المؤلفون: Gisch, D.L., Brennan, M., Lake, B.B., Basta, J., Keller, M.S., Melo, Ferreira, R., Akilesh, S., Ghag, R., Lu, C., Cheng, Y.-H., Collins, K.S., Parikh, S.V., Rovin, B.H., Robbins, L., Stout, L., Conklin, K.Y., Diep, D., Zhang, B., Knoten, A., Barwinska, D., Asghari, M., Sabo, A.R., Ferkowicz, M.J., Sutton, T.A., Kelly, K.J., De, Boer, I.H., Rosas, S.E., Kiryluk, K., Hodgin, J.B., Alakwaa, F., Winfree, S., Jefferson, N., Türkmen, A., Gaut, J.P., Gehlenborg, N., Phillips, C.L., El-Achkar, T.M., Dagher, P.C., Hato, T., Zhang, K., Himmelfarb, J., Kretzler, M., Mollah, S., Lake, B., Morales, A., Stillman, I., Lecker, S., Bogen, S., Verma, A., Yu, G., Schmidt, I., Henderson, J., Beck, L., Yadati, P., Waikar, S., Amodu, A.A., Maikhor, S., Ilori, T., Colona, M.R., Weins, A., McMahon, G., Hacohen, N., Greka, A., Marshall, J.L., Hoover, P.J., Viswanathan, V.S., Crawford, D., Aulisio, M., Bush, W., Chen, Y., Madabhushi, A., O’Malley, C., Gadegbeku, C., Sendrey, D., Poggio, E., O’Toole, J., Sedor, J., Taliercio, J., Bush, L., Herlitz, L., Palmer, E., Nguyen, J., Spates-Harden, K., Cooperman, L., Jolly, S., Vinovskis, C., Bomback, A., Barasch, J., Appelbaum, P., D’Agati, V., Berrouet, C., Mehl, K., Sabatello, M., Shang, N., Balderes, O., Canetta, P.A., Kudose, S., de, Pinho, Gonçalves, J., Migas, L., Van, de, Plas, R., Lardenoije, R., Barisoni, L., Rennke, H., Verdoes, A., Sabo, A., Williams, J., Kelly, K., Dunn, K., Eadon, M., Ferkowicz, M., Dagher, P., Bledsoe, S., Wofford, S., (El-Achkar), T.A., Sutton, T., Bowen, W., Slade, A., Record, E., Cheng, Y., Jain, Y., Herr, B., Quardokus, E., Wang, A., Villalobos, C.P.C., Parikh, C., Atta, M., Menez, S., Wen, Y., Xu, A., Bernard, L., Johansen, C., Chen, S., Rosas, S., Donohoe, I., Sun, J., Knight, R., Shpigel, A., Bebiak, J., Saul, J., Ardayfio, J., Koewler, R., Pinkeney, R., Campbell, T., Azeloglu, E., Nadkarni, G., He, J., Tokita, J., Campbell, K., Patel, M., Lefferts, S., Iyengar, S.R., Ward, S., Coca, S., He, C., Xiong, Y., Prasad, P., Rovin, B., Shapiro, J.P., Parikh, S., Madhavan, S.M., Lukowski, J., Velickovic, D., Pasa-Tolic, L., Oliver, G.H., Troyanskaya, O., Sealfon, R., Mao, W., Wong, A., Pollack, A., Goltsev, Y., Ginley, B., Lutnick, B., Nolan, G., Anjani, K., Mukatash, T., Laszik, Z.G., Campos, B., Thajudeen, B., Beyda, D., Bracamonte, E., Brosius, F., Woodhead, G., Mendoza, K., Marquez, N., Scott, R., Tsosie, R., Saunders, M., Rike, A., Woodle, E.S., Lee, P.J., Alloway, R.R., Shi, T., Hsieh, E., Kendrick, J., Thurman, J., Wrobel, J., Pyle, L., Bjornstad, P., Lucarelli, N., Sarder, P., Renteria, A., Ricardo, A., Srivastava, A., Redmond, D., Carmona-Powell, E., Bui, J., Lash, J., Fox, M., Meza, N., Gaba, R., Setty, S., Kelly, T., Lienczewski, C., Demeke, D., Otto, E., Ascani, H., Hodgin, J., Schaub, J., Hartman, J., Mariani, L., Bitzer, M., Rose, M., Bonevich, N., Conser, N., McCown, P., Dull, R., Menon, R., Reamy, R., Eddy, S., Balis, U., Blanc, V., Nair, V., He, Y.O., Wright, Z., Steck, B., Luo, J., Frey, R., Coleman, A., Henderson-Brown, D., Berge, J., Caramori, M.L., Adeyi, O., Nachman, P., Safadi, S., Flanagan, S., Ma, S., Klett, S., Wolf, S., Harindhanavudhi, T., Rao, V., Mottl, A., Froment, A., Zeitler, E., Bream, P., Kelley, S., Rosengart, M., Elder, M., Palevsky, P., Murugan, R., Hall, D.E., Bender, F., Winters, J., Kellum, J.A., Gilliam, M., Tublin, M., Tan, R., Zhang, G., Sharma, K., Venkatachalam, M., Hendricks, A., Kermani, A., Torrealba, J., Vazquez, M., Wang, N., Cai, Q., Miller, R.T., Hedayati, S., Hoofnagle, A., Wangperawong, A., Berglund, A., Dighe, A.L., Young, B., Larson, B., Berry, B., Alpers, C., Limonte, C., Stutzke, C., Roberts, G., de, Boer, I., Snyder, J., Phuong, J., Carson, J., Rezaei, K., Tuttle, K., Brown, K., Blank, K., Sarkisova, N., McClelland, R., Mooney, S., Nam, Y., Wilcox, A., Park, C., Dowd, F., Williams, K., Grewenow, S.M., Daniel, S., Shankland, S., Pamreddy, A., Ye, H., Montellano, R., Bansal, S., Pillai, A., Zhang, D., Park, H., Patel, J., Sambandam, K., Basit, M., Wen, N., Moe, O.W., Toto, R.D., Lee, S.C., Sharman, K., Caprioli, R.M., Fogo, A., Allen, J., Spraggins, J., Djambazova, K., de, Caestecker, M., Dufresne, M., Farrow, M., Vijayan, A., Minor, B., Nwanne, G., Gaut, J., Conlon, K., Kaushal, M., Diettman, S.M., Victoria, Castro, A.M., Moledina, D., Wilson, F.P., Moeckel, G., Cantley, L., Shaw, M., Kakade, V., Arora, T., Jain, S., Rauchman, M., Eadon, M.T.

المساهمون: University of Arizona

المصدر: Nature Communications

الوصف: There is a need to define regions of gene activation or repression that control human kidney cells in states of health, injury, and repair to understand the molecular pathogenesis of kidney disease and design therapeutic strategies. Comprehensive integration of gene expression with epigenetic features that define regulatory elements remains a significant challenge. We measure dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and H3K27ac, H3K4me1, H3K4me3, and H3K27me3 histone modifications to decipher the chromatin landscape and gene regulation of the kidney in reference and adaptive injury states. We establish a spatially-anchored epigenomic atlas to define the kidney’s active, silent, and regulatory accessible chromatin regions across the genome. Using this atlas, we note distinct control of adaptive injury in different epithelial cell types. A proximal tubule cell transcription factor network of ELF3, KLF6, and KLF10 regulates the transition between health and injury, while in thick ascending limb cells this transition is regulated by NR2F1. Further, combined perturbation of ELF3, KLF6, and KLF10 distinguishes two adaptive proximal tubular cell subtypes, one of which manifested a repair trajectory after knockout. This atlas will serve as a foundation to facilitate targeted cell-specific therapeutics by reprogramming gene regulatory networks. © 2024, The Author(s). ; Open access journal ; This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.

العلاقة: Gisch, D.L., Brennan, M., Lake, B.B. et al. The chromatin landscape of healthy and injured cell types in the human kidney. Nat Commun 15, 433 (2024). https://doi.org/10.1038/s41467-023-44467-6Test; http://hdl.handle.net/10150/671737Test; Nature Communications

الإتاحة: https://doi.org/10.1038/s41467-023-44467-6Test
http://hdl.handle.net/10150/671737Test

المؤلفون: Billi, A.C., Gharaee-Kermani, M., Fullmer, J., Tsoi, A., Hill, B., Gruszka, D., Ludwig, J., Xing, X., Estadt, S., Wolf, S., Rizvi, S.M., Berthier, C.C., Hodgin, J.B., Beamer, M., Sarkar, M.K., Uppala, R., Shao, S., Harms, P., Verhaegen, M.E., Voorhees, J., Wen, F., Ward, N.L., Dlugosz, A.A., Kahlenberg, M., Gudjonsson, J.

المصدر: Journal of Investigative Dermatology ; volume 139, issue 5, page S110 ; ISSN 0022-202X

مصطلحات موضوعية: Cell Biology, Dermatology, Molecular Biology, Biochemistry

الإتاحة: https://doi.org/10.1016/j.jid.2019.03.716Test
https://api.elsevier.com/content/article/PII:S0022202X19309078?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0022202X19309078?httpAccept=text/plainTest

المؤلفون: Jayapandian, C.P., Chen, Y., Janowczyk, A.R., Palmer, M.B., Cassol, C.A., Sekulic, M., Hodgin, J.B., Zee, J., Hewitt, S.M., O'Toole, J., Toro, P., Sedor, J.R., Barisoni, L., Madabhushi, A.

المساهمون: Nephrotic Syndrome Study Network (NEPTUNE), Sedor, J., Dell, K., Schachere, M., Negrey, J., Lemley, K., Lim, E., Srivastava, T., Garrett, A., Sethna, C., Laurent, K., Appel, G., Toledo, M., Barisoni, L., Greenbaum, L., Wang, C., Kang, C., Adler, S., Nast, C., LaPage, J., Stroger, J.H., Athavale, A., Itteera, M., Neu, A., Boynton, S., Fervenza, F., Hogan, M., Lieske, J., Chernitskiy, V., Kaskel, F., Kumar, N., Flynn, P., Kopp, J., Blake, J., Trachtman, H., Zhdanova, O., Modersitzki, F., Vento, S., Lafayette, R., Mehta, K., Gadegbeku, C., Johnstone, D., Quinn-Boyle, S., Cattran, D., Hladunewich, M., Reich, H., Ling, P., Romano, M., Fornoni, A., Bidot, C., Kretzler, M., Gipson, D., Williams, A., LaVigne, J., Derebail, V., Gibson, K., Froment, A., Grubbs, S., Holzman, L., Meyers, K., Kallem, K., Lalli, J., Sambandam, K., Wang, Z., Rogers, M., Jefferson, A., Hingorani, S., Tuttle, K., Bray, M., Kelton, M., Cooper, A., Freedman, B., Lin, J.J.

المصدر: Kidney international, vol. 99, no. 1, pp. 86-101

مصطلحات موضوعية: Biopsy, Coloring Agents, Deep Learning, Kidney, Kidney Cortex/diagnostic imaging, computerized morphologic assessment, digital pathology, kidney histologic primitives, large-scale tissue interrogation, renal biopsy interpretation

الوصف: The application of deep learning for automated segmentation (delineation of boundaries) of histologic primitives (structures) from whole slide images can facilitate the establishment of novel protocols for kidney biopsy assessment. Here, we developed and validated deep learning networks for the segmentation of histologic structures on kidney biopsies and nephrectomies. For development, we examined 125 biopsies for Minimal Change Disease collected across 29 NEPTUNE enrolling centers along with 459 whole slide images stained with Hematoxylin & Eosin (125), Periodic Acid Schiff (125), Silver (102), and Trichrome (107) divided into training, validation and testing sets (ratio 6:1:3). Histologic structures were manually segmented (30048 total annotations) by five nephropathologists. Twenty deep learning models were trained with optimal digital magnification across the structures and stains. Periodic Acid Schiff-stained whole slide images yielded the best concordance between pathologists and deep learning segmentation across all structures (F-scores: 0.93 for glomerular tufts, 0.94 for glomerular tuft plus Bowman's capsule, 0.91 for proximal tubules, 0.93 for distal tubular segments, 0.81 for peritubular capillaries, and 0.85 for arteries and afferent arterioles). Optimal digital magnifications were 5X for glomerular tuft/tuft plus Bowman's capsule, 10X for proximal/distal tubule, arteries and afferent arterioles, and 40X for peritubular capillaries. Silver stained whole slide images yielded the worst deep learning performance. Thus, this largest study to date adapted deep learning for the segmentation of kidney histologic structures across multiple stains and pathology laboratories. All data used for training and testing and a detailed online tutorial will be publicly available.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/32835732; info:eu-repo/semantics/altIdentifier/eissn/1523-1755; https://serval.unil.ch/notice/serval:BIB_6E8CC43CC1A4Test; urn:issn:0085-2538

الإتاحة: https://doi.org/10.1016/j.kint.2020.07.044Test
https://serval.unil.ch/notice/serval:BIB_6E8CC43CC1A4Test

المؤلفون: Zee, J., McNulty, M.T., Hodgin, J.B., Zhdanova, O., Hingorani, S., Jefferson, J.A., Gibson, K.L., Trachtman, H., Fornoni, A., Dell, K.M., Reich, H.N., Bagnasco, S., Greenbaum, L.A., Lafayette, R.A., Gipson, D.S., Brown, E., Kretzler, M., Appel, G., Sambandam, K.K., Tuttle, K.R., Chen, D., Atkinson, M.A., Hogan, M.C., Kaskel, F.J., Meyers, K.E., O'Toole, J., Srivastava, T., Sethna, C.B., Hladunewich, M.A., Lin, J., Nast, C.C., Derebail, V.K., Patel, J., Vento, S., Holzman, L.B., Athavale, A.M., Adler, S.G., Lemley, K.V., Lieske, J.C., Hogan, J.J., Gadegbeku, C.A., Fervenza, F.C., Wang, C.-S., Matar, R.B., Singer, P., Kopp, J.B., Barisoni, L., Sampson, M.G.

المصدر: Pediatric Nephrology

مصطلحات موضوعية: Minimal change disease, APOL1, Pediatric, Morphology, Focal segmental glomerulosclerosis

الوصف: Background: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1’s natural absence in laboratory animals makes studying its pathobiology challenging. Methods: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes. Results: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features. Conclusions: While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes.

العلاقة: https://doi.org/10.17615/scd6-8y68Test; https://cdr.lib.unc.edu/downloads/0z709518p?file=thumbnailTest; https://cdr.lib.unc.edu/downloads/0z709518pTest

الإتاحة: https://doi.org/10.17615/scd6-8y68Test
https://cdr.lib.unc.edu/downloads/0z709518p?file=thumbnailTest
https://cdr.lib.unc.edu/downloads/0z709518pTest

المؤلفون: Hodgin, J.B., Corey, H.E., Kaplan, B.S., D'Agati, V.D.

المصدر: Kidney International ; volume 73, issue 11, page 1320-1323 ; ISSN 0085-2538

مصطلحات موضوعية: Nephrology

الإتاحة: https://doi.org/10.1038/sj.ki.5002785Test
https://api.elsevier.com/content/article/PII:S0085253815529025?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0085253815529025?httpAccept=text/plainTest

المؤلفون: Gipson, D.S., Troost, J.P., Lafayette, R.A., Hladunewich, M.A., Trachtman, H., Gadegbeku, C.A., Sedor, J.R., Holzman, L.B., Moxey-Mims, M.M., Perumal, K., Kaskel, F.J., Nelson, P.J., Tuttle, K.R., Bagnasco, S.M., Hogan, M.C., Dell, K.M., Appel, G.B., Lieske, J.C., Ilori, T.O., Sethna, C.B., Fervenza, F.C., Hogan, S.L., Nachman, P.H., Rosenberg, A.Z., Greenbaum, L.A., Meyers, K.E.C., Hewitt, S.M., Choi, M.J., Kopp, J.B., Zhdanova, O., Hodgin, J.B., Johnstone, D.B., Adler, S.G., Avila-Casado, C., Neu, A.M., Hingorani, S.R., Lemley, K.V., Nast, C.C., Brady, T.M., Barisoni-Thomas, L., Fornoni, A., Jennette, J.C., Cattran, D.C., Palmer, M.B., Gibson, K.L., Reich, H.N., Mokrzycki, M.H., Sambandam, K.K., Zilleruelo, G.E., Licht, C., Sampson, M.G., Song, P., Mariani, L.H., Kretzler, M.

المصدر: Clinical Journal of the American Society of Nephrology, 11(1)

مصطلحات موضوعية: Cohort Studies, Outcome Assessment (Health Care), Adolescent, Adult, Biopsy, Remission Induction, Female, Proportional Hazards Models, Humans, Kidney Failure, Chronic, Male, Glomerular Filtration Rate, Prospective Studies, Kidney, Proteinuria, Middle Aged, Nephrotic Syndrome

الوصف: Background and objectives This analysis from the Nephrotic Syndrome Study Network (NEPTUNE) assessed the phenotypic and pathology characteristics of proteinuric patients undergoing kidney biopsy and defined the frequency and factors associated with complete proteinuria remission (CRever). Design, setting, participants, & measurements We enrolled adults and children with proteinuria ≥0.5 g/d at the time of first clinically indicated renal biopsy at 21 sites in North America from April 2010 to June 2014 into a prospective cohort study. NEPTUNE central pathologists assigned participants to minimal-change disease (MCD), FSGS, membranous nephropathy, or other glomerulopathy cohorts. Outcome measures for this analysis were (1) CRever with urine protein-to-creatinine ratio (UPC)<0.3 g/g with preserved native kidney function and (2) ESRD. Continuous variables are reported as median and interquartile range (IQR; 25th, 75th percentile). Cox proportional hazards modeling was used to assess factors associated with CRever. Results We enrolled 441 patients: 116 (27%) had MCD, 142 (32%) had FSGS, 66 (15%) had membranous nephropathy, and 117 (27%) had other glomerulopathy. The baseline UPC was 4.1 g/g (IQR, 1.9, 7.7) and the eGFR was 81 ml/min per 1.73 m2 (IQR, 50, 105). Median duration of observation was 19 months (IQR, 11, 30). CRever occurred in 46% of patients, and 4.6% progressed to ESRD. Multivariate analysis demonstrated that higher prebiopsy proteinuria (hazard ratio, 0.3; 95% confidence interval, 0.2 to 0.5) and pathology diagnosis (FSGS versus MCD; hazard ratio, 0.2; 95% confidence interval, 0.1 to 0.5) were inversely associated with CRever. The effect of immunosuppressive therapy on remission varied by pathology diagnosis. Conclusions In NEPTUNE, the high frequency of other pathology in proteinuric patients affirms the value of the diagnostic kidney biopsy. Clinical factors, including level of proteinuria before biopsy, pathology diagnosis, and immunosuppression, are associated with complete remission.

العلاقة: https://doi.org/10.17615/1ehh-y665Test; https://cdr.lib.unc.edu/downloads/mc87q0810?file=thumbnailTest; https://cdr.lib.unc.edu/downloads/mc87q0810Test

الإتاحة: https://doi.org/10.17615/1ehh-y665Test
https://cdr.lib.unc.edu/downloads/mc87q0810?file=thumbnailTest
https://cdr.lib.unc.edu/downloads/mc87q0810Test

المؤلفون: McDougall, K.E., Perry, M.J., Gibson, R.L., Bright, J.M., Colley, S.M., Hodgin, J.B., Smithies, O., Tobias, J.H.

المصدر: American Journal of Physiology: Endocrinology & Metabolism; Oct2002, Vol. 46 Issue 4, pE817, 7p, 6 Black and White Photographs, 2 Charts, 8 Graphs

مصطلحات موضوعية: ESTROGEN receptors, BONE growth

مستخلص: We recently found that estrogen receptor (ER) antagonists prevent highdose estrogen from inducing the formation of new cancellous bone within the medullary cavity of mouse long bones. In the present investigation, we studied the role of specific ER subtypes in this response by examining whether this is impaired in female ERβ[sup -/-] mice previously generated by targeted gene deletion. Vehicle or 17β-estradiol (E[sub 2]) (range 4-4,000 µg·kg[sup -1]·day[sup -1]) was administered to intact female ERβ[sup -/-] mice and wild-type littermates by subcutaneous injection for 28 days. The osteogenic response was subsequently assessed by histomorphometry performed on longitudinal and cross sections of the tibia. E[sub 2] was found to cause an equivalent increase in cancellous bone formation in ERβ[sup -/-] mice and littermate controls, as assessed at the proximal and distal regions of the proximal tibial metaphysis. E[sub 2] also resulted in a similar increase in endosteal mineral apposition rate in these two genotypes, as assessed at the tibial diaphysis. In contrast, cortical area in ERβ[sup -/-] mice was found to be greater than that in wild types irrespective of E[sub 2] treatment, as was tibial bone mineral density as measured by dual-energy X-ray absorptiometry, consistent with previous reports of increased cortical bone mass in these animals. We conclude that, although ERβ acts as a negative modulator of cortical modeling, this isoform does not appear to contribute to high-dose estrogen's ability to induce new cancellous bone formation in mouse long bones. [ABSTRACT FROM AUTHOR]

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