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The dorsal aortic compartment is a developmental source of brown adipose tissue in mice
Full text linkWhite adipose tissue primarily stores energy while brown adipose tissue dissipates energy as heat, holding promise for therapeutic use. Brown adipose tissue in the anterior trunk is believed to derive from the somitic mesoderm, although some depots are of partially unknown origin. Here we show that the subscapular, lateral, cervical and peri-aortic brown adipose depots, but not the interscapular depot, are in part formed by a non-somitic source. Single-cell sequencing along with genetic lineage tracing indicates that at embryonic day 9.5 the dorsal aorta compartment harbors multipotent mesenchymal progenitors expressing the transcription factor Osr1. Spreading laterally from the dorsal aortic midline, these cells contribute to adipose, cartilage and myogenic lineages. This study uncovers an alternative source of brown adipose tissue and suggests that a fraction of dorsal aorta-associated mesenchymal Osr1(+) cells may represent the in vivo correlate of a multipotent progenitor cell type so far only characterized in vitro, the mesoangioblast
CT radiomic features of the crystalline lens and association with age, hypertension and cerebral white matter lesions
Full text linkBACKGROUND: Radiomic analyses have been extensively explored in oncologic imaging and more recently in neuroimaging. However, radiomic characterization of the crystalline lens using computed tomography has not yet been systematically investigated. METHODS: In this retrospective study, semiautomatic segmentation of the eye lens on orbital CT was performed on 112 patients (mean age 48 ± 20 years, 38% female). After radiomics feature extraction, a Boruta feature selection approach based on the random forest algorithm was applied to select the most relevant radiomics features. Severity of white matter lesions were graded according to the Fazekas scale for each patient on axial non-contrast head CT. RESULTS: In total, 17 important features were associated with age-related changes in the eye lens and three important radiomic features for the differentiation between patients with a Fazekas score > 1 and a control group. Significantly higher values were found in patients with a Fazekas score > 1 compared to the control group regarding all three features, "ClusterShade", "Skewness" and "DifferenceVariance" (p = 0.0006, 0.0023 and 0.0376, respectively), which are all measures of heterogeneity. No important radiomic features of the eye lens were confirmed between patients with and without hypertension. CONCLUSIONS: To the best of our knowledge, this is the first study to use CT-based radiomic analysis of the crystalline lens to detect differences among demographic or clinical groups with small vessel disease. The present results might help to expand the range of applications of radiomics regarding ophthalmic (patho-)physiology and suggest a possible new biomarker for systemic vascular diseases
Molecular evolution of animal aging
No full textComparative biology plays a crucial role in uncovering fundamental biological mechanisms and providing evolutionary models for their variation. This approach is particularly valuable for studying aging, given the remarkable diversity in aging trajectories across the tree of life. Many evolutionary theories of aging were proposed well before the discovery of the molecular mechanisms involved, and they remain largely theoretical. Moreover, the growing number of model organisms and the expanding array of experimental and theoretical approaches used to study aging have often remained compartmentalized. As a result, integrating these diverse insights into a unified framework has become increasingly important. As a step toward this goal, this field perspective outlines general biological mechanisms that help explain the variability in aging patterns and longevity across the animal kingdom
3D whole-kidney T(1) mapping using look-locker inversion recovery in conjunction with balanced SSFP readout and dictionary matching
No full textPURPOSE: To develop and validate dual breath-hold Look-Locker inversion recovery (Dual 3DLL) MRI for 3D whole-kidney T(1) quantification using dictionary matching.
METHODS: Dual 3DLL employs two breath-hold Look-Locker prepared acquisitions using nonselective adiabatic inversion in conjunction with 3D balanced SSFP readouts at three inversion times for each breath-hold. Retrospective registration of T(1)-weighted images was implemented to reduce misalignment between two breath-holds. For T(1) quantification, Bloch equation-based dictionary matching was applied. Dual 3DLL was validated in phantoms using inversion recovery spin-echo (IRSE) based T(1) mapping as a reference and in 11 healthy subjects, where 2D MOLLI-based renal T(1) mapping was used as a reference.
RESULTS: Validation in the phantom showed an agreement between Dual 3DLL and IRSE (precision: coefficient of variation = 2.5%, relative error compared to IRSE: 4.3% ± 2.0%). The human feasibility study demonstrated the clinical applicability of Dual 3DLL. Averaged T(1) derived from whole-kidney coverage Dual 3DLL was in accordance with that of 2D MOLLI (renal cortex: T(1,Dual 3DLL) = 1413.41 ± 114.73 ms, T(1,MOLLI) = 1394.39 ± 58.01 ms; medulla: T(1,Dual 3DLL) = 1827.48 ± 108 ms, T(1,MOLLI) = 1843.67 ± 91.54 ms). The coefficients of variation between T(1) obtained from Dual 3DLL and MOLLI were 6.1% for the renal cortex and 4.4% for the medulla.
CONCLUSION: This study demonstrates the feasibility of 3D whole kidney T(1) mapping using dual breath-hold Look-Locker T(1)-weighting in conjunction with balanced SSFP readouts and dictionary matching, and provides a technical foundation for improving our understanding of renal (patho-)physiology
Cell surface remodeling caused by the loss of TMEM30A in immune cells
Full text linkPlasma membrane lipid asymmetry is tightly regulated and fundamental to mammalian cell physiology. TMEM30A is the β-subunit of P4-ATPases, flippase enzymes that maintain strict phosphatidylserine (PS) asymmetry by pumping it from the outer to the cytosolic leaflet. Loss of TMEM30A function causes constitutive PS externalization and has been implicated in diseases such as diffuse large B-cell lymphoma and tumour immune evasion. Here, we systematically define the biophysical and molecular consequences of TMEM30A deletion in transformed immune cells. Using live-cell lipid reporters, membrane order probes and surface proteome mapping, we show that TMEM30A-knockout cells display robust PS externalization accompanied by faster lateral diffusion of membrane constituents and decreased plasma membrane order. Surface proteome reorganization includes increased abundance of tetraspanins and CD47. Further, TMEM30A loss triggers glycocalyx remodeling via ADAM10-dependent shedding that removes major mucins, including CD43 and CD162. Together, these data reveal a coordinated reorganization of lipids, glycans, and proteins upon TMEM30A loss that mechanistically links flippase dysfunction to immune evasion, increased plasma membrane dynamics and sensitization to anti-CD47 therapy. Moreover, Furthermore, our study provides an integrated surfaceome framework that illuminates the relationship between TMEM30A expression and clinical outcomes in cancer
Disclaimers and referral patterns for medical advice across urgency levels: large language model evaluation study
Full text linkBACKGROUND: "I'm not a doctor, but..." is a typical response when asking considerate laypeople for health advice. However, seeking medical advice has also shifted to digital settings, where the expertise of the other party is less transparent than in face-to-face interactions. Recently, large language models (LLMs) have emerged as easily accessible tools, offering a novel way to formulate medical questions and receive seemingly qualified advice. Given the sensitive nature of health-related queries and the lack of professional supervision, incorrect advice can pose serious health risks. Therefore, including explicit disclaimers and precise referrals in LLM responses to medical queries is crucial. However, little is known about how LLMs adapt their safety implementations in response to different urgency levels.
OBJECTIVE: This study evaluates disclaimer and referral patterns in responses from LLMs to authentic medical queries of different urgency levels using a systematic evaluation framework.
METHODS: This prospective, multimodel evaluation study generated and analyzed 908 responses from 4 popular LLMs (GPT-4o, Claude Sonnet-4, Grok-3, and DeepSeek-V3) to 227 authentic patient queries from a public dataset. Two human raters classified all 227 patient queries using a 3-level urgency scale. LLM responses were evaluated using a 5-point ordinal classification system for disclaimer and referral advice, ranging from "no disclaimer" to "urgent advice to consult a medical professional." GPT-4o served as the primary rater model for this task after conducting a subset validation against human expert annotations. Statistical analyses included Jonckheere-Terpstra tests to examine the relationship between case urgency and disclaimer ratings and Kruskal-Wallis tests for intermodel comparisons.
RESULTS: The 227 patient queries were distributed as 77 (34%) low-urgency, 110 (48%) intermediate-urgency, and 40 (18%) high-urgency cases. All 4 LLMs demonstrated statistically significant ordered trends (all P<.001), with higher-urgency queries receiving more explicit referral advice. Disclaimer and referral advice clustered toward higher categories across all models, with 97% (881/908) of responses indicating that a medical professional should be consulted. Sonnet-4, Grok-3, and GPT-4o demonstrated a conservative approach, with 89%, 89%, and 88%, respectively, of their responses being either explicit or urgent referrals. In contrast, DeepSeek-V3 showed a broader distribution, with 74% of responses falling into these categories. Interrater reliability between GPT-4o and human raters achieved moderate to substantial agreement, with weighted Cohen κ values between 0.415 and 0.707.
CONCLUSIONS: Current LLMs exhibit urgency-responsive safety mechanisms when providing medical advice. All evaluated models adaptively incorporate more explicit disclaimers and urgent referrals for higher-urgency queries. However, variability between LLMs highlights the need for standardized safety measures and appropriate regulatory frameworks. Although these findings indicate progress regarding safety concerns, the public availability of LLMs requires careful consideration to ensure consistent protection against patient harm while preserving the benefits of low-threshold access to health information
A CD22-specific T-cell receptor enables effective adoptive T-cell therapy for B-cell malignancies
No full textCD19 chimeric antigen receptor (CAR) T-cell therapy has become the standard of care in relapse and/or refractory B-cell malignancies. Up to 30% to 60% of patients experience relapsed disease because of the emergence of CD19(low) or CD19(−) tumor cell clones. Although bispecific CD19/CD22 CAR T cells have been explored, limited persistence and antigen downregulation of CD19 and/or CD22 have compromised their efficacy in relapsing patients. A comprehensive analysis of CD22 expression revealed that CD22 is ubiquitously expressed across all subgroups of B-cell lymphomas and B-cell leukemias, establishing CD22 as a valuable immunotherapeutic target. Using a humanized mouse model with a diverse human T-cell receptor (TCR) repertoire, we identified a high-affinity TCR targeting a CD22 epitope presented by HLA-A*02:01. In vitro, this TCR demonstrated high specificity and efficacy in both CD22(+) cell lines and primary patient-derived tumor samples. Importantly, CD22 TCR T cells outperformed CD22 CAR T cells in recognizing cells with low CD22 surface expression, including CD22(low) Nalm6 cells that emerged after in vivo CD19 T-cell treatment. Unlike CD22 CAR T cells, CD22 TCR T cells effectively recognized tumor cells that predominantly express intracellular CD22. Notably, in vivo validation in a Nalm6 B-cell leukemia model confirmed the superior activity of CD22 TCR T cells against CD22(low) cells compared to CD22 CAR T cells. In conclusion, our findings provide strong preclinical evidence supporting CD22 TCR-based therapy as a potent treatment option for CD22(low) B-cell malignancies, including patients who relapsed after CD19 CAR T-cell therapy
Bruton tyrosine kinase inhibition limits multiple sclerosis disease-driving inflammation while promoting regulatory B cells
Full text linkBACKGROUND AND OBJECTIVES: In multiple sclerosis (MS), a variety of immunosuppressive treatments are available. While effective, these approaches often lead to sustained impairment of essential components of the immune system, posing long-term safety concerns. Consequently, there is a growing interest in alternative therapeutic approaches that selectively limit pathogenic B-cell functions while preserving their physiologic roles. In this study, we investigated the therapeutic potential of inhibiting the enzyme Bruton tyrosine kinase (BTK), a key signaling molecule in both B-cell and myeloid cell activation. METHODS: The effects of the BTK inhibitor evobrutinib were evaluated in various experimental in vivo models of CNS demyelination, each representing different aspects of disease pathology as well as a naïve healthy condition. The impact on disease onset and severity was determined, and phenotypical alterations in different cell populations were assessed via flow cytometry. Furthermore, functional changes in both murine and human myeloid cells induced by BTK inhibition under specific Fc receptor–dependent stimulation were analyzed in in vitro settings using flow cytometry. RESULTS: In a naïve, healthy environment, evobrutinib promoted the development of regulatory B-cell properties. In various experimental models of CNS demyelination, BTK inhibition limited the differentiation of proinflammatory B cells while supporting their regulatory properties. Beyond modulating B-cell responses, BTK inhibition also attenuated the activation of myeloid cells after Fc receptor–mediated antigen uptake, a process assumed to be of importance in conditions, such as neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein–antibody associated disease. In addition, BTK inhibition was shown to suppress the secretion of proinflammatory cytokines and reduce antigen presentation, further dampening pathogenic immune responses. DISCUSSION: These findings highlight the potential of BTK inhibition as a selective and sustainable immunomodulatory strategy for both B cells and myeloid cells in the context of chronic CNS inflammation. Despite their efficacy, broad-spectrum immunosuppressive therapies often fail to provide targeted immune modulation. By contrast, BTK inhibition promotes regulatory B-cell properties while leaving other B-cell functions intact, providing the basis for its broad use—potentially in combination with established anti-inflammatory agents