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Notch ligands present during interactions between T cells and dendritic cells (DCs) dictate cell phenotype through a myriad of effects including the induction of T cell regulation, survival, and cytokine response. The presence of Notch ligands on DCs varies with the context of the inflammatory response; Jagged-1 is constitutively expressed, whereas Delta-like 1 and Delta-like 4 are induced in response to pathogen exposure. Although Delta-like and Jagged ligands send different signals through the same Notch receptor, the role of these two ligands in peripheral T cell immunity is not clear. The goal of our studies was to determine the role of Jagged-1 in the pathogen-free inflammation induced by OVA during allergic airway disease in mice. Our studies show that a deletion in DC-expressed Jagged-1 causes a significant increase in cytokine production, resulting in increased mucus production and increased eosinophilia in the lungs of mice sensitized and challenged with OVA. We also observed that a reduction of Jagged-1 expression is correlated with increased expression of the Notch 1 receptor on the surface of CD4+ T cells in both the lung and lymph node. Through transfer studies using OT-II transgenic T cells, we demonstrate that Jagged-1 represses the expansion of CD44+CD62L+CCR7+ memory cells and promotes the expansion of CD44+CD62L− effector cells, but it has no effect on the expansion of naive cells during allergic airway disease. These data suggest that Jagged-1 may have different roles in Ag-specific T cell responses, depending on the maturity of the stimulated T cell.

In Part II, two classes of vertical motions, fixed (associated with vertically propagating gravity waves tied to flow over topography) and transient (associated primarily with vertical wind shear and conditional instability within passing weather systems), were diagnosed over the Payette River basin of Idaho during the Seeded and Natural Orographic Wintertime Clouds: The Idaho Experiment (SNOWIE). This paper compares vertical motions retrieved from airborne Doppler radial velocity measurements with those from a 900-m-resolution model simulation to determine the impact of transient vertical motions on trajectories of ice particles initiated by airborne cloud seeding. An orographic forcing index, developed to compare vertical motion fields retrieved from the radar with the model, showed that fixed vertical motions were well resolved by the model while transient vertical motions were not. Particle trajectories were calculated for 75 cross-sectional pairs, each differing only by the observed and modeled vertical motion field. Wind fields and particle terminal velocities were otherwise identical in both trajectories so that the impact of transient vertical circulations on particle trajectories could be isolated. In 66.7% of flight-leg pairs, the distance traveled by particles in the model and observations differed by less than 5 km with transient features having minimal impact. In 9.3% of the pairs, model and observation trajectories landed within the ideal target seeding elevation range (>2000 m), whereas, in 77.3% of the pairs, both trajectories landed below the ideal target elevation. Particles in the observations and model descended into valleys on the mountains’ lee sides in 94.2% of cases in which particles traveled less than 37 km.

Updrafts in wintertime cloud systems over mountainous regions can be described as fixed, mechanically driven by the terrain under a given ambient wind and stability profile (i.e., vertically propagating gravity waves tied to flow over topography), and transient, associated primarily with vertical wind shear and conditional instability within passing weather systems. This analysis quantifies the magnitude of fixed and transient updraft structures over the Payette River basin sampled during the Seeded and Natural Orographic Wintertime Clouds: The Idaho Experiment (SNOWIE). Vertical motions were retrieved from Wyoming Cloud Radar measurements of radial velocity using the algorithm presented in Part I. Transient circulations were removed, and fixed orographic circulations were quantified by averaging vertical circulations along repeated cross sections over the same terrain during the campaign. Fixed orographic vertical circulations had magnitudes of 0.3–0.5 m s−1. These fixed vertical circulations were composed of a background circulation in which transient circulations were embedded. Transient vertical circulations are shown to be associated with transient wave motions, cloud-top generating cells, convection, and turbulence. Representative transient vertical circulations are illustrated, and data from rawinsondes over the Payette River basin are used to infer the relationship of the vertical circulations to shear and instability. Maximum updrafts are shown to exceed 5 m s−1 within Kelvin–Helmholtz waves, 4 m s−1 associated with transient gravity waves, 3 m s−1 in generating cells, 6 m s−1 in elevated convection, 4 m s−1 in surface-based deep convection, 5 m s−1 in boundary layer turbulence, and 9 m s−1 in shear-induced turbulence.

Vertical motions over the complex terrain of Idaho’s Payette River basin were observed by the Wyoming Cloud Radar (WCR) during 23 flights of the Wyoming King Air during the Seeded and Natural Orographic Wintertime Clouds: The Idaho Experiment (SNOWIE) field campaign. The WCR measured radial velocity Vr, which includes the reflectivity-weighted terminal velocity of hydrometeors Vt, vertical air velocity w, horizontal wind contributions as a result of aircraft attitude deviations, and aircraft motion. Aircraft motion was removed through standard processing. To retrieve vertical radial velocity W, Vr was corrected using rawinsonde data and aircraft attitude measurements; w was then calculated by subtracting the mean W () at a given height along a flight leg long enough for to equal the mean reflectivity-weighted terminal velocity at that height. The accuracy of the w and retrievals were dependent on satisfying assumptions along a given flight leg that the winds at a given altitude above/below the aircraft did not vary, the vertical air motions at a given altitude sum to 0 m s−1, and at a given altitude did not vary. The uncertainty in the w retrieval associated with each assumption is evaluated. Case studies and a projectwide summary show that this methodology can provide estimates of w that closely match gust probe measurements of w at the aircraft level. Flight legs with little variation in equivalent reflectivity factor at a given height and large horizontal echo extent were associated with the least retrieval uncertainty. The greatest uncertainty occurred in regions with isolated convective turrets or at altitudes where split cloud layers were present.

To determine cell-specific gene expression profiles that contribute to development of abdominal aortic aneurysms (AAAs).AAAs represent the most common pathological aortic dilation leading to the fatal consequence of aortic rupture. Both immune and structural cells contribute to aortic degeneration, however, gene specific alterations in these cellular subsets are poorly understood.We performed single-cell RNA sequencing (scRNA-seq) analysis of AAAs and control tissues. AAA-related changes were examined by comparing gene expression profiles as well as detailed receptor-ligand interactions. An integrative analysis of scRNA-seq data with large genome-wide association study data was conducted to identify genes critical for AAA development.Using scRNA-seq we provide the first comprehensive characterization of the cellular landscape in human AAA tissues. Unbiased clustering analysis of transcriptional profiles identified seventeen clusters representing 8 cell lineages. For immune cells, clustering analysis identified 4 T-cell and 5 monocyte/macrophage subpopulations, with distinct transcriptional profiles in AAAs compared to controls. Gene enrichment analysis on immune subsets identified multiple pathways only expressed in AAA tissue, including those involved in mitochondrial dysfunction, proliferation, and cytokine secretion. Moreover, receptor-ligand analysis defined robust interactions between vascular smooth muscle cells and myeloid populations in AAA tissues. Lastly, integrated analysis of scRNA-seq data with genome-wide association study studies determined that vascular smooth muscle cell expression of SORT1 is critical for maintaining normal aortic wall function.Here we provide the first comprehensive evaluation of single-cell composition of the abdominal aortic wall and reveal how the gene expression landscape is altered in human AAAs.

Graphical abstract, Highlights • Spred2-/- mice developed exacerbated Con A-induced liver damage with increased IFNγ production. • MEK/ERK inhibitor U0126 markedly inhibited the damage and reduced IFNγ production. • Neutralization of IFNγ abolished the damage with down-regulated hepatic STAT1 activation. • Depletion of CD4+/CD8+ T cells improved the damage with decreased IFNγ production. • Transplantation of CD4+/CD8+ T cells into RAG1-/- mice reproduced severe liver damage. • Liver damage and IFNγ production were significantly lower in Spred2 transgenic mice., Introduction Mitogen-activated protein kinases (MAPKs) are involved in T cell-mediated liver damage. However, the inhibitory mechanism(s) that controls T cell-mediated liver damage remains unknown. Objectives We investigated whether Spred2 (Sprouty-related, EVH1 domain-containing protein 2) that negatively regulates ERK-MAPK pathway has a biological impact on T cell-mediated liver damage by using a murine model. Methods We induced hepatotoxicity in genetically engineered mice by intravenously injecting Concanavalin A (Con A) and analyzed the mechanisms using serum chemistry, histology, ELISA, qRT-PCR, Western blotting and flow cytometry. Results Spred2-deficient mice (Spred2-/-) developed more sever liver damage than wild-type (WT) mice with increased interferon-γ (IFNγ) production. Hepatic ERK phosphorylation was enhanced in Spred2-/- mice, and pretreatment of Spred2-/- mice with the MAPK/ERK inhibitor U0126 markedly inhibited the liver damage and reduced IFNγ production. Neutralization of IFNγ abolished the damage with decreased hepatic Stat1 activation in Spred2-/- mice. IFNγ was mainly produced from CD4+ and CD8+ T cells, and their depletion decreased liver damage and IFNγ production. Transplantation of CD4+ and/or CD8+ T cells from Spred2-/- mice into RAG1-/- mice deficient in both T and B cells caused more severe liver damage than those from WT mice. Hepatic expression of T cell attractants, CXCL9 and CXCL10, was augmented in Spred2-/- mice as compared to WT mice. Conversely, liver damage, IFNγ production and the recruitment of CD4+ and CD8+ T cells in livers after Con A challenge were lower in Spred2 transgenic mice, and Spred2-overexpressing CD4+ and CD8+ T cells produced lower levels of IFNγ than WT cells upon stimulation with Con A in vitro. Conclusion We demonstrated, for the first time, that Spred2 functions as an endogenous regulator of T cell IFNγ production and Spred2-mediated inhibition of ERK-MAPK pathway may be an effective remedy for T cell-dependent liver damage.

The spatial distribution and magnitude of snowfall resulting from cloud seeding with silver iodide (AgI) is closely linked to atmospheric conditions, seeding operations, and dynamical, thermodynamical, and microphysical processes. Here, microphysical processes leading to ice and snow production are analyzed in orographic clouds for three cloud-seeding events, each with light or no natural precipitation and well-defined, traceable seeding lines. Airborne and ground-based radar observations are linked to in situ cloud and precipitation measurements to determine the spatiotemporal evolution of ice initiation, particle growth, and snow fallout in seeded clouds. These processes and surface snow amounts are explored as particle plumes evolve from varying amounts of AgI released, and within changing environmental conditions, including changes in liquid water content (LWC) along and downwind of the seeding track, wind speed, and shear. More AgI did not necessarily produce more liquid equivalent snowfall (LESnow). The greatest amount of LESnow, largest area covered by snowfall, and highest peak snowfall produced through seeding occurred on the day with the largest and most widespread occurrence of supercooled drizzle, highest wind shear, and greater LWC along and downwind of the seeding track. The day with the least supercooled drizzle and the lowest LWC downwind of the seeding track produced the smallest amount of LESnow through seeding. The stronger the wind was, the farther away the snowfall occurred from the seeding track.

Understanding how context (e.g., host species, environmental conditions) drives disease susceptibility is an essential goal of disease ecology. We hypothesized that in bat white-nose syndrome (WNS), species-specific host–pathogen interactions may partly explain varying disease outcomes among host species. We characterized bat and pathogen transcriptomes in paired samples of lesion-positive and lesion-negative wing tissue from bats infected with Pseudogymnoascus destructans in three parallel experiments. The first two experiments analyzed samples collected from the susceptible Nearctic Myotis lucifugus and the less-susceptible Nearctic Eptesicus fuscus, following experimental infection and hibernation in captivity under controlled conditions. The third experiment applied the same analyses to paired samples from infected, free-ranging Myotis myotis, a less susceptible, Palearctic species, following natural infection and hibernation (n = 8 sample pairs/species). Gene expression by P. destructans was similar among the three host species despite varying environmental conditions among the three experiments and was similar within each host species between saprophytic contexts (superficial growth on wings) and pathogenic contexts (growth in lesions on the same wings). In contrast, we observed qualitative variation in host response: M. lucifugus and M. myotis exhibited systemic responses to infection, while E. fuscus up-regulated a remarkably localized response. Our results suggest potential phylogenetic determinants of response to WNS and can inform further studies of context-dependent host–pathogen interactions.

Cloud seeding has been used as one water management strategy to overcome the increasing demand for water despite decades of inconclusive results on the efficacy of cloud seeding. In this study snowfall accumulation from glaciogenic cloud seeding is quantified based on snow gauge and radar observations from three days in January 2017, when orographic clouds in the absent of natural precipitation were seeded with silver iodide (AgI) in the Payette basin of Idaho during the Seeded and Natural Orographic Wintertime Clouds: The Idaho Experiment (SNOWIE). On each day, a seeding aircraft equipped with AgI flares flew back and forth on a straight-line flight track producing a zig-zag pattern representing two to eight lines of clouds visible through enhancements in radar reflectivity. As these seeding lines started to form precipitation, they passed over several snow gauges and through the radar observational domain. For the three cases presented here, precipitation gauges measured increases between 0.05-0.3 mm as precipitation generated by cloud seeding pass over the instruments. A variety of relationships between radar reflectivity factor and liquid equivalent snowfall rate were used to quantify snowfall within the radar observation domain. For the three cases, snowfall occurred within the radar observational domain between 25 -160 min producing a total amount of water generated by cloud seeding ranging from 123,220 to 339,540 m3 using the best-match Ze-S relationship. Uncertainties in radar reflectivity estimated snowfall are provided by considering not only the best-match Ze-S relationship but also an ensemble of Ze-S relationships based on the range of coefficients published from previous studies and then examining the percentile of snowfall estimates based on all of the Ze-S relationships within the ensemble. Considering the interquartile range and 5th/95th percentiles, uncertainties in total amount of water generated by cloud seeding can range between 20-45% compared to the best-math estimates. These results provide new insights towards understanding how cloud seeding impacts precipitation and its distribution across a region.

Macrophage plasticity is critical for normal tissue repair following injury. In pathologic states such as diabetes, macrophage plasticity is impaired, and macrophages remain in a persistent proinflammatory state; however, the reasons for this are unknown. Here, using single-cell RNA sequencing of human diabetic wounds, we identified increased JMJD3 in diabetic wound macrophages, resulting in increased inflammatory gene expression. Mechanistically, we report that in wound healing, JMJD3 directs early macrophage-mediated inflammation via JAK1,3/STAT3 signaling. However, in the diabetic state, we found that IL-6, a cytokine increased in diabetic wound tissue at later time points post-injury, regulates JMJD3 expression in diabetic wound macrophages via the JAK1,3/STAT3 pathway and that this late increase in JMJD3 induces NFκB-mediated inflammatory gene transcription in wound macrophages via an H3K27me3 mechanism. Interestingly, RNA sequencing of wound macrophages isolated from mice with JMJD3-deficient myeloid cells (Jmjd3f/fLyz2Cre+) identified that the STING gene (Tmem173) is regulated by JMJD3 in wound macrophages. STING limits inflammatory cytokine production by wound macrophages during healing. However, in diabetic mice, its role changes to limit wound repair and enhance inflammation. This finding is important since STING is associated with chronic inflammation, and we found STING to be elevated in human and murine diabetic wound macrophages at late time points. Finally, we demonstrate that macrophage-specific, nanoparticle inhibition of JMJD3 in diabetic wounds significantly improves diabetic wound repair by decreasing inflammatory cytokines and STING. Taken together, this work highlights the central role of JMJD3 in tissue repair and identifies cell-specific targeting as a viable therapeutic strategy for nonhealing diabetic wounds.

The proteomic composition of amphibian gametes is largely a molecular mystery, particularly for Urodeles (salamanders and newts) which have few genomic-scale resources. Lungless salamanders (family Plethodontidae) include approximately two thirds of all extant salamander species and are classic models of vertebrate mating behavior. As part of an extended, multi-stage courtship ritual, male plethodontid salamanders deliver rapidly evolving protein pheromones that modify female behavior and improve male reproductive success. Despite great interest in this set of pre-mating reproductive barriers, limited characterization of plethodontid gametes has prohibited investigation of post-mating pre-zygotic barriers such as sperm-egg recognition. In this study, we performed transcriptomic analyses of testis and ovary using long-read PacBio sequencing and proteomic analyses of sperm using mass spectrometry for two evolutionary divergent plethodontid species, Plethodon shermani and Desmognathus ocoee. In both species, many of the most abundant sperm proteins were paralogs of the courtship pheromones Plethodontid Receptivity Factor (PRF), Plethodontid Modulating Factor (PMF), and Sodefrin Precursor-like Factor (SPF). Sperm-specific paralogs of PMF and SPF are likely the most abundant secreted proteins in P. shermani and D. ocoee, respectively. In contrast, sperm PRF lacks a signal peptide and may be expressed in cytoplasm. PRF pheromone genes evolved independently multiple times through repeated gene duplication of sperm PRF genes and signal peptides recovered by recombination with PMF genes. Phylogenetic analysis of courtship pheromones and their sperm paralogs support that each protein family evolved for these two reproductive contexts at distinct evolutionary time points between 17 and 360 million years ago. As the first molecular characterization of salamander gametes, this study expands our knowledge of amphibian fertilization beyond frogs and provides novel insight into the evolutionary processes by which new, rapidly evolving reproductive proteins may evolve.

Full list of authors: Acciari, V. A.; Ansoldi, S.; Antonelli, L. A.; Arbet Engels, A.; Artero, M.; Asano, K.; Babić, A.; Baquero, A.; Barres de Almeida, U.; Barrio, J. A.; Batković, I.; Becerra González, J.; Bednarek, W.; Bellizzi, L.; Bernardini, E.; Bernardos, M.; Berti, A.; Besenrieder, J.; Bhattacharyya, W.; Bigongiari, C.; Blanch, O.; Bošnjak, Ž.; Busetto, G.; Carosi, R.; Ceribella, G.; Cerruti, M.; Chai, Y.; Chilingarian, A.; Cikota, S.; Colak, S. M.; Colombo, E.; Contreras, J. L.; Cortina, J.; Covino, S.; D'Amico, G.; D'Elia, V.; da Vela, P.; Dazzi, F.; de Angelis, A.; de Lotto, B.; Delfino, M.; Delgado, J.; Delgado Mendez, C.; Depaoli, D.; di Pierro, F.; di Venere, L.; Do Souto Espiñeira, E.; Dominis Prester, D.; Donini, A.; Doro, M.; Fallah Ramazani, V.; Fattorini, A.; Ferrara, G.; Fonseca, M. V.; Font, L.; Fruck, C.; Fukami, S.; García López, R. J.; Garczarczyk, M.; Gasparyan, S.; Gaug, M.; Giglietto, N.; Giordano, F.; Gliwny, P.; Godinović, N.; Green, J. G.; Green, D.; Hadasch, D.; Hahn, A.; Heckmann, L.; Herrera, J.; Hoang, J.; Hrupec, D.; Hütten, M.; Inada, T.; Inoue, S.; Ishio, K.; Iwamura, Y.; Jiménez, I.; Jormanainen, J.; Jouvin, L.; Kajiwara, Y.; Karjalainen, M.; Kerszberg, D.; Kobayashi, Y.; Kubo, H.; Kushida, J.; Lamastra, A.; Lelas, D.; Leone, F.; Lindfors, E.; Lombardi, S.; Longo, F.; López-Coto, R.; López-Moya, M.; López-Oramas, A.; Loporchio, S.; Machado de Oliveira Fraga, B.; Maggio, C.; Majumdar, P.; Makariev, M.; Mallamaci, M.; Maneva, G.; Manganaro, M.; Maraschi, L.; Mariotti, M.; Martínez, M.; Mazin, D.; Menchiari, S.; Mender, S.; Mićanović, S.; Miceli, D.; Miener, T.; Minev, M.; Miranda, J. M.; Mirzoyan, R.; Molina, E.; Moralejo, A.; Morcuende, D.; Moreno, V.; Moretti, E.; Neustroev, V.; Nigro, C.; Nilsson, K.; Nishijima, K.; Noda, K.; Nozaki, S.; Ohtani, Y.; Oka, T.; Otero-Santos, J.; Paiano, S.; Palatiello, M.; Paneque, D.; Paoletti, R.; Paredes, J. M.; Pavletić, L.; Peñil, P.; Perennes, C.; Persic, M.; Prada Moroni, P. G.; Prandini, E.; Priyadarshi, C.; Puljak, I.; Ribó, M.; Rico, J.; Righi, C.; Rugliancich, A.; Saha, L.; Sahakyan, N.; Saito, T.; Sakurai, S.; Satalecka, K.; Saturni, F. G.; Schmidt, K.; Schweizer, T.; Sitarek, J.; Šnidarić, I.; Sobczynska, D.; Spolon, A.; Stamerra, A.; Strom, D.; Strzys, M.; Suda, Y.; Surić, T.; Takahashi, M.; Tavecchio, F.; Temnikov, P.; Terzić, T.; Teshima, M.; Tosti, L.; Truzzi, S.; Tutone, A.; Ubach, S.; van Scherpenberg, J.; Vanzo, G.; Vazquez Acosta, M.; Ventura, S.; Verguilov, V.; Vigorito, C. F.; Vitale, V.; Vovk, I.; Will, M.; Wunderlich, C.; Zarić, D.; Baack, D.; Balbo, M.; Biederbeck, N.; Biland, A.; Bretz, T.; Buss, J.; Dorner, D.; Eisenberger, L.; Elsaesser, D.; Hildebrand, D.; Iotov, R.; Mannheim, K.; Neise, D.; Noethe, M.; Paravac, A.; Rhode, W.; Schleicher, B.; Sliusar, V.; Walter, R.; D'Ammando, F.; Horan, D.; Lien, A. Y.; Baloković, M.; Madejski, G. M.; Perri, M.; Verrecchia, F.; Leto, C.; Lähteenmäki, A.; Tornikoski, M.; Ramakrishnan, V.; Järvelä, E.; Vera, R. J. C.; Chamani, W.; Villata, M.; Raiteri, C. M.; Gupta, A. C.; Pandey, A.; Fuentes, A.; Agudo, I.; Casadio, C.; Semkov, E.; Ibryamov, S.; Marchini, A.; Bachev, R.; Strigachev, A.; Ovcharov, E.; Bozhilov, V.; Valcheva, A.; Zaharieva, E.; Damljanovic, G.; Vince, O.; Larionov, V. M.; Borman, G. A.; Grishina, T. S.; Hagen-Thorn, V. A.; Kopatskaya, E. N.; Larionova, E. G.; Larionova, L. V.; Morozova, D. A.; Nikiforova, A. A.; Savchenko, S. S.; Troitskiy, I. S.; Troitskaya, Y. V.; Vasilyev, A. A.; Merkulova, O. A.; Chen, W. P; Samal, M.; Lin, H. C.; Moody, J. W.; Sadun, A. C.; Jorstad, S. G.; Marscher, A. P.; Weaver, Z. R.; Feige, M.; Kania, J.; Kopp, M.; Kunkel, L.; Reinhart, D.; Scherbantin, A.; Schneider, L.; Lorey, C.; Acosta-Pulido, J. A.; Carnerero, M. I.; Carosati, D.; Kurtanidze, S. O.; Kurtanidze, O. M.; Nikolashvili, M. G.; Chigladze, R. A.; Ivanidze, R. Z.; Kimeridze, G. N.; Sigua, L. A.; Joner, M. D.; Spencer, M.; Giroletti, M.; Marchili, N.; Righini, S.; Rizzi, N.; Bonnoli, G.; MAGIC Collaboration; Fact Collaboration.-- This is an Open Access article, published by EDP Sciences, under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited., Aims. We present a detailed characterisation and theoretical interpretation of the broadband emission of the paradigmatic TeV blazar Mrk 421, with a special focus on the multi-band flux correlations. Methods. The dataset has been collected through an extensive multi-wavelength campaign organised between 2016 December and 2017 June. The instruments involved are MAGIC, FACT, Fermi-LAT, Swift, GASP-WEBT, OVRO, Medicina, and Metsahovi. Additionally, four deep exposures (several hours long) with simultaneous MAGIC and NuSTAR observations allowed a precise measurement of the falling segments of the two spectral components. Results. The very-high-energy (VHE; E 100 GeV) gamma rays and X-rays are positively correlated at zero time lag, but the strength and characteristics of the correlation change substantially across the various energy bands probed. The VHE versus X-ray fluxes follow dierent patterns, partly due to substantial changes in the Compton dominance for a few days without a simultaneous increase in the X-ray flux (i.e., orphan gamma-ray activity). Studying the broadband spectral energy distribution (SED) during the days including NuSTAR observations, we show that these changes can be explained within a one-zone leptonic model with a blob that increases its size over time. The peak frequency of the synchrotron bump varies by two orders of magnitude throughout the campaign. Our multi-band correlation study also hints at an anti-correlation between UV-optical and X-ray at a significance higher than 3. A VHE flare observed on MJD 57788 (2017 February 4) shows gamma-ray variability on multi-hour timescales, with a factor ten increase in the TeV flux but only a moderate increase in the keV flux. The related broadband SED is better described by a two-zone leptonic scenario rather than by a one-zone scenario.We find that the flare can be produced by the appearance of a compact second blob populated by high energetic electrons spanning a narrow range of Lorentz factors, from 0 min = 2104 to 0 max = 6105. © 2021 Georg Thieme Verlag. All rights reserved., The MAGIC Collaboration would like to thank the Instituto de Astrofísica de Canarias for the excellent working conditions at the Observatorio del Roque de los Muchachos in La Palma. The financial support of the German BMBF, MPG and HGF; the Italian INFN and INAF; the Swiss National Fund SNF; the ERDF under the Spanish Ministerio de Ciencia e Innovación (MICINN) (FPA2017-87859-P, FPA2017-85668-P, FPA2017-82729-C6-5-R, FPA2017-90566-REDC, PID2019-104114RB-C31, PID2019-104114RB-C32, PID2019-105510GB-C31,PID2019-107847RB-C41, PID2019-107847RB-C42, PID2019-107847RB-C44, PID2019-107988GB-C22); the Indian Department of Atomic Energy; the Japanese ICRR, the University of Tokyo, JSPS, and MEXT; the Bulgarian Ministry of Education and Science, National RI Roadmap Project DO1-268/16.12.2019 and the Academy of Finland grant nr. 320045 is gratefully acknowledged. This work was also supported by the Spanish Centro de Excelencia “Severo Ochoa” SEV-2016-0588, SEV-2017-0709 and CEX2019-000920-S, and “María de Maeztu” CEX2019-000918-M, the Unidad de Excelencia “María de Maeztu” MDM-2015-0509-18-2 and the “la Caixa” Foundation (fellowship LCF/BQ/PI18/11630012) and by the CERCA program of the Generalitat de Catalunya; by the Croatian Science Foundation (HrZZ) Project IP-2016-06-9782 and the University of Rijeka Project 13.12.1.3.02; by the DFG Collaborative Research Centers SFB823/C4 and SFB876/C3; the Polish National Research Centre grant UMO-2016/22/M/ST9/00382; and by the Brazilian MCTIC, CNPq and FAPERJ. The important contributions from ETH Zurich grants ETH-10.08-2 and ETH-27.12-1 as well as the funding by the Swiss SNF and the German BMBF (Verbundforschung Astro- und Astroteilchenphysik) and HAP (Helmoltz Alliance for Astroparticle Physics) are gratefully acknowledged. Part of this work is supported by Deutsche Forschungsgemeinschaft (DFG) within the Collaborative Research Center SFB 876 “Providing Information by Resource-Constrained Analysis”, project C3. We are thankful for the very valuable contributions from E. Lorenz, D. Renker and G. Viertel during the early phase of the project. We thank the Instituto de Astrofísica de Canarias for allowing us to operate the telescope at the Observatorio del Roque de los Muchachos in La Palma, the Max-Planck-Institut für Physik for providing us with the mount of the former HEGRA CT3 telescope, and the MAGIC collaboration for their support. The Fermi LAT Collaboration acknowledges generous ongoing support from a number of agencies and institutes that have supported both the development and the operation of the LAT as well as scientific data analysis. These include the National Aeronautics and Space Administration and the Department of Energy in the United States, the Commissariat à l’Energie Atomique and the Centre National de la Recherche Scientifique/Institut National de Physique Nucléaire et de Physique des Particules in France, the Agenzia Spaziale Italiana and the Istituto Nazionale di Fisica Nucleare in Italy, the Ministry of Education, Culture, Sports, Science and Technology (MEXT), High Energy Accelerator Research Organization (KEK) and Japan Aerospace Exploration Agency (JAXA) in Japan, and the K. A. Wallenberg Foundation, the Swedish Research Council and the Swedish National Space Board in Sweden. Additional support for science analysis during the operations phase is gratefully acknowledged from the Istituto Nazionale di Astrofisica in Italy and the Centre National d’Études Spatiales in France. This work performed in part under DOE Contract DE-AC02-76SF00515. This work made use of data from the NuSTAR mission, a project led by the California Institute of Technology, managed by the Jet Propulsion Laboratory, and funded by the National Aeronautics and Space Administration. We thank the NuSTAR Operations, Software, and Calibration teams for support with the execution and analysis of these observations. This research has made use of the NuSTAR Data Analysis Software (NuSTARDAS) jointly developed by the ASI Science Data Center (ASDC; Italy) and the California Institute of Technology (USA). This research has also made use of the XRT Data Analysis Software (XRTDAS) developed under the responsibility of the ASI Science Data Center (ASDC), Italy. A.A.E and D.P acknowledge support from the Deutsche Forschungs gemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC-2094 – 390783311. M. B. acknowledges support from the YCAA Prize Postdoctoral Fellowship and from the Black Hole Initiative at Harvard University, which is funded in part by the Gordon and Betty Moore Foundation (grant GBMF8273) and in part by the John Templeton Foundation. This publication makes use of data obtained at the Metsähovi Radio Observatory, operated by Aalto University in Finland. This research has made use of data from the OVRO 40-m monitoring program (Richards et al. 2011) which is supported in part by NASA grants NNX08AW31G, NNX11A043G, and NNX14AQ89G and NSF grants AST-0808050 and AST-1109911. I.A. acknowledges financial support from the Spanish “Ministerio de Ciencia e Innovación” (MCINN) through the “Center of Excellence Severo Ochoa” award for the Instituto de Astrofísica de Andalucía-CSIC (SEV-2017-0709). Acquisition and reduction of the MAPCAT data was supported in part by MICINN through grants AYA2016-80889-P and PID2019-107847RB-C44. The MAPCAT observations were carried out at the German-Spanish Calar Alto Observatory, which is jointly operated by Junta de Andalucía and Consejo Superior de Investigaciones Científicas. C.C. acknowledges support from the European Research Council (ERC) under the European Union Horizon 2020 research and innovation program under the grant agreement No 771282. This research was partially supported by the Bulgarian National Science Fund of the Ministry of Education and Science under grants KP-06-H28/3 (2018), KP-06-H38/4 (2019) and KP-06-KITAJ/2 (2020). We acknowledge support by Bulgarian National Science Fund under grant DN18-10/2017 and National RI Roadmap Projects DO1-277/16.12.2019 and DO1-268/16.12.2019 of the Ministry of Education and Science of the Republic of Bulgaria. This research was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (contract No 451-03-68/2020-14/200002). G.D. acknowledges observing grant support from the Institute of Astronomy and Rozhen NAO BAS through the bilateral joint research project “Gaia Celestial Reference Frame (CRF) and fast variable astronomical objects” (2020–2022, head – G. Damljanovic). The BU group was supported in part by NASA Fermi guest investigator program grants 80NSSC19K1505 and 80NSSC20K1566. This study was based in part on observations conducted using the 1.8 m Perkins Telescope Observatory (PTO) in Arizona, which is owned and operated by Boston University. This article is partly based on observations made with the LCOGT Telescopes, one of whose nodes is located at the Observatorios de Canarias del IAC on the island of Tenerife in the Observatorio del Teide. This article is also based partly on data obtained with the STELLA robotic telescopes in Tenerife, an AIP facility jointly operated by AIP and IAC. The Abastumani team acknowledges financial support by the Shota Rustaveli National Science Foundation under contract FR-19-6174. Based on observations with the Medicina telescope operated by INAF – Istituto di Radioastronomia.

Stem cell factor (SCF) and its receptor c-kit have been implicated in inflammation, tissue remodeling, and fibrosis. Ingenuity Integrated Pathway Analysis of gene expression array data sets showed an upregulation of SCF transcripts in idiopathic pulmonary fibrosis (IPF) lung biopsies compared with tissue from nonfibrotic lungs that are further increased in rapid progressive disease. SCF248, a cleavable isoform of SCF, was abundantly and preferentially expressed in human lung fibroblasts and fibrotic mouse lungs relative to the SCF220 isoform. In fibroblast-mast cell coculture studies, blockade of SCF248 using a novel isoform-specific anti-SCF248 monoclonal antibody (anti-SCF248), attenuated the expression of COL1A1, COL3A1, and FN1 transcripts in cocultured IPF but not normal lung fibroblasts. Administration of anti-SCF248 on days 8 and 12 after bleomycin instillation in mice significantly reduced fibrotic lung remodeling and col1al, fn1, acta2, tgfb, and ccl2 transcript expression. In addition, bleomycin increased numbers of c-kit+ mast cells, eosinophils, and ILC2 in lungs of mice, whereas they were not significantly increased in anti-SCF248-treated animals. Finally, mesenchymal cell-specific deletion of SCF significantly attenuated bleomycin-mediated lung fibrosis and associated fibrotic gene expression. Collectively, these data demonstrate that SCF is upregulated in diseased IPF lungs and blocking SCF248 isoform significantly ameliorates fibrotic lung remodeling in vivo suggesting that it may be a therapeutic target for fibrotic lung diseases.

This paper reviews research conducted over the last six decades to understand and quantify the efficacy of wintertime orographic cloud seeding to increase winter snowpack and water supplies within a mountain basin. The fundamental hypothesis underlying cloud seeding as a method to enhance precipitation from wintertime orographic cloud systems is that a cloud’s natural precipitation efficiency can be enhanced by converting supercooled water to ice upstream and over a mountain range in such a manner that newly created ice particles can grow and fall to the ground as additional snow on a specified target area. The review summarizes the results of physical, statistical, and modeling studies aimed at evaluating this underlying hypothesis, with a focus on results from more recent experiments that take advantage of modern instrumentation and advanced computation capabilities. Recent advances in assessment and operations are also reviewed, and recommendations for future experiments, based on the successes and failures of experiments of the past, are given.

Myeloid cells are critical for orchestrating regulated inflammation during wound healing. TLRs, particularly TLR4, and its downstream-signaling MyD88 pathway play an important role in regulating myeloid-mediated inflammation. Because an initial inflammatory phase is vital for tissue repair, we investigated the role of TLR4-regulated, myeloid-mediated inflammation in wound healing. In a cutaneous tissue injury murine model, we found that TLR4 expression is dynamic in wound myeloid cells during the course of normal wound healing. We identified that changes in myeloid TLR4 during tissue repair correlated with increased expression of the histone methyltransferase, mixed-lineage leukemia 1 (MLL1), which specifically trimethylates the histone 3 lysine 4 (H3K4me3) position of the TLR4 promoter. Furthermore, we used a myeloid-specific Mll1 knockout (Mll1f/fLyz2Cre+) to determine MLL1 drives Tlr4 expression during wound healing. To understand the critical role of myeloid-specific TLR4 signaling, we used mice deficient in Tlr4 (Tlr4−/−), Myd88 (Myd88−/−), and myeloid-specific Tlr4 (Tlr4f/fLyz2Cre+) to demonstrate delayed wound healing at early time points postinjury. Furthermore, in vivo wound myeloid cells isolated from Tlr4−/− and Myd88−/− wounds demonstrated decreased inflammatory cytokine production. Importantly, adoptive transfer of monocyte/macrophages from wild-type mice trafficked to wounds with restoration of normal healing and myeloid cell function in Tlr4-deficient mice. These results define a role for myeloid-specific, MyD88-dependent TLR4 signaling in the inflammatory response following cutaneous tissue injury and suggest that MLL1 regulates TLR4 expression in wound myeloid cells.

Significance The COVID-19 pandemic has disproportionately affected patients with comorbidities, namely, obesity and type 2 diabetes. Macrophages (Mφs) are a key innate immune cell primarily responsible for the harmful, hyperinflammatory “cytokine storm” in patients that develop severe COVID-19. We describe a mechanism for this Mφ-mediated cytokine storm in response to coronavirus. In response to coronavirus infection, expression of the chromatin-modifying enzyme, SETDB2, decreases in Mφs, leading to increased transcription of inflammatory cytokines. Further, we find SETDB2 is regulated by an interferon beta (IFNβ)/JaK/STAT3 mechanism, and that exogenous administration of IFNβ can reverse inflammation, particularly in diabetic Mφs via an increase in SETDB2. Together, these results suggest therapeutic targeting of the IFNβ/SETDB2 axis in diabetic patients with COVID-19 may decrease pathologic inflammation., COVID-19 induces a robust, extended inflammatory “cytokine storm” that contributes to an increased morbidity and mortality, particularly in patients with type 2 diabetes (T2D). Macrophages are a key innate immune cell population responsible for the cytokine storm that has been shown, in T2D, to promote excess inflammation in response to infection. Using peripheral monocytes and sera from human patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and a murine hepatitis coronavirus (MHV-A59) (an established murine model of SARS), we identified that coronavirus induces an increased Mφ-mediated inflammatory response due to a coronavirus-induced decrease in the histone methyltransferase, SETDB2. This decrease in SETDB2 upon coronavirus infection results in a decrease of the repressive trimethylation of histone 3 lysine 9 (H3K9me3) at NFkB binding sites on inflammatory gene promoters, effectively increasing inflammation. Mφs isolated from mice with a myeloid-specific deletion of SETDB2 displayed increased pathologic inflammation following coronavirus infection. Further, IFNβ directly regulates SETDB2 in Mφs via JaK1/STAT3 signaling, as blockade of this pathway altered SETDB2 and the inflammatory response to coronavirus infection. Importantly, we also found that loss of SETDB2 mediates an increased inflammatory response in diabetic Mϕs in response to coronavirus infection. Treatment of coronavirus-infected diabetic Mφs with IFNβ reversed the inflammatory cytokine production via up-regulation of SETDB2/H3K9me3 on inflammatory gene promoters. Together, these results describe a potential mechanism for the increased Mφ-mediated cytokine storm in patients with T2D in response to COVID-19 and suggest that therapeutic targeting of the IFNβ/SETDB2 axis in T2D patients may decrease pathologic inflammation associated with COVID-19.

Wound repair following acute injury requires a coordinated inflammatory response. Type I IFN signaling is important for regulating the inflammatory response after skin injury. IFN-κ, a type I IFN, has recently been found to drive skin inflammation in lupus and psoriasis; however, the role of IFN-κ in the context of normal or dysregulated wound healing is unclear. Here, we show that Ifnk expression is upregulated in keratinocytes early after injury and is essential for normal tissue repair. Under diabetic conditions, IFN-κ was decreased in wound keratinocytes, and early inflammation was impaired. Furthermore, we found that the histone methyltransferase mixed-lineage leukemia 1 (MLL1) is upregulated early following injury and regulates Ifnk expression in diabetic wound keratinocytes via an H3K4me3-mediated mechanism. Using a series of in vivo studies with a geneticall y engineered mouse model (Mll1fl/fl K14cre-) and human wound tissues from patients with T2D, we demonstrate that MLL1 controls wound keratinocyte-mediated Ifnk expression and that Mll1 expression is decreased in T2D keratinocytes. Importantly, we found the administration of IFN-κ early following injury improves diabetic tissue repair through increasing early inflammation, collagen deposition, and reepithelialization. These findings have significant implications for understanding the complex role type I IFNs play in keratinocytes in normal and diabetic wound healing. Additionally, they suggest that IFN may be a viable therapeutic target to improve diabetic wound repair.

Abdominal aortic aneurysms (AAAs) are a life-threatening disease characterized by macrophage infiltration contributing to pathological vascular remodeling. Herein, we demonstrate that the histone demethylase JMJD3 is a critical regulator of inflammation during AAA development and cell-specific inhibition reduces AAA progression., Abdominal aortic aneurysms (AAAs) are a life-threatening disease for which there is a lack of effective therapy preventing aortic rupture. During AAA formation, pathological vascular remodeling is driven by macrophage infiltration, and the mechanisms regulating macrophage-mediated inflammation remain undefined. Recent evidence suggests that an epigenetic enzyme, JMJD3, plays a critical role in establishing macrophage phenotype. Using single-cell RNA sequencing of human AAA tissues, we identified increased JMJD3 in aortic monocyte/macrophages resulting in up-regulation of an inflammatory immune response. Mechanistically, we report that interferon-β regulates Jmjd3 expression via JAK/STAT and that JMJD3 induces NF-κB–mediated inflammatory gene transcription in infiltrating aortic macrophages. In vivo targeted inhibition of JMJD3 with myeloid-specific genetic depletion (JMJD3f/fLyz2Cre+) or pharmacological inhibition in the elastase or angiotensin II–induced AAA model preserved the repressive H3K27me3 on inflammatory gene promoters and markedly reduced AAA expansion and attenuated macrophage-mediated inflammation. Together, our findings suggest that cell-specific pharmacologic therapy targeting JMJD3 may be an effective intervention for AAA expansion., Graphical Abstract

While the PCMH is the primary care model of choice for many healthcare systems, it is a relatively new area for college communities. The college health setting provides an important and challenging primary care platform because of developmental milestones that young adults face at this time of their lives. The Brown Primary Care Transformation Initiative (BPCTI) facilitated PCMH practice transformation efforts within a university center from 2013-2015. A mixed methods evaluative approach was used for baseline and follow-up periods as part of a broader transformation initiative that included interviews, surveys, focus groups, and observations. The college health practice was engaged in a number of other transformation activities concurrently. Results suggest that these multiple efforts, of which BPCTI's facilitation was one, together had a positive effect in this college health setting. This intervention provides a unique window into strengths and challenges for a college health practice as it seeks to transform its provision of primary care.

Macrophages are a primary immune cell involved in inflammation, and their cell plasticity allows for transition from an inflammatory to a reparative phenotype and is critical for normal tissue repair following injury. Evidence suggests that epigenetic alterations play a critical role in establishing macrophage phenotype and function during normal and pathologic wound repair. Here, we find in human and murine wound macrophages that cyclooxygenase 2/prostaglandin E2 (COX-2/PGE2) is elevated in diabetes and regulates downstream macrophage-mediated inflammation and host defense. Using single-cell RNA sequencing of human wound tissue, we identify increased NF-κB–mediated inflammation in diabetic wounds and show increased COX-2/PGE2 in diabetic macrophages. Further, we identify that COX-2/PGE2 production in wound macrophages requires epigenetic regulation of 2 key enzymes in the cytosolic phospholipase A2/COX-2/PGE2 (cPLA2/COX-2/PGE2) pathway. We demonstrate that TGF-β–induced miRNA29b increases COX-2/PGE2 production via inhibition of DNA methyltransferase 3b–mediated hypermethylation of the Cox-2 promoter. Further, we find mixed-lineage leukemia 1 (MLL1) upregulates cPLA2 expression and drives COX-2/PGE2. Inhibition of the COX-2/PGE2 pathway genetically (Cox2fl/fl Lyz2Cre+) or with a macrophage-specific nanotherapy targeting COX-2 in tissue macrophages reverses the inflammatory macrophage phenotype and improves diabetic tissue repair. Our results indicate the epigenetically regulated PGE2 pathway controls wound macrophage function, and cell-targeted manipulation of this pathway is feasible to improve diabetic wound repair., Epigenetic modification of the COX-2/PGE2 pathway modulates diabetic macrophage phenotype, and cell-targeted manipulation improves diabetic tissue repair.

The Seeded and Natural Orographic Wintertime Clouds: The Idaho Experiment (SNOWIE) project aims to study the impacts of cloud seeding on winter orographic clouds. The field campaign took place in Idaho between 7 January and 17 March 2017 and employed a comprehensive suite of instrumentation, including ground-based radars and airborne sensors, to collect in situ and remotely sensed data in and around clouds containing supercooled liquid water before and after seeding with silver iodide aerosol particles. The seeding material was released primarily by an aircraft. It was hypothesized that the dispersal of the seeding material from aircraft would produce zigzag lines of silver iodide as it dispersed downwind. In several cases, unambiguous zigzag lines of reflectivity were detected by radar, and in situ measurements within these lines have been examined to determine the microphysical response of the cloud to seeding. The measurements from SNOWIE aim to address long-standing questions about the efficacy of cloud seeding, starting with documenting the physical chain of events following seeding. The data will also be used to evaluate and improve computer modeling parameterizations, including a new cloud-seeding parameterization designed to further evaluate and quantify the impacts of cloud seeding.

Heterotopic ossification (HO) is an aberrant regenerative process with ectopic bone induction in response to musculoskeletal trauma, in which mesenchymal stem cells (MSC) differentiate into osteochondrogenic cells instead of myocytes or tenocytes. Despite frequent cases of hospitalized musculoskeletal trauma, the inflammatory responses and cell population dynamics that regulate subsequent wound healing and tissue regeneration are still unclear. Here we examine, using a mouse model of trauma-induced HO, the local microenvironment of the initial post-injury inflammatory response. Single cell transcriptome analyses identify distinct monocyte/macrophage populations at the injury site, with their dynamic changes over time elucidated using trajectory analyses. Mechanistically, transforming growth factor beta-1 (TGFβ1)-producing monocytes/macrophages are associated with HO and aberrant chondrogenic progenitor cell differentiation, while CD47-activating peptides that reduce systemic macrophage TGFβ levels and help ameliorate HO. Our data thus implicate CD47 activation as a therapeutic approach for modulating monocyte/macrophage phenotypes, MSC differentiation and HO formation during wound healing., Aberrant tissue repair may result in heterotopic ossification (HO), but how this process is regulated by local inflammatory responses is still unclear. Here the authors show, using a mouse burn/trauma model, that TGFβ-producing monocytes/macrophages at the injury site contribute to HO induction, while CD47 activation helps antagonize this process.

Throughout the western United States and other semiarid mountainous regions across the globe, water supplies are fed primarily through the melting of snowpack. Growing populations place higher demands on water, while warmer winters and earlier springs reduce its supply. Water managers are tantalized by the prospect of cloud seeding as a way to increase winter snowfall, thereby shifting the balance between water supply and demand. Little direct scientific evidence exists that confirms even the basic physical hypothesis upon which cloud seeding relies. The intent of glaciogenic seeding of orographic clouds is to introduce aerosol into a cloud to alter the natural development of cloud particles and enhance wintertime precipitation in a targeted region. The hypothesized chain of events begins with the introduction of silver iodide aerosol into cloud regions containing supercooled liquid water, leading to the nucleation of ice crystals, followed by ice particle growth to sizes sufficiently large such that snow falls to the ground. Despite numerous experiments spanning several decades, no direct observations of this process exist. Here, measurements from radars and aircraft-mounted cloud physics probes are presented that together show the initiation, growth, and fallout to the mountain surface of ice crystals resulting from glaciogenic seeding. These data, by themselves, do not address the question of cloud seeding efficacy, but rather form a critical set of observations necessary for such investigations. These observations are unambiguous and provide details of the physical chain of events following the introduction of glaciogenic cloud seeding aerosol into supercooled liquid orographic clouds.

Objective There is a clear need for improved biomarkers to diagnose HIV/TB coinfection. Although numerous tests can identify the existence of both of these microbes within the host, a parallel assessment of the host response to HIV/TB coinfection may prove as useful confirmation in cases where microbiological tests are inconclusive. To this end we assessed the levels of Notch ligands found in serum samples of patients with TB, HIV or HIV/TB coinfection. The Notch system is involved in almost every stage of development, including the maturation of the immune response. Upon exposure to a pathogen, the innate immune system will increase expression of Notch ligands Delta-like 1 and Delta-like 4. Previous research has demonstrated that Notch ligand expression is increased on monocytes from patients diagnosed with tuberculosis. We hypothesized that if Notch ligands were present in the peripheral blood of individuals diagnosed with TB, they may serve as a novel marker for infection. Design: Serum samples from patients with HIV, TB or HIV/TB coinfection were compared to serum from uninfected individuals to determine levels of DLL1 and DLL4 in a case controlled study. Methods DLL1 and DLL4 were measured by ELISA. Linear regression with post tests were used to determine if levels of DLL1 and DLL4 were increased in individuals with HIV/TB coinfection as compared to individuals infected with either HIV or TB or healthy controls. Results Delta-like 1 and Delta-like 4 were significantly increased in the serum of patients with HIV and HIV/ M. tuberculosis coinfection compared to other groups. Conclusions Assessment of Notch ligands in peripheral blood may enhance the diagnosis of individuals with active TB that are co-infected with HIV. The study will also need to be validated in in a larger cohort.