Nephrologisches Zentrum Goettingen

Transactive response DNA binding protein 43 kDa (TDP-43) pathology, is a central molecular hallmark of amyotrophic lateral sclerosis (ALS). However, the underlying triggers are incompletely understood. Here, we show that infection with herpes simplex virus (HSV) induces molecular hallmarks of ALS in various in vitro and in vivo models and is associated with an increased risk of ALS in human population data. German healthcare provider data (n = 238,440) and herpesvirus serology of an ALS patient and control cohort (n = 1,100) showed that HSV infection elevated the ALS risk by 210% and odds by ~65%, respectively. On a molecular level, HSV infection promoted TDP-43 pathology in neuronal cell models, human iPSC-derived motoneurons and cerebral organoids, mice, and human tissue sections. This effect was triggered by HSV-1 or 2, but not by several other related herpesviruses. Mechanistically, the infected cell protein 0 (ICP0) of HSV-1/2 drives TDP-43 pathology by disturbance of promyelocytic leukemia nuclear bodies (PML-NBs), thereby abrogating TDP-43 SUMO2/3ylation. Taken together, we reveal a previously unrecognized association between HSV infection and ALS and clarify the underlying molecular mechanism that drives TDP-43 pathology. Our data may guide future studies into therapeutic and prophylactic interventions against ALS.

Mechanical ventilation (MV) can induce or exacerbate ventilator-induced lung injury (VILI), particularly in mechanically heterogeneous lungs with pre-existing injury. We investigated VILI in a rat model of bleomycin-induced lung injury and compared it with healthy controls using a combined in-vivo and ex-vivo imaging approach. Previously acquired in-vivo data from four-dimensional (4D) phase-contrast synchrotron micro-computed tomography (microCT) and forced oscillation measurements showed increased lung elastance and reduced local acinar strain in bleomycin-induced injured lungs at baseline and after injurious MV. To identify structural and mechanical correlates, we performed automated three-dimensional (3D) pore analysis and atomic force microscopy (AFM) on formalin-fixed, paraffin-embedded lung tissue, complemented by histology and spatial co-registration. Ex-vivo analysis revealed pronounced airspace enlargement after injurious MV of healthy lungs, whereas this effect was attenuated in fibrotic lungs. AFM demonstrated region-specific mechanical responses, and correlation analyses linked pore geometry and nanoscale stiffness to in-vivo lung mechanics. Spatial analysis further showed colocalization of VILI-associated airspace damage with injured regions. Overall, extracellular matrix remodelling modifies the lung’s mechanical response to injurious MV. This multiscale correlative approach provides mechanistic insight into the interplay between lung injury and VILI and informs ventilation strategies in structurally altered lungs.

Europe is warming at the fastest rate of all continents, experiencing a temperature increase of about 1 ∘ C higher than the corresponding global increase. Aiming to be the first climate-neutral continent by 2050 under the European Green Deal, Europe requires an in-depth understanding of the potential energy transition pathways. In this paper, we develop four qualitative long-term scenarios covering the European energy landscape until 2060, considering key uncertainty pillars— categorised under social, technological, economic, political, and geopolitical dimensions. First, we place the scenarios in a three-dimensional space defined by Social dynamics, Innovation, and Geopolitical instabilities. These scenarios are brought to life by defining their narratives and focus areas according to their location in this three-dimensional space. The scenarios envision diverse futures and include distinct features. The EU Trinity scenario pictures how internal divisions among EU member states, in the context of global geopolitical instability, affect the EU climate targets. The REPowerEU++ scenario outlines the steps needed for a self-sufficient, independent European energy system by 2050. The Go RES scenario examines the feasibility of achieving carbon neutrality earlier than 2050 given favourable uncertain factors. The NECP Essentials scenario extends current national energy and climate plans until 2060 to assess their role in realising climate neutrality. The scenarios are extended by incorporating policies and economic factors. They are then detailed in a Qualitative to Quantitative (Q2Q) matrix, linking narratives to quantification. Finally, two scenarios (Go RES and REPowerEU++) are quantified using the open-source energy system model GENeSYS-MOD to illustrate the quantification process. • Net-zero emissions by 2050 and the EU Green Deal goals face major uncertainties. • Social, technological, and geopolitical dimensions are central to designing energy transition scenarios. • An Energy Vision for mapping long-term energy scenarios and identifying key factors. • Review, comparative analysis and advancement of European Energy Transition Scenarios. • Develop a qualitative-to-quantitative matrix to facilitate energy model implementation.

BackgroundThe anterolateral thigh (ALT) free flap is a workhorse in head and neck reconstruction, offering versatility, long pedicle length, and low donor site morbidity. Nevertheless, anatomical variability of its perforators can occasionally result in absent or unusable vessels, jeopardizing intraoperative feasibility. In such cases, harvesting an additional donor site increases operative time, morbidity, and aesthetic results. Salvage solutions within the same vascular territory are therefore essential to ensure safe and efficient reconstruction.Case presentationWe report a 70-year-old female with oral squamous cell carcinoma of the right retromolar triangle requiring composite resection with flap reconstruction. A patient-specific reconstructive plate and ALT free flap were planned. Intraoperatively, no usable perforators of the descending branch of the lateral circumflex femoral artery were identified. Proximal dissection revealed reliable perforators supplying the tensor fascia lata (TFL) territory, allowing elevation of a TFL free flap through the same incision. Microvascular anastomosis was performed successfully. The postoperative course was uneventful, and the flap remained viable throughout follow-up.ConclusionThis case highlights the importance of intraoperative flexibility when encountering ALT perforator absence. The TFL free flap represents a dependable salvage solution, characterized by more consistent vascular anatomy and minimal additional donor site morbidity. By enabling conversion within the same surgical field, the TFL flap reduces operative time and avoids the drawbacks of a second donor site. Incorporating this strategy into a structured decision-making algorithm enhances reconstructive safety and broadens the armamentarium for complex head and neck reconstruction.

This study aimed to assess the sex-specific prevalence and patterns of complementary and alternative medicine (CAM) use in patients undergoing radiotherapy, using the standardized questionnaire developed as part of the S3 Guideline on Complementary Medicine in Oncology. Between August and December 2022, 112 out of 697 eligible cancer patients receiving radiotherapy were prospectively enrolled and completed a structured questionnaire assessing CAM use. The questionnaire included 38 CAM methods classified according to their potential for interactions. Female participants generally used more CAM methods than male participants (median methods: 3 vs. 1, p<0.001). The most frequently used CAM methods were vitamin D (46.4%), sports/exercise (33%) and vitamin A/C/E or beta-carotene (25%). At least one of the listed CAM methods was used by 79.5%. At least three of the listed CAM methods were used by 52 (46.4%) patients. Thirty-six (32.1%) and 54 (48.2%) patients used CAM methods with known or potential interactions, while 76 (67.9%) used methods with no known interactions. In addition, a higher number of female patients used uncertain methods or medications compared to males (p=0.022). The desire for counseling was very similar between both sexes, with no significant difference (p=0.973). The high rate of CAM utility before radiotherapy, especially among females, and the use of uncertain methods, highlights the need for standardized questionnaires to identify potential interactions. This would help enhance patient safety through structured screening and counseling.

Geographic separation from the partner is a reality for many expatriates, yet little is known about its effects on expatriates and their partners. Drawing on attachment theory, we develop a theoretical model linking the effects of geographic separation to expatriates’ repatriation intentions and eventual repatriation and reunion with their partners via an increase in depressive symptoms of both expatriates and their partners. Moreover, we propose that dyadic trust and the frequency of virtual communication between expatriates and partners buffer the negative effects of geographic separation on the depressive symptoms and repatriation. Results from a multi-wave dyadic survey of 132 expatriates and their partners provide strong support for our theoretical model. Findings from a follow-up interview study with 20 expatriates and partners offer additional insights into the underlying reasons and mechanisms of separation, depression and repatriation. We discuss important implications for theory and practice.

Abstract RATIONALE Cellular NAD+ levels are maintained through a biosynthetic pathway that is rate-limited by the enzyme NAMPT (nicotinamide phosphoribosyltransferase). Acute kidney injury (AKI), a common condition characterized by rapid loss of kidney function often associated with sepsis, correlates with reduced NAD+ levels. In murine models of acute systemic inflammation, NAMPT transcription is surprisingly upregulated in the whole kidney, suggesting that inflammatory triggers may drive NAMPT expression within specific renal cell populations. METHODS In vivo, a murine model of systemic inflammation was utilized with LPS at 17.5 mg/kg BW. SiRNA was used to reduce NAMPT expression and plasmid to overexpress NAMPT in human umbilical vein endothelial cells (HUVECs) and human kidney cells (HK2). In vitro, septic conditions were simulated, and various assessments were conducted, including bulk RNAseq, RT-qPCR, Western Blot, NAD(H) level measurements, immunohistochemistry, Seahorse Assays, and transendothelial electrical resistance. RESULTS Endotoxemic mice developed AKI and, unexpectedly, exhibited whole-kidney elevation of NAMPT (p&amp;lt;0.05). To further model this, we inflamed HK2 and HUVECs with TNFα. While HUVECs showed NAMPT induction (p&amp;lt;0.001), HK2 did not (p&amp;gt;0.05). Knockdown of NAMPT blunted TNFα-dependent expression of inflammatory markers ICAM-1 (Intercellular adhesion molecule 1) (p&amp;lt;0.05) and IL-6 (Interleukin-6) (p&amp;lt;0.05) in HUVECs, as well as thrombosis-associated markers in the RNAseq, and prevented inflammatory barrier dysfunction (p&amp;lt;0.01). Conversely, in HK2, NAMPT knockdown increased TNFα-dependent expression of the injury marker LCN2 (Lipocalin-2) (p&amp;lt;0.01). CONCLUSION Despite a decline in kidney NAD+ levels during endotoxemia, we observe an upregulation of NAMPT, the primary enzyme responsible for its biosynthesis. Inflammatory induction of NAMPT may be restricted to the vascular endothelium, potentially enhancing inflammatory responses through as-yet-unknown mechanisms. These findings support the development of inducible NAMPT knockout mouse models specific to endothelial and epithelial cells to investigate cell-specific mechanisms of inflammation.

Abstract Mitochondria contain their own DNA (mtDNA) and a dedicated gene expression machinery. As the mitochondrial dimensions are close to the diffraction limit of classical light microscopy, the spatial distribution of mitochondrial proteins and in particular of mitochondrial mRNAs remains underexplored. Here, we establish single-molecule fluorescence in situ hybridization (smFISH) combined with STED and MINFLUX super-resolution microscopy (nanoscopy) to visualize individual mitochondrial mRNA molecules and associated proteins. STED nanoscopy revealed the spatial relationships between distinct mRNA species and proteins such as the RNA granule marker GRSF1, demonstrating adaptive changes in mRNA distribution and quantity in challenged mammalian cells and patient-derived cell lines. Notably, STED-smFISH showed the release of mRNAs during apoptosis, while MINFLUX revealed the folding of the mRNAs into variable shapes, as well as their spatial proximity to mitochondrial ribosomes. These protocols are transferable to various cell types and open new avenues for understanding mitochondrial gene regulation in health and disease.

SummaryBackgroundUp to now, the optimal duration of immune checkpoint inhibitors (ICI) has not been evaluated in prospective studies. However, current clinical practice requires decisions to be made regarding the duration of ICI in complete responders.Material and MethodsA survey was sent to 80 DeCOG skin cancer centers to assess how decisions are made on treatment duration of ICI in melanoma after having reached complete response, and staging intervals after ICI discontinuation. All responses received by March 10, 2024 (51 centers) were included.ResultsThe duration of ICI after having achieved complete remission varies between centers from three to 36 months. In total, 66% of the DeCOG centers continue treatment for up to 6 months, after having achieved complete remission (CR) with ICI. In the first year after discontinuation of ICI, most centers perform staging intervals (CT/MRI) every 3 months. More than 60% of centers continue staging at least once per year even in the 4th and 5th year after discontinuation.ConclusionsThere are significant differences between the centers regarding staging intervals and duration of ICI upon CR. Prospective studies are necessary to determine the optimal time point of ICI discontinuation and follow‐up.