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.
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.
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.
The intrinsic magnetic topological insulatorMnBi2Te4exhibits rich topological effects such as quantum anomalous Hall effect and axion electrodynamics. Here, by combining the use of synchrotron and ...laser light sources, we carry out comprehensive and high-resolution angle-resolved photoemission spectroscopy studies onMnBi2Te4and clearly identify its topological electronic structure. In contrast to theoretical predictions and previous studies, we observe topological surface states with diminished gap forming a characteristic Dirac cone. We argue that the topological surface states are mediated by multidomains of different magnetization orientations. In addition, the temperature evolution of the energy bands clearly reveals their interplay with the magnetic phase transition by showing interesting differences between the bulk and surface states, respectively. The investigation of the detailed electronic structure ofMnBi2Te4and its temperature evolution provides important insight into not only the exotic properties ofMnBi2Te4, but also the generic understanding of the interplay between magnetism and topological electronic structure in magnetic topological quantum materials.
Background The role of intestinal microbiota in the development and function of host physiology is of high interest, especially with respect to the nervous system. While strong evidence has accrued ...that intestinal bacteria alter host nervous system function, mechanisms by which this occurs have remained elusive. For this reason, we have carried out experiments examining the electrophysiological properties of neurons in the myenteric plexus of the enteric nervous system (ENS) in germ‐free (GF) mice compared with specific pathogen‐free (SPF) control mice and adult germ‐free mice that have been conventionalized (CONV‐GF) with intestinal bacteria.
Methods Segments of jejunum from 8 to 12 week old GF, SPF, and CONV‐GF mice were dissected to expose the myenteric plexus. Intracellular recordings in current‐clamp mode were made by impaling cells with sharp microelectrodes. Action potential (AP) shapes, firing thresholds, the number of APs fired at 2× threshold, and passive membrane characteristics were measured.
Key Results In GF mice, excitability was decreased in myenteric afterhyperpolarization (AH) neurons as measured by a lower resting membrane potential and by the number of APs generated at 2× threshold. The post AP slow afterhyperpolarization (sAHP) was prolonged for GF compared with SPF and CONV‐GF animals. Passive membrane characteristics were also altered in GF mice by a decrease in input resistance.
Conclusions & Inferences Here, we report the novel finding that commensal intestinal microbiota are necessary for normal excitability of gut sensory neurons and thus provide a potential mechanism for the transfer of information between the microbiota and nervous system.
Background Commensal bacteria such as probiotics that are neuroactive acutely affect the amplitudes of intestinal migrating motor complexes (MMCs). What is lacking for an improved understanding of ...these motility effects are region specific measurements of velocity and frequency. We have combined intraluminal pressure recordings with spatiotemporal diameter maps to analyze more completely effects of different strains of beneficial bacteria on motility.
Methods Intraluminal peak pressure (PPr) was measured and video recordings made of mouse ex vivo jejunum and colon segments before and after intraluminal applications of Lactobacillus rhamnosus (JB‐1) or Lactobacillus reuteri (DSM 17938). Migrating motor complex frequency and velocity were calculated.
Key Results JB‐1 decreased jejunal frequencies by 56% and 34% in colon. Jejunal velocities increased 171%, but decreased 31% in colon. Jejunal PPr decreased by 55% and in colon by 21%. DSM 17938 increased jejunal frequencies 63% and in colon 75%; jejunal velocity decreased 57%, but increased in colon 146%; jejunal PPr was reduced 26% and 12% in colon. TRAM‐34 decreased frequency by 71% and increased velocity 200% for jejunum, but increased frequency 46% and velocity 50% for colon; PPr was decreased 59% for jejunum and 39% for colon.
Conclusions & Inferences The results show that probiotics and other beneficial bacteria have strain and region‐specific actions on gut motility that can be successfully discriminated using spatiotemporal mapping of diameter changes. Effects are not necessarily the same in colon and jejunum. Further research is needed on the detailed effects of the strains on enteric neuron currents for each gut region.
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