Submillimetre galaxies (SMGs) are among the most luminous dusty galaxies in the Universe, but their true nature remains unclear; are SMGs the progenitors of the massive elliptical galaxies we see in ...the local Universe, or are they just a short-lived phase among more typical star-forming galaxies? To explore this problem further, we investigate the clustering of SMGs identified in the SCUBA-2 Cosmology Legacy Survey. We use a catalogue of submillimetre (850 mu m) source identifications derived using a combination of radio counterparts and colour/infrared selection to analyse a sample of 610 SMG counterparts in the United Kingdom Infrared Telescope (UKIRT) Infrared Deep Survey (UKIDSS) Ultra Deep Survey (UDS), making this the largest high-redshift sample of these galaxies to date. Using angular cross-correlation techniques, we estimate the halo masses for this large sample of SMGs and compare them with passive and star-forming galaxies selected in the same field. We find that SMGs, on average, occupy high-mass dark matter haloes ... at redshifts z > 2.5, consistent with being the progenitors of massive quiescent galaxies in present-day galaxy clusters. We also find evidence of downsizing, in which SMG activity shifts to lower mass haloes at lower redshifts. In terms of their clustering and halo masses, SMGs appear to be consistent with other star-forming galaxies at a given redshift. (ProQuest: ... denotes formulae/symbols omitted.)
Successful control of falciparum malaria depends greatly on treatment with artemisinin combination therapies. Thus, reports that resistance to artemisinins (ARTs) has emerged, and that the prevalence ...of this resistance is increasing, are alarming. ART resistance has recently been linked to mutations in the K13 propeller protein. We undertook a detailed kinetic analysis of the drug responses of K13 wild-type and mutant isolates of Plasmodium falciparum sourced from a region in Cambodia (Pailin). We demonstrate that ART treatment induces growth retardation and an accumulation of ubiquitinated proteins, indicative of a cellular stress response that engages the ubiquitin/proteasome system. We show that resistant parasites exhibit lower levels of ubiquitinated proteins and delayed onset of cell death, indicating an enhanced cell stress response. We found that the stress response can be targeted by inhibiting the proteasome. Accordingly, clinically used proteasome inhibitors strongly synergize ART activity against both sensitive and resistant parasites, including isogenic lines expressing mutant or wild-type K13. Synergy is also observed against Plasmodium berghei in vivo. We developed a detailed model of parasite responses that enables us to infer, for the first time, in vivo parasite clearance profiles from in vitro assessments of ART sensitivity. We provide evidence that the clinical marker of resistance (delayed parasite clearance) is an indirect measure of drug efficacy because of the persistence of unviable parasites with unchanged morphology in the circulation, and we suggest alternative approaches for the direct measurement of viability. Our model predicts that extending current three-day ART treatment courses to four days, or splitting the doses, will efficiently clear resistant parasite infections. This work provides a rationale for improving the detection of ART resistance in the field and for treatment strategies that can be employed in areas with ART resistance.
Interleukin-1β (IL-1β) is activated by inflammasome-associated caspase-1 in rare autoinflammatory conditions and in a variety of other inflammatory diseases. Therefore, IL-1β activity must be ...fine-tuned to enable anti-microbial responses whilst limiting collateral damage. Here, we show that precursor IL-1β is rapidly turned over by the proteasome and this correlates with its decoration by K11-linked, K63-linked and K48-linked ubiquitin chains. The ubiquitylation of IL-1β is not just a degradation signal triggered by inflammasome priming and activating stimuli, but also limits IL-1β cleavage by caspase-1. IL-1β K133 is modified by ubiquitin and forms a salt bridge with IL-1β D129. Loss of IL-1β K133 ubiquitylation, or disruption of the K133:D129 electrostatic interaction, stabilizes IL-1β. Accordingly, Il1b
mice have increased levels of precursor IL-1β upon inflammasome priming and increased production of bioactive IL-1β, both in vitro and in response to LPS injection. These findings identify mechanisms that can limit IL-1β activity and safeguard against damaging inflammation.
Abstract
We have used the Submillimeter Array (SMA) at 860 $\mu$m to observe the brightest sources in the Submillimeter Common User Bolometer Array-2 (SCUBA-2) Cosmology Legacy Survey (S2CLS). The ...goal of this survey is to exploit the large field of the S2CLS along with the resolution and sensitivity of the SMA to construct a large sample of these rare sources and to study their statistical properties. We have targeted 70 of the brightest single-dish SCUBA-2 850 $\mu$m sources down to S850 ≈ 8 mJy, achieving an average synthesized beam of 2.4 arcsec and an average rms of σ860 = 1.5 mJy beam−1 in our primary beam-corrected maps. We searched our SMA maps for 4σ peaks, corresponding to S860 ≳ 6 mJy sources, and detected 62, galaxies, including three pairs. We include in our study 35 archival observations, bringing our sample size to 105 bright single-dish submillimetre sources with interferometric follow-up. We compute the cumulative and differential number counts, finding them to overlap with previous single-dish survey number counts within the uncertainties, although our cumulative number count is systematically lower than the parent S2CLS cumulative number count by 14 ± 6 per cent between 11 and 15 mJy. We estimate the probability that a ≳10 mJy single-dish submillimetre source resolves into two or more galaxies with similar flux densities to be less than 15 per cent. Assuming the remaining 85 per cent of the targets are ultraluminous starburst galaxies between z = 2 and 3, we find a likely volume density of ≳400 M⊙ yr−1 sources to be ${\sim }\,3^{+0.7}_{-0.6}\,{\times }\,10^{-7}$ Mpc−3. We show that the descendants of these galaxies could be ≳4 × 1011 M⊙ local quiescent galaxies, and that about 10 per cent of their total stellar mass would have formed during these short bursts of star formation.
Gene expression occurs either as an episodic process, characterized by pulsatile bursts, or as a constitutive process, characterized by a Poisson-like accumulation of gene products. It is not clear ...which mode of gene expression (constitutive versus bursty) predominates across a genome or how transcriptional dynamics are influenced by genomic position and promoter sequence. Here, we use time-lapse fluorescence microscopy to analyze 8,000 individual human genomic loci and find that at virtually all loci, episodic bursting—as opposed to constitutive expression—is the predominant mode of expression. Quantitative analysis of the expression dynamics at these 8,000 loci indicates that both the frequency and size of the transcriptional bursts varies equally across the human genome, independent of promoter sequence. Strikingly, weaker expression loci modulate burst frequency to increase activity, whereas stronger expression loci modulate burst size to increase activity. Transcriptional activators such as trichostatin A (TSA) and tumor necrosis factor α (TNF) only modulate burst size and frequency along a constrained trend line governed by the promoter. In summary, transcriptional bursting dominates across the human genome, both burst frequency and burst size vary by chromosomal location, and transcriptional activators alter burst frequency and burst size, depending on the expression level of the locus.
The pyroptotic cell death effector gasdermin D (GSDMD) is required for murine models of hereditary inflammasome-driven, IL-1β-dependent, autoinflammatory disease, making it an attractive therapeutic ...target. However, the importance of GSDMD for more common conditions mediated by pathological IL-1β activation, such as gout, remain unclear. In this study, we address whether GSDMD and the recently described GSDMD inhibitor necrosulfonamide (NSA) contribute to monosodium urate (MSU) crystal-induced cell death, IL-1β release, and autoinflammation. We demonstrate that MSU crystals, the etiological agent of gout, rapidly activate GSDMD in murine macrophages. Despite this, the genetic deletion of GSDMD or the other lytic effector implicated in MSU crystal killing, mixed lineage kinase domain-like (MLKL), did not prevent MSU crystal-induced cell death. Consequently, GSDMD or MLKL loss did not hinder MSU crystal-mediated release of bioactive IL-1β. Consistent with in vitro findings, IL-1β induction and autoinflammation in MSU crystal-induced peritonitis was not reduced in GSDMD-deficient mice. Moreover, we show that the reported GSDMD inhibitor, NSA, blocks inflammasome priming and caspase-1 activation, thereby preventing pyroptosis independent of GSDMD targeting. The inhibition of cathepsins, widely implicated in particle-induced macrophage killing, also failed to prevent MSU crystal-mediated cell death. These findings 1) demonstrate that not all IL-1β-driven autoinflammatory conditions will benefit from the therapeutic targeting of GSDMD, 2) document a unique mechanism of MSU crystal-induced macrophage cell death not rescued by pan-cathepsin inhibition, and 3) show that NSA inhibits inflammasomes upstream of GSDMD to prevent pyroptotic cell death and IL-1β release.
Reports of emerging resistance to first-line artemisinin antimalarials make it critical to define resistance mechanisms and identify in vitro correlates of resistance. Here we combine unique in vitro ...experimental and analytical approaches to mimic in vivo drug exposure in an effort to provide insight into mechanisms of drug resistance. Tightly synchronized parasites exposed to short drug pulses exhibit large stage-dependent differences in their drug response that correlate with hemoglobin digestion throughout most of the asexual cycle. As a result, ring-stage parasites can exhibit >100-fold lower sensitivity to short drug pulses than trophozoites, although we identify a subpopulation of rings (2–4 h postinvasion) that exhibits hypersensitivity. We find that laboratory strains that show little differences in drug sensitivity in standard in vitro assays exhibit substantial (>95-fold) difference in sensitivity when exposed to short drug pulses. These stage- and strain-dependent differences in drug sensitivity reflect differential response lag times with rings exhibiting lag times of up to 4 h. A simple model that assumes that the parasite experiences a saturable effective drug dose describes the complex dependence of parasite viability on both drug concentration and exposure time and is used to demonstrate that small changes in the parasite’s drug response profile can dramatically alter the sensitivity to artemisinins. This work demonstrates that effective resistance can arise from the interplay between the short in vivo half-life of the drug and the stage-specific lag time and provides the framework for understanding the mechanisms of drug action and parasite resistance.
Psychiatric disorders are characterized by major fluctuations in psychological function over the course of weeks and months, but the dynamic characteristics of brain function over this timescale in ...healthy individuals are unknown. Here, as a proof of concept to address this question, we present the MyConnectome project. An intensive phenome-wide assessment of a single human was performed over a period of 18 months, including functional and structural brain connectivity using magnetic resonance imaging, psychological function and physical health, gene expression and metabolomics. A reproducible analysis workflow is provided, along with open access to the data and an online browser for results. We demonstrate dynamic changes in brain connectivity over the timescales of days to months, and relations between brain connectivity, gene expression and metabolites. This resource can serve as a testbed to study the joint dynamics of human brain and metabolic function over time, an approach that is critical for the development of precision medicine strategies for brain disorders.
Carbon-negative synthesis of biochemical products has the potential to mitigate global CO
emissions. An attractive route to do this is the reverse β-oxidation (r-BOX) pathway coupled to the ...Wood-Ljungdahl pathway. Here, we optimize and implement r-BOX for the synthesis of C4-C6 acids and alcohols. With a high-throughput in vitro prototyping workflow, we screen 762 unique pathway combinations using cell-free extracts tailored for r-BOX to identify enzyme sets for enhanced product selectivity. Implementation of these pathways into Escherichia coli generates designer strains for the selective production of butanoic acid (4.9 ± 0.1 gL
), as well as hexanoic acid (3.06 ± 0.03 gL
) and 1-hexanol (1.0 ± 0.1 gL
) at the best performance reported to date in this bacterium. We also generate Clostridium autoethanogenum strains able to produce 1-hexanol from syngas, achieving a titer of 0.26 gL
in a 1.5 L continuous fermentation. Our strategy enables optimization of r-BOX derived products for biomanufacturing and industrial biotechnology.
Abstract
We examine the robustness of the color–color selection of quiescent galaxies (QGs) against contamination of dusty star-forming galaxies using the latest submillimeter data. We selected ...18,304 QG candidates out to
z
∼ 3 using the commonly adopted
NUV
–
r
–
J
selection based on the high-quality multiwavelength COSMOS2015 catalog. Using extremely deep 450 and 850
μ
m catalogs from the latest JCMT SCUBA-2 Large Programs, S2COSMOS and STUDIES, as well as the Atacama Large Millimeter/submillimeter Array submillimeter, VLA 3 GHz, and Spitzer MIPS 24
μ
m catalogs, we identified luminous, dusty, star-forming galaxies among the QG candidates. We also conducted stacking analyses in the SCUBA-2 450 and 850
μ
m images to look for less-luminous dusty galaxies among the QG candidates. By cross matching to the 24
μ
m and 3 GHz data, we were able to identify a subgroup of “IR-radio-bright” QGs that possess strong 450 and 850
μ
m stacking signals. The potential contamination of these luminous and less-luminous dusty galaxies accounts for approximately 10% of the color-selected QG candidates. In addition, there exists a spatial correlation between the luminous star-forming galaxies and the QGs at a ≲60 kpc scale. Finally, we found a high QG fraction among radio active galactic nuclei (AGNs) at
z
< 1.5. Our data show a strong correlation between QGs and radio AGNs, which may suggest a connection between the quenching process and the radio-mode AGN feedback.
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