Withdrawal from Extended, Intermittent Access to A Highly Palatable Diet Impairs Hippocampal Memory Function and Neurogenesis: Effects of Memantine.

BACKGROUND: Compulsive eating can be promoted by intermittent access to palatable food and is often accompanied by cognitive deficits and reduction in hippocampal plasticity. Here, we investigated the effects of intermittent access to palatable food on hippocampal function and neurogenesis. METHODS: Male Wistar rats were either fed chow for 7 days/week (Chow/Chow group), or fed chow intermittently for 5 days/week followed by a palatable diet for 2 days/week (Chow/Palatable group). Hippocampal function and neurogenesis were assessed either during withdrawal or following renewed access to palatable food. Furthermore, the ability of the uncompetitive N-methyl-d-aspartate receptor (NMDAR) antagonist memantine to prevent the diet-induced memory deficits and block the maladaptive feeding was tested. RESULTS: Palatable food withdrawn Chow/Palatable rats showed both a weakened ability for contextual spatial processing and a bias in their preference for a "novel cue" over a "novel place," compared to controls. They also showed reduced expression of immature neurons in the dentate gyrus of the hippocampus as well as a withdrawal-dependent decrease of proliferating cells. Memantine treatment was able both to reverse the memory deficits and to reduce the excessive intake of palatable diet and the withdrawal-induced hypophagia in food cycling rats. CONCLUSIONS: In summary, our results provide evidence that withdrawal from highly palatable food produces NMDAR-dependent deficits in hippocampal function and a reduction in hippocampal neurogenesis

Exploring the Coronal Magnetic Field with Galactic Cosmic Rays: The Sun Shadow Observed by HAWC

Galactic cosmic rays (GCRs) are charged particles that reach the heliosphere almost isotropically in a wide energy range. In the inner heliosphere, the GCR flux is modulated by solar activity so that only energetic GCRs reach the lower layers of the solar atmosphere. In this work, we propose that high-energy GCRs can be used to explore the solar magnetic fields at low coronal altitudes. We used GCR data collected by the High-Altitude Water Cherenkov observatory to construct maps of GCR flux coming from the Sun’s sky direction and studied the observed GCR deficit, known as Sun shadow (SS), over a 6 yr period (2016-2021) with a time cadence of 27.3 days. We confirm that the SS is correlated with sunspot number, but we focus on the relationship between the photospheric solar magnetic field measured at different heliolatitudes and the relative GCR deficit at different energies. We found a linear relationship between the relative deficit of GCRs represented by the depth of the SS and the solar magnetic field. This relationship is evident in the observed energy range of 2.5-226 TeV, but is strongest in the range of 12.4 33.4 TeV, which implies that this is the best energy range to study the evolution of magnetic fields in the low solar atmosphere

Galactic Gamma-Ray Diffuse Emission at TeV Energies with HAWC Data

Galactic gamma-ray diffuse emission (GDE) is emitted by cosmic rays (CRs), ultra-relativistic protons, and electrons, interacting with gas and electromagnetic radiation fields in the interstellar medium. Here we present the analysis of teraelectronvolt diffuse emission from a region of the Galactic plane over the range in longitude of l ∈ [43°, 73°], using data collected with the High Altitude Water Cherenkov (HAWC) detector. Spectral, longitudinal, and latitudinal distributions of the teraelectronvolt diffuse emission are shown. The radiation spectrum is compatible with the spectrum of the emission arising from a CR population with an index similar to that of the observed CRs. When comparing with the DRAGON base model, the HAWC GDE flux is higher by about a factor of 2. Unresolved sources such as pulsar wind nebulae and teraelectronvolt halos could explain the excess emission. Finally, deviations of the Galactic CR flux from the locally measured CR flux may additionally explain the difference between the predicted and measured diffuse fluxes

Probing the Extragalactic Mid-infrared Background with HAWC

The extragalactic background light (EBL) contains all the radiation emitted by nuclear and accretion processes in stars and compact objects since the epoch of recombination. Measuring the EBL density directly is challenging, especially in the near-to-far-infrared wave band, mainly due to the zodiacal light foreground. Instead, gamma-ray astronomy offers the possibility to indirectly set limits on the EBL by studying the effects of gamma-ray absorption in the very high energy (VHE: \u3e100 GeV) spectra of distant blazars. The High Altitude Water Cherenkov Gamma Ray Observatory (HAWC) is one of the few instruments sensitive to gamma rays with energies above 10 TeV. This offers the opportunity to probe the EBL in the near/mid-IR region: λ = 1-100 μm. In this study, we fit physically motivated emission models to Fermi-LAT gigaelectronvolt data to extrapolate the intrinsic teraelectronvolt spectra of blazars. We then simulate a large number of absorbed spectra for different randomly generated EBL model shapes and calculate Bayesian credible bands in the EBL intensity space by comparing and testing the agreement between the absorbed spectra and HAWC extragalactic observations of two blazars. The resulting bands are in agreement with current EBL lower and upper limits, showing a downward trend toward higher wavelength values λ \u3e 10 μm also observed in previous measurements

Search for decaying dark matter in the Virgo cluster of galaxies with HAWC

The decay or annihilation of dark matter particles may produce a steady flux of very-high-energy gamma rays detectable above the diffuse background. Nearby clusters of galaxies provide excellent targets to search for the signatures of particle dark matter interactions. In particular, the Virgo cluster spans several degrees across the sky and can be efficiently probed with a wide field-of-view instrument. The High Altitude Water Cherenkov (HAWC) observatory, due to its wide field of view and sensitivity to gamma rays at an energy scale of 300 GeV-100 TeV is well-suited for this search. Using 2141 days of data, we search for γ-ray emission from the Virgo cluster, assuming well-motivated dark matter substructure models. Our results provide some of the strongest constraints on the decay lifetime of dark matter for masses above 10 TeV

Searching for TeV Dark Matter in Irregular Dwarf Galaxies with HAWC Observatory

We present the results of dark matter (DM) searches in a sample of 31 dwarf irregular (dIrr) galaxies within the field of view of the HAWC Observatory. dIrr galaxies are DM-dominated objects in which astrophysical gamma-ray emission is estimated to be negligible with respect to the secondary gamma-ray flux expected by annihilation or decay of weakly interacting massive particles (WIMPs). While we do not see any statistically significant DM signal in dIrr galaxies, we present the exclusion limits (95% C.L.) for annihilation cross section and decay lifetime for WIMP candidates with masses between 1 and 100 TeV. Exclusion limits from dIrr galaxies are relevant and complementary to benchmark dwarf Spheroidal (dSph) galaxies. In fact, dIrr galaxies are targets kinematically different from benchmark dSph, preserving the footprints of different evolution histories. We compare the limits from dIrr galaxies to those from ultrafaint and classical dSph galaxies previously observed with HAWC. We find that the constraints are comparable to the limits from classical dSph galaxies and ∼2 orders of magnitude weaker than the ultrafaint dSph limits

Study of the Very High Energy Emission of M87 through its Broadband Spectral Energy Distribution

The radio galaxy M87 is the central dominant galaxy of the Virgo Cluster. Very high-energy (VHE, ≳0.1 TeV) emission from M87 has been detected by imaging air Cherenkov telescopes. Recently, marginal evidence for VHE long-term emission has also been observed by the High Altitude Water Cherenkov Observatory, a gamma-ray and cosmic-ray detector array located in Puebla, Mexico. The mechanism that produces VHE emission in M87 remains unclear. This emission originates in its prominent jet, which has been spatially resolved from radio to X-rays. In this paper, we construct a spectral energy distribution from radio to gamma rays that is representative of the nonflaring activity of the source, and in order to explain the observed emission, we fit it with a lepto-hadronic emission model. We found that this model is able to explain nonflaring VHE emission of M87 as well as an orphan flare reported in 2005

HAWC Study of the Ultra-high-energy Spectrum of MGRO J1908+06

We report TeV gamma-ray observations of the ultra-high-energy source MGRO J1908+06 using data from the High Altitude Water Cherenkov Observatory. This source is one of the highest-energy known gamma-ray sources, with emission extending past 200 TeV. Modeling suggests that the bulk of the TeV gamma-ray emission is leptonic in nature, driven by the energetic radio-faint pulsar PSR J1907+0602. Depending on what assumptions are included in the model, a hadronic component may also be allowed. Using the results of the modeling, we discuss implications for detection prospects by multi-messenger campaigns

Detailed Analysis of the TeV γ-Ray Sources 3HWC J1928+178, 3HWC J1930+188, and the New Source HAWC J1932+192

The latest High Altitude Water Cherenkov (HAWC) point-like source catalog up to 56 TeV reported the detection of two sources in the region of the Galactic plane at galactic longitude 52° \u3c ℓ \u3c 55°, 3HWC J1930+188 and 3HWC J1928+178. The first one is associated with a known TeV source, the supernova remnant SNR G054.1+00.3. It was discovered by one of the currently operating Imaging Atmospheric Cherenkov Telescope (IACT), the Very Energetic Radiation Imaging Telescope Array System (VERITAS), detected by the High Energy Stereoscopic System (H.E.S.S), and identified as a composite SNR. However, the source 3HWC J1928+178, discovered by HAWC and coincident with the pulsar PSR J1928+1746, was not detected by any IACT despite their long exposure on the region, until a recent new analysis of H.E.S.S. data was able to confirm it. Moreover, no X-ray counterpart has been detected from this pulsar. We present a multicomponent fit of this region using the latest HAWC data. This reveals an additional new source, HAWC J1932+192, which is potentially associated with the pulsar PSR J1932+1916, whose γ-ray emission could come from the acceleration of particles in its pulsar wind nebula. In the case of 3HWC J1928+178, several possible explanations are explored, in an attempt to unveil the origins of the very-high-energy γ-ray emission

Discovery of conformationally constrained ALK2 inhibitors

Despite decades of research on new diffuse intrinsic pontine glioma (DIPG) treatments, little or no progress has been made on improving patient outcomes. In this work, we explored novel scaffold modifications of M4K2009, a 3,5-diphenylpyridine ALK2 inhibitor previously reported by our group. Here we disclose the design, synthesis, and evaluation of a first-in-class set of 5- to 7-membered ether-linked and 7-membered amine-linked constrained inhibitors of ALK2. This rigidification strategy led us to the discovery of the ether-linked inhibitors M4K2308 and M4K2281 and the amine-linked inhibitors M4K2304 and M4K2306, each with superior potency against ALK2. Notably, M4K2304 and M4K2306 exhibit exceptional selectivity for ALK2 over ALK5, surpassing the reference compound. Preliminary studies on their in vivo pharmacokinetics, including blood-brain barrier penetration, revealed that these constrained scaffolds have favorable exposure and do open a novel chemical space for further optimization and future evaluation in orthotopic models of DIPG