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

Lipid phosphate phosphatase-1 regulates lysophosphatidic acid- and platelet-derived-growth-factor-induced cell migration

LPPs (lipid phosphate phosphatases) are members of a family of enzymes that catalyse the dephosphorylation of lipid phosphates. The only known form of regulation of this family of enzymes is via de novo expression of LPP isoforms in response to growth factors. In this respect, we evaluated the effect of moderate increases in the expression of recombinant LPP1 on signal transduction by both G-protein-coupled receptors and receptor tyrosine kinases. We present evidence for a novel role of LPP1 in reducing PDGF (platelet-derived growth factor)- and lysophosphatidic acid-induced migration of embryonic fibroblasts. We demonstrate that the overexpression of LPP1 inhibits cell migration by reducing the PDGF-induced activation of p42/p44 MAPK (mitogen-activated protein kinase). This appears to occur via a mechanism that involves the LPP1-induced down-regulation of typical PKC (protein kinase C) isoform(s), which are normally required for PDGF-induced activation of p42/p44 MAPK and migration. In this regard, DAG (diacylglycerol) levels are high and sustained in cells overexpressing LPP1, suggesting a dynamic interconversion of phosphatidic acid into DAG by LPP1. This may account for the effects of LPP1 on cell migration, as sustained DAG is known to down-regulate PKC isoforms in cells. Therefore the physiological changes in the expression levels of LPP1 might represent a heterologous desensitization mechanism for attenuating PKC-mediated signalling and regulation of cell migration

Autophagy suppresses the formation of hepatocyte-derived cancer-initiating ductular progenitor cells in the liver

Hepatocellular carcinoma (HCC) is driven by repeated rounds of inflammation, leading to fibrosis, cirrhosis, and, ultimately, cancer. A critical step in HCC formation is the transition from fibrosis to cirrhosis, which is associated with a change in the liver parenchyma called ductular reaction. Here, we report a genetically engineered mouse model of HCC driven by loss of macroautophagy and hemizygosity of phosphatase and tensin homolog, which develops HCC involving ductular reaction. We show through lineage tracing that, following loss of autophagy, mature hepatocytes dedifferentiate into biliary-like liver progenitor cells (ductular reaction), giving rise to HCC. Furthermore, this change is associated with deregulation of yes-associated protein and transcriptional coactivator with PDZ-binding motif transcription factors, and the combined, but not individual, deletion of these factors completely reverses the dedifferentiation capacity and tumorigenesis. These findings therefore increase our understanding of the cell of origin of HCC development and highlight new potential points for therapeutic intervention

DRAM-1 is required for mTORC1 activation by facilitating lysosomal amino acid efflux

Sensing nutrient availability is essential for appropriate cellular growth, and mTORC1 is a major regulator of this process. Mechanisms causing mTORC1 activation are, however, complex and diverse. We report here an additional important step in the activation of mTORC1, which regulates the efflux of amino acids from lysosomes into the cytoplasm. This process requires DRAM-1, which binds the membrane carrier protein SCAMP3 and the amino acid transporters SLC1A5 and LAT1, directing them to lysosomes and permitting efficient mTORC1 activation. Consequently, we show that loss of DRAM-1 also impacts pathways regulated by mTORC1, including insulin signaling, glycemic balance, and adipocyte differentiation. Interestingly, although DRAM-1 can promote autophagy, this effect on mTORC1 is autophagy independent, and autophagy only becomes important for mTORC1 activation when DRAM-1 is deleted. These findings provide important insights into mTORC1 activation and highlight the importance of DRAM-1 in growth control, metabolic homeostasis, and differentiation

LRRK2 phosphorylation status and kinase activity regulate (macro)autophagy in a Rab8a/Rab10-dependent manner

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson’s disease (PD), with growing importance also for Crohn’s disease and cancer. LRRK2 is a large and complex protein possessing both GTPase and kinase activity. Moreover, LRRK2 activity and function can be influenced by its phosphorylation status. In this regard, many LRRK2 PD-associated mutants display decreased phosphorylation of the constitutive phosphorylation cluster S910/S935/S955/S973, but the role of these changes in phosphorylation status with respect to LRRK2 physiological functions remains unknown. Here, we propose that the S910/S935/S955/S973 phosphorylation sites act as key regulators of LRRK2-mediated autophagy under both basal and starvation conditions. We show that quadruple LRRK2 phosphomutant cells (4xSA; S910A/S935A/S955A/S973A) have impaired lysosomal functionality and fail to induce and proceed with autophagy during starvation. In contrast, treatment with the specific LRRK2 kinase inhibitors MLi-2 (100 nM) or PF-06447475 (150 nM), which also led to decreased LRRK2 phosphorylation of S910/S935/S955/S973, did not affect autophagy. In explanation, we demonstrate that the autophagy impairment due to the 4xSA LRRK2 phospho-dead mutant is driven by its enhanced LRRK2 kinase activity. We show mechanistically that this involves increased phosphorylation of LRRK2 downstream targets Rab8a and Rab10, as the autophagy impairment in 4xSA LRRK2 cells is counteracted by expression of phosphorylation-deficient mutants T72A Rab8a and T73A Rab10. Similarly, reduced autophagy and decreased LRRK2 phosphorylation at the constitutive sites were observed in cells expressing the pathological R1441C LRRK2 PD mutant, which also displays increased kinase activity. These data underscore the relation between LRRK2 phosphorylation at its constitutive sites and the importance of increased LRRK2 kinase activity in autophagy regulation and PD pathology

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

Bromodomain protein BRD4 is a transcriptional repressor of autophagy and lysosomal function

Autophagy is a membrane-trafficking process that directs degradation of cytoplasmic material in lysosomes. The process promotes cellular fidelity, and while the core machinery of autophagy is known, the mechanisms that promote and sustain autophagy are less well defined. Here we report that the epigenetic reader BRD4 and the methyltransferase G9a repress a TFEB/TFE3/MITF-independent transcriptional program that promotes autophagy and lysosome biogenesis. We show that BRD4 knockdown induces autophagy in vitro and in vivo in response to some, but not all, situations. In the case of starvation, a signaling cascade involving AMPK and histone deacetylase SIRT1 displaces chromatin-bound BRD4, instigating autophagy gene activation and cell survival. Importantly, this program is directed independently and also reciprocally to the growth-promoting properties of BRD4 and is potently repressed by BRD4-NUT, a driver of NUT midline carcinoma. These findings therefore identify a distinct and selective mechanism of autophagy regulation