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Modulating phosphatase DUSP22 with BML-260 ameliorates skeletal muscle wasting via Akt independent JNK-FOXO3a repression
No full textSkeletal muscle wasting results from numerous conditions, such as sarcopenia, glucocorticoid therapy or intensive care. It prevents independent living in the elderly, predisposes to secondary diseases, and ultimately reduces lifespan. There is no approved drug therapy and the major causative mechanisms are not fully understood. Dual specificity phosphatase 22 (DUSP22) is a pleiotropic signaling molecule that plays important roles in immunity and cancer. However, the role of DUSP22 in skeletal muscle wasting is unknown. In this study, DUSP22 was found to be upregulated in sarcopenia patients and models of skeletal muscle wasting. DUSP22 knockdown or treatment with BML-260 (a small molecule previously reported to target DUSP22) prevented multiple forms of muscle wasting. Mechanistically, targeting DUSP22 suppressed FOXO3a, a master regulator of skeletal muscle wasting, via downregulation of the stress-activated kinase JNK, which occurred independently of aberrant Akt activation. DUSP22 targeting was also effective in human skeletal muscle cells undergoing atrophy. In conclusion, phosphatase DUSP22 is a novel target for preventing skeletal muscle wasting and BML-260 treatment is therapeutically effective. The DUSP22-JNK-FOXO3a axis could be exploited to treat sarcopenia or related aging disorders. © The Author(s) 2025.TRUEsciescopu
Effects of Loneliness on Stress in Middle-Aged and Older Adults: Sequential Dual Mediating Roles of Social Interaction Anxiety and Self-Control
No full text본 연구는 중고령자(40∼71세) 580명을 대상으로 외로움이 스트레스에 미치는 심리적 경로를 규명하고자 하였다. 온라인 설문을 통해 외로움, 사회적 상호작용 불안, 자기통제력, 스트레스 수준을 측정하고 구조방정식을 통해 순차적 매개효과를 검증하였다. 분석 결과, 외로움은 사회적 상호작용 불안을 증가시키고이는 자기통제력을 떨어뜨려 스트레스를 높이는 경로가 유의하였다. 특히, 사회적 상호작용 불안은 다른영향들(성별, 연령, 결혼 여부, 만성질환 유무, 우울, 외향성)을 통제한 이후에도 독립적인 매개 경로로 확인되었다. 본 연구는 외로움이 스트레스에 영향을 미치는 다중 심리 기제의 통합적 이해를 제공하며, 중고령자의 정신건강 개입 설계에 이론적ㆍ실천적 시사점을 제시한다.FALSEkc
Long-Term Selective Photoelectrochemical Glycerol Oxidation via Oxygen Vacancy Modulated Tungsten Oxide with Self-Healing
No full textThe photoelectrochemical selective oxidation of biowaste glycerol into the high value-added material, along with hydrogen production, holds significant promise for advancing renewable and sustainable energy technologies. Here, the surface oxygen state of tungsten oxide is modified to selectively oxidize glycerol into glyceraldehyde, a high-value-added material, and the selectivity is maintained over a prolonged period using the photo-stimulated self-recovery capability. The surface-coordinated photoelectrode exhibits high charge transfer efficiency to glycerol and favorable glycerol adsorption capacity, enabling the selective conversion of glycerol. At 1.2 VTRUEsciescopu
Pathways to Low-Iridium Loading in Proton Exchange Membrane Water Electrolyzer Anodes: From Catalyst Design to Catalyst Layer Integration
No full textProton exchange membrane water electrolyzers (PEMWEs) are a promising technology for large-scale green hydrogen production; however, the high cost and scarcity of iridium (Ir) remain major obstacles to commercialization. Reducing Ir loading while maintaining catalytic activity and durability is therefore essential to achieving cost-effective hydrogen production. Among various strategies, the development of supported oxygen evolution reaction catalysts has emerged as a particularly effective approach. By anchoring Ir nanostructures onto acid-stable, high-surface-area metal oxide supports, such as TiO2, SnO2, and Ta2O5, researchers have demonstrated enhanced catalyst utilization, improved stability, and significantly reduced precious metal content. These supports not only disperse active sites more effectively but also promote strong metal-support interactions, enabling robust performance under harsh PEMWE operating conditions. This perspective highlights recent advances in structure engineering, oxidation state modulation, and support material design that collectively enable the fabrication of low-Ir anodes with high efficiency. This work further focuses on the integration of these supported catalysts into membrane electrode assemblies (MEAs) and proposes future research directions aimed at achieving the Ir loading target (0.125 mgIr cm-2) suggested by the U.S. Department of Energy. Together, these innovations offer a path forward toward scalable and economically viable PEMWE systems for a sustainable hydrogen economy.FALSEsciescopu
The role of cereblon-AMPK (AMP-activated protein kinase) axis in osteoarthritis and development of disease-modifying osteoarthritis drugs
No full textOsteoarthritis (OA), now recognized as a whole-joint disease, involves cartilage destruction, subchondral bone sclerosis, osteophyte formation, and synovial inflammation. Currently, there are no pharmacological interventions that effectively modulate OA progression. Recent studies suggest that abnormal energy metabolism in joint tissues is a critical risk factor for OA, with dysregulation of AMP-activated protein kinase (AMPK) implicated in its pathogenesis. However, the mechanisms driving this dysregulation remain unclear. In this research, I investigated the pathological mechanisms of metabolic dysfunction-mediated OA to identify potential therapeutic targets and develop novel candidates for disease-modifying osteoarthritis drugs (DMOADs). In part Ⅰ, I demonstrate that the cereblon-AMPK axis plays a critical catabolic role within the pathogenesis of OA. Elevated cereblon expression levels were observed in both human and mouse cartilage affected by OA. Adenoviral overexpression of cereblon in mouse joint tissues exacerbated cartilage destruction induced by destabilization of the medial meniscus (DMM) surgery. Conversely, in DMM model mice, cartilage destruction was inhibited in both global (OARSI grade difference; -2.50 [95% CI: -3.00 to -1.17]) and cartilage- specific (-2.17 [95% CI: -3.14 to -1.06]) cereblon-deficient mice compared to wild-type (WT) mice. The inhibitory effects became more pronounced in mice fed a high-fat diet (HFD) compared to those on a regular diet (RD). Moreover, specific degradation of cereblon via intra-articular (IA) injection of the proteolysis- targeting chimera (PROTAC) system, TD-165, considerably inhibited OA cartilage destruction (-2.47 [95% CI: -3.22 to -1.56]). Mechanistically, cereblon was found to downregulate AMPK activity in chondrocytes within OA cartilage. These findings suggest that the cereblon-AMPK axis holds promising potential as a therapeutic target in preclinical models of OA. In part Ⅱ, I explored the potential of the selected rhodanine derivatives (R-501, R-502, R-503) as DMOADs in various animal OA models. All three rhodanine derivatives suppressed OA progression caused by DMM surgery, as well as by the overexpression of hypoxia inducible factor-2α (HIF-2α) or Zrt- and Irt-like protein 8 (ZIP8). In DMM-operated mice, IA injection of R-501 reduced the median OARSI grade from 3.78 (IQR 3.00-5.00) to 1.89 (IQR 0.94-2.00, p = 0.0001). R-502 and R-503 also reduced the grade from 3.67 (IQR 2.11-4.56) to 2.00 (IQR 1.00-2.00, p = 0.0030) and 2.00 (IQR 1.83-2.67, p = 0.0378), respectively. Mechanistically, the rhodanine derivatives inhibited the nuclear localization and transcriptional activity of HIF- 2α in chondrocytes and fibroblast-like synoviocytes (FLS). They did not bind to Zn2+ or disrupt cellular Zn2+ homeostasis in chondrocytes or FLS; instead, they suppressed the nuclear localization and transcriptional activity of the Zn2+-dependent transcription factor, metal regulatory transcription factor 1 (MTF1). Although HIF-2α, ZIP8, and interleukin-1β are known to upregulate matrix-degrading enzymes in chondrocytes and FLS, the rhodanine derivatives appeared to inhibit these effects. Collectively, this study demonstrates that the cereblon-AMPK axis plays a pivotal role in OA especially under HFD conditions, and that targeting this axis offers a promising approach for addressing metabolic OA. This study additionally characterized novel rhodanine derivatives as potential DMOADs. Keywords Osteoarthritis, Cartilage, Chondrocytes, Mice, Cereblon, AMPK, Rhodanine, DMOADsDoctorABSTRACT ⅰ
CONTENTS ⅲ
LIST OF FIGURES ⅵ
LIST OF TABLES ⅷ
LIST OF ABBREVIATIONS ⅸ
PART Ⅰ
The critical role of cereblon-AMPK axis in osteoarthritis pathogenesis
and its potential as a therapeutic target
Ⅰ. INTRODUCTION 2
Ⅱ. MATERIALS AND METHODS 4
1. Human OA cartilage 4
2. Mice and experimental OA 4
3. von Frey assay 5
4. Histology and immunohistochemistry (IHC) 5
5. Skeletal staining 5
6. Primary culture of articular chondrocytes 6
7. Reverse transcription-polymerase chain reaction (RT-PCR) and quantitative PCR (qRT-PCR) 6
8. Western blotting 6
9. Statistical analysis 7
Ⅲ. RESULTS 8
1. Cereblon is upregulated in chondrocytes of human and mouse OA cartilage 8
2. Adenovirus-mediated overexpression of cereblon in mouse joint tissues exacerbates OA cartilage
destruction 9
3. Genetic deletion of cereblon in mice protects against experimental OA cartilage destruction 9
4. Cartilage-specific knockout of Crbn provides protection against experimental OA 10
5. Cereblon suppresses AMPK activity in chondrocytes 11
6. Cereblon regulates OA cartilage destruction via AMPK signaling 12
7. The therapeutic potential of the PROTAC-based cereblon degrader, TD-165, in OA 12
Ⅳ. DISCUSSION 32
Ⅴ. REFERENCES 35
PART Ⅱ
Characterization of rhodanine derivatives as disease-modifying osteoarthritis drugs
Ⅰ. INTRODUCTION 40
Ⅱ. MATERIALS AND METHODS 42
1. Novel rhodanine derivative compounds 42
2. Experimental OA models in mice 42
3. Histology and immunohistochemistry 43
4. Primary-culture chondrocytes and fibroblast-like synoviocytes (FLS) 43
5. Imaging and measurement of intracellular Zn2+ levels 44
6. Immunofluorescence microscopy 44
7. Reporter gene assays for HIF-2α and MTF1 45
8. RT-PCR and qRT-PCR analyses 45
9. Western blot analysis 45
10. Isothermal titration calorimetry (ITC) 46
11. Statistical analysis 46
Ⅲ. RESULTS 47
1. Rhodanine derivatives inhibit DMM-induced post-traumatic OA in mice 47
2. Rhodanine derivatives suppress HIF-2α-mediated OA progression in mice 47
3. Rhodanine derivatives suppress ZIP8-mediated OA progression in mice 48
4. Rhodanine derivatives downregulate the expression levels of the catabolic matrix-degrading
enzymes 49
5. The functions of fibroblast-like synoviocytes (FLS) are modulated by the rhodanine derivatives 49
Ⅳ. DISCUSSION 68
Ⅴ. REFERENCES 70
ABSTRACT IN KOREAN 74
ACKNOWLEDGEMENT 7
Identification of novel immune checkpoint targets and metabolic biomarkers for enhancing cancer immunotherapy efficacy
No full textImmune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yielding durable responses in various tumors. However, a major challenge remains, as only a subset of patients shows strong responses, while many patients exhibit resistance. To overcome these limitations, the discovery of novel immune checkpoint (ICP) targets and predictive biomarkers has emerged as a promising approach to enhance ICI efficacy. In the first part of the study, we identified contactin-4 (CNTN4) as a promising ICP that impairs T cell functions. CNTN4 was highly expressed in tumor tissues, and its interaction with amyloid precursor protein (APP) on T cells diminished TCR-related signaling and impaired antitumor immune responses. To counteract this, we developed antibodies targeting CNTN4 (GENA-104A16) and APP (5A7), both of which effectively disrupted the CNTN4-APP interaction. These antibodies restored T cell functions, increased tumor-infiltrating lymphocytes, and promoted antitumor responses in a syngeneic mouse model. These results suggest that CNTN4-APP represents a potential ICP axis that can be targeted to boost immune responses in cancer therapy. In the second part of the study, we investigated the role of metabolic pathways—particularly amino acid and bile acid metabolism—in shaping ICI efficacy in non-small cell lung cancer (NSCLC) patients. Through metabolomic profiling and machine learning analysis, we identified histidine (His) as a positive predictor of ICI response, while homocysteine (HCys), phenylalanine (Phe), and sarcosine (Sar) were associated with poor outcomes. The His/HCys+Phe+Sar ratio emerged as a robust biomarker for predicting therapeutic outcomes. Additionally, bile acids such as glycochenodeoxycholic acid (GCDCA) and taurolithocholic acid (TLCA) were linked to improved survival probability and response to ICIs, with TLCA enhancing T cell proliferation and anti-tumor immunity. We also uncovered a relationship between the gut microbiota and TLCA levels, with the Eubacterium genus influencing TLCA-related metabolism. In summary, this research provides novel insights into overcoming the limitations of ICIs through the discovery of a novel ICP target and the identification of metabolic biomarkers that influence ICI response. Our findings suggest potential strategies to enhance the efficacy of immunotherapy and pave the way for more personalized treatment approaches in cancer immunotherapy.DoctorAbstract
Contents
List of Figures
Part 1. Therapeutic potential of targeting the CNTN4-APP axis in enhancing T cell mediated anti-cancer
response 1
1. Introduction 1
2. Materials and Methods 2
2.1. Cells 2
2.2. Animals 2
2.3. Cancer cell characterization (proliferation, migration, and invasion) 3
2.4. Tumor graft 3
2.5. Whole transcriptomic analysis of tumor tissues 4
2.6. In vitro plate-bound T cell proliferation or neutralization assay 4
2.7. Measurement of cytokine secretion 4
2.8. Affinity of GENA-104A16 against recombinant proteins or overexpressing HEK293FT cells 5
2.9. Biolayer interferometry 5
2.10. In vitro cytotoxicity assay 6
2.11. In vitro conjugation assay 6
2.12. Western blotting 6
2.13. Subcellular fractionation 7
2.14. Immune cell profiling 7
2.15. scRNA analysis for tumor-infiltrating immune cells in mouse tumor tissues 8
2.16. Statistical analyses 9
3. Results 10
3.1. Suppression of T cell activity by CNTN4 10
3.2. Neutralization of CNTN4-induced T cell suppression by GENA-104A16 14
3.3. In vivo effectiveness of GENA-104A16 17
3.4. Impact of GENA-104A16 on tumor immune landscape 19
3.5. Interaction between CNTN4 and APP 22
3.6. Role of APP in CNTN4-mediated T cell inhibition 24
3.7. In vivo effectiveness of anti-APP antibody (5A7) 26
3.8. Clinical implications of CNTN4 expression 28
3.9. Clinical implications of APP expression 33
4. Discussion 35
Part 2. Exploring the immunometabolic landscape: amino acid and bile acid metabolism as biomarkers
for NSCLC immunotherapy efficacy 38
1. Introduction 38
2. Materials and Methods 39
2.1. Patient cohort and characteristics 39
2.2. Targeted metabolic profiling using Biocrates kit 40
2.3. Analysis of bile acids in plasma samples 40
2.4. T cell assay 41
2.5. Mice 42
2.6. Immune cell profiling 43
2.7. Metagenomic 16S rRNA sequencing 43
2.8. CatBoost classification analysis 44
2.9. Random forest model analysis 44
2.10. RNA sequencing analysis 45
2.11. Single-cell RNA sequencing analysis 45
2.12. Statistical analysis 46
3. Results 47
3.1. Patients characteristics 47
3.2. The role of amino acid metabolism in predicting cancer immunotherapy outcomes 48
3.3. Clinical and immune significance of the His/HCys+Phe+Sar ratio in NSCLC patients 58
3.4. Identification of key bile acids modulating T cell function and immunotherapy response 61
3.5. Pivotal role of TLCA in boosting T cell activation and enhancing anti-tumor immune response 68
3.6. Association between TLCA levels and gut microbiota in NSCLC patients 72
4. Discussion 75
IV. Summary 78
V. References 78
VI. Acknowledgements 82
VII. Curriculum Vitae 8
Hollow raspberry-like nanoaggregates for sensitive SERS detection of PAHs in water
No full textPolycyclic aromatic hydrocarbons (PAHs) are significant environmental contaminants with considerable health risks, emphasizing the need for effective monitoring and identification. On-site detection of PAHs using surface-enhanced Raman scattering (SERS) remains challenging due to their weak adsorption on substrates and potential interference from the substrates themselves. To address these challenges, we developed hollow raspberry-like plasmonic nanoaggregates made of functionalized-polystyrene hollow microspheres (HM) decorated with gold nanoparticles (Au NPs). These nanoaggregates feature a hydrophobic inner cavity that effectively enriches PAHs, improving detection sensitivity. Through enhanced plasmonic coupling by carefully controlling Au NPs coverage on polystyrene (PS) surfaces, functionalizing the amino groups on the microsphere surface, and fine-tuning the Au NP to PS ratio, our method achieved detection limits of 4 × 10−8 M for pyrene, 6 × 10−7 M for fluorene, and 4 × 10−7 M for benzo[a]anthracene. Moreover, this approach was effectively utilized for detecting PAHs in both Yellow River water and tap water. This study highlights the capabilities of hollow raspberry-like plasmonic nanoaggregates for qualitative and quantitative analysis of PAHs, thereby broadening the use of advanced nanomaterials in monitoring environmental water quality. © 2025 The AuthorsTRUEsciescopu
Effects of Walking Speed and Visual Stimulus on the Axis Orientation of the Metatarsophalangeal Joint and Foot Progression Angle During Gait
No full text본 연구는 보행 시 시각적 자극과 보행 속도가 발허리발가락(Metatarsophalangeal, MP) 관절 축 방향과 발 디딤 각도 변화에 미치는 영향을 규명하는 것을 목표로 한다. 이를 위해 6개의 반사 마커와 9대의 모션 캡처 카메라, 트레드밀을 사용하여 발 움직임 데이터를 수집하였으며, 6명의 성인을 대상으로 시각적 자극(TV 시청)과 세 가지 보행 속도(느림, 보통, 빠름) 조건에서 실험을 진행하였다. 발허리발가락관절 축 방향은 heel-off부터 toe-off까지 구간 동안 관절 각속도 벡터를 기반으로 정의하였으며, 발 디딤 각도는 heel-off 시작 시점에서 발 방향과 보행 진행 방향 사이의 각도로 측정하였다. 분석 결과, 시각적 자극은 발허리발가락(MTP) 관절 축 평균 각도에 유의미한 영향을 미치지 않는 것으로 나타났다. 반면, 보행 속도는 MTP 관절 축 각도에 큰 영향을 미 쳤으며, 느린 속도에서는 안정성과 균형을 유지하기 위해 비스듬 축(oblique axis)이 더 많이 활용되었고, 빠른 속도에서는 에너지 효율성과 추진력을 최적화하기 위해 가로축 (transverse axis)이 주로 사용되었다. 또한, 시각적 자극과 보행 속도의 상호작용은 발꿈치 들림 중기 단계에서 MTP 관절 축 각도에 유의미한 영향을 미쳤다. 느린 속도와 보통 속도에서 시각적 자극은 발의 전족부 하중을 증가시켜 가로축 활용도를 높이는 경향을 보였다. 시각적 자극 조건에서는 발 디딤 각도의 범위가 확대되었고, 팔자걸음 빈도가 증가하여 무릎 부하를 줄이기 위한 적응 전략으로 작용한 것으로 해석된다. 본 연구는 보행 속도와 시각적 자극이 발가락 관절 축과 발 디딤 각도에 미치는 영향을 규명하며, 발과 발허리발가락관절의 움직임에 대한 생체역학적 이해를 높이고, 의족 및 보조기기의 발 구조 설계 방향을 제시한다|This study aimed to investigate the effects of visual stimulus and walking speed on the metatarsophalangeal (MTP) joint axis orientation and foot progression angle during walking. To achieve this, foot movement data were collected using six reflective markers, nine motion capture cameras, and a treadmill. Experiments were conducted on six adult participants under visual stimulus conditions (TV viewing) and three walking speed conditions (slow, normal, and fast). The MTP joint axis orientation was defined based on angular velocity vectors during the heel-off to toe-off phases, while the foot progression angle was measured as the angle between the foot direction and the walking direction at the onset of heel-off. The analysis revealed that visual stimulus did not have a statistically significant effect on the MTP joint axis orientation. However, walking speed had a considerable impact on the MTP joint axis orientation, with the oblique axis being more utilized at slow speeds to maintain stability and balance, and the transverse axis being predominantly used at fast speeds to optimize energy efficiency and propulsion. Additionally, the interaction between visual stimulus and walking speed significantly influenced the MTP joint axis angle during the mid heel-off phase. At slow and normal speeds, visual stimulus tended to increase the forefoot load, leading to greater reliance on the transverse axis. Under visual stimulus conditions, the range of foot progression angles expanded, and the frequency of out-toeing gait increased, which was interpreted as an adaptive strategy to reduce knee load. This study investigates the effects of walking speed and visual stimulus on the MTP joint axis orientation and foot progression angle, enhancing the biomechanical understanding of foot and metatarsophalangeal (MTP) joint movements. Additionally, it provides guidance for the design of foot structures in prosthetics and assistive devices.MasterAbstract (English) i
Abstract (Korean) iii
List of Contents v
List of Tables vii
List of Figures viii
1 Introduction 1
1.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 The Axis Orientation of the Metatarsophalangeal Joint . . . . . . . . . 2
1.3 The Foot Progression Angle . . . . . . . . . . . . . . . . . . . . . . . . 2
1.4 Visual Stimulus Conditions in Gait . . . . . . . . . . . . . . . . . . . . 3
1.5 Walking Speed Conditions in Gait . . . . . . . . . . . . . . . . . . . . . 3
1.6 Research Objectives and Hypothesis . . . . . . . . . . . . . . . . . . . . 4
2 Literature Review 6
2.1 The Metatarsophalangeal Joint Axis . . . . . . . . . . . . . . . . . . . 6
2.1.1 Literature Overview . . . . . . . . . . . . . . . . . . . . . . . . 6
2.1.2 Limitation of Existing Papers . . . . . . . . . . . . . . . . . . . 7
2.2 The Foot Progression angle . . . . . . . . . . . . . . . . . . . . . . . . 8
2.2.1 Literature Overview . . . . . . . . . . . . . . . . . . . . . . . . 8
2.2.2 Limitation of Existing Paper . . . . . . . . . . . . . . . . . . . . 8
2.3 The Effect of Visual Stimulus in Gait . . . . . . . . . . . . . . . . . . . 9
2.3.1 Literature Overview . . . . . . . . . . . . . . . . . . . . . . . . 9
2.3.2 Limitation of Existing Paper . . . . . . . . . . . . . . . . . . . . 9
2.4 The Effect of Walking Speed in Gait . . . . . . . . . . . . . . . . . . . 10
2.4.1 Literature Overview . . . . . . . . . . . . . . . . . . . . . . . . 10
2.4.2 Limitations in Existing Paper . . . . . . . . . . . . . . . . . . . 10
3 Method and Experiments 11
3.1 Experiment Setup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
3.1.1 Experiment Environment . . . . . . . . . . . . . . . . . . . . . . 11
3.1.2 Marker Positions and Foot Model . . . . . . . . . . . . . . . . . 12
3.1.3 Participants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3.1.4 Protocol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.2 Data Processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
4 Result 17
4.1 The Axis Orientation of the Metatarsophalangeal Joint . . . . . . . . . 17
4.1.1 Effects of Visual Stimulus Conditions in Gait . . . . . . . . . . 18
4.1.2 Effects of Walking Speed Conditions in Gait . . . . . . . . . . . 18
4.1.3 Effects of the Interaction between the Two Conditions . . . . . 20
4.2 The Foot Progression Angle . . . . . . . . . . . . . . . . . . . . . . . . 22
5 Discussion 24
5.1 The Axis Oreintation of the Metatarsophalangeal Joint . . . . . . . . . 24
5.1.1 Effects of Visual Stimulus Conditions in Gait . . . . . . . . . . 24
5.1.2 Effects of Walking Speed Conditions in Gait . . . . . . . . . . . 25
5.1.3 Effects of the Interaction between the Two Conditions . . . . . 26
5.2 The Foot Progression Angle . . . . . . . . . . . . . . . . . . . . . . . . 27
6 Conclusion 29
7 Limitations and Future work 31
7.1 Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
7.2 Future Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
References 33
A Additional Figures 37
Acknowledgements 3
Mouse Model of STAT3 Mutation Resulting in Job’s Syndrome Diverges from Human Pathology
No full textSTAT3 mutations are commonly observed in human pathology yet have no uniform patient presentation. Their effects range from cancer and autoimmunity to primary immunodeficiencies and bone deformity. Designing animal models of those mutations can help researchers identify their direct effects to better inform the clinical setting. In this manuscript, we report a mouse model harboring the same mutation as an autosomal-dominant hyper-IgE syndrome (AD-HIES) patient reported in the literature. Surprisingly, while the deletion of five amino acids in the SH2 domain of STAT3 did result in frequency changes in several immune populations as measured by complete blood count and flow cytometry analysis, it did not yield the expected phenotype of AD-HIES, with no increase in serum IgE or eosinophil count. We additionally provide structural analysis of the STAT3G656_M660del deletion, visualizing changes in protein architecture and potential effects on the neighboring Y705 phosphorylation site. Our model showcases the sexually dimorphic immune dysregulation caused by a STAT3 mutation and highlights that predicted gain- and loss-of-function mutations can yield unexpected phenotypes. © 2025 Elsevier B.V., All rights reserved.TRUEsciescopu