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Circulating proteins associated with transforming growth factor-β (TGF-β) signaling are implicated in the development of diabetic kidney disease (DKD). No study has comprehensively examined which of these proteins are involved in the pathogenesis of DKD and its progression to end-stage kidney disease (ESKD) in humans. Using the SOMAscan proteomic platform, we measured concentrations of 25 TGF-β-signaling family proteins, in 4 different cohorts comprised of 754 Caucasian and Pima Indian subjects with type 1 and type 2 diabetes. Of these 25 circulating proteins, we identified neuroblastoma suppressor of tumorigenicity 1 (NBL1, aliases DAN & DAND1), a small, secreted protein known to inhibit members of the bone morphogenic protein family, to be most strongly and independently associated with progression to ESKD during 10-year follow-up in all cohorts. The extent of damage to podocytes and other glomerular structures measured morphometrically in 105 research kidney biopsies correlated strongly with circulating NBL1 concentrations. Also, in vitro exposure to NBL1 induced apoptosis in podocytes. In conclusion, concentration of NBL1 in circulation may identify subjects with diabetes at increased risk of progression to ESKD and may serve as a target for pharmacological intervention of the TGF-β signaling pathway to slow the development and progression of DKD.

Parkinson’s disease (PD) is a complex neurodegenerative disease with etiology rooted in genetic vulnerability and environmental factors. Here we combine quantitative epidemiologic study of pesticide exposures and PD with toxicity screening in dopaminergic neurons derived from PD patient induced pluripotent stem cells (iPSCs) to identify Parkinson’s-relevant pesticides. Agricultural records enable investigation of 288 specific pesticides and PD risk in a comprehensive, pesticide-wide association study. We associate long-term exposure to 53 pesticides with PD and identify co-exposure profiles. We then employ a live-cell imaging screening paradigm exposing dopaminergic neurons to 39 PD-associated pesticides. We find that 10 pesticides are directly toxic to these neurons. Further, we analyze pesticides typically used in combinations in cotton farming, demonstrating that co-exposures result in greater toxicity than any single pesticide. We find trifluralin is a driver of toxicity to dopaminergic neurons and leads to mitochondrial dysfunction. Our paradigm may prove useful to mechanistically dissect pesticide exposures implicated in PD risk and guide agricultural policy.

Androgen withdrawal induces the regression of human prostate cancers, but such cancers eventually become androgen-independent and metastasize. Thus, deciphering the mechanism of androgen withdrawal–induced apoptosis is critical to designing new therapies for prostate cancer. Previously, we showed that in the rat, castration-induced apoptosis is accompanied by a reduction in the expression of the apical caspase inhibitor FLICE-like inhibitory protein (FLIP). To test the functional role of FLIP in inhibiting prostate epithelial cell apoptosis, we employed the rat prostate epithelial cell line NRP-152, which differentiates to a secretory phenotype in a low-mitogen medium and then undergoes apoptosis following the addition of transforming growth factor β1 (TGFβ1), mimicking androgen withdrawal–induced apoptosis. FLIP levels decline with TGFβ1 treatment, suggesting that apoptosis is mediated by caspase-8 and indeed the caspase inhibitor crmA blocks TGFβ1-induced apoptosis. Small interfering RNA–mediated knockdown of FLIP recapitulates and enhances TGFβ1-induced cell death. NRP-152 cells stably transfected with constitutively expressed FLIP were refractory to TGFβ1-induced apoptosis. TGFβ1-induced caspase-3 activity is proportional to the level of cell death and inversely proportional to the level of FLIP expression in various clones. Moreover, neither caspase-3 nor PARP is cleaved in clones expressing high levels of FLIP. Furthermore, insulin, which inhibits differentiation, increases FLIP and inhibits TGFβ-induced death in a FLIP-dependent manner. Although neither Fas-Fc, sTNFRII-Fc, nor DR5-Fc blocked TGFβ1-induced cell death, there is a significant increase in tumor necrosis factor mRNA following TGFβ stimulation, suggesting both an unexpected role for tumor necrosis factor in this model system and the possibility that FLIP blocks another unknown caspase-dependent mediator of apoptosis. (Mol Cancer Res 2008;6(2):231–12)

High power image of neutrophil elastase localization in a xenograft.

High CD33 expression predicts poor outcomes in prostate cancer patients.

Tissue infiltration and elevated peripheral circulation of granulocytic myeloid-derived cells is associated with poor outcomes in prostate cancer and other malignancies. Although myeloid-derived cells have the ability to suppress T-cell function, little is known about the direct impact of these innate cells on prostate tumor growth. Here, it is reported that granulocytic myeloid-derived suppressor cells (MDSC) are the predominant tumor-infiltrating cells in prostate cancer xenografts established in athymic nude mice. MDSCs significantly increased in number in the peripheral circulation as a function of xenograft growth and were successfully depleted in vivo by Gr-1 antibody treatment. Importantly, MDSC depletion significantly decreased xenograft growth. We hypothesized that granulocytic MDSCs might exert their protumorigenic actions in part through neutrophil elastase (ELANE), a serine protease released upon granulocyte activation. Indeed, it was determined that NE is expressed by infiltrating immune cells and is enzymatically active in prostate cancer xenografts and in prostate tumors of prostate-specific Pten-null mice. Importantly, treatment with sivelestat, a small-molecule inhibitor specific for NE, significantly decreased xenograft growth, recapitulating the phenotype of Gr-1 MDSC depletion. Mechanistically, NE activated MAPK signaling and induced MAPK-dependent transcription of the proliferative gene cFOS in prostate cancer cells. Functionally, NE stimulated proliferation, migration, and invasion of prostate cancer cells in vitro. IHC on human prostate cancer clinical biopsies revealed coexpression of NE and infiltrating CD33+ MDSCs.Implications: This report suggests that MDSCs and NE are physiologically important mediators of prostate cancer progression and may serve as potential biomarkers and therapeutic targets. Mol Cancer Res; 15(9); 1138–52. ©2017 AACR.

The frontal pole (Brodmann area 10, BA10) is the largest cytoarchitectonic region of the human cortex, performing complex integrative functions. BA10 undergoes intensive adolescent grey matter pruning prior to the age of onset for bipolar disorder (BP) and schizophrenia (SCHIZ), and its dysfunction is likely to underly aspects of their shared symptomology. In this study, we investigated the role of BA10 neurotransmission-related gene expression in BP and SCHIZ. We performed qPCR to measure the expression of 115 neurotransmission-related targets in control, BP, and SCHIZ postmortem samples (n = 72). We chose this method for its high sensitivity to detect low-level expression. We then strengthened our findings by performing a meta-analysis of publicly released BA10 microarray data (n = 101) and identified sources of convergence with our qPCR results. To improve interpretation, we leveraged the unusually large database of clinical metadata accompanying our samples to explore the relationship between BA10 gene expression, therapeutics, substances of abuse, and symptom profiles, and validated these findings with publicly available datasets. Using these convergent sources of evidence, we identified 20 neurotransmission-related genes that were differentially expressed in BP and SCHIZ in BA10. These results included a large diagnosis-related decrease in two important therapeutic targets with low levels of expression, HTR2B and DRD4, as well as other findings related to dopaminergic, GABAergic and astrocytic function. We also observed that therapeutics may produce a differential expression that opposes diagnosis effects. In contrast, substances of abuse showed similar effects on BA10 gene expression as BP and SCHIZ, potentially amplifying diagnosis-related dysregulation.

BACKGROUND: Mechanisms underlying the pro gression of diabetic kidney disease to ESKD are not fully understood. METHODS: We performed global microRNA (miRNA) analysis on plasma from two cohorts consisting of 375 individuals with type 1 and type 2 diabetes with late diabetic kidney disease, and targeted proteomics analysis on plasma from four cohorts consisting of 746 individuals with late and early diabetic kidney disease. We examined structural lesions in kidney biopsy specimens from the 105 individuals with early diabetic kidney disease. Human umbilical vein endothelial cells were used to assess the effects of miRNA mimics or inhibitors on regulation of candidate proteins. RESULTS: In the late diabetic kidney disease cohorts, we identified 17 circulating miRNAs, represented by four exemplars (miR-1287-5p, miR-197-5p, miR-339-5p, and miR-328-3p), that were strongly associated with 10-year risk of ESKD. These miRNAs targeted proteins in the axon guidance pathway. Circulating levels of six of these proteins—most notably, EFNA4 and EPHA2—were strongly associated with 10-year risk of ESKD in all cohorts. Furthermore, circulating levels of these proteins correlated with severity of structural lesions in kidney biopsy specimens. In contrast, expression levels of genes encoding these proteins had no apparent effects on the lesions. In in vitro experiments, mimics of miR-1287-5p and miR-197-5p and inhibitors of miR-339-5p and miR-328-3p upregulated concentrations of EPHA2 in either cell lysate, supernatant, or both. CONCLUSIONS: This study reveals novel mechanisms involved in progression to ESKD and points to the importance of systemic factors in the development of diabetic kidney disease. Some circulating miRNAs and axon guidance pathway proteins represent potential targets for new therapies to prevent and treat this condition.

MIP correlates with OS.

Heat map showing relative levels of mRNA expression for each gene, specifying the gene represented by each row.

Comparison of patient demographics in validation cohort to original publication discovery and test cohorts.

Figure legends for supplementary figures.

Purpose:Biomarkers are needed to stratify patients with stage II–III melanoma for clinical trials of adjuvant therapy because, while immunotherapy is protective, it also confers the risk of severe toxicity. We previously defined and validated a 53-immune gene melanoma immune profile (MIP) predictive both of distant metastatic recurrence and of disease-specific survival (DSS). Here, we test MIP on a third independent population.Experimental Design:A retrospective cohort of 78 patients with stage II–III primary melanoma was analyzed using the NanoString assay to measure expression of 53 target genes, and MIP score was calculated. Statistical analysis correlating MIP with DSS, overall survival, distant metastatic recurrence, and distant metastasis-free interval was performed using ROC curves, Kaplan–Meier curves, and standard univariable and multivariable Cox proportional hazards models.Results:MIP significantly distinguished patients with distant metastatic recurrence from those without distant metastatic recurrence using ROC curve analysis (AUC = 0.695; P = 0.008). We defined high- and low-risk groups based on the cutoff defined by this ROC curve and find that MIP correlates with both DSS and overall survival by ROC curve analysis (AUC = 0.719; P = 0.004 and AUC = 0.698; P = 0.004, respectively). Univariable Cox regression reveals that a high-risk MIP score correlates with DSS (P = 0.015; HR = 3.2).Conclusions:MIP identifies patients with low risk of death from melanoma and may constitute a clinical tool to stratify patients with stage II–III melanoma for enrollment in clinical trials.

Melanoma Immune Profile (MIP) correlates with metastasis cohort including patients with local recurrence only.

Patient characteristics in metastasis cohort.

The Nancy Grace Roman Space Telescope is capable of delivering an unprecedented all-sky, high-spatial resolution, multi-epoch infrared map to the astronomical community. This opportunity arises in the midst of numerous ground- and space-based surveys that will provide extensive spectroscopy and imaging together covering the entire sky (such as Rubin/LSST, Euclid, UNIONS, SPHEREx, DESI, SDSS-V, GALAH, 4MOST, WEAVE, MOONS, PFS, UVEX, NEO Surveyor, etc.). Roman can uniquely provide uniform high-spatial-resolution (~0.1 arcsec) imaging over the entire sky, vastly expanding the science reach and precision of all of these near-term and future surveys. This imaging will not only enhance other surveys, but also facilitate completely new science. By imaging the full sky over two epochs, Roman can measure the proper motions for stars across the entire Milky Way, probing 100 times fainter than Gaia out to the very edge of the Galaxy. Here, we propose NANCY: a completely public, all-sky survey that will create a high-value legacy dataset benefiting innumerable ongoing and forthcoming studies of the universe. NANCY is a pure expression of Roman's potential: it images the entire sky, at high spatial resolution, in a broad infrared bandpass that collects as many photons as possible. The majority of all ongoing astronomical surveys would benefit from incorporating observations of NANCY into their analyses, whether these surveys focus on nearby stars, the Milky Way, near-field cosmology, or the broader universe., Comment: Submitted to the call for white papers for the Roman Core Community Survey (June 16th, 2023), and to the Bulletin of the AAS

The Dark Energy Spectroscopic Instrument (DESI) was designed to conduct a survey covering 14,000 deg$^2$ over five years to constrain the cosmic expansion history through precise measurements of Baryon Acoustic Oscillations (BAO). The scientific program for DESI was evaluated during a five month Survey Validation (SV) campaign before beginning full operations. This program produced deep spectra of tens of thousands of objects from each of the stellar (MWS), bright galaxy (BGS), luminous red galaxy (LRG), emission line galaxy (ELG), and quasar target classes. These SV spectra were used to optimize redshift distributions, characterize exposure times, determine calibration procedures, and assess observational overheads for the five-year program. In this paper, we present the final target selection algorithms, redshift distributions, and projected cosmology constraints resulting from those studies. We also present a `One-Percent survey' conducted at the conclusion of Survey Validation covering 140 deg$^2$ using the final target selection algorithms with exposures of a depth typical of the main survey. The Survey Validation indicates that DESI will be able to complete the full 14,000 deg$^2$ program with spectroscopically-confirmed targets from the MWS, BGS, LRG, ELG, and quasar programs with total sample sizes of 7.2, 13.8, 7.46, 15.7, and 2.87 million, respectively. These samples will allow exploration of the Milky Way halo, clustering on all scales, and BAO measurements with a statistical precision of 0.28% over the redshift interval $z, Comment: 42 pages, 16 figures, submitted to AJ

The joint analysis of different cosmological probes, such as galaxy clustering and weak lensing, can potentially yield invaluable insights into the nature of the primordial Universe, dark energy and dark matter. However, the development of high-fidelity theoretical models that cover a wide range of scales and redshifts is a necessary stepping-stone. Here, we present public high-resolution weak lensing maps on the light cone, generated using the $N$-body simulation suite AbacusSummit in the Born approximation, and accompanying weak lensing mock catalogues, tuned via fits to the Early Data Release small-scale clustering measurements of the Dark Energy Spectroscopic Instrument (DESI). Available in this release are maps of the cosmic shear, deflection angle and convergence fields at source redshifts ranging from $z = 0.15$ to 2.45 with $\Delta z = 0.05$ as well as CMB convergence maps ($z \approx 1090$) for each of the 25 ${\tt base}$-resolution simulations ($L_{\rm box} = 2000\,h^{-1}{\rm Mpc}$, $N_{\rm part} = 6912^3$) as well as for the two ${\tt huge}$ simulations ($L_{\rm box} = 7500\,h^{-1}{\rm Mpc}$, $N_{\rm part} = 8640^3$) at the fiducial AbacusSummit cosmology ($Planck$ 2018). The pixel resolution of each map is 0.21 arcmin, corresponding to a HEALPiX $N_{\rm side}$ of 16384. The sky coverage of the ${\tt base}$ simulations is an octant until $z \approx 0.8$ (decreasing to about 1800 deg$^2$ at $z \approx 2.4$), whereas the ${\tt huge}$ simulations offer full-sky coverage until $z \approx 2.2$. Mock lensing source catalogues are sampled matching the ensemble properties of the Kilo-Degree Survey, Dark Energy Survey, and Hyper-Suprime Cam weak lensing datasets. The produced mock catalogues are validated against theoretical predictions for various clustering and lensing statistics such as galaxy clustering multipoles, galaxy-shear and shear-shear, showing excellent agreement., Comment: 21 pages, 13 figures, data available at https://app.globus.org/file-manager?origin_id=3dd6566c-eed2-11ed-ba43-09d6a6f08166&path=%2F

Benign prostatic hyperplasia (BPH) is a non-neoplastic proliferative disease producing lower urinary tract symptoms related to the enlarged prostate. BPH is pathologically characterized by hyperplastic growth in both epithelial and stromal compartments. Androgen signaling is essential for prostate function and androgen blockade is the second-line medical therapy to relieve symptoms of BPH. Here we examined the prostates of probasin promoter-driven prolactin (Pb-PRL) transgenic mice, a robust model of BPH that spontaneously develops prostate enlargement, to investigate prostate regression in response to surgical castration. Serial ultrasound imaging demonstrated very uniform self-limited growth of Pb-PRL prostate volume that is consistent with the benign, limited cellular proliferation characteristic of BPH and that contrasts with the highly variable, exponential growth of murine prostate cancer models. Castration elicited only a partial reduction in prostate volume, relative to castration-induced regression of the normal prostate gland. The anti-androgen finasteride induced a diminished reduction of Pb-PRL prostate volume versus castration alone. The limited extent of Pb-PRL mouse prostate volume regression correlated with the initial volume of the stromal compartment, suggesting a differential sensitivity to androgen withdrawal of the epithelial and stroma compartments. Indeed, two-dimensional morphometric analyses revealed a distinctly reduced rate of regression for the stromal compartment in Pb-PRL mice. The myofibroblast component of the Pb-PRL prostate stroma appeared normal, but contained more fibroblasts and extracellular collagen deposition. Like normal prostate, the rate of regression of the Pb-PRL prostate was partially dependent on TGFß and TNF signaling, but unlike the normal prostate, the extent of castration-induced regression was not affected by TGFß or TNF blockade. Our studies show that androgen deprivation can effectively reduce the overall volume of hyperplastic prostate, but the stromal compartment is relatively resistant, suggesting additional therapies might be required to offer an effective treatment for the clinical manifestations of BPH.

Full list of authors: Abareshi, B.; Aguilar, J.; Ahlen, S.; Alam, Shadab; Alexander, David M.; Alfarsy, R.; Allen, L.; Allende Prieto, C.; Alves, O.; Ameel, J.; Armengaud, E.; Asorey, J.; Aviles, Alejandro; Bailey, S.; Balaguera-Antolinez, A.; Ballester, O.; Baltay, C.; Bault, A.; Beltran, S. F.; Benavides, B.; BenZvi, S.; Berti, A.; Besuner, R.; Beutler, Florian; Bianchi, D.; Blake, C.; Blanc, P.; Blum, R.; Bolton, A.; Bose, S.; Bramall, D.; Brieden, S.; Brodzeller, A.; Brooks, D.; Brownewell, C.; Buckley-Geer, E.; Cahn, R. N.; Cai, Z.; Canning, R.; Capasso, R.; Carnero Rosell, A.; Carton, P.; Casas, R.; Castander, F. J.; Cervantes-Cota, J. L.; Chabanier, S.; Chaussidon, E.; Chuang, C.; Circosta, C.; Cole, S.; Cooper, A. P.; da Costa, L.; Cousinou, M-C; Cuceu, A.; Davis, T. M.; Dawson, K.; De la Cruz-Noriega, R.; de la Macorra, A.; de Mattia, A.; Della Costa, J.; Demmer, P.; Derwent, M.; Dey, A.; Dey, B.; Dhungana, G.; Ding, Z.; Dobson, C.; Doel, P.; Donald-McCann, J.; Donaldson, J.; Douglass, K.; Duan, Y.; Dunlop, P.; Edelstein, J.; Eftekharzadeh, S.; Eisenstein, D. J.; Enriquez-Vargas, M.; Escoffier, S.; Evatt, M.; Fagrelius, P.; Fan, X.; Fanning, K.; Fawcett, V. A.; Ferraro, S.; Ereza, J.; Flaugher, B.; Font-Ribera, A.; Forero-Romero, J. E.; Frenk, C. S.; Fromenteau, S.; Gansicke, B. T.; Garcia-Quintero, C.; Garrison, L.; Gaztanaga, E.; Gerardi, F.; Gil-Marin, H.; Gontcho, S. Gontcho A.; Gonzalez-Morales, Alma X.; Gonzalez-de-Rivera, G.; Gonzalez-Perez, V; Gordon, C.; Graur, O.; Green, D.; Grove, C.; Gruen, D.; Gutierrez, G.; Guy, J.; Hahn, C.; Harris, S.; Herrera, D.; Herrera-Alcantar, Hiram K.; Honscheid, K.; Howlett, C.; Huterer, D.; Irsic, V; Ishak, M.; Jelinsky, P.; Jiang, L.; Jimenez, J.; Jing, Y. P.; Joyce, R.; Jullo, E.; Juneau, S.; Karacayli, N. G.; Karamanis, M.; Karcher, A.; Karim, T.; Kehoe, R.; Kent, S.; Kirkby, D.; Kisner, T.; Kitaura, F.; Koposov, S. E.; Kovacs, A.; Kremin, A.; Krolewski, Alex; L'Huillier, B.; Lahav, O.; Lambert, A.; Lamman, C.; Lan, Ting-Wen; Landriau, M.; Lane, S.; Lang, D.; Lange, J. U.; Lasker, J.; Le Guillou, L.; Leauthaud, A.; Suu, A. Le Van; Levi, Michael E.; Li, T. S.; Magneville, C.; Manera, M.; Manser, Christopher J.; Marshall, B.; Martini, Paul; McCollam, W.; McDonald, P.; Meisner, Aaron M.; Mena-Fernandez, J.; Meneses-Rizo, J.; Mezcua, M.; Miller, T.; Miquel, R.; Montero-Camacho, P.; Moon, J.; Moustakas, J.; Mueller, E.; Munoz-Gutierrez, Andrea; Myers, Adam D.; Nadathur, S.; Najita, J.; Napolitano, L.; Neilsen, E.; Newman, Jeffrey A.; Nie, J. D.; Ning, Y.; Niz, G.; Norberg, P.; Noriega, Hernan E.; O'Brien, T.; Obuljen, A.; Palanque-Delabrouille, N.; Palmese, A.; Zhiwei, P.; Pappalardo, D.; Peng, X.; Percival, W. J.; Perruchot, S.; Pogge, R.; Poppett, C.; Porredon, A.; Prada, F.; Prochaska, J.; Pucha, R.; Perez-Fernandez, A.; Perez-Rafols, I; Rabinowitz, D.; Raichoor, A.; Ramirez-Solano, S.; Ramirez-Perez, Cesar; Ravoux, C.; Reil, K.; Rezaie, M.; Rocher, A.; Rockosi, C.; Roe, N. A.; Roodman, A.; Ross, A. J.; Rossi, G.; Ruggeri, R.; Ruhlmann-Kleider, V; Sabiu, C. G.; Safonova, S.; Said, K.; Saintonge, A.; Catonga, Javier Salas; Samushia, L.; Sanchez, E.; Saulder, C.; Schaan, E.; Schlafly, E.; Schlegel, D.; Schmoll, J.; Scholte, D.; Schubnell, M.; Secroun, A.; Seo, H.; Serrano, S.; Sharples, Ray M.; Sholl, Michael J.; Silber, Joseph Harry; Silva, D. R.; Sirk, M.; Siudek, M.; Smith, A.; Sprayberry, D.; Staten, R.; Stupak, B.; Tan, T.; Tarle, Gregory; Tie, Suk Sien; Tojeiro, R.; Urena-Lopez, L. A.; Valdes, F.; Valenzuela, O.; Valluri, M.; Vargas-Magana, M.; Verde, L.; Walther, M.; Wang, B.; Wang, M. S.; Weaver, B. A.; Weaverdyck, C.; Wechsler, R.; Wilson, Michael J.; Yang, J.; Yu, Y.; Yuan, S.; Yeche, Christophe; Zhang, H.; Zhang, K.; Zhao, Cheng; Zhou, Rongpu; Zhou, Zhimin; Zou, H.; Zou, J.; Zou, S.; Zu, Y.; DESI Collaboration.--This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited., The Dark Energy Spectroscopic Instrument (DESI) embarked on an ambitious 5 yr survey in 2021 May to explore the nature of dark energy with spectroscopic measurements of 40 million galaxies and quasars. DESI will determine precise redshifts and employ the baryon acoustic oscillation method to measure distances from the nearby universe to beyond redshift z > 3.5, and employ redshift space distortions to measure the growth of structure and probe potential modifications to general relativity. We describe the significant instrumentation we developed to conduct the DESI survey. This includes: a wide-field, 3fdg2 diameter prime-focus corrector; a focal plane system with 5020 fiber positioners on the 0.812 m diameter, aspheric focal surface; 10 continuous, high-efficiency fiber cable bundles that connect the focal plane to the spectrographs; and 10 identical spectrographs. Each spectrograph employs a pair of dichroics to split the light into three channels that together record the light from 360–980 nm with a spectral resolution that ranges from 2000–5000. We describe the science requirements, their connection to the technical requirements, the management of the project, and interfaces between subsystems. DESI was installed at the 4 m Mayall Telescope at Kitt Peak National Observatory and has achieved all of its performance goals. Some performance highlights include an rms positioner accuracy of better than 0farcs1 and a median signal-to-noise ratio of 7 of the [O ii] doublet at 8 × 10−17 erg s−1 cm−2 in 1000 s for galaxies at z = 1.4–1.6. We conclude with additional highlights from the on-sky validation and commissioning, key successes, and lessons learned. © 2022. The Author(s). Published by the American Astronomical Society., This research is supported by the Director, Office of Science, Office of High Energy Physics of the U.S. Department of Energy under contract No. DE-AC02-05CH11231, and by the National Energy Research Scientific Computing Center, a DOE Office of Science User Facility under the same contract. Additional support for DESI is provided by the U.S. National Science Foundation, Division of Astronomical Sciences under contract No. AST-0950945 to the NSF's National Optical-Infrared Astronomy Research Laboratory; the Science and Technologies Facilities Council of the United Kingdom; the Gordon and Betty Moore Foundation; the Heising–Simons Foundation; the French Alternative Energies and Atomic Energy Commission (CEA); the National Council of Science and Technology of Mexico (CONACYT); the Ministry of Science and Innovation of Spain, and by the DESI Member Institutions: Aix-Marseille University; Argonne National Laboratory; Barcelona-Madrid Regional Participation Group; Brookhaven National Laboratory; Boston University; Brazil Regional Participation Group; Carnegie Mellon University; CEA-IRFU, Saclay; China Participation Group; Cornell University; Durham University; École Polytechnique Fédérale de Lausanne; Eidgenössische Technische Hochschule, Zürich; Fermi National Accelerator Laboratory; Granada-Madrid-Tenerife Regional Participation Group; Harvard University; Kansas State University; Korea Astronomy and Space Science Institute; Korea Institute for Advanced Study; Lawrence Berkeley National Laboratory; Laboratoire de Physique Nucléaire et de Hautes Energies; Ludwig Maximilians University; Max Planck Institute; Mexico Regional Participation Group; New York University; NSF's National Optical-Infrared Astronomy Research Laboratory; Ohio University; Perimeter Institute; Shanghai Jiao Tong University; Siena College; SLAC National Accelerator Laboratory; Southern Methodist University; Swinburne University; The Ohio State University; Universidad de los Andes; University of Arizona; University of Barcelona; University of California, Berkeley; University of California, Irvine; University of California, Santa Cruz; University College London; University of Florida; University of Michigan at Ann Arbor; University of Pennsylvania; University of Pittsburgh; University of Portsmouth; University of Queensland; University of Rochester; University of Toronto; University of Utah; University of Waterloo; University of Wyoming; University of Zurich; UK Regional Participation Group; and Yale University. This work has made use of data from the European Space Agency (ESA) mission Gaia (https://www.cosmos.esa.int/gaia), processed by the Gaia Data Processing and Analysis Consortium (DPAC; https://www.cosmos.esa.int/web/gaia/dpac/consortium). Funding for the DPAC has been provided by national institutions, in particular the institutions participating in the Gaia Multilateral Agreement., With funding from the Spanish government through the Severo Ochoa Centre of Excellence accreditation SEV-2017-0709.

Multiple system atrophy (MSA) is a fatal neurodegenerative disease of unknown etiology characterized by widespread aggregation of the protein alpha-synuclein in neurons and glia. Its orphan status, biological relationship to Parkinson’s disease (PD), and rapid progression have sparked interest in drug development. One significant obstacle to therapeutics is disease heterogeneity. Here, we share our process of developing a clinical trial-ready cohort of MSA patients (69 patients in 2 years) within an outpatient clinical setting, and recruiting 20 of these patients into a longitudinal “n-of-few” clinical trial paradigm. First, we deeply phenotype our patients with clinical scales (UMSARS, BARS, MoCA, NMSS, and UPSIT) and tests designed to establish early differential diagnosis (including volumetric MRI, FDG-PET, MIBG scan, polysomnography, genetic testing, autonomic function tests, skin biopsy) or disease activity (PBR06-TSPO). Second, we longitudinally collect biospecimens (blood, CSF, stool) and clinical, biometric, and imaging data to generate antecedent disease-progression scores. Third, in our Mass General Brigham SCiN study (stemcellsinneurodegeneration), we generate induced pluripotent stem cell (iPSC) models from our patients, matched to biospecimens, including postmortem brain. We present 38 iPSC lines derived from MSA patients and relevant disease controls (spinocerebellar ataxia and PD, including alpha-synuclein triplication cases), 22 matched to whole-genome sequenced postmortem brain. iPSC models may facilitate matching patients to appropriate therapies, particularly in heterogeneous diseases for which patient-specific biology may elude animal models. We anticipate that deeply phenotyped and genotyped patient cohorts matched to cellular models will increase the likelihood of success in clinical trials for MSA.

Brodmann Area 10 (BA10) is the largest cytoarchitectonic region of the human cortex, performing complex integrative functions. BA10 undergoes intensive adolescent grey matter pruning around the average age of onset for Bipolar disorder (BP) and Schizophrenia (SCHIZ), and its dysfunction is likely to underly aspects of their shared symptomology. In this study, we investigated the role of BA10 neurotransmission-related gene expression in BP and SCHIZ. We performed qPCR to measure the expression of 115 neurotransmission-related targets in control, BP, and SCHIZ post-mortem samples (n=72). We chose this method for its high sensitivity to detect low-level expression. We then bolstered our findings by performing a meta-analysis of publicly-released BA10 microarray data (n=101) and identified sources of convergence with our qPCR results. To improve interpretation, we compiled an unusually large database of clinical metadata for our samples. We used this data to explore the relationship between BA10 gene expression, therapeutics, substances of abuse, and symptom profiles, and validated these findings with publicly-available datasets. Using these convergent sources of evidence, we identified 20 neurotransmission-related genes that were differentially expressed in BP and SCHIZ in BA10. These results included a large diagnosis-related decrease in two important therapeutic targets with low-levels of expression, HTR2B and DRD4, as well as other findings related to dopaminergic, GABA-ergic and astrocytic function. We also observed that therapeutics may produce differential expression that opposes the effects of diagnosis. In contrast, substances of abuse showed similar effects on BA10 gene expression as BP and SCHIZ, potentially amplifying diagnosis-related dysregulation.

This study applies a large proteomics panel to search for new circulating biomarkers associated with progression to kidney failure in individuals with diabetic kidney disease. Four independent cohorts encompassing 754 individuals with type 1 and type 2 diabetes and early and late diabetic kidney disease were followed to ascertain progression to kidney failure. During ten years of follow-up, 227 of 754 individuals progressed to kidney failure. Using the SOMAscan proteomics platform, we measured baseline concentration of 1129 circulating proteins. In our previous publications, we analyzed 334 of these proteins that were members of specific candidate pathways involved in diabetic kidney disease and found 35 proteins strongly associated with risk of progression to kidney failure. Here, we examined the remaining 795 proteins using an untargeted approach. Of these remaining proteins, 11 were significantly associated with progression to kidney failure. Biological processes previously reported for these proteins were related to neuron development (DLL1, MATN2, NRX1B, KLK8, RTN4R and ROR1) and were implicated in the development of kidney fibrosis (LAYN, DLL1, MAPK11, MATN2, endostatin, and ROR1) in cellular and animal studies. Specific mechanisms that underlie involvement of these proteins in progression of diabetic kidney disease must be further investigated to assess their value as targets for kidney-protective therapies. Using multivariable LASSO regression analysis, five proteins (LAYN, ESAM, DLL1, MAPK11 and endostatin) were found independently associated with risk of progression to kidney failure. Thus, our study identified proteins that may be considered as new candidate prognostic biomarkers to predict risk of progression to kidney failure in diabetic kidney disease. Furthermore, three of these proteins (DLL1, ESAM, and MAPK11) were selected as candidate biomarkers when all SOMAscan results were evaluated.

The non-linear mass is a characteristic scale in halo formation that has many applications across cosmology. Naively, computing it requires repeated numerical integration to calculate the variance of the power spectrum on different scales and determine which scales exceed the threshold for non-linear collapse. We accelerate calculation of both the non-linear mass and the rms amplitude of the power spectrum σ(R) by working in configuration space and approximating the correlation function as a polynomial at r ≤ 5 h−1 Mpc. This enables an analytic rather than numerical solution for the non-linear mass, accurate across a variety of cosmologies to 0.1–$1{{\ \rm per\ cent}}$ in mass (depending on redshift) and 20–60× faster than the standard numerical method. We also present a further acceleration of the non-linear mass (400–1000× faster than the standard method) in which we determine the polynomial coefficients using a Taylor expansion in the cosmological parameters rather than re-fitting a polynomial to the correlation function. Our method is also 500× faster than the standard method for σ(R) for a typical case of NR = 100 desired R values, with timing essentially independent of NR. Our approach can be used for quick calculation of the halo mass function, halo mass–bias relation, and cosmological calculations involving the non-linear mass.

The mainstay treatment for locally advanced, recurrent, or metastatic prostate cancer (PrCa) is androgen deprivation therapy (ADT). ADT causes prostate cancers to shrink in volume, or regress, by inducing epithelial tumor cell apoptosis. In normal, non-neoplastic murine prostate, androgen deprivation via castration induces prostate gland regression that is dependent on TNF signaling. Besides this direct mechanism of action, castration has also been implicated in an indirect mechanism of prostate epithelial cell death which has been described as vascular regression. The initiating event is endothelial cell apoptosis and/or increased vascular permeability. This subsequently leads to reduced blood flow and perfusion, and then hypoxia, which may enhance epithelial cell apoptosis. Castration-induced vascular regression has been observed in both normal and neoplastic prostate. We used photoacoustic, power Doppler, and contrast-enhanced ultrasound imaging, and CD31 immunohistochemical staining of the microvasculature to assess vascular integrity in the period immediately following castration, enabling us to test the role of TNF signaling in vascular regression. In two mouse models of androgen-responsive prostate cancer, TNF signaling blockade using a soluble TNFR2 ligand trap reversed the functional aspects of vascular regression as well as structural changes in the microvasculature, including reduced vessel wall thickness, cross-sectional area and vessel perimeter length. These results demonstrate that TNF signaling is required for vascular regression, most likely inducing endothelial cell apoptosis and increasing vessel permeability. Since TNF is also the critical death receptor ligand for prostate epithelial cells, we propose that TNF is a multi-purpose, comprehensive signal within the prostate cancer micro-environment mediating prostate cancer regression following androgen deprivation.SIGNIFICANCEThese studies define TNF as the mediator of androgen deprivation therapy-induced functional and structural vascular damage in prostate tumors.

We measure the Hubble constant of the Universe using spatial cross-correlation between gravitational wave (GW) sources without electromagnetic counterparts from the third GW Transient Catalog (GWTC-3), and the photometric galaxy surveys 2MPZ and WISE-SuperCOSMOS. Using the eight well-localised GW events, we obtain Hubble constant $H_0= 68.2_{-6.2}^{+26.0}$ km/s/Mpc (median and 68.3$\%$ equal-tailed interval (ETI)) after marginalizing over the matter density and the GW bias parameters. Though the constraints are weak due to a limited number of GW sources and poor sky localization, they are not subject to assumptions regarding the GW mass distribution. By combining this measurement with the Hubble constant measurement from binary neutron star GW170817, we find a value of Hubble constant $H_0= 67.0_{-3.8}^{+6.3}$ km/s/Mpc (median and 68.3$\%$ ETI)., Comment: 9 pages, 6 figures

The kinetic Sunyaev-Zel'dovich (kSZ) effect, i.e., the Doppler boost of cosmic microwave background (CMB) photons caused by their scattering off free electrons in galaxy clusters and groups with non-zero bulk velocity, is a powerful window on baryons in the universe. We present the first halo-model computation of the cross-power spectrum of the “projected-field” kSZ signal with large-scale structure (LSS) tracers. We compare and validate our calculations against previous studies, which relied on N-body-calibrated effective formulas rather than the halo model. We forecast results for CMB maps from the Atacama Cosmology Telescope (AdvACT), Simons Observatory (SO), and CMB-S4, and LSS survey data from the Dark Energy Survey, the Vera C. Rubin Observatory (VRO), and Euclid. In cross-correlation with galaxy number density, for AdvACT × unWISE we forecast an 18σ projected-field kSZ detection using data already in hand. Combining SO CMB maps and unWISE galaxy catalogs, we expect a 62σ detection, yielding precise measurements of the gas density profile radial slopes. Additionally, we forecast first detections of the kSZ — galaxy weak lensing cross-correlation with AdvACT × VRO/Euclid (at 6σ) and of the kSZ — CMB weak lensing cross-correlation with SO (at 16σ). Finally, ≈ 10-20% precision measurements of the shape of the gas density profile should be possible with CMB-S4 kSZ — CMB lensing cross-correlation without using any external datasets.

Diabetic kidney disease (DKD) and its major clinical manifestation, progressive renal decline that leads to end-stage renal disease (ESRD), are a major health burden for individuals with diabetes. The disease process that underlies progressive renal decline comprises factors that increase risk as well as factors that protect against this outcome. Using untargeted proteomic profiling of circulating proteins from individuals in two independent cohorts with type 1 and type 2 diabetes and varying stages of DKD followed for 7 to 15 years, we identified three elevated plasma proteins-fibroblast growth factor 20 (OR, 0.69; 95% CI, 0.54 to 0.88), angiopoietin-1 (OR, 0.72; 95% CI, 0.57 to 0.91), and tumor necrosis factor ligand superfamily member 12 (OR, 0.75; 95% CI, 0.59 to 0.95)-that were associated with protection against progressive renal decline and progression to ESRD. The combined effect of these three protective proteins was demonstrated by very low cumulative risk of ESRD in those who had baseline concentrations above median for all three proteins, whereas the cumulative risk of ESRD was high in those with concentrations below median for these proteins at the beginning of follow-up. This protective effect was shown to be independent from circulating inflammatory proteins and clinical covariates and was confirmed in a third cohort of diabetic individuals with normal renal function. These three protective proteins may serve as biomarkers to stratify diabetic individuals according to risk of progression to ESRD and might also be investigated as potential therapeutics to delay or prevent the onset of ESRD.

We recently identified a kidney risk inflammatory signature (KRIS), comprising 6 TNF receptors (including TNFR1 and TNFR2) and 11 inflammatory proteins. Elevated levels of these proteins in circulation were strongly associated with risk of the development of end-stage kidney disease (ESKD) during 10-year follow-up. It has been hypothesized that elevated levels of these proteins in circulation might reflect (be markers of) systemic exposure to TNFα. In this in vitro study, we examined intracellular and extracellular levels of these proteins in human umbilical vein endothelial cells (HUVECs) exposed to TNFα in the presence of hyperglycemia. KRIS proteins as well as 1300 other proteins were measured using the SOMAscan proteomics platform. Four KRIS proteins (including TNFR1) were down-regulated and only 1 protein (IL18R1) was up-regulated in the extracellular fraction of TNFα-stimulated HUVECs. In the intracellular fraction, one KRIS protein was down-regulated (CCL14) and 1 protein was up-regulated (IL18R1). The levels of other KRIS proteins were not affected by exposure to TNFα. HUVECs exposed to a hyperglycemic and inflammatory environment also showed significant up-regulation of a distinct set of 53 proteins (mainly in extracellular fraction). In our previous study, circulating levels of these proteins were not associated with progression to ESKD in diabetes.

Adiponectin, encoded by ADIPOQ, is an insulin-sensitizing, anti-inflammatory, and renoprotective adipokine that activates receptors with intrinsic ceramidase activity. We identified a family harboring a 10-nucleotide deletion mutation in ADIPOQ that cosegregates with diabetes and end-stage renal disease. This mutation introduces a frameshift in exon 3, resulting in a premature termination codon that disrupts translation of adiponectin’s globular domain. Subjects with the mutation had dramatically reduced circulating adiponectin and increased long-chain ceramides levels. Functional studies suggest that the mutated protein acts as a dominant negative through its interaction with non-mutated adiponectin, decreasing circulating adiponectin levels, and correlating with metabolic disease.

SUMMARYAndrogen deprivation therapy (ADT) induces regression of recurrent and advanced prostate cancer (PrCa), but many tumors recur. To understand the response to ADT, changes in tumor volume were imaged after castration of murine PrCa models. While mouse (non-tumor) prostate begins to regress within two days of castration, murine PrCa regresses after a delay of 3-14 days in two distinct mouse models. Intra-tumoral androgens are undetectable after castration, but tumor cells proliferate during this period. Intratumoral glucocorticoids and glucocorticoid receptor (GR) protein increase, as does GR mRNA and a set of GR-regulated genes specifically in tumor epithelial cells identified using scRNAseq. A selective GR antagonist (CORT125281, relacorilant), in clinical trials for late-state PrCa, eliminates the delayed regression phenotype in both models. Thus, activated GR signaling and murine tumor proliferation following castration resembles the GR-dependent escape mechanism of castrate resistant PrCa. These results suggest simultaneous inhibition of GR and androgen receptor signaling could improve PrCa therapy.In briefAndrogen deprivation therapy for high risk and recurrent prostate cancers is initially effective, but ultimately fails; better understanding the mechanisms should improve therapy. In two murine prostate cancer models, GR signaling is activated immediately following castration, substituting for the acute reduction in AR signaling, and allowing for continued tumor growth. This continued growth is blocked by relacorilant, selective GR antagonist in clinical trials for late-state PrCa.HighlightsAndrogen deprivation therapy induces regression of prostate cancer, but tumors recurMurine PrCa continues to proliferate for 3-14 days in two distinct mouse prostate cancer modelsTumor cells proliferate during this period, and intratumoral glucocorticoids and glucocorticoid receptor (GR) protein increase, as does GR mRNA and a set of GR-regulated genesRelacorilant, a selective GR antagonist in clinical trials for late-state PrCa, eliminates the delayed regression

We present the second data release of the COSMOS Lyα Mapping And Tomography Observations Survey conducted with the Low Resolution Imaging Spectrometer on the Keck I telescope. This project used Lyα forest absorption in the spectra of faint star-forming galaxies and quasars at z ∼ 2–3 to trace neutral hydrogen in the intergalactic medium. In particular, we use 320 objects over a footprint of ∼0.2 deg2 to reconstruct the absorption field at 2.05 < z < 2.55 at ∼2 h −1 Mpc resolution. We apply a Wiener filtering technique to the observed data to reconstruct three-dimensional (3D) maps of the field over a volume of 4.1 × 105 h −3 Mpc3. In addition to the filtered flux maps, for the first time we infer the underlying dark matter field through a forward-modeling framework from a joint likelihood of galaxy and Lyα forest data, finding clear examples of the detailed cosmic web consisting of cosmic voids, sheets, filaments, and nodes. In addition to traditional figures, we present a number of interactive 3D models to allow exploration of the data and qualitative comparisons to known galaxy surveys. We find that our inferred overdensities are consistent with those found from galaxy fields. We will make all our reduced spectra, extracted Lyα forest pixel data, and reconstructed tomographic maps publicly available upon publication.

The kinematic Sunyaev-Zel'dovich (kSZ) effect---the Doppler boosting of Cosmic Microwave Background (CMB) photons scattering off free electrons with nonzero line-of-sight velocity---is an excellent probe of the distribution of baryons in the Universe. In this paper, we measure the kSZ effect due to ionized gas traced by infrared-selected galaxies from the $unWISE$ catalog. We employ the ``projected-field'' kSZ estimator, which does not require spectroscopic galaxy redshifts. To suppress contributions from non-kSZ signals associated with the galaxies (e.g., dust emission and thermal SZ), this estimator requires foreground-cleaned CMB maps, which we obtain from $Planck$ and $WMAP$ data. Using a new ``asymmetric'' estimator that combines different foreground-cleaned CMB maps to maximize the signal-to-noise, we measure the ${\mathrm{kSZ}}^{2}$-galaxy cross-power spectrum for three subsamples of the $unWISE$ galaxy catalog. These subsamples peak at mean redshifts $z\ensuremath{\approx}0.6$, 1.1, and 1.5, have average halo mass $\ensuremath{\sim}1--5\ifmmode\times\else\texttimes\fi{}{10}^{13}\text{ }\text{ }{h}^{\ensuremath{-}1}{M}_{\ensuremath{\bigodot}}$, and in total contain over 500 million galaxies. After marginalizing over contributions from CMB lensing, we measure the amplitude of the kSZ signal ${A}_{{\mathrm{kSZ}}^{2}}=0.42\ifmmode\pm\else\textpm\fi{}0.31(\mathrm{stat})\ifmmode\pm\else\textpm\fi{}0.02(\mathrm{sys})$, $5.02\ifmmode\pm\else\textpm\fi{}1.01(\mathrm{stat})\ifmmode\pm\else\textpm\fi{}0.49(\mathrm{sys})$, and $8.23\ifmmode\pm\else\textpm\fi{}3.23(\mathrm{stat})\ifmmode\pm\else\textpm\fi{}0.57(\mathrm{sys})$, for the three subsamples, where ${A}_{{\mathrm{kSZ}}^{2}}=1$ corresponds to our fiducial theoretical model. The combined statistical significance of our kSZ detection exceeds $5\ensuremath{\sigma}$. Our theoretical model includes the first calculation of lensing magnification contributions to the ${\mathrm{kSZ}}^{2}$-galaxy cross-power spectrum, which are significant for the $z\ensuremath{\approx}1.1$ and 1.5 subsamples. We discuss possible explanations for the excess kSZ signal associated with the $z\ensuremath{\approx}1.1$ sample, and show that foreground contamination in the CMB maps is very unlikely to be the cause. From our measurements of ${A}_{{\mathrm{kSZ}}^{2}}$, we constrain the product of the baryon fraction ${f}_{b}$ and free electron fraction ${f}_{\mathrm{free}}$ to be $({f}_{b}/0.158)({f}_{\mathrm{free}}/1.0)=0.65\ifmmode\pm\else\textpm\fi{}0.24$, $2.24\ifmmode\pm\else\textpm\fi{}0.25$, and $2.87\ifmmode\pm\else\textpm\fi{}0.57$ at $z\ensuremath{\approx}0.6$, 1.1, and 1.5, respectively, consistent with a large fraction of the cosmic baryon abundance existing in an ionized state at low redshifts.

Background Characterization of prediagnostic Parkinson’s Disease (PD) and early prediction of subsequent development are critical for preventive interventions, risk stratification and understanding of disease pathology. This study aims to characterize the role of the prediagnostic period in PD and, using selected features from this period as novel interception points, construct a prediction model to accelerate the diagnosis in a real-world setting. Methods We constructed two sets of machine learning models: a retrospective approach highlighting exposures up to 5 years prior to PD diagnosis, and an alternative model that prospectively predicted future PD diagnosis from all individuals at their first diagnosis of a gait or tremor disorder, these being features that appeared to represent the initiation of a differential diagnostic window. Results We found many novel features captured by the retrospective models; however, the high accuracy was primarily driven from surrogate diagnoses for PD, such as gait and tremor disorders, suggesting the presence of a distinctive differential diagnostic period when the clinician already suspected PD. The model utilizing a gait/tremor diagnosis as the interception point, achieved a validation AUC of 0.874 with potential time compression to a future PD diagnosis of more than 300 days. Comparisons of predictive diagnoses between the prospective and prediagnostic cohorts suggest the presence of distinctive trajectories of PD progression based on comorbidity profiles. Conclusions Overall, our machine learning approach allows for both guiding clinical decisions such as the initiation of neuroprotective interventions and importantly, the possibility of earlier diagnosis for clinical trials for disease modifying therapies.

Rare variants in MAGEC3, members of the melanoma antigen gene family, are associated with BRCA-independent early onset ovarian cancers, while somatic mutations of this gene have been associated with kidney cancers. In this report, we quantified normal and tumor protein expression of MAGEC3 via immunohistochemistry in N=394 ovarian cancers and N=220 renal cell carcinomas. MAGEC3 protein levels fell into two categories – normal MAGEC3 and MAGEC3 loss – characterized by expression equivalent to normal tissue or significantly lower than normal tissue, respectively. Interestingly, cases with MAGEC3 loss demonstrated better overall survival in both ovarian cancers and renal cell carcinomas, which resembles patient outcomes with BRCA2 loss. MAGEC3 protein expression was associated with upregulation of pathways regulating G2/M checkpoint (NES: 4.13, FDRSTATEMENT OF TRANSLATIONAL RELEVANCEMAGEC3 protein is expressed in multiple tissues and is dysregulated in cancer. In this work, we show that ovarian and kidney cancer patients with loss of MAGEC3 protein have favorable prognosis, indicating that MAGEC3 protein level may be used as a prognostic biomarker. Integrative genomic analysis of patients spanning more than nine cancer types showed an association between MAGEC3 protein and genes affecting stress response, including those involved in cell cycle and DNA damage repair. Additionally, it is correlated with tumor mutational burden in patients with mutated oncogenes. These associations suggest that MAGEC3 protein levels may be used to identify patients with deficient DNA damage repair mechanisms that can be targeted by PARP inhibitors. To operationalize this idea, we use machine learning to predict MAGEC3 protein levels from RNA sequencing data which can facilitate the identification of patients for treatment stratification according to their MAGEC3 status.

The kinematic Sunyaev-Zel'dovich (kSZ) effect -- the Doppler boosting of cosmic microwave background (CMB) photons scattering off free electrons with non-zero line-of-sight velocity -- is an excellent probe of the distribution of baryons in the Universe. In this paper, we measure the kSZ effect due to ionized gas traced by infrared-selected galaxies from the \emph{unWISE} catalog. We employ the "projected-field" kSZ estimator, which does not require spectroscopic galaxy redshifts. To suppress non-kSZ foreground signals associated with the galaxies (e.g., dust emission and thermal SZ), this estimator requires cleaned CMB maps, which we obtain from \emph{Planck} and \emph{WMAP} data. Using a new "asymmetric" estimator that combines different foreground-cleaned CMB maps to maximize the signal-to-noise, we measure the kSZ$^2$-galaxy cross-power spectrum for three subsamples of the \emph{unWISE} galaxy catalog, which peak at mean redshifts $z \approx$ 0.6, 1.1, and 1.5, have average halo mass $\sim 1$-$5\times 10^{13}$ $h^{-1} M_{\odot}$, and in total contain over 500 million galaxies. After marginalizing over CMB lensing contributions, we measure the amplitude of the kSZ signal $A_{\rm kSZ^2} = 0.42 \pm 0.31(stat.) \pm 0.14(sys.)$, $5.02 \pm 1.01(stat.) \pm 0.47(sys.)$, and $8.23 \pm 3.23(stat.) \pm 1.60(sys.)$, for the three subsamples, where $A_{\rm kSZ^2} = 1$ corresponds to our fiducial model. The combined kSZ detection S/N $>$ 5. We discuss possible explanations for the excess kSZ signal associated with the $z \approx 1.1$ sample, and show that foreground contamination in the CMB maps is very unlikely to be the cause. Our measurements illustrate clearly that no baryons are missing on large scales at low redshifts., Matches the version accepted for publication in PRD (https://journals.aps.org/prd/accepted/d907bQ13Oae1fd21e4ff4f13177300acb1c23e88e)

We present the second data release of the COSMOS Lyman-Alpha Mapping And Tomography Observations (CLAMATO) Survey conducted with the LRIS spectrograph on the Keck-I telescope. This project used Lyman-alpha forest absorption in the spectra of faint star forming galaxies and quasars at z ~ 2-3 to trace neutral hydrogen in the intergalactic medium. In particular, we use 320 objects over a footprint of ~0.2 deg^2 to reconstruct the absorption field at 2.05 < z < 2.55 at ~2 h^{-1}Mpc resolution. We apply a Wiener filtering technique to the observed data to reconstruct three dimensional maps of the field over a volume of 4.1 x 10^5 comoving cubic Mpc. In addition to the filtered flux maps, for the first time we infer the underlying dark matter field through a forward modeling framework from a joint likelihood of galaxy and Lyman-alpha forest data, finding clear examples of the detailed cosmic web consisting of cosmic voids, sheets, filaments, and nodes. In addition to traditional figures, we present a number of interactive three dimensional models to allow exploration of the data and qualitative comparisons to known galaxy surveys. We find that our inferred over-densities are consistent with those found from galaxy fields. Our reduced spectra, extracted Lyman-alpha forest pixel data, and reconstructed tomographic maps are available publicly at https://doi.org/10.5281/zenodo.7524313, 20 pages, 15 figures. Data is available at https://doi.org/10.5281/zenodo.7524313 arXiv admin note: text overlap with arXiv:1710.02894

Additional file 1: Supplemental Material 1. Role of NRF2 in non-cancerous disease prevention and aging retardation. Supplemental Table S1. Summary of the datasets collected from publicly available kidney tumor tissues versus normal tissue samples*. Supplemental Table S2. Somatic Mutation Analysis Summary of relevant genes*. Supplemental Table S3. Classification of KIRP/pRCC tumor and normal tissues into Type 1 pRCC and Type 2 pRCC. Supplemental Figure S1. NRF2 expression in Type 1 pRCC and Type 2 pRCC tumor tissues versus in normal renal tissues: Boxplots of the NRF2 expression level across TCGA Type 1 or Type 2 pRCC tumor tissues (red) versus the normal renal tissues (blue) were presented (A). NRF2 expression among different stages of Type 1 pRCC tumor tissues versus the matched normal tissue (B) or versus all normal tissues (C) was box-plotted. NRF2 expression among different stages of Type 2 pRCC tumor tissues versus matched normal tissue was box-plotted (D). NRF2 expression was presented in the log2 (TPM + 1) scale format. Data was presented as the mean ± standard deviation (SD). A t-test was used to evaluate the statistical significance of the NRF2 mRNA expression level in renal normal tissues versus either Type 1 or type 2 pRCC tumor tissues. One-way ANOVA was used to compare NRF2 expression among renal normal tissues versus different stages of Type 1 or Type 2 pRCC tumor tissues. The figure was performed using R version 4.0.3. Supplemental Figure S2. Effects of NRF2 expression on Type 1 pRCC patient survival probability: Kaplan-Meier survival analyses of overall survival (OS) from TCGA-Type 1 (A) or Type 2 (B) pRCC cohorts were presented. Patients were grouped into the high NRF2 expression group versus the low NRF2 expression group based on the median NRF2 mRNA expression level in either Type 1 (A) or Type 2 (B) pRCC tumor tissues. Each p-value for the significance from high versus low NRF2 expression was calculated using the log-rank test. The figures were performed using R version 4.0.3. Supplemental Figure S3. Mdm4/MdmX expression in RCC tumor tissues versus in normal tissues: Boxplots of the Mdm4MdmX expression level across TCGA-RCC subtypes in renal tumor (red) versus the associated normal renal tissues (blue) were presented (A). Mdm4MdmX expression among different stages of chRCC (B), ccRCC (C) and pRCC (D) versus normal renal tissues was box-plotted. Mdm4MdmX expression was presented in the log2 (TPM + 1) scale format. Data was presented as the mean ± SD. A t-test was used to evaluate the statistical significance of the mRNA expression level in renal normal versus tumor tissues. One-way ANOVA was used to compare Mdm4MdmX expression among renal normal tissues versus different stages of RCC tumor tissues. The figure was performed using R version 4.0.3. Supplemental Figure S4. Effects of Mdm4/MdmX expression on RCC patient survival probability: Kaplan-Meier survival analyses of OS from TCGA-RCC cohorts of ccRCC (A), chRCC (B) and pRCC(C) were presented. Patients were grouped into the high Mdm4/MdmX expression group versus the low Mdm4/MdmX expression group based on the median Mdm4/MdmX mRNA expression. Each p-value for the significance from high versus low Mdm4/MdmX expression was calculated using the log-rank test. The figures were performed using R version 4.0.3. Supplemental Figure S5. AKT2 expression in RCC tumor tissues versus in normal tissues: Boxplots of the AKT2 expression level across TCGA-RCC subtypes in renal tumor (red) versus the associated normal renal tissues (blue) were presented (A). AKT2 expression among different stages of chRCC (B), ccRCC (C) and pRCC (D) versus normal renal tissues was box-plotted. AKT2 expression was presented in the log2 (TPM + 1) scale format. Data was presented as the mean ± SD. A t-test was used to evaluate the statistical significance of the mRNA expression level in renal normal versus tumor tissues. One-way ANOVA was used to compare AKT2 expression among renal normal tissues versus different stages of RCC tumor tissues. The figure was performed using R version 4.0.3. Supplemental Figure S6. Effects of AKT2 expression on RCC patient survival probability: Kaplan-Meier survival analyses of OS from TCGA-RCC cohorts of ccRCC (A), chRCC (B) and pRCC (C) were presented. Patients were grouped into the high AKT2 expression group versus the low AKT2 expression group based on the median AKT2 mRNA expression. Each p-value for the significance from high versus low AKT2 expression was calculated using the log-rank test. The figures were performed using R version 4.0.3.

Additional file 1: Supplementary Methods. Table S1. Included and excluded codes for initial analysis. Table S2. Included and excluded codes for feature tracking and gait/tremor indexed analysis. Table S3. Tremor-only Cohort, PD associated Diagnoses. Table S4: Gait-only Cohort, PD associated Diagnoses.

CMB photons redshift and blueshift as they move through gravitational potentials $\Phi$ while propagating across the Universe. If the potential is not constant in time, the photons will pick up a net redshift or blueshift, known as the Integrated Sachs-Wolfe (ISW) effect. In the $z \ll 1000$ universe, $\dot{\Phi}$ is nonzero on large scales when the Universe transitions from matter to dark energy domination. This effect is only detectable in cross-correlation with large-scale structure at $z \sim 1$. In this paper we present a 3.2$\sigma$ detection of the ISW effect using cross-correlations between unWISE infrared galaxies and Planck CMB temperature maps. We use 3 tomographic galaxy samples spanning $0 < z < 2$, allowing us to fully probe the dark energy domination era and the transition into matter domination. This measurement is consistent with $\Lambda$CDM ($A_{\rm ISW} = 0.96 \pm 0.30$). We study constraints on a particular class of dynamical dark energy models (where the dark energy equation of state is different in matter and dark energy domination), finding that unWISE-ISW improves constraints from type Ia supernovae due to improved constraints on the time evolution of dark energy. When combining with BAO measurements, we obtain the tightest constraints on specific dynamical dark energy models. In the context of a phenomenological model for freezing quintessence, the Mocker model, we constrain the dark energy density within 10% at $z < 2$ using ISW, BAO and supernovae. Moreover, the ISW measurement itself provides an important independent check when relaxing assumptions about the theory of gravity, as it is sensitive to the gravitational potential rather than the expansion history., Comment: 23 pages, 8 figures. To be submitted to JCAP. Comments welcome!

OBJECTIVE: The role of fibrosis in early progressive renal decline in type 2 diabetes is unknown. Circulating WFDC2 (WAP four-disulfide core domain protein 2) and matrix metalloproteinase 7 (MMP-7; Matrilysin) are postulated to be biomarkers of renal fibrosis. This study examined an association of circulating levels of these proteins with early progressive renal decline. RESEARCH DESIGN AND METHODS: Individuals with type 2 diabetes enrolled in the Joslin Kidney Study with an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m(2) were monitored for 6–12 years to ascertain fast early progressive renal decline, defined as eGFR loss ≥5 mL/min/1.73 m(2)/year. RESULTS: A total of 1,181 individuals were studied: 681 without and 500 with albuminuria. Median eGFR and albumin-to-creatinine ratio (ACR) at baseline were 97 mL/min/1.73 m(2) and 24 mg/g, respectively. During follow-up, 152 individuals experienced fast early progressive renal decline: 6.9% in those with normoalbuminuria and 21% with albuminuria. In both subgroups, the risk of renal decline increased with increasing baseline levels of WFDC2 (P < 0.0001) and MMP-7 (P < 0.0001). After adjustment for relevant clinical characteristics and known biomarkers, an increase by one quartile in the fibrosis index (combination of levels of WFDC2 and MMP-7) was associated with higher risk of renal decline (odds ratio 1.63; 95% CI 1.30–2.04). The association was similar and statistically significant among patients with and without albuminuria. CONCLUSIONS: Elevation of circulating profibrotic proteins is associated with the development of early progressive renal decline in type 2 diabetes. This association is independent from albuminuria status and points to the importance of the fibrotic process in the development of early renal decline.

We study the cross correlation of damped Ly$��$ systems (DLAs) and their background quasars, using the most updated DLA catalog and the Planck 2018 CMB lensing convergence field. Our measurement suggests that the DLA bias $b_{\rm DLA}$ is smaller than $3.1$, corresponding to $\log(M/M_\odot h^{-1})\leq 12.3$ at a confidence of $90\%$. These constraints are broadly consistent with Alonso et al. (2018) and previous measurements by cross-correlation between DLAs and the Ly$��$ forest (e.g. Font-Ribera et al. 2012; Perez-Rafols et al. 2018). Further, our results demonstrate the potential of obtaining a more precise measurement of the halo mass of high-redshift sources using next generation CMB experiments with a higher angular resolution. The python-based codes and data products of our analysis are available at https://github.com/LittleLin1999/CMB-lensingxDLA., Accepted for Publication in ApJ; 16 pages, 9 figures

Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage.Gene-based exome array analyses of 15,449 genes in five large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time to ESKD, testing the top gene in a sixth cohort (Protein coding variants in the hydroxysteroid 17

OBJECTIVE: The role of fibrosis in early progressive renal decline in type 2 diabetes is unknown. Circulating WFDC2 (WAP four-disulfide core domain protein 2) and MMP-7 (Matrilysin) are postulated to be biomarkers of renal fibrosis. This study examined an association of circulating levels of these proteins with early progressive renal decline. RESEARCH DESIGN AND METHODS: Individuals with type 2 diabetes enrolled in the Joslin Kidney Study with eGFR ≥60 ml/min/1.73m2 were followed for 6-12 years to ascertain fast early progressive renal decline defined as eGFR loss ≥5 ml/min/1.73m2/year. RESULTS: A total of 1,181 individuals were studied: 681 without and 500 with albuminuria. Median eGFR and ACR at baseline were 97 ml/min/1.73m2 and 24 mg/g, respectively. During follow-up, 152 individuals experienced fast early progressive renal decline: 6.9% in those with normoalbuminuria and 21% with albuminuria. In both subgroups risk of renal decline increased with increasing baseline levels of WFDC2 (p CONCLUSIONS: Elevation of circulating profibrotic proteins is associated with the development of early progressive renal decline in type 2 diabetes. This association is independent from albuminuria status and points to the importance of the fibrotic process in development of early renal decline.

CMB lensing tomography, or the cross-correlation between CMB lensing maps and large-scale structure tracers over a well-defined redshift range, has the potential to map the amplitude and growth of structure over cosmic time, provide some of the most stringent tests of gravity, and break important degeneracies between cosmological parameters. In this work, we use the unWISE galaxy catalog to provide three samples at median redshifts $z \sim 0.6, 1.1$ and 1.5, fully spanning the Dark Energy dominated era, together with the most recent Planck CMB lensing maps. We obtain a combined cross-correlation significance $S/N = 79.3$ over the range of scales $100 < \ell < 1000$. We measure the redshift distribution of unWISE sources by a combination of cross-matching with the COSMOS photometric catalog and cross-correlation with BOSS galaxies and quasars and eBOSS quasars. We also show that magnification bias must be included in our analysis and perform a number of null tests. In a companion paper, we explore the derived cosmological parameters by modeling the non-linearities and propagating the redshift distribution uncertainties., 51 pages, 22 figures. Comments welcome! Revisions reflect version accepted by JCAP

Rare variants in MAGEC3 are associated with BRCA negative, early-onset ovarian cancers. Given this association, we evaluated the impact of MAGEC3 protein expression on prognosis and transcription. We quantified normal and tumor protein expression of MAGEC3 via immunohistochemistry in n = 394 advanced ovarian cancers, assessed the correlation of these values with clinicopathologic and immunological features and modeled survival using univariate and multivariate models. To extend these results, we quantified MAGEC3 protein expression in n = 180 cancers and used matching RNA sequencing data to determine MAGEC3-associated differentially expressed genes and to build an RNA-based model of MAGEC3 protein levels. This model was tested in a third independent cohort of patients from TCGA’s OV dataset (n = 282). MAGEC3 protein was sporadically lost in ovarian cancers, with half of the cases falling below the 9.5th percentile of normal tissue expression. Cases with MAGEC3 loss demonstrated better progression-free survival [HR = 0.71, p = 0.004], and analyses performed on predicted protein scores were consistent [HR = 0.57 p = 0.002]. MAGEC3 protein was correlated with CD8 protein expression [Pearson’s r = 0.176, p = 0.011], NY-ESO-1 seropositivity, and mRNA expression of tumor antigens at Xq28. Results of gene set enrichment analysis showed that genes associated with MAGEC3 protein expression cluster around G2/M checkpoint (NES = 3.20, FDR < 0.001) and DNA repair (NES = 2.28, FDR < 0.001) hallmark pathways. These results show that MAGEC3 is a prognostic biomarker in ovarian cancer.

Background: Sarcopenia, the age-related loss of skeletal muscle, is a side effect of androgen deprivation therapy (ADT) for prostate cancer patients. Resident stem cells of skeletal muscle, satellite cells (SCs), are an essential source of progenitors for the growth and regeneration of skeletal muscle. Decreased androgen signaling and deficits in the number and function of SCs are features of aging. Although androgen signaling is known to regulate skeletal muscle, the cellular basis for ADT-induced exacerbation of sarcopenia is unknown. Furthermore, the consequences of androgen deprivation on SC fate in adult skeletal muscle remain largely unexplored. Methods: We examined SC fate in an androgen-deprived environment using immunofluorescence and fluorescence-activated cell sorting (FACS) with SC-specific markers in young castrated mice. To study the effects of androgen deprivation on SC function and skeletal muscle regenerative capacity, young castrated mice were subjected to experimental regenerative paradigms. SC-derived-cell contributions to skeletal muscle maintenance were examined in castrated Pax7 CreER/+ ; ROSA26 mTmG/+ mice. SCs were depleted in Pax7 CreER/+ ; ROSA26 DTA/+ mice to ascertain the consequences of SC ablation in sham and castrated skeletal muscles. Confocal immunofluorescence analysis of neuromuscular junctions (NMJs), and assessment of skeletal muscle physiology, contractile properties, and integrity were conducted. Results: Castration led to SC activation, however this did not result in a decline in SC function or skeletal muscle regenerative capacity. Surprisingly, castration induced SC-dependent maintenance of young skeletal muscle. The functional dependence of skeletal muscles on SCs in young castrated mice was demonstrated by an increase in SC-derived-cell fusion within skeletal muscle fibers. SC depletion was associated with further atrophy and functional decline, as well as the induction of partial innervation and the loss of NMJ-associated myonuclei in skeletal muscles from castrated mice. Conclusion: The maintenance of skeletal muscles in young castrated mice relies on the cellular contributions of SCs. Considering the well-described age-related decline in SCs, the results in this study highlight the need to devise strategies that promote SC maintenance and activity to attenuate or reverse the progression of sarcopenia in elderly androgen-deprived individuals.