Autophagy is a critical regulator of cellular homeostasis and metabolism. Interference with this process is considered a new approach for the treatment of disease, in particular cancer and ...neurological disorders. Therefore, novel small‐molecule autophagy modulators are in high demand. We describe the discovery of autophinib, a potent autophagy inhibitor with a novel chemotype. Autophinib was identified by means of a phenotypic assay monitoring the formation of autophagy‐induced puncta, indicating accumulation of the lipidated cytosolic protein LC3 on the autophagosomal membrane. Target identification and validation revealed that autophinib inhibits autophagy induced by starvation or rapamycin by targeting the lipid kinase VPS34.
PI(3)KC(3)ing autophagy apart: Phenotypic screening followed by target identification reveals a novel autophagy‐inhibiting chemotype that inhibits the lipid kinase PIK3C3 (VPS34) with high potency, disrupting autophagosome biogenesis.
Signaling pathways are frequently activated through signal-receiving membrane proteins, and the discovery of small molecules targeting these receptors may yield insights into their biology. However, ...due to their intrinsic properties, membrane protein targets often cannot be identified by means of established approaches, in particular affinity-based proteomics, calling for the exploration of new methods. Here, we report the identification of indophagolin as representative member of an indoline-based class of autophagy inhibitors through a target-agnostic phenotypic assay. Thermal proteome profiling and subsequent biochemical validation identified the purinergic receptor P2X4 as a target of indophagolin, and subsequent investigations suggest that indophagolin targets further purinergic receptors. These results demonstrate that thermal proteome profiling may enable the de novo identification of membrane-bound receptors as cellular targets of bioactive small molecules.
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•An indoline-containing autophagy inhibitor was identified through a phenotypic screen•Target identification using thermal proteome profiling suggested P2X4 as a target•P2X4 was confirmed as a target through CETSA, ITDRF, and calcium influx assays•Computational target ID and further profiling confirmed activity at several receptors
Carnero Corrales et al. employed thermal proteome profiling (TPP) to enable the identification of membrane-bound receptors as cellular targets of a small-molecule autophagy inhibitor. This work showcases TPP as an important technique for target identification of membrane proteins and provides a link between purinergic receptors and autophagy.
Most if not all neoplasias show a directly or indirectly deregulated cell cycle. Targeting its regulatory molecules, the cyclin-dependent kinases, as a therapeutic mode to develop new anticancer ...drugs, is being currently explored in both academia and pharmaceutical companies. The development of new compounds is being focused on the many features of the cell cycle with promising preclinical data in most fields. Moreover, a few compounds have entered clinical trials with excellent results maintaining the high hopes. Thus, although too early to provide a cell cycle target based new commercial drug, there is no doubt that it will be an excellent source of new anticancer compounds.
The Dark Energy Survey Data Release 2 Abbott, T. M. C.; Amon, A.; Avila, S. ...
The Astrophysical journal. Supplement series,
08/2021, Letnik:
255, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Abstract
We present the second public data release of the Dark Energy Survey, DES DR2, based on optical/near-infrared imaging by the Dark Energy Camera mounted on the 4 m Blanco telescope at Cerro ...Tololo Inter-American Observatory in Chile. DES DR2 consists of reduced single-epoch and coadded images, a source catalog derived from coadded images, and associated data products assembled from 6 yr of DES science operations. This release includes data from the DES wide-area survey covering ∼5000 deg
2
of the southern Galactic cap in five broad photometric bands,
grizY
. DES DR2 has a median delivered point-spread function FWHM of
g
= 1.11″,
r
= 0.95″,
i
= 0.88″,
z
= 0.83″, and
Y
= 0.″90, photometric uniformity with a standard deviation of < 3 mmag with respect to Gaia DR2
G
band, a photometric accuracy of ∼11 mmag, and a median internal astrometric precision of ∼27 mas. The median coadded catalog depth for a 1.″95 diameter aperture at signal-to-noise ratio = 10 is
g
= 24.7,
r
= 24.4,
i
= 23.8,
z
= 23.1, and
Y
= 21.7 mag. DES DR2 includes ∼691 million distinct astronomical objects detected in 10,169 coadded image tiles of size 0.534 deg
2
produced from 76,217 single-epoch images. After a basic quality selection, benchmark galaxy and stellar samples contain 543 million and 145 million objects, respectively. These data are accessible through several interfaces, including interactive image visualization tools, web-based query clients, image cutout servers, and Jupyter notebooks. DES DR2 constitutes the largest photometric data set to date at the achieved depth and photometric precision.
We detect the kinematic Sunyaev-Zel'dovich (kSZ) effect with a statistical significance of 4.2σ by combining a cluster catalogue derived from the first year data of the Dark Energy Survey with cosmic ...microwave background temperature maps from the South Pole Telescope Sunyaev-Zel'dovich Survey. This measurement is performed with a differential statistic that isolates the pairwise kSZ signal, providing the first detection of the large-scale, pairwise motion of clusters using redshifts derived from photometric data. By fitting the pairwise kSZ signal to a theoretical template, we measure the average central optical depth of the cluster sample,
$\bar{\tau }_e = (3.75 \pm 0.89)\times 10^{-3}$
. We compare the extracted signal to realistic simulations and find good agreement with respect to the signal to noise, the constraint on
$\bar{\tau }_e$
, and the corresponding gas fraction. High-precision measurements of the pairwise kSZ signal with future data will be able to place constraints on the baryonic physics of galaxy clusters, and could be used to probe gravity on scales ≳100 Mpc.
The gut microbiome is emerging as a key modulator of human energy balance. Prior studies in humans lacked the environmental and dietary controls and precision required to quantitatively evaluate the ...contributions of the gut microbiome. Using a Microbiome Enhancer Diet (MBD) designed to deliver more dietary substrates to the colon and therefore modulate the gut microbiome, we quantified microbial and host contributions to human energy balance in a controlled feeding study with a randomized crossover design in young, healthy, weight stable males and females (NCT02939703). In a metabolic ward where the environment was strictly controlled, we measured energy intake, energy expenditure, and energy output (fecal and urinary). The primary endpoint was the within-participant difference in host metabolizable energy between experimental conditions Control, Western Diet (WD) vs. MBD. The secondary endpoints were enteroendocrine hormones, hunger/satiety, and food intake. Here we show that, compared to the WD, the MBD leads to an additional 116 ± 56 kcals (P < 0.0001) lost in feces daily and thus, lower metabolizable energy for the host (89.5 ± 0.73%; range 84.2-96.1% on the MBD vs. 95.4 ± 0.21%; range 94.1-97.0% on the WD; P < 0.0001) without changes in energy expenditure, hunger/satiety or food intake (P > 0.05). Microbial 16S rRNA gene copy number (a surrogate of biomass) increases (P < 0.0001), beta-diversity changes (whole genome shotgun sequencing; P = 0.02), and fermentation products increase (P < 0.01) on an MBD as compared to a WD along with significant changes in the host enteroendocrine system (P < 0.0001). The substantial interindividual variability in metabolizable energy on the MBD is explained in part by fecal SCFAs and biomass. Our results reveal the complex host-diet-microbiome interplay that modulates energy balance.
Abstract
We quantify evolution in the cluster-scale stellar mass–halo mass (SMHM) relation’s parameters using 2323 clusters and brightest central galaxies (BCGs) over the redshift range 0.03 ≤
z
≤ ...0.60. The precision on the inferred SMHM parameters is improved by including the magnitude gap (
m
gap
) between the BCG and fourth-brightest cluster member (M14) as a third parameter in the SMHM relation. At fixed halo mass, accounting for
m
gap
, through a stretch parameter, reduces the SMHM relation’s intrinsic scatter. To explore this redshift range, we use clusters, BCGs, and cluster members identified using the Sloan Digital Sky Survey C4 and redMaPPer cluster catalogs and the Dark Energy Survey redMaPPer catalog. Through this joint analysis, we detect no systematic differences in BCG stellar mass,
m
gap
, and cluster mass (inferred from richness) between the data sets. We utilize the Pareto function to quantify each parameter’s evolution. We confirm prior findings of negative evolution in the SMHM relation’s slope (3.5
σ
), and detect negative evolution in the stretch parameter (4.0
σ
) and positive evolution in the offset parameter (5.8
σ
). This observed evolution, combined with the absence of BCG growth, when stellar mass is measured within 50 kpc, suggests that this evolution results from changes in the cluster’s
m
gap
. For this to occur, late-term growth must be in the intracluster light surrounding the BCG. We also compare the observed results to IllustrisTNG 300-1 cosmological hydrodynamic simulations and find modest qualitative agreement. However, the simulations lack the evolutionary features detected in the real data.
We report the results of a systematic search for ultra-faint Milky Way satellite galaxies using data from the Dark Energy Survey (DES) and Pan-STARRS1 (PS1). Together, DES and PS1 provide multi-band ...photometry in optical/near-infrared wavelengths over ∼80% of the sky. Our search for satellite galaxies targets ∼25,000 deg2 of the high-Galactic-latitude sky reaching a 10 point-source depth of 22.5 mag in the g and r bands. While satellite galaxy searches have been performed independently on DES and PS1 before, this is the first time that a self-consistent search is performed across both data sets. We do not detect any new high-significance satellite galaxy candidates, recovering the majority of satellites previously detected in surveys of comparable depth. We characterize the sensitivity of our search using a large set of simulated satellites injected into the survey data. We use these simulations to derive both analytic and machine-learning models that accurately predict the detectability of Milky Way satellites as a function of their distance, size, luminosity, and location on the sky. To demonstrate the utility of this observational selection function, we calculate the luminosity function of Milky Way satellite galaxies, assuming that the known population of satellite galaxies is representative of the underlying distribution. We provide access to our observational selection function to facilitate comparisons with cosmological models of galaxy formation and evolution.
The SPTpol Extended Cluster Survey Bleem, L. E.; Bocquet, S.; Stalder, B. ...
The Astrophysical journal. Supplement series,
03/2020, Letnik:
247, Številka:
1
Journal Article
Recenzirano
Odprti dostop
We describe the observations and resultant galaxy cluster catalog from the 2770 deg2 SPTpol Extended Cluster Survey (SPT-ECS). Clusters are identified via the Sunyaev-Zel'dovich (SZ) effect and ...confirmed with a combination of archival and targeted follow-up data, making particular use of data from the Dark Energy Survey (DES). With incomplete follow-up we have confirmed as clusters 244 of 266 candidates at a detection significance ≥ 5 and an additional 204 systems at 4 < < 5. The confirmed sample has a median mass of and a median redshift of z = 0.49, and we have identified 44 strong gravitational lenses in the sample thus far. Radio data are used to characterize contamination to the SZ signal; the median contamination for confirmed clusters is predicted to be ∼1% of the SZ signal at the > 4 threshold, and <4% of clusters have a predicted contamination >10% of their measured SZ flux. We associate SZ-selected clusters, from both SPT-ECS and the SPT-SZ survey, with clusters from the DES redMaPPer sample, and we find an offset distribution between the SZ center and central galaxy in general agreement with previous work, though with a larger fraction of clusters with significant offsets. Adopting a fixed Planck-like cosmology, we measure the optical richness-SZ mass ( ) relation and find it to be 28% shallower than that from a weak-lensing analysis of the DES data-a difference significant at the 4 level-with the relations intersecting at λ = 60. The SPT-ECS cluster sample will be particularly useful for studying the evolution of massive clusters and, in combination with DES lensing observations and the SPT-SZ cluster sample, will be an important component of future cosmological analyses.
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