TY - JOUR AB - Previous health impact assessments of temperature-related mortality in Europe indicated that the mortality burden attributable to cold is much larger than for heat. Questions remain as to whether climate change can result in a net decrease in temperature-related mortality. In this study, we estimated how climate change could affect future heat-related and cold-related mortality in 854 European urban areas, under several climate, demographic and adaptation scenarios. We showed that, with no adaptation to heat, the increase in heat-related deaths consistently exceeds any decrease in cold-related deaths across all considered scenarios in Europe. Under the lowest mitigation and adaptation scenario (SSP3-7.0), we estimate a net death burden due to climate change increasing by 49.9% and cumulating 2,345,410 (95% confidence interval = 327,603 to 4,775,853) climate change-related deaths between 2015 and 2099. This net effect would remain positive even under high adaptation scenarios, whereby a risk attenuation of 50% is still insufficient to reverse the trend under SSP3-7.0. Regional differences suggest a slight net decrease of death rates in Northern European countries but high vulnerability of the Mediterranean region and Eastern Europe areas. Unless strong mitigation and adaptation measures are implemented, most European cities should experience an increase of their temperature-related mortality burden. AU - Masselot, P.* AU - Mistry, M.N.* AU - Rao, S.* AU - Huber, V. AU - Monteiro, A.* AU - Samoli, E.* AU - Stafoggia, M.* AU - de'Donato, F.* AU - García-León, D.* AU - Ciscar, J.C.* AU - Feyen, L.* AU - Schneider, A.E. AU - Katsouyanni, K.* AU - Vicedo-Cabrera, A.M.* AU - Aunan, K.* AU - Gasparrini, A.* C1 - 73193 C2 - 56952 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Estimating future heat-related and cold-related mortality under climate change, demographic and adaptation scenarios in 854 European cities. JO - Nat. Med. PB - Nature Portfolio PY - 2025 SN - 1078-8956 ER - TY - JOUR AB - Prevention research aims to understand, mitigate and ultimately avert the onset and progression of disease and the spillover of pathogens. Such research includes the analysis of risk factors and fundamental mechanisms of disease emergence, early detection and screening, stratification into risk groups, and the development and evaluation of preventive interventions. In the face of population aging and escalating planetary health challenges, such as the climate crisis1, prevention research is crucial in mitigating the burden of both non-communicable and communicable diseases. AU - Peters, A. AU - Knauthe, N.* AU - Hamann, S.* AU - Leendertz, F.H.* AU - Lange, B.* AU - Guzman, C.A.* AU - Grün, B.* AU - Jewell, S.* AU - Breteler, M.M.B.* AU - Aziz, N.A.* AU - Schiattarella, G.G.* AU - Lee, Y.A.* AU - Landthaler, M.* AU - Gorski, S.A.* AU - Steindorf, K.* AU - Hoffmeister, M.* AU - Braun, A.* AU - Ziegler, A.-G. AU - von Mutius, E. AU - Krüger, J. AU - Mons, U.* AU - Zeggini, E. C1 - 74258 C2 - 57371 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 1386–1387 TI - Helmholtz Health task force to strengthen prevention research and its translation globally. JO - Nat. Med. VL - 31 PB - Nature Portfolio PY - 2025 SN - 1078-8956 ER - TY - JOUR AB - Clinical practice guidelines recommend defined weight loss goals for the prevention of type 2 diabetes (T2D) in those individuals with increased risk, such as prediabetes. However, achieving prediabetes remission, that is, reaching normal glucose regulation according to American Diabetes Association criteria, is more efficient in preventing T2D than solely reaching weight loss goals. Here we present a post hoc analysis of the large, multicenter, randomized, controlled Prediabetes Lifestyle Intervention Study (PLIS), demonstrating that prediabetes remission is achievable without weight loss or even weight gain, and that it also protects against incident T2D. The underlying mechanisms include improved insulin sensitivity, β-cell function and increments in β-cell-GLP-1 sensitivity. Weight gain was similar in those achieving prediabetes remission (responders) compared with nonresponders; however, adipose tissue was differentially redistributed in responders and nonresponders when compared against each other-while nonresponders increased visceral adipose tissue mass, responders increased adipose tissue in subcutaneous depots. The findings were reproduced in the US Diabetes Prevention Program. These data uncover essential pathways for prediabetes remission without weight loss and emphasize the need to include glycemic targets in current clinical practice guidelines to improve T2D prevention. AU - Sandforth, A. AU - Arreola, E.V.* AU - Hanson, R.L.* AU - Wewer Albrechtsen, N.J.* AU - Holst, J.J.* AU - Ahrends, R.* AU - Coman, C.* AU - Gerst, F. AU - Lorza-Gil, E. AU - Cheng, Y. AU - Sandforth, L. AU - Katzenstein, S. AU - Ganslmeier, M. AU - Seissler, J.* AU - Hauner, H.* AU - Perakakis, N. AU - Wagner, R.* AU - Machann, J. AU - Schick, F. AU - Peter, A. AU - Lehmann, R. AU - Weigert, C. AU - Maurer, J. AU - Preissl, H. AU - Heni, M.* AU - Szendrödi, J.* AU - Kopf, S.* AU - Solimena, M. AU - Schwarz, P.* AU - Blüher, M. AU - Häring, H.-U. AU - Hrabě de Angelis, M. AU - Schürmann, A.* AU - Kabisch, S.* AU - Mai, K.* AU - Pfeiffer, A.F.H.* AU - Bornstein, S.* AU - Stumvoll, M. AU - Roden, M.* AU - Stefan, N. AU - Fritsche, A. AU - Birkenfeld, A.L. AU - Jumpertz von Schwartzenberg, R. C1 - 75668 C2 - 58069 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 3330-3340 TI - Prevention of type 2 diabetes through prediabetes remission without weight loss. JO - Nat. Med. VL - 31 IS - 10 PB - Nature Portfolio PY - 2025 SN - 1078-8956 ER - TY - JOUR AB - Polygenic scores (PGSs) for body mass index (BMI) may guide early prevention and targeted treatment of obesity. Using genetic data from up to 5.1 million people (4.6% African ancestry, 14.4% American ancestry, 8.4% East Asian ancestry, 71.1% European ancestry and 1.5% South Asian ancestry) from the GIANT consortium and 23andMe, Inc., we developed ancestry-specific and multi-ancestry PGSs. The multi-ancestry score explained 17.6% of BMI variation among UK Biobank participants of European ancestry. For other populations, this ranged from 16% in East Asian-Americans to 2.2% in rural Ugandans. In the ALSPAC study, children with higher PGSs showed accelerated BMI gain from age 2.5 years to adolescence, with earlier adiposity rebound. Adding the PGS to predictors available at birth nearly doubled explained variance for BMI from age 5 onward (for example, from 11% to 21% at age 8). Up to age 5, adding the PGS to early-life BMI improved prediction of BMI at age 18 (for example, from 22% to 35% at age 5). Higher PGSs were associated with greater adult weight gain. In intensive lifestyle intervention trials, individuals with higher PGSs lost modestly more weight in the first year (0.55 kg per s.d.) but were more likely to regain it. Overall, these data show that PGSs have the potential to improve obesity prediction, particularly when implemented early in life. AU - Smit, R.A.J.* AU - Wade, K.H.* AU - Hui, Q.* AU - Arias, J.D.* AU - Yin, X.* AU - Christiansen, M.R.* AU - Yengo, L.* AU - Preuss, M.H.* AU - Nakabuye, M.* AU - Rocheleau, G.* AU - Graham, S.E.* AU - Buchanan, V.L.* AU - Sakaue, S.* AU - Vedantam, S.* AU - Wilson, E.P.* AU - Chen, S.H.* AU - Ferreira, T.* AU - Lüll, K.* AU - Akiyama, M.* AU - Allison, M.A.* AU - Alvarez, M.* AU - Andersen, M.K.* AU - Cañadas-Garre, M.* AU - Chai, J.F.* AU - Chesi, A.* AU - Choi, S.H.* AU - Christofidou, P.* AU - Delgado, G.E.* AU - Delitala, A.* AU - Deng, X.* AU - Eichelmann, F.* AU - Faul, J.D.* AU - Fernandez-Lopez, J.C.* AU - Guo, X.* AU - Gustafsson, S.* AU - Haworth, S.J.* AU - Heard-Costa, N.* AU - Hemerich, D.* AU - Highland, H.M.* AU - Katsuya, T.* AU - Kawaguchi, T.* AU - Leonard, H.L.* AU - Li, H.* AU - Liang, J.* AU - Lin, H.* AU - Lin, K.* AU - Lorés-Motta, L.* AU - Lyytikäinen, L.P.* AU - Malik, M.Z.* AU - Mattheisen, M.* AU - Melendez, T.L.* AU - Milaneschi, Y.* AU - Mononen, N.* AU - Mucha, S.* AU - Mykkänen, J.* AU - Nho, C.W.* AU - Nielsen, A.A.* AU - Ntalla, I.* AU - Pauper, M.* AU - Petersen, E.R.B.* AU - Petersen, L.V.* AU - Raffield, L.M.* AU - Rasheed, A.* AU - Rayner, N.W. AU - Ruggiero, D.* AU - Shin, J.H.* AU - Sidore, C.* AU - Sim, X.* AU - Smith, J.A.* AU - Smyth, L.J.* AU - Southam, L. AU - Tayo, B.O.* AU - Tesolin, P.* AU - Trompet, S.* AU - van Klinken, J.B.* AU - van Setten, J.* AU - Wang, C.A.* AU - Wang, Z.* AU - Wielscher, M.* AU - Zhou, W.* AU - Asselbergs, F.W.* AU - Åsvold, B.O.* AU - Bennett, D.A.* AU - Borja, J.B.* AU - Brandslund, I.* AU - Brumpton, B.* AU - Chandak, G.R.* AU - Chanock, S.J.* AU - Chaturvedi, N.* AU - Chen, Z.* AU - Cole, J.W.* AU - Dedoussis, G.V.* AU - den Hollander, A.I.* AU - Evans, M.K.* AU - Ferrucci, L.* AU - Fornage, M.* AU - Gieger, C. AU - González-Villalpando, C.* AU - Gordon-Larsen, P.* AU - Grallert, H. AU - Griffiths, L.* AU - Hansen, T.* AU - Hartman, C.A.* AU - Hattersley, A.T.* AU - Huang, W.* AU - Huffman, J.E.* AU - Ichihara, S.* AU - Ikram, M.A.* AU - Jöckel, K.H.* AU - Kardia, S.L.R.* AU - Karpe, F.* AU - Kiemeney, L.A.L.M.* AU - Kirchhof, P.* AU - Kraaijeveld, A.O.* AU - Kumari, M.* AU - Laakso, M.* AU - Lee, N.R.* AU - Lehtimäki, T.* AU - London, B.* AU - Lubitz, S.A.* AU - Mitchell, B.D.* AU - Mitchell, P.* AU - Nalls, M.A.* AU - Newton-Cheh, C.* AU - Niinikoski, H.* AU - Nikus, K.* AU - Oldehinkel, A.J.* AU - Parra, E.J.* AU - Pennell, C.E.* AU - Peters, A. AU - Province, M.A.* AU - Fatumo, S.* AU - McCaffery, J.M.* AU - Timpson, N.J.* AU - Hirschhorn, J.N.* AU - Sun, Y.V.* AU - Berndt, S.I.* AU - Loos, R.J.F.* C1 - 75197 C2 - 57853 TI - Polygenic prediction of body mass index and obesity through the life course and across ancestries. JO - Nat. Med. PY - 2025 SN - 1078-8956 ER - TY - JOUR AB - To fully harness precision medicine and transform cancer care for the better will require a strategic shift to highly personalized interventions that embrace innovation and adaptability. AU - Subbiah, V.* AU - Curigliano, G.* AU - Sicklick, J.K.* AU - Kato, S.* AU - Taskén, K.* AU - Medford, A.* AU - Rieke, D.T.* AU - Chen, H.Z.* AU - Wahida, A. AU - Buschhorn, L.* AU - Horgan, D.* AU - Kurzrock, R.* C1 - 74677 C2 - 57545 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Cancer treatment paradigms in the precision medicine era. JO - Nat. Med. PB - Nature Portfolio PY - 2025 SN - 1078-8956 ER - TY - JOUR AB - Early-onset SCN2A developmental and epileptic encephalopathy is caused by SCN2A gain-of-function variants. Here we describe the clinical experience with intrathecally administered elsunersen, a gapmer antisense oligonucleotide targeting SCN2A, in a female preterm infant with early-onset SCN2A developmental and epileptic encephalopathy, in an expanded access program. Before elsunersen treatement, the patient was in status epilepticus for 7 weeks with a seizure frequency of 20-25 per hour. Voltage-clamp experiments confirmed impaired channel inactivation and increased persistent current consistent with a gain-of-function mechanism. Elsunersen treatment demonstrated a favorable safety profile with no severe or serious adverse events reported after 19 intrathecal administrations over 20 months. After administration in combination with sodium channel blockers, status epilepticus was interrupted intermittently and ultimately ceased after continued dosing. A >60% reduction in seizure frequency corresponding to five to seven seizures per hour was observed, which has been sustained during follow-up until the age of 22 months. These data provide preliminary insights on the safety and efficacy of elsunersen in a preterm infant. Additional investigation on the benefits of elsunersen in clinical trials is warranted. AU - Wagner, M. AU - Berecki, G.* AU - Fazeli, W.* AU - Nussbaum, C.* AU - Flemmer, A.W.* AU - Frizzo, S.* AU - Heer, F.* AU - Heinen, F.* AU - Horton, R.* AU - Jacotin, H.* AU - Motel, W.* AU - Spar, B.* AU - Klein, C.* AU - Siegel, C.* AU - Hübener, C.* AU - Stöcklein, S.* AU - Paolini, M.* AU - Staudt, M.* AU - Tacke, M.* AU - Wolff, M.* AU - Petrou, S.* AU - Souza, M.* AU - Borggraefe, I.* C1 - 74168 C2 - 57359 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Antisense oligonucleotide treatment in a preterm infant with early-onset SCN2A developmental and epileptic encephalopathy. JO - Nat. Med. PB - Nature Portfolio PY - 2025 SN - 1078-8956 ER - TY - JOUR AB - Causal machine learning (ML) offers flexible, data-driven methods for predicting treatment outcomes including efficacy and toxicity, thereby supporting the assessment and safety of drugs. A key benefit of causal ML is that it allows for estimating individualized treatment effects, so that clinical decision-making can be personalized to individual patient profiles. Causal ML can be used in combination with both clinical trial data and real-world data, such as clinical registries and electronic health records, but caution is needed to avoid biased or incorrect predictions. In this Perspective, we discuss the benefits of causal ML (relative to traditional statistical or ML approaches) and outline the key components and steps. Finally, we provide recommendations for the reliable use of causal ML and effective translation into the clinic. AU - Feuerriegel, S.* AU - Frauen, D.* AU - Melnychuk, V.* AU - Schweisthal, J.* AU - Hess, K.* AU - Curth, A.* AU - Bauer, S. AU - Kilbertus, N. AU - Kohane, I.S.* AU - van der Schaar, M.* C1 - 70532 C2 - 55648 SP - 958-968 TI - Causal machine learning for predicting treatment outcomes. JO - Nat. Med. VL - 30 IS - 4 PY - 2024 SN - 1078-8956 ER - TY - JOUR AB - Clinical decision-making is one of the most impactful parts of a physician's responsibilities and stands to benefit greatly from artificial intelligence solutions and large language models (LLMs) in particular. However, while LLMs have achieved excellent performance on medical licensing exams, these tests fail to assess many skills necessary for deployment in a realistic clinical decision-making environment, including gathering information, adhering to guidelines, and integrating into clinical workflows. Here we have created a curated dataset based on the Medical Information Mart for Intensive Care database spanning 2,400 real patient cases and four common abdominal pathologies as well as a framework to simulate a realistic clinical setting. We show that current state-of-the-art LLMs do not accurately diagnose patients across all pathologies (performing significantly worse than physicians), follow neither diagnostic nor treatment guidelines, and cannot interpret laboratory results, thus posing a serious risk to the health of patients. Furthermore, we move beyond diagnostic accuracy and demonstrate that they cannot be easily integrated into existing workflows because they often fail to follow instructions and are sensitive to both the quantity and order of information. Overall, our analysis reveals that LLMs are currently not ready for autonomous clinical decision-making while providing a dataset and framework to guide future studies. AU - Hager, P.* AU - Jungmann, F.* AU - Holland, R.* AU - Bhagat, K.* AU - Hubrecht, I.* AU - Knauer, M.* AU - Vielhauer, J.* AU - Makowski, M.* AU - Braren, R.* AU - Kaissis, G. AU - Rueckert, D.* C1 - 71056 C2 - 55900 TI - Evaluation and mitigation of the limitations of large language models in clinical decision-making. JO - Nat. Med. PY - 2024 SN - 1078-8956 ER - TY - JOUR AB - With progressive digitalization of healthcare systems worldwide, large-scale collection of electronic health records (EHRs) has become commonplace. However, an extensible framework for comprehensive exploratory analysis that accounts for data heterogeneity is missing. Here we introduce ehrapy, a modular open-source Python framework designed for exploratory analysis of heterogeneous epidemiology and EHR data. ehrapy incorporates a series of analytical steps, from data extraction and quality control to the generation of low-dimensional representations. Complemented by rich statistical modules, ehrapy facilitates associating patients with disease states, differential comparison between patient clusters, survival analysis, trajectory inference, causal inference and more. Leveraging ontologies, ehrapy further enables data sharing and training EHR deep learning models, paving the way for foundational models in biomedical research. We demonstrate ehrapy's features in six distinct examples. We applied ehrapy to stratify patients affected by unspecified pneumonia into finer-grained phenotypes. Furthermore, we reveal biomarkers for significant differences in survival among these groups. Additionally, we quantify medication-class effects of pneumonia medications on length of stay. We further leveraged ehrapy to analyze cardiovascular risks across different data modalities. We reconstructed disease state trajectories in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on imaging data. Finally, we conducted a case study to demonstrate how ehrapy can detect and mitigate biases in EHR data. ehrapy, thus, provides a framework that we envision will standardize analysis pipelines on EHR data and serve as a cornerstone for the community. AU - Heumos, L. AU - Ehmele, P. AU - Treis, T. AU - Upmeier Zu Belzen, J.* AU - Roellin, E. AU - May, L. AU - Namsaraeva, A. AU - Horlava, N. AU - Shitov, V.A. AU - Zhang, X. AU - Zappia, L. AU - Knöll, R.* AU - Lang, N.J. AU - Hetzel, L. AU - Virshup, I. AU - Sikkema, L. AU - Curion, F. AU - Eils, R.* AU - Schiller, H. AU - Hilgendorff, A. AU - Theis, F.J. C1 - 71707 C2 - 56380 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - An open-source framework for end-to-end analysis of electronic health record data. JO - Nat. Med. PB - Nature Portfolio PY - 2024 SN - 1078-8956 ER - TY - JOUR AU - Manco, M.* AU - Helgason, T.* AU - Körner, A. AU - Nowicka, P.* AU - O'Malley, G.* AU - Baker, J.L.* C1 - 71970 C2 - 56408 TI - Time for a new framework that treats obesity in children as an adiposity-based chronic disease. JO - Nat. Med. PY - 2024 SN - 1078-8956 ER - TY - JOUR AB - Acute and chronic coronary syndromes (ACS and CCS) are leading causes of mortality. Inflammation is considered a key pathogenic driver of these diseases, but the underlying immune states and their clinical implications remain poorly understood. Multiomic factor analysis (MOFA) allows unsupervised data exploration across multiple data types, identifying major axes of variation and associating these with underlying molecular processes. We hypothesized that applying MOFA to multiomic data obtained from blood might uncover hidden sources of variance and provide pathophysiological insights linked to clinical needs. Here we compile a longitudinal multiomic dataset of the systemic immune landscape in both ACS and CCS (n = 62 patients in total, n = 15 women and n = 47 men) and validate this in an external cohort (n = 55 patients in total, n = 11 women and n = 44 men). MOFA reveals multicellular immune signatures characterized by distinct monocyte, natural killer and T cell substates and immune-communication pathways that explain a large proportion of inter-patient variance. We also identify specific factors that reflect disease state or associate with treatment outcome in ACS as measured using left ventricular ejection fraction. Hence, this study provides proof-of-concept evidence for the ability of MOFA to uncover multicellular immune programs in cardiovascular disease, opening new directions for mechanistic, biomarker and therapeutic studies. AU - Pekayvaz, K.* AU - Losert, C. AU - Knottenberg, V.* AU - Gold, C.* AU - van Blokland, I.V.* AU - Oelen, R.* AU - Groot, H.E.* AU - Benjamins, J.W.* AU - Brambs, S.* AU - Kaiser, R.* AU - Gottschlich, A.* AU - Hoffmann, G.V.* AU - Eivers, L.* AU - Martinez-Navarro, A.* AU - Bruns, N.* AU - Stiller, S.* AU - Akgöl, S.* AU - Yue, K.* AU - Polewka, V.* AU - Escaig, R.* AU - Joppich, M.* AU - Janjic, A.* AU - Popp, O.* AU - Kobold, S. AU - Petzold, T.* AU - Zimmer, R.* AU - Enard, W.* AU - Saar, K.* AU - Mertins, P.* AU - Huebner, N.* AU - van der Harst, P.* AU - Franke, L.H.* AU - van der Wijst, M.G.P.* AU - Massberg, S.* AU - Heinig, M. AU - Nicolai, L.* AU - Stark, K.* C1 - 70727 C2 - 55727 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 1696-1710 TI - Multiomic analyses uncover immunological signatures in acute and chronic coronary syndromes. JO - Nat. Med. VL - 30 IS - 6 PB - Nature Portfolio PY - 2024 SN - 1078-8956 ER - TY - JOUR AB - Glial cells influence brain function and disease progression. This study identifies signals that elicit hemorrhage-specific glia plasticity, including proliferation and the acquisition of neural stem cell properties. It thereby sets a foundation for aligning glia reactivity with disease progression and for attempting to use this endogenous stem cell pool for brain repair. AU - Götz, M. AU - Sirko, S.* C1 - 69095 C2 - 53887 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 3018-3019 TI - Injury-specific signals elicit plasticity in glial cells from patients with brain injury. JO - Nat. Med. VL - 29 IS - 12 PB - Nature Portfolio PY - 2023 SN - 1078-8956 ER - TY - JOUR AB - Human immunodeficiency virus type 1 (HIV-1)-neutralizing antibodies (nAbs) that prevent infection are the main goal of HIV vaccine discovery. But as no nAb-eliciting vaccines are yet available, only data from HIV-1 neutralizers-persons with HIV-1 who naturally develop broad and potent nAbs-can inform about the dynamics and durability of nAb responses in humans, knowledge which is crucial for the design of future HIV-1 vaccine regimens. To address this, we assessed HIV-1-neutralizing immunoglobulin G (IgG) from 2,354 persons with HIV-1 on or off antiretroviral therapy (ART). Infection with non-clade B viruses, CD4+ T cell counts <200 µl-1, being off ART and a longer time off ART were independent predictors of a more potent and broad neutralization. In longitudinal analyses, we found nAb half-lives of 9.3 and 16.9 years in individuals with no- or low-level viremia, respectively, and 4.0 years in persons who newly initiated ART. Finally, in a potent HIV-1 neutralizer, we identified lower fractions of serum nAbs and of nAb-encoding memory B cells after ART initiation, suggesting that a decreasing neutralizing serum activity after antigen withdrawal is due to lower levels of nAbs. These results collectively show that HIV-1-neutralizing responses can persist for several years, even at low antigen levels, suggesting that an HIV-1 vaccine may elicit a durable nAb response. AU - Schommers, P.* AU - Kim, D.S.* AU - Schlotz, M.* AU - Kreer, C.* AU - Eggeling, R.* AU - Hake, A.* AU - Stecher, M.* AU - Park, J.* AU - Radford, C.E.* AU - Dingens, A.S.* AU - Ercanoglu, M.S.* AU - Gruell, H.* AU - Odidika, S.* AU - Dahlhaus, M.* AU - Gieselmann, L.* AU - Ahmadov, E.* AU - Lawong, R.Y.* AU - Heger, E.* AU - Knops, E.* AU - Wyen, C.* AU - Kümmerle, T.* AU - Römer, K.* AU - Scholten, S.* AU - Wolf, T.* AU - Stephan, C.* AU - Suárez, I.* AU - Raju, N.* AU - Adhikari, A.* AU - Esser, S.* AU - Streeck, H.* AU - Duerr, R.* AU - Nanfack, A.J.* AU - Zolla-Pazner, S.* AU - Geldmacher, C.* AU - Geisenberger, O.* AU - Kroidl, A.* AU - William, W.* AU - Maganga, L.* AU - Ntinginya, N.E.* AU - Georgiev, I.S.* AU - Vehreschild, J.J.* AU - Hoelscher, M. AU - Fätkenheuer, G.* AU - Lavinder, J.J.* AU - Bloom, J.D.* AU - Seaman, M.S.* AU - Lehmann, C.* AU - Pfeifer, N.* AU - Georgiou, G.* AU - Klein, F.* C1 - 68748 C2 - 54958 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 2763-2774 TI - Dynamics and durability of HIV-1 neutralization are determined by viral replication. JO - Nat. Med. VL - 29 IS - 11 PB - Nature Portfolio PY - 2023 SN - 1078-8956 ER - TY - JOUR AB - Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1+ profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas. AU - Sikkema, L. AU - Ramirez Suastegui, C. AU - Strobl, D.C. AU - Gillett, T.E.* AU - Zappia, L. AU - Madissoon, E.* AU - Markov, N.S.* AU - Zaragosi, L.E.* AU - Ji, Y. AU - Ansari, M. AU - Arguel, M.J.* AU - Apperloo, L.* AU - Banchero, M.* AU - Bécavin, C.* AU - Berg, M.* AU - Chichelnitskiy, E.* AU - Chung, M.I.* AU - Collin, A.* AU - Gay, A.C.A.* AU - Schniering, J. AU - Hooshiar Kashani, B. AU - Inecik, K. AU - Jain, M.* AU - Kapellos, T. AU - Kole, T.M.* AU - Leroy, S.* AU - Mayr, C. AU - Oliver, A.J.* AU - von Papen, M.* AU - Peter, L.* AU - Taylor, C.J.* AU - Walzthoeni, T. AU - Xu, C.* AU - Bui, L.T.* AU - De Donno, C. AU - Dony, L. AU - Faiz, A.* AU - Guo, M.* AU - Gutierrez, A.J.* AU - Heumos, L. AU - Huang, N.* AU - Ibarra Del Rio, I.A. AU - Jackson, N.D.* AU - Kadur Lakshminarasimha Murthy, P.* AU - Lotfollahi, M. AU - Tabib, T.* AU - Talavera Lopez, C.N. AU - Travaglini, K.J.* AU - Wilbrey-Clark, A.* AU - Worlock, K.B.* AU - Yoshida, M.* AU - van den Berge, M.* AU - Bossé, Y.* AU - Desai, T.J.* AU - Eickelberg, O.* AU - Kaminski, N.* AU - Krasnow, M.A.* AU - Lafyatis, R.* AU - Nikolić, M.Z.* AU - Powell, J.E.* AU - Rajagopal, J.* AU - Rojas, M.* AU - Rozenblatt-Rosen, O.* AU - Seibold, M.A.* AU - Sheppard, D.* AU - Shepherd, D.P.* AU - Sin, D.D.* AU - Timens, W.* AU - Tsankov, A.M.* AU - Whitsett, J.* AU - Xu, Y.* AU - Banovich, N.E.* AU - Barbry, P.* AU - Duong, T.E.* AU - Falk, C.S.* AU - Meyer, K.B.* AU - Kropski, J.A.* AU - Pe'er, D.* AU - Schiller, H. AU - Tata, P.R.* AU - Schultze, J.L.* AU - Teichmann, S.A.* AU - Misharin, A.V.* AU - Nawijn, M.C.* AU - Luecken, M. AU - Theis, F.J. C1 - 67837 C2 - 54315 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 1563-1577 TI - An integrated cell atlas of the lung in health and disease. JO - Nat. Med. VL - 29 IS - 6 PB - Nature Portfolio PY - 2023 SN - 1078-8956 ER - TY - JOUR AB - The Human Lung Cell Atlas (HLCA), which includes data from 36 studies, is the most comprehensive representation of cellular gene expression in the human respiratory system to date. The HLCA serves as a reference for future cellular studies of the lung, enabling a better understanding of lung biology in health and disease. AU - Sikkema, L. AU - Luecken, M. C1 - 69634 C2 - 53881 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 1338-1339 TI - A cellular reference atlas of the human lung. JO - Nat. Med. VL - 29 IS - 6 PB - Nature Portfolio PY - 2023 SN - 1078-8956 ER - TY - JOUR AB - The glial environment influences neurological disease progression, yet much of our knowledge still relies on preclinical animal studies, especially regarding astrocyte heterogeneity. In murine models of traumatic brain injury, beneficial functions of proliferating reactive astrocytes on disease outcome have been unraveled, but little is known regarding if and when they are present in human brain pathology. Here we examined a broad spectrum of pathologies with and without intracerebral hemorrhage and found a striking correlation between lesions involving blood-brain barrier rupture and astrocyte proliferation that was further corroborated in an assay probing for neural stem cell potential. Most importantly, proteomic analysis unraveled a crucial signaling pathway regulating this astrocyte plasticity with GALECTIN3 as a novel marker for proliferating astrocytes and the GALECTIN3-binding protein LGALS3BP as a functional hub mediating astrocyte proliferation and neurosphere formation. Taken together, this work identifies a therapeutically relevant astrocyte response and their molecular regulators in different pathologies affecting the human cerebral cortex. AU - Sirko, S. AU - Schichor, C.* AU - Della Vecchia, P.* AU - Metzger, F.* AU - Sonsalla, G. AU - Simon, T.* AU - Bürkle, M.* AU - Kalpazidou, S.* AU - Ninkovic, J. AU - Masserdotti, G. AU - Sauniere, J.F.* AU - Iacobelli, V.* AU - Iacobelli, S.* AU - Delbridge, C.* AU - Hauck, S.M. AU - Tonn, J.C.* AU - Götz, M. C1 - 68930 C2 - 53773 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 3149–3161 TI - Injury-specific factors in the cerebrospinal fluid regulate astrocyte plasticity in the human brain. JO - Nat. Med. VL - 29 PB - Nature Portfolio PY - 2023 SN - 1078-8956 ER - TY - JOUR AB - Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine. AU - Tobias, D.K.* AU - Merino, J.* AU - Ahmad, A.* AU - Aiken, C.* AU - Benham, J.L.* AU - Bodhini, D.* AU - Clark, A.L.* AU - Colclough, K.* AU - Corcoy, R.* AU - Cromer, S.J.* AU - Duan, D.* AU - Felton, J.L.* AU - Francis, E.C.* AU - Gillard, P.* AU - Gingras, V.* AU - Gaillard, R.* AU - Haider, E.* AU - Hughes, A.* AU - Ikle, J.M.* AU - Jacobsen, L.M.* AU - Kahkoska, A.R.* AU - Kettunen, J.L.T.* AU - Kreienkamp, R.J.* AU - Lim, L.L.* AU - Männistö, J.M.E.* AU - Massey, R.* AU - Mclennan, N.M.* AU - Miller, R.G.* AU - Morieri, M.L.* AU - Most, J.* AU - Naylor, R.N.* AU - Ozkan, B.* AU - Patel, K.A.* AU - Pilla, S.J.* AU - Prystupa, K.* AU - Raghavan, S.* AU - Rooney, M.R.* AU - Schön, M.* AU - Semnani-Azad, Z.* AU - Sevilla-Gonzalez, M.* AU - Svalastoga, P.* AU - Takele, W.W.* AU - Tam, C.H.T.* AU - Thuesen, A.C.B.* AU - Tosur, M.* AU - Wallace, A.S.* AU - Wang, C.C.* AU - Wong, J.J.* AU - Yamamoto, J.M.* AU - Young, K.* AU - Amouyal, C.* AU - Andersen, M.K.* AU - Bonham, M.P.* AU - Chen, M.* AU - Cheng, F.* AU - Chikowore, T.* AU - Chivers, S.C.* AU - Clemmensen, C.* AU - Dabelea, D.* AU - Dawed, A.Y.* AU - Deutsch, A.J.* AU - Dickens, L.T.* AU - Dimeglio, L.A.* AU - Dudenhöffer-Pfeifer, M.* AU - Evans-Molina, C.* AU - Fernández-Balsells, M.M.* AU - Fitipaldi, H.* AU - Fitzpatrick, S.L.* AU - Gitelman, S.E.* AU - Goodarzi, M.O.* AU - Grieger, J.A.* AU - Guasch-Ferré, M.* AU - Habibi, N.* AU - Hansen, T.* AU - Huang, C.* AU - Harris-Kawano, A.* AU - Ismail, H.M.* AU - Hoag, B.* AU - Johnson, R.K.* AU - Jones, A.G.* AU - Koivula, R.W.* AU - Leong, A.* AU - Leung, G.K.W.* AU - Libman, I.M.* AU - Liu, K.* AU - Long, S.A.* AU - Lowe, W.L.* AU - Morton, R.W.* AU - Motala, A.A.* AU - Onengut-Gumuscu, S.* AU - Pankow, J.S.* AU - Pathirana, M.* AU - Pazmino, S.* AU - Perez, D.* AU - Petrie, J.R.* AU - Powe, C.E.* AU - Quinteros, A.* AU - Jain, R.* AU - Ray, D.* AU - Ried-Larsen, M.* AU - Stefan, N. AU - Franks, P.W.* C1 - 68180 C2 - 54808 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 2438-2457 TI - Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine. JO - Nat. Med. VL - 29 IS - 10 PB - Nature Portfolio PY - 2023 SN - 1078-8956 ER - TY - JOUR AU - Ferrat, L.A.* AU - Vehik, K.* AU - Sharp, S.A.* AU - Lernmark, Å.* AU - Rewers, M.J.* AU - She, J.X.* AU - TEDDY Study Group (Ziegler, A.-G. AU - Gezginci, C. AU - Heublein, A. AU - Hummel, S. AU - Knopff, A. AU - Koch, C. AU - Schmidt, J. AU - Scholz, M. AU - Stock, J. AU - Warncke, K. AU - Wendel, L. AU - Winkler, C.) AU - Toppari, J.* AU - Akolkar, B.* AU - Krischer, J.P.* AU - Weedon, M.N.* AU - Oram, R.A.* AU - Hagopian, W.A.* C1 - 64367 C2 - 51896 TI - Author Correction:  A combined risk score enhances prediction of type 1 diabetes among susceptible children. JO - Nat. Med. VL - 28 IS - 3 PY - 2022 SN - 1078-8956 ER - TY - JOUR AB - In the version of this article initially published, Abhishek Chauhan (Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham, Liver Biomedical Research Unit, Birmingham, UK) was missing from the author list. In Fig. 6h, the bar colors were incorrect (reversed). The correct colors are gray for the left bar and white for the right bar. In Supplementary Fig. 3c, the label along the vertical axis of the middle plot (Plasma Insulin) was incorrect. The correct label is “Serum Insulin”. In Supplementary Figure 24f, the label in red above the images (Neutrophils) was incorrect. The correct red label is “Granulocytes”. The errors have been corrected in the HTML and PDF versions of the article. AU - Malehmir, M.* AU - Pfister, D.* AU - Gallage, S.* AU - Szydlowska, M.* AU - Inverso, D.* AU - Kotsiliti, E. AU - Leone, V. AU - Peiseler, M.* AU - Surewaard, B.G.J.* AU - Rath, D.* AU - Ali, A.* AU - Wolf, M.J.* AU - Drescher, H.* AU - Healy, M.E.* AU - Dauch, D.* AU - Kroy, D.* AU - Krenkel, O.* AU - Kohlhepp, M.* AU - Engleitner, T.* AU - Olkus, A.* AU - Sijmonsma, T.* AU - Volz, J.* AU - Deppermann, C.* AU - Stegner, D.* AU - Helbling, P.* AU - Nombela-Arrieta, C.* AU - Rafiei, A.* AU - Hinterleitner, M.* AU - Rall, M.* AU - Baku, F.* AU - Borst, O.* AU - Wilson, C.L.* AU - Leslie, J.* AU - O'Connor, T. AU - Weston, C.J.* AU - Chauhan, A.* AU - Adams, D.H.* AU - Sheriff, L.* AU - Teijeiro, A.* AU - Prinz, M.* AU - Bogeska, R.* AU - Anstee, N.* AU - Bongers, M.N.* AU - Notohamiprodjo, M.* AU - Geisler, T.* AU - Withers, D.J.* AU - Ware, J.* AU - Mann, D.A.* AU - Augustin, H.G.* AU - Vegiopoulos, A.* AU - Milsom, M.D.* AU - Rose, A.J.* AU - Lalor, P.F.* AU - Llovet, J.M.* AU - Pinyol, R.* AU - Tacke, F.* AU - Rad, R.* AU - Matter, M.* AU - Djouder, N.* AU - Kubes, P.* AU - Knolle, P.A.* AU - Unger, K. AU - Zender, L.* AU - Nieswandt, B.* AU - Gawaz, M.* AU - Weber, A.* AU - Heikenwälder, M. C1 - 64347 C2 - 51895 TI - Author Correction: Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. JO - Nat. Med. VL - 28 PY - 2022 SN - 1078-8956 ER - TY - JOUR AB - Garrod's concept of 'chemical individuality' has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant-metabolite associations (P < 1.25 × 10-11) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant-metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships. AU - Surendran, P.* AU - Stewart, I.D.* AU - Au Yeung, V.P.W.* AU - Pietzner, M.* AU - Raffler, J. AU - Wörheide, M. AU - Li, C.* AU - Smith, R.F.* AU - Wittemans, L.B.L.* AU - Bomba, L.* AU - Menni, C.* AU - Zierer, J.* AU - Rossi, N.* AU - Sheridan, P.A.* AU - Watkins, N.A.* AU - Mangino, M.* AU - Hysi, P.G.* AU - Falchi, M.* AU - Spector, T.D.* AU - Michelotti, G.A.* AU - Arlt, W.* AU - Lotta, L.A.* AU - Denaxas, S.* AU - Hemingway, H.* AU - Gamazon, E.R.* AU - Howson, J.M.M.* AU - Wareham, N.J.* AU - Kastenmüller, G. AU - Fauman, E.B.* AU - Suhre, K.* AU - Butterworth, A.S.* AU - Langenberg, C.* C1 - 66672 C2 - 53262 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 2321-2332 TI - Rare and common genetic determinants of metabolic individuality and their effects on human health. JO - Nat. Med. VL - 28 IS - 11 PB - Nature Portfolio PY - 2022 SN - 1078-8956 ER - TY - JOUR AU - Wagner, S. AU - Matek, C. AU - Shetab Boushehri, S. AU - Boxberg, M.* AU - Lamm, L. AU - Sadafi, A. AU - Waibel, D.J.E. AU - Marr, C. AU - Peng, T. C1 - 65908 C2 - 52558 TI - Make deep learning algorithms in computational pathology more reproducible and reusable. JO - Nat. Med. PY - 2022 SN - 1078-8956 ER - TY - JOUR AB - Infection-neutralizing antibody responses after SARS-CoV-2 infection or COVID-19 vaccination are an essential component of antiviral immunity. Antibody-mediated protection is challenged by the emergence of SARS-CoV-2 variants of concern (VoCs) with immune escape properties, such as omicron (B.1.1.529) that is rapidly spreading worldwide. Here, we report neutralizing antibody dynamics in a longitudinal cohort of COVID-19 convalescent and infection-naive individuals vaccinated with mRNA BNT162b2 by quantifying anti-SARS-CoV-2-spike antibodies and determining their avidity and neutralization capacity in serum. Using live-virus neutralization assays, we show that a superior infection-neutralizing capacity against all VoCs, including omicron, developed after either two vaccinations in convalescents or after a third vaccination or breakthrough infection of twice-vaccinated, naive individuals. These three consecutive spike antigen exposures resulted in an increasing neutralization capacity per anti-spike antibody unit and were paralleled by stepwise increases in antibody avidity. We conclude that an infection-plus-vaccination-induced hybrid immunity or a triple immunization can induce high-quality antibodies with superior neutralization capacity against VoCs, including omicron. AU - Wratil, P.R.* AU - Stern, M.* AU - Priller, A.* AU - Willmann, A. AU - Almanzar, G.* AU - Vogel, E. AU - Feuerherd, M. AU - Cheng, C.-C. AU - Yazici, S.* AU - Christa, C. AU - Jeske, S. AU - Lupoli, G.* AU - Vogt, T.* AU - Albanese, M.* AU - Mejias-Perez, E.* AU - Bauernfried, S.* AU - Graf, N. AU - Mijočević, H. AU - Vu, M. AU - Tinnefeld, K. AU - Wettengel, J.M. AU - Hoffmann, D. AU - Muenchhoff, M.* AU - Daechert, C.* AU - Mairhofer, H.* AU - Krebs, S.* AU - Fingerle, V.* AU - Graf, A.* AU - Steininger, P.* AU - Blum, H.* AU - Hornung, V.* AU - Liebl, B.* AU - Überla, K.* AU - Prelog, M.* AU - Knolle, P.* AU - Keppler, O.T.* AU - Protzer, U. C1 - 64225 C2 - 51800 SP - 496–503 TI - Three exposures to the spike protein of SARS-CoV-2 by either infection or vaccination elicit superior neutralizing immunity to all variants of concern. JO - Nat. Med. VL - 28 IS - 3 PY - 2022 SN - 1078-8956 ER - TY - JOUR AB - Mitochondrial DNA (mtDNA) variants influence the risk of late-onset human diseases, but the reasons for this are poorly understood. Undertaking a hypothesis-free analysis of 5,689 blood-derived biomarkers with mtDNA variants in 16,220 healthy donors, here we show that variants defining mtDNA haplogroups Uk and H4 modulate the level of circulating N-formylmethionine (fMet), which initiates mitochondrial protein translation. In human cytoplasmic hybrid (cybrid) lines, fMet modulated both mitochondrial and cytosolic proteins on multiple levels, through transcription, post-translational modification and proteolysis by an N-degron pathway, abolishing known differences between mtDNA haplogroups. In a further 11,966 individuals, fMet levels contributed to all-cause mortality and the disease risk of several common cardiovascular disorders. Together, these findings indicate that fMet plays a key role in common age-related disease through pleiotropic effects on cell proteostasis. AU - Cai, N. AU - Gomez-Duran, A.* AU - Yonova-Doing, E.* AU - Kundu, K.* AU - Burgess, A.I.* AU - Golder, Z.J.* AU - Calabrese, C.* AU - Bonder, M.J.* AU - Camacho, M.* AU - Lawson, R.A.* AU - Li, L.* AU - Williams-Gray, C.H.* AU - ICICLE-PD Study Group* AU - di Angelantonio, E.* AU - Roberts, D.J.* AU - Watkins, N.A.* AU - Ouwehand, W.H.* AU - Butterworth, A.S.* AU - Stewart, I.D.* AU - Pietzner, M.* AU - Wareham, N.J.* AU - Langenberg, C.* AU - Walter, K.* AU - Rothwell, P.M.* AU - Howson, J.M.M.* AU - Stegle, O.* AU - Chinnery, P.F.* AU - Soranzo, N.* C1 - 62884 C2 - 51139 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 1564-1575 TI - Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases. JO - Nat. Med. VL - 27 IS - 9 PB - Nature Portfolio PY - 2021 SN - 1078-8956 ER - TY - JOUR AB - Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention. AU - Muus, C.* AU - Luecken, M. AU - Eraslan, G.* AU - Sikkema, L. AU - Waghray, A.* AU - Heimberg, G.* AU - Kobayashi, Y.* AU - Vaishnav, E.D.* AU - Subramanian, A.* AU - Smillie, C.* AU - Jagadeesh, K.A.* AU - Duong, E.T.* AU - Fiskin, E.* AU - Triglia, E.T.* AU - Ansari, M. AU - Cai, P.* AU - Lin, B.* AU - Buchanan, J.* AU - Chen, S.* AU - Shu, J.* AU - Haber, A.L.* AU - Chung, H.* AU - Montoro, D.T.* AU - Adams, T.* AU - Aliee, H. AU - Allon, S.J.* AU - Andrusivova, Z.* AU - Angelidis, I. AU - Ashenberg, O.* AU - Bassler, K.* AU - Bécavin, C.* AU - Benhar, I.* AU - Bergenstråhle, J.* AU - Bergenstråhle, L.* AU - Bolt, L.* AU - Braun, E.* AU - Bui, L.T.* AU - Callori, S.* AU - Chaffin, M.* AU - Chichelnitskiy, E.* AU - Chiou, J.* AU - Conlon, T.M. AU - Cuoco, M.S.* AU - Cuomo, A.S.E.* AU - Deprez, M.* AU - Duclos, G.* AU - Fine, D.* AU - Fischer, D.S. AU - Ghazanfar, S.* AU - Gillich, A.* AU - Giotti, B.* AU - Gould, J.* AU - Guo, M.* AU - Gutierrez, A.J.* AU - Habermann, A.C.* AU - Harvey, T.* AU - He, P.* AU - Hou, X.* AU - Hu, L.* AU - Hu, Y.* AU - Jaiswal, A.* AU - Ji, L.* AU - Jiang, P.* AU - Kapellos, T.S.* AU - Kuo, C.S.* AU - Larsson, L.* AU - Leney-Greene, M.A.* AU - Lim, K.* AU - Litviňuková, M.* AU - Ludwig, L.S.* AU - Lukassen, S.* AU - Luo, W.* AU - Maatz, H.* AU - Madissoon, E.* AU - Mamanova, L.* AU - Manakongtreecheep, K.* AU - Leroy, S.* AU - Mayr, C. AU - Mbano, I.M.* AU - McAdams, A.M.* AU - Nabhan, A.N.* AU - Nyquist, S.K.* AU - Penland, L.* AU - Poirion, O.B.* AU - Poli, S.* AU - Qi, C.* AU - Queen, R.* AU - Reichart, D.* AU - Rosas, I.* AU - Schupp, J.C.* AU - Shea, C.V.* AU - Shi, X.* AU - Sinha, R.* AU - Sit, R.V.* AU - Slowikowski, K.* AU - Slyper, M.* AU - Smith, N.P.* AU - Sountoulidis, A.* AU - Strunz, M. AU - Sullivan, T.B.* AU - Sun, D.* AU - Talavera-López, C.* AU - Tan, P.* AU - Tantivit, J.* AU - Travaglini, K.J.* AU - Tucker, N.R.* AU - Vernon, K.A.* AU - Wadsworth, M.H.* AU - Waldman, J.* AU - Wang, X.* AU - Xu, K.* AU - Yan, W.* AU - Zhao, W.* AU - Ziegler, C.G.K.* C1 - 61456 C2 - 49984 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 546–559 TI - Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics. JO - Nat. Med. VL - 27 PB - Nature Research PY - 2021 SN - 1078-8956 ER - TY - JOUR AB - Multimorbidity, the simultaneous presence of multiple chronic conditions, is an increasing global health problem and research into its determinants is of high priority. We used baseline untargeted plasma metabolomics profiling covering >1,000 metabolites as a comprehensive readout of human physiology to characterize pathways associated with and across 27 incident noncommunicable diseases (NCDs) assessed using electronic health record hospitalization and cancer registry data from over 11,000 participants (219,415 person years). We identified 420 metabolites shared between at least 2 NCDs, representing 65.5% of all 640 significant metabolite-disease associations. We integrated baseline data on over 50 diverse clinical risk factors and characteristics to identify actionable shared pathways represented by those metabolites. Our study highlights liver and kidney function, lipid and glucose metabolism, low-grade inflammation, surrogates of gut microbial diversity and specific health-related behaviors as antecedents of common NCD multimorbidity with potential for early prevention. We integrated results into an open-access webserver ( https://omicscience.org/apps/mwasdisease/ ) to facilitate future research and meta-analyses. AU - Pietzner, M.* AU - Stewart, I.D.* AU - Raffler, J. AU - Khaw, K.T.* AU - Michelotti, G.A.* AU - Kastenmüller, G. AU - Wareham, N.J.* AU - Langenberg, C.* C1 - 61549 C2 - 50338 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 471-479 TI - Plasma metabolites to profile pathways in noncommunicable disease multimorbidity. JO - Nat. Med. VL - 27 IS - 3 PB - Nature Research PY - 2021 SN - 1078-8956 ER - TY - JOUR AB - The state of intermediate hyperglycemia is indicative of elevated risk of developing type 2 diabetes1. However, the current definition of prediabetes neither reflects subphenotypes of pathophysiology of type 2 diabetes nor is predictive of future metabolic trajectories. We used partitioning on variables derived from oral glucose tolerance tests, MRI-measured body fat distribution, liver fat content and genetic risk in a cohort of extensively phenotyped individuals who are at increased risk for type 2 diabetes2,3 to identify six distinct clusters of subphenotypes. Three of the identified subphenotypes have increased glycemia (clusters 3, 5 and 6), but only individuals in clusters 5 and 3 have imminent diabetes risks. By contrast, those in cluster 6 have moderate risk of type 2 diabetes, but an increased risk of kidney disease and all-cause mortality. Findings were replicated in an independent cohort using simple anthropomorphic and glycemic constructs4. This proof-of-concept study demonstrates that pathophysiological heterogeneity exists before diagnosis of type 2 diabetes and highlights a group of individuals who have an increased risk of complications without rapid progression to overt type 2 diabetes. AU - Wagner, R. AU - Heni, M. AU - Tabak, A.G.* AU - Machann, J. AU - Randrianarisoa, E. AU - Hrabě de Angelis, M. AU - Birkenfeld, A.L. AU - Stefan, N. AU - Peter, A. AU - Häring, H.-U. AU - Fritsche, A. AU - Schick, F.* C1 - 60924 C2 - 49674 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 49-57 TI - Pathophysiology-based subphenotyping of individuals at elevated risk for type 2 diabetes. JO - Nat. Med. VL - 27 IS - 1 PB - Nature Research PY - 2021 SN - 1078-8956 ER - TY - JOUR AB - Direct evidence in humans for the impact of the microbiome on nutrient absorption is lacking. We conducted an extended inpatient study using two interventions that we hypothesized would alter the gut microbiome and nutrient absorption. In each, stool calorie loss, a direct proxy of nutrient absorption, was measured. The first phase was a randomized cross-over dietary intervention in which all participants underwent in random order 3 d of over- and underfeeding. The second was a randomized, double-blind, placebo-controlled pharmacologic intervention using oral vancomycin or matching placebo (NCT02037295). Twenty-seven volunteers (17 men and 10 women, age 35.1 ± 7.3, BMI 32.3 ± 8.0), who were healthy other than having impaired glucose tolerance and obesity, were enrolled and 25 completed the entire trial. The primary endpoints were the effects of dietary and pharmacological intervention on stool calorie loss. We hypothesized that stool calories expressed as percentage of caloric intake would increase with underfeeding compared with overfeeding and increase during oral vancomycin treatment. Both primary endpoints were met. Greater stool calorie loss was observed during underfeeding relative to overfeeding and during vancomycin treatment compared with placebo. Key secondary endpoints were to evaluate the changes in gut microbial community structure as evidenced by amplicon sequencing and metagenomics. We observed only a modest perturbation of gut microbial community structure with under- versus overfeeding but a more widespread change in community structure with reduced diversity with oral vancomycin. Increase in Akkermansia muciniphila was common to both interventions that resulted in greater stool calorie loss. These results indicate that nutrient absorption is sensitive to environmental perturbations and support the translational relevance of preclinical models demonstrating a possible causal role for the gut microbiome in dietary energy harvest. AU - Basolo, A.* AU - Hohenadel, M.* AU - Ang, Q.Y.* AU - Piaggi, P.* AU - Heinitz, S. AU - Walter, M.* AU - Walter, P.* AU - Parrington, S.* AU - Trinidad, D.D.* AU - von Schwartzenberg, R.J.* AU - Turnbaugh, P.J.* AU - Krakoff, J.* C1 - 58765 C2 - 48349 CY - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa SP - 589–598 TI - Effects of underfeeding and oral vancomycin on gut microbiome and nutrient absorption in humans. JO - Nat. Med. VL - 26 IS - 4 PB - Nature Publishing Group PY - 2020 SN - 1078-8956 ER - TY - JOUR AB - Growing up on a farm is associated with an asthma-protective effect, but the mechanisms underlying this effect are largely unknown. In the Protection against Allergy: Study in Rural Environments (PASTURE) birth cohort, we modeled maturation using 16S rRNA sequence data of the human gut microbiome in infants from 2 to 12 months of age. The estimated microbiome age (EMA) in 12-month-old infants was associated with previous farm exposure (beta = 0.27 (0.12-0.43), P = 0.001, n = 618) and reduced risk of asthma at school age (odds ratio (OR) = 0.72 (0.56-0.93), P = 0.011). EMA mediated the protective farm effect by 19%. In a nested case-control sample (n = 138), we found inverse associations of asthma with the measured level of fecal butyrate (OR = 0.28 (0.09-0.91), P = 0.034), bacterial taxa that predict butyrate production (OR = 0.38 (0.17-0.84), P = 0.017) and the relative abundance of the gene encoding butyryl-coenzyme A (CoA):acetate-CoA-transferase, a major enzyme in butyrate metabolism (OR = 0.43 (0.19-0.97), P = 0.042). The gut microbiome may contribute to asthma protection through metabolites, supporting the concept of a gut-lung axis in humans.Growing up in the rich microbial environment of a farm strongly influences the maturation of the gut microbiome in the first year of life, which helps protect against the development of asthma in children. AU - Depner, M. AU - Taft, D.H.* AU - Kirjavainen, P.V.* AU - Kalanetra, K.M.* AU - Karvonen, A.M.* AU - Peschel, S. AU - Schmaußer-Hechfellner, E. AU - Roduit, C.* AU - Frei, R.* AU - Lauener, R.* AU - Divaret-Chauveau, A.* AU - Dalphin, J.C.* AU - Riedler, J.* AU - Roponen, M.* AU - Kabesch, M.* AU - Renz, H.* AU - Pekkanen, J.* AU - Farquharson, F.M.* AU - Louis, P.* AU - Mills, D.A.* AU - PASTURE Study Group (Illi, S. AU - von Mutius, E.) AU - Ege, M.J.* C1 - 60482 C2 - 49475 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 1766-1775 TI - Maturation of the gut microbiome during the first year of life contributes to the protective farm effect on childhood asthma. JO - Nat. Med. VL - 26 IS - 11 PB - Nature Research PY - 2020 SN - 1078-8956 ER - TY - JOUR AB - Type 1 diabetes (T1D)-an autoimmune disease that destroys the pancreatic islets, resulting in insulin deficiency-often begins early in life when islet autoantibody appearance signals high risk(1). However, clinical diabetes can follow in weeks or only after decades, and is very difficult to predict. Ketoacidosis at onset remains common(2,3)and is most severe in the very young(4,5), in whom it can be life threatening and difficult to treat(6-9). Autoantibody surveillance programs effectively prevent most ketoacidosis(10-12)but require frequent evaluations whose expense limits public health adoption(13). Prevention therapies applied before onset, when greater islet mass remains, have rarely been feasible(14)because individuals at greatest risk of impending T1D are difficult to identify. To remedy this, we sought accurate, cost-effective estimation of future T1D risk by developing a combined risk score incorporating both fixed and variable factors (genetic, clinical and immunological) in 7,798 high-risk children followed closely from birth for 9.3 years. Compared with autoantibodies alone, the combined model dramatically improves T1D prediction at >= 2 years of age over horizons up to 8 years of age (area under the receiver operating characteristic curve >= 0.9), doubles the estimated efficiency of population-based newborn screening to prevent ketoacidosis, and enables individualized risk estimates for better prevention trial selection.In a study of children with high genetic risk aged 2 years or older, a risk score integrating pancreatic islet autoantibodies, genetic factors and family history is highly predictive of type 1 diabetes in the subsequent 8 years. AU - Ferrat, L.A.* AU - Vehik, K.* AU - Sharp, S.A.* AU - Lernmark, Å.* AU - Rewers, M.J.* AU - She, J.X.* AU - Germany clinical center (Ziegler, A.-G.) AU - Toppari, J.* AU - Akolkar, B.* AU - Krischer, J.P.* AU - Weedon, M.N.* AU - Oram, R.A.* AU - Hagopian, W.A.* AU - German Clinical Center (Gezginci, C.) AU - German Clinical Center (Hummel, S.) AU - German Clinical Center (Knopff, A.) AU - German Clinical Center (Scholz, M.) AU - German Clinical Center (Stock, J.) AU - German Clinical Center (Warncke, K.) AU - German Clinical Center (Wendel, L.) AU - German Climical Center (Winkler, C.) C1 - 59886 C2 - 49097 CY - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa SP - 1247-1255 TI - A combined risk score enhances prediction of type 1 diabetes among susceptible children. JO - Nat. Med. VL - 26 IS - 8 PB - Nature Publishing Group PY - 2020 SN - 1078-8956 ER - TY - JOUR AB - Frameshift mutations in the DMD gene, encoding dystrophin, cause Duchenne muscular dystrophy (DMD), leading to terminal muscle and heart failure in patients. Somatic gene editing by sequence-specific nucleases offers new options for restoring the DMD reading frame, resulting in expression of a shortened but largely functional dystrophin protein. Here, we validated this approach in a pig model of DMD lacking exon 52 of DMD (DMDΔ52), as well as in a corresponding patient-derived induced pluripotent stem cell model. In DMDΔ52 pigs1, intramuscular injection of adeno-associated viral vectors of serotype 9 carrying an intein-split Cas9 (ref. 2) and a pair of guide RNAs targeting sequences flanking exon 51 (AAV9-Cas9-gE51) induced expression of a shortened dystrophin (DMDΔ51-52) and improved skeletal muscle function. Moreover, systemic application of AAV9-Cas9-gE51 led to widespread dystrophin expression in muscle, including diaphragm and heart, prolonging survival and reducing arrhythmogenic vulnerability. Similarly, in induced pluripotent stem cell-derived myoblasts and cardiomyocytes of a patient lacking DMDΔ52, AAV6-Cas9-g51-mediated excision of exon 51 restored dystrophin expression and amelioreate skeletal myotube formation as well as abnormal cardiomyocyte Ca2+ handling and arrhythmogenic susceptibility. The ability of Cas9-mediated exon excision to improve DMD pathology in these translational models paves the way for new treatment approaches in patients with this devastating disease. AU - Moretti, A.* AU - Fonteyne, L.* AU - Giesert, F. AU - Hoppmann, P.* AU - Meier, A.B.* AU - Bozoglu, T.* AU - Baehr, A.* AU - Schneider, C.M.* AU - Sinnecker, D.* AU - Klett, K.* AU - Fröhlich, T.* AU - Rahman, F.A.* AU - Haufe, T.* AU - Sun, S.* AU - Jurisch, V.* AU - Kessler, B.* AU - Hinkel, R.* AU - Dirschinger, R.* AU - Martens, E.* AU - Jilek, C.* AU - Graf, A.* AU - Krebs, S.* AU - Santamaria, G.* AU - Kurome, M.* AU - Zakhartchenko, V.* AU - Campbell, B.* AU - Voelse, K.* AU - Wolf, A.* AU - Ziegler, T.* AU - Reichert, S.* AU - Lee, S.* AU - Flenkenthaler, F.* AU - Dorn, T.* AU - Jeremias, I. AU - Blum, H.* AU - Dendorfer, A.* AU - Schnieke, A.* AU - Krause, S.* AU - Walter, M.C.* AU - Klymiuk, N.* AU - Laugwitz, K.L.* AU - Wolf, E.* AU - Wurst, W. AU - Kupatt, C.* C1 - 58686 C2 - 48238 SP - 207-214 TI - Somatic gene editing ameliorates skeletal and cardiac muscle failure in pig and human models of Duchenne muscular dystrophy. JO - Nat. Med. VL - 26 IS - 2 PY - 2020 SN - 1078-8956 ER - TY - JOUR AB - We investigated SARS-CoV-2 potential tropism by surveying expression of viral entry-associated genes in single-cell RNA-sequencing data from multiple tissues from healthy human donors. We co-detected these transcripts in specific respiratory, corneal and intestinal epithelial cells, potentially explaining the high efficiency of SARS-CoV-2 transmission. These genes are co-expressed in nasal epithelial cells with genes involved in innate immunity, highlighting the cells’ potential role in initial viral infection, spread and clearance. The study offers a useful resource for further lines of inquiry with valuable clinical samples from COVID-19 patients and we provide our data in a comprehensive, open and user-friendly fashion at www.covid19cellatlas.org. AU - Sungnak, W.* AU - Huang, N.* AU - Bécavin, C.* AU - Berg, M.* AU - Queen, R.* AU - Litvinukova, M.* AU - Talavera-López, C.* AU - Maatz, H.* AU - Reichart, D.* AU - Sampaziotis, F.* AU - Worlock, K.B.* AU - Yoshida, M.* AU - Barnes, J.L.* AU - HCA Lung Biological Network (Schiller, H. B. AU - Theis, F.J.) C1 - 59021 C2 - 48495 SP - 681–687 TI - SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. JO - Nat. Med. VL - 26 PY - 2020 SN - 1078-8956 ER - TY - JOUR AB - Asthma prevalence has increased in epidemic proportions with urbanization, but growing up on traditional farms offers protection even today(1). The asthma-protective effect of farms appears to be associated with rich home dust microbiota(2,3), which could be used to model a health-promoting indoor microbiome. Here we show by modeling differences in house dust microbiota composition between farm and non-farm homes of Finnish birth cohorts(4) that in children who grow up in non-farm homes, asthma risk decreases as the similarity of their home bacterial microbiota composition to that of farm homes increases. The protective microbiota had a low abundance of Streptococcaceae relative to outdoor-associated bacterial taxa. The protective effect was independent of richness and total bacterial load and was associated with reduced proinflammatory cytokine responses against bacterial cell wall components ex vivo. We were able to reproduce these findings in a study among rural German children(2) and showed that children living in German non-farm homes with an indoor microbiota more similar to Finnish farm homes have decreased asthma risk. The indoor dust microbiota composition appears to be a definable, reproducible predictor of asthma risk and a potential modifiable target for asthma prevention. AU - Kirjavainen, P.V.* AU - Karvonen, A.M.* AU - Adams, R.I.* AU - Täubel, M.* AU - Roponen, M.* AU - Tuoresmäki, P.* AU - Loss, G.* AU - Jayaprakash, B.* AU - Depner, M. AU - Ege, M.J.* AU - Renz, H.* AU - Pfefferle, P.I.* AU - Schaub, B.* AU - Lauener, R.* AU - Hyvärinen, A.* AU - Knight, R.* AU - Heederik, D.J.J.* AU - von Mutius, E. AU - Pekkanen, J.* C1 - 56345 C2 - 47196 CY - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa SP - 1089-1095 TI - Farm-like indoor microbiota in non-farm homes protects children from asthma development. JO - Nat. Med. VL - 25 IS - 7 PB - Nature Publishing Group PY - 2019 SN - 1078-8956 ER - TY - JOUR AB - In the version of this article originally published, several competing interests for Erika von Mutius were missing. This sentence was added to the competing interests section: “E.v.M. is an inventor on the patents EP1637147, EP1964570, LU101064 and EP1411977; E.v.M. is an inventor on and has received royalties from the patent EP2361632.” The error has been corrected in the HTML and PDF versions of this article. AU - Kirjavainen, P.V.* AU - Karvonen, A.M.* AU - Adams, R.I.* AU - Täubel, M.* AU - Roponen, M.* AU - Tuoresmäki, P.* AU - Loss, G.* AU - Jayaprakash, B.* AU - Depner, M. AU - Ege, M.J.* AU - Renz, H.* AU - Pfefferle, P.I.* AU - Schaub, B.* AU - Lauener, R.* AU - Hyvärinen, A.* AU - Knight, R.* AU - Heederik, D.J.J.* AU - von Mutius, E. AU - Pekkanen, J.* C1 - 56597 C2 - 47167 TI - Author Correction: Farm-like indoor microbiota in non-farm homes protects children from asthma development (Nature Medicine, (2019), 25, 7, (1089-1095), 10.1038/s41591-019-0469-4). JO - Nat. Med. PY - 2019 SN - 1078-8956 ER - TY - JOUR AB - Malformations of the human cortex represent a major cause of disability1. Mouse models with mutations in known causal genes only partially recapitulate the phenotypes and are therefore not unlimitedly suited for understanding the molecular and cellular mechanisms responsible for these conditions(2). Here we study periventricular heterotopia (PH) by analyzing cerebral organoids derived from induced pluripotent stem cells (iPSCs) of patients with mutations in the cadherin receptor-ligand pair DCHS1 and FAT4 or from isogenic knockout (KO) lines(1,3). Our results show that human cerebral organoids reproduce the cortical heterotopia associated with PH. Mutations in DCHS1 and FAT4 or knockdown of their expression causes changes in the morphology of neural progenitor cells and result in defective neuronal migration dynamics only in a subset of neurons. Single-cell RNA-sequencing (scRNA-seq) data reveal a subpopulation of mutant neurons with dysregulated genes involved in axon guidance, neuronal migration and patterning. We suggest that defective neural progenitor cell (NPC) morphology and an altered navigation system in a subset of neurons underlie this form of PH. AU - Klaus, J.* AU - Kanton, S.* AU - Kyrousi, C.* AU - Ayo-Martin, A.C.* AU - Di Giaimo, R.* AU - Riesenberg, S.* AU - O'Neill, A.C. AU - Camp, J.G.* AU - Tocco, C.* AU - Santel, M.* AU - Rusha, E. AU - Drukker, M. AU - Schroeder, M.* AU - Götz, M. AU - Robertson, S.P.* AU - Treutlein, B.* AU - Cappello, S.* C1 - 55657 C2 - 46443 CY - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa SP - 561–568 TI - Altered neuronal migratory trajectories in human cerebral organoids derived from individuals with neuronal heterotopia. JO - Nat. Med. VL - 25 IS - 4 PB - Nature Publishing Group PY - 2019 SN - 1078-8956 ER - TY - JOUR AB - Non-alcoholic fatty liver disease ranges from steatosis to non-alcoholic steatohepatitis (NASH), potentially progressing to cirrhosis and hepatocellular carcinoma (HCC). Here, we show that platelet number, platelet activation and platelet aggregation are increased in NASH but not in steatosis or insulin resistance. Antiplatelet therapy (APT; aspirin/clopidogrel, ticagrelor) but not nonsteroidal anti-inflammatory drug (NSAID) treatment with sulindac prevented NASH and subsequent HCC development. Intravital microscopy showed that liver colonization by platelets depended primarily on Kupffer cells at early and late stages of NASH, involving hyaluronan-CD44 binding. APT reduced intrahepatic platelet accumulation and the frequency of platelet–immune cell interaction, thereby limiting hepatic immune cell trafficking. Consequently, intrahepatic cytokine and chemokine release, macrovesicular steatosis and liver damage were attenuated. Platelet cargo, platelet adhesion and platelet activation but not platelet aggregation were identified as pivotal for NASH and subsequent hepatocarcinogenesis. In particular, platelet-derived GPIbα proved critical for development of NASH and subsequent HCC, independent of its reported cognate ligands vWF, P-selectin or Mac-1, offering a potential target against NASH. AU - Malehmir, M.* AU - Pfister, D.* AU - Gallage, S.* AU - Szydlowska, M.* AU - Inverso, D.* AU - Kotsiliti, E. AU - Leone, V. AU - Peiseler, M.* AU - Surewaard, B.G.J.* AU - Rath, D.* AU - Ali, A.* AU - Wolf, M.J.* AU - Drescher, H.* AU - Healy, M.E.* AU - Dauch, D.* AU - Kroy, D.* AU - Krenkel, O.* AU - Kohlhepp, M.* AU - Engleitner, T.* AU - Olkus, A.* AU - Sijmonsma, T.* AU - Volz, J.* AU - Deppermann, C.* AU - Stegner, D.* AU - Helbling, P.* AU - Nombela-Arrieta, C.* AU - Rafiei, A.* AU - Hinterleitner, M.* AU - Rall, M.* AU - Baku, F.* AU - Borst, O.* AU - Wilson, C.L.* AU - Leslie, J.* AU - O'Connor, T. AU - Weston, C.J.* AU - Adams, D.H.* AU - Sheriff, L.* AU - Teijeiro, A.* AU - Prinz, M.* AU - Bogeska, R.* AU - Anstee, N.* AU - Bongers, M.N.* AU - Notohamiprodjo, M.* AU - Geisler, T.* AU - Withers, D.J.* AU - Ware, J.* AU - Mann, D.A.* AU - Augustin, H.G.* AU - Vegiopoulos, A.* AU - Milsom, M.D.* AU - Rose, A.J.* AU - Lalor, P.F.* AU - Llovet, J.M.* AU - Pinyol, R.* AU - Tacke, F.* AU - Rad, R.* AU - Matter, M.* AU - Djouder, N.* AU - Kubes, P.* AU - Knolle, P.A.* AU - Unger, K. AU - Zender, L.* AU - Nieswandt, B.* AU - Gawaz, M.* AU - Weber, A.* AU - Heikenwälder, M. C1 - 55792 C2 - 46567 CY - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa SP - 641-655 TI - Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. JO - Nat. Med. VL - 25 IS - 4 PB - Nature Publishing Group PY - 2019 SN - 1078-8956 ER - TY - JOUR AB - Viruses are implicated in autoimmune destruction of pancreatic islet beta cells, which results in insulin deficiency and type 1 diabetes (T1D)(1-4). Certain enteroviruses can infect beta cells in vitro(5), have been detected in the pancreatic islets of patients with T1D(6) and have shown an association with T1D in meta-analyses(4). However, establishing consistency in findings across studies has proven difficult. Obstacles to convincingly linking RNA viruses to islet autoimmunity may be attributed to rapid viral mutation rates, the cyclical periodicity of viruses(7) and the selection of variants with altered pathogenicity and ability to spread in populations. beta cells strongly express cell-surface coxsackie and adenovirus receptor (CXADR) genes, which can facilitate enterovirus infection(8). Studies of human pancreata and cultured islets have shown significant variation in enteroviral virulence to beta cells between serotypes and within the same serotype(9,10). In this large-scale study of known eukaryotic DNA and RNA viruses in stools from children, we evaluated fecally shed viruses in relation to islet autoimmunity and T1D. This study showed that prolonged enterovirus B rather than independent, short-duration enterovirus B infections may be involved in the development of islet autoimmunity, but not T1D, in some young children. Furthermore, we found that fewer early-life human mastadenovirus C infections, as well as CXADR rs6517774, independently correlated with islet autoimmunity. AU - Vehik, K.* AU - Lynch, K.F.* AU - Wong, M.C.* AU - Tian, X.* AU - Ross, M.C.* AU - Gibbs, R.A.* AU - Ajami, N.J.* AU - Petrosino, J.F.* AU - Rewers, M.* AU - Toppari, J.* AU - Ziegler, A.-G. AU - She, J.X.* AU - Lernmark, A.* AU - Akolkar, B.* AU - Hagopian, W.A.* AU - Schatz, D.A.* AU - Krischer, J.P.* AU - Hyöty, H.* AU - Lloyd, R.E.* C1 - 57497 C2 - 47815 CY - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa SP - 1865-1872 TI - Prospective virome analyses in young children at increased genetic risk for type 1 diabetes. JO - Nat. Med. VL - 25 IS - 12 PB - Nature Publishing Group PY - 2019 SN - 1078-8956 ER - TY - JOUR AB - Human lungs enable efficient gas exchange and form an interface with the environment, which depends on mucosal immunity for protection against infectious agents. Tightly controlled interactions between structural and immune cells are required to maintain lung homeostasis. Here, we use single-cell transcriptomics to chart the cellular landscape of upper and lower airways and lung parenchyma in healthy lungs, and lower airways in asthmatic lungs. We report location-dependent airway epithelial cell states and a novel subset of tissue-resident memory T cells. In the lower airways of patients with asthma, mucous cell hyperplasia is shown to stem from a novel mucous ciliated cell state, as well as goblet cell hyperplasia. We report the presence of pathogenic effector type 2 helper T cells (T(H)2) in asthmatic lungs and find evidence for type 2 cytokines in maintaining the altered epithelial cell states. Unbiased analysis of cell-cell interactions identifies a shift from airway structural cell communication in healthy lungs to a T(H)2-dominated interactome in asthmatic lungs. AU - Vieira Braga, F.A.* AU - Kar, G.* AU - Berg, M.* AU - Carpaij, O.A.* AU - Polanski, K.* AU - Simon, L. AU - Brouwer, S.* AU - Gomes, T.* AU - Hesse, L.* AU - Jiang, J.* AU - Fasouli, E.S.* AU - Efremova, M.* AU - Vento-Tormo, R.* AU - Talavera-López, C.* AU - Jonker, M.R.* AU - Affleck, K.* AU - Palit, S. AU - Strzelecka, P.M.* AU - Firth, H.V.* AU - Mahbubani, K.T.* AU - Cvejic, A.* AU - Meyer, K.B.* AU - Saeb-Parsy, K.* AU - Luinge, M.* AU - Brandsma, C.A.* AU - Timens, W.* AU - Angelidis, I. AU - Strunz, M. AU - Koppelman, G.H.* AU - van Oosterhout, A.J.* AU - Schiller, H. B. AU - Theis, F.J. AU - van den Berge, M.* AU - Nawijn, M.C.* AU - Teichmann, S.A.* C1 - 56344 C2 - 47013 CY - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa SP - 1153-1163 TI - A cellular census of human lungs identifies novel cell states in health and in asthma. JO - Nat. Med. VL - 25 IS - 7 PB - Nature Publishing Group PY - 2019 SN - 1078-8956 ER - TY - JOUR AB - The stress-responsive epigenetic repressor histone deacetylase 4 (HDAC4) regulates cardiac gene expression. Here we show that the levels of an N-terminal proteolytically derived fragment of HDAC4, termed HDAC4-NT, are lower in failing mouse hearts than in healthy control hearts. Virus-mediated transfer of the portion of the Hdac4 gene encoding HDAC4-NT into the mouse myocardium protected the heart from remodeling and failure; this was associated with decreased expression of Nr4a1, which encodes a nuclear orphan receptor, and decreased NR4A1-dependent activation of the hexosamine biosynthetic pathway (HBP). Conversely, exercise enhanced HDAC4-NT levels, and mice with a cardiomyocyte-specific deletion of Hdac4 show reduced exercise capacity, which was characterized by cardiac fatigue and increased expression of Nr4a1. Mechanistically, we found that NR4A1 negatively regulated contractile function in a manner that depended on the HBP and the calcium sensor STIM1. Our work describes a new regulatory axis in which epigenetic regulation of a metabolic pathway affects calcium handling. Activation of this axis during intermittent physiological stress promotes cardiac function, whereas its impairment in sustained pathological cardiac stress leads to heart failure. AU - Lehmann, L.H.* AU - Jebessa, Z.H.* AU - Kreusser, M.M.* AU - Horsch, A.* AU - He, T.* AU - Kronlage, M.* AU - Dewenter, M.* AU - Sramek, V.* AU - Oehl, U.* AU - Krebs-Haupenthal, J.* AU - Von Der Lieth, A.H.* AU - Schmidt, A.* AU - Sun, Q.* AU - Ritterhoff, J.* AU - Finke, D.* AU - Völkers, M.* AU - Jungmann, A.* AU - Sauer, S.W.* AU - Thiel, C.* AU - Nickel, A.* AU - Kohlhaas, M.* AU - Schäfer, M AU - Sticht, C.* AU - Maack, C.* AU - Gretz, N.* AU - Wagner, M.* AU - El-Armouche, A.* AU - Maier, L.S.* AU - Londoño, J.E.C.* AU - Meder, B.* AU - Freichel, M.* AU - Gröne, H.J.* AU - Most, P.* AU - Müller, O.J.* AU - Herzig, S. AU - Furlong, E.E.M.* AU - Katus, H.A.* AU - Backs, J.* C1 - 52747 C2 - 44220 SP - 62-72 TI - A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway. JO - Nat. Med. VL - 24 IS - 1 PY - 2018 SN - 1078-8956 ER - TY - JOUR AB - Adaptive thermogenesis is the process of heat generation in response to cold stimulation. It is under the control of the sympathetic nervous system, whose chief effector is the catecholamine norepinephrine (NE). NE enhances thermogenesis through β3-adrenergic receptors to activate brown adipose tissue and by 'browning' white adipose tissue. Recent studies have reported that alternative activation of macrophages in response to interleukin (IL)-4 stimulation induces the expression of tyrosine hydroxylase (TH), a key enzyme in the catecholamine synthesis pathway, and that this activation provides an alternative source of locally produced catecholamines during the thermogenic process. Here we report that the deletion of Th in hematopoietic cells of adult mice neither alters energy expenditure upon cold exposure nor reduces browning in inguinal adipose tissue. Bone marrow-derived macrophages did not release NE in response to stimulation with IL-4, and conditioned media from IL-4-stimulated macrophages failed to induce expression of thermogenic genes, such as uncoupling protein 1 (Ucp1), in adipocytes cultured with the conditioned media. Furthermore, chronic treatment with IL-4 failed to increase energy expenditure in wild-type, Ucp1(-/-) and interleukin-4 receptor-α double-negative (Il4ra(-/-)) mice. In agreement with these findings, adipose-tissue-resident macrophages did not express TH. Thus, we conclude that alternatively activated macrophages do not synthesize relevant amounts of catecholamines, and hence, are not likely to have a direct role in adipocyte metabolism or adaptive thermogenesis. AU - Fischer, K. AU - Ruiz, H.H.* AU - Jhun, K.* AU - Finan, B. AU - Oberlin, D.J.* AU - van der Heide, V.* AU - Kalinovich, A.V.* AU - Petrovic, N.* AU - Wolf, Y.* AU - Clemmensen, C. AU - Shin, A.C.* AU - Divanovic, S.* AU - Brombacher, F.* AU - Glasmacher, E. AU - Keipert, S. AU - Jastroch, M. AU - Nagler, J. AU - Schramm, K.-W. AU - Medrikova, D. AU - Collden, G. AU - Woods, S.C.* AU - Herzig, S. AU - Homann, D.* AU - Jung, S.* AU - Nedergaard, J.* AU - Cannon, B.* AU - Tschöp, M.H. AU - Müller, T.D. AU - Buettner, C.* C1 - 50940 C2 - 42551 CY - New York SP - 623-630 TI - Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis. JO - Nat. Med. VL - 23 IS - 5 PB - Nature Publishing Group PY - 2017 SN - 1078-8956 ER - TY - JOUR AB - Nonalcoholic fatty liver disease (NAFLD), a common prelude to cirrhosis and hepatocellular carcinoma, is the most common chronic liver disease worldwide. Defining the molecular mechanisms underlying the pathogenesis of NAFLD has been hampered by a lack of animal models that closely recapitulate the severe end of the disease spectrum in humans, including bridging hepatic fibrosis. Here we demonstrate that a novel experimental model employing thermoneutral housing, as opposed to standard housing, resulted in lower stress-driven production of corticosterone, augmented mouse proinflammatory immune responses and markedly exacerbated high-fat diet (HFD)-induced NAFLD pathogenesis. Disease exacerbation at thermoneutrality was conserved across multiple mouse strains and was associated with augmented intestinal permeability, an altered microbiome and activation of inflammatory pathways that are associated with the disease in humans. Depletion of Gram-negative microbiota, hematopoietic cell deletion of Toll-like receptor 4 (TLR4) and inactivation of the IL-17 axis resulted in altered immune responsiveness and protection from thermoneutral-housing-driven NAFLD amplification. Finally, female mice, typically resistant to HFD-induced obesity and NAFLD, develop full disease characteristics at thermoneutrality. Thus, thermoneutral housing provides a sex-independent model of exacerbated NAFLD in mice and represents a novel approach for interrogation of the cellular and molecular mechanisms underlying disease pathogenesis. AU - Giles, D.A.* AU - Moreno-Fernandez, M.E.* AU - Stankiewicz, T.E.* AU - Graspeuntner, S.* AU - Cappelletti, M.* AU - Wu, D.* AU - Mukherjee, R.* AU - Chan, C.C.* AU - Lawson, M.J.* AU - Klarquist, J.* AU - Sünderhauf, A.* AU - Softic, S.* AU - Kahn, C.R.* AU - Stemmer, K. AU - Iwakura, Y.* AU - Aronow, B.J.* AU - Karns, R.* AU - Steinbrecher, K.A.* AU - Karp, C.L.* AU - Sheridan, R.* AU - Shanmukhappa, S.K.* AU - Reynaud, D.* AU - Haslam, D.B.* AU - Sina, C.* AU - Rupp, J.* AU - Hogan, S.P.* AU - Divanovic, S.* C1 - 51292 C2 - 43158 CY - New York SP - 829-838 TI - Thermoneutral housing exacerbates nonalcoholic fatty liver disease in mice and allows for sex-independent disease modeling. JO - Nat. Med. VL - 23 IS - 7 PB - Nature Publishing Group PY - 2017 SN - 1078-8956 ER - TY - JOUR AB - In acute myeloid leukemia (AML), therapy resistance frequently occurs, leading to high mortality among patients. However, the mechanisms that render leukemic cells drug resistant remain largely undefined. Here, we identified loss of the histone methyltransferase EZH2 and subsequent reduction of histone H3K27 trimethylation as a novel pathway of acquired resistance to tyrosine kinase inhibitors (TKIs) and cytotoxic drugs in AML. Low EZH2 protein levels correlated with poor prognosis in AML patients. Suppression of EZH2 protein expression induced chemoresistance of AML cell lines and primary cells in vitro and in vivo. Low EZH2 levels resulted in derepression of HOX genes, and knockdown of HOXB7 and HOXA9 in the resistant cells was sufficient to improve sensitivity to TKIs and cytotoxic drugs. The endogenous loss of EZH2 expression in resistant cells and primary blasts from a subset of relapsed AML patients resulted from enhanced CDK1-dependent phosphorylation of EZH2 at Thr487. This interaction was stabilized by heat shock protein 90 (HSP9O) and followed by proteasomal degradation of EZH2 in drug-resistant cells. Accordingly, inhibitors of HSP9O, CDK1 and the proteasome prevented EZH2 degradation, decreased HOX gene expression and restored drug sensitivity. Finally, patients with reduced EZH2 levels at progression to standard therapy responded to the combination of bortezomib and cytarabine, concomitant with the re-establishment of EZH2 expression and blast clearance. These data suggest restoration of EZH2 protein as a viable approach to overcome treatment resistance in this AML patient population. AU - Göllner, S.* AU - Oellerich, T.* AU - Agrawal-Singh, S.* AU - Schenk, T.* AU - Klein, H.* AU - Rohde, C.* AU - Pabst, C.* AU - Sauer, T.* AU - Lerdrup, M.* AU - Tavor, S.* AU - Stoelzel, F.* AU - Herold, S.* AU - Ehninger, G.* AU - Koehler, G.* AU - Pan, K.* AU - Urlaub, H.* AU - Serve, H.* AU - Dugas, M.* AU - Spiekermann, K.* AU - Vick, B. AU - Jeremias, I. AU - Berdel, W.E.* AU - Hansen, K.* AU - Zelent, A.* AU - Wickenhauser, C.* AU - Mueller, L.P.* AU - Thiede, C.* AU - Mueller-Tidow, C.* C1 - 50431 C2 - 42321 CY - New York SP - 69-78 TI - Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia. JO - Nat. Med. VL - 23 IS - 1 PB - Nature Publishing Group PY - 2017 SN - 1078-8956 ER - TY - JOUR AB - Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease. AU - Eisenberg, T.* AU - Abdellatif, M.* AU - Schroeder, S.* AU - Primessnig, U.* AU - Stekovic, S.* AU - Pendl, T.* AU - Harger, A.* AU - Schipke, J.* AU - Zimmermann, A.* AU - Schmidt, A.* AU - Tong, M.* AU - Ruckenstuhl, C.* AU - Dammbrueck, C.* AU - Gross, A.S.* AU - Herbst, V.* AU - Magnes, C.* AU - Trausinger, G.* AU - Narath, S.* AU - Meinitzer, A.* AU - Hu, Z.* AU - Kirsch, A.* AU - Eller, K.* AU - Carmona-Gutierrez, D.* AU - Büttner, S.* AU - Pietrocola, F.* AU - Knittelfelder, O.* AU - Schrepfer, E.* AU - Rockenfeller, P.* AU - Simonini, C.* AU - Rahn, A.* AU - Horsch, M. AU - Moreth, K. AU - Beckers, J. AU - Fuchs, H. AU - Gailus-Durner, V. AU - Neff, F. AU - Janik, D. AU - Rathkolb, B. AU - Rozman, J. AU - Hrabě de Angelis, M. AU - Moustafa, T.* AU - Haemmerle, G.* AU - Mayr, M.* AU - Willeit, P.* AU - von Frieling-Salewsky, M.* AU - Pieske, B.* AU - Scorrano, L.* AU - Pieber, T.R.* AU - Pechlaner, R.* AU - Willeit, J.* AU - Sigrist, S.J.* AU - Linke, W.A.* AU - Mühlfeld, C.* AU - Sadoshima, J.* AU - Dengjel, J.* AU - Kiechl, S.* AU - Kroemer, G.* AU - Sedej, S.* AU - Madeo, F.* C1 - 49912 C2 - 41909 CY - New York SP - 1428-1438 TI - Cardioprotection and lifespan extension by the natural polyamine spermidine. JO - Nat. Med. VL - 22 IS - 12 PB - Nature Publishing Group PY - 2016 SN - 1078-8956 ER - TY - JOUR AB - Genetically engineered mouse models (GEMMs) have dramatically improved our understanding of tumor evolution and therapeutic resistance. However, sequential genetic manipulation of gene expression and targeting of the host is almost impossible using conventional Cre-loxP-based models. We have developed an inducible dual-recombinase system by combining flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies to improve GEMMs of pancreatic cancer. This enables investigation of multistep carcinogenesis, genetic manipulation of tumor subpopulations (such as cancer stem cells), selective targeting of the tumor microenvironment and genetic validation of therapeutic targets in autochthonous tumors on a genome-wide scale. As a proof of concept, we performed tumor cell-autonomous and nonautonomous targeting, recapitulated hallmarks of human multistep carcinogenesis, validated genetic therapy by 3-phosphoinositide-dependent protein kinase inactivation as well as cancer cell depletion and show that mast cells in the tumor microenvironment, which had been thought to be key oncogenic players, are dispensable for tumor formation. AU - Schönhuber, N.* AU - Seidler, B.* AU - Schuck, K.* AU - Veltkamp, C.* AU - Schachtler, C.* AU - Zukowska, M.* AU - Eser, S.* AU - Feyerabend, T.B.* AU - Paul, M.C.* AU - Eser, P.* AU - Klein, S.* AU - Lowy, A.M.* AU - Banerjee, R.* AU - Yang, F.* AU - Lee, C.L.* AU - Moding, E.J.* AU - Kirsch, D.G.* AU - Scheideler, A. AU - Alessi, D.R.* AU - Varela, I.* AU - Bradley, A.* AU - Kind, A.* AU - Schnieke, A.E.* AU - Rodewald, H.R.* AU - Rad, R.* AU - Schmid, R.M.* AU - Schneider, G.* AU - Saur, D.* C1 - 32576 C2 - 35129 SP - 1340-1347 TI - A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer. JO - Nat. Med. VL - 20 IS - 11 PY - 2014 SN - 1078-8956 ER -