Native extracellular matrix probes to target patient- and tissue-specific cell-microenvironment interactions by force spectroscopy

Atomic Force Microscopy (AFM) is successfully used for the quantitative investigation of the cellular mechanosensing of the microenvironment. To this purpose, several force spectroscopy approaches aim at measuring the adhesive forces between two living cells and also between a cell and an appropriate reproduction of the extracellular matrix (ECM), typically exploiting tips suitably functionalised with single components (e.g. collagen, fibronectin) of the ECM. However, these probes only poorly reproduce the complexity of the native cellular microenvironment and consequently of the biological interactions. We developed a novel approach to produce AFM probes that faithfully retain the structural and biochemical complexity of the ECM; this was achieved by attaching to an AFM cantilever a micrometric slice of native decellularised ECM, which was cut by laser microdissection. We demonstrate that these probes preserve the morphological, mechanical, and chemical heterogeneity of the ECM. Native ECM probes can be used in force spectroscopy experiments aimed at targeting cell-microenvironment interactions. Here, we demonstrate the feasibility of dissecting mechanotransductive cell-ECM interactions in the 10 pN range. As proof-of-principle, we tested a rat bladder ECM probe against the AY-27 rat bladder cancer cell line. On the one hand, we obtained reproducible results using different probes derived from the same ECM regions; on the other hand, we detected differences in the adhesion patterns of distinct bladder ECM regions (submucosa, detrusor, and adventitia), in line with the disparities in composition and biophysical properties of these ECM regions. Our results demonstrate that native ECM probes, produced from patient-specific regions of organs and tissues, can be used to investigate cell-microenvironment interactions and early mechanotransductive processes by force spectroscopy. This opens new possibilities in the field of personalised medicine

Unresolved Gamma-Ray Sky through its Angular Power Spectrum

The gamma-ray sky has been observed with unprecedented accuracy in the last decade by the Fermi -large area telescope (LAT), allowing us to resolve and understand the high-energy Universe. The nature of the remaining unresolved emission [unresolved gamma-ray background (UGRB)] below the LAT source detection threshold can be uncovered by characterizing the amplitude and angular scale of the UGRB fluctuation field. This Letter presents a measurement of the UGRB autocorrelation angular power spectrum based on eight years of Fermi-LAT Pass 8 data products. The analysis is designed to be robust against contamination from resolved sources and noise systematics. The sensitivity to subthreshold sources is greatly enhanced with respect to previous measurements. We find evidence (with ∼3.7σ significance) that the scenario in which two classes of sources contribute to the UGRB signal is favored over a single class. A double power law with exponential cutoff can explain the anisotropy energy spectrum well, with photon indices of the two populations being 2.55±0.23 and 1.86±0.15

Search for extended gamma-ray emission from the Virgo galaxy cluster with Fermi-LAT

Galaxy clusters are one of the prime sites to search for dark matter (DM) annihilation signals. Depending on the substructure of the DM halo of a galaxy cluster and the cross sections for DM annihilation channels, these signals might be detectable by the latest generation of $\gamma$-ray telescopes. Here we use three years of Fermi Large Area Telescope (LAT) data, which are the most suitable for searching for very extended emission in the vicinity of nearby Virgo galaxy cluster. Our analysis reveals statistically significant extended emission which can be well characterized by a uniformly emitting disk profile with a radius of 3\deg that moreover is offset from the cluster center. We demonstrate that the significance of this extended emission strongly depends on the adopted interstellar emission model (IEM) and is most likely an artifact of our incomplete description of the IEM in this region. We also search for and find new point source candidates in the region. We then derive conservative upper limits on the velocity-averaged DM pair annihilation cross section from Virgo. We take into account the potential $\gamma$-ray flux enhancement due to DM sub-halos and its complex morphology as a merging cluster. For DM annihilating into $b\overline{b}$, assuming a conservative sub-halo model setup, we find limits that are between 1 and 1.5 orders of magnitude above the expectation from the thermal cross section for $m_{\mathrm{DM}}\lesssim100\,\mathrm{GeV}$. In a more optimistic scenario, we exclude $\langle \sigma v \rangle\sim3\times10^{-26}\,\mathrm{cm^{3}\,s^{-1}}$ for $m_{\mathrm{DM}}\lesssim40\,\mathrm{GeV}$ for the same channel. Finally, we derive upper limits on the $\gamma$-ray-flux produced by hadronic cosmic-ray interactions in the inter cluster medium. We find that the volume-averaged cosmic-ray-to-thermal pressure ratio is less than $\sim6\%$.Comment: 15 pages, 11 figures, 4 tables, accepted for publication in ApJ; corresponding authors: T. Jogler, S. Zimmer & A. Pinzk

Search for Early Gamma-ray Production in Supernovae Located in a Dense Circumstellar Medium with the Fermi LAT

Supernovae (SNe) exploding in a dense circumstellar medium (CSM) are hypothesized to accelerate cosmic rays in collisionless shocks and emit GeV gamma rays and TeV neutrinos on a time scale of several months. We perform the first systematic search for gamma-ray emission in Fermi LAT data in the energy range from 100 MeV to 300 GeV from the ensemble of 147 SNe Type IIn exploding in dense CSM. We search for a gamma-ray excess at each SNe location in a one year time window. In order to enhance a possible weak signal, we simultaneously study the closest and optically brightest sources of our sample in a joint-likelihood analysis in three different time windows (1 year, 6 months and 3 months). For the most promising source of the sample, SN 2010jl (PTF10aaxf), we repeat the analysis with an extended time window lasting 4.5 years. We do not find a significant excess in gamma rays for any individual source nor for the combined sources and provide model-independent flux upper limits for both cases. In addition, we derive limits on the gamma-ray luminosity and the ratio of gamma-ray-to-optical luminosity ratio as a function of the index of the proton injection spectrum assuming a generic gamma-ray production model. Furthermore, we present detailed flux predictions based on multi-wavelength observations and the corresponding flux upper limit at 95% confidence level (CL) for the source SN 2010jl (PTF10aaxf).Comment: Accepted for publication in ApJ. Corresponding author: A. Franckowiak ([email protected]), updated author list and acknowledgement

High-energy emission from a magnetar giant flare in the Sculptor galaxy

Magnetars are the most highly magnetized neutron stars in the cosmos (with magnetic field 1013–1015 G). Giant flares from magnetars are rare, short-duration (about 0.1 s) bursts of hard X-rays and soft γ rays1,2. Owing to the limited sensitivity and energy coverage of previous telescopes, no magnetar giant flare has been detected at gigaelectronvolt (GeV) energies. Here, we report the discovery of GeV emission from a magnetar giant flare on 15 April 2020 (refs. 3,4 and A. J. Castro-Tirado et al., manuscript in preparation). The Large Area Telescope (LAT) on board the Fermi Gamma-ray Space Telescope detected GeV γ rays from 19 s until 284 s after the initial detection of a signal in the megaelectronvolt (MeV) band. Our analysis shows that these γ rays are spatially associated with the nearby (3.5 megaparsecs) Sculptor galaxy and are unlikely to originate from a cosmological γ-ray burst. Thus, we infer that the γ rays originated with the magnetar giant flare in Sculptor. We suggest that the GeV signal is generated by an ultra-relativistic outflow that first radiates the prompt MeV-band photons, and then deposits its energy far from the stellar magnetosphere. After a propagation delay, the outflow interacts with environmental gas and produces shock waves that accelerate electrons to very high energies; these electrons then emit GeV γ rays as optically thin synchrotron radiation. This observation implies that a relativistic outflow is associated with the magnetar giant flare, and suggests the possibility that magnetars can power some short γ-ray bursts

Multiwavelength Evidence for Quasi-periodic Modulation in the Gamma-ray Blazar PG 1553+113

We report for the first time a gamma-ray and multi-wavelength nearly-periodic oscillation in an active galactic nucleus. Using the Fermi Large Area Telescope (LAT) we have discovered an apparent quasi-periodicity in the gamma-ray flux (E >100 MeV) from the GeV/TeV BL Lac object PG 1553+113. The marginal significance of the 2.18 +/-0.08 year-period gamma-ray cycle is strengthened by correlated oscillations observed in radio and optical fluxes, through data collected in the OVRO, Tuorla, KAIT, and CSS monitoring programs and Swift UVOT. The optical cycle appearing in ~10 years of data has a similar period, while the 15 GHz oscillation is less regular than seen in the other bands. Further long-term multi-wavelength monitoring of this blazar may discriminate among the possible explanations for this quasi-periodicity.Comment: 8 pages, 5 figures. Accepted to The Astrophysical Journal Letters. Corresponding authors: S. Ciprini (ASDC/INFN), S. Cutini (ASDC/INFN), S. Larsson (Stockholm Univ/KTH), A. Stamerra (INAF/SNS), D. J. Thompson (NASA GSFC

Fermi and Swift Observations of GRB 190114C: Tracing the Evolution of High-energy Emission from Prompt to Afterglow

We report on the observations of gamma-ray burst (GRB) 190114C by the Fermi Gamma-ray Space Telescope and the Neil Gehrels Swift Observatory. The prompt gamma-ray emission was detected by the Fermi GRB Monitor (GBM), the Fermi Large Area Telescope (LAT), and the Swift Burst Alert Telescope (BAT) and the long-lived afterglow emission was subsequently observed by the GBM, LAT, Swift X-ray Telescope (XRT), and Swift UV Optical Telescope. The early-time observations reveal multiple emission components that evolve independently, with a delayed power-law component that exhibits significant spectral attenuation above 40 MeV in the first few seconds of the burst. This power-law component transitions to a harder spectrum that is consistent with the afterglow emission observed by the XRT at later times. This afterglow component is clearly identifiable in the GBM and BAT light curves as a slowly fading emission component on which the rest of the prompt emission is superimposed. As a result, we are able to observe the transition from internal-shock- to external-shock-dominated emission. We find that the temporal and spectral evolution of the broadband afterglow emission can be well modeled as synchrotron emission from a forward shock propagating into a wind-like circumstellar environment. We estimate the initial bulk Lorentz factor using the observed high-energy spectral cutoff. Considering the onset of the afterglow component, we constrain the deceleration radius at which this forward shock begins to radiate in order to estimate the maximum synchrotron energy as a function of time. We find that even in the LAT energy range, there exist high-energy photons that are in tension with the theoretical maximum energy that can be achieved through synchrotron emission from a shock. These violations of the maximum synchrotron energy are further compounded by the detection of very high-energy (VHE) emission above 300 GeV by MAGIC concurrent with our observations. We conclude that the observations of VHE photons from GRB 190114C necessitates either an additional emission mechanism at very high energies that is hidden in the synchrotron component in the LAT energy range, an acceleration mechanism that imparts energy to the particles at a rate that is faster than the electron synchrotron energy-loss rate, or revisions of the fundamental assumptions used in estimating the maximum photon energy attainable through the synchrotron process