Identification of novel synthetic lethal vulnerability in non small cell lung cancer by co targeting TMPRSS4 and DDR1

Finding novel targets in non-small cell lung cancer (NSCLC) is highly needed and identification of synthetic lethality between two genes is a new approach to target NSCLC. We previously found that TMPRSS4 promotes NSCLC growth and constitutes a prognostic biomarker. Here, through large-scale analyses across 5 public databases we identified consistent co-expression between TMPRSS4 and DDR1. Similar to TMPRSS4, DDR1 promoter was hypomethylated in NSCLC in 3 independent cohorts and hypomethylation was an independent prognostic factor of disease-free survival. Treatment with 5-azacitidine increased DDR1 levels in cell lines, suggesting an epigenetic regulation. Cells lacking TMPRSS4 were highly sensitive to the cytotoxic effect of the DDR1 inhibitor dasatinib. TMPRSS4/DDR1 double knock-down (KD) cells, but not single KD cells suffered a G0/G1 cell cycle arrest with loss of E2F1 and cyclins A and B, increased p21 levels and a larger number of cells in apoptosis. Moreover, double KD cells were highly sensitized to cisplatin, which caused massive apoptosis (~40%). In vivo studies demonstrated tumor regression in double KD-injected mice. In conclusion, we have identified a novel vulnerability in NSCLC resulting from a synthetic lethal interaction between DDR1 and TMPRSS4

All-particle cosmic ray energy spectrum measured by the HAWC experiment from 10 to 500 TeV

We report on the measurement of the all-particle cosmic ray energy spectrum with the High Altitude Water Cherenkov (HAWC) Observatory in the energy range 10 to 500 TeV. HAWC is a ground based air-shower array deployed on the slopes of Volcan Sierra Negra in the state of Puebla, Mexico, and is sensitive to gamma rays and cosmic rays at TeV energies. The data used in this work were taken from 234 days between June 2016 to February 2017. The primary cosmic-ray energy is determined with a maximum likelihood approach using the particle density as a function of distance to the shower core. Introducing quality cuts to isolate events with shower cores landing on the array, the reconstructed energy distribution is unfolded iteratively. The measured all-particle spectrum is consistent with a broken power law with an index of $-2.49\pm0.01$ prior to a break at $(45.7\pm0.1$) TeV, followed by an index of $-2.71\pm0.01$. The spectrum also respresents a single measurement that spans the energy range between direct detection and ground based experiments. As a verification of the detector response, the energy scale and angular resolution are validated by observation of the cosmic ray Moon shadow's dependence on energy.Comment: 16 pages, 11 figures, 4 tables, submission to Physical Review

Constraining the pˉ/p\bar{p}/p Ratio in TeV Cosmic Rays with Observations of the Moon Shadow by HAWC

An indirect measurement of the antiproton flux in cosmic rays is possible as the particles undergo deflection by the geomagnetic field. This effect can be measured by studying the deficit in the flux, or shadow, created by the Moon as it absorbs cosmic rays that are headed towards the Earth. The shadow is displaced from the actual position of the Moon due to geomagnetic deflection, which is a function of the energy and charge of the cosmic rays. The displacement provides a natural tool for momentum/charge discrimination that can be used to study the composition of cosmic rays. Using 33 months of data comprising more than 80 billion cosmic rays measured by the High Altitude Water Cherenkov (HAWC) observatory, we have analyzed the Moon shadow to search for TeV antiprotons in cosmic rays. We present our first upper limits on the $\bar{p}/p$ fraction, which in the absence of any direct measurements, provide the tightest available constraints of $\sim1\%$ on the antiproton fraction for energies between 1 and 10 TeV.Comment: 10 pages, 5 figures. Accepted by Physical Review

Search for very-high-energy emission from Gamma-ray Bursts using the first 18 months of data from the HAWC Gamma-ray Observatory

The High Altitude Water Cherenkov (HAWC) Gamma-ray Observatory is an extensive air shower detector operating in central Mexico, which has recently completed its first two years of full operations. If for a burst like GRB 130427A at a redshift of 0.34 and a high-energy component following a power law with index -1.66, the high-energy component is extended to higher energies with no cut-off other than from extragalactic background light attenuation, HAWC would observe gamma rays with a peak energy of $\sim$300 GeV. This paper reports the results of HAWC observations of 64 gamma-ray bursts (GRBs) detected by $\mathit{Swift}$ and $\mathit{Fermi}$, including three GRBs that were also detected by the Large Area Telescope ($\mathit{Fermi}$-LAT). An ON/OFF analysis method is employed, searching on the time scale given by the observed light curve at keV-MeV energies and also on extended time scales. For all GRBs and time scales, no statistically significant excess of counts is found and upper limits on the number of gamma rays and the gamma-ray flux are calculated. GRB 170206A, the third brightest short GRB detected by the Gamma-ray Burst Monitor on board the $\mathit{Fermi}$ satellite ($\mathit{Fermi}$-GBM) and also detected by the LAT, occurred very close to zenith. The LAT measurements can neither exclude the presence of a synchrotron self-Compton (SSC) component nor constrain its spectrum. Instead, the HAWC upper limits constrain the expected cut-off in an additional high-energy component to be less than $100~\rm{GeV}$ for reasonable assumptions about the energetics and redshift of the burst.Comment: 19 pages, 6 figures, published in Ap

Assessment of the Degradation Mechanisms of Cu Electrodes during the CO

Catalyst degradation and product selectivity changes are two of the key challenges in the electrochemical reduction of CO on copper electrodes. Yet, these aspects are often overlooked. Here, we combine X-ray spectroscopy, electron microscopy, and characterization techniques to follow the long-term evolution of the catalyst morphology, electronic structure, surface composition, activity, and product selectivity of Cu nanosized crystals during the CO reduction reaction. We found no changes in the electronic structure of the electrode under cathodic potentiostatic control over time, nor was there any build-up of contaminants. In contrast, the electrode morphology is modified by prolonged CO electroreduction, which transforms the initially faceted Cu particles into a rough/rounded structure. In conjunction with these morphological changes, the current increases and the selectivity changes from value-added hydrocarbons to less valuable side reaction products, , hydrogen and CO. Hence, our results suggest that the stabilization of a faceted Cu morphology is pivotal for ensuring optimal long-term performance in the selective reduction of CO into hydrocarbons and oxygenated products

High Altitude characterization of the Hunga Pressure Wave with Cosmic Rays by the HAWC Observatory

High-energy cosmic rays that hit the Earth can be used to study large-scale atmospheric perturbations. After a first interaction in the upper parts of the atmosphere, cosmic rays produce a shower of particles that sample the atmosphere down to the detector level. The HAWC (High-Altitude Water Cherenkov) cosmic-ray observatory in Central Mexico at 4,100 m elevation detects air shower particles continuously with 300 water Cherenkov detectors with an active area of 12,500 m$^{2}$. On January 15th, 2022, HAWC detected the passage of the pressure wave created by the explosion of the Hunga volcano in the Tonga islands, 9,000 km away, as an anomaly in the measured rate of shower particles. The HAWC measurements are used to characterize the shape of four pressure wave passages, determine the propagation speed of each one, and correlate the variations of the shower particle rates with the barometric pressure changes, extracting a barometric parameter. The profile of the shower particle rate and atmospheric pressure variations for the first transit of the pressure wave at HAWC is compared to the pressure measurements at Tonga island, near the volcanic explosion. This work opens the possibility of using large particle cosmic-ray air shower detectors to trace large atmospheric transient waves.Comment: Contact about this analysis: A. Sandoval ([email protected]), A. Lara ([email protected]) & H. Le\'on Vargas ([email protected]

HAWC Study of Very-High-Energy γ\gamma-ray Spectrum of HAWC J1844-034

Recently, the region surrounding eHWC J1842-035 has been studied extensively by gamma-ray observatories due to its extended emission reaching up to a few hundred TeV and potential as a hadronic accelerator. In this work, we use 1,910 days of cumulative data from the High Altitude Water Cherenkov (HAWC) observatory to carry out a dedicated systematic source search of the eHWC J1842-035 region. During the search we have found three sources in the region, namely, HAWC J1844-034, HAWC J1843-032, and HAWC J1846-025. We have identified HAWC J1844-034 as the extended source that emits photons with energies up to 175 TeV. We compute the spectrum for HAWC J1844-034 and by comparing with the observational results from other experiments, we have identified HESS J1843-033, LHAASO J1843-0338, and TASG J1844-038 as very-high-energy gamma-ray sources with a matching origin. Also, we present and use the multi-wavelength data to fit the hadronic and leptonic particle spectra. We have identified four pulsar candidates in the nearby region from which PSR J1844-0346 is found to be the most likely candidate due to its proximity to HAWC J1844-034 and the computed energy budget. We have also found SNR G28.6-0.1 as a potential counterpart source of HAWC J1844-034 for which both leptonic and hadronic scenarios are feasible.Comment: 13 pages, 9 figures, published in Ap