a target of Treg suppression, since neutrophil depletion in Treg-depleted DEREG mice reduced excess BAL cytokines. These results show that CD86-dependent Tregs contribute to the resolution of disease after IAV infection, in part by suppressing neutrophil-driven cytokine release into the airways.

Influenza A virus (IAV) infection can produce severe pulmonary inflammation and injury. The host immune response to infection mediates virus clearance but also contributes to pulmonary inflammation and injury, marking the immune response as a potential therapeutic target after severe infections. Host factors mediating IAV clearance and lung inflammation are well-studied, however, factors controlling recovery from disease following IAV clearance are ill-defined. The costimulatory ligand CD86 mediates interactions between immune cells via its receptors CD28 and CTLA-4. We observed in infected mice that blockade of CD86 signaling in vivo after IAV clearance delays recovery and promotes accumulation of neutrophils in the respiratory tract. Furthermore, CD86 blockade reduces both IL-2 and T regulatory cells (Treg) in the lungs. Depletion of Tregs using DREG mice or Treg depleting antibody after IAV clearance also delays recovery and leads to pulmonary neutrophilia. These data suggest that Tregs may play a crucial role in regulating pulmonary inflammation after IAV infection and are in turn dependent on CD86 ligand engagement. We are continuing to explore the role of CD86 in recovery and resolution of inflammation after IAV infection with the long-term goal of exploring the therapeutic potential of optimizing CD86 signaling to promote Treg function in recovery from infection.