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Article ; Online: Author Correction: Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice.

Lee, Jiyeon / Dimitry, Julie M / Song, Jong Hee / Son, Minsoo / Sheehan, Patrick W / King, Melvin W / Travis Tabor, G / Goo, Young Ah / Lazar, Mitchell A / Petrucelli, Leonard / Musiek, Erik S

Nature communications

2023 Volume 14, Issue 1, Page(s) 7760

Language	English
Publishing date	2023-11-27
Publishing country	England
Document type	Published Erratum
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-43360-6
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice.

Lee, Jiyeon / Dimitry, Julie M / Song, Jong Hee / Son, Minsoo / Sheehan, Patrick W / King, Melvin W / Travis Tabor, G / Goo, Young Ah / Lazar, Mitchell A / Petrucelli, Leonard / Musiek, Erik S

Nature communications

2023 Volume 14, Issue 1, Page(s) 5197

Abstract: Alzheimer's disease, the most common age-related neurodegenerative disease, is characterized by tau aggregation and associated with disrupted circadian rhythms and dampened clock gene expression. REV-ERBα is a core circadian clock protein which also ... ...

Abstract	Alzheimer's disease, the most common age-related neurodegenerative disease, is characterized by tau aggregation and associated with disrupted circadian rhythms and dampened clock gene expression. REV-ERBα is a core circadian clock protein which also serves as a nuclear receptor and transcriptional repressor involved in lipid metabolism and macrophage function. Global REV-ERBα deletion has been shown to promote microglial activation and mitigate amyloid plaque formation. However, the cell-autonomous effects of microglial REV-ERBα in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia. These events impair microglial tau phagocytosis, which can be partially rescued by blockage of LD formation. In vivo, microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in two mouse tauopathy models, specifically in male mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.
MeSH term(s)	Animals ; Male ; Mice ; Disease Models, Animal ; Inflammation/genetics ; Lipid Droplets ; Microglia ; Neurodegenerative Diseases ; Tauopathies/genetics
Chemical Substances	Nr1d1 protein, mouse
Language	English
Publishing date	2023-08-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-40927-1
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Article ; Online: Author Correction

Jiyeon Lee / Julie M. Dimitry / Jong Hee Song / Minsoo Son / Patrick W. Sheehan / Melvin W. King / G. Travis Tabor / Young Ah Goo / Mitchell A. Lazar / Leonard Petrucelli / Erik S. Musiek

Nature Communications, Vol 14, Iss 1, Pp 1-

Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice

2023 Volume 2

Keywords	Science ; Q
Language	English
Publishing date	2023-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Primate conservation: A public issue?

Cosby, Alexandria E / Bertrand, Andriatsitohaina / Raquel, Archie / Cora, Jules / McGoogan, Keriann C / Maya, Persram / Mamy, Razafitsalama / Arayelle, Young / Steffens, Travis S

American journal of primatology

2024 , Page(s) e23632

Abstract: Nonhuman primates (primates) are one of the most endangered mammalian taxa in the world. In the Global North, primates are considered exotic species and, as such, humans' impact on primate conservation and responsibility to protect primates is often ... ...

Abstract	Nonhuman primates (primates) are one of the most endangered mammalian taxa in the world. In the Global North, primates are considered exotic species and, as such, humans' impact on primate conservation and responsibility to protect primates is often ignored. This view differs from the spectrum of relations and attitudes of humans that live in connection to primates, which can include viewing these animals as culturally/religiously significant, cohabitors of forests, nuisances, or sources of protein. While conservationists argue that primates deserve our protection, the conservation crisis facing primates is rarely framed as a public issue, in contrast to other global crises, such as climate change. However, over half of the world's human population lives within 100 km of primate habitat. Thus, humans and primates share the same environments. We suggest leveraging a holistic approach, such as One Health, that considers the interconnectedness of primates, humans, and their shared environments, through the lens of public anthropology. By approaching primate conservation as an intersectional issue that affects and is affected by humans, researchers and conservationists can identify strategies that simultaneously protect primates and address global inequities that frequently affect people in primate range countries. Reflexive research practices further allow academics to consider the broader impact of their ecological research through means such as publicly accessible dissemination of results, equitable capacity-building of high-quality personnel in primate range countries, and social activism. The use of inter-, multi-, and transdisciplinary concepts and methodology can address the intersectional challenges associated with implementing ethical and sustainable primate conservation measures.
Language	English
Publishing date	2024-04-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	1495834-X
ISSN	1098-2345 ; 0275-2565
ISSN (online)	1098-2345
ISSN	0275-2565
DOI	10.1002/ajp.23632
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Article ; Online: Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice

Jiyeon Lee / Julie M. Dimitry / Jong Hee Song / Minsoo Son / Patrick W. Sheehan / Melvin W. King / G. Travis Tabor / Young Ah Goo / Mitchell A. Lazar / Leonard Petrucelli / Erik S. Musiek

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 17

Abstract: Abstract Alzheimer’s disease, the most common age-related neurodegenerative disease, is ...

Abstract	Abstract Alzheimer’s disease, the most common age-related neurodegenerative disease, is characterized by tau aggregation and associated with disrupted circadian rhythms and dampened clock gene expression. REV-ERBα is a core circadian clock protein which also serves as a nuclear receptor and transcriptional repressor involved in lipid metabolism and macrophage function. Global REV-ERBα deletion has been shown to promote microglial activation and mitigate amyloid plaque formation. However, the cell-autonomous effects of microglial REV-ERBα in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia. These events impair microglial tau phagocytosis, which can be partially rescued by blockage of LD formation. In vivo, microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in two mouse tauopathy models, specifically in male mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.
Keywords	Science ; Q
Subject code	572
Language	English
Publishing date	2023-08-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: MR-guided stereotactic radiation therapy for head and neck cancers.

Wang, He / Yang, Jinzhong / Lee, Anna / Phan, Jack / Lim, Tze Yee / Fuller, Clifton D / Han, Eun Young / Rhee, Dong Joo / Salzillo, Travis / Zhao, Yao / Chopra, Nitish / Pham, Mary / Castillo, Pam / Sobremonte, Angela / Moreno, Amy C / Reddy, Jay P / Rosenthal, David / Garden, Adam S / Wang, Xin

Clinical and translational radiation oncology

2024 Volume 46, Page(s) 100760

Abstract: Purpose: MR-guided radiotherapy (MRgRT) has the advantage of utilizing high soft tissue contrast imaging to track daily changes in target and critical organs throughout the entire radiation treatment course. Head and neck (HN) stereotactic body ... ...

Abstract	Purpose: MR-guided radiotherapy (MRgRT) has the advantage of utilizing high soft tissue contrast imaging to track daily changes in target and critical organs throughout the entire radiation treatment course. Head and neck (HN) stereotactic body radiation therapy (SBRT) has been increasingly used to treat localized lesions within a shorter timeframe. The purpose of this study is to examine the dosimetric difference between the step-and-shot intensity modulated radiation therapy (IMRT) plans on Elekta Unity and our clinical volumetric modulated arc therapy (VMAT) plans on Varian TrueBeam for HN SBRT. Method: Fourteen patients treated on TrueBeam sTx with VMAT treatment plans were re-planned in the Monaco treatment planning system for Elekta Unity MR-Linac (MRL). The plan qualities, including target coverage, conformity, homogeneity, nearby critical organ doses, gradient index and low dose bath volume, were compared between VMAT and Monaco IMRT plans. Additionally, we evaluated the Unity adaptive plans of adapt-to-position (ATP) and adapt-to-shape (ATS) workflows using simulated setup errors for five patients and assessed the outcomes of our treated patients. Results: Monaco IMRT plans achieved comparable results to VMAT plans in terms of target coverage, uniformity and homogeneity, with slightly higher target maximum and mean doses. The critical organ doses in Monaco IMRT plans all met clinical goals; however, the mean doses and low dose bath volumes were higher than in VMAT plans. The adaptive plans demonstrated that the ATP workflow may result in degraded target coverage and OAR doses for HN SBRT, while the ATS workflow can maintain the plan quality. Conclusion: The use of Monaco treatment planning and online adaptation can achieve dosimetric results comparable to VMAT plans, with the additional benefits of real-time tracking of target volume and nearby critical structures. This offers the potential to treat aggressive and variable tumors in HN SBRT and improve local control and treatment toxicity.
Language	English
Publishing date	2024-03-07
Publishing country	Ireland
Document type	Journal Article
ISSN	2405-6308
ISSN (online)	2405-6308
DOI	10.1016/j.ctro.2024.100760
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Article ; Online: Frameshift mutations in peripheral blood as a biomarker for surveillance of lynch syndrome.

Journal of the National Cancer Institute

2024

Abstract: Background: Lynch syndrome (LS) is a hereditary cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes, which lead to high microsatellite instability (MSI-H) and frameshift mutations (FSMs) at coding ... ...

Abstract	Background: Lynch syndrome (LS) is a hereditary cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes, which lead to high microsatellite instability (MSI-H) and frameshift mutations (FSMs) at coding mononucleotide repeats (cMNRs) in the genome. Recurrent FSMs in these regions are thought to play a central role in the increased risk of various cancers. However, there are no biomarkers currently available for the surveillance of MSI-H-associated cancers. Methods: An FSM-based biomarker panel was developed and validated by targeted next generation sequencing of supernatant DNA from cultured MSI-H colorectal cancer cells. This supported selection of 122-FSM targets as potential biomarkers. This biomarker panel was then tested using matched tumor, adjacent normal tissue, and buffy coat (53 samples), and blood-derived cell-free DNA (cfDNA; 38 samples) obtained from 45 cases of MSI-H/MMR deficient (MMRd) patients/carriers. cfDNA from 84 healthy individuals was also sequenced to assess background noise. Results: Recurrent FSMs at cMNRs were detectable not only in tumors, but also in cfDNA from MSI-H/MMRd cases including a LS carrier with a varying range of target detection (up to 85.2%), whereas they were virtually undetectable in healthy individuals. ROC analysis showed high sensitivity and specificity (AUC = 0.94) of the investigated panel. Conclusions: We demonstrated that FSMs can be detected in cfDNA from MSI-H/MMRd cases and asymptomatic carriers. The 122-target FSM panel described here has promise as a tool for improved surveillance of MSI-H/MMRd carriers with the potential to reduce the frequency of invasive screening methods for this high-cancer-risk cohort.
Language	English
Publishing date	2024-03-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	2992-0
ISSN	1460-2105 ; 0027-8874 ; 0198-0157
ISSN (online)	1460-2105
ISSN	0027-8874 ; 0198-0157
DOI	10.1093/jnci/djae060
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Article ; Online: Human CD19-specific switchable CAR T-cells are efficacious as constitutively active CAR T-cells but cause less morbidity in a mouse model of human CD19

Pennell, Christopher A / Campbell, Heather / Storlie, Meghan D / Bolivar-Wagers, Sara / Osborn, Mark J / Refaeli, Yosef / Jensen, Michael / Viaud, Sophie / Young, Travis S / Blazar, Bruce R

Journal for immunotherapy of cancer

2022 Volume 10, Issue 12

Abstract: Current Food and Drug Administration (FDA)-approved CD19-specific chimeric antigen receptor (CAR) T-cell therapies for B-cell malignancies are constitutively active and while efficacious, can cause morbidity and mortality. Their toxicities might be ... ...

Abstract	Current Food and Drug Administration (FDA)-approved CD19-specific chimeric antigen receptor (CAR) T-cell therapies for B-cell malignancies are constitutively active and while efficacious, can cause morbidity and mortality. Their toxicities might be reduced if CAR T-cell activity was regulatable rather than constitutive. To test this, we compared the efficacies and morbidities of constitutively active (conventional) and regulatable (switchable) CAR (sCAR) T-cells specific for human CD19 (huCD19) in an immune-competent huCD19
MeSH term(s)	United States ; Humans ; Mice ; Animals ; Mice, Inbred C57BL ; Antigens, CD19 ; T-Lymphocytes ; Lymphoma, B-Cell/therapy ; Disease Models, Animal ; Mice, Transgenic ; Morbidity ; Weight Loss
Chemical Substances	CD19-specific chimeric antigen receptor ; Antigens, CD19
Language	English
Publishing date	2022-12-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2022-005934
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Article ; Online: The bicipital groove as a landmark for humeral version reference during shoulder arthroplasty: a computed tomography study of normal humeral rotation.

Dacombe, Peter J / Young, Daniel J / Moulton, Lawrence S / Prentice, Matthew G / Falconer, Travis M / Spencer, Jonathan M F

Journal of shoulder and elbow surgery

2021 Volume 30, Issue 10, Page(s) e613–e620

Abstract: Background: Accurate reproduction of humeral version is important in shoulder arthroplasty. Traditional referencing relative to the transepicondylar axis (TEA) is prone to error as it is absent on preoperative imaging and inaccurately reproduced ... ...

Abstract	Background: Accurate reproduction of humeral version is important in shoulder arthroplasty. Traditional referencing relative to the transepicondylar axis (TEA) is prone to error as it is absent on preoperative imaging and inaccurately reproduced intraoperatively. The bicipital groove is present on preoperative imaging and in the operative field and thus may be a useful landmark for accurate reproduction of humeral version. Materials and methods: Two trained observers analyzed 101 full-humerus computed tomography scans of patients undergoing a myeloma screening protocol. Measurements of humeral retroversion relative to the TEA (angle A), humeral articular axis retroversion relative to the bicipital groove (angle B), and the bicipital groove axis relative to the TEA (angle C) were made with comparison of the measurement properties of each. Results: Humeral retroversion relative to the TEA was 23.7° ± 8° (range, 0.2°-48.7°; 95% confidence interval, 22°-26°). The humeral articular axis was retroverted to the bicipital groove axis (angle B) by 33.5° ± 9.4° (range, 15.5°-61.7°; 95% confidence interval, 32°-35°). Overall inter-rater reliability was 0.88. Discussion: Measurement of humeral head retroversion relative to the bicipital groove is not inferior to the gold-standard measurement. The bicipital groove is present both on preoperative imaging and in the operative field, making it a potential reference landmark for accurate reproduction of humeral version in shoulder arthroplasty.
Language	English
Publishing date	2021-03-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	1170782-3
ISSN	1532-6500 ; 1058-2746
ISSN (online)	1532-6500
ISSN	1058-2746
DOI	10.1016/j.jse.2021.02.006
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Article ; Online: JAML promotes CD8 and γδ T cell antitumor immunity and is a novel target for cancer immunotherapy.

McGraw, Joseph M / Thelen, Flavian / Hampton, Eric N / Bruno, Nelson E / Young, Travis S / Havran, Wendy L / Witherden, Deborah A

The Journal of experimental medicine

2021 Volume 218, Issue 10

Abstract: T cells are critical mediators of antitumor immunity and a major target for cancer immunotherapy. Antibody blockade of inhibitory receptors such as PD-1 can partially restore the activity of tumor-infiltrating lymphocytes (TILs). However, the activation ... ...

Abstract	T cells are critical mediators of antitumor immunity and a major target for cancer immunotherapy. Antibody blockade of inhibitory receptors such as PD-1 can partially restore the activity of tumor-infiltrating lymphocytes (TILs). However, the activation signals required to promote TIL responses are less well characterized. Here we show that the antitumor activity of CD8 and γδ TIL is supported by interactions between junctional adhesion molecule-like protein (JAML) on T cells and its ligand coxsackie and adenovirus receptor (CXADR) within tumor tissue. Loss of JAML through knockout in mice resulted in accelerated tumor growth that was associated with an impaired γδ TIL response and increased CD8 TIL dysfunction. In mouse tumor models, therapeutic treatment with an agonistic anti-JAML antibody inhibited tumor growth, improved γδ TIL activation, decreased markers of CD8 TIL dysfunction, and significantly improved response to anti-PD-1 checkpoint blockade. Thus, JAML represents a novel therapeutic target to enhance both CD8 and γδ TIL immunity.
MeSH term(s)	Animals ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/pathology ; Cell Adhesion Molecules/genetics ; Cell Adhesion Molecules/immunology ; Coxsackie and Adenovirus Receptor-Like Membrane Protein/genetics ; Coxsackie and Adenovirus Receptor-Like Membrane Protein/metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Immune Checkpoint Inhibitors/pharmacology ; Immunotherapy/methods ; Melanoma/genetics ; Melanoma/mortality ; Melanoma/pathology ; Melanoma, Experimental/genetics ; Melanoma, Experimental/pathology ; Mice, Inbred C57BL ; Mice, Knockout ; Neoplasms/genetics ; Neoplasms/mortality ; Receptors, Antigen, T-Cell, gamma-delta/immunology ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/pathology ; Mice
Chemical Substances	CLMP protein, mouse ; Cell Adhesion Molecules ; Coxsackie and Adenovirus Receptor-Like Membrane Protein ; Immune Checkpoint Inhibitors ; JAML protein, human ; JAML protein, mouse ; Receptors, Antigen, T-Cell, gamma-delta
Language	English
Publishing date	2021-08-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20202644
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