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Article ; Online: ENTPD3 Marks Mature Stem Cell-Derived β-Cells Formed by Self-Aggregation In Vitro.

Docherty, Fiona M / Riemondy, Kent A / Castro-Gutierrez, Roberto / Dwulet, JaeAnn M / Shilleh, Ali H / Hansen, Maria S / Williams, Shane P M / Armitage, Lucas H / Santostefano, Katherine E / Wallet, Mark A / Mathews, Clayton E / Triolo, Taylor M / Benninger, Richard K P / Russ, Holger A

Diabetes

2021 Volume 70, Issue 11, Page(s) 2554–2567

Abstract: Stem cell-derived β-like cells (sBC) carry the promise of providing an abundant source of insulin-producing cells for use in cell replacement therapy for patients with diabetes, potentially allowing widespread implementation of a practical cure. To ... ...

Abstract	Stem cell-derived β-like cells (sBC) carry the promise of providing an abundant source of insulin-producing cells for use in cell replacement therapy for patients with diabetes, potentially allowing widespread implementation of a practical cure. To achieve their clinical promise, sBC need to function comparably with mature adult β-cells, but as yet they display varying degrees of maturity. Indeed, detailed knowledge of the events resulting in human β-cell maturation remains obscure. Here we show that sBC spontaneously self-enrich into discreet islet-like cap structures within in vitro cultures, independent of exogenous maturation conditions. Multiple complementary assays demonstrate that this process is accompanied by functional maturation of the self-enriched sBC (seBC); however, the seBC still contain distinct subpopulations displaying different maturation levels. Interestingly, the surface protein ENTPD3 (also known as nucleoside triphosphate diphosphohydrolase-3 [NDPTase3]) is a specific marker of the most mature seBC population and can be used for mature seBC identification and sorting. Our results illuminate critical aspects of in vitro sBC maturation and provide important insights toward developing functionally mature sBC for diabetes cell replacement therapy.
MeSH term(s)	Adenosine Triphosphatases/genetics ; Adenosine Triphosphatases/metabolism ; Calcium/metabolism ; DNA, Mitochondrial ; Embryonic Stem Cells/metabolism ; Gene Expression Regulation ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Insulin-Secreting Cells/metabolism ; Transcriptome
Chemical Substances	DNA, Mitochondrial ; Adenosine Triphosphatases (EC 3.6.1.-) ; ectoATPase (EC 3.6.1.-) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2021-08-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db20-0873
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Article ; Online: Influence of

Armitage, Lucas H / Wallet, Mark A / Mathews, Clayton E

Frontiers in immunology

2021 Volume 12, Page(s) 636618

Abstract: Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) regulates a panoply of leukocyte signaling pathways. A single nucleotide polymorphism (SNP) ... ...

Abstract	Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) regulates a panoply of leukocyte signaling pathways. A single nucleotide polymorphism (SNP) in
MeSH term(s)	Adaptive Immunity ; Alleles ; Autoimmunity ; Diabetes Mellitus, Type 1/genetics ; Genetic Association Studies ; Genetic Predisposition to Disease ; Humans ; Immunity, Innate ; Polymorphism, Single Nucleotide ; Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics ; Receptors, Antigen, T-Cell/metabolism ; T-Lymphocytes/immunology
Chemical Substances	Receptors, Antigen, T-Cell ; PTPN22 protein, human (EC 3.1.3.48) ; Protein Tyrosine Phosphatase, Non-Receptor Type 22 (EC 3.1.3.48)
Language	English
Publishing date	2021-02-25
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.636618
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Article ; Online: Role of Nitric Oxide-Releasing Glycosaminoglycans in Wound Healing.

Maloney, Sara E / Broberg, Christopher A / Grayton, Quincy E / Picciotti, Samantha L / Hall, Hannah R / Wallet, Shannon M / Maile, Robert / Schoenfisch, Mark H

ACS biomaterials science & engineering

2022 Volume 8, Issue 6, Page(s) 2537–2552

Abstract: Two glycosaminoglycan (GAG) biopolymers, hyaluronic acid (HA) and chondroitin sulfate (CS), were chemically modified via carbodiimide chemistry to facilitate the loading and release of nitric oxide (NO) to develop a multi-action wound healing agent. The ... ...

Abstract	Two glycosaminoglycan (GAG) biopolymers, hyaluronic acid (HA) and chondroitin sulfate (CS), were chemically modified via carbodiimide chemistry to facilitate the loading and release of nitric oxide (NO) to develop a multi-action wound healing agent. The resulting NO-releasing GAGs released 0.2-0.9 μmol NO mg
MeSH term(s)	Animals ; Fibroblasts ; Glycosaminoglycans/pharmacology ; Glycosaminoglycans/therapeutic use ; Humans ; Hyaluronic Acid/pharmacology ; Mice ; Nitric Oxide/chemistry ; Wound Healing/physiology
Chemical Substances	Glycosaminoglycans ; Nitric Oxide (31C4KY9ESH) ; Hyaluronic Acid (9004-61-9)
Language	English
Publishing date	2022-05-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2373-9878
ISSN (online)	2373-9878
DOI	10.1021/acsbiomaterials.2c00392
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Article ; Online: Pregnancy and cardiac maternal outcomes in women with inherited cardiomyopathy: interest of the CARPREG II risk score.

Wallet, Thomas / Legrand, Lise / Isnard, Richard / Gandjbakhch, Estelle / Pousset, Françoise / Proukhnitzky, Julie / Dommergues, Marc / Nizard, Jacky / Charron, Philippe

ESC heart failure

2024

Abstract: Aims: Inherited cardiomyopathies are relatively rare but carry a high risk of cardiac maternal morbidity and mortality during pregnancy and postpartum. However, data for risk stratification are scarce. The new CARPREG II score improves prediction of ... ...

Abstract	Aims: Inherited cardiomyopathies are relatively rare but carry a high risk of cardiac maternal morbidity and mortality during pregnancy and postpartum. However, data for risk stratification are scarce. The new CARPREG II score improves prediction of prognosis in pregnancies associated with heart disease, though its role in inherited cardiomyopathies is unclear. We aim to describe characteristics and cardiac maternal outcomes in patients with inherited cardiomyopathy during pregnancy, and to evaluate the interest of the CARPREG II risk score in this population. Methods and results: In this retrospective single-centre study, 90 consecutive pregnancies in 74 patients were included (mean age 32 ± 5 years), including 28 cases of dilated cardiomyopathy (DCM), 46 of hypertrophic cardiomyopathy, 11 of arrhythmogenic right ventricular cardiomyopathy and 5 of left ventricular noncompaction, excluding peripartum cardiomyopathy. The discriminatory power of several risk scores was assessed by the area under the receiver-operating characteristic curve (AUC). Median CARPREG II score was 2 [0;3] and was higher in the DCM subgroup. A severe cardiac maternal complication was observed in 18 (20%) pregnancies, mainly driven by arrhythmia and heart failure (each event in 10 pregnancies), with 3 cardiovascular deaths. Forty-three pregnancies (48%) presented foetal/neonatal complications (18 premature delivery, 3 foetal/neonatal death). CARPREG II was significantly associated with cardiac maternal complications (P < 0.05 for all) and showed a higher AUC (0.782) than CARPREG (0.755), mWHO (0.697) and ZAHARA (0.604). Conclusions: Pregnancy in women with inherited cardiomyopathy carries a high risk of maternal cardiovascular complications. CARPREG II is the most efficient predictor of cardiovascular complications in this population.
Language	English
Publishing date	2024-02-15
Publishing country	England
Document type	Journal Article
ZDB-ID	2814355-3
ISSN	2055-5822 ; 2055-5822
ISSN (online)	2055-5822
ISSN	2055-5822
DOI	10.1002/ehf2.14694
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Article ; Online: Harmine enhances the activity of the HIV-1 latency-reversing agents ingenol A and SAHA.

Taylor, Jared P / Armitage, Lucas H / Aldridge, Daniel L / Cash, Melanie N / Wallet, Mark A

Biology open

2020 Volume 9, Issue 12

Abstract: Infection with human immunodeficiency virus 1 (HIV-1) remains incurable because long-lived, latently-infected cells persist during prolonged antiretroviral therapy. Attempts to pharmacologically reactivate and purge the latent reservoir with latency ... ...

Abstract	Infection with human immunodeficiency virus 1 (HIV-1) remains incurable because long-lived, latently-infected cells persist during prolonged antiretroviral therapy. Attempts to pharmacologically reactivate and purge the latent reservoir with latency reactivating agents (LRAs) such as protein kinase C (PKC) agonists (e.g. ingenol A) or histone deacetylase (HDAC) inhibitors (e.g. SAHA) have shown promising but incomplete efficacy. Using the J-Lat T cell model of HIV latency, we found that the plant-derived compound harmine enhanced the efficacy of existing PKC agonist LRAs in reactivating latently-infected cells. Treatment with harmine increased not only the number of reactivated cells but also increased HIV transcription and protein expression on a per-cell basis. Importantly, we observed a synergistic effect when harmine was used in combination with ingenol A and the HDAC inhibitor SAHA. An investigation into the mechanism revealed that harmine, when used with LRAs, increased the activity of NFκB, MAPK p38, and ERK1/2. Harmine treatment also resulted in reduced expression of HEXIM1, a negative regulator of transcriptional elongation. Thus, harmine enhanced the effects of LRAs by increasing the availability of transcription factors needed for HIV reactivation and promoting transcriptional elongation. Combination therapies with harmine and LRAs could benefit patients by achieving deeper reactivation of the latent pool of HIV provirus.
MeSH term(s)	CD4-Positive T-Lymphocytes/drug effects ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; Diterpenes/pharmacology ; Gene Expression Regulation/drug effects ; HIV Infections/immunology ; HIV Infections/metabolism ; HIV Infections/virology ; HIV-1/drug effects ; HIV-1/physiology ; Harmine/pharmacology ; Humans ; Lymphocyte Activation/drug effects ; Nylons/pharmacology ; Protein Kinase C/metabolism ; Pyrroles/pharmacology ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Virus Activation/drug effects ; Virus Latency/drug effects
Chemical Substances	Diterpenes ; HEXIM1 protein, human ; Nylons ; Pyrroles ; RNA-Binding Proteins ; SAHA-PIP-delta ; Transcription Factors ; Harmine (4FHH5G48T7) ; Protein Kinase C (EC 2.7.11.13) ; ingenol (IC77UZI9G8)
Language	English
Publishing date	2020-12-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2632264-X
ISSN	2046-6390 ; 2046-6390
ISSN (online)	2046-6390
ISSN	2046-6390
DOI	10.1242/bio.052969
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Article ; Online: Dendritic Cells Treated with Exogenous Indoleamine 2,3-Dioxygenase Maintain an Immature Phenotype and Suppress Antigen-specific T cell Proliferation.

Bracho-Sanchez, Evelyn / Hassanzadeh, Azadeh / Brusko, Maigan A / Wallet, Mark A / Keselowsky, Benjamin G

Journal of immunology and regenerative medicine

2019 Volume 5

Abstract: Indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme responsible for catalyzing the rate limiting step of tryptophan catabolism, plays a critical role in immune cell suppression and tolerance. Indoleamine 2,3-dioxygenase-mediated depletion of the ... ...

Abstract	Indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme responsible for catalyzing the rate limiting step of tryptophan catabolism, plays a critical role in immune cell suppression and tolerance. Indoleamine 2,3-dioxygenase-mediated depletion of the essential amino acid tryptophan increases susceptibility of T cells to apoptosis, while kynurenine and its downstream metabolites, such as 3-hydroxyanthranilic acid and quinolinic acid, have a direct cytotoxic effect on conventional effector T cells. Additionally, IDO-expressing antigen presenting cells (APCs) induce proliferation of regulatory T cells. When expressed by an APC, the immunosuppressive effects of IDO may act directly on the APC as well as indirectly upon local T cells. One approach to elicit immune tolerance or reduce inflammation therefore is to promote expression of IDO. However, this approach is constrained by several factors including the potential for deleterious biologic effects of conventional IDO-inducing agents such as interferon gamma (IFNγ), and the potential limitations of constitutive gene transfection. Alternatively, direct action of recombinant IDO enzyme supplied exogenously as a potential therapeutic in the extracellular space has not been investigated previously, and is the focus of this work. Results indicate exogenous recombinant human IDO supplementation influences murine dendritic cell (DC) maturation and ability to suppress antigen specific T cell proliferation. Following treatment, DCs were refractory to maturation by LPS as defined by co-stimulatory molecule expression (CD80 and CD86) and major histocompatibility complex II (MHC-II) expression. Dendritic cells exhibited skewing toward an anti-inflammatory cytokine release profile, with reduced secretion of IL-12p70 and maintained basal level of secreted IL-10. Notably, IDO-treated DCs suppressed proliferation of ovalbumin (OVA) antigen-specific CD4
Language	English
Publishing date	2019-02-10
Publishing country	Netherlands
Document type	Journal Article
ISSN	2468-4988
ISSN (online)	2468-4988
DOI	10.1016/j.regen.2019.100015
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Article: Isogenic Cellular Systems Model the Impact of Genetic Risk Variants in the Pathogenesis of Type 1 Diabetes.

Wallet, Mark A / Santostefano, Katherine E / Terada, Naohiro / Brusko, Todd M

Frontiers in endocrinology

2017 Volume 8, Page(s) 276

Abstract: At least 57 independent loci within the human genome confer varying degrees of risk for the development of type 1 diabetes (T1D). The majority of these variants are thought to contribute to overall genetic risk by modulating host innate and adaptive ... ...

Abstract	At least 57 independent loci within the human genome confer varying degrees of risk for the development of type 1 diabetes (T1D). The majority of these variants are thought to contribute to overall genetic risk by modulating host innate and adaptive immune responses, ultimately resulting in a loss of immunological tolerance to β cell antigens. Early efforts to link specific risk variants with functional alterations in host immune responses have employed animal models or genotype-selected individuals from clinical bioresource banks. While some notable genotype:phenotype associations have been described, there remains an urgent need to accelerate the discovery of causal variants and elucidate the molecular mechanisms by which susceptible alleles alter immune functions. One significant limitation has been the inability to study human T1D risk loci on an isogenic background. The advent of induced pluripotent stem cells (iPSCs) and genome-editing technologies have made it possible to address a number of these outstanding questions. Specifically, the ability to drive multiple cell fates from iPSC under isogenic conditions now facilitates the analysis of causal variants in multiple cellular lineages. Bioinformatic analyses have revealed that T1D risk genes cluster within a limited number of immune signaling pathways, yet the relevant immune cell subsets and cellular activation states in which candidate risk genes impact cellular activities remain largely unknown. In this review, we summarize the functional impact of several candidate risk variants on host immunity in T1D and present an isogenic disease-in-a-dish model system for interrogating risk variants, with the goal of expediting precision therapeutics in T1D.
Language	English
Publishing date	2017-10-18
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2017.00276
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Article ; Online: Politique publique et développement des chaînes alimentaires courtes de proximité

Fredéric Wallet / Melise Dantas Machado Bouroullec

Développement Durable et Territoires, Vol

une analyse des PDR de la Région Occitanie

2021 Volume 12

Abstract: ... but more marked in Languedoc-Roussillon. The contours of the future CAP (decrease in the budget, transition ...

Abstract	This article analyzes the place of short local chains (SLC) in rural development policy (RDP) in Occitanie Region. We identify measures related to SLCs through a textual analysis of the Midi-Pyrenees and Languedoc-Roussillon 2014-2020 PDRs and their respective calls for projects. The results underline a timid support but more marked in Languedoc-Roussillon. The contours of the future CAP (decrease in the budget, transition to a single national strategic plan, etc.) will condition the autonomy left to the Regions to define support measures for SLCs adapted to local requirements. In addition to support for physical investments, installation and cooperation, training and networking of actors in the territory should be supported.
Keywords	rural development policy ; short local chains ; proximity ; CAP ; Occitanie ; public support ; Environmental sciences ; GE1-350 ; Social Sciences ; H
Language	French
Publishing date	2021-05-01T00:00:00Z
Publisher	Réseau Développement Durable et Territoires Fragiles
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: CRISPR/Cas9 knockout of USP18 enhances type I IFN responsiveness and restricts HIV-1 infection in macrophages.

Taylor, Jared P / Cash, Melanie N / Santostefano, Katherine E / Nakanishi, Mahito / Terada, Naohiro / Wallet, Mark A

Journal of leukocyte biology

2018

Abstract: The IFN-stimulated gene ubiquitin-specific proteinase 18 (USP18) encodes a protein that negatively regulates T1 IFN signaling via stearic inhibition of JAK1 recruitment to the IFN-α receptor 2 subunit (IFNAR2). Here, we demonstrate that USP18 expression ... ...

Abstract	The IFN-stimulated gene ubiquitin-specific proteinase 18 (USP18) encodes a protein that negatively regulates T1 IFN signaling via stearic inhibition of JAK1 recruitment to the IFN-α receptor 2 subunit (IFNAR2). Here, we demonstrate that USP18 expression is induced by HIV-1 in a T1 IFN-dependent manner. Experimental depletion of USP18 by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene editing results in a significant restriction of HIV-1 replication in an induced pluripotent stem cell (iPSC)-derived macrophage model. In the absence of USP18, macrophages have increased responsiveness to stimulation with T1 IFNs with prolonged phosphorylation of STAT1 and STAT2 and increased expression of IFN-stimulated genes that are key for antiviral responses. Interestingly, HIV-1 requires some signaling through the T1 IFN receptor to replicate efficiently because a neutralizing antibody that inhibits T1 IFN activity reduces HIV-1 replication rate in monocyte-derived macrophages. USP18 induction by HIV-1 tunes the IFN response to optimal levels allowing for efficient transcription from the HIV-1 LTR promoter while minimizing the T1 IFN-induced antiviral response that would otherwise restrict viral replication and spread. Finally, iPSC and CRISPR/Cas9 gene targeting offer a powerful tool to study host factors that regulate innate immune responses.
Keywords	covid19
Language	English
Publishing date	2018-02-13
Publishing country	England
Document type	Journal Article
ZDB-ID	605722-6
ISSN	1938-3673 ; 0741-5400
ISSN (online)	1938-3673
ISSN	0741-5400
DOI	10.1002/JLB.3MIA0917-352R
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Zs.A 603: Show issues

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Article ; Online: Neutrophil Cytosolic Factor 1 in Dendritic Cells Promotes Autoreactive CD8

Liu, Chao / Whitener, Robert L / Lin, Andrea / Xu, Yuan / Chen, Jing / Savinov, Alexei / Leiding, Jennifer W / Wallet, Mark A / Mathews, Clayton E

Frontiers in immunology

2019 Volume 10, Page(s) 952

Abstract: Aims: ...

Abstract	Aims:
MeSH term(s)	Animals ; Autoimmunity/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cross-Priming/immunology ; Dendritic Cells/immunology ; Diabetes Mellitus, Type 1/immunology ; Lymphocyte Activation/immunology ; Mice ; Mice, Inbred NOD ; Mice, Mutant Strains ; NADPH Oxidases/immunology
Chemical Substances	NADPH Oxidases (EC 1.6.3.-) ; neutrophil cytosolic factor 1 (EC 1.6.3.1)
Language	English
Publishing date	2019-05-01
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2019.00952
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