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We present the first results from an ongoing survey to characterize the circumgalactic medium (CGM) of massive high-redshift galaxies detected as submillimeter galaxies (SMGs). We constructed a parent sample of 163 SMG–QSO pairs with separations less than ∼36″ by cross-matching far-infrared-selected galaxies from Herschel with spectroscopically confirmed QSOs. The Herschel sources were selected to match the properties of the SMGs. We determined the sub-arcsecond positions of six Herschel sources with the Very Large Array and obtained secure redshift identification for three of those with near-infrared spectroscopy. The QSO sightlines probe transverse proper distances of 112, 157, and 198 kpc at foreground redshifts of 2.043, 2.515, and 2.184, respectively, which are comparable to the virial radius of the ∼1013M⊙ halos expected to host SMGs. High-quality absorption-line spectroscopy of the QSOs reveals systematically strong H i Lyα absorption around all three SMGs, with rest-frame equivalent widths of ∼2–3 Å. However, none of the three absorbers exhibit compelling evidence for optically thick H i gas or metal absorption, in contrast to the dominance of strong neutral absorbers in the CGM of luminous z ∼ 2 QSOs. The low covering factor of optically thick H i gas around SMGs tentatively indicates that SMGs may not have as prominent cool gas reservoirs in their halos as the coeval QSOs and that they may inhabit less massive halos than previously thought. [ABSTRACT FROM AUTHOR]

We report the results of our observing campaign on GRB 140903A, a nearby (z = 0.351) short-duration (T90 ∼ 0.3 s) gamma-ray burst discovered by Swift. We monitored the X-ray afterglow with Chandra up to 15 days after the burst and detected a steeper decay of the X-ray flux after tj ≈ 1 day. Continued monitoring at optical and radio wavelengths showed a similar decay in flux at nearly the same time, and we interpret it as evidence of a narrowly collimated jet. By using the standard fireball model to describe the afterglow evolution, we derive a jet opening angle θj ≈ 5° and a collimation-corrected total energy release E ≈ 2 erg. We further discuss the nature of the GRB progenitor system. Three main lines disfavor a massive star progenitor: the properties of the prompt gamma-ray emission, the age and low star formation rate of the host galaxy, and the lack of a bright supernova. We conclude that this event likely originated from a compact binary merger. [ABSTRACT FROM AUTHOR]

Supernovae (SNe) embedded in dense circumstellar material (CSM) may show prominent emission lines in their early-time spectra (≤10 days after the explosion), owing to recombination of the CSM ionized by the shock-breakout flash. From such spectra (“flash spectroscopy”), we can measure various physical properties of the CSM, as well as the mass-loss rate of the progenitor during the year prior to its explosion. Searching through the Palomar Transient Factory (PTF and iPTF) SN spectroscopy databases from 2009 through 2014, we found 12 SNe II showing flash-ionized (FI) signatures in their first spectra. All are younger than 10 days. These events constitute 14% of all 84 SNe in our sample having a spectrum within 10 days from explosion, and 18% of SNe II observed at ages <5 days, thereby setting lower limits on the fraction of FI events. We classified as “blue/featureless” (BF) those events having a first spectrum that is similar to that of a blackbody, without any emission or absorption signatures. It is possible that some BF events had FI signatures at an earlier phase than observed, or that they lack dense CSM around the progenitor. Within 2 days after explosion, 8 out of 11 SNe in our sample are either BF events or show FI signatures. Interestingly, we found that 19 out of 21 SNe brighter than an absolute magnitude MR = −18.2 belong to the FI or BF groups, and that all FI events peaked above MR = −17.6 mag, significantly brighter than average SNe II. [ABSTRACT FROM AUTHOR]

iPTF13ehe is a hydrogen-poor superluminous supernova (SLSN) at z = 0.3434, with a slow-evolving light curve and spectral features similar to SN2007bi. It rises in 83–148 days to reach a peak bolometric luminosity of ∼1.3 × 1044 erg s−1, then decays slowly at 0.015 mag day−1. The measured ejecta velocity is ∼ 13,000 km s−1. The inferred explosion characteristics, such as the ejecta mass (70–220 M⊙), and the total radiative and kinetic energy (Erad ∼ 1051 erg, Ekin ∼ 2 × 1053 erg), are typical of slow-evolving H-poor SLSN events. However, the late-time spectrum taken at +251 days (rest, post-peak) reveals a Balmer Hα emission feature with broad and narrow components, which has never been detected before among other H-poor SLSNe. The broad component has a velocity width of ∼4500 km s−1 and a ∼300 km s−1 blueward shift relative to the narrow component. We interpret this broad Hα emission with a luminosity of ∼2 × 1041 erg s−1 as resulting from the interaction between the supernova ejecta and a discrete H-rich shell, located at a distance of ∼4 × 1016 cm from the explosion site. This interaction causes the rest-frame r-band LC to brighten at late times. The fact that the late-time spectra are not completely absorbed by the shock-ionized H-shell implies that its Thomson scattering optical depth is likely ≤1, thus setting upper limits on the shell mass ≤30 M⊙. Of the existing models, a Pulsational Pair Instability supernova model can naturally explain the observed 30 M⊙ H-shell, ejected from a progenitor star with an initial mass of (95–150) M⊙ about 40 years ago. We estimate that at least ∼15% of all SLSNe-I may have late-time Balmer emission lines. [ABSTRACT FROM AUTHOR]

Whole genome sequencing (WGS) at high-depth (30X) allows the accurate discovery of variants in the coding and non-coding DNA regions and helps elucidate the genetic underpinnings of human health and diseases. Yet, due to the prohibitive cost of high-depth WGS, most large-scale genetic association studies use genotyping arrays or high-depth whole exome sequencing (WES). Here we propose a cost-effective method which we call "Whole Exome Genome Sequencing" (WEGS), that combines low-depth WGS and high-depth WES with up to 8 samples pooled and sequenced simultaneously (multiplexed). We experimentally assess the performance of WEGS with four different depth of coverage and sample multiplexing configurations. We show that the optimal WEGS configurations are 1.7-2.0 times cheaper than standard WES (no-plexing), 1.8-2.1 times cheaper than high-depth WGS, reach similar recall and precision rates in detecting coding variants as WES, and capture more population-specific variants in the rest of the genome that are difficult to recover when using genotype imputation methods. We apply WEGS to 862 patients with peripheral artery disease and show that it directly assesses more known disease-associated variants than a typical genotyping array and thousands of non-imputable variants per disease-associated locus., (© 2024. The Author(s).)

Responses of cells to stimuli are increasingly discovered to involve the binding of sequence-specific transcription factors outside of known target genes. We wanted to determine to what extent the genome-wide binding and function of a transcription factor are shaped by the cell type versus the stimulus. To do so, we induced the Heat Shock Response pathway in two different cancer cell lines with two different stimuli and related the binding of its master regulator HSF1 to nascent RNA and chromatin accessibility. Here, we show that HSF1 binding patterns retain their identity between basal conditions and under different magnitudes of activation, so that common HSF1 binding is globally associated with distinct transcription outcomes. HSF1-induced increase in DNA accessibility was modest in scale, but occurred predominantly at remote genomic sites. Apart from regulating transcription at existing elements including promoters and enhancers, HSF1 binding amplified during responses to stimuli may engage inactive chromatin., (© 2023. The Author(s).)

White dwarfs, the extremely dense remnants left behind by most stars after their death, are characterized by a mass comparable to that of the Sun compressed into the size of an Earth-like planet. In the resulting strong gravity, heavy elements sink towards the centre and the upper layer of the atmosphere contains only the lightest element present, usually hydrogen or helium 1,2 . Several mechanisms compete with gravitational settling to change a white dwarf's surface composition as it cools 3 , and the fraction of white dwarfs with helium atmospheres is known to increase by a factor of about 2.5 below a temperature of about 30,000 kelvin 4-8 ; therefore, some white dwarfs that appear to have hydrogen-dominated atmospheres above 30,000 kelvin are bound to transition to be helium-dominated as they cool below it. Here we report observations of ZTF J203349.8+322901.1, a transitioning white dwarf with two faces: one side of its atmosphere is dominated by hydrogen and the other one by helium. This peculiar nature is probably caused by the presence of a small magnetic field, which creates an inhomogeneity in temperature, pressure or mixing strength over the surface 9-11 . ZTF J203349.8+322901.1 might be the most extreme member of a class of magnetic, transitioning white dwarfs-together with GD 323 (ref. 12 ), a white dwarf that shows similar but much more subtle variations. This class of white dwarfs could help shed light on the physical mechanisms behind the spectral evolution of white dwarfs., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Viral infection, particularly respiratory syncytial virus (RSV), causes inflammation in the bronchiolar airways (bronchial wall thickening, also known as bronchiolitis). This bronchial wall thickening is a common pathophysiological feature in RSV infection, but it causes more fatalities in infants than in children and adults. However, the molecular mechanism of RSV-induced bronchial wall thickening remains unknown, particularly in healthy adults. Using highly differentiated pseudostratified airway epithelium generated from primary human bronchial epithelial cells, we revealed RSV-infects primarily ciliated cells. The infected ciliated cells expanded substantially without compromising epithelial membrane integrity and ciliary functions and contributed to the increased height of the airway epithelium. Furthermore, we identified multiple factors, e.g., cytoskeletal (ARP2/3-complex-driven actin polymerization), immunological (IP10/CXCL10), and viral (NS2), contributing to RSV-induced uneven epithelium height increase in vitro. Thus, RSV-infected expanded cells contribute to a noncanonical inflammatory phenotype, which contributes to bronchial wall thickening in the airway, and is termed cytoskeletal inflammation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Detecting gravitationally lensed supernovae is among the biggest challenges in astronomy. It involves a combination of two very rare phenomena: catching the transient signal of a stellar explosion in a distant galaxy and observing it through a nearly perfectly aligned foreground galaxy that deflects light towards the observer. Here we describe how high-cadence optical observations with the Zwicky Transient Facility, with its unparalleled large field of view, led to the detection of a multiply imaged type Ia supernova, SN Zwicky, also known as SN 2022qmx. Magnified nearly 25-fold, the system was found thanks to the standard candle nature of type Ia supernovae. High-spatial-resolution imaging with the Keck telescope resolved four images of the supernova with very small angular separation, corresponding to an Einstein radius of only θ E  = 0.167″ and almost identical arrival times. The small θ E and faintness of the lensing galaxy are very unusual, highlighting the importance of supernovae to fully characterize the properties of galaxy-scale gravitational lenses, including the impact of galaxy substructures., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2023, corrected publication 2023.)

Background: Global RNA sequencing technologies have revealed widespread RNA polymerase II (Pol II) transcription outside of gene promoters. Small 5'-capped RNA sequencing (Start-seq) originally developed for the detection of promoter-proximal Pol II pausing has helped improve annotation of Transcription Start Sites (TSSs) of genes as well as identification of non-genic regulatory elements. However, apart from the most well studied genomes of human and mouse, mammalian transcription has not been profiled with sufficiently high precision., Results: We prepared and sequenced Start-seq libraries from rat (Rattus norgevicus) primary neural progenitor cells. Over 48 million uniquely mappable reads from two independent biological replicates allowed us to define the TSSs of 7365 known genes in the rn6 genome, reannotating 2503 TSSs by more than 5 base pairs, characterize promoter-associated antisense transcription, and profile Pol II pausing. By combining TSS data with polyA-selected RNA sequencing, we also identified thousands of potential new genes producing stable RNA as well as non-genic transcripts representing possible regulatory elements., Conclusions: Our study has produced the first Start-seq dataset for the rat. Apart from profiling transcription initiation, our data reaffirm the prevalence of Pol II pausing across the rat genome and indicate conservation of pausing mechanisms across metazoan genomes. We suggest that pausing location, at least in mammals, is constrained by a distance from initiation of transcription, whether it occurs at or outside of a gene promoter. Abundant antisense transcription initiation around protein coding genes indicates that Pol II recruited to the vicinity of a promoter is distributed to available start sites of transcription at either DNA strand. Transcriptome profiling of neural progenitors presented here will facilitate further studies of other rat cell types as well as other organisms.

Calcium influx into cells via plasma membrane protein channels is tightly regulated to maintain cellular homeostasis. Calcium channel proteins in the plasma membrane and endoplasmic reticulum have been linked to cancer, specifically during the epithelial-mesenchymal transition (EMT), a cell state transition process implicated in both cancer cell migration and drug resistance. The transcription factor SNAI1 (SNAIL) is upregulated during EMT and is responsible for gene expression changes associated with EMT, but the calcium channels required for Snai1 expression remain unknown. In this study, we show that blocking store-operated calcium entry (SOCE) with 2-aminoethoxydiphenylborane (2APB) reduces cell migration but, paradoxically, increases the level of TGF-β dependent Snai1 gene activation. We determined that this increased Snai1 transcription involves signaling through the AKT pathway and subsequent binding of NF-κB (p65) at the Snai1 promoter in response to TGF-β. We also demonstrated that the calcium channel protein ORAI3 and the stromal interaction molecule 1 (STIM1) are required for TGF-β dependent Snai1 transcription. These results suggest that calcium channels differentially regulate cell migration and Snai1 transcription, indicating that each of these steps could be targeted to ensure complete blockade of cancer progression., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest to declare.

The merger of two neutron stars is predicted to give rise to three major detectable phenomena: a short burst of γ-rays, a gravitational-wave signal, and a transient optical-near-infrared source powered by the synthesis of large amounts of very heavy elements via rapid neutron capture (the r-process). Such transients, named 'macronovae' or 'kilonovae', are believed to be centres of production of rare elements such as gold and platinum. The most compelling evidence so far for a kilonova was a very faint near-infrared rebrightening in the afterglow of a short γ-ray burst at redshift z = 0.356, although findings indicating bluer events have been reported. Here we report the spectral identification and describe the physical properties of a bright kilonova associated with the gravitational-wave source GW170817 and γ-ray burst GRB 170817A associated with a galaxy at a distance of 40 megaparsecs from Earth. Using a series of spectra from ground-based observatories covering the wavelength range from the ultraviolet to the near-infrared, we find that the kilonova is characterized by rapidly expanding ejecta with spectral features similar to those predicted by current models. The ejecta is optically thick early on, with a velocity of about 0.2 times light speed, and reaches a radius of about 50 astronomical units in only 1.5 days. As the ejecta expands, broad absorption-like lines appear on the spectral continuum, indicating atomic species produced by nucleosynthesis that occurs in the post-merger fast-moving dynamical ejecta and in two slower (0.05 times light speed) wind regions. Comparison with spectral models suggests that the merger ejected 0.03 to 0.05 solar masses of material, including high-opacity lanthanides.

The location of nucleosomes in SV40 virions and minichromosomes isolated during infection were determined by next generation sequencing (NGS). The patterns of reads within the regulatory region of chromatin from wild-type virions indicated that micrococcal nuclease-resistant nucleosomes were specifically positioned at nt 5223 and nt 363, while in minichromosomes isolated 48 h post-infection we observed nuclease-resistant nucleosomes at nt 5119 and nt 212. The nucleosomes at nt 5223 and nt 363 in virion chromatin would be expected to repress early and late transcription, respectively. In virions from the mutant cs1085, which does not repress early transcription, we found that these two nucleosomes were significantly reduced compared to wild-type virions confirming a repressive role for them. In chromatin from cells infected for only 30min with wild-type virus, we observed a significant reduction in the nucleosomes at nt 5223 and nt 363 indicating that the potential repression by these nucleosomes appeared to be relieved very early in infection., (Copyright © 2017. Published by Elsevier Inc.)

Lyme disease is caused by infection with the bacterium Borrelia burgdorferi (Bb), which is transmitted to humans by deer ticks. The infection manifests usually as a rash and minor systemic symptoms; however, the bacteria can spread to other tissues, causing joint pain, carditis, and neurological symptoms. Lyme neuroborreliosis presents itself in several ways, such as Bell's palsy, meningitis, and encephalitis. The molecular basis for neuroborreliosis is poorly understood. Analysis of the changes in the expression levels of messenger RNAs and non-coding RNAs, including microRNAs, following Bb infection could therefore provide vital information on the pathogenesis and clinical symptoms of neuroborreliosis. To this end, we used cultured primary human astrocytes, key responders to CNS infection and important components of the blood-brain barrier, as a model system to study RNA and microRNA changes in the CNS caused by Bb. Using whole transcriptome RNA-seq, we found significant changes in 38 microRNAs and 275 mRNAs at 24 and 48 hours following Bb infection. Several of the RNA changes affect pathways involved in immune response, development, chromatin assembly (including histones) and cell adhesion. Further, several of the microRNA predicted target mRNAs were also differentially regulated. Overall, our results indicate that exposure to Bb causes significant changes to the transcriptome and microRNA profile of astrocytes, which has implications in the pathogenesis, and hence potential treatment strategies to combat this disease., Competing Interests: The authors have declared that no competing interests exist.

Desire-based research provides people and communities the opportunity to share their dreams and hopes for a better future. However, conflicting desires are difficult to reconcile. We suggest that sociological research to understand conflicting desires is required to support reconciliation work by Indigenous and non-Indigenous people in Canada. Our contribution begins by identifying much of current and past sociological research about Indigenous people and communities as damaged-centered, that is, identifying problems and obstacles in the hope that the knowledge will lead to change. This model of social change is flawed. We believe that most Canadians desire justice for Indigenous peoples while at the same time desiring land and access to resources, desires that deny that justice. How we as a society reconcile these desires will determine the extent to which true justice for Indigenous peoples will be achieved. We propose a sociology of the reconciliation of conflicting desires and suggest some practical ways that this type of research could move forward., (© 2016 Canadian Sociological Association/La Société canadienne de sociologie.)

Three photoaffinity ligands (PALs) for the human serotonin transporter (hSERT) were synthesized based on the selective serotonin reuptake inhibitor (SSRI), (S)-citalopram (1). The classic 4-azido-3-iodo-phenyl group was appended to either the C-1 or C-5 position of the parent molecule, with variable-length linkers, to generate ligands 15, 22, and 26. These ligands retained high to moderate affinity binding (K(i) = 24-227 nM) for hSERT, as assessed by [(3)H]5-HT transport inhibition. When tested against Ser438Thr hSERT, all three PALs showed dramatic rightward shifts in inhibitory potency, with Ki values ranging from 3.8 to 9.9 μM, consistent with the role of Ser438 as a key residue for high-affinity binding of many SSRIs, including (S)-citalopram. Photoactivation studies demonstrated irreversible adduction to hSERT by all ligands, but the reduced (S)-citalopram inhibition of labeling by [(125)I]15 compared to that by [(125)I]22 and [(125)I]26 suggests differences in binding mode(s). These radioligands will be useful for characterizing the drug-protein binding interactions for (S)-citalopram at hSERT.

The serotonin (5-HT) transporter (SERT) is an integral membrane protein that functions to reuptake 5-HT released into the synapse following neurotransmission. This role serves an important regulatory mechanism in neuronal homeostasis. Previous studies have demonstrated that several clinically important antimalarial compounds inhibit serotonin (5-hydroxytryptamine, 5-HT) reuptake. In this study, we examined the details of antimalarial inhibition of 5-HT transport in both Drosophila (dSERT) and human SERT (hSERT) using electrophysiologic, biochemical and computational approaches. We found that the cinchona alkaloids quinidine and cinchonine, which have identical stereochemistry about carbons 8 and 9, exhibited the greatest inhibition of dSERT and hSERT transporter function whereas quinine and cinchonidine, enantiomers of quinidine and cinchonine, respectively, were weaker inhibitors of dSERT and hSERT. Furthermore, SERT mutations known to decrease the binding affinity of many antidepressants affected the cinchona alkaloids in a stereo-specific manner where the similar inhibitory profiles for quinine and cinchonidine (8S,9R) were distinct from quinidine and cinchonine (8R,9S). Small molecule docking studies with hSERT homology models predict that quinine and cinchonidine bind to the central 5-HT binding site (S1) whereas quinidine and cinchonine bind to the S2 site. Taken together, the data presented here support binding of cinchona alkaloids to two different sites on SERT defined by their stereochemistry which implies separate modes of transporter inhibition. Notably, the most potent antimalarial inhibitors of SERT appear to preferentially bind to the S2 site. Our findings provide important insight related to how this class of drugs can modulate the serotonergic system as well as identify compounds that may discriminate between the S1 and S2 binding sites and serve as lead compounds for novel SERT inhibitors., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The explosive fate of massive Wolf-Rayet stars (WRSs) is a key open question in stellar physics. An appealing option is that hydrogen-deficient WRSs are the progenitors of some hydrogen-poor supernova explosions of types IIb, Ib and Ic (ref. 2). A blue object, having luminosity and colours consistent with those of some WRSs, has recently been identified in pre-explosion images at the location of a supernova of type Ib (ref. 3), but has not yet been conclusively determined to have been the progenitor. Similar work has so far only resulted in non-detections. Comparison of early photometric observations of type Ic supernovae with theoretical models suggests that the progenitor stars had radii of less than 10(12) centimetres, as expected for some WRSs. The signature of WRSs, their emission line spectra, cannot be probed by such studies. Here we report the detection of strong emission lines in a spectrum of type IIb supernova 2013cu (iPTF13ast) obtained approximately 15.5 hours after explosion (by 'flash spectroscopy', which captures the effects of the supernova explosion shock breakout flash on material surrounding the progenitor star). We identify Wolf-Rayet-like wind signatures, suggesting a progenitor of the WN(h) subclass (those WRSs with winds dominated by helium and nitrogen, with traces of hydrogen). The extent of this dense wind may indicate increased mass loss from the progenitor shortly before its explosion, consistent with recent theoretical predictions.

Long-duration gamma-ray bursts (GRBs) are thought to result from the explosions of certain massive stars, and some are bright enough that they should be observable out to redshifts of z > 20 using current technology. Hitherto, the highest redshift measured for any object was z = 6.96, for a Lyman-alpha emitting galaxy. Here we report that GRB 090423 lies at a redshift of z approximately 8.2, implying that massive stars were being produced and dying as GRBs approximately 630 Myr after the Big Bang. The burst also pinpoints the location of its host galaxy.

It is now accepted that long-duration gamma-ray bursts (GRBs) are produced during the collapse of a massive star. The standard 'collapsar' model predicts that a broad-lined and luminous type Ic core-collapse supernova accompanies every long-duration GRB. This association has been confirmed in observations of several nearby GRBs. Here we report that GRB 060505 (ref. 10) and GRB 060614 (ref. 11) were not accompanied by supernova emission down to limits hundreds of times fainter than the archetypal supernova SN 1998bw that accompanied GRB 980425, and fainter than any type Ic supernova ever observed. Multi-band observations of the early afterglows, as well as spectroscopy of the host galaxies, exclude the possibility of significant dust obscuration and show that the bursts originated in actively star-forming regions. The absence of a supernova to such deep limits is qualitatively different from all previous nearby long-duration GRBs and suggests a new phenomenological type of massive stellar death.