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Article ; Online: The TCR Cα Domain Regulates Responses to Self-pMHC Class II.

Kim, Caleb Y / Parrish, Heather L / Kuhns, Michael S

Journal of immunology (Baltimore, Md. : 1950)

2022 Volume 209, Issue 10, Page(s) 2033–2041

Abstract: T cells play a central role in adaptive immunity by recognizing peptide Ags presented by MHC molecules (pMHC) via their clonotypic TCRs. αβTCRs are heterodimers, consisting of TCRα and TCRβ subunits that are composed of variable (Vα, Vβ) and constant (Cα, ...

Abstract	T cells play a central role in adaptive immunity by recognizing peptide Ags presented by MHC molecules (pMHC) via their clonotypic TCRs. αβTCRs are heterodimers, consisting of TCRα and TCRβ subunits that are composed of variable (Vα, Vβ) and constant (Cα, Cβ) domains. Whereas the Vα, Vβ, and Cβ domains adopt typical Ig folds in the extracellular space, the Cα domain lacks a top β sheet and instead has two loosely associated top strands (C- and F-strands) on its surface. Previous results suggest that this unique Ig-like fold mediates homotypic TCR interactions and influences signaling in vitro. To better understand why evolution has selected this unique structure, we asked, what is the fitness cost for development and function of mouse CD4+ T cells bearing a mutation in the Cα C-strand? In both TCR retrogenic and transgenic mice we observed increased single-positive thymocytes bearing mutant TCRs compared with those expressing wild-type TCRs. Furthermore, our analysis of mutant TCR transgenic mice revealed an increase in naive CD4+ T cells experiencing strong tonic TCR signals, increased homeostatic survival, and increased recruitment of responders to cognate pMHC class II upon immunization compared with the wild-type. The mutation did not, however, overtly impact CD4+ T cell proliferation or differentiation after immunization. We interpret these data as evidence that the unique Cα domain has evolved to fine-tune TCR signaling, particularly in response to weak interactions with self-pMHC class II.
MeSH term(s)	Animals ; Mice ; Receptors, Antigen, T-Cell ; Cell Membrane ; DNA Repair ; Thymocytes ; Mice, Transgenic
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2022-11-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2200377
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Article ; Online: The CD4 transmembrane GGXXG and juxtamembrane (C/F)CV+C motifs mediate pMHCII-specific signaling independently of CD4-LCK interactions.

Lee, Mark S / Tuohy, Peter J / Kim, Caleb Y / Yost, Philip P / Lichauco, Katrina / Parrish, Heather L / Van Doorslaer, Koenraad / Kuhns, Michael S

eLife

2024 Volume 12

Abstract: ... ...

Abstract	CD4
MeSH term(s)	Pregnancy ; Animals ; Female ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/genetics ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism ; Placenta/metabolism ; Signal Transduction/genetics ; Receptors, Antigen, T-Cell/metabolism ; Receptor-CD3 Complex, Antigen, T-Cell/metabolism ; Phosphorylation ; CD4 Antigens ; Mammals/metabolism
Chemical Substances	Lymphocyte Specific Protein Tyrosine Kinase p56(lck) (EC 2.7.10.2) ; Receptors, Antigen, T-Cell ; Receptor-CD3 Complex, Antigen, T-Cell ; CD4 Antigens
Language	English
Publishing date	2024-04-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.88225
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Article ; Online: Bedaquiline, pretomanid and linezolid in multidrug-resistant and pre-extensively drug-resistant tuberculosis in refugees from Ukraine and Somalia in Germany.

Trauth, Janina / Kantelhardt, Vera / Usenko, Bohdan / Knipper, Michael / Kuhns, Martin / Friesen, Inna / Herold, Susanne

The European respiratory journal

2024 Volume 63, Issue 5

MeSH term(s)	Humans ; Linezolid/therapeutic use ; Refugees/statistics & numerical data ; Antitubercular Agents/therapeutic use ; Diarylquinolines/therapeutic use ; Germany ; Tuberculosis, Multidrug-Resistant/drug therapy ; Tuberculosis, Multidrug-Resistant/epidemiology ; Somalia ; Male ; Ukraine/epidemiology ; Female ; Adult ; Extensively Drug-Resistant Tuberculosis/drug therapy ; Oxazolidinones/therapeutic use ; Middle Aged ; Nitroimidazoles ; Oxazoles
Chemical Substances	Linezolid (ISQ9I6J12J) ; Antitubercular Agents ; bedaquiline (78846I289Y) ; Diarylquinolines ; OPC-67683 ; Oxazolidinones ; Nitroimidazoles ; Oxazoles
Language	English
Publishing date	2024-05-02
Publishing country	England
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	639359-7
ISSN	1399-3003 ; 0903-1936
ISSN (online)	1399-3003
ISSN	0903-1936
DOI	10.1183/13993003.00303-2024
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Zs.A 2322: 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)
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Article: The CD4 transmembrane GGXXG and juxtamembrane (C/F)CV+C motifs mediate pMHCII-specific signaling independently of CD4-LCK interactions.

Lee, Mark S / Tuohy, Peter J / Kim, Caleb Y / Yost, Philip / Lichauco, Katrina / Parrish, Heather L / Van Doorslaer, Koenraad / Kuhns, Michael S

bioRxiv : the preprint server for biology

2023

Abstract: ... ...

Abstract	CD4
Language	English
Publishing date	2023-11-29
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.05.05.539613
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Article: Evaluating the Morphology of Unique Superficial Fissured Cartilage Lesions at the Femoral Head-Neck Junction in Patients with Femoroacetabular Impingement Syndrome.

Yamaura, Kohei / Nishimura, Haruki / Ruzbarsky, Joseph J / Kuhns, Benjamin D / Mullen, Michael T / Duke, Victoria R / O'Hara, Kelsey M / Brown, Jarrod M / Comfort, Spencer M / Hambright, William S / Bahney, Chelsea S / Huard, Johnny / Philippon, Marc J

Orthopaedic journal of sports medicine

2024 Volume 12, Issue 2, Page(s) 23259671231219217

Abstract: Background: While an association between femoroacetabular impingement (FAI) and osteoarthritis (OA) has been reported, the mechanistic differences and transition between the 2 conditions is not fully understood. In FAI, cartilage lesions at the femoral ... ...

Abstract	Background: While an association between femoroacetabular impingement (FAI) and osteoarthritis (OA) has been reported, the mechanistic differences and transition between the 2 conditions is not fully understood. In FAI, cartilage lesions at the femoral head-neck junction can sometimes be visualized during hip arthroscopy. Purpose/hypothesis: The purpose of this study was to describe a unique dimpled pattern of superficial fissured cartilage lesions on the femoral head-neck junction at impingement site in patients with FAI syndrome (FAIS) and to evaluate the clinical, histological, and genetic phenotype of this cartilage. We hypothesized that the cartilage lesions may indicate risk for, or predict occurrence of, OA. Study design: Controlled laboratory study. Methods: Six hips (6 patients; mean age, 34.2 ± 12.9 years; range, 19-54 years) with dimpled or fissured cartilage were included among patients who underwent hip arthroscopy for treatment of FAIS from October 2020 through December 2021. This affected cartilage (dimple-pattern group) and normal cartilage (control group) on the femoral head-neck junction were collected from the same patients and evaluated for histological quantification by Mankin scores and expression of proteins related to cartilage degeneration (eg, matrix metalloproteinase [MMP]-1, MMP-2, MMP-3, MMP-10, and MMP-12, tissue inhibitor of metalloproteinase [TIMP]-1 and TMP-2, aggrecan neopepitope CS846, and hyaluronic acid [HA]) with the use of Milliplex Multiplex Assays. Results: All 6 hips were of the mixed FAI subtype. Preoperatively, 4 of 6 hips had Tönnis grade 1 radiographic changes, which was associated with greater femoral head chondral damage visualized intraoperatively. Mankin scores for the normal cartilage group and the dimple-pattern group were 0.67 ± 0.82 and 3.3 ± 0.82, respectively. Dimple pattern fissured cartilage showed a significant increase in Mankin score ( Conclusion: The dimple pattern fissured cartilage, compared to normal cartilage, showed histologically significant cartilage degeneration and a significant increase in protein expression of CS846, a biomarker for early OA. Clinical relevance: This lesion serves as helpful visual indicator of early degeneration of the cartilage of femoral head-neck junction caused by FAIS.
Language	English
Publishing date	2024-02-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2706251-X
ISSN	2325-9671
ISSN	2325-9671
DOI	10.1177/23259671231219217
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Article ; Online: Enhancing and inhibitory motifs regulate CD4 activity.

Lee, Mark S / Tuohy, Peter J / Kim, Caleb Y / Lichauco, Katrina / Parrish, Heather L / Van Doorslaer, Koenraad / Kuhns, Michael S

eLife

2022 Volume 11

Abstract: ... ...

Abstract	CD4
MeSH term(s)	Animals ; CD3 Complex/metabolism ; CD4 Antigens/genetics ; CD4 Antigens/metabolism ; Histocompatibility Antigens Class II/genetics ; Histocompatibility Antigens Class II/metabolism ; Lymphocyte Activation ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/genetics ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism ; Receptor-CD3 Complex, Antigen, T-Cell/metabolism ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; src-Family Kinases/metabolism
Chemical Substances	CD3 Complex ; CD4 Antigens ; Histocompatibility Antigens Class II ; Receptor-CD3 Complex, Antigen, T-Cell ; Receptors, Antigen, T-Cell ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) (EC 2.7.10.2) ; src-Family Kinases (EC 2.7.10.2)
Language	English
Publishing date	2022-07-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.79508
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Article: Analytical and Functional Similarity of Aflibercept Biosimilar ABP 938 with Aflibercept Reference Product.

Seo, Neungseon / Guan, Xiaoyan / Wang, Tian / Chung, Hyo S Helen / Wikström, Mats / Padaki, Rupa / Kalenian, Kevin / Kuhns, Scott / Matthies, Kelli / Crouse-Zeineddini, Jill / Wong, Helen Y / Ng, Michael / Foltz, Ian N / Cao, Shawn / Liu, Jennifer

Ophthalmology and therapy

2024 Volume 13, Issue 5, Page(s) 1303–1320

Abstract: Introduction: ABP 938 is being developed as a biosimilar candidate to aflibercept reference product (RP), a biologic used for certain angiogenic eye disorders. This study was designed to provide a comparative analytical assessment of the structural and ... ...

Abstract	Introduction: ABP 938 is being developed as a biosimilar candidate to aflibercept reference product (RP), a biologic used for certain angiogenic eye disorders. This study was designed to provide a comparative analytical assessment of the structural and functional attributes of ABP 938 and aflibercept RP sourced from the United States (US) and the European Union (EU). Methods: Structural and functional characterization studies were performed using state-of-the-art analytical techniques that were appropriate to assess relevant quality attributes and capable of detecting qualitative and quantitative differences in primary structure, higher-order structure and biophysical properties, product-related substances and impurities, general properties, and biological activities. Results: ABP 938 had the same amino acid sequence and exhibited similar secondary and tertiary structures, and biological activity as aflibercept RP. There were minor differences in a small number of biochemical attributes which are not expected to impact clinical performance. In addition, aflibercept RP sourced from the US and EU were analytically similar. Conclusions: ABP 938 was structurally and functionally similar to aflibercept RP. Since aflibercept RP sourced from the US and EU were analytically similar, this allows for the development of a scientific bridge such that a single-source RP can be used in nonclinical and clinical studies.
Language	English
Publishing date	2024-03-20
Publishing country	England
Document type	Journal Article
ISSN	2193-8245
ISSN	2193-8245
DOI	10.1007/s40123-024-00914-1
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Article ; Online: Bonds Voyage! A Dissociative Model of TCR-CD3 Triggering Is Proposed.

Lichauco, Katrina / Lee, Mark S / Kuhns, Michael S

Immunity

2018 Volume 49, Issue 5, Page(s) 786–788

Abstract: How the T cell receptor (TCR)-CD3 complex activates T cells is debated. In this issue of Immunity, Brazin et al. (2018) propose that TCR engagement under force releases the CD3 signaling modules to disperse and adopt signaling active states. ...

Abstract	How the T cell receptor (TCR)-CD3 complex activates T cells is debated. In this issue of Immunity, Brazin et al. (2018) propose that TCR engagement under force releases the CD3 signaling modules to disperse and adopt signaling active states.
MeSH term(s)	Receptor-CD3 Complex, Antigen, T-Cell ; Receptors, Antigen, T-Cell ; Receptors, Antigen, T-Cell, alpha-beta ; Signal Transduction ; T-Lymphocytes
Chemical Substances	Receptor-CD3 Complex, Antigen, T-Cell ; Receptors, Antigen, T-Cell ; Receptors, Antigen, T-Cell, alpha-beta
Language	English
Publishing date	2018-11-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Comment
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2018.11.008
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Article ; Online: Academic Orthopaedics As a Driver of Gender Diversity in the Orthopaedic Workforce: A Review of 4,519 Orthopaedic Faculty Members.

Kuhns, Benjamin / Haws, Brittany E / Kaupp, Shannon / Maloney, Michael D / Carmody, Emily E / Mannava, Sandeep

Journal of the American Academy of Orthopaedic Surgeons. Global research & reviews

2022 Volume 6, Issue 2

Abstract: Background: The purpose of this study was to perform a cross-sectional analysis on the gender composition of practicing academic orthopaedic surgeons using three databases composed of clinical orthopaedic surgeons.: Methods: A comprehensive database ... ...

Abstract	Background: The purpose of this study was to perform a cross-sectional analysis on the gender composition of practicing academic orthopaedic surgeons using three databases composed of clinical orthopaedic surgeons. Methods: A comprehensive database of 4,519 clinically active academic orthopaedic surgeons was compiled for this study after the review of publicly available data. The complied data set was evaluated alongside orthopaedic databases obtained from the 2017 Association of American Medical Colleges (AAMC) Faculty Administrative Management Online User System and the 2016 American Academy of Orthopaedic Surgery (AAOS) Orthopaedic Practice in the US census representing the entire academy membership orthopaedic workforce. Gender status was obtained and compared between the three databases. Results: Of the 4,519 clinically active academic orthopaedic surgeons analyzed, 435 (10%) were female compared with 19% for the AAMC faculty database and 7% for the AAOS members. Fourteen percent of women had achieved the rank of professor compared with 25% of the men (P < 0.001). AAMC faculty had a significantly higher percentages of female representation compared with both the clinical faculty (19% versus 10%; P < 0.001) and AAOS members (19% versus 7%; P < 0.001). Conclusion: Despite multiple initiatives designed to increase diversity, the 7% female representation in the orthopaedic workforce identified in this study remains markedly lower than other medical and surgical specialties. A higher percentage of women were associated with the AAMC orthopaedic faculty compared with clinically active female surgeons at these institutions. Academic orthopaedic surgeons had greater female representation than the general orthopaedic workforce, highlighting the importance of training institutions at promoting gender equity.
MeSH term(s)	Cross-Sectional Studies ; Faculty, Medical ; Female ; Humans ; Male ; Orthopedic Procedures ; Orthopedics ; Physicians, Women ; United States ; Workforce
Language	English
Publishing date	2022-02-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2898328-2
ISSN	2474-7661 ; 1067-151X
ISSN (online)	2474-7661
ISSN	1067-151X
DOI	10.5435/JAAOSGlobal-D-21-00028
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Article: Impact of Sports Participation on Achievement of Clinically Relevant Outcomes 2 Years After ACL Reconstruction.

Kuhns, Benjamin D / Sholtis, Connor D / Reuter, John M / Goldblatt, John / Bronstein, Robert / Baumhauer, Judith F / Maloney, Michael D / Mannava, Sandeep

Orthopaedic journal of sports medicine

2023 Volume 11, Issue 8, Page(s) 23259671231187327

Abstract: Background: Clinically relevant threshold values associated with patient-reported outcome measures after orthopaedic procedures such as anterior cruciate ligament reconstruction (ACLR) are important for relating these scores to meaningful postoperative ... ...

Abstract	Background: Clinically relevant threshold values associated with patient-reported outcome measures after orthopaedic procedures such as anterior cruciate ligament reconstruction (ACLR) are important for relating these scores to meaningful postoperative improvement. Purpose/hypothesis: The purpose of this study was to determine the Patient Acceptable Symptom State (PASS) for the Patient-Reported Outcomes Measurement Information System Computer Adaptive Test (PROMIS-CAT) after ACLR. It was hypothesized that preoperative sport participation would have an impact on PASS achievement. Study design: Case series; Level of evidence, 4. Methods: Included were consecutive patients who underwent primary assisted ACLR between January 4 and August 1, 2016. Patients were administered the PROMIS-CAT Physical Function (PF) and Pain Interference domains preoperatively and at a minimum 2 years postoperatively, with external anchor questions used to determine the PASS. Receiver operating characteristic (ROC) curves were constructed for the entire study population as well as separately for athletes and nonathletes to determine PROMIS PASS thresholds for each population. A previously published PROMIS-PF minimal clinically important difference was used to evaluate postoperative improvement. A post hoc multivariate nominal logistic multivariate analysis was constructed to assess the effects of preoperative patient characteristics on the likelihood of attaining both the minimal clinically important difference and PASS. Results: In total, 112 patients were included in the study, with 79 (71%) having recreational or higher levels of athletic participation. The PASS for the study population was 56.0 (area under the ROC curve, 0.86) and was unaffected by baseline PROMIS-PF scores but was affected by preoperative athletic participation (56.0 for athletes, 49.0 for nonathletes). A post hoc analysis found 57 patients (51%) achieved the PASS for the PROMIS-PF (cutoff, 56.0), but when the athlete and nonathlete thresholds were applied to their respective patient groups, 66% of athletes and 64% of nonathletes achieved the PASS postoperatively. The multivariate analysis found that sport participation (odds ratio, 6.2; Conclusion: Preoperative athletic participation significantly affected the ability to achieve PASS.
Language	English
Publishing date	2023-08-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2706251-X
ISSN	2325-9671
ISSN	2325-9671
DOI	10.1177/23259671231187327
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