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Article: Villification of the intestinal epithelium is driven by Foxl1.

Zhu, Guoli / Lahori, Deeksha / Schug, Jonathan / Kaestner, Klaus H

bioRxiv : the preprint server for biology

2024

Abstract: The primitive gut tube of mammals initially forms as a simple cylinder consisting of the endoderm-derived, pseudostratified epithelium and the mesoderm-derived surrounding mesenchyme. During mid-gestation a dramatic transformation occurs in which the ... ...

Abstract	The primitive gut tube of mammals initially forms as a simple cylinder consisting of the endoderm-derived, pseudostratified epithelium and the mesoderm-derived surrounding mesenchyme. During mid-gestation a dramatic transformation occurs in which the epithelium is both restructured into its final cuboidal form and simultaneously folded and refolded to create intestinal villi and intervillus regions, the incipient crypts. Here we show that the mesenchymal winged helix transcription factor Foxl1, itself induced by epithelial hedgehog signaling, controls villification by activating BMP and PDGFRα as well as planar cell polarity genes in epithelial-adjacent telocyte progenitors, both directly and in a feed-forward loop with Foxo3.
Language	English
Publishing date	2024-02-28
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.27.582300
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Article ; Online: Single-cell expression profiling of islets generated by the Human Pancreas Analysis Program.

Patil, Abhijeet R / Schug, Jonathan / Naji, Ali / Kaestner, Klaus H / Faryabi, Robert B / Vahedi, Golnaz

Nature metabolism

2023 Volume 5, Issue 5, Page(s) 713–715

MeSH term(s)	Humans ; Pancreas/metabolism ; Islets of Langerhans/metabolism
Language	English
Publishing date	2023-05-13
Publishing country	Germany
Document type	Letter ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	2522-5812
ISSN (online)	2522-5812
DOI	10.1038/s42255-023-00806-x
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Article ; Online: Diurnal retinal and choroidal gene expression patterns support a role for circadian biology in myopia pathogenesis.

Stone, Richard A / Tobias, John W / Wei, Wenjie / Schug, Jonathan / Wang, Xia / Zhang, Lixin / Iuvone, P Michael / Nickla, Debora L

Scientific reports

2024 Volume 14, Issue 1, Page(s) 533

Abstract: The prevalence of myopia (nearsightedness) is increasing to alarming levels, but its etiology remains poorly understood. Because both laboratory and clinical findings suggest an etiologic role for circadian rhythms in myopia development, we assayed gene ... ...

Abstract	The prevalence of myopia (nearsightedness) is increasing to alarming levels, but its etiology remains poorly understood. Because both laboratory and clinical findings suggest an etiologic role for circadian rhythms in myopia development, we assayed gene expression by RNA-Seq in retina and choroid at the onset of unilateral experimental myopia in chick, isolating tissues every 4 h during a single 24-h period from myopic and contralateral control eyes. Occluded versus open eye gene expression differences varied considerably over the 24-h sampling period, with some occurring at multiple times of day but with others showing differences at only a single investigated timepoint. Some of the genes identified in retina or choroid of chick myopia were previously identified as candidate genes for common human myopia. Like differentially expressed genes, pathways identified by Gene Set Enrichment Analysis also varied dramatically by sampling time. Considered with other laboratory data, human genetic and epidemiology data, these findings further implicate circadian events in myopia pathogenesis. The present results emphasize a need to include time of day in mechanistic studies of myopia and to assess circadian biology directly in trying to understand better the origin of myopia and to develop more effective therapies.
MeSH term(s)	Humans ; Animals ; Retina/metabolism ; Myopia/genetics ; Myopia/metabolism ; Choroid/metabolism ; Circadian Rhythm/genetics ; Gene Expression ; Biology ; Chickens/genetics
Language	English
Publishing date	2024-01-04
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-50684-2
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Article: Computational workflow and interactive analysis of single-cell expression profiling of islets generated by the Human Pancreas Analysis Program.

Patil, Abhijeet R / Schug, Jonathan / Naji, Ali / Kaestner, Klaus H / Faryabi, Robert B / Vahedi, Golnaz

bioRxiv : the preprint server for biology

2023

Abstract: Type 1 and Type 2 diabetes are distinct genetic diseases of the pancreas which are defined by the abnormal level of blood glucose. Understanding the initial molecular perturbations that occur during the pathogenesis of diabetes is of critical importance ... ...

Abstract	Type 1 and Type 2 diabetes are distinct genetic diseases of the pancreas which are defined by the abnormal level of blood glucose. Understanding the initial molecular perturbations that occur during the pathogenesis of diabetes is of critical importance in understanding these disorders. The inability to biopsy the human pancreas of living donors hampers insights into early detection, as the majority of diabetes studies have been performed on peripheral leukocytes from the blood, which is not the site of pathogenesis. Therefore, efforts have been made by various teams including the Human Pancreas Analysis Program (HPAP) to collect pancreatic tissues from deceased organ donors with different clinical phenotypes. HPAP is designed to define the molecular pathogenesis of islet dysfunction by generating detailed datasets of functional, cellular, and molecular information in pancreatic tissues of clinically well-defined organ donors with Type 1 and Type 2 diabetes. Moreover, data generated by HPAP continously become available through a centralized database, PANC-DB, thus enabling the diabetes research community to access these multi-dimensional data prepublication. Here, we present the computational workflow for single-cell RNA-seq data analysis of 258,379 high-quality cells from the pancreatic islets of 67 human donors generated by HPAP, the largest existing scRNA-seq dataset of human pancreatic tissues. We report various computational steps including preprocessing, doublet removal, clustering and cell type annotation across single-cell RNA-seq data from islets of four distintct classes of organ donors, i.e. non-diabetic control, autoantibody positive but normoglycemic, Type 1 diabetic, and Type 2 diabetic individuals. Moreover, we present an interactive tool, called CellxGene developed by the Chan Zuckerberg initiative, to navigate these high-dimensional datasets. Our data and interactive tools provide a reliable reference for singlecell pancreatic islet biology studies, especially diabetes-related conditions.
Language	English
Publishing date	2023-01-03
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.03.522578
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Article ; Online: Diurnal retinal and choroidal gene expression patterns support a role for circadian biology in myopia pathogenesis

Richard A. Stone / John W. Tobias / Wenjie Wei / Jonathan Schug / Xia Wang / Lixin Zhang / P. Michael Iuvone / Debora L. Nickla

Scientific Reports, Vol 14, Iss 1, Pp 1-

2024 Volume 13

Abstract: Abstract The prevalence of myopia (nearsightedness) is increasing to alarming levels, but its etiology remains poorly understood. Because both laboratory and clinical findings suggest an etiologic role for circadian rhythms in myopia development, we ... ...

Abstract	Abstract The prevalence of myopia (nearsightedness) is increasing to alarming levels, but its etiology remains poorly understood. Because both laboratory and clinical findings suggest an etiologic role for circadian rhythms in myopia development, we assayed gene expression by RNA-Seq in retina and choroid at the onset of unilateral experimental myopia in chick, isolating tissues every 4 h during a single 24-h period from myopic and contralateral control eyes. Occluded versus open eye gene expression differences varied considerably over the 24-h sampling period, with some occurring at multiple times of day but with others showing differences at only a single investigated timepoint. Some of the genes identified in retina or choroid of chick myopia were previously identified as candidate genes for common human myopia. Like differentially expressed genes, pathways identified by Gene Set Enrichment Analysis also varied dramatically by sampling time. Considered with other laboratory data, human genetic and epidemiology data, these findings further implicate circadian events in myopia pathogenesis. The present results emphasize a need to include time of day in mechanistic studies of myopia and to assess circadian biology directly in trying to understand better the origin of myopia and to develop more effective therapies.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2024-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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Article ; Online: Use of a Continuous Stirred Tank Reactor for the Determination of Electrospray Response Factors and Its Application to Underivatized Sugars Under Various Solvent Parameters.

Thacker, Jonathan B / Schug, Kevin A

Journal of the American Society for Mass Spectrometry

2018 Volume 30, Issue 3, Page(s) 439–447

Abstract: The relationship between the electrospray ionization (ESI)-mass spectrometric (MS) response of an analyte and its concentration has been well studied for permanently charged and basic analytes in the positive ionization mode, but there has been a lack of ...

Abstract	The relationship between the electrospray ionization (ESI)-mass spectrometric (MS) response of an analyte and its concentration has been well studied for permanently charged and basic analytes in the positive ionization mode, but there has been a lack of research effort for other analytes, and for the negative ionization mode, in general. In this study, this relationship was investigated for various adducts and deprotonated species of glucose, sucrose, and raffinose using a continuous stirred tank reactor (CSTR) coupled with ESI-tandem MS to obtain a continuum of response factors across a wide concentration range in both the positive and negative ionization modes with a single injection under 18 different combinations of solvents and additives. Profiles of response factors vs. concentrations varied widely and were dependent upon the analyte and solvent parameters. The use of ammonium trifluoroacetate resulted in the highest response factors for methanol-based and acetonitrile-based solvents in the positive and negative ionization modes, respectively. Ammonium acetate, ammonium formate, and sodium chloride in 80:20 acetonitrile:water in the negative ionization mode resulted in good linearities, useful for quantitative analysis. In the positive ionization mode, response factors tended to increase with an increase in the molecular weight of the analyte, and acetonitrile was generally found to decrease response factors. We have also demonstrated the ability of CSTR-ESI-MS to visualize ionization suppression in the presence of co-analytes. These data should be useful for liquid chromatography-ESI-MS method development for sugar analysis, to help guide the choice of mobile phase that will result in high sensitivity and linearity. Graphical Abstract.
Language	English
Publishing date	2018-12-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	1073671-2
ISSN	1879-1123 ; 1044-0305
ISSN (online)	1879-1123
ISSN	1044-0305
DOI	10.1007/s13361-018-2112-x
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Zs.A 4618: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 241: Show issues

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Article ; Online: Effects of solvent parameters on the electrospray ionization tandem mass spectrometry response of glucose.

Thacker, Jonathan B / Schug, Kevin A

Rapid communications in mass spectrometry : RCM

2018 Volume 32, Issue 15, Page(s) 1191–1198

Abstract: Rationale: The importance of saccharides, the most abundant biomolecules on Earth, extends beyond their biological roles and to consumer products and industrial processes. Electrospray ionization tandem mass spectrometry (ESI-MS/MS) is an attractive ... ...

Abstract	Rationale: The importance of saccharides, the most abundant biomolecules on Earth, extends beyond their biological roles and to consumer products and industrial processes. Electrospray ionization tandem mass spectrometry (ESI-MS/MS) is an attractive tool for the analysis of underivatized saccharides (US), but they tend to have relatively low sensitivities due to their low surface activities and lack of easily protonable or deprotonable chemical groups. An understanding of the influences that solvent parameters have on their signal intensities would enhance the usefulness of ESI-MS/MS for their analysis. Methods: Solutions of glucose, a model analyte for US, in various combinations of solvent, additive, additive concentration, and pH were analyzed by flow injection analysis ESI-MS/MS in both the positive and negative ionization mode. The blank-corrected signal intensities of the solvent parameter combinations were then compared. Results: The addition of acetonitrile led to severe ionization suppression in the positive ionization mode through its competition with glucose for cation adduction. High signal intensity was achieved under wide pH and concentration ranges for methanol: water solutions containing ammonium trifluoroacetate in the positive ionization mode. The highest signal intensities for acetonitrile: water solutions were those containing ammonium formate or lithium fluoride in the negative ionization mode. Conclusions: An understanding of the influence of solvent parameters on the signal intensity of a given analyte is useful for guiding the selection process of mobile phases/flow solvents that lead to low limits of detection or the minimization of matrix effects by allowing its detection at high dilution factors.
MeSH term(s)	Acetonitriles ; Glucose/analysis ; Glucose/chemistry ; Hydrogen-Ion Concentration ; Limit of Detection ; Methanol ; Reproducibility of Results ; Solvents/chemistry ; Spectrometry, Mass, Electrospray Ionization/standards ; Tandem Mass Spectrometry/standards ; Trifluoroacetic Acid
Chemical Substances	Acetonitriles ; Solvents ; Trifluoroacetic Acid (E5R8Z4G708) ; Glucose (IY9XDZ35W2) ; Methanol (Y4S76JWI15) ; acetonitrile (Z072SB282N)
Language	English
Publishing date	2018-05-04
Publishing country	England
Document type	Journal Article
ZDB-ID	58731-x
ISSN	1097-0231 ; 0951-4198
ISSN (online)	1097-0231
ISSN	0951-4198
DOI	10.1002/rcm.8155
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Zs.A 3461: Show issues

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Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Mu-opioid receptor-expressing neurons in the paraventricular thalamus modulate chronic morphine-induced wake alterations.

Eacret, Darrell / Manduchi, Elisabetta / Noreck, Julia / Tyner, Emma / Fenik, Polina / Dunn, Amelia D / Schug, Jonathan / Veasey, Sigrid C / Blendy, Julie A

Translational psychiatry

2023 Volume 13, Issue 1, Page(s) 78

Abstract: Disrupted sleep is a symptom of many psychiatric disorders, including substance use disorders. Most drugs of abuse, including opioids, disrupt sleep. However, the extent and consequence of opioid-induced sleep disturbance, especially during chronic drug ... ...

Abstract	Disrupted sleep is a symptom of many psychiatric disorders, including substance use disorders. Most drugs of abuse, including opioids, disrupt sleep. However, the extent and consequence of opioid-induced sleep disturbance, especially during chronic drug exposure, is understudied. We have previously shown that sleep disturbance alters voluntary morphine intake. Here, we examine the effects of acute and chronic morphine exposure on sleep. Using an oral self-administration paradigm, we show that morphine disrupts sleep, most significantly during the dark cycle in chronic morphine, with a concomitant sustained increase in neural activity in the Paraventricular Nucleus of the Thalamus (PVT). Morphine binds primarily to Mu Opioid Receptors (MORs), which are highly expressed in the PVT. Translating Ribosome Affinity Purification (TRAP)-Sequencing of PVT neurons that express MORs showed significant enrichment of the circadian entrainment pathway. To determine whether MOR + cells in the PVT mediate morphine-induced sleep/wake properties, we inhibited these neurons during the dark cycle while mice were self-administering morphine. This inhibition decreased morphine-induced wakefulness but not general wakefulness, indicating that MORs in the PVT contribute to opioid-specific wake alterations. Overall, our results suggest an important role for PVT neurons that express MORs in mediating morphine-induced sleep disturbance.
MeSH term(s)	Animals ; Mice ; Morphine ; Analgesics, Opioid ; Receptors, Opioid, mu ; Neurons ; Sleep Wake Disorders ; Thalamus
Chemical Substances	Morphine (76I7G6D29C) ; Analgesics, Opioid ; Receptors, Opioid, mu
Language	English
Publishing date	2023-03-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-023-02382-w
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Article ; Online: Sample preparation and fractionation techniques for intact proteins for mass spectrometric analysis.

Thomas, Shannon L / Thacker, Jonathan B / Schug, Kevin A / Maráková, Katarína

Journal of separation science

2020 Volume 44, Issue 1, Page(s) 211–246

Abstract: The analysis of proteins in biological samples is highly desirable, given their connection to myriad biological functions and disease states, as well as the growing interest in the development of protein-based pharmaceuticals. The introduction and ... ...

Abstract	The analysis of proteins in biological samples is highly desirable, given their connection to myriad biological functions and disease states, as well as the growing interest in the development of protein-based pharmaceuticals. The introduction and maturation of "soft" ionization methods, such as electrospray ionization and matrix-assisted laser desorption/ionization, have made mass spectrometry an indispensable tool for the analysis of proteins. Despite the availability of powerful instrumentation, sample preparation and fractionation remain among the most challenging aspects of protein analysis. This review summarizes these challenges and provides an overview of the state-of-the-art in sample preparation and fractionation of proteins for mass spectrometric analysis, with an emphasis on those used for top-down proteomic approaches. Biological fluids, particularly important for clinical and pharmaceutical applications and their characteristics are also discussed. While immunoaffinity-based methods are addressed, more attention is given to non-immunoaffinity-based methods, such as precipitation, coacervation, size exclusion, dialysis, solid-phase extraction, and electrophoresis. These techniques are presented in the context of a significant number of studies where they have been developed and utilized.
Language	English
Publishing date	2020-11-19
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	2047990-6
ISSN	1615-9314 ; 1615-9306
ISSN (online)	1615-9314
ISSN	1615-9306
DOI	10.1002/jssc.202000936
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Article ; Online: Advanced precision modeling reveals divergent responses of hepatocellular carcinoma to combinatorial immunotherapy.

Liu, Jinping / Cheng, Lan / El-Mekkoussi, Hilana / Assenmacher, Charles-Antoine / Lee, Michelle Y Y / Jaffe, Danielle R / Garvin-Darby, Kaisha / Morgan, Ashleigh / Manduchi, Elisabetta / Schug, Jonathan / Kaestner, Klaus H

Cancer communications (London, England)

2023 Volume 43, Issue 6, Page(s) 706–710

MeSH term(s)	Humans ; Carcinoma, Hepatocellular/pathology ; Liver Neoplasms/pathology ; Immunotherapy
Language	English
Publishing date	2023-04-10
Publishing country	United States
Document type	Letter ; Research Support, N.I.H., Extramural
ISSN	2523-3548
ISSN (online)	2523-3548
DOI	10.1002/cac2.12421
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