TY  - JOUR
AB  - Atherosclerosis is a major cause of cardiovascular disease, and accurate preclinical models are essential for developing effective therapies. The Ossabaw pig model has high potential due to its physiological similarity to humans, but its molecular characterization remains limited. To address this, we performed single-nucleus RNA sequencing of over 36,000 nuclei from aortas of Ossabaw pigs fed chow or atherogenic diets. Our analysis revealed activation of brain-derived neurotrophic factor (BDNF), transforming growth factor β (TGF-β), SPP1, and interleukin-2 (IL-2) signaling pathways in atherosclerosis, along with smooth muscle cell transitions to synthetic and pro-osteogenic states, endothelial-to-mesenchymal transition, and TREM2+ immune cell phenotypes. Advanced fibrotic, immune cell-infiltrated plaques with calcification sites paired with molecular changes closely resembled those seen in human atherosclerosis. Together, our findings establish the Ossabaw pig as a valuable translational model and provide high-resolution data to support its use in preclinical cardiovascular research.
AU  - Bondareva, O.
AU  - Hausner, M.
AU  - Konert, M.
AU  - Branzan, D.
AU  - Noreikat, K.*
AU  - Oßmann, S.*
AU  - Sopromadze, L.*
AU  - Geisler, A.*
AU  - Heegaard, P.M.H.*
AU  - Sheikh, B.
AU  - Steiner, S.
C1  - 75750
C2  - 58113
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Single-nucleus profiling of Ossabaw pig atherosclerosis model.
JO  - iScience
VL  - 28
IS  - 10
PB  - Cell Press
PY  - 2025
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - During tissue development and regeneration, cells interpret and exert mechanical forces that are challenging to measure in vivo. Stress inference algorithms have thus emerged as powerful tools to estimate tissue stresses. Yet, effectively incorporating tissue dynamics into these algorithms remains elusive. Here, we introduce ForSys, a Python-based software that infers intercellular stresses and intracellular pressures from time-lapse microscopy. After validation, we applied ForSys to the migrating zebrafish lateral-line primordium, revealing increased stress during the cell rounding that precedes mitosis and accurately predicting the onset of epithelial rosettogenesis. We further used ForSys to study neuromast development and uncovered mechanical asymmetries linked to cell type-specific adhesion. The software performs both static and dynamic stress inference, supports command-line use, scripting, and a user-friendly graphical interface within Fiji, and accepts segmentation inputs from EPySeg and Cellpose. This versatility of ForSys enables the analysis of spatiotemporal patterns of mechanical forces during tissue morphogenesis in vivo.
AU  - Borges, A.
AU  - Miranda-Rodríguez, J.R.
AU  - Ceccarelli, A.S.*
AU  - Ventura, G.*
AU  - Sedzinski, J.*
AU  - López-Schier, H.
AU  - Chara, O.*
C1  - 75842
C2  - 58127
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - ForSys: Non-invasive stress inference from time-lapse microscopy.
JO  - iScience
VL  - 28
IS  - 11
PB  - Cell Press
PY  - 2025
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Brown adipose tissue (BAT) thermogenesis dissipates energy through heat production and thereby it opposes metabolic disease. It is mediated by mitochondrial membrane uncoupling, yet the mechanisms sustaining the mitochondrial membrane potential (ΔΨm) in brown adipocytes are poorly understood. Here we show that isocitrate dehydrogenase (IDH) activity and the expression of the soluble adenylate cyclase 10 (ADCY10), a CO2/bicarbonate sensor residing in mitochondria, are upregulated in BAT of cold-exposed mice. IDH inhibition or ADCY10 deficiency reduces cold resistance of mice. Mechanistically, IDH increases the ΔΨm in brown adipocytes via ADCY10. ADCY10 sustains complex I activity and the ΔΨm via exchange protein activated by cAMP1 (EPAC1). However, neither IDH nor ADCY10 inhibition affect uncoupling protein 1 (UCP1) expression. Hence, we suggest that ADCY10, acting as a CO2/bicarbonate sensor, mediates the effect of IDH on complex I activity through cAMP-EPAC1 signaling, thereby maintaining the ΔΨm and enabling thermogenesis in brown adipocytes.
AU  - Das, A.*
AU  - Mund, C.*
AU  - Hagag, E.*
AU  - Garcia-Martin, R.*
AU  - Karadima, E.*
AU  - Witt, A.*
AU  - Peitzsch, M.*
AU  - Deussen, A.*
AU  - Chavakis, T.
AU  - Noll, T.*
AU  - Alexaki, V.I.*
C1  - 73294
C2  - 56987
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Adenylate cyclase 10 promotes brown adipose tissue thermogenesis.
JO  - iScience
VL  - 28
IS  - 2
PB  - Cell Press
PY  - 2025
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - ABCB5 is a member of the ATP-binding cassette transporter superfamily that is expressed as a full transporter (ABCB5FL) and half transporter (ABCB5β). The ABCB5FL transporter mediates low-level multidrug resistance in cancer and is normally expressed in the prostate and testis, while ABCB5β has been found to be a marker of melanoma and limbal stem cells and is expressed in pigmented cells. To explore ABCB5’s role in normal physiology, we generated Abcb5-deficient C57BL/6J mice by the deletion of Abcb5 exon 2, knocking out both forms of ABCB5, which were completely phenotyped. The mice were fertile and demonstrated altered bioenergetics and fat metabolism, along with alterations in their blood composition, including anisocytosis and decreased white blood cells and platelet counts. This study uncovers further avenues of investigation into the role of Abcb5 in intermediary metabolism, particularly in relation to atherogenesis.
AU  - Gillet, J.P.*
AU  - Gerard, L.*
AU  - Vieira, W.*
AU  - Fourrez, M.*
AU  - Gaudray, F.*
AU  - Rathkolb, B.
AU  - Rozman, J.
AU  - Klein-Rodewald, T.
AU  - Becker, L.
AU  - Aguilar-Pimentel, J.A.
AU  - Horsch, M.
AU  - Spielmann, N.
AU  - Prehn, C.
AU  - Bihin, B.*
AU  - Beckers, J.
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
AU  - Southon, E.*
AU  - Tessarollo, L.*
AU  - Xia, D.*
AU  - Gottesman, M.M.*
C1  - 75765
C2  - 57966
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Abcb5-deficient mice show a subtle, pleiotropic phenotype indicating a role for this transporter in intermediary metabolism.
JO  - iScience
VL  - 28
IS  - 10
PB  - Cell Press
PY  - 2025
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Immune-derived opioid peptides have been implicated in immune regulation and inflammatory processes. Here, we investigate the effects of nociceptin/orphanin FQ (N/OFQ) on metabolic function and inflammation in obesity. Selectively targeting N/OFQ, encoded by the Pnoc gene, in B cells mitigates the adverse metabolic effects of diet-induced obesity and enhances insulin sensitivity and glucose tolerance. Notably, B cell-specific Pnoc knockout mice display a marked reduction in markers of immune cell migration and diminished macrophage recruitment in adipose tissue and liver. Mechanistically, we identify that N/OFQ promotes macrophage recruitment and metabolic inflammation, exacerbating glucose intolerance and insulin resistance during obesity. Overall, the immunomodulatory properties exhibited by the N/OFQ-NOP system render it a promising therapeutic target for mitigating metabolic inflammation.
AU  - Puente-Ruiz, S.C.
AU  - Ide, L.
AU  - Schuller, J.
AU  - Ben-Kraiem, A.
AU  - Hoffmann, A.
AU  - Ghosh, A.*
AU  - Noé, F.*
AU  - Wolfrum, C.*
AU  - Krause, K.*
AU  - Gericke, M.*
AU  - Klöting, N.
AU  - Brüning, J.C.*
AU  - Wunderlich, F.T.*
AU  - Blüher, M.
AU  - Jais, A.
C1  - 75043
C2  - 57725
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - B cell-derived nociceptin/orphanin FQ contributes to impaired glucose tolerance and insulin resistance in obesity.
JO  - iScience
VL  - 28
IS  - 7
PB  - Cell Press
PY  - 2025
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Isoform-specific expression patterns have been linked to stress-related psychiatric disorders such as major depressive disorder (MDD). To further explore their involvement, we constructed co-expression networks using total gene expression (TE) and isoform ratio (IR) data from affected (n = 210, 81% with depressive symptoms) and unaffected (n = 95) individuals. Networks were validated using advanced graph generation methods. Our analysis revealed distinct differences in network topology and structure. Shared hubs exhibited unique co-regulatory patterns in each network, with key master hubs in the affected network showing association with psychiatric disorders. Gene Ontology enrichment highlighted condition-specific biological processes linked to each network's master hubs. Notably, isoform-level data uncovered unique co-regulatory interactions and enrichments not observed at the gene level. This is the first study to show network-level differences of gene and isoform co-expression between affected and unaffected individuals of stress-related psychiatric disorders, emphasizing the importance of isoforms in understanding the molecular mechanisms of these conditions.
AU  - Rehawi, G.
AU  - Hagenberg, J.
AU  - Sämann, P.G.*
AU  - Moyon, L.
AU  - Binder, E.*
AU  - List, M.*
AU  - Marsico, A.
AU  - Knauer-Arloth, J.
C1  - 75483
C2  - 58079
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Integrative gene and isoform co-expression networks reveal regulatory rewiring in stress-related psychiatric disorders.
JO  - iScience
VL  - 28
IS  - 9
PB  - Cell Press
PY  - 2025
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron breakthrough infection (BTI) induced better protection than triple vaccination. To address the underlying immunological mechanisms, we studied antibody and T cell response dynamics during vaccination and after BTI. Each vaccination significantly increased peak neutralization titers with simultaneous increases in circulating spike-specific T cell frequencies. Neutralization titers significantly associated with a reduced hazard rate for SARS-CoV-2 infection. Yet, 97% of triple vaccinees became SARS-CoV-2 infected. BTI further boosted neutralization magnitude and breadth, broadened virus-specific T cell responses to non-vaccine-encoded antigens, and protected with an efficiency of 88% from further infections by December 2022. This effect was then assessed by utilizing mathematical modeling, which accounted for time-dependent infection risk, the antibody, and T cell concentration at any time point after BTI. Our findings suggest that cross-variant protective hybrid immunity induced by vaccination and BTI was an important contributor to the reduced virus transmission observed in Bavaria in late 2022 and thereafter.
AU  - Ahmed, M.I.M.*
AU  - Einhauser, S.*
AU  - Peiter, C.*
AU  - Senninger, A.*
AU  - Baranov, O.*
AU  - Eser, T.M.*
AU  - Huth, M.
AU  - Olbrich, L.*
AU  - Castelletti, N.*
AU  - Rubio-Acero, R.*
AU  - Carnell, G.*
AU  - Heeney, J.*
AU  - Kroidl, I.*
AU  - Held, K.*
AU  - Wieser, A.*
AU  - Janke, C.*
AU  - Hoelscher, M.
AU  - Hasenauer, J.
AU  - Wagner, R.*
AU  - Geldmacher, C.*
C1  - 70848
C2  - 55735
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Evolution of protective SARS-CoV-2-specific B and T cell responses upon vaccination and Omicron breakthrough infection.
JO  - iScience
VL  - 27
IS  - 6
PB  - Cell Press
PY  - 2024
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Obesity, characterized by enlarged and dysfunctional adipose tissue, is among today's most pressing global public health challenges with continuously increasing prevalence. Despite the importance of post-translational protein modifications (PTMs) in cellular signaling, knowledge of their impact on adipogenesis remains limited. Here, we studied the temporal dynamics of transcriptome, proteome, central carbon metabolites, and the acetyl- and phosphoproteome during adipogenesis using LC-MS/MS combined with PTM enrichment strategies on human (SGBS) and mouse (3T3-L1) adipocyte models. Both cell lines exhibited unique PTM profiles during adipogenesis, with acetylated proteins being enriched for central energy metabolism, while phosphorylated proteins related to insulin signaling and organization of cellular structures. As candidates with strong correlation to the adipogenesis timeline we identified CD44 and the acetylation sites FASN_K673 and IDH_K272. While results generally aligned between SGBS and 3T3-L1 cells, details appeared cell line specific. Our datasets on SGBS and 3T3-L1 adipogenesis dynamics are accessible for further mining.
AU  - Aldehoff, A.S.*
AU  - Karkossa, I.*
AU  - Goerdeler, C.*
AU  - Krieg, L.*
AU  - Schor, J.*
AU  - Engelmann, B.*
AU  - Wabitsch, M.*
AU  - Landgraf, K.*
AU  - Hackermüller, J.*
AU  - Körner, A.
AU  - Rolle-Kampczyk, U.*
AU  - Schubert, K.*
AU  - von Bergen, M.*
C1  - 70806
C2  - 55938
TI  - Unveiling the dynamics of acetylation and phosphorylation in SGBS and 3T3-L1 adipogenesis.
JO  - iScience
VL  - 27
IS  - 6
PY  - 2024
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Mitochondrial function relies on the coordinated transcription of mitochondrial and nuclear genomes to assemble respiratory chain complexes. Across species, the SIN3 coregulator influences mitochondrial functions, but how its loss impacts mitochondrial homeostasis and metabolism in the context of a whole organism is unknown. Exploring this link is important because SIN3 haploinsufficiency causes intellectual disability/autism syndromes and SIN3 plays a role in tumor biology. Here we show that loss of C. elegans SIN-3 results in transcriptional deregulation of mitochondrial- and nuclear-encoded mitochondrial genes, potentially leading to mito-nuclear imbalance. Consistent with impaired mitochondrial function, sin-3 mutants show extensive mitochondrial fragmentation by transmission electron microscopy (TEM) and in vivo imaging, and altered oxygen consumption. Metabolomic analysis of sin-3 mutant animals revealed a mitochondria stress signature and deregulation of methionine flux, resulting in decreased S-adenosyl methionine (SAM) and increased polyamine levels. Our results identify SIN3 as a key regulator of mitochondrial dynamics and metabolic flux, with important implications for human pathologies.
AU  - Giovannetti, M.*
AU  - Rodríguez-Palero, M.J.*
AU  - Fabrizio, P.*
AU  - Nicolle, O.*
AU  - Bedet, C.*
AU  - Michaux, G.*
AU  - Witting, M.
AU  - Artal-Sanz, M.*
AU  - Palladino, F.*
C1  - 70668
C2  - 55565
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - SIN-3 transcriptional coregulator maintains mitochondrial homeostasis and polyamine flux.
JO  - iScience
VL  - 27
IS  - 5
PB  - Cell Press
PY  - 2024
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Difference-in-differences (DID) is a key tool for causal impact evaluation but faces challenges when applied to sensitive data restricted by privacy regulations. Obtaining consent can shrink sample sizes and reduce statistical power, limiting the analysis's effectiveness. Federated learning addresses these issues by sharing aggregated statistics rather than individual data, though advanced federated DID software is limited. We developed a federated version of the Callaway and Sant'Anna difference-in-differences (CSDID), integrated into the DataSHIELD platform, adhering to stringent privacy protocols. Our approach reproduces key estimates and standard errors while preserving confidentiality. Using simulated and real-world data from a malaria intervention in Mozambique, we demonstrate that federated estimates increase sample sizes, reduce estimation uncertainty, and enable analyses when data owners cannot share treated or untreated group data. Our work contributes to facilitating the evaluation of policy interventions or treatments across centers and borders.
AU  - Huth, M.
AU  - Garavito, C.A.*
AU  - Seep, L.*
AU  - Cirera, L.*
AU  - Saúte, F.*
AU  - Sicuri, E.*
AU  - Hasenauer, J.
C1  - 72229
C2  - 56513
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Federated difference-in-differences with multiple time periods in DataSHIELD.
JO  - iScience
VL  - 27
IS  - 11
PB  - Cell Press
PY  - 2024
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Clinical data on the types of respiratory pathogens which are most frequently engaged in respiratory co-infections of children and adults are lacking. We analyzed 10 years of data on a total of over 15,000 tests for 16 viral and bacterial pathogens detected in clinical samples at the University Hospital of Augsburg, Germany. Co-infection frequencies and their seasonal patterns were examined using a proportional distribution model. Co-infections were detected in 7.3% of samples, with a higher incidence in children and males. The incidence of interbacterial and interviral co-infections was higher than expected, whereas bacterial-viral co-infections were less frequent. H. influenzae, S. pneumoniae, rhinovirus, and respiratory syncytial virus (RSV) were most frequently involved. Most co-infections occurred in winter, but distinct summer peaks were also observed, which occurred even in children, albeit less pronounced than in adults. Seasonality of respiratory (co-)infections decreased with age. Our results suggest to adjust existing testing strategies during high-incidence periods.
AU  - Krammer, M.*
AU  - Hoffmann, R.*
AU  - Ruf, H.G.*
AU  - Neumann, A.U.
AU  - Traidl-Hoffmann, C.
AU  - Gökkaya, M.
AU  - Gilles, S.
C1  - 70849
C2  - 55734
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Ten-year retrospective data analysis reveals frequent respiratory co-infections in hospitalized patients in Augsburg.
JO  - iScience
VL  - 27
IS  - 6
PB  - Cell Press
PY  - 2024
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Cellular quiescence is a reversible and tightly regulated stem cell function essential for healthy aging. However, the elements that control quiescence during aging remain poorly defined. Using melanocyte stem cells (McSCs), we find that stem cell quiescence is neither passive nor static. For example, gene expression profiling of the transition from proliferating melanoblasts to quiescent melanocyte stem cells reveals tissue-specific regulation of the immune checkpoint protein PD-L1. In vitro, quiescence assays demonstrate that PD-L1 expression is a physiological attribute of quiescence in this cell lineage and reinforces this cell state. In vivo, a subset of quiescent McSCs is marked by PD-L1. While the overall number of McSCs decreases with age, PD-L1+ McSCs appear resistant to depletion. This phenomenon coincides with an aged McSC pool that exhibits a deeper transcriptomic quiescence. We predict that quiescent PD-L1+ stem cells retained with age may serve as cellular targets for reactivation.
AU  - Palmer, J.W.*
AU  - Villavicencio, K.M.*
AU  - Idris, M.*
AU  - Baranyk, I.J.*
AU  - Polycarp, N.*
AU  - Dawson, A.D.*
AU  - Weddle, D.*
AU  - Pavan, W.J.*
AU  - Filipp, F.V.
AU  - Harris, M.L.*
C1  - 71882
C2  - 56746
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Quiescence and aging of melanocyte stem cells and a novel association with programmed death-ligand 1.
JO  - iScience
VL  - 27
IS  - 10
PB  - Cell Press
PY  - 2024
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - There is an unmet need for a biomarker of liver fat. We identified dimethylguanidino valeric acid (DMGV) as a circulating biomarker of liver fat. Here, we assess its two isoforms—symmetric (SDGV) and asymmetric (ADGV)—as biomarkers of steatosis. We determined plasma ADGV, SDGV, related metabolites, alanine aminotransferase (ALT), and the fatty liver index (FLI) in two cohorts and compared their diagnostic performance for liver fat detection. SDGV was the strongest predictor of moderate to severe steatosis. Changes in SDGV correlated with changes in liver fat % in a prospective cohort. In a murine model of fatty liver disease, protein levels and activity of alanine:glyoxylate aminotransferase 2 (AGXT2), which produces SDGV, were increased and coincided with elevation of SDGV concentrations. SDGV is a biomarker of liver fat and its increase in hepatic steatosis results from the upregulation of AGXT2 activity.
AU  - Rodionov, R.N.*
AU  - Jarzebska, N.*
AU  - Koay, Y.C.*
AU  - Li, M.*
AU  - Kuhn, M.*
AU  - Bornstein, S.R.*
AU  - Martens-Lobenhoffer, J.*
AU  - Eslam, M.*
AU  - Chen, F.W.*
AU  - Rubets, E.*
AU  - Markov, A.G.*
AU  - Weiss, N.*
AU  - Birkenfeld, A.L.
AU  - Schwarz, P.E.
AU  - Bode-Böger, S.M.*
AU  - Perakakis, N.
AU  - O'Sullivan, J.F.*
AU  - George, J.*
C1  - 72584
C2  - 56628
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Symmetric dimethylguanidino valeric acid, a novel single biomarker of hepatic steatosis.
JO  - iScience
VL  - 27
IS  - 12
PB  - Cell Press
PY  - 2024
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - The Bruton tyrosine kinase inhibitor ibrutinib is an effective treatment for patients with chronic lymphocytic leukemia (CLL). While it rapidly reduces lymph node and spleen size, it initially increases the number of lymphocytes in the blood due to cell redistribution. A previously published mathematical model described and quantified those cell kinetics. Here, we propose an alternative mechanistic model that outperforms the previous model in 26 of 29 patients. Our model introduces constant subcompartments for healthy lymphocytes and benign tissue and treats spleen and lymph nodes as separate compartments. This three-compartment model (comprising blood, spleen, and lymph nodes) performed significantly better in patients without a mutation in the IGHV gene, indicating a diverse response to ibrutinib for cells residing in lymph nodes and spleen. Additionally, high ZAP-70 expression was linked to less cell death in the spleen. Overall, our study enhances understanding of CLL genetics and patient response to ibrutinib and provides a framework applicable to the study of similar drugs.
AU  - Schulz, M.
AU  - Bleser, S.
AU  - Groels, M.
AU  - Bošnački, D.*
AU  - Burger, J.A.*
AU  - Chiorazzi, N.*
AU  - Marr, C.
C1  - 72391
C2  - 56562
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Mathematical multi-compartment modeling of chronic lymphocytic leukemia cell kinetics under ibrutinib.
JO  - iScience
VL  - 27
IS  - 12
PB  - Cell Press
PY  - 2024
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Low birthweight (LBW) increases the risk of adult-onset diseases, including kidney diseases, with intergenerational consequences; however, the underlying mechanisms and effective interventions are unclear. To examine the cross-generational effects of LBW, we established an LBW mouse model through reduced uterine perfusion pressure (RUPP) and investigated the therapeutic potential of tadalafil, a phosphodiesterase 5 inhibitor, on LBW-associated consequences. RUPP-pups (R1) had lower fetal and birth weights, delayed renal development, and fewer glomeruli than Sham-pups. In adulthood, R1 mice exhibited persistently fewer glomeruli and elevated blood pressure, while Tadalafil-R1 mice showed reduced hypertension in both sexes and improved renal pathological changes in males. Additionally, pregnant R1 mice displayed inadequate gestational liver hypertrophy, impaired hepatic purine metabolism, and diminished placental angiogenesis, resulting in fetal growth restriction in the subsequent generation. These findings underscore the lasting impact of LBW on adult health and future generations and suggest tadalafil's potential to mitigate LBW-associated risks.
AU  - Sekimoto, A.*
AU  - Takaso, Y.*
AU  - Saruyama, H.*
AU  - Ookawa, M.*
AU  - Yamamoto, M.*
AU  - Toyohara, T.*
AU  - Saigusa, D.*
AU  - Fukuuchi, T.*
AU  - Otsuka, M.*
AU  - Fushiki, Y.*
AU  - Yamakoshi, S.*
AU  - Tanaka, K.*
AU  - Ikeda, T.*
AU  - Tanaka, T.*
AU  - Takahashi, N.*
AU  - Mishima, E.
AU  - Sato, E.*
C1  - 72253
C2  - 56520
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Impacts of low birthweight on kidney development and intergenerational growth of the offspring.
JO  - iScience
VL  - 27
IS  - 11
PB  - Cell Press
PY  - 2024
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Visual cortical plasticity is high during early life, but gradually decreases with development. This is due to the Otx2-driven maturation of intracortical inhibition that parallels the condensation of extracellular matrix components into perineuronal nets mainly around parvalbumin-positive GABAergic neurons. Repressor Element 1 Silencing Transcription (REST) epigenetically controls the expression of a plethora of neuron-specific genes. We demonstrate that the conditional knockout of REST in the primary visual cortex of adult mice induces a shift of ocular dominance after short-term monocular deprivation and promotes the recovery of vision in long-term deprived animals after reverse suture. These phenomena paralleled a reduction of perineuronal net density and increased expression of REST target genes, but not of the homeoprotein Otx2 in the visual cortex contralateral to the deprived eye. This shows that REST regulates adult visual cortical plasticity and is a potential therapeutic target to restore vision in adult amblyopia by enhancing V1 plasticity.
AU  - Shmal, D.*
AU  - Mantero, G.*
AU  - Floss, T.
AU  - Benfenati, F.*
AU  - Maya-Vetencourt, J.F.*
C1  - 70417
C2  - 55609
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Restoring vision in adult amblyopia by enhancing plasticity through deletion of the transcriptional repressor REST.
JO  - iScience
VL  - 27
IS  - 4
PB  - Cell Press
PY  - 2024
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Deconvolution algorithms mostly rely on single-cell RNA-sequencing (scRNA-seq) data applied onto bulk RNA-sequencing (bulk RNA-seq) to estimate tissues’ cell-type composition, with performance accuracy validated on deposited databases. Adipose tissues’ cellular composition is highly variable, and adipocytes can only be captured by single-nucleus RNA-sequencing (snRNA-seq). Here we report the development of sNucConv, a Scaden deep-learning-based deconvolution tool, trained using 5 hSAT and 7 hVAT snRNA-seq-based data corrected by (i) snRNA-seq/bulk RNA-seq highly correlated genes and (ii) individual cell-type regression models. Applying sNucConv on our bulk RNA-seq data resulted in cell-type proportion estimation of 15 and 13 cell types, with accuracy of R = 0.93 (range: 0.76–0.97) and R = 0.95 (range: 0.92–0.98) for hVAT and hSAT, respectively. This performance level was further validated on an independent set of samples (5 hSAT; 5 hVAT). The resulting model was depot specific, reflecting depot differences in gene expression patterns. Jointly, sNucConv provides proof-of-concept for producing validated deconvolution models for tissues un-amenable to scRNA-seq.
AU  - Sorek, G.*
AU  - Haim, Y.*
AU  - Chalifa-Caspi, V.*
AU  - Lazarescu, O.*
AU  - Ziv-Agam, M.*
AU  - Hagemann, T.
AU  - Nono Nankam, P.A.
AU  - Blüher, M.
AU  - Liberty, I.F.*
AU  - Dukhno, O.*
AU  - Kukeev, I.*
AU  - Yeger-Lotem, E.*
AU  - Rudich, A.*
AU  - Levin, L.*
C1  - 71110
C2  - 55909
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - sNucConv: A bulk RNA-seq deconvolution method trained on single-nucleus RNA-seq data to estimate cell-type composition of human adipose tissues.
JO  - iScience
VL  - 27
IS  - 7
PB  - Cell Press
PY  - 2024
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Clonal hematopoiesis of indeterminate potential (CHIP) describes the age-related acquisition of somatic mutations in hematopoietic stem/progenitor cells (HSPC) leading to clonal blood cell expansion. Although CHIP mutations drive myeloid malignancies like myelodysplastic syndromes (MDS) it is unknown if clonal expansion is attributable to changes in cell type kinetics, or involves reorganization of the hematopoietic hierarchy. Using computational modeling we analyzed differentiation and proliferation kinetics of cultured hematopoietic stem cells (HSC) from 8 healthy individuals, 7 CHIP, and 10 MDS patients. While the standard hematopoietic hierarchy explained HSPC kinetics in healthy samples, 57% of CHIP and 70% of MDS samples were best described with alternative hierarchies. Deregulated kinetics were found at various HSPC compartments with high inter-individual heterogeneity in CHIP and MDS, while altered HSC rates were most relevant in MDS. Quantifying kinetic heterogeneity in detail, we show that reorganization of the HSPC compartment is already detectable in the premalignant CHIP state.
AU  - Buck, M.C.*
AU  - Bast, L.
AU  - Hecker, J.S.*
AU  - Riviere, J.*
AU  - Rothenberg-Thurley, M.*
AU  - Vogel, L.*
AU  - Wang, D.
AU  - Andrä, I.*
AU  - Theis, F.J.
AU  - Bassermann, F.*
AU  - Metzeler, K.H.*
AU  - Oostendorp, R.A.J.*
AU  - Marr, C.
AU  - Götze, K.S.*
C1  - 68046
C2  - 54524
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Progressive disruption of hematopoietic architecture from clonal hematopoiesis to MDS.
JO  - iScience
VL  - 26
IS  - 8
PB  - Cell Press
PY  - 2023
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - G protein-coupled receptors (GPCRs) modulate the function of adipose tissue (AT) in general and of adipocytes, specifically. Although it is well-established that GPCRs are widely expressed in AT, their repertoire as well as their regulation and function in (patho)physiological conditions (e.g., obesity) is not fully resolved. Here, we established FATTLAS, an interactive public database, for improved access and analysis of RNA-seq data of mouse and human AT. After extracting the GPCRome of non-obese and obese individuals, highly expressed and differentially regulated GPCRs were identified. Exemplarily, we describe four receptors (GPR146, MRGPRF, FZD5, PTGER2) and analyzed their functions in a (pre)adipocyte cell model. Besides all receptors being involved in adipogenesis, MRGPRF is essential for adipocyte viability and regulates cAMP levels, while GPR146 modulates adipocyte lipolysis via constitutive activation of Gi proteins. Taken together, by implementing and using FATTLAS we describe four hitherto unrecognized GPCRs associated with AT function and adipogenesis.
AU  - Kaczmarek, I.*
AU  - Wower, I.*
AU  - Ettig, K.*
AU  - Kuhn, C.K.*
AU  - Kraft, R.*
AU  - Landgraf, K.*
AU  - Körner, A.
AU  - Schöneberg, T.*
AU  - Horn, S.*
AU  - Thor, D.*
C1  - 68267
C2  - 54828
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Identifying G protein-coupled receptors involved in adipose tissue function using the innovative RNA-seq database FATTLAS.
JO  - iScience
VL  - 26
IS  - 10
PB  - Cell Press
PY  - 2023
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Autoimmunity plays a role in certain types of lung fibrosis, notably connective tissue disease-associated interstitial lung disease (CTD-ILD). In idiopathic pulmonary fibrosis (IPF), an incurable and fatal lung disease, diagnosis typically requires clinical exclusion of autoimmunity. However, autoantibodies of unknown significance have been detected in IPF patients. We conducted computational analysis of B cell transcriptomes in published transcriptomics datasets and developed a proteomic Differential Antigen Capture (DAC) assay that captures plasma antibodies followed by affinity purification of lung proteins coupled to mass spectrometry. We analyzed antibody capture in two independent cohorts of IPF and CTL-ILD patients over two disease progression time points. Our findings revealed significant upregulation of specific immunoglobulins with V-segment bias in IPF across multiple cohorts. We identified a predictive autoimmune signature linked to reduced transplant-free survival in IPF, persisting over time. Notably, autoantibodies against thrombospondin-1 were associated with decreased survival, suggesting their potential as predictive biomarkers.
AU  - Leuschner, G.
AU  - Semenova, A.
AU  - Mayr, C.
AU  - Kapellos, T.
AU  - Ansari, M.
AU  - Seeliger, B.*
AU  - Frankenberger, M.
AU  - Kneidinger, N.*
AU  - Hatz, R.A.*
AU  - Hilgendorff, A.
AU  - Prasse, A.*
AU  - Behr, J.*
AU  - Mann, M.*
AU  - Schiller, H.
C1  - 68816
C2  - 55020
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Mass spectrometry-based autoimmune profiling reveals predictive autoantigens in idiopathic pulmonary fibrosis.
JO  - iScience
VL  - 26
IS  - 11
PB  - Cell Press
PY  - 2023
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - In this study, we interrogate molecular mechanisms underlying the specification of lung progenitors from human pluripotent stem cells (hPSCs). We employ single-cell RNA-sequencing with high temporal precision, alongside an optimized differentiation protocol, to elucidate the transcriptional hierarchy of lung specification to chart the associated single-cell trajectories. Our findings indicate that Sonic hedgehog, TGF-β, and Notch activation are essential within an ISL1/NKX2-1 trajectory, leading to the emergence of lung progenitors during the foregut endoderm phase. Additionally, the induction of HHEX delineates an alternate trajectory at the early definitive endoderm stage, preceding the lung pathway and giving rise to a significant hepatoblast population. Intriguingly, neither KDR+ nor mesendoderm progenitors manifest as intermediate stages in the lung and hepatic lineage development. Our multistep model offers insights into lung organogenesis and provides a foundation for in-depth study of early human lung development and modeling using hPSCs.
AU  - Ori, C.
AU  - Ansari, M.
AU  - Angelidis, I.
AU  - Olmer, R.*
AU  - Martin, U.*
AU  - Theis, F.J.
AU  - Schiller, H. B.
AU  - Drukker, M.
C1  - 68799
C2  - 55036
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Human pluripotent stem cell fate trajectories toward lung and hepatocyte progenitors.
JO  - iScience
VL  - 26
IS  - 11
PB  - Cell Press
PY  - 2023
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Bayesian inference is an important method in the life and natural sciences for learning from data. It provides information about parameter and prediction uncertainties. Yet, generating representative samples from the posterior distribution is often computationally challenging. Here, we present an approach that lowers the computational complexity of sample generation for dynamical models with scaling, offset, and noise parameters. The proposed method is based on the marginalization of the posterior distribution. We provide analytical results for a broad class of problems with conjugate priors and show that the method is suitable for a large number of applications. Subsequently, we demonstrate the benefit of the approach for applications from the field of systems biology. We report an improvement up to 50 times in the effective sample size per unit of time. As the scheme is broadly applicable, it will facilitate Bayesian inference in different research fields.
AU  - Raimundez, E.*
AU  - Fedders, M.*
AU  - Hasenauer, J.
C1  - 68708
C2  - 54917
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Posterior marginalization accelerates Bayesian inference for dynamical models of biological processes.
JO  - iScience
VL  - 26
IS  - 11
PB  - Cell Press
PY  - 2023
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Microbial communities reside at the interface between humans and their environment. Whether the microbiome can be leveraged to gain information on human interaction with museum objects is unclear. To investigate this, we selected objects from the Museum für Naturkunde and the Pergamonmuseum in Berlin, Germany, varying in material and size. Using swabs, we collected 126 samples from natural and cultural heritage objects, which were analyzed through 16S rRNA sequencing. By comparing the microbial composition of touched and untouched objects, we identified a microbial signature associated with human skin microbes. Applying this signature to cultural heritage objects, we identified areas with varying degrees of exposure to human contact on the Ishtar gate and Sam'al gate lions. Furthermore, we differentiated objects touched by two different individuals. Our findings demonstrate that the microbiome of museum objects provides insights into the level of human contact, crucial for conservation, heritage science, and potentially provenance research.
AU  - Simon, L.M.*
AU  - Flocco, C.*
AU  - Burkart, F.*
AU  - Methner, A.*
AU  - Henke, D.*
AU  - Rauer, L.
AU  - Müller, C.L.
AU  - Vogel, J.*
AU  - Quaisser, C.*
AU  - Overmann, J.*
AU  - Simon, S.*
C1  - 68356
C2  - 54748
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Microbial fingerprints reveal interaction between museum objects, curators, and visitors.
JO  - iScience
VL  - 26
IS  - 9
PB  - Cell Press
PY  - 2023
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Monitoring disease response after intensive chemotherapy for acute myeloid leukemia (AML) currently requires invasive bone marrow biopsies, imposing a significant burden on patients. In contrast, cell-free tumor DNA (ctDNA) in peripheral blood, carrying tumor-specific mutations, offers a less-invasive assessment of residual disease. However, the relationship between ctDNA levels and bone marrow blast kinetics remains unclear. We explored this in 10 AML patients with NPM1 and IDH2 mutations undergoing initial chemotherapy. Comparison of mathematical mixed-effect models showed that (1) inclusion of blast cell death in the bone marrow, (2) transition of ctDNA to peripheral blood, and (3) ctDNA decay in peripheral blood describes kinetics of blast cells and ctDNA best. The fitted model allows prediction of residual bone marrow blast content from ctDNA, and its scaling factor, representing clonal heterogeneity, correlates with relapse risk. Our study provides precise insights into blast and ctDNA kinetics, offering novel avenues for AML disease monitoring.
AU  - Wang, D.
AU  - Rausch, C.*
AU  - Buerger, S.A.*
AU  - Tschuri, S.*
AU  - Rothenberg-Thurley, M.*
AU  - Schulz, M.
AU  - Hasenauer, J.
AU  - Ziemann, F.*
AU  - Metzeler, K.H.*
AU  - Marr, C.
C1  - 68795
C2  - 55078
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Modeling early treatment response in AML from cell-free tumor DNA.
JO  - iScience
VL  - 26
IS  - 12
PB  - Cell Press
PY  - 2023
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - lncRAP2 is a conserved cytoplasmic lncRNA enriched in adipose tissue and required for adipogenesis. Using purification and in vivo interactome analyses, we show that lncRAP2 forms complexes with proteins that stabilize mRNAs and modulate translation, among them Igf2bp2. Surveying transcriptome-wide Igf2bp2 client mRNAs in white adipocytes reveals selective binding to mRNAs encoding adipogenic regulators and energy expenditure effectors, including adiponectin. These same target proteins are downregulated when either Igf2bp2 or lncRAP2 is downregulated, hindering adipocyte lipolysis. Proteomics and ribosome profiling show this occurs predominantly through mRNA accumulation, as lncRAP2-Igf2bp2 complex binding does not impact translation efficiency. Phenome-wide association studies reveal specific associations of genetic variants within both lncRAP2 and Igf2bp2 with body mass and type 2 diabetes, and both lncRAP2 and Igf2bp2 are suppressed in adipose depots of obese and diabetic individuals. Thus, the lncRAP2-Igf2bp2 complex potentiates adipose development and energy expenditure and is associated with susceptibility to obesity-linked diabetes.
AU  - Alvarez-Dominguez, J.R.*
AU  - Winther, S.*
AU  - Hansen, J.B.*
AU  - Lodish, H.F.*
AU  - Knoll, M.
C1  - 64030
C2  - 52045
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - An adipose lncRAP2-Igf2bp2 complex enhances adipogenesis and energy expenditure by stabilizing target mRNAs.
JO  - iScience
VL  - 25
IS  - 1
PB  - Cell Press
PY  - 2022
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Pathogen recognition and TNF receptors signal via receptor interacting serine/threonine kinase-3 (RIPK3) to cause cell death, including MLKL-mediated necroptosis and caspase-8-dependent apoptosis. However, the post-translational control of RIPK3 is not fully understood. Using mass-spectrometry, we identified that RIPK3 is ubiquitylated on K469. The expression of mutant RIPK3 K469R demonstrated that RIPK3 ubiquitylation can limit both RIPK3-mediated apoptosis and necroptosis. The enhanced cell death of overexpressed RIPK3 K469R and activated endogenous RIPK3 correlated with an overall increase in RIPK3 ubiquitylation. Ripk3K469R/K469R mice challenged with Salmonella displayed enhanced bacterial loads and reduced serum IFNγ. However, Ripk3K469R/K469R macrophages and dermal fibroblasts were not sensitized to RIPK3-mediated apoptotic or necroptotic signaling suggesting that, in these cells, there is functional redundancy with alternate RIPK3 ubiquitin-modified sites. Consistent with this idea, the mutation of other ubiquitylated RIPK3 residues also increased RIPK3 hyper-ubiquitylation and cell death. Therefore, the targeted ubiquitylation of RIPK3 may act as either a brake or accelerator of RIPK3-dependent killing.
AU  - Frank, D.*
AU  - Garnish, S.E.*
AU  - Sandow, J.J.*
AU  - Weir, A.*
AU  - Liu, L.*
AU  - Clayer, E.
AU  - Meza, L.*
AU  - Rashidi, M.*
AU  - Cobbold, S.A.*
AU  - Scutts, S.R.*
AU  - Doerflinger, M.*
AU  - Anderton, H.*
AU  - Lawlor, K.E.*
AU  - Lalaoui, N.*
AU  - Kueh, A.J.*
AU  - Eng, V.V.*
AU  - Ambrose, R.L.*
AU  - Herold, M.J.*
AU  - Samson, A.L.*
AU  - Feltham, R.*
AU  - Murphy, J.M.*
AU  - Ebert, G.
AU  - Pearson, J.S.*
AU  - Vince, J.E.*
C1  - 65624
C2  - 52747
TI  - Ubiquitylation of RIPK3 beyond-the-RHIM can limit RIPK3 activity and cell death.
JO  - iScience
VL  - 25
IS  - 7
PY  - 2022
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - The respective value of clinical data and CT examinations in predicting COVID-19 progression is unclear, because the CT scans and clinical data previously used are not synchronized in time. To address this issue, we collected 119 COVID-19 patients with 341 longitudinal CT scans and paired clinical data, and developed an AI system for the prediction of COVID-19 deterioration. By combining features extracted from CT and clinical data with our system, we can predict whether a patient will develop severe symptoms during hospitalization. Complementary to clinical data, CT examinations show significant add-on values for the prediction of COVID-19 progression in the early stage of COVID-19, especially in the 6th to 8th day after the symptom onset, indicating that this is the ideal time window for the introduction of CT examinations. We release our AI system to provide clinicians with additional assistance to optimize CT usage in the clinical workflow.
AU  - Han, X.*
AU  - Yu, Z.*
AU  - Zhuo, Y.*
AU  - Zhao, B.*
AU  - Ren, Y.*
AU  - Lamm, L.
AU  - Xue, X.*
AU  - Feng, J.*
AU  - Marr, C.
AU  - Shan, F.*
AU  - Peng, T.
AU  - Zhang, X.Y.*
C1  - 64783
C2  - 52481
TI  - The value of longitudinal clinical data and paired CT scans in predicting the deterioration of COVID-19 revealed by an artificial intelligence system.
JO  - iScience
VL  - 25
IS  - 5
PY  - 2022
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Childhood-onset myocardial hypertrophy and cardiomyopathic changes are associated with significant morbidity and mortality in early life, particularly in patients with Noonan syndrome, a multisystemic genetic disorder caused by autosomal dominant mutations in genes of the Ras-MAPK pathway. Although the cardiomyopathy associated with Noonan syndrome (NS-CM) shares certain cardiac features with the hypertrophic cardiomyopathy caused by mutations in sarcomeric proteins (HCM), such as pathological myocardial remodeling, ventricular dysfunction, and increased risk for malignant arrhythmias, the clinical course of NS-CM significantly differs from HCM. This suggests a distinct pathophysiology that remains to be elucidated. Here, through analysis of sarcomeric myosin conformational states, histopathology, and gene expression in left ventricular myocardial tissue from NS-CM, HCM, and normal hearts complemented with disease modeling in cardiomyocytes differentiated from patient-derived PTPN11N308S/+ induced pluripotent stem cells, we demonstrate distinct disease phenotypes between NS-CM and HCM and uncover cell cycle defects as a potential driver of NS-CM.
AU  - Meier, A.B.*
AU  - Raj Murthi, S.*
AU  - Rawat, H.*
AU  - Toepfer, C.N.*
AU  - Santamaria, G.*
AU  - Schmid, M.*
AU  - Mastantuono, E.
AU  - Schwarzmayr, T.
AU  - Berutti, R.
AU  - Cleuziou, J.*
AU  - Ewert, P.*
AU  - Görlach, A.*
AU  - Klingel, K.*
AU  - Laugwitz, K.L.*
AU  - Seidman, C.E.*
AU  - Seidman, J.G.*
AU  - Moretti, A.*
AU  - Wolf, C.M.*
C1  - 63861
C2  - 51728
TI  - Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome.
JO  - iScience
VL  - 25
IS  - 1
PY  - 2022
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Foxp3+ regulatory T cells (Tregs) are critical mediators of peripheral tolerance and immune homeostasis and exert tissue-specific functions. In many nonlymphoid tissues, Tregs show enriched expression of the IL-33 receptor ST2. Through comprehensive profiling of murine ST2+ and ST2- Tregs, we found that Treg transcriptomes and phenotypes formed a hierarchical relationship across tissues. Only a small core signature distinguished ST2+ Tregs from ST2- Tregs across all tissues, and differences in transcriptional profiles were predominantly tissue-specific. We also identified unique, highly proliferative, circulating ST2+ Tregs with high migratory potential. In adoptive transfers, both ST2+ and ST2- Tregs seeded various host tissues and demonstrated plasticity in ST2 expression. Furthermore, Tregs from donor lungs were differentially recovered from host nonlymphoid tissues in an IL-33-dependent manner. In summary, our work identified tissue residency rather than ST2 expression as a primary driver of tissue Treg identity and highlights the unique, tissue-specific adaption of ST2+ Tregs.
AU  - Spath, S.*
AU  - Roan, F.*
AU  - Presnell, S.R.*
AU  - Höllbacher, B.
AU  - Ziegler, S.F.*
C1  - 66078
C2  - 53085
TI  - Profiling of Tregs across tissues reveals plasticity in ST2 expression and hierarchies in tissue-specific phenotypes.
JO  - iScience
VL  - 25
IS  - 9
PY  - 2022
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Reconstruction of shapes and sizes of three-dimensional (3D) objects from two- dimensional (2D) information is an intensely studied subject in computer vision. We here consider the level of single cells and nuclei and present a neural network-based SHApe PRediction autoencoder. For proof-of-concept, SHAPR reconstructs 3D shapes of red blood cells from single view 2D confocal microscopy images more accurately than naïve stereological models and significantly increases the feature-based prediction of red blood cell types from F1 = 79% to F1 = 87.4%. Applied to 2D images containing spheroidal aggregates of densely grown human induced pluripotent stem cells, we find that SHAPR learns fundamental shape properties of cell nuclei and allows for prediction-based morphometry. Reducing imaging time and data storage, SHAPR will help to optimize and up-scale image-based high-throughput applications for biomedicine.
AU  - Waibel, D.J.E.
AU  - Kiermeyer, N.
AU  - Atwell, S.
AU  - Sadafi, A.
AU  - Meier, M.
AU  - Marr, C.
C1  - 66501
C2  - 52856
TI  - SHAPR predicts 3D cell shapes from 2D microscopic images.
JO  - iScience
VL  - 25
IS  - 11
PY  - 2022
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Less than 80 Sumatran rhinos (SR, Dicerorhinus sumatrensis) are left on earth. Habitat loss and limited breeding possibilities are the greatest threats to the species and lead to a continuous population decline. To stop the erosion of genetic diversity, reintroduction of genetic material is indispensable. However, as the propagation rate of captive breeding is far too low, innovative technologies have to be developed. Induced pluripotent stem cells (iPSCs) are a powerful tool to fight extinction. They give rise to each cell within the body including gametes and provide a unique modality to preserve genetic material across time. Additionally, they enable studying species-specific developmental processes. Here, we generate iPSCs from the last male Malaysian SR Kertam, who died in 2019, and characterize them comprehensively. Differentiation in cells of the three germ layers and cerebral organoids demonstrate their high quality and great potential for supporting the rescue of this critically endangered species.
AU  - Zywitza, V.*
AU  - Frahm, S.*
AU  - Krüger, N.*
AU  - Weise, A.*
AU  - Göritz, F.*
AU  - Hermes, R.*
AU  - Holtze, S.*
AU  - Colleoni, S.*
AU  - Galli, C.*
AU  - Drukker, M.
AU  - Hildebrandt, T.B.*
AU  - Diecke, S.*
C1  - 66705
C2  - 53280
TI  - Induced pluripotent stem cells and cerebral organoids from the critically endangered Sumatran rhinoceros.
JO  - iScience
VL  - 25
IS  - 11
PY  - 2022
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - In this study, we analyzed norovirus (NoV) evolution in sequential samples of six chronically infected patients. The capsid gene was amplified from stool samples, and deep sequencing was performed. The role of amino acid flexibility in structural changes and ligand binding was studied with molecular dynamics (MD) simulations. Concentrations of capsid-specific antibodies increased in sequential sera. Capsid sequences accumulated mutations during chronic infection, particularly in the surface-exposed antigenic epitopes A, D, and E. The number of quasispecies increased in infections lasting for >1 month. Interestingly, high genetic complexity and distances were followed by ongoing NoV replication, whereas lower genetic complexity and distances preceded cure. MD simulation revealed that surface-exposed amino acid substitutions of the P2 domain caused fluctuation of blockade epitopes. In conclusion, the capsid protein accumulates numerous mutations during chronic infection; however, only those on the protein surface change the protein structure substantially and may lead to immune escape.
AU  - Afridi, S.Q.
AU  - Usman, Z.*
AU  - Donakonda, S.*
AU  - Wettengel, J.M.
AU  - Velkov, S.
AU  - Beck, R.*
AU  - Gerhard, M.*
AU  - Knolle, P.*
AU  - Frishman, D.*
AU  - Protzer, U.
AU  - Moeini, H.
AU  - Hoffmann, D.
C1  - 62549
C2  - 50817
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 102802
TI  - Prolonged norovirus infections correlate to quasispecies evolution resulting in structural changes of surface-exposed epitopes.
JO  - iScience
VL  - 24
IS  - 7
PB  - Cell Press
PY  - 2021
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Classically, hematopoietic stem cell (HSC) differentiation is assumed to
       occur via progenitor compartments of decreasing plasticity and 
      increasing maturity in a specific, hierarchical manner. The classical 
      hierarchy has been challenged in the past by alternative differentiation
       pathways. We abstracted experimental evidence into 10 differentiation 
      hierarchies, each comprising 7 cell type compartments. By fitting 
      ordinary differential equation models with realistic waiting time 
      distributions to time-resolved data of differentiating HSCs from 10 
      healthy human donors, we identified plausible lineage hierarchies and 
      rejected others. We found that, for most donors, the classical model of 
      hematopoiesis is preferred. Surprisingly, multipotent lymphoid 
      progenitor differentiation into granulocyte-monocyte progenitors is 
      plausible in 90% of samples. An in silico analysis confirmed 
      that, even for strong noise, the classical model can be identified 
      robustly. Our computational approach infers differentiation hierarchies 
      in a personalized fashion and can be used to gain insights into kinetic 
      alterations of diseased hematopoiesis.
AU  - Bast, L.
AU  - Buck, M.C.*
AU  - Hecker, J.S.*
AU  - Oostendorp, R.A.J.*
AU  - Götze, K.S.*
AU  - Marr, C.
C1  - 61396
C2  - 50207
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Computational modeling of stem and progenitor cell kinetics identifies plausible hematopoietic lineage hierarchies.
JO  - iScience
VL  - 24
IS  - 2
PB  - Cell Press
PY  - 2021
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Protein AMPylation is a posttranslational modification with an emerging role in neurodevelopment. In metazoans two highly conserved protein AMP-transferases together with a diverse group of AMPylated proteins have been identified using chemical proteomics and biochemical techniques. However, the function of AMPylation remains largely unknown. Particularly problematic is the localization of thus far identified AMPylated proteins and putative AMP-transferases. We show that protein AMPylation is likely a posttranslational modification of luminal lysosomal proteins characteristic in differentiating neurons. Through a combination of chemical proteomics, gel-based separation of modified and unmodified proteins, and an activity assay, we determine that the modified, lysosomal soluble form of exonuclease PLD3 increases dramatically during neuronal maturation and that AMPylation correlates with its catalytic activity. Together, our findings indicate that AMPylation is a so far unknown lysosomal posttranslational modification connected to neuronal differentiation and it may provide a molecular rationale behind lysosomal storage diseases and neurodegeneration.
AU  - Becker, T.*
AU  - Cappel, C.*
AU  - Di Matteo, F.*
AU  - Sonsalla, G.
AU  - Kaminska, E.*
AU  - Spada, F.*
AU  - Cappello, S.*
AU  - Damme, M.*
AU  - Kielkowski, P.*
C1  - 63768
C2  - 51624
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - AMPylation profiling during neuronal differentiation reveals extensive variation on lysosomal proteins.
JO  - iScience
VL  - 24
IS  - 12
PB  - Cell Press
PY  - 2021
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Complex human airway cellular organization where extracellular matrix (ECM) and epithelial and stromal lineages interact present challenges for organ study in vitro. Current in vitro lung models that focus on the lung epithelium do not represent complex airway morphology and cell-ECM interactions seen in vivo. Models including stromal populations often separate them via a semipermeable barrier precluding cell-cell interaction or the effect of ECM mechanics. We investigated the effect of stromal cells on basal epithelial cell-derived bronchosphere structure and function through a triple culture of human bronchial epithelial, lung fibroblast, and airway smooth muscle cells. Epithelial-stromal cross-talk resulted in epithelial cell-driven branching tubules with stromal cells surrounding epithelial cells termed bronchotubules. Agarose- Matrigel scaffold (Agrigel) formed a mechanically tuneable ECM, with adjustable viscoelasticity and stiffness enabling long-term tubule survival. Bronchotubule models may enable research into how epithelial-stromal cell and cell-ECM communication drive tissue patterning, repair, and development of disease.
AU  - Güney, T.
AU  - Herranz, A.M.*
AU  - Mumby, S.*
AU  - Dunlop, I.E.*
AU  - Adcock, I.M.*
C1  - 63196
C2  - 51238
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Epithelial-stromal cell interactions and extracellular matrix mechanics drive the formation of airway-mimetic tubular morphology in lung organoids.
JO  - iScience
VL  - 24
IS  - 9
PB  - Cell Press
PY  - 2021
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Transmembrane epithelial cell adhesion molecule (EpCAM) is expressed in epithelia, carcinoma, teratoma, and embryonic stem cells (ESCs). EpCAM displays spatiotemporal patterning during embryogenesis, tissue morphogenesis, cell differentiation, and epithelial-to-mesenchymal transition (EMT) in carcinomas. Potential interactors of EpCAM were identified in murine F9 teratoma cells using a stable isotope labeling with amino acids in cell culture-based proteomic approach (n = 77, enrichment factor >3, p value ≤ 0.05). Kyoto Encyclopedia of Genes and Genomes and gene ontology terms revealed interactions with regulators of endosomal trafficking and membrane recycling, which were further validated for Rab5, Rab7, and Rab11. Endocytosis and membrane recycling of EpCAM were confirmed in mF9 cells, E14TG2α ESC, and Kyse30 carcinoma cells. Reduction of EpCAM during mesodermal differentiation and TGFβ-induced EMT correlated with enhanced endocytosis and block or reduction of recycling in ESCs and esophageal carcinoma cells. Hence, endocytosis and membrane recycling are means of regulation of EpCAM protein levels during differentiation of ESC and EMT induction in carcinoma cells.
AU  - Pan, M.*
AU  - Kohlbauer, V.*
AU  - Blancke Soares, A.*
AU  - Schinke, H.*
AU  - Huang, Y.*
AU  - Kranz, G.*
AU  - Quadt, T.*
AU  - Hachmeister, M.*
AU  - Gires, O.
C1  - 63450
C2  - 51538
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Interactome analysis reveals endocytosis and membrane recycling of EpCAM during differentiation of embryonic stem cells and carcinoma cells.
JO  - iScience
VL  - 24
IS  - 10
PB  - Cell Press
PY  - 2021
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Rab GTPases are central regulators of intracellular vesicular 
      trafficking. They are frequently targeted by bacterial pathogens through
       post-translational modifications. Salmonella typhimurium 
      secretes the cysteine protease GtgE during infection, leading to a 
      regioselective proteolytic cleavage of the regulatory switch I loop in 
      the small GTPases of the Rab32 subfamily. Here, using a combination of 
      biochemical methods, molecular dynamics simulations, NMR spectroscopy, 
      and single-pair Förster resonance energy transfer, we demonstrate that 
      the cleavage of Rab32 causes a local increase of conformational 
      flexibility in both switch regions. Cleaved Rab32 maintains its ability 
      to interact with the GDP dissociation inhibitor (GDI). Interestingly, 
      the Rab32 cleavage enables GDI binding also with an active GTP-bound 
      Rab32 in vitro. Furthermore, the Rab32 proteolysis provokes 
      disturbance in the interaction with its downstream effector VARP. Thus, 
      the proteolysis of Rab32 is not a globally degradative mechanism but 
      affects various biochemical and structural properties of the GTPase in a
       diverse manner.
AU  - Savitskiy, S.*
AU  - Wachtel, R.*
AU  - Pourjafar-Dehkordi, D.*
AU  - Kang, H.-S.
AU  - Trauschke, V.*
AU  - Lamb, D.C.*
AU  - Sattler, M.
AU  - Zacharias, M.*
AU  - Itzen, A.*
C1  - 60910
C2  - 49986
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Proteolysis of Rab32 by Salmonella GtgE induces an inactive GTPase conformation.
JO  - iScience
VL  - 24
IS  - 1
PB  - Cell Press
PY  - 2021
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - PINK1 loss-of-function mutations cause early onset Parkinson disease. PINK1-Parkin mediated mitophagy has been well studied, but the relevance of the endogenous process in the brain is debated.Here, the absence of PINK1 in human dopaminergic neurons inhibits ionophore-induced mitophagy and reduces mitochondrial membrane potential. Compensatory, mitochondrial renewal maintains mitochondrial morphology and protects the respiratory chain. This is paralleled by metabolic changes, including inhibition of the TCA cycle enzyme mAconitase, accumulation of NAD(+), and metabolite depletion. Loss of PINK1 disrupts dopamine metabolism by critically affecting its synthesis and uptake. The mechanism involves steering of key amino acids toward energy production rather than neurotransmitter metabolism and involves cofactors related to the vitamin B6 salvage pathway identified using unbiased multi-omics approaches.We propose that reduction of mitochondrial membrane potential that cannot be controlled by PINK1 signaling initiates metabolic compensation that has neurometabolic consequences relevant to Parkinson disease.
AU  - Bus, C.*
AU  - Zizmare, L.*
AU  - Feldkaemper, M.*
AU  - Geisler, S.*
AU  - Zarani, M.*
AU  - Schaedler, A.*
AU  - Klose, F.*
AU  - Admard, J.*
AU  - Mageean, C.J.*
AU  - Arena, G.*
AU  - Fallier-Becker, P.*
AU  - Ugun-Klusek, A.*
AU  - Maruszczak, K.K.*
AU  - Kapolou, K.*
AU  - Schmid, B.*
AU  - Rapaport, D.*
AU  - Ueffing, M.*
AU  - Casadei, N.*
AU  - Kruger, R.*
AU  - Gasser, T.*
AU  - Weisenhorn, D.M.
AU  - Kahle, P.J.*
AU  - Trautwein, C.*
AU  - Gloeckner, C.J.*
AU  - Fitzgerald, J.C.*
C1  - 61120
C2  - 49772
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Human dopaminergic neurons lacking PINK1 exhibit disrupted dopamine metabolism related to vitamin B6 co-factors.
JO  - iScience
VL  - 23
IS  - 12
PB  - Cell Press
PY  - 2020
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - While the analysis of mitochondrial morphology has emerged as a key tool in the study of mitochondrial function, efficient quantification of mitochondrial microscopy images presents a challenging task and bottleneck for statistically robust conclusions. Here, we present Mitochondrial Segmentation Network (MitoSegNet), a pretrained deep learning segmentation model that enables researchers to easily exploit the power of deep learning for the quantification of mitochondrial morphology. We tested the performance of MitoSegNet against three feature-based segmentation algorithms and the machine-learning segmentation tool Ilastik. MitoSegNet outperformed all other methods in both pixelwise and morphological segmentation accuracy. We successfully applied MitoSegNet to unseen fluorescence microscopy images of mitoGFP expressing mitochondria in wild-type and catp-6ATP13A2 mutant C. elegans adults. Additionally, MitoSegNet was capable of accurately segmenting mitochondria in HeLa cells treated with fragmentation inducing reagents. We provide MitoSegNet in a toolbox for Windows and Linux operating systems that combines segmentation with morphological analysis.
AU  - Fischer, C.A,
AU  - Besora-Casals, L.*
AU  - Rolland, S.G.*
AU  - Haeussler, S.*
AU  - Singh, K.*
AU  - Duchen, M.*
AU  - Conradt, B.*
AU  - Marr, C.
C1  - 60292
C2  - 49368
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - MitoSegNet: Easy-to-use deep learning segmentation for analyzing mitochondrial morphology.
JO  - iScience
VL  - 23
IS  - 10
PB  - Cell Press
PY  - 2020
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Regulation of glucose homeostasis is a fundamental process to maintain blood glucose at a physiological level, and its dysregulation is associated with the development of several metabolic diseases. Here, we report on a zebrafish mutant for Aldo-keto-reductase 1a1b (akr1a1b) as a regulator of gluconeogenesis. Adult akr1a1b
                              -/-
                           mutant zebrafish developed fasting hypoglycemia, which was caused by inhibiting phosphoenolpyruvate carboxykinase (PEPCK) expression as rate-limiting enzyme of gluconeogenesis. Subsequently, glucogenic amino acid glutamate as substrate for gluconeogenesis accumulated in the kidneys, but not in livers, and induced structural and functional pronephros alterations in 48-hpf akr1a1b
                              -/-
                           embryos. Akr1a1b
                              -/-
                           mutants displayed increased nitrosative stress as indicated by increased nitrotyrosine, and increased protein-S-nitrosylation. Inhibition of nitrosative stress using the NO synthase inhibitor L-NAME prevented kidney damage and normalized PEPCK expression in akr1a1b
                              -/-
                           mutants. Thus, the data have identified Akr1a1b as a regulator of gluconeogenesis in zebrafish and thereby controlling glucose homeostasis.
AU  - Li, X.*
AU  - Schmöhl, F.*
AU  - Qi, H.*
AU  - Bennewitz, K.*
AU  - Tabler, C.T.*
AU  - Poschet, G.*
AU  - Hell, R.*
AU  - Volk, N.*
AU  - Poth, T.*
AU  - Hausser, I.*
AU  - Morgenstern, J.*
AU  - Fleming, T.*
AU  - Nawroth, P.P.
AU  - Kroll, J.*
C1  - 60632
C2  - 49508
TI  - Regulation of guconeogenesis by aldo-keto-reductase 1a1b in zebrafish.
JO  - iScience
VL  - 23
IS  - 12
PY  - 2020
SN  - 2589-0042
ER  - 

TY  - JOUR
AB  - Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is characterized by progressive muscle weakness. Even though DMD manifests first in skebtal muscic, heart failure is a major cause of death in late-stage DMD. To get insights into DMD-associated cardiomyopathy, we performed a proteome analysis of myocardium from a genetically engineered porcine DMD model resembling clinical and pathological hallmarks of human DMD. To capture DMD progression, samples from 2-day. and 3-month-old animals were analyzed. Dystrophin was absent in all DMD samples, and components of the dystrophin-associated protein complex were decreased, suggesting destabilization of the cardiomyocyte plasma membrane and impaired cellular signaling. Furthermore, abundance alterations of proteins known to be associated with human cardiomyopathy were observed. Compared with data from skeletal muscle, we found clear evidence that DMD progression in myocardium is not only slower than in skeletal muscle but also involves different biological and biochemical pathways.
AU  - Tamiyakul, H.*
AU  - Kemter, E.*
AU  - Kösters, M.*
AU  - Ebner, S.*
AU  - Blutke, A.
AU  - Klymiuk, N.*
AU  - Flenkenthaler, F.*
AU  - Wolf, E.*
AU  - Arnold, G.J.*
AU  - Fröhlich, T.*
C1  - 60084
C2  - 49236
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
TI  - Progressive proteome changes in the myocardium of a pig model for Duchenne. muscular dystrophy.
JO  - iScience
VL  - 23
IS  - 9
PB  - Cell Press
PY  - 2020
SN  - 2589-0042
ER  -