DKFZ-ZMBH Alliance

Brl1 and Brr6 are integral membrane proteins of the yeast nuclear envelope (NE) that transiently associate with nuclear pore complexes (NPCs). The exact roles of Brl1 and Brr6 during NPC assembly are unclear. Here, we demonstrate that Brr6 operates at both early and late stages of NPC assembly. Its early function is supported by amphipathic α-helix mutants, which impact nucleoporin recruitment without nuclear envelope deformation, whereas mutations in conserved cysteine residues result in NE deformation accompanied by defective NE fusion. The N-terminus of Brl1 interacts with the nucleoporin Nic96, promoting Nic96 recruitment to early assembly sites. AlphaFold predictions, the essential role of the conserved PAL motif, and the inhibition of NE fusion upon overexpression of PAL mutants together suggest that the perinuclear domains of Brl1 and Brr6 interact across the perinuclear space. Extending the length of the perinuclear-space regions of Brl1 and Brr6 causes uncontrolled NE fusion, as indicated by nuclear envelope disintegration dependent on the conserved cysteine residues. Together, Brl1 and Brr6 promote NE fusion by bridging the perinuclear space through PAL motif interactions, followed by nuclear envelope fusion and NPC insertion.

Radiology is integral to the multimodal diagnostic and treatment pathway of extremity soft tissue sarcomas in DGK-certified sarcoma centers (DGK: Deutsche Krebsgesellschaft, German Cancer Society), working in close interdisciplinary collaboration with sarcoma surgery, pathology, radiation oncology, and medical oncology. Treatment decisions rely on guideline- and recommendation-based imaging and histological confirmation by biopsy. When clinical warning signs (red flags) are present, radiological imaging is essential for triage and early referral to asarcoma center. For local staging, magnetic resonance imaging (MRI) is the modality of choice. It provides crucial information for diagnosis, prognosis, and treatment within the sarcoma board and serves as the basis for adequate biopsy planning. Diagnostic pitfalls arise from overlapping MRI appearances, particularly within the lipomatous spectrum and in lesions with myxoid and cystic patterns. Afurther focus is on avoidable procedural biopsy errors, inadequate targeting, and an inadequate biopsy tract that is not amenable to enbloc resection or that contaminates additional compartments/joints or neurovascular structures. The article outlines arisk-adapted diagnostic approach and provides practice-oriented principles for biopsy planning. It highlights typical problem MRI constellations to avoid misdiagnosis and underestimation of malignancy (grading), ultimately establishing optimal prerequisites for therapy.

Nontraumatic diaphragmatic rupture is a rare condition with clinical presentations ranging from asymptomatic to severe respiratory or gastrointestinal symptoms. Owing to its nonspecific nature, it can be difficult to differentiate from other diaphragmatic disorders. We present a case of a 35-year-old German woman with a right-sided nontraumatic diaphragmatic rupture, presenting with recurrent hypertensive crises and acute dyspnea. Although initially misdiagnosed, further clinical and radiological evaluations suggestive of diaphragmatic elevation led to the decision to proceed with robot-assisted thoracoscopic surgery. This case underscores the diagnostic challenges of non-traumatic diaphragmatic rupture, especially in complex clinical scenarios. It highlights the importance of thorough clinical assessment, appropriate imaging, and timely surgical intervention. Robot-assisted thoracoscopic surgery proved to be a safe and effective therapeutic option and should be considered in select cases where conventional diagnostics fail to provide definitive answers.

Membrane protection against oxidative insults is achieved by the concerted action of glutathione peroxidase 4 (GPX4) and endogenous lipophilic antioxidants such as ubiquinone and vitamin E. More recently, ferroptosis suppressor protein 1 (FSP1) was identified as a critical ferroptosis inhibitor, acting via the regeneration of membrane-embedded antioxidants. Yet, regulators of FSP1 are largely uncharacterized, and their identification is essential for understanding the mechanisms buffering phospholipid peroxidation and ferroptosis. Here we report a focused CRISPR-Cas9 screen to uncover factors influencing FSP1 function, identifying riboflavin (vitamin B2) as a modulator of ferroptosis sensitivity. We demonstrate that riboflavin supports FSP1 stability and the recycling of lipid-soluble antioxidants, thereby mitigating phospholipid peroxidation. Furthermore, we show that the riboflavin antimetabolite roseoflavin markedly impairs FSP1 function and sensitizes cancer cells to ferroptosis. Our findings provide a rational strategy to modulate the FSP1-antioxidant recycling pathway and underscore the therapeutic potential of targeting riboflavin metabolism, with implications for understanding the interaction of nutrients, as well as their contributions to a cell's antioxidant capacity.

Abstract Das deutsche Gesundheitssystem hat einen Umfang und einen Komplexitätsgrad erreicht, der zu Intransparenz und Ineffizienz bei hohen Kosten und mittelmäßigen Outcomes führt. Zugleich beruht es auf ökonomischen Voraussetzungen, die aufgrund der krisenhaften Entwicklung der Gesamtwirtschaft gefährdet sind. Als Teil einer notwendigen Reformagenda sollte die Neujustierung des dualen Systems von Gesetzlichen und Privaten Krankenversicherungen hin zu einem komplementären System aus obligatorischer Grundversicherung und freiwillig versicherten Zusatzleistungen bedacht werden.

Due to the observation that kinetic rates can be better correlated with in vivo drug efficacy than simple affinities, significant efforts have been made to develop experimental and computational methods to predict drug-target residence times over the last years. Here, we summarize the discussions and reflections from an international CECAM workshop which took place in March 2025 with participants from both academia and industry, including experimentalists as well as computational scientists, and was dedicated to computational methods for protein-ligand binding kinetics prediction. As currently standing challenges, we identify the need for standardized benchmark data sets, the need to move from simple to more complex and biomedically relevant targets and the question how academia and industry can work together to move the field of drug-target binding kinetics forward. We also discuss what level of accuracy can be expected from computational methods, and highlight that the field would benefit from blind challenges to enable a fair comparison of different computational methods to predict kinetic rates.

Type 2 diabetes (T2D) is a chronic disease currently affecting around 500 million people worldwide with often severe health consequences. Yet, histopathological analyses are still inadequate to infer the glycaemic state of a person based on morphological alterations linked to impaired insulin secretion and β-cell failure in T2D. Giga-pixel microscopy can capture subtle morphological changes, but data complexity exceeds human analysis capabilities. In response, we generate a dataset of pancreas whole-slide images from living donors with multiple chromogenic and multiplex immunofluorescence stainings and train deep learning models to predict the T2D status. Using explainable AI, we make the learned relationships interpretable, quantify them as biomarkers, and assess their association with T2D. Remarkably, the highest prediction performance is achieved by simultaneously focusing on islet α- and δ-cells and neuronal axons, alongside subtle pancreatic alterations in T2D donors such as larger adipocyte clusters, altered islet-adipocyte proximity and smaller islets. This data-driven approach provides a foundation for future research into relevant diagnostic and therapeutic targets, refining several hypotheses regarding tissue alterations associated with T2D.

The human hindbrain controls essential motor and autonomic functions and is the site of neurodevelopmental diseases. Yet, its cellular diversity, developmental trajectories and underlying regulatory logic remain poorly understood. We present a comprehensive multi-omics atlas of human hindbrain development spanning embryonic to adult stages, encompassing 594,817 transcriptomic and 422,568 chromatin-accessibility single-nucleus profiles. This dataset resolved the cellular architecture of hindbrain cellular lineages, and delineated coordinated gene expression, cis-regulatory programs and regulatory grammar guiding their developmental trajectories. By integrating multi-omics data, we discovered context-specific roles of transcription factors across cell types and deciphered the role of HOX genes in driving divergent cellular identity in related lineages. We further leveraged the atlas to contextualize pediatric gliomas to decode how subtle yet coordinated shifts in gene expression context can define oncogenic transformation. Together, this atlas provides a foundational resource for hindbrain biology and establishes a gene-regulatory framework linking development and disease.

Spatiotemporal changes in the nuclear lamina and cell metabolism shape cell fate, yet their interplay is poorly understood. Here we identify lamin A/C as a key regulator of cysteine catabolic flux essential for proper cell fate and longevity. Its loss in naive mouse pluripotent stem cells leads to upregulation of the cysteine-generating and catabolizing enzymes, cystathionine γ-lyase (CTH) and cystathionine β-synthase (CBS), thereby promoting de novo cysteine synthesis. Increased cysteine flux into acetyl-CoA fosters histone H3K9 and H3K27 acetylation, triggering a transition from naive to primed pluripotency and abnormal cell fate and function. Conversely, the toxic gain-of-function mutation of Lmna, encoding lamin A/C and associated with premature ageing, reduces CTH and CBS levels. This reroutes cysteine catabolic flux and alters the balance between H3K9 acetylation and methylation, crucially impacting germ layer formation and genome stability. Notably, modulation of Cth and Cbs rescues the abnormal cell fate and function, restores the DNA damage repair capacity and alleviates the senescent phenotype caused by lamin A/C mutations, highlighting the potential of modulating cell metabolism to mitigate epigenetic diseases.