An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition

Mitogen-activated protein kinase (MAPK) pathway antagonists induce profound clinical responses in advanced cutaneous melanoma, but complete remissions are frustrated by the development of acquired resistance. Before resistance emerges, adaptive responses establish a mutation-independent drug tolerance. Antagonizing these adaptive responses could improve drug effects, thereby thwarting the emergence of acquired resistance. In this study, we reveal that inflammatory niches consisting of tumor-associated macrophages and fibroblasts contribute to treatment tolerance through a cytokine-signaling network that involves macrophage-derived IL-1β and fibroblast-derived CXCR2 ligands. Fibroblasts require IL-1β to produce CXCR2 ligands, and loss of host IL-1R signaling in vivo reduces melanoma growth. In tumors from patients on treatment, signaling from inflammatory niches is amplified in the presence of MAPK inhibitors. Signaling from inflammatory niches counteracts combined BRAF/MEK (MAPK/extracellular signal–regulated kinase kinase) inhibitor treatment, and consequently, inhibiting IL-1R or CXCR2 signaling in vivo enhanced the efficacy of MAPK inhibitors. We conclude that melanoma inflammatory niches adapt to and confer drug tolerance toward BRAF and MEK inhibitors early during treatmen

Climate drives the geography of marine consumption by changing predator communities

Este artículo contiene 7 páginas, 3 figuras, 1 tabla.The global distribution of primary production and consumption by humans (fisheries) is well-documented, but we have no map linking the central ecological process of consumption within food webs to temperature and other ecological drivers. Using standardized assays that span 105° of latitude on four continents, we show that rates of bait consumption by generalist predators in shallow marine ecosystems are tightly linked to both temperature and the composition of consumer assemblages. Unexpectedly, rates of consumption peaked at midlatitudes (25 to 35°) in both Northern and Southern Hemispheres across both seagrass and unvegetated sediment habitats. This pattern contrasts with terrestrial systems, where biotic interactions reportedly weaken away from the equator, but it parallels an emerging pattern of a subtropical peak in marine biodiversity. The higher consumption at midlatitudes was closely related to the type of consumers present, which explained rates of consumption better than consumer density, biomass, species diversity, or habitat. Indeed, the apparent effect of temperature on consumption was mostly driven by temperature-associated turnover in consumer community composition. Our findings reinforce the key influence of climate warming on altered species composition and highlight its implications for the functioning of Earth’s ecosystems.We acknowledge funding from the Smithsonian Institution and the Tula Foundation.Peer reviewe

The ABC130 barrel module prototyping programme for the ATLAS strip tracker

For the Phase-II Upgrade of the ATLAS Detector, its Inner Detector, consisting of silicon pixel, silicon strip and transition radiation sub-detectors, will be replaced with an all new 100 % silicon tracker, composed of a pixel tracker at inner radii and a strip tracker at outer radii. The future ATLAS strip tracker will include 11,000 silicon sensor modules in the central region (barrel) and 7,000 modules in the forward region (end-caps), which are foreseen to be constructed over a period of 3.5 years. The construction of each module consists of a series of assembly and quality control steps, which were engineered to be identical for all production sites. In order to develop the tooling and procedures for assembly and testing of these modules, two series of major prototyping programs were conducted: an early program using readout chips designed using a 250 nm fabrication process (ABCN-25) and a subsequent program using a follow-up chip set made using 130 nm processing (ABC130 and HCC130 chips). This second generation of readout chips was used for an extensive prototyping program that produced around 100 barrel-type modules and contributed significantly to the development of the final module layout. This paper gives an overview of the components used in ABC130 barrel modules, their assembly procedure and findings resulting from their tests.Comment: 82 pages, 66 figure

Study of n-on-p sensors breakdown in presence of dielectrics placed on top surface

The ATLAS Experiment at LHC will have several upgrade projects for High Luminosity LHC operations. Its tracking system will be replaced to cope with the higher interaction rate and radiation levels. The Strip portion of the tracker will be significantly expanded in radius and instrumented area to control the occupancy and momentum resolution. The strip modules are based on large-area n-on-p sensors with short strips, designed to work with the larger particle fluxes and radiation hardness requirements. The strip module design has readout flex circuit glued directly on top of the sensors’ active area to facilitate the assembly process and minimize the radiation length. Adhesive spread outward to the guard ring (GR) region is typically avoided to control the sensor breakdown. However, due to the large number of modules to be constructed, on the order of 20000, such occasions may in principle happen, depending on the process precision control. Therefore, the adhesive influence on the sensor breakdown and the breakdown mechanism are of interest. In this contribution we report on the studies of the breakdown behavior with prototype sensors, where adhesives were placed on top of the sensor, either directly in the GR region, or in the active area far away from it. Several adhesives under consideration for module building were used in these measurements. The measurements after thermo-cycling and after irradiation were also performed

Distinct mechanisms regulate IL1B gene transcription in lymphoid CD4 T cells and monocytes

Interleukin 1? is a pro-inflammatory cytokine important for both normal immune responses and chronic inflammatory diseases. The regulation of the 31 kDa proIL-1? precursor coded by the IL1B gene has been extensively studied in myeloid cells, but not in lymphoid-derived CD4 T cells. Surprisingly, we found that some CD4 T cell subsets express higher levels of proIL-1? than unstimulated monocytes, despite relatively low IL1B mRNA levels. We observed a significant increase in IL1B transcription and translation in CD4 T cells upon ex vivo CD3/CD28 activation, and a similar elevation in the CCR5+ effector memory population compared to CCR5? T cells in vivo. The rapid and vigorous increase in IL1B gene transcription for stimulated monocytes has previously been associated with the presence of Spi-1/PU.1 (Spi1), a myeloid-lineage transcription factor, pre-bound to the promoter. In the case of CD4 T cells, this increase occurred despite the lack of detectable Spi1 at the IL1B promoter. Additionally, we found altered epigenetic regulation of the IL1B locus in CD3/CD28–activated CD4 T cells. Unlike monocytes, activated CD4 T cells possess bivalent H3K4me3+/H3K27me3+ nucleosome marks at the IL1B promoter, reflecting low transcriptional activity. These results support a model in which the IL1B gene in CD4 T cells is transcribed from a low-activity bivalent promoter independent of Spi1. Accumulated cytoplasmic proIL-1? may ultimately be cleaved to mature 17 kDa bioactive IL-1?, regulating T cell polarization and pathogenic chronic inflammation

Strip sensor performance in prototype modules built for ATLAS ITk

The ATLAS Phase-II Upgrade for the High-Luminosity LHC features replacement of the Inner Detector with an all-silicon Inner Tracker (ITk). The majority of the instrumented area in ITk is occupied by strip modules covering 165 m2. A vigorous R&D program has been on-going for many years to prepare for the scale of the project and to work out technical issues at all key components of the system, including the strip sensors, readout ASICs, hybrids, modules, and staves. In this submission we report on the performance of silicon strip sensors used in the last completed round of module prototyping. Over 80 modules were built and tested with electrical readout on the per-channel basis and the sensor performance was assessed. In general, an excellent performance was observed, consistent with previous ASIC-level and sensor-level tests. However, the lessons learned included two phenomena important for the future phases of the project. First was the need to store and test the modules in a dry environment due to humidity sensitivity of the sensors. The second was a rare observation of high noise on some channels, at the rate of about 3%. The high noise regions were tested further in several ways, including monitoring the performance as a function of time and bias voltage. Additionally, direct sensor-level tests were performed on the affected channels. The inter-strip resistance and bias resistance tests showed low values, indicating a temporary loss of the inter-strip isolation. A subsequent recovery of the noise performance was observed. We present the test details, an analysis of how the inter-strip isolation affects the module noise, and relationship with sensor-level quality control tests