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The IFNγ ‐ CIITA ‐ MHC II axis modulates melanoma cell susceptibility to NK ‐cell‐mediated cytotoxicity
No full textMelanoma, the deadliest form of skin cancer, poses a significant challenge due to its genetic heterogeneity and high metastatic potential. While cytotoxic T cell (CTL)‐based immunotherapies have made remarkable progress in recent years, the therapeutic potential of natural killer‐(NK) cells is increasingly recognized. However, resistance mechanisms to both CTL‐ and NK‐cell‐mediated immunotherapies hinder effective treatment. To evaluate the exclusive role of NK‐cells in anti‐melanoma immunity, we performed 2D and 3D co‐culture‐based cytotoxicity assays under varying conditions. Our findings revealed a protective phenotype in melanoma cells following prolonged exposure to primary NK‐cells. By combining experimental data with bioinformatic analyses, we identified key genes and pathways involved in melanoma cell adaptation to NK‐cell‐mediated killing (NKmK). We found that cytokines such as IFNγ play a major role in suppressing NKmK with MHC II surface expression being a critical factor. Targeting the master regulator CIITA, which governs MHC II expression and is affected by IFNγ, significantly reduced melanoma cell resistance to NKmK. This study provides potential strategies to overcome resistance to NK‐cell‐based immunotherapies and offers novel insights into melanoma immune escape mechanisms.Studienstiftung des Deutschen Volkes https://doi.org/10.13039/501100004350Deutsche Forschungsgemeinschaft https://doi.org/10.13039/50110000165
Erosive tooth wear in 3- to 6-year-old children: Prevalence trends and risk factors over two decades
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Synthesis and Electrochemistry of Formazan(ate) Re(I) Complexes: Ligand-Based Reactivity toward CO 2
No full textWhite matter tracts associated with iTBS-induced heart rate deceleration and treatment response in major depressive disorder
No full textAbstract Intermittent theta burst stimulation (iTBS) is a well-established treatment for major depressive disorder (MDD), but predicting clinical outcomes remains challenging. Heart rate deceleration induced by iTBS has emerged as a potential biomarker for treatment response, yet the role of white matter (WM) properties in mediating these effects is largely unexplored. In this quadruple-blind, crossover study, we investigated the relationship between WM microstructure, iTBS-driven heart rate modulation, and antidepressant effects. Using correlational tractography, we focused on four major WM tracts—the cingulum, fornix, superior longitudinal fasciculus, and uncinate fasciculus—to examine short-term microstructural changes in relation to therapeutic outcomes. At baseline, findings revealed that fractional anisotropy (FA) in the fornix and right dorsal cingulum was negatively correlated with heart rate deceleration, while radial and mean diffusivity (MD, RD) in the fornix were positively correlated. In the right ventral cingulum, FA showed a positively correlation, while MD and RD were negatively correlated with symptom improvement. Longitudinally, FA increases in the left cingulum were significantly associated with greater symptom alleviation post-treatment. Notably, the correlation between iTBS-induced heart rate modulations and clinical improvement after six weeks, previously demonstrated in this cohort, was identified, while WM microstructural properties in the fornix and cingulum demonstrated predictive value for both heart rate modulation and treatment response. WM changes in the cingulum, evident as early as four weeks, highlight its unique neuroplasticity potential along iTBS intervention. Together, these findings provide novel insights into the structural connectivity patterns influencing iTBS outcomes, offering a novel foundation for more personalized therapeutic strategies in MDD
UBE2J2 sensitizes the ERAD ubiquitination cascade to changes in membrane lipid saturation
No full textAbstract Protein–lipid crosstalk is fundamental to homeostasis in the endoplasmic reticulum (ER). The ER-associated degradation (ERAD) pathway, a branch of the ubiquitin–proteasome system, maintains ER membrane properties by degrading lipid metabolic enzymes. However, the ERAD components that sense membrane properties and their mechanisms remain poorly defined. Using reconstituted systems with purified ERAD factors, we show that membrane composition modulates the ubiquitination cascade at multiple levels. The membrane-anchored E2 UBE2J2 acts as a sensor for lipid packing: in loosely packed membranes, UBE2J2 becomes inactive due to membrane association that impedes ubiquitin loading, while tighter packing promotes its active conformation and interaction with E1. UBE2J2 activity directs ubiquitin transfer by the E3 ligases RNF145, MARCHF6, and RNF139, targeting both themselves and the substrate squalene monooxygenase. Additionally, RNF145 senses cholesterol, altering its oligomerization and activity. These findings reveal that ERAD integrates multiple lipid signals, with UBE2J2 relaying and extending the effect of lipid signals through its cooperation with multiple E3 ligases
On the replicability of diffusion weighted MRI-based brain-behavior models
No full textAbstract Replicability of anatomical and functional MRI-based inter-individual BWAS has been extensively discussed recently. This study reports a comprehensive evaluation of BWAS replicability based on structural connectomes (streamlines, FA, MD, RD, AD). Overall, 36%(21/58) of brain-phenotype associations were replicable in the HCP dataset with atleast one of the DWI metrics, and a discovery sample size n ≤ 425 (total sample size = discovery + replication samples). Temporally stable, trait-like phenotypes were found to be more replicable (50%, 16/32), than state-like measures (19%, 5/26). Streamline-based connectomes (SC) provided the highest replicability across all metrics (29% and 42% of phenotypes in the HCP and AOMIC datasets, respectively). In line with theoretical expectations, replicability was found to be directly related to effect size. Phenotypes that needed n > 400 discovery samples to replicate displayed very low effect sizes 425 samples will necessarily display limited practical relevance due to their small predictive performance. Large sample sizes remain crucial for explainability and for assessing fairness and generalizability to new populations
The flexible behaviour of a trigonal arylimido iron complex
No full textA chemically versatile, low-coordinate imido iron complex is reported.A trigonal arylimido iron complex is reported, which is found in an intermediate spin state. The iron bound imido unit is electronically flexible and acts as a nucleophile, reductant, or H atom abstractor. The latter is used for catalytic intramolecular C–H bond amination.A chemically versatile, low-coordinate imido iron complex is reported.A trigonal arylimido iron complex is reported, which is found in an intermediate spin state. The iron bound imido unit is electronically flexible and acts as a nucleophile, reductant, or H atom abstractor. The latter is used for catalytic intramolecular C–H bond amination.Deutsche Forschungsgemeinschaft https://doi.org/10.13039/501100001659Niedersächsisches Ministerium für Wissenschaft und Kultur https://doi.org/10.13039/50110001057
Herzinsuffizienz in Deutschland: Epidemiologie und neueste Entwicklungen
No full textWas ist neu? Neben der Herzinsuffizienz an sich sind auch die begleitenden Erkrankungen wie Diabetes, Niereninsuffizienz, chronisch-obstruktive Lungenerkrankung (COPD) und Vorhofflimmern prognoseentscheidend, weshalb auch diese einer adäquaten Therapie bedürfen. Die Herzinsuffizienz-Therapie besteht aus 4 Säulen, zumindest bei Herzinsuffizienz mit reduzierter Pumpfunktion: Betablocker, Sacubitril/Valsartan (bzw. ACE-Hemmer), Mineralokortikoid-Rezeptor-Antagonisten und SGLT-2-Inhibitoren. Bei Herzinsuffizienz mit reduzierter Pumpfunktion sind sie prognoseverbessernd. Die Therapie von Komorbiditäten wie etwa Eisenmangel ist entscheidend. Auch Eisenmangel hat eine hohe Prävalenz. Im klinischen Alltag und auch in den meisten Studien werden vorwiegend Eisen(III)-Carboxymaltose und Eisen(III)-Derisomaltose zur intravenösen Substitution verwendet. Hierbei liegt die durchschnittlich benötigte Dosis bei 1000–1500mg