Targeting the immune checkpoint pathway has demonstrated antitumor cytotoxicity in treatment-refractory head and neck squamous cell carcinoma (HNSC). To understand the molecular mechanisms ...underpinning its antitumor response, we characterized the immune landscape of HNSC by their tumor and stromal compartments to identify novel immune molecular subgroups.
A training cohort of 522 HNSC samples from the Cancer Genome Atlas profiled by RNA sequencing was analyzed. We separated gene expression patterns from tumor, stromal, and immune cell gene using a non-negative matrix factorization algorithm. We correlated the expression patterns with a set of immune-related gene signatures, potential immune biomarkers, and clinicopathological features. Six independent datasets containing 838 HNSC samples were used for validation.
Approximately 40% of HNSCs in the cohort (211/522) were identified to show enriched inflammatory response, enhanced cytolytic activity, and active interferon-γ signaling (all, P < 0.001). We named this new molecular class of tumors the Immune Class. Then we found it contained two distinct microenvironment-based subtypes, characterized by markers of active or exhausted immune response. The Exhausted Immune Class was characterized by enrichment of activated stroma and anti-inflammatory M2 macrophage signatures, WNT/transforming growth factor-β signaling pathway activation and poor survival (all, P < 0.05). An enriched proinflammatory M1 macrophage signature, enhanced cytolytic activity, abundant tumor-infiltrating lymphocytes, high human papillomavirus (HPV) infection, and favorable prognosis were associated with Active Immune Class (all, P < 0.05). The robustness of these immune molecular subgroups was verified in the validation cohorts, and Active Immune Class showed potential response to programmed cell death-1 blockade (P = 0.01).
This study revealed a novel Immune Class in HNSC; two subclasses characterized by active or exhausted immune responses were also identified. These findings provide new insights into tailoring immunotherapeutic strategies for different HNSC subgroups.
The population of Milky Way (MW) satellites contains the faintest known galaxies and thus provides essential insight into galaxy formation and dark matter microphysics. Here we combine a model of the ...galaxy-halo connection with newly derived observational selection functions based on searches for satellites in photometric surveys over nearly the entire high Galactic latitude sky. In particular, we use cosmological zoom-in simulations of MW-like halos that include realistic Large Magellanic Cloud (LMC) analogs to fit the position-dependent MW satellite luminosity function. We report decisive evidence for the statistical impact of the LMC on the MW satellite population due to an estimated 6 2 observed LMC-associated satellites, consistent with the number of LMC satellites inferred from Gaia proper-motion measurements, confirming the predictions of cold dark matter models for the existence of satellites within satellite halos. Moreover, we infer that the LMC fell into the MW within the last 2 Gyr at high confidence. Based on our detailed full-sky modeling, we find that the faintest observed satellites inhabit halos with peak virial masses below at 95% confidence, and we place the first robust constraints on the fraction of halos that host galaxies in this regime. We predict that the faintest detectable satellites occupy halos with peak virial masses above , highlighting the potential for powerful galaxy formation and dark matter constraints from future dwarf galaxy searches.
Abstract
The DECam Local Volume Exploration survey (DELVE) is a 126-night survey program on the 4 m Blanco Telescope at the Cerro Tololo Inter-American Observatory in Chile. DELVE seeks to understand ...the characteristics of faint satellite galaxies and other resolved stellar substructures over a range of environments in the Local Volume. DELVE will combine new DECam observations with archival DECam data to cover ∼15,000 deg
2
of high Galactic latitude (∣
b
∣ > 10°) southern sky to a 5
σ
depth of
g
,
r
,
i
,
z
∼ 23.5 mag. In addition, DELVE will cover a region of ∼2200 deg
2
around the Magellanic Clouds to a depth of
g
,
r
,
i
∼ 24.5 mag and an area of ∼135 deg
2
around four Magellanic analogs to a depth of
g
,
i
∼ 25.5 mag. Here, we present an overview of the DELVE program and progress to date. We also summarize the first DELVE public data release (DELVE DR1), which provides point-source and automatic aperture photometry for ∼520 million astronomical sources covering ∼5000 deg
2
of the southern sky to a 5
σ
point-source depth of
g
= 24.3 mag,
r
= 23.9 mag,
i
= 23.3 mag, and
z
= 22.8 mag. DELVE DR1 is publicly available via the NOIRLab Astro Data Lab science platform.
ABSTRACT We report the discovery of eight new ultra-faint dwarf galaxy candidates in the second year of optical imaging data from the Dark Energy Survey (DES). Six of these candidates are detected at ...high confidence, while two lower-confidence candidates are identified in regions of non-uniform survey coverage. The new stellar systems are found by three independent automated search techniques and are identified as overdensities of stars, consistent with the isochrone and luminosity function of an old and metal-poor simple stellar population. The new systems are faint (MV > −4.7 ) and span a range of physical sizes (17 < r1/2 < 181 ) and heliocentric distances (25 kpc < D < 214 kpc). All of the new systems have central surface brightnesses consistent with known ultra-faint dwarf galaxies ( 27.5 −2). Roughly half of the DES candidates are more distant, less luminous, and/or have lower surface brightnesses than previously known Milky Way satellite galaxies. Most of the candidates are found in the southern part of the DES footprint close to the Magellanic Clouds. We find that the DES data alone exclude (p < 10−3) a spatially isotropic distribution of Milky Way satellites and that the observed distribution can be well, though not uniquely, described by an association between several of the DES satellites and the Magellanic system. Our model predicts that the full sky may hold ∼100 ultra-faint galaxies with physical properties comparable to the DES satellites and that 20%-30% of these would be spatially associated with the Magellanic Clouds.
Drug can cause almost all known types of acute, subacute, and chronic liver injuries. Drug-induced liver injury (DILI) is an important cause of unexplained liver injury in clinical practice. Correct ...diagnosis of DILI is challenging due to lack of specific diagnostic biomarkers, especially in patients with pre-existing liver disease and multiple concomitant drugs. A comprehensive understanding of the risk factors, clinical features, and prognosis of liver injury caused by different drugs will help physicians to recognize, diagnose, and manage it timely. Although the guideline was developed based on evidence-based medicine provided by the latest studies, there is limited high-quality evidence in the field of DILI. Therefore, this guideline should be interpreted with caution, and physicians should adopt an optimal diagnostic and therapeutic strategy for individual patients within the framework of the guideline.
We perform a comprehensive study of Milky Way (MW) satellite galaxies to constrain the fundamental properties of dark matter (DM). This analysis fully incorporates inhomogeneities in the spatial ...distribution and detectability of MW satellites and marginalizes over uncertainties in the mapping between galaxies and DM halos, the properties of the MW system, and the disruption of subhalos by the MW disk. Our results are consistent with the cold, collisionless DM paradigm and yield the strongest cosmological constraints to date on particle models of warm, interacting, and fuzzy dark matter. At 95% confidence, we report limits on (i) the mass of thermal relic warm DM, m_{WDM}>6.5 keV (free-streaming length, λ_{fs}≲10h^{-1} kpc), (ii) the velocity-independent DM-proton scattering cross section, σ_{0}<8.8×10^{-29} cm^{2} for a 100 MeV DM particle mass DM-proton coupling, c_{p}≲(0.3 GeV)^{-2}, and (iii) the mass of fuzzy DM, m_{ϕ}>2.9×10^{-21} eV (de Broglie wavelength, λ_{dB}≲0.5 kpc). These constraints are complementary to other observational and laboratory constraints on DM properties.
ABSTRACT
Obtaining accurately calibrated redshift distributions of photometric samples is one of the great challenges in photometric surveys like LSST, Euclid, HSC, KiDS, and DES. We present an ...inference methodology that combines the redshift information from the galaxy photometry with constraints from two-point functions, utilizing cross-correlations with spatially overlapping spectroscopic samples, and illustrate the approach on CosmoDC2 simulations. Our likelihood framework is designed to integrate directly into a typical large-scale structure and weak lensing analysis based on two-point functions. We discuss efficient and accurate inference techniques that allow us to scale the method to the large samples of galaxies to be expected in LSST. We consider statistical challenges like the parametrization of redshift systematics, discuss and evaluate techniques to regularize the sample redshift distributions, and investigate techniques that can help to detect and calibrate sources of systematic error using posterior predictive checks. We evaluate and forecast photometric redshift performance using data from the CosmoDC2 simulations, within which we mimic a DESI-like spectroscopic calibration sample for cross-correlations. Using a combination of spatial cross-correlations and photometry, we show that we can provide calibration of the mean of the sample redshift distribution to an accuracy of at least 0.002(1 + z), consistent with the LSST-Y1 science requirements for weak lensing and large-scale structure probes.
The successful market availability of immune checkpoint inhibitors (ICIs) has brought revolutionary changes to the treatment of hepatocellular carcinoma (HCC). With the widespread application of ICIs ...in HCC patients, the impact or even termination of antitumor therapy due to ICIs hepatotoxicity is a clinical problem that must be faced. However, it is currently unclear whether there are differences in the occurrence and risk factors of ICI hepatotoxicity between HCC patients and other tumors. At the same time, the chronic liver disease that often accompanies HCC patients also poses great challenges to their diagnosis and management. Therefore, clinical physicians need to understand the coping strategies for ICIs hepatotoxicity so as to improve the benefit of immunotherapy for patients.
Virtual photons can mediate interaction between atoms, resulting in an energy shift known as a collective Lamb shift. Observing the collective Lamb shift is challenging, since it can be obscured by ...radiative decay and direct atom-atom interactions. Here, we place two superconducting qubits in a transmission line terminated by a mirror, which suppresses decay. We measure a collective Lamb shift reaching 0.8% of the qubit transition frequency and twice the transition linewidth. We also show that the qubits can interact via the transmission line even if one of them does not decay into it.
Aims
To identify the native‐occurring adipate pathway in a previously engineered Thermobifida fusca B6 strain and optimize the adipic acid production of this strain on glucose and corncob.
Methods ...and Results
The native‐occurring adipate pathway in T. fusca B6 was identified to be the reverse adipate degradation pathway, including five steps: β‐ketothiolase (Tfu_0875), 3‐hydroxyacyl‐CoA dehydrogenase (Tfu_2399), 3‐hydroxyadipyl‐CoA dehydrogenase (Tfu_0067), 5‐Carboxy‐2‐pentenoyl‐CoA reductase (Tfu_1647) and succinyl‐CoA synthetase (Tfu_2576, Tfu_2577). The cell lysates of T. fusca wild‐type strain with the addition of the Tfu_1647 protein produced trace adipic acid, while no adipic acid was produced in the absence of this protein. The above results prove that the low expression of Tfu_1647 in the wild‐type strain was the reason why it did not produce any adipic acid. We then demonstrated that in T. fusca B6, the maximal titre of adipic acid on 50 g l−1 glucose was 2·23 g l−1 with 0·045 g g−1‐glucose yield and 0·22 g l−1 adipic acid was produced from 19·38 g l−1 milled corncob.
Conclusions
The reverse adipate degradation pathway was found to be responsible for the adipate synthesis in T. fusca B6 and Tfu_1647 was the regulatory node on this pathway.
Significance and Impact of the Study
Thermobifida fusca B6 was the first reported micro‐organism using its native‐occurring pathway to accumulate adipic acid. It had the highest reported yield and titre of adipic acid so far.
PDF
