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Article ; Online: Conditioning of the immune system by the microbiome.

Graham, Daniel B / Xavier, Ramnik J

2023 Volume 44, Issue 7, Page(s) 499–511

Abstract: The human intestinal microbiome has coevolved with its host to establish a stable homeostatic relationship with hallmark features of mutualistic symbioses, yet the mechanistic underpinnings of host-microbiome interactions are incompletely understood. ... ...

Abstract	The human intestinal microbiome has coevolved with its host to establish a stable homeostatic relationship with hallmark features of mutualistic symbioses, yet the mechanistic underpinnings of host-microbiome interactions are incompletely understood. Thus, it is an opportune time to conceive a common framework for microbiome-mediated regulation of immune function. We propose the term conditioned immunity to describe the multifaceted mechanisms by which the microbiome modulates immunity. In this regard, microbial colonization is a conditioning exposure that has durable effects on immune function through the action of secondary metabolites, foreign molecular patterns, and antigens. Here, we discuss how spatial niches impact host exposure to microbial products at the level of dose and timing, which elicit diverse conditioned responses.
MeSH term(s)	Humans ; Microbiota ; Intestines ; Gastrointestinal Microbiome ; Immune System ; Symbiosis
Language	English
Publishing date	2023-05-24
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2036831-8
ISSN	1471-4981 ; 1471-4906
ISSN (online)	1471-4981
ISSN	1471-4906
DOI	10.1016/j.it.2023.05.002
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Article ; Online: Turbulence in Magnetic Reconnection Jets from Injection to Sub-Ion Scales.

Richard, Louis / Sorriso-Valvo, Luca / Yordanova, Emiliya / Graham, Daniel B / Khotyaintsev, Yuri V

Physical review letters

2024 Volume 132, Issue 10, Page(s) 105201

Abstract: We investigate turbulence in magnetic reconnection jets in the Earth's magnetotail using data from the Magnetospheric Multiscale spacecraft. We show that signatures of a limited inertial range are observed in many reconnection jets. The observed ... ...

Abstract	We investigate turbulence in magnetic reconnection jets in the Earth's magnetotail using data from the Magnetospheric Multiscale spacecraft. We show that signatures of a limited inertial range are observed in many reconnection jets. The observed turbulence develops on the timescale of a few ion gyroperiods, resulting in intermittent multifractal energy cascade from the characteristic scale of the jet down to the ion scales. We show that at sub-ion scales, the fluctuations are close to monofractal and predominantly kinetic Alfvén waves. The observed energy transfer rate across the inertial range is ∼10^{8} J kg^{-1} s^{-1}, which is the largest reported for space plasmas so far.
Language	English
Publishing date	2024-03-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	208853-8
ISSN	1079-7114 ; 0031-9007
ISSN (online)	1079-7114
ISSN	0031-9007
DOI	10.1103/PhysRevLett.132.105201
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Article ; Online: Pathway paradigms revealed from the genetics of inflammatory bowel disease.

Graham, Daniel B / Xavier, Ramnik J

Nature

2020 Volume 578, Issue 7796, Page(s) 527–539

Abstract: Inflammatory bowel disease (IBD) is a complex genetic disease that is instigated and amplified by the confluence of multiple genetic and environmental variables that perturb the immune-microbiome axis. The challenge of dissecting pathological mechanisms ... ...

Abstract	Inflammatory bowel disease (IBD) is a complex genetic disease that is instigated and amplified by the confluence of multiple genetic and environmental variables that perturb the immune-microbiome axis. The challenge of dissecting pathological mechanisms underlying IBD has led to the development of transformative approaches in human genetics and functional genomics. Here we describe IBD as a model disease in the context of leveraging human genetics to dissect interactions in cellular and molecular pathways that regulate homeostasis of the mucosal immune system. Finally, we synthesize emerging insights from multiple experimental approaches into pathway paradigms and discuss future prospects for disease-subtype classification and therapeutic intervention.
MeSH term(s)	Animals ; Cytokines/immunology ; Exome/genetics ; Fibrosis/immunology ; Fibrosis/pathology ; Genetic Predisposition to Disease ; Homeostasis ; Humans ; Immunity, Cellular ; Immunity, Humoral ; Immunity, Innate ; Immunity, Mucosal/genetics ; Immunity, Mucosal/immunology ; Inflammation/immunology ; Inflammation/pathology ; Inflammatory Bowel Diseases/genetics ; Inflammatory Bowel Diseases/immunology ; Inflammatory Bowel Diseases/pathology ; Inflammatory Bowel Diseases/therapy ; Intestinal Mucosa/immunology ; Intestinal Mucosa/microbiology ; Single-Cell Analysis
Chemical Substances	Cytokines
Language	English
Publishing date	2020-02-26
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-020-2025-2
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Article ; Online: Fast Ion Isotropization by Current Sheet Scattering in Magnetic Reconnection Jets.

Richard, Louis / Khotyaintsev, Yuri V / Graham, Daniel B / Vaivads, Andris / Gershman, Daniel J / Russell, Christopher T

Physical review letters

2023 Volume 131, Issue 11, Page(s) 115201

Abstract: We present a statistical analysis of ion distributions in magnetic reconnection jets using data from the Magnetospheric Multiscale spacecraft. Compared with the quiet plasma in which the jet propagates, we often find anisotropic and non-Maxwellian ion ... ...

Abstract	We present a statistical analysis of ion distributions in magnetic reconnection jets using data from the Magnetospheric Multiscale spacecraft. Compared with the quiet plasma in which the jet propagates, we often find anisotropic and non-Maxwellian ion distributions in the plasma jets. We observe magnetic field fluctuations associated with unstable ion distributions, but the wave amplitudes are not large enough to scatter ions during the observed travel time of the jet. We estimate that the phase-space diffusion due to chaotic and quasiadiabatic ion motion in the current sheet is sufficiently fast to be the primary process leading to isotropization.
Language	English
Publishing date	2023-09-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	208853-8
ISSN	1079-7114 ; 0031-9007
ISSN (online)	1079-7114
ISSN	0031-9007
DOI	10.1103/PhysRevLett.131.115201
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Article ; Online: A Cardiolipin from

Bang, Sunghee / Shin, Yern-Hyerk / Ma, Xiao / Park, Sung-Moo / Graham, Daniel B / Xavier, Ramnik J / Clardy, Jon

Journal of the American Chemical Society

2023 Volume 145, Issue 43, Page(s) 23422–23426

Abstract: An systematic phenotypic screen of the mouse gut microbiome for metabolites with an immunomodulatory effect ... ...

Abstract	An systematic phenotypic screen of the mouse gut microbiome for metabolites with an immunomodulatory effect identified
MeSH term(s)	Animals ; Mice ; Cytokines ; Cardiolipins ; Toll-Like Receptor 6/metabolism ; Bacteroidetes ; Mammals/metabolism
Chemical Substances	Cytokines ; Cardiolipins ; Toll-Like Receptor 6
Language	English
Publishing date	2023-10-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.3c09734
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Article ; Online: Identification of host regulators of Mycobacterium tuberculosis phenotypes uncovers a role for the MMGT1-GPR156 lipid droplet axis in persistence.

Kalam, Haroon / Chou, Chih-Hung / Kadoki, Motohiko / Graham, Daniel B / Deguine, Jacques / Hung, Deborah T / Xavier, Ramnik J

Cell host & microbe

2023 Volume 31, Issue 6, Page(s) 978–992.e5

Abstract: The ability of Mycobacterium tuberculosis (Mtb) to establish latency affects disease and response to treatment. The host factors that influence the establishment of latency remain elusive. We engineered a multi-fluorescent Mtb strain that reports ... ...

Abstract	The ability of Mycobacterium tuberculosis (Mtb) to establish latency affects disease and response to treatment. The host factors that influence the establishment of latency remain elusive. We engineered a multi-fluorescent Mtb strain that reports survival, active replication, and stressed non-replication states and determined the host transcriptome of the infected macrophages in these states. Additionally, we conducted a genome-wide CRISPR screen to identify host factors that modulated the phenotypic state of Mtb. We validated hits in a phenotype-specific manner and prioritized membrane magnesium transporter 1 (MMGT1) for a detailed mechanistic investigation. Mtb infection of MMGT1-deficient macrophages promoted a switch to persistence, upregulated lipid metabolism genes, and accumulated lipid droplets during infection. Targeting triacylglycerol synthesis reduced both droplet formation and Mtb persistence. The orphan G protein-coupled receptor GPR156 is a key inducer of droplet accumulation in ΔMMGT1 cells. Our work uncovers the role of MMGT1-GPR156-lipid droplets in the induction of Mtb persistence.
MeSH term(s)	Mycobacterium tuberculosis/genetics ; Lipid Droplets/metabolism ; Macrophages/microbiology ; Lipid Metabolism
Language	English
Publishing date	2023-06-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2278004-X
ISSN	1934-6069 ; 1931-3128
ISSN (online)	1934-6069
ISSN	1931-3128
DOI	10.1016/j.chom.2023.05.009
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Book ; Online: On the applicability of single-spacecraft interferometry methods using electric field probes

Steinvall, Konrad / Khotyaintsev, Yuri V. / Graham, Daniel B.

2021

Abstract: When analyzing plasma waves, a key parameter to determine is the phase velocity. It enables us to, for example, compute wavelengths, wave potentials, and determine the energy of resonant particles. The phase velocity of a wave, observed by a single ... ...

Abstract	When analyzing plasma waves, a key parameter to determine is the phase velocity. It enables us to, for example, compute wavelengths, wave potentials, and determine the energy of resonant particles. The phase velocity of a wave, observed by a single spacecraft equipped with electric field probes, can be determined using interferometry techniques. While several methods have been developed to do this, they have not been documented in detail. In this study, we use an analytical model to analyze and compare three interferometry methods applied on the probe geometry of the Magnetospheric Multiscale spacecraft. One method relies on measured probe potentials, whereas the other two use different E-field measurements: one by reconstructing the E-field between two probes and the spacecraft, the other by constructing four pairwise parallel E-field components in the spacecraft spin-plane. We find that the potential method is sensitive both to how planar the wave is, and to spacecraft potential changes due to the wave. The E-field methods are less affected by the spacecraft potential, and while the reconstructed E-field method is applicable in some cases, the second E-field method is almost always preferable. We conclude that the potential based interferometry method is useful when spacecraft potential effects are negligible and the signals of the different probes are very well correlated. The method using two pairs of parallel E-fields is practically always preferable to the reconstructed E-field method and produces the correct velocity in the spin-plane, but it requires knowledge of the propagation direction to provide the full velocity. Comment: 35 pages, 9 figures, 1 table
Keywords	Physics - Space Physics
Subject code	621 ; 535
Publishing date	2021-11-19
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: SAC1 regulates autophagosomal phosphatidylinositol-4-phosphate for xenophagy-directed bacterial clearance.

Liu, Kai / Kong, Lingjia / Graham, Daniel B / Carey, Kimberly L / Xavier, Ramnik J

Cell reports

2021 Volume 36, Issue 4, Page(s) 109434

Abstract: Phosphoinositides are important molecules in lipid signaling, membrane identity, and trafficking that are spatiotemporally controlled by factors from both mammalian cells and intracellular pathogens. Here, using small interfering RNA (siRNA) directed ... ...

Abstract	Phosphoinositides are important molecules in lipid signaling, membrane identity, and trafficking that are spatiotemporally controlled by factors from both mammalian cells and intracellular pathogens. Here, using small interfering RNA (siRNA) directed against phosphoinositide kinases and phosphatases, we screen for regulators of the host innate defense response to intracellular bacterial replication. We identify SAC1, a transmembrane phosphoinositide phosphatase, as an essential regulator of xenophagy. Depletion or inactivation of SAC1 compromises fusion between Salmonella-containing autophagosomes and lysosomes, leading to increased bacterial replication. Mechanistically, the loss of SAC1 results in aberrant accumulation of phosphatidylinositol-4-phosphate [PI(4)P] on Salmonella-containing autophagosomes, thus facilitating recruitment of SteA, a PI(4)P-binding Salmonella effector protein, which impedes lysosomal fusion. Replication of Salmonella lacking SteA is suppressed by SAC-1-deficient cells, however, demonstrating bacterial adaptation to xenophagy. Our findings uncover a paradigm in which a host protein regulates the level of its substrate and impairs the function of a bacterial effector during xenophagy.
MeSH term(s)	Humans ; Autophagosomes/metabolism ; Bacterial Proteins/metabolism ; Cytosol/microbiology ; HEK293 Cells ; HeLa Cells ; Lipids/chemistry ; Lysosomes/metabolism ; Macroautophagy ; Phosphatidylinositol Phosphates/metabolism ; Phosphoinositide Phosphatases/metabolism ; Salmonella/growth & development ; Salmonella/metabolism
Chemical Substances	Bacterial Proteins ; Lipids ; phosphatidylinositol 4-phosphate ; Phosphatidylinositol Phosphates ; Phosphoinositide Phosphatases (EC 3.1.3.36) ; SACM1L protein, human (EC 3.1.3.64)
Language	English
Publishing date	2021-07-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2021.109434
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Article ; Online: Resources for the design of CRISPR gene editing experiments.

Graham, Daniel B / Root, David E

Genome biology

2015 Volume 16, Page(s) 260

Abstract: CRISPR-based approaches have quickly become a favored method to perturb genes to uncover their functions. Here, we review the key considerations in the design of genome editing experiments, and survey the tools and resources currently available to assist ...

Abstract	CRISPR-based approaches have quickly become a favored method to perturb genes to uncover their functions. Here, we review the key considerations in the design of genome editing experiments, and survey the tools and resources currently available to assist users of this technology.
MeSH term(s)	Bacterial Proteins/genetics ; CRISPR-Associated Protein 9 ; CRISPR-Cas Systems/genetics ; Endonucleases/genetics ; Escherichia coli/genetics ; Gene Expression Regulation ; Gene Targeting ; RNA Editing/genetics ; RNA, Guide, CRISPR-Cas Systems/genetics
Chemical Substances	Bacterial Proteins ; RNA, Guide, CRISPR-Cas Systems ; CRISPR-Associated Protein 9 (EC 3.1.-) ; Cas9 endonuclease Streptococcus pyogenes (EC 3.1.-) ; Endonucleases (EC 3.1.-)
Language	English
Publishing date	2015-11-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2040529-7
ISSN	1474-760X ; 1474-760X
ISSN (online)	1474-760X
ISSN	1474-760X
DOI	10.1186/s13059-015-0823-x
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Article ; Online: Therapeutic Opportunities in Inflammatory Bowel Disease: Mechanistic Dissection of Host-Microbiome Relationships.

Plichta, Damian R / Graham, Daniel B / Subramanian, Sathish / Xavier, Ramnik J

Cell

2019 Volume 178, Issue 5, Page(s) 1041–1056

Abstract: The current understanding of inflammatory bowel disease (IBD) pathogenesis implicates a complex interaction between host genetics, host immunity, microbiome, and environmental exposures. Mechanisms gleaned from genetics and molecular pathogenesis offer ... ...

Abstract	The current understanding of inflammatory bowel disease (IBD) pathogenesis implicates a complex interaction between host genetics, host immunity, microbiome, and environmental exposures. Mechanisms gleaned from genetics and molecular pathogenesis offer clues to the critical triggers of mucosal inflammation and guide the development of therapeutic interventions. A complex network of interactions between host genetic factors, microbes, and microbial metabolites governs intestinal homeostasis, making classification and mechanistic dissection of involved pathways challenging. In this Review, we discuss these challenges, areas of active translation, and opportunities for development of next-generation therapies.
MeSH term(s)	Adaptive Immunity ; Animals ; Bacteria/genetics ; Bacteria/metabolism ; Biological Products/pharmacology ; Cytokines/genetics ; Cytokines/metabolism ; Humans ; Inflammatory Bowel Diseases/genetics ; Inflammatory Bowel Diseases/microbiology ; Inflammatory Bowel Diseases/pathology ; Intestines/immunology ; Intestines/microbiology ; Microbiota/drug effects ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
Chemical Substances	Biological Products ; Cytokines
Language	English
Publishing date	2019-08-22
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2019.07.045
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