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Excitation/inhibition (E/I) balance plays important roles in mental disorders. Bioactive phospholipids like lysophosphatidic acid (LPA) are synthesized by the enzyme autotaxin (ATX) at cortical synapses and modulate glutamatergic transmission, and eventually alter E/I balance of cortical networks. Here, we analyzed functional consequences of altered E/I balance in 25 human subjects induced by genetic disruption of the synaptic lipid signaling modifier PRG-1, which were compared to 25 age and sex matched control subjects. Furthermore, we tested therapeutic options targeting ATX in a related mouse line. Using EEG combined with TMS in an instructed fear paradigm, neuropsychological analysis and an fMRI based episodic memory task, we found intermediate phenotypes of mental disorders in human carriers of a loss-of-function single nucleotide polymorphism of PRG-1(PRG-1R345T/WT). Prg-1R346T/WTanimals phenocopied human carriers showing increased anxiety, a depressive phenotype and lower stress resilience. Network analysis revealed that coherence and phase-amplitude coupling were altered by PRG-1deficiency in memory related circuits in humans and mice alike. Brain oscillation phenotypes were restored by inhibtion of ATX in Prg-1deficient mice indicating an interventional potential for mental disorders.

Biomolecular research traditionally revolves around comprehending the mechanisms through which peptides or proteins facilitate specific functions, often driven by their relevance to clinical ailments. This conventional approach assumes that unraveling mechanisms is a prerequisite for wielding control over functionality, which stands as the ultimate research goal. However, an alternative perspective emerges from physics-based inverse design, shifting the focus from mechanisms to the direct acquisition of functional control strategies. By embracing this methodology, we can uncover solutions that might not have direct parallels in natural systems, yet yield crucial insights into the isolated molecular elements dictating functionality. This provides a distinctive comprehension of the underlying mechanisms.In this context, we elucidate how physics-based inverse design, facilitated by evolutionary algorithms and coarse-grained molecular simulations, charts a promising course for innovating the reverse engineering of biopolymers interacting with intricate fluid phases such as lipid membranes and liquid protein phases. We introduce evolutionary molecular dynamics (Evo-MD) simulations, an approach that merges evolutionary algorithms with the Martini coarse-grained force field. This method directs the evolutionary process from random amino acid sequences toward peptides interacting with complex fluid phases such as biological lipid membranes, offering significant promises in the development of peptide-based sensors and drugs. This approach can be tailored to recognize or selectively target specific attributes such as membrane curvature, lipid composition, membrane phase (e.g., lipid rafts), and protein fluid phases. Although the resulting optimal solutions may not perfectly align with biological norms, physics-based inverse design excels at isolating relevant physicochemical principles and thermodynamic driving forces governing optimal biopolymer interaction within complex fluidic environments. In addition, we expound upon how physics-based evolution using the Evo-MD approach can be harnessed to extract the evolutionary optimization fingerprints of protein–lipid interactions from native proteins. Finally, we outline how such an approach is uniquely able to generate strategic training data for predictive neural network models that cover the whole relevant physicochemical domain. Exploring challenges, we address key considerations such as choosing a fitting fitness function to delineate the desired functionality. Additionally, we scrutinize assumptions tied to system setup, the targeted protein structure, and limitations posed by the utilized (coarse-grained) force fields and explore potential strategies for guiding evolution with limited experimental data. This discourse encapsulates the potential and remaining obstacles of physics-based inverse design, paving the way for an exciting frontier in biomolecular research.

Purpose: Minimally invasive mitral valve surgery (MIMVS) and transcatheter edge-to-edge repair (TEER) are complex procedures used to treat mitral valve (MV) pathologies, but with limited training opportunities available. To enable training, a realistic hemodynamic environment is needed. In this work we aimed to develop and validate a simulator that enables investigation of MV pathologies and their repair by MIMVS and TEER in a hemodynamic setting. Methods: Different MVs were installed in the simulator, and pressure, flow, and transesophageal echocardiographic measurements were obtained. To confirm the simulator’s physiological range, we first installed a biological prosthetic, a mechanical prosthetic, and a competent excised porcine MV. Subsequently, we inserted two porcine MVs—one with induced chordae tendineae rupture and the other with a dilated annulus, along with a patient-specific silicone valve extracted from echocardiography with bi-leaflet prolapse. Finally, TEER and MIMVS procedures were conducted by experts to repair the MVs. Results: Systolic pressures, cardiac outputs, and regurgitations volumes (RVol) with competent MVs were 119 ± 1 mmHg, 4.78 ± 0.16 l min−1, and 5 ± 3 ml respectively, and thus within the physiological range. In contrast, the pathological MVs displayed increased RVols. MIMVS and TEER resulted in a decrease in RVols and mitigated the severity of mitral regurgitation. Conclusion: Ex-vivo modelling of MV pathologies and repair procedures using the described simulator realistically replicated physiological in-vivo conditions. Furthermore, we showed the feasibility of performing MIMVS and TEER at the simulator, also at patient-specific level, thus providing new clinical perspectives in terms of training modalities and personalized planning.

Die zunehmende Prävalenz der morbiden Adipositas geht auch in Deutschland mit einem deutlichen Anstieg adipositas- und metabolisch-chirurgischer Eingriffe einher. Diese sind effektiv, um die klinischen und biochemischen Manifestationen des metabolischen Syndroms positiv zu beeinflussen. Es ist nicht nur die Gewichtsreduktion durch Restriktion und Hypoabsorption, sondern es sind die bisher in ihrer Komplexität nicht verstandenen neurohumoralen Mechanismen, durch die die metabolische Chirurgie verändernd eingreift. Das Verständnis neurohumoraler Mechanismen sowie neue Techniken und Innovationen haben das Spektrum adipositas- und metabolisch-chirurgischer Eingriffe in den letzten Jahren beeinflusst. Im vorliegenden Beitrag werden die Standardmethoden mit Ausblick auf innovative Verfahren dargestellt. Ihre Auswahl und ihr Einsatz sollten sich streng an der S3-Leitlinie der CAADIP (Chirurgische Arbeitsgemeinschaft Adipositastherapie und metabolische Chirurgie) zur Adipositas und metabolischen Chirurgie orientieren [1].

Wet clutches in their open state add losses caused by drag torque to the drive train, making the optimization of the disk design and drag torque reduction a core development aspect. The present work focuses on the influence of the chosen disk-groove geometry on the resulting flow topology in open wet clutches. Therefore, the flow topology of six different disk designs is investigated experimentally and numerically. Other influences of the operating conditions such as volume flow or other design elements such as wave springs are not considered. New parameters for the flow topology are derived, for a better description of the influence of the flow topology on the drag torque. Based on these insights strategies for further understanding of the complex flow topology on open wet clutches are derived and optimization approaches proposed.

Coarse-grained force fields (CG FFs) such as the Martini model entail a predefined, fixed set of Lennard-Jones parameters (building blocks) to model virtually all possible nonbonded interactions between chemically relevant molecules. Owing to its universality and transferability, the building-block coarse-grained approach has gained tremendous popularity over the past decade. The parametrization of molecules can be highly complex and often involves the selection and fine-tuning of a large number of parameters (e.g., bead types and bond lengths) to optimally match multiple relevant targets simultaneously. The parametrization of a molecule within the building-block CG approach is a mixed-variable optimization problem: the nonbonded interactions are discrete variables, whereas the bonded interactions are continuous variables. Here, we pioneer the utility of mixed-variable particle swarm optimization in automatically parametrizing molecules within the Martini 3 coarse-grained force field by matching both structural (e.g., RDFs) as well as thermodynamic data (phase-transition temperatures). For the sake of demonstration, we parametrize the linker of the lipid sphingomyelin. The important advantage of our approach is that both bonded and nonbonded interactions are simultaneously optimized while conserving the search efficiency of vector guided particle swarm optimization (PSO) methods over other metaheuristic search methods such as genetic algorithms. In addition, we explore noise-mitigation strategies in matching the phase-transition temperatures of lipid membranes, where nucleation and concomitant hysteresis introduce a dominant noise term within the objective function. We propose that noise-resistant mixed-variable PSO methods can both improve and automate parametrization of molecules within building-block CG FFs, such as Martini.

Milk carotenoids may support preterm infant health and neurodevelopment. Infants fed human milk often have higher blood and tissue carotenoid concentrations than infants fed carotenoid-containing infant formula (IF). Donor human milk (DHM) is a supplement to mother’s own milk, used to support preterm infant nutrition.

•Germline heterozygosity for a thrombocytopenia 5–associated ETV6variant impairs the repopulating capacity of mouse HSPCs.•In HSPCs, ETV6 binds to Tnfand other inflammatory gene loci and represses their expression during stress hematopoiesis.

The battery tray is an essential component that protects and controls battery-cell temperatures in electric and plug-in hybrid vehicles. The functional stress limit of the battery tray heavily depends on the residual stress acquired from the manufacturing process. Consequently, exceeding the stress limit of the battery tray during operation could compromise the battery-cell banks and may risk the vehicle's safety. Hence, understanding residual stress formation is vital for design and safety concerns. In the current study, AA 6061-plates were friction stir welded to an A365 high-pressure die-cast battery tray to create sealed coolant channels in the battery tray. However, this multi-material lap friction stir weld introduces residual stress into the battery tray, resulting in distortion. This distortion was mitigated using burnishing or coining operations, though straightening the battery tray had initially unknown effects on the residual stress. Therefore, neutron diffraction was utilized to characterize residual stresses after straightening. The results indicate that the friction stir welding (FSW) operation generated residual stresses exceeding the yield strength of the material, consequently deforming the battery tray by ±3 mm from the pre-weld geometry. The burnishing operation reduced the residual stresses below the material's yield strength while restoring the tray to within ±0.75 mm of the pre-weld geometry. Similarly, the coining operation restored the battery tray to within ±0.75 mm of the pre-weld geometry, however, increasing the number of locations where the residual stress exceeds the yield strength of the material.

In response to the emergence of SARS-CoV-2 variants of concern, the global scientific community, through unprecedented effort, has sequenced and shared over 11 million genomes through GISAID, as of May 2022. This extraordinarily high sampling rate provides a unique opportunity to track the evolution of the virus in near real-time. Here, we present outbreak.info, a platform that currently tracks over 40 million combinations of Pango lineages and individual mutations, across over 7,000 locations, to provide insights for researchers, public health officials and the general public. We describe the interpretable visualizations available in our web application, the pipelines that enable the scalable ingestion of heterogeneous sources of SARS-CoV-2 variant data and the server infrastructure that enables widespread data dissemination via a high-performance API that can be accessed using an R package. We show how outbreak.infocan be used for genomic surveillance and as a hypothesis-generation tool to understand the ongoing pandemic at varying geographic and temporal scales.

Oncogenic KRAS is the key driver oncogene for several of the most aggressive human cancers. One key feature of oncogenic KRAS expression is an early increase in cellular reactive oxygen species (ROS) which promotes cellular transformation if cells manage to escape cell death, mechanisms of which remain incompletely understood. Here, we identify that expression of oncogenic as compared to WT KRAS in isogenic cellular systems renders cells more resistant to ferroptosis, a recently described type of regulated necrosis. Mechanistically, we find that cells with mutant KRAS show a specific lack of ferroptosis-induced lipid peroxidation. Interestingly, KRAS-mutant cells upregulate expression of ferroptosis suppressor protein 1 (FSP1). Indeed, elevated levels of FSP1 in KRAS-mutant cells are responsible for mediating ferroptosis resistance and FSP1 is upregulated as a consequence of MAPK and NRF2 pathway activation downstream of KRAS. Strikingly, FSP1 activity promotes cellular transformation in soft agar and its overexpression is sufficient to promote spheroid growth in 3D in KRAS WT cells. Moreover, FSP1 expression and its activity in ferroptosis inhibition accelerates tumor onset of KRAS WT cells in the absence of oncogenic KRAS in vivo. Consequently, we find that pharmacological induction of ferroptosis in pancreatic organoids derived from the LsL-KRASG12Dexpressing mouse model is only effective in combination with FSP1 inhibition. Lastly, FSP1 is upregulated in non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) as compared to the respective normal tissue of origin and correlates with NRF2 expression in PDAC patient datasets. Based on these data, we propose that KRAS-mutant cells must navigate a ferroptosis checkpoint by upregulating FSP1 during tumor establishment. Consequently, ferroptosis-inducing therapy should be combined with FSP1 inhibitors for efficient therapy of KRAS-mutant cancers.

Digital technologies such as 5G, augmented reality, and artificial intelligence (AI) are currently being used in various ways by manufacturing companies. As the fourth industrial revolution progresses, it has become apparent that reckless use and inadequate regulation of these technologies have a detrimental effect on the environment in which they are utilized. Therefore, regulation of digital technologies is imperative today to ensure more responsible and sustainable use. While governments usually establish regulations, progress is not keeping pace with the demands and hazards of employing digital technologies. The European AI law serves as an example of the considerable distance yet to be covered before binding guidelines are established. Consequently, companies must take proactive measures today to ensure that they use digital technologies responsibly in their environments. In this context, identifying which digital technologies are pertinent to manufacturing companies in terms of regulation is crucial. Furthermore, a comprehensive approach is required to design compliance holistically for digital technologies and to systematically derive the corresponding guidelines. This paper introduces a set of models that not only determine the importance of compliance in the application of different technologies but also present a framework for methodically designing compliance. Furthermore, the paper contributes to the development of an AI platform in the German research project PAIRS by investigating the compliance relevance of applications such as artificial intelligence.

Precision medicine promises to transform healthcare for groups and individuals through early disease detection, refining diagnoses and tailoring treatments. Analysis of large-scale genomic–phenotypic databases is a critical enabler of precision medicine. Although Asia is home to 60% of the world’s population, many Asian ancestries are under-represented in existing databases, leading to missed opportunities for new discoveries, particularly for diseases most relevant for these populations. The Singapore National Precision Medicine initiative is a whole-of-government 10-year initiative aiming to generate precision medicine data of up to one million individuals, integrating genomic, lifestyle, health, social and environmental data. Beyond technologies, routine adoption of precision medicine in clinical practice requires social, ethical, legal and regulatory barriers to be addressed. Identifying driver use cases in which precision medicine results in standardized changes to clinical workflows or improvements in population health, coupled with health economic analysis to demonstrate value-based healthcare, is a vital prerequisite for responsible health system adoption.

The drive to lower the carbon footprint of the automotive industry has led to the development of high efficiency diesel engines. The materials used for diesel engine components must withstand greater thermomechanical loading, as compared to gasoline engines. Thus, to determine the feasibility of using conventional aluminum-based powertrain alloys for next generation high efficiency engines, the present study evaluates the elevated temperature (250 and 300 °C) tensile and creep performance of a T7 319-type alloy. To represent real-world conditions, the 319 samples used in this study were extracted from the cylinder bridges of a sand cast engine block and then conditioned at their respective test temperatures for 200 hours. The results indicate that at 250 °C (~30–50 °C above current engine operating temperatures), the tensile strength and creep resistance of the T7 319 alloy will be able to withstand current cylinder pressures (i.e., 22 MPa) and may allow for an increase up to 30–35 MPa. However, at 300 °C, the strength decreases by more than 50% and tertiary creep initiates at 40 MPa. As such, the inherent evolution of residual stress during current engine block manufacturing technologies prevents the safe use of the 319 alloy in engine applications operating at 300 °C.

Introduction: One of the most severe side effects of sleeve gastrectomy (SG) is the development or aggravation of reflux disease. This study investigates the effect of SG on the development of reflux disease and the variables that may impact this development. In addition, trends in revision surgery, weight, and comorbidity are examined among patients with reflux disease and SG and those without reflux disease and SG. This study includes 3379 individuals without reflux disease who had primary SG and were followed for three years. The demographic characteristics, comorbidities, technical features, and complications of SG were analyzed. Data were collected by the German Bariatric Surgery Registry (GBSR). 860 (25.45%) Group A patients had reflux disease following SG (Group B: no reflux after SG; 74.55%). Patients with reflux disease had longer operating times (83.8 min vs. 77.5 min, p< 0.001) and longer postoperative hospital admissions (6 days vs. 5.5 days). In group A, the %EWL was substantially greater than in group B (64.1 vs. 61.1%). 42 patients were converted from SG to RYGB (4.88%), 2 had hiatoplasty, and 5 got Endostim. There is no significant variation in perioperative complications (pvalue > 0.05). The incidence of complete remission of sleep apnea was higher in group A than in group B (p= 0.013; 50% vs. 44.8%). Other comorbidities were not substantially different. Reflux illness after SG is still poorly understood, despite much research. Technical and preoperative variables may promote its development. However, these assumptions remain theoretical and are not confirmed by scientific data. The majority of patients may be successfully treated using non-invasive methods, although sometimes further surgery is necessary. Despite our results and the literature, this subject is intriguing for further research. Graphical abstract:

In biological systems, proteins can be attracted to curved or stretched regions of lipid bilayers by sensing hydrophobic defects in the lipid packing on the membrane surface. Here, we present an efficient end-state free energy calculation method to quantify such sensing in molecular dynamics simulations. We illustrate that lipid packing defect sensing can be defined as the difference in mechanical work required to stretch a membrane with and without a peptide bound to the surface. We also demonstrate that a peptide’s ability to concurrently induce excess leaflet area (tension) and elastic softening─a property we call the “characteristic area of sensing” (CHAOS)─and lipid packing sensing behavior are in fact two sides of the same coin. In essence, defect sensing displays a peptide’s propensity to generate tension. The here-proposed mechanical pathway is equally accurate yet, computationally, about 40 times less costly than the commonly used alchemical pathway (thermodynamic integration), allowing for more feasible free energy calculations in atomistic simulations. This enabled us to directly compare the Martini 2 and 3 coarse-grained and the CHARMM36 atomistic force fields in terms of relative binding free energies for six representative peptides including the curvature sensor ALPS and two antiviral amphipathic helices (AH). We observed that Martini 3 qualitatively reproduces experimental trends while producing substantially lower (relative) binding free energies and shallower membrane insertion depths compared to atomistic simulations. In contrast, Martini 2 tends to overestimate (relative) binding free energies. Finally, we offer a glimpse into how our end-state-based free energy method can enable the inverse design of optimal lipid packing defect sensing peptides when used in conjunction with our recently developed evolutionary molecular dynamics (Evo-MD) method. We argue that these optimized defect sensors─aside from their biomedical and biophysical relevance─can provide valuable targets for the development of lipid force fields.

Biomarkers that predict response to lenalidomide maintenance therapy in patients with multiple myeloma (MM) have remained elusive. We have shown that immunomodulatory drugs (IMiDs) exert anti-MM activity via destabilization of MCT1 and CD147. In this study, cell samples of 654 patients with MM who received lenalidomide (n = 455), thalidomide (n = 98), or bortezomib (n = 101) maintenance were assessed by gene expression profiling and RNA sequencing, followed by correlation of MCT1 and CD147 expression with data for progression-free survival (PFS) and overall survival (OS). Patients with high expression levels of MCT1 showed significantly reduced PFS (31.9 months vs 48.2 months in MCT1high vs MCT1low; P = .03) and OS (75.9 months vs not reached [NR] in MCT1high vs MCT1low; P = .001) in cases with lenalidomide maintenance, whereas MCT1 expression had no significant impact on PFS or OS in cases with bortezomib maintenance. We validated the predictive role of MCT1 for IMiD-based maintenance in an independent cohort of patients who received thalidomide (OS, 83.6 months vs NR in MCT1high vs MCT1low; P = .03). Functional validation showed that MCT1 overexpression in human MM cell lines significantly reduced the efficacy of lenalidomide, whereas no change was observed with bortezomib treatment, either in vitro or in a MM xenograft model. Our findings have established MCT1 expression as a predictive marker for response to lenalidomide-based maintenance in patients with MM.

Biomarkers that predict response to lenalidomide maintenance therapy in patients with multiple myeloma (MM) have remained elusive. We have shown that immunomodulatory drugs (IMiDs) exert anti-MM activity via destabilization of MCT1 and CD147. In this study, cell samples of 654 patients with MM who received lenalidomide (n = 455), thalidomide (n = 98), or bortezomib (n = 101) maintenance were assessed by gene expression profiling and RNA sequencing, followed by correlation of MCT1and CD147expression with data for progression-free survival (PFS) and overall survival (OS). Patients with high expression levels of MCT1showed significantly reduced PFS (31.9 months vs 48.2 months in MCT1highvs MCT1low; P= .03) and OS (75.9 months vs not reached [NR] in MCT1highvs MCT1low; P= .001) in cases with lenalidomide maintenance, whereas MCT1expression had no significant impact on PFS or OS in cases with bortezomib maintenance. We validated the predictive role of MCT1for IMiD-based maintenance in an independent cohort of patients who received thalidomide (OS, 83.6 months vs NR in MCT1highvs MCT1low; P= .03). Functional validation showed that MCT1 overexpression in human MM cell lines significantly reduced the efficacy of lenalidomide, whereas no change was observed with bortezomib treatment, either in vitro or in a MM xenograft model. Our findings have established MCT1expression as a predictive marker for response to lenalidomide-based maintenance in patients with MM.

Focused on improving the elevated-temperature performance of the B319 aluminum alloy, this paper investigates, for the first time, the effects that varying Ce additions (i.e., 0.1, 0.3, 0.5, and 1.0 wt% Ce) have on the microstructure, hardness, and tensile properties of the alloy, following a conditioning process. The hardness tests were performed at room temperature before and after exposing the samples to 250 and 300 °C for 250 h. It was found that the hardness of the B319 + 0.1%Ce alloy was the highest in all three conditions, showing improvements of 9–11%. For the tensile tests, the cast alloys were tested at room temperature, 250 °C before conditioning, and at 250 and 300 °C after conditioning at their test temperatures (i.e., 250 and 300 °C) for 250 h. In all conditions, the B319 + 0.1%Ce demonstrated the greatest strength during the tensile test and consistently had YS and UTS values 6–10% greater than the unmodified B319 alloy. However, by comparing the YS and UTS values before and after conditioning, it was observed that the Ce additions had little effect on the strength retention, and in some cases (i.e., higher Ce concentrations), the strength retention was worse than for the unmodified B319 alloy.

Climate risk factors, including wildfire, sea level rise, inland flooding, and extreme heat, as well as gentrification displacement pressures will be primary drivers of migration in the coming years. Travel demand modeling relies on reasonable and appropriate forecasts of demographic totals at the detail of travel analysis zones. Methodologies for developing scenarios in response to individual and combined climate risk factors are described, drawing on work undertaken for the Southern California Association of Governments SoCal Regional Climate Adaptation Framework. Methodologies for developing scenarios in response to gentrification displacement pressures of low-income workers are described, drawing on work carried out for the California Statewide Freight Forecasting and Travel Demand Model. These methodologies leverage modeling tools that are readily available to agencies, allowing for rapid testing of scenarios and integration with other planning processes. Climate adaptation and housing policy, respectively, are currently in need of greater integration and coordination. Future directions are explored to integrate these methodologies and create a combined demographic relocation model, sensitive to both climate risk factors and the affordability and gentrification displacement pressures arising out of shifting demand–supply dynamics and population–job balance in high growth areas.

Bariatric surgery has expanded tremendously internationally over the past decade. In recent years, bariatric surgery has experienced a significant growth in Germany. However, the question arises as to whether this development is in line with international developments or whether there is still room for improvement that could be challenged. 63,990 primary bariatric procedures recorded in the German Bariatric Surgery Registry (GBSR) were analyzed from 2005 to April 2021. The distribution of procedures according to different variants was analyzed and presented. In the last 16 years, 17 different procedures have been performed. The most common surgical procedure was sleeve gastrectomy (SG), followed by Roux-Y gastric bypass (RYGB) (42%). Adjustable gastric banding (AGB) has declined over time, from 23.5% in the first 5 years to 0.2% in recent years. In comparison, omega-loop gastric bypass has increased over the past 5 years (from 0.4% in the first 5 years to 5.9% in the last 5 years). Laparoscopic procedures have accounted for 96.4% of all bariatric surgeries in recent years. The frequency of some procedures has decreased and some bariatric procedures have lost significance. Overall, bariatric surgery in Germany has developed positively compared to the international trend. Nevertheless, there is one area that needs to be optimized: the development of robotic bariatric surgery, which crawls behind in Germany compared to other countries. To establish the technology in bariatric surgery in a timely manner, a balance must be found between cost neutrality and patient-oriented applications.

Mitochondrial-derived vesicles (MDVs) are implicated in diverse physiological processes—for example, mitochondrial quality control—and are linked to various neurodegenerative diseases. However, their specific cargo composition and complex molecular biogenesis are still unknown. Here we report the proteome and lipidome of steady-state TOMM20+MDVs. We identified 107 high-confidence MDV cargoes, which include all β-barrel proteins and the TOM import complex. MDV cargoes are delivered as fully assembled complexes to lysosomes, thus representing a selective mitochondrial quality control mechanism for multi-subunit complexes, including the TOM machinery. Moreover, we define key biogenesis steps of phosphatidic acid-enriched MDVs starting with the MIRO1/2-dependent formation of thin membrane protrusions pulled along microtubule filaments, followed by MID49/MID51/MFF-dependent recruitment of the dynamin family GTPase DRP1 and finally DRP1-dependent scission. In summary, we define the function of MDVs in mitochondrial quality control and present a mechanistic model for global GTPase-driven MDV biogenesis.

Claviceps purpureais an ergot fungus known for its neurotropic alkaloids, which have been identified as the main cause of ergotism, a livestock and human disease triggered by ergot consumption. Tetrahydroxanthone dimers, the so-called ergopigments, presumably also contribute to this toxic effect. Overexpression of the cluster-specific transcription factor responsible for the formation of these pigments in C. purpurealed to the isolation of three new metabolites (8–10). The new pigments were characterized utilizing HRMS, NMR techniques, and CD spectroscopy and shown to be xanthone dimers. Secalonic acid A and its 2,4′- and 4,4′-linked isomers were also isolated, and their absolute configuration was investigated. The contribution of secalonic acid A, its isomers, and new metabolites to the toxicity of C. purpureawas investigated in HepG2 and CCF-STTG1 cells. Along with cytotoxic properties, secalonic acid A was found to inhibit topoisomerase I and II activity.