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Article ; Online: Differential isoform expression and alternative splicing in sex determination in mice.

Planells, Benjamín / Gómez-Redondo, Isabel / Pericuesta, Eva / Lonergan, Patrick / Gutiérrez-Adán, Alfonso

BMC genomics

2019 Volume 20, Issue 1, Page(s) 202

Abstract: Background: Alternative splicing (AS) may play an important role in gonadal sex determination (GSD) in mammals. The present study was designed to identify differentially expressed isoforms and AS modifications accompanying GSD in mice.: Results: ... ...

Abstract	Background: Alternative splicing (AS) may play an important role in gonadal sex determination (GSD) in mammals. The present study was designed to identify differentially expressed isoforms and AS modifications accompanying GSD in mice. Results: Using deep RNA-sequencing, we performed a transcriptional analysis of XX and XY gonads during sex determination on embryonic days 11 (E11) and 12 (E12). Analysis of differentially expressed genes (DEG) identified hundreds of genes related to GSD and early sex differentiation that may represent good candidates for sex reversal. Expression at time point E11 in males was significantly enriched in RNA splicing and mRNA processing Gene Ontology terms. Differentially expressed isoform analysis identified hundreds of specific isoforms related to GSD, many of which showed no differences in the DEG analysis. Hundreds of AS events were identified as modified at E11 and E12. Female E11 gonads featured sex-biased upregulation of intron retention (in genes related to regulation of transcription, protein phosphorylation, protein transport and mRNA splicing) and exon skipping (in genes related to chromatin repression) suggesting AS as a post-transcription mechanism that controls sex determination of the bipotential fetal gonad. Conclusion: Our data suggests an important role of splicing regulatory mechanisms for sex determination in mice.
MeSH term(s)	Alternative Splicing ; Animals ; Biomarkers/metabolism ; Female ; Gene Expression Profiling ; Gonads/metabolism ; High-Throughput Nucleotide Sequencing/methods ; Male ; Mice ; Protein Isoforms ; Sex Differentiation
Chemical Substances	Biomarkers ; Protein Isoforms
Language	English
Publishing date	2019-03-12
Publishing country	England
Document type	Journal Article
ISSN	1471-2164
ISSN (online)	1471-2164
DOI	10.1186/s12864-019-5572-x
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Article ; Online: Erratum to "Modulation of Akt vs Stat3 activity by the focal adhesion kinase in non-neoplastic mouse fibroblasts" [Exp. Cell Res. 404 (1) (2021) 112601].

Geletu, Mulu / Adan, Hanad / Niit, Maximillian / Arulanandam, Rozanne / Carefoot, Esther / Hoskin, Victoria / Sina, Diana / Elliott, Bruce / Gunning, Patrick / Raptis, Leda

Experimental cell research

2021 Volume 411, Issue 1, Page(s) 112732

Language	English
Publishing date	2021-07-30
Publishing country	United States
Document type	Published Erratum
ZDB-ID	1493-x
ISSN	1090-2422 ; 0014-4827
ISSN (online)	1090-2422
ISSN	0014-4827
DOI	10.1016/j.yexcr.2021.112732
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Article ; Online: Modulation of Akt vs Stat3 activity by the focal adhesion kinase in non-neoplastic mouse fibroblasts.

Geletu, Mulu / Adan, Hanad / Niit, Maximillian / Arulanandam, Rozanne / Carefoot, Esther / Hoskin, Victoria / Sina, Diana / Elliott, Bruce / Gunning, Patrick / Raptis, Leda

Experimental cell research

2021 Volume 411, Issue 1, Page(s) 112731

Abstract: Adhesion of cells to each other and to the extracellular matrix (ECM) are both required for cellular functions. Cell-to-cell adhesion is mediated by cadherins, and their engagement triggers the activation of Stat3, which offers a potent survival signal. ... ...

Abstract	Adhesion of cells to each other and to the extracellular matrix (ECM) are both required for cellular functions. Cell-to-cell adhesion is mediated by cadherins, and their engagement triggers the activation of Stat3, which offers a potent survival signal. Adhesion to the ECM on the other hand, activates FAK which attracts and activates Src, as well as receptor tyrosine kinases (RTKs), the PI3k/Akt and Ras/Erk pathways. However, the effect of cell density upon FAK and Akt activity has not been examined. We now demonstrate that, interestingly, despite being potent Stat3 activators, Src and RTKs are unable to activate Stat3 in sparsely growing (i.e., without cadherin engagement), non-neoplastic cells attached to the ECM. In contrast, cell aggregation (i.e., cadherin engagement in the absence of adhesion to a solid substratum) was found to activate both Stat3 and Akt. Pharmacologic or genetic reduction of FAK activity abolished Akt activity at low densities, indicating that FAK is an important activator of Akt in this setting. Notably, FAK knockout increased cellular sensitivity to the Stat3 inhibitor CPA7, while FAK reintroduction restored resistance to this drug. These findings suggest a complementary role of integrin/FAK/Akt and cadherin/Stat3-mediated pro-survival pathways, which may be of significance during neoplastic transformation and metastasis.
Language	English
Publishing date	2021-07-14
Publishing country	United States
Document type	Published Erratum
ZDB-ID	1493-x
ISSN	1090-2422 ; 0014-4827
ISSN (online)	1090-2422
ISSN	0014-4827
DOI	10.1016/j.yexcr.2021.112731
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Article ; Online: Modulation of Akt vs Stat3 activity by the focal adhesion kinase in non-neoplastic mouse fibroblasts.

Geletu, Mulu / Adan, Hanad / Niit, Maximillian / Arulanandam, Rozanne / Carefoot, Esther / Hoskin, Victoria / Sina, Diana / Elliott, Bruce / Gunning, Patrick / Raptis, Leda

Experimental cell research

2021 Volume 404, Issue 1, Page(s) 112601

Abstract: Adhesion of cells to each other and to the extracellular matrix (ECM) are both required for cellular functions. Cell-to-cell adhesion is mediated by cadherins and their engagement triggers the activation of Stat3, which offers a potent survival signal. ... ...

Abstract	Adhesion of cells to each other and to the extracellular matrix (ECM) are both required for cellular functions. Cell-to-cell adhesion is mediated by cadherins and their engagement triggers the activation of Stat3, which offers a potent survival signal. Adhesion to the ECM on the other hand, activates FAK which attracts and activates Src, as well as receptor tyrosine kinases (RTKs), the PI3k/Akt and Ras/Erk pathways. However, the effect of cell density upon FAK and Akt activity has not been examined. We now demonstrate that, interestingly, despite being potent Stat3 activators, Src and RTKs are unable to activate Stat3 in sparsely growing (i.e., without cadherin engagement), non-neoplastic cells attached to the ECM. In contrast, cell aggregation (i.e., cadherin engagement in the absence of adhesion to a solid substratum) was found to activate both Stat3 and Akt. Pharmacologic or genetic reduction of FAK activity abolished Akt activity at low densities, indicating that FAK is an important activator of Akt in this setting. Notably, FAK knockout increased cellular sensitivity to the Stat3 inhibitor CPA7, while FAK reintroduction restored resistance to this drug. These findings suggest a complementary role of integrin/FAK/Akt and cadherin/Stat3-mediated pro-survival pathways, which may be of significance during neoplastic transformation and metastasis.
MeSH term(s)	Animals ; Cadherins/metabolism ; Cell Adhesion/physiology ; Cell Survival/physiology ; Cell Transformation, Neoplastic/metabolism ; Extracellular Matrix/metabolism ; Fibroblasts/metabolism ; Focal Adhesion Protein-Tyrosine Kinases/metabolism ; Humans ; Mice ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; STAT3 Transcription Factor/metabolism ; Signal Transduction/physiology
Chemical Substances	Cadherins ; STAT3 Transcription Factor ; STAT3 protein, human ; Focal Adhesion Protein-Tyrosine Kinases (EC 2.7.10.2) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2021-05-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1493-x
ISSN	1090-2422 ; 0014-4827
ISSN (online)	1090-2422
ISSN	0014-4827
DOI	10.1016/j.yexcr.2021.112601
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Article ; Online: Gene expression profiles of bovine genital ridges during sex determination and early differentiation of the gonads†.

Planells, Benjamín / Gómez-Redondo, Isabel / Sánchez, José María / McDonald, Michael / Cánovas, Ángela / Lonergan, Patrick / Gutiérrez-Adán, Alfonso

Biology of reproduction

2019 Volume 102, Issue 1, Page(s) 38–52

Abstract: Most current knowledge of sex determination in mammals has emerged from mouse and human studies. To investigate the molecular regulation of the sex determination process in cattle, we used an RNA sequencing strategy to analyze the transcriptome landscape ...

Abstract	Most current knowledge of sex determination in mammals has emerged from mouse and human studies. To investigate the molecular regulation of the sex determination process in cattle, we used an RNA sequencing strategy to analyze the transcriptome landscape of male and female bovine fetal gonads collected in vivo at key developmental stages: before, during, and after SRY gene activation on fetal days D35 (bipotential gonad formation), D39 (peak SRY expression), and D43 (early gonad differentiation). Differentially expressed genes (DEGs) were identified in male vs. female germinal ridges and among group genes showing similar expression profiles during the three periods. There were 143, 96, and 658 DEG between males and female fetuses at D35, D39, and D43, respectively. On D35, genes upregulated in females were enriched in translation, nuclear export, RNA localization, and mRNA splicing events, whereas those upregulated in males were enriched in cell proliferation regulation and male sex determination terms. In time-course experiments, 767 DEGs in males and 545 DEGs in females were identified between D35 vs. D39, and 3157 DEGs in males and 2008 in females were identified between D39 vs. D43. Results highlight unique aspects of sex determination in cattle, such as the expression of several Y chromosome genes (absent in mice and humans) before SRY expression and an abrupt increase in the nuclear expression of SOX10 (instead of SOX9 expression in the Sertoli cell cytoplasm as observed in mice) during male determination and early differentiation.
MeSH term(s)	Animals ; Cattle ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Gonads/metabolism ; Male ; SOX9 Transcription Factor/genetics ; SOX9 Transcription Factor/metabolism ; SOXE Transcription Factors/genetics ; SOXE Transcription Factors/metabolism ; Sertoli Cells/metabolism ; Sex Determination Processes/physiology ; Sex-Determining Region Y Protein/genetics ; Sex-Determining Region Y Protein/metabolism ; Transcriptome
Chemical Substances	SOX9 Transcription Factor ; SOXE Transcription Factors ; Sex-Determining Region Y Protein
Language	English
Publishing date	2019-10-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1118-6
ISSN	1529-7268 ; 0006-3363
ISSN (online)	1529-7268
ISSN	0006-3363
DOI	10.1093/biolre/ioz170
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Article ; Online: EDGE COVID-19: a web platform to generate submission-ready genomes from SARS-CoV-2 sequencing efforts.

Lo, Chien-Chi / Shakya, Migun / Connor, Ryan / Davenport, Karen / Flynn, Mark / Gutiérrez, Adán Myers Y / Hu, Bin / Li, Po-E / Jackson, Elais Player / Xu, Yan / Chain, Patrick S G

Bioinformatics (Oxford, England)

2022 Volume 38, Issue 10, Page(s) 2700–2704

Abstract: Summary: Genomics has become an essential technology for surveilling emerging infectious disease outbreaks. A range of technologies and strategies for pathogen genome enrichment and sequencing are being used by laboratories worldwide, together with ... ...

Abstract	Summary: Genomics has become an essential technology for surveilling emerging infectious disease outbreaks. A range of technologies and strategies for pathogen genome enrichment and sequencing are being used by laboratories worldwide, together with different and sometimes ad hoc, analytical procedures for generating genome sequences. A fully integrated analytical process for raw sequence to consensus genome determination, suited to outbreaks such as the ongoing COVID-19 pandemic, is critical to provide a solid genomic basis for epidemiological analyses and well-informed decision making. We have developed a web-based platform and integrated bioinformatic workflows that help to provide consistent high-quality analysis of SARS-CoV-2 sequencing data generated with either the Illumina or Oxford Nanopore Technologies (ONT). Using an intuitive web-based interface, this workflow automates data quality control, SARS-CoV-2 reference-based genome variant and consensus calling, lineage determination and provides the ability to submit the consensus sequence and necessary metadata to GenBank, GISAID and INSDC raw data repositories. We tested workflow usability using real world data and validated the accuracy of variant and lineage analysis using several test datasets, and further performed detailed comparisons with results from the COVID-19 Galaxy Project workflow. Our analyses indicate that EC-19 workflows generate high-quality SARS-CoV-2 genomes. Finally, we share a perspective on patterns and impact observed with Illumina versus ONT technologies on workflow congruence and differences. Availability and implementation: https://edge-covid19.edgebioinformatics.org, and https://github.com/LANL-Bioinformatics/EDGE/tree/SARS-CoV2. Supplementary information: Supplementary data are available at Bioinformatics online.
MeSH term(s)	COVID-19 ; Genome, Viral ; Genomics ; Humans ; Pandemics ; SARS-CoV-2/genetics
Language	English
Publishing date	2022-05-12
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btac176
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Article ; Online: Characterization of initial ankle-foot prosthesis prescription patterns in U.S. Service members following unilateral transtibial amputation.

Monaghan, Patrick G / Knight, Ashley D / Brinkerhoff, Sarah A / Harrison, Kenneth D / Dearth, Christopher L / Hendershot, Brad D / Sefton, JoEllen M / Zabala, Michael / Vazquez, Adan / Shannon, David / Crumbley, David / Roper, Jaimie A

Frontiers in rehabilitation sciences

2023 Volume 4, Page(s) 1235693

Abstract: Introduction: The purpose of this study was to explore relationships between patient-specific characteristics and initial ankle-foot prosthesis prescription patterns among U.S. Service members with unilateral transtibial limb loss.: Methods: A ... ...

Abstract	Introduction: The purpose of this study was to explore relationships between patient-specific characteristics and initial ankle-foot prosthesis prescription patterns among U.S. Service members with unilateral transtibial limb loss. Methods: A retrospective review of health records identified 174 individuals with unilateral transtibial limb loss who received care at Walter Reed National Military Medical Center between 2001 and 2019. We examined patient-specific factors such as demographics, participant duty status at injury and amputation, amputation etiology, and timing between injury, amputation, and initial prescription. The type of first prescribed ankle-foot prosthesis was categorized as energy storing and return - nonarticulating, energy storing and return - articulating, or computer controlled. Results: Sex, amputation etiology, time from injury to initial prescription, and time from amputation to initial prescription differed by type of initial ankle-foot prosthesis prescription. Service members with shorter intervals between injury-initial prescription and amputation-initial prescription, and those injured by combat blast, were more likely to receive a non-articulating device. Incorporating sex, time from injury-initial prescription, time from amputation-initial prescription, and amputation etiology as predictors of prosthesis type, we were able to correctly classify 72% of all first prostheses prescribed. Discussion: Patient-specific characteristics such as sex, the time between injury-initial prescription, time from amputation-initial prescription and amputation etiology are essential characteristics that influence initial ankle-foot prosthesis prescription patterns in U.S. Service members.
Language	English
Publishing date	2023-08-25
Publishing country	Switzerland
Document type	Journal Article
ISSN	2673-6861
ISSN (online)	2673-6861
DOI	10.3389/fresc.2023.1235693
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Article ; Online: Adenylate kinase 9 is essential for sperm function and male fertility in mammals.

O'Callaghan, Elena / Navarrete-Lopez, Paula / Štiavnická, Miriama / Sánchez, José M / Maroto, Maria / Pericuesta, Eva / Fernández-González, Raul / O'Meara, Ciara / Eivers, Bernard / Kelleher, Margaret M / Evans, Ross D / Mapel, Xena M / Lloret-Villas, Audald / Pausch, Hubert / Balastegui-Alarcón, Miriam / Avilés, Manuel / Sanchez-Rodriguez, Ana / Roldan, Eduardo R S / McDonald, Michael /

Kenny, David A / Fair, Sean / Gutiérrez-Adán, Alfonso / Lonergan, Patrick

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 42, Page(s) e2305712120

Abstract: Despite passing routine laboratory tests for semen quality, bulls used in artificial insemination exhibit significant variation in fertility. Routine analysis of fertility data identified a dairy bull with extreme subfertility (10% pregnancy rate). To ... ...

Abstract	Despite passing routine laboratory tests for semen quality, bulls used in artificial insemination exhibit significant variation in fertility. Routine analysis of fertility data identified a dairy bull with extreme subfertility (10% pregnancy rate). To characterize the subfertility phenotype, a range of in vitro, in vivo, and molecular assays were carried out. Sperm from the subfertile bull exhibited reduced motility and severely reduced caffeine-induced hyperactivation compared to controls. Ability to penetrate the zona pellucida, cleavage rate, cleavage kinetics, and blastocyst yield after IVF or AI were significantly lower than in control bulls. Whole-genome sequencing from semen and RNA sequencing of testis tissue revealed a critical mutation in adenylate kinase 9 (
MeSH term(s)	Animals ; Cattle ; Female ; Male ; Mice ; Pregnancy ; Adenylate Kinase/genetics ; Adenylate Kinase/metabolism ; Fertility ; Infertility ; Mammals ; Semen/metabolism ; Semen Analysis ; Sperm Motility ; Spermatozoa/metabolism
Chemical Substances	Adenylate Kinase (EC 2.7.4.3)
Language	English
Publishing date	2023-10-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2305712120
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Article ; Online: Differentiation of Mouse Breast Epithelial HC11 and EpH4 Cells.

Geletu, Mulu / Hoskin, Victoria / Starova, Blerta / Niit, Maximilian / Adan, Hanad / Elliott, Bruce / Gunning, Patrick / Raptis, Leda

Journal of visualized experiments : JoVE

2020 , Issue 156

Abstract: Cadherins play an important role in the regulation of cell differentiation as well as neoplasia. Here we describe the origins and methods of the induction of differentiation of two mouse breast epithelial cell lines, HC11 and EpH4, and their use to study ...

Abstract	Cadherins play an important role in the regulation of cell differentiation as well as neoplasia. Here we describe the origins and methods of the induction of differentiation of two mouse breast epithelial cell lines, HC11 and EpH4, and their use to study complementary stages of mammary gland development and neoplastic transformation. The HC11 mouse breast epithelial cell line originated from the mammary gland of a pregnant Balb/c mouse. It differentiates when grown to confluence attached to a plastic Petri dish surface in medium containing fetal calf serum and Hydrocortisone, Insulin and Prolactin (HIP medium). Under these conditions, HC11 cells produce the milk proteins β-casein and whey acidic protein (WAP), similar to lactating mammary epithelial cells, and form rudimentary mammary gland-like structures termed "domes". The EpH4 cell line was derived from spontaneously immortalized mouse mammary gland epithelial cells isolated from a pregnant Balb/c mouse. Unlike HC11, EpH4 cells can fully differentiate into spheroids (also called mammospheres) when cultured under three-dimensional (3D) growth conditions in HIP medium. Cells are trypsinized, suspended in a 20% matrix consisting of a mixture of extracellular matrix proteins produced by Engelbreth-Holm-Swarm (EHS) mouse sarcoma cells, plated on top of a layer of concentrated matrix coating a plastic Petri dish or multiwell plate, and covered with a layer of 10% matrix-containing HIP medium. Under these conditions, EpH4 cells form hollow spheroids that exhibit apical-basal polarity, a hollow lumen, and produce β-casein and WAP. Using these techniques, our results demonstrated that the intensity of the cadherin/Rac signal is critical for the differentiation of HC11 cells. While Rac1 is necessary for differentiation and low levels of activated Rac
MeSH term(s)	Animals ; Cadherins/metabolism ; Cell Culture Techniques ; Cell Differentiation ; Cell Line ; Cell Transformation, Neoplastic ; Culture Media/chemistry ; Epithelial Cells/cytology ; Epithelial Cells/metabolism ; Female ; Mammary Glands, Animal/cytology ; Mammary Glands, Animal/growth & development ; Mice ; Milk Proteins/metabolism ; Spheroids, Cellular/cytology ; Spheroids, Cellular/metabolism ; rac GTP-Binding Proteins/metabolism
Chemical Substances	Cadherins ; Culture Media ; Milk Proteins ; rac GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2020-02-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Video-Audio Media
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/60147
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Article ; Online: A comparison of curated gene sets versus transcriptomics-derived gene signatures for detecting pathway activation in immune cells.

Liu, Bin / Lindner, Patrick / Jirmo, Adan Chari / Maus, Ulrich / Illig, Thomas / DeLuca, David S

BMC bioinformatics

2020 Volume 21, Issue 1, Page(s) 28

Abstract: Background: Despite the significant contribution of transcriptomics to the fields of biological and biomedical research, interpreting long lists of significantly differentially expressed genes remains a challenging step in the analysis process. Gene set ...

Abstract	Background: Despite the significant contribution of transcriptomics to the fields of biological and biomedical research, interpreting long lists of significantly differentially expressed genes remains a challenging step in the analysis process. Gene set enrichment analysis is a standard approach for summarizing differentially expressed genes into pathways or other gene groupings. Here, we explore an alternative approach to utilizing gene sets from curated databases. We examine the method of deriving custom gene sets which may be relevant to a given experiment using reference data sets from previous transcriptomics studies. We call these data-derived gene sets, "gene signatures" for the biological process tested in the previous study. We focus on the feasibility of this approach in analyzing immune-related processes, which are complicated in their nature but play an important role in the medical research. Results: We evaluate several statistical approaches to detecting the activity of a gene signature in a target data set. We compare the performance of the data-derived gene signature approach with comparable GO term gene sets across all of the statistical tests. A total of 61 differential expression comparisons generated from 26 transcriptome experiments were included in the analysis. These experiments covered eight immunological processes in eight types of leukocytes. The data-derived signatures were used to detect the presence of immunological processes in the test data with modest accuracy (AUC = 0.67). The performance for GO and literature based gene sets was worse (AUC = 0.59). Both approaches were plagued by poor specificity. Conclusions: When investigators seek to test specific hypotheses, the data-derived signature approach can perform as well, if not better than standard gene-set based approaches for immunological signatures. Furthermore, the data-derived signatures can be generated in the cases that well-defined gene sets are lacking from pathway databases and also offer the opportunity for defining signatures in a cell-type specific manner. However, neither the data-derived signatures nor standard gene-sets can be demonstrated to reliably provide negative predictions for negative cases. We conclude that the data-derived signature approach is a useful and sometimes necessary tool, but analysts should be weary of false positives.
MeSH term(s)	Animals ; Data Curation ; Databases, Genetic ; Gene Expression Profiling ; Humans ; Leukocytes/immunology ; Leukocytes/metabolism ; Mice ; Sensitivity and Specificity
Language	English
Publishing date	2020-01-28
Publishing country	England
Document type	Comparative Study ; Journal Article
ZDB-ID	2041484-5
ISSN	1471-2105 ; 1471-2105
ISSN (online)	1471-2105
ISSN	1471-2105
DOI	10.1186/s12859-020-3366-4
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