Searching Far and Long I: Pilot ALMA 2mm Follow-up of Bright Dusty Galaxies as a Redshift Filter

A complete census of dusty star-forming galaxies (DSFGs) at early epochs is necessary to constrain the obscured contribution to the cosmic star formation rate density (CSFRD), however DSFGs beyond $z \sim 4$ are both rare and hard to identify from photometric data alone due to degeneracies in submillimeter photometry with redshift. Here, we present a pilot study obtaining follow-up Atacama Large Millimeter Array (ALMA) $2\,$mm observations of a complete sample of 39 $850\,\rm\mu m$-bright dusty galaxies in the SSA22 field. Empirical modeling suggests $2\,$mm imaging of existing samples of DSFGs selected at $850\,\rm\mu m - 1\,$mm can quickly and easily isolate the "needle in a haystack" DSFGs that sit at $z>4$ or beyond. Combining archival submillimeter imaging with our measured ALMA $2\,$mm photometry ($1\sigma \sim 0.08\,$mJy$\,$beam$^{-1}$ rms), we characterize the galaxies' IR SEDs and use them to constrain redshifts. With available redshift constraints fit via the combination of six submillimeter bands, we identify 6/39 high-$z$ candidates each with $>50\%$ likelihood to sit at $z > 4$, and find a positive correlation between redshift and $2\,$mm flux density. Specifically, our models suggest the addition of $2\,$mm to a moderately constrained IR SED will improve the accuracy of a millimeter-derived redshift from $\Delta z/(1+z) = 0.3$ to $\Delta z/(1+z) = 0.2$. Our IR SED characterizations provide evidence for relatively high emissivity spectral indices ($\langle \beta \rangle = 2.4\pm0.3$) in the sample. We measure that especially bright ($S_{850\rm\mu m}>5.55\,$mJy) DSFGs contribute $\sim10$% to the cosmic-averaged CSFRD from $2<z<5$, confirming findings from previous work with similar samples.Comment: 22 pages, 7 figures, accepted for publication in Ap

A Mixture of LBG Overdensities in the Fields of Three 6<z<76 < z < 7 Quasars: Implications for the Robustness of Photometric Selection

The most luminous quasars at $z > 6$ are suspected to be both highly clustered and reside in the most massive dark matter halos in the early Universe, making them prime targets to search for galaxy overdensities and/or protoclusters. We search for Lyman-break dropout-selected galaxies using HST WFC3/ACS broadband imaging in the fields of three $6 < z < 7$ quasars, as well as their simultaneously observed coordinated-parallel fields, and constrain their photometric redshifts using EAZY. One field, J0305-3150, shows a volume density 10$\times$ higher than the blank-field UV luminosity function (UVLF) at M$_{UV} < -20$, with tentative evidence of a 3$\sigma$ overdensity in its parallel field located 15 cMpc away. Another field, J2054-0005, shows an angular overdensity within 500 ckpc from the quasar but still consistent with UVLF predictions within 3$\sigma$, while the last field, J2348-3054, shows no enhancement. We discuss methods for reducing uncertainty in overdensity measurements when using photometric selection and show that we can robustly select LBGs consistent with being physically associated with the quasar, corroborated by existing JWST/NIRCam WFSS data in the J0305 field. Even accounting for incompleteness, the overdensities in J0305 and J2054 are higher for brighter galaxies at short angular separations, suggesting preferential enhancement of more massive galaxies in the immediate vicinity of the quasar. Finally, we compare the LBG population with previously-identified [CII] and mm-continuum companions; the LBG overdensities are not accompanied by an enhanced number of dusty galaxies, suggesting that the overdense quasar fields are not in the bursty star-forming phase sometimes seen in high-redshift protoclusters.Comment: 22 pages (main text), 12 figures, 10 tables, 2 appendices. Final version after addressing referee report, accepted to ApJ May 202

Missing Giants: Predictions on Dust-Obscured Galaxy Stellar Mass Assembly Throughout Cosmic Time

Due to their extremely dust-obscured nature, much uncertainty still exists surrounding the stellar mass growth and content in dusty, star-forming galaxies (DSFGs) at $z>1$. In this work, we present a numerical model built using empirical data on DSFGs to estimate their stellar mass contributions across the first $\sim$10 Gyr of cosmic time. We generate a dust-obscured stellar mass function that extends beyond the mass limit of star-forming stellar mass functions in the literature, and predict that massive DSFGs constitute as much as $50-100\%$ of all star-forming galaxies with M $\ge10^{11}$M$_\odot$ at $z>1$. We predict the number density of massive DSFGs and find general agreement with observations, although more data is needed to narrow wide observational uncertainties. We forward model mock massive DSFGs to their quiescent descendants and find remarkable agreement with observations from the literature demonstrating that, to first order, massive DSFGs are a sufficient ancestral population to describe the prevalence of massive quiescent galaxies at $z>1$. We predict that massive DSFGs and their descendants contribute as much as $25-60\%$ to the cosmic stellar mass density during the peak of cosmic star formation, and predict an intense epoch of population growth during the $\sim1$ Gyr from $z=6$ to 3 during which the majority of the most massive galaxies at high-$z$ grow and then quench. Future studies seeking to understand massive galaxy growth and evolution in the early Universe should strategize synergies with data from the latest observatories (e.g. JWST and ALMA) to better include the heavily dust-obscured galaxy population.Comment: 22 pages, 9 figures, submitted to Ap

Swine ANP32A supports avian influenza virus polymerase

Avian influenza viruses occasionally infect and adapt to mammals, including humans. Swine are often described as 'mixing vessels', being susceptible to both avian and human origin viruses, which allows the emergence of novel reassortants, such as the precursor to the 2009 H1N1 pandemic. ANP32 proteins are host factors that act as influenza virus polymerase cofactors. In this study we describe how swine ANP32A, uniquely among the mammalian ANP32 proteins tested, supports activity of avian origin influenza virus polymerases, and avian influenza virus replication. We further show that after the swine-origin influenza virus emerged in humans and caused the 2009 pandemic it evolved polymerase gene mutations that enabled it to more efficiently use human ANP32 proteins. We map the enhanced pro-viral activity of swine ANP32A to a pair of amino acids, 106 and 156, in the leucine-rich repeat and central domains and show these mutations enhance binding to influenza virus trimeric polymerase. These findings help elucidate the molecular basis for the 'mixing vessel' trait of swine and further our understanding of the evolution and ecology of viruses in this host.Importance Avian influenza viruses can jump from wild birds and poultry into mammalian species such as humans or swine, but only continue to transmit if they accumulate mammalian adapting mutations. Pigs appear uniquely susceptible to both avian and human strains of influenza and are often described as virus 'mixing vessels'. In this study, we describe how a host factor responsible for regulating virus replication, ANP32A, is different between swine and humans. Swine ANP32A allows a greater range of influenza viruses, specifically those from birds, to replicate. It does this through binding the virus polymerase more tightly than the human version of the protein. This work helps to explain the unique properties of swine as 'mixing vessels'

Detection of BRAF splicing variants in plasma-derived cell-free nucleic acids and extracellular vesicles of melanoma patients failing targeted therapy therapies

The analysis of plasma circulating tumour nucleic acids provides a non-invasive approach to assess disease burden and the genetic evolution of tumours in response to therapy. BRAF splicing variants are known to confer melanoma resistance to BRAF inhibitors. We developed a test to screen cell-free RNA (cfRNA) for the presence of BRAF splicing variants. Custom droplet digital PCR assays were designed for the detection of BRAF splicing variants p61, p55, p48 and p41 and then validated using RNA from cell lines carrying these variants. Evaluation of plasma from patients with reported objective response to BRAF/MEK inhibition followed by disease progression was revealed by increased circulating tumour DNA (ctDNA) in 24 of 38 cases at the time of relapse. Circulating BRAF splicing variants were detected in cfRNA from 3 of these 38 patients; two patients carried the BRAF p61 variant and one the p55 variant. In all three cases the presence of the splicing variant was apparent only at the time of progressive disease. BRAF p61 was also detectable in plasma of one of four patients with confirmed BRAF splicing variants in their progressing tumours. Isolation and analysis of RNA from extracellular vesicles (EV) from resistant cell lines and patient plasma demonstrated that BRAF splicing variants are associated with EVs. These findings indicate that in addition to plasma ctDNA, RNA carried by EVs can provide important tumour specific information

Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours

Uveal melanoma (UM) is the most common intraocular tumour in adults and despite surgical or radiation treatment of primary tumours, ~50% of patients progress to metastatic disease. Therapeutic options for metastatic UM are limited, with clinical trials having little impact. Here we perform whole-genome sequencing (WGS) of 103 UM from all sites of the uveal tract (choroid, ciliary body, iris). While most UM have low tumour mutation burden (TMB), two subsets with high TMB are seen; one driven by germline MBD4 mutation, and another by ultraviolet radiation (UVR) exposure, which is restricted to iris UM. All but one tumour have a known UM driver gene mutation (GNAQ, GNA11, BAP1, PLCB4, CYSLTR2, SF3B1, EIF1AX). We identify three other significantly mutated genes (TP53, RPL5 and CENPE)

The Web Epoch of Reionization Lyman-α\alpha Survey (WERLS) I. MOSFIRE Spectroscopy of z∼7−8\mathbf{z \sim 7-8} Lyman-α\alpha Emitters

We present the first results from the Web Epoch of Reionization Lyman-$\alpha$ Survey (WERLS), a spectroscopic survey of Lyman-$\alpha$ emission using Keck I/MOSFIRE and LRIS. WERLS targets bright ($J<26$) galaxy candidates with photometric redshifts of $5.5\lesssim z \lesssim 8$ selected from pre-JWST imaging embedded in the Epoch of Reionization (EoR) within three JWST deep fields: CEERS, PRIMER, and COSMOS-Web. Here, we report 11 $z\sim7-8$ Lyman-$\alpha$ emitters (LAEs; 3 secure and 8 tentative candidates) detected in the first five nights of WERLS MOSFIRE data. We estimate our observed LAE yield is $\sim13$%, broadly consistent with expectations assuming some loss from redshift uncertainty, contamination from sky OH lines, and that the Universe is approximately half-ionized at this epoch, whereby observable Lyman-$\alpha$ emission is unlikely for galaxies embedded in a neutral intergalactic medium. Our targets are selected to be UV-bright, and span a range of absolute UV magnitudes with $-23.1 < M_{\text{UV}} < -19.8$. With two LAEs detected at $z=7.68$, we also consider the possibility of an ionized bubble at this redshift. Future synergistic Keck+JWST efforts will provide a powerful tool for pinpointing beacons of reionization and mapping the large scale distribution of mass relative to the ionization state of the Universe.Comment: 27 pages, 8 figures; ApJ submitte

The Role of Oestrogen Receptor Beta (ERβ) in the Aetiology and Treatment of Type 2 Diabetes Mellitus

Introduction: Challenges facing the treatment of type 2 diabetes necessitate the search for agents which act via alternative pathways to provide better therapeutic outcomes. Recently, an increasing body of evidence implicates the activation of oestrogen receptors (ERα and ERβ) in the development and treatment of underlying conditions in type 2 diabetes. This article summarizes available evidence for the involvement of oestrogen receptors in insulin secretion, insulin resistance as well as glucose uptake and highlights the potential of ERβ as a therapeutic target. Background: Recent studies indicate an association between the activation of each of the isoforms of ER and recent findings indicate that ERβ shows promise as a potential target for antidiabetic drugs. In vitro and in vivo studies in receptor knockout mice indicate beneficial actions of selective agonists of ERβ receptor and underscore its therapeutic potential. Conclusion: Studies are needed to further elucidate the exact mechanism underlying the role of ERβ activation as a therapeutic approach in the management of type 2 diabetes

COSMOS-Web: Intrinsically Luminous z≳\gtrsim10 Galaxy Candidates Test Early Stellar Mass Assembly

We report the discovery of 15 exceptionally luminous $10\lesssim z\lesssim14$ candidate galaxies discovered in the first 0.28 deg$^2$ of JWST/NIRCam imaging from the COSMOS-Web Survey. These sources span rest-frame UV magnitudes of $-20.5>M_{\rm UV}>-22$, and thus constitute the most intrinsically luminous $z\gtrsim10$ candidates identified by JWST to-date. Selected via NIRCam imaging with Hubble ACS/F814W, deep ground-based observations corroborate their detection and help significantly constrain their photometric redshifts. We analyze their spectral energy distributions using multiple open-source codes and evaluate the probability of low-redshift solutions; we conclude that 12/15 (80%) are likely genuine $z\gtrsim10$ sources and 3/15 (20%) likely low-redshift contaminants. Three of our $z\sim12$ candidates push the limits of early stellar mass assembly: they have estimated stellar masses $\sim5\times10^{9}\,M_\odot$, implying an effective stellar baryon fraction of $\epsilon_{\star}\sim0.2-0.5$, where $\epsilon_{\star}\equiv M_{\star}/(f_{b}M_{halo})$. The assembly of such stellar reservoirs is made possible due to rapid, burst-driven star formation on timescales $<$100\,Myr where the star-formation rate may far outpace the growth of the underlying dark matter halos. This is supported by the similar volume densities inferred for $M_\star\sim10^{10}\,M_\odot$ galaxies relative to $M_\star\sim10^{9}\,M_\odot$ -- both about $10^{-6}$ Mpc$^{-3}$ -- implying they live in halos of comparable mass. At such high redshifts, the duty cycle for starbursts would be of order unity, which could cause the observed change in the shape of the UVLF from a double powerlaw to Schechter at $z\approx8$. Spectroscopic redshift confirmation and ensuing constraints of their masses will be critical to understanding how, and if, such early massive galaxies push the limits of galaxy formation in $\Lambda$CDM.Comment: 30 pages, 9 figures; ApJ submitte

A Pro-Cathepsin L Mutant Is a Luminal Substrate for Endoplasmic-Reticulum-Associated Degradation in C. elegans

Endoplasmic-reticulum associated degradation (ERAD) is a major cellular misfolded protein disposal pathway that is well conserved from yeast to mammals. In yeast, a mutant of carboxypeptidase Y (CPY*) was found to be a luminal ER substrate and has served as a useful marker to help identify modifiers of the ERAD pathway. Due to its ease of genetic manipulation and the ability to conduct a genome wide screen for modifiers of molecular pathways, C. elegans has become one of the preferred metazoans for studying cell biological processes, such as ERAD. However, a marker of ERAD activity comparable to CPY* has not been developed for this model system. We describe a mutant of pro-cathepsin L fused to YFP that no longer targets to the lysosome, but is efficiently eliminated by the ERAD pathway. Using this mutant pro-cathepsin L, we found that components of the mammalian ERAD system that participate in the degradation of ER luminal substrates were conserved in C. elegans. This transgenic line will facilitate high-throughput genetic or pharmacological screens for ERAD modifiers using widefield epifluorescence microscopy