TY  - JOUR
AB  - Hyperspectral optoacoustic microscopy (OAM) enables obtaining images 
      with label-free biomolecular contrast, offering excellent perspectives 
      as a diagnostic tool to assess freshly excised and unprocessed 
      biological samples. However, time-consuming raster scanning image 
      formation currently limits the translation potential of OAM into the 
      clinical setting, for instance, in intraoperative histopathological 
      assessments, where micrographs of excised tissue need to be taken within
       a few minutes for fast clinical decision-making. Here, we present a 
      non-data-driven computational framework tailored to enable fast OAM by 
      rapid data acquisition and model-based image reconstruction, termed 
      Bayesian raster-computed optoacoustic microscopy (BayROM). Unlike 
      data-driven approaches, BayROM does not require training datasets, but 
      instead, it uses probabilistic model-based reconstruction to facilitate 
      fast high-resolution imaging. We show that BayROM enables acquiring 
      micrographs 10 times faster on average than conventional raster scanning
       microscopy and provides sufficient image quality to facilitate the 
      intraoperative histological assessment of processed fat grafts for 
      autologous fat transfer.
AU  - Berger, C.
AU  - Kim, M.
AU  - Platz, L.I.
AU  - Eigenberger, A.*
AU  - Prantl, L.*
AU  - Liu, P.
AU  - Gujrati, V.
AU  - Ntziachristos, V.
AU  - Jüstel, D.
AU  - Pleitez, M.A.
C1  - 75385
C2  - 57916
TI  - Bayesian reconstruction of rapidly scanned mid-infrared optoacoustic signals enables fast, label-free chemical microscopy.
JO  - Sci. Adv.
VL  - 11
IS  - 34
PY  - 2025
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Exposure to airborne particulate matter (PM) has been attributed to millions of deaths annually. However, the PM components responsible for observed health effects remain unclear. Oxidative potential (OP) has gained increasing attention as a key property that may explain PM toxicity. Using online measurement methods that impinge particles for OP quantification within seconds, we reveal that 60 to 99% of reactive oxygen species (ROS) and OP in secondary organic aerosol and combustion-generated PM have a lifetime of minutes to hours and that the ROS activity of ambient PM decays substantially before offline analysis. This implies that current offline measurement methods substantially underestimate the true OP of PM. We demonstrate that short-lived OP components activate different toxicity pathways upon direct deposition onto reconstituted human bronchial epithelia. Therefore, we suggest that future air pollution and health studies should include online OP quantification, allowing more accurate assessments of links between OP and health effects.
AU  - Campbell, S.J.*
AU  - Utinger, B.*
AU  - Barth, A.*
AU  - Leni, Z.*
AU  - Zhang, Z.H.*
AU  - Resch, J.*
AU  - Li, K.*
AU  - Steimer, S.S.*
AU  - Banach, C.*
AU  - Gfeller, B.*
AU  - Wragg, F.P.H.*
AU  - Westwood, J.*
AU  - Wolfer, K.*
AU  - Bukowiecki, N.*
AU  - Ihalainen, M.*
AU  - Yli-Pirilä, P.*
AU  - Somero, M.*
AU  - Kortelainen, M.*
AU  - Louhisalmi, J.*
AU  - Sklorz, M.
AU  - Czech, H.
AU  - Di Bucchianico, S.
AU  - Streibel, T.
AU  - Delaval, M.N.
AU  - Rüger, C.*
AU  - Baumlin, N.*
AU  - Salathe, M.*
AU  - Fang, Z.*
AU  - Pardo, M.*
AU  - D'Aronco, S.*
AU  - Giorio, C.*
AU  - Shi, Z.*
AU  - Harrison, R.M.*
AU  - Green, D.C.*
AU  - Kelly, F.J.*
AU  - Rudich, Y.*
AU  - Paulson, S.E.*
AU  - Sippula, O.*
AU  - Zimmermann, R.
AU  - Geiser, M.*
AU  - Kalberer, M.*
C1  - 73717
C2  - 57186
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Short-lived reactive components substantially contribute to particulate matter oxidative potential.
JO  - Sci. Adv.
VL  - 11
IS  - 12
PB  - Amer Assoc Advancement Science
PY  - 2025
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - HIV-1 evades immune responses by modulating plasma membrane receptors. Using a flow cytometry-based screening, we profiled 332 surface receptors on HIV-1-infected primary CD4+ T cells and identified 23 down-regulated receptors, including known targets such as CD4, MHCI, CCR7, and CD62L. CD96, an inhibitory natural killer (NK) cell receptor poorly studied in human CD4+ T cells, was markedly down-regulated. This modulation, mediated by the viral proteins Nef and Vpu, surpassed that of other NK-associated receptors such as CD155 and NTB-A and is conserved across lentiviruses. CD96Hi CD4+ T cells exhibited a proinflammatory TH1/TH17 phenotype characterized by IFN-γ and IL-17 secretion and displayed impaired migration in vivo. Furthermore, CD96 ligation enhanced IFN-γ release upon viral peptide stimulation and promoted the secretion of TH1/TH17-associated cytokines. Our findings suggest that CD96 regulates antiviral immune responses and maintains proinflammatory properties in CD4+ T cells. Thus, its down-regulation represents a previously unknown HIV-1 immune evasion strategy, with implications for exploiting CD96 as immunotherapeutic target.
AU  - Dehn, S.*
AU  - Burkhard, R.*
AU  - Leyens, J.*
AU  - Kaiser, T.*
AU  - Brandimarte, S.*
AU  - Heiligensetzer, D.*
AU  - Koppensteiner, H.
AU  - Bajoghli, B.*
AU  - Hailfinger, S.*
AU  - Schilbach, K.*
AU  - Schindler, M.
C1  - 75464
C2  - 58016
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - HIV-1 manipulates CD96 on CD4+ T cells to subvert antiviral immunity.
JO  - Sci. Adv.
VL  - 11
IS  - 36
PB  - Amer Assoc Advancement Science
PY  - 2025
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Tailpipe emissions from road traffic contribute substantially to the burden of fine inhalable particulate matter (PM2.5) and deteriorate air quality. Exhaust emission standards, forcing improvements in combustion and exhaust after-treatment technology, considerably decreases combustion-related PM2.5 emitted by modern cars. A549 cancerous alveolar and BEAS-2B normal bronchial epithelial cells were exposed at the air-liquid interface to the total aerosol or gas phase of either fresh or photochemically aged tailpipe emissions from a gasoline EURO 6d car equipped with a gasoline particulate filter. Diluted fresh emissions contained particle number concentrations comparable to low ambient air levels and induced no detectable cytotoxicity. Photochemical aging led to the formation of secondary aerosols and caused significant cytotoxicity. While the aged aerosol induced significant DNA damage, oxidative stress was more associated with volatile secondary species. Our results call for the consideration of the exhaust emission atmospheric transformation processes in future emission standards toward health effect-driven emission regulations.
AU  - Delaval, M.N.
AU  - Czech, H.
AU  - Almasaleekh, M.
AU  - Offer, S.
AU  - Pantzke, J.
AU  - Ihalainen, M.*
AU  - Yli-Pirilä, P.*
AU  - Somero, M.*
AU  - Kortelainen, M.*
AU  - Gawlitta, N.
AU  - Orasche, J.
AU  - Jakobi, G.
AU  - Shukla, D.
AU  - Martens, P.*
AU  - Paul, A.*
AU  - Fang, Z.*
AU  - Pardo, M.*
AU  - Barth, A.*
AU  - Utinger, B.*
AU  - Jeong, S.
AU  - Rastak, N.
AU  - Kuhn, E.
AU  - Huber, A.
AU  - Mukherjee, A.*
AU  - Mesceriakovas, A.*
AU  - Joutsensaari, J.*
AU  - Leskinen, J.*
AU  - Hartikainen, A.*
AU  - Passig, J.*
AU  - Oeder, S.
AU  - Schnelle-Kreis, J.
AU  - Hohaus, T.*
AU  - Kiendler-Scharr, A.*
AU  - Kalberer, M.*
AU  - Di Bucchianico, S.
AU  - Rudich, Y.*
AU  - Sippula, O.*
AU  - Zimmermann, R.
C1  - 74810
C2  - 57601
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - The efficiency of EURO 6d car particulate filters is compromised by atmospheric aging: In vitro toxicity of gasoline car exhaust.
JO  - Sci. Adv.
VL  - 11
IS  - 22
PB  - Amer Assoc Advancement Science
PY  - 2025
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Disruptions in the tightly regulated process of human brain development have been linked to increased risk for brain and mental illnesses. While the genetic contribution to these diseases is well established, important environmental factors have been less studied at molecular and cellular levels. Here, we used single-cell and cell type-specific techniques to investigate the effect of glucocorticoid (GC) exposure, a mediator of antenatal environmental risk, on gene regulation and lineage specification in unguided human neural organoids. We characterized the transcriptional response to chronic GC exposure during neural differentiation and studied the underlying gene regulatory networks by integrating single-cell transcriptomics with chromatin accessibility data. We found lasting cell type-specific changes that included autism risk genes and several transcription factors associated with neurodevelopment. Chronic GC exposure influenced lineage specification primarily by priming the inhibitory neuron lineage through transcription factors like PBX3. We provide evidence for convergence of genetic and environmental risk factors through a common mechanism of altering lineage specification.
AU  - Dony, L.
AU  - Krontira, A.C.*
AU  - Kaspar, L.*
AU  - Ahmad, R.*
AU  - Demirel, I.S.*
AU  - Grochowicz, M.*
AU  - Schäfer, T.*
AU  - Begum, F.*
AU  - Sportelli, V.*
AU  - Raimundo, C.*
AU  - Koedel, M.*
AU  - Labeur, M.*
AU  - Cappello, S.*
AU  - Theis, F.J.
AU  - Cruceanu, C.*
AU  - Binder, E.B.*
C1  - 73387
C2  - 57036
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Chronic exposure to glucocorticoids amplifies inhibitory neuron cell fate during human neurodevelopment in organoids.
JO  - Sci. Adv.
VL  - 11
IS  - 7
PB  - Amer Assoc Advancement Science
PY  - 2025
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Psychiatric disorders like schizophrenia, bipolar disorder, and major depressive disorder exhibit substantial genetic and clinical overlap. However, their molecular architecture remains elusive due to their polygenic nature and complex brain cell interactions. We integrated clinical data with genetic susceptibility to investigate gene expression and chromatin accessibility in the orbitofrontal cortex of 92 postmortem human brain samples at the single-nucleus (sn) level. Using snRNA-seq and snATAC-seq, we analyzed ~800,000 and 400,000 nuclei, respectively. We observed cell-type-specific dysregulation related to clinical diagnosis and genetic risk. Dysregulation in gene expression and chromatin accessibility associated with diagnosis was pronounced in excitatory neurons. Conversely, genetic risk predominantly affected glial and endothelial cells. Notably, INO80E and HCN2 genes exhibited dysregulation in excitatory neurons' superficial layers 2/3 influenced by schizophrenia polygenic risk. This study unveils the complex genetic and epigenetic landscape of psychiatric disorders, emphasizing the importance of cell-type-specific analyses in understanding their pathogenesis and contrasting genetic predisposition with clinical diagnosis.
AU  - Gerstner, N.
AU  - Fröhlich, A.S.*
AU  - Matosin, N.*
AU  - Gagliardi, M.*
AU  - Cruceanu, C.*
AU  - Ködel, M.*
AU  - Rex-Haffner, M.*
AU  - Tu, X.*
AU  - Mostafavi, S.*
AU  - Ziller, M.J.*
AU  - Binder, E.B.*
AU  - Knauer-Arloth, J.
C1  - 73594
C2  - 57127
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Contrasting genetic predisposition and diagnosis in psychiatric disorders: A multi-omic single-nucleus analysis of the human OFC.
JO  - Sci. Adv.
VL  - 11
IS  - 10
PB  - Amer Assoc Advancement Science
PY  - 2025
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Adipocyte hypertrophy during obesity triggers chronic inflammation, leading to metabolic disorders. However, the role of adipocyte-specific inflammatory signaling in metabolic syndrome remains unclear. The linear ubiquitin chain assembly complex, LUBAC, is an E3-ligase that generates nondegradative linear ubiquitination (Lin-Ub). LUBAC regulates NF-κB/MAPK-driven inflammation and prevents cell death triggered by immune receptors like TNF receptor-1. Here, we show that mice lacking HOIP, the Lin-E3 ligase catalytic subunit of LUBAC, in adipocytes (HoipA-KO) display lipodystrophy and heightened susceptibility to obesity-induced metabolic syndrome, particularly metabolic dysfunction-associated steatotic liver disease (MASLD). Mechanistically, loss of HOIP attenuates TNF-induced NF-κB activation and promotes cell death in human adipocytes. Inhibiting caspase-8-mediated cell death is sufficient to prevent lipodystrophy and MASLD in HoipA-KO obese mice. HOIP expression in adipose tissue positively correlates with metabolic fitness in obese individuals. Overall, our findings reveal a fundamental developmental role for Lin-Ub in adipocytes by mitigating cell death-driven adipose tissue inflammation and protecting against obesity-related metabolic syndrome.
AU  - Hildebrandt, X.*
AU  - Veli, Ö.*
AU  - Hyoubi, A.*
AU  - Zinngrebe, J.*
AU  - Abdallah, A.T.*
AU  - Rodefeld, J.*
AU  - Hoffmann, A.
AU  - Gardeweg, L.*
AU  - Kaya, Ö.*
AU  - Wagner, E.*
AU  - Lindhorst, A.*
AU  - Poggenberg, M.*
AU  - Wang, Y.*
AU  - Dimmler, J.*
AU  - Schillings, J.*
AU  - Koci, P.*
AU  - Bonechi, F.*
AU  - Capuccino, L.V.*
AU  - Kiefer, C.*
AU  - Kelepouras, K.*
AU  - Ghosh, A.*
AU  - Noé, F.*
AU  - Wolfrum, C.*
AU  - Singer, M.*
AU  - Liccardi, G.*
AU  - Luedde, T.*
AU  - Yavas, A.*
AU  - Ghallab, A.*
AU  - Hengsler, J.G.*
AU  - Antczak, P.*
AU  - Gericke, M.*
AU  - Winkels, H.*
AU  - Blüher, M.
AU  - Walczak, H.*
AU  - Annibaldi, A.*
AU  - Fischer-Posovszky, P.*
AU  - Peltzer, N.*
C1  - 75572
C2  - 58042
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Linear ubiquitination prevents lipodystrophy and obesity-associated metabolic syndrome.
JO  - Sci. Adv.
VL  - 11
IS  - 38
PB  - Amer Assoc Advancement Science
PY  - 2025
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Psoriasis (Pso) is a chronic inflammatory skin disease driven by T helper 17 (TH17) cells, with several clinical subtypes. While self-reactive immune responses have been observed, the role of autoantigens in Pso remains unclear. Using immunopeptidomics, we identified serpin family B member 3 (SERPINB3) and SERPINB4 as candidate autoantigens in Pso skin. In a mouse model, the SERPINB3 ortholog Serpinb3b enhanced inflammation, promoted tissue-resident memory T cells, and skewed immunity toward a TH2 phenotype. In humans, SERPINB3 reactivity was specifically associated with "eczematized psoriasis" (EczPso), a subtype marked by TH2/TH17 immune signatures. SERPINB3 protein was enriched in EczPso lesions and highly secreted by keratinocytes under combined TH2/TH17 stimulation. Lesional T cells from EczPso-but not from eczema or classical plaque Pso-proliferated in response to SERPINB3 and induced EczPso-like features in a skin model. Our findings identify SERPINB3 as an autoantigen driving a distinct Pso subtype, supporting more precise diagnosis and therapy.
AU  - Jargosch, M.
AU  - Kuruvila, J.*
AU  - Scala, E.*
AU  - Grosch, J.
AU  - Eigemann, J.
AU  - Wasserer, S.
AU  - Lekiashvili, S.*
AU  - Trautwein, N.*
AU  - Kowalewski, D.J.*
AU  - Böhner, A.*
AU  - Köseoglu, Y.
AU  - Hillig, C.
AU  - Thomas, J.
AU  - Lauffer, F.
AU  - Schmidt-Weber, C.B.
AU  - Menden, M.P.
AU  - Walz, J.S.*
AU  - Kaesler, S.*
AU  - Eyerich, S.
AU  - Blank, S.
AU  - Rammensee, H.G.*
AU  - Biedermann, T.*
AU  - Eyerich, K.*
AU  - Kurgyis, Z.*
AU  - Freudenmann, L.K.*
AU  - Garzorz-Stark, N.*
C1  - 75827
C2  - 58098
SP  - eadx0637
TI  - Immunopeptidome analysis reveals SERPINB3 as an autoantigen driving eczematized psoriasis.
JO  - Sci. Adv.
VL  - 11
IS  - 43
PY  - 2025
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Cell type-specific regulatory programs that drive type 1 diabetes (T1D) in the pancreas are poorly understood. Here, we performed single-nucleus multiomics and spatial transcriptomics in up to 32 nondiabetic (ND), autoantibody-positive (AAB+), and T1D pancreas donors. Genomic profiles from 853,005 cells mapped to 12 pancreatic cell types, including multiple exocrine subtypes. β, Acinar, and other cell types, and related cellular niches, had altered abundance and gene activity in T1D progression, including distinct pathways altered in AAB+ compared to T1D. We identified epigenomic drivers of gene activity in T1D and AAB+ which, combined with genetic association, revealed causal pathways of T1D risk including antigen presentation in β cells. Last, single-cell and spatial profiles together revealed widespread changes in cell-cell signaling in T1D including signals affecting β cell regulation. Overall, these results revealed drivers of T1D in the pancreas, which form the basis for therapeutic targets for disease prevention.
AU  - Melton, R.*
AU  - Jimenez, S.
AU  - Elison, W.*
AU  - Tucciarone, L.*
AU  - Howell, A.*
AU  - Wang, G.*
AU  - Berti, D.*
AU  - Beebe, E.T.*
AU  - Miller, M.*
AU  - Zeng, C.*
AU  - McGrail, C.*
AU  - VanderStel, K.*
AU  - Korgaonkar, K.*
AU  - Elgamal, R.*
AU  - Mummey, H.*
AU  - Chiou, J.*
AU  - Griffin, E.*
AU  - Kusmartseva, I.*
AU  - Atkinson, M.*
AU  - Preissl, S.*
AU  - Theis, F.J.
AU  - Sander, M.*
AU  - Gaulton, K.J.*
C1  - 75535
C2  - 58034
TI  - Single-cell multiome and spatial profiling reveals pancreas cell type-specific gene regulatory programs of type 1 diabetes progression.
JO  - Sci. Adv.
VL  - 11
IS  - 37
PY  - 2025
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Most advances in early human postimplantation development depend on animal studies and stem cell-based embryo models. Here, we present self-organized three-dimensional human gastruloids (hGs) derived from embryonic stem cells. The transcriptome profile of day 3 hGs aligned with Carnegie stage 7 human gastrula, with cell types and differentiation trajectories consistent with human gastrulation. Notably, we observed the emergence of nascent primordial germ cell-like cells (PGCLCs), but without exogenous bone morphogenetic protein (BMP) signaling, which is essential for the PGCLC fate. A mutation in the ISL1 gene affects amnion-like cells and leads to a loss of PGCLCs; the addition of exogenous BMP2 rescues the PGCLC fate, indicating that the amnion may provide endogenous BMP signaling. Our model of early human embryogenesis will enable further exploration of the germ line and other early human lineages.
AU  - Neupane, J.*
AU  - Lubatti, G.
AU  - Gross-Thebing, T.*
AU  - Ruiz Tejada Segura, M.L.
AU  - Butler, R.H.*
AU  - Gross-Thebing, S.*
AU  - Dietmann, S.*
AU  - Scialdone, A.
AU  - Surani, M.A.*
C1  - 73788
C2  - 57104
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - The emergence of human primordial germ cell-like cells in stem cell-derived gastruloids.
JO  - Sci. Adv.
VL  - 11
IS  - 13
PB  - Amer Assoc Advancement Science
PY  - 2025
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Harmful algal blooms (HABs) of the toxigenic haptophyte Chrysochromulina are known to cause fish mortalities and collateral ecosystem damage. The ichthyotoxic mechanisms are poorly understood but likely dependent on toxigenesis by polyketide synthases (PKSs). We hypothesize that induction of PKS activity facilitates mixotrophic behavior during nutrient-depleted bloom conditions. To identify potential in situ stimuli for growth, toxigenicity, and bloom persistence, we compared environmental factors and biological processes identified by metaomics to Chrysochromulina leadbeateri HABs between two fjords in northern Norway. We identified the polyketide ichthyotoxin leadbeaterin-1 from the C. leadbeateri bloom and found potentially associated candidate PKS genes of which most were higher expressed at bloom stations. A relative depletion of inorganic nitrogen and phosphate during the bloom was correlated with higher expression of genes involved in endocytosis, autophagy, and lysosomal activity. Mixotrophy is evidently a compensatory nutritional strategy coupled to induction of toxigenesis and other metabolomic processes as biotic factors linked to Chrysochromulina bloom dynamics.
AU  - Otte, A.*
AU  - Wohlrab, S.*
AU  - Moritz, F.
AU  - Müller, C.
AU  - Janouškovec, J.*
AU  - Michálek, J.*
AU  - Cembella, A.*
AU  - Voss, D.*
AU  - Wang, X.*
AU  - Tebben, J.*
AU  - Larsen, T.O.*
AU  - Edvardsen, B.*
AU  - Schmitt-Kopplin, P.
AU  - John, U.*
C1  - 75015
C2  - 57696
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - High-resolution multiomics links nutrients and mixotrophy to toxicity in a harmful bloom of the haptophyte Chrysochromulina leadbeateri.
JO  - Sci. Adv.
VL  - 11
IS  - 26
PB  - Amer Assoc Advancement Science
PY  - 2025
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Brain geometry affects brain function. A quantitative encoding of form is provided by the Laplace-Beltrami operator's spectrum of eigenvalues (LBS). We examined LBS genetics of 22 subcortical brain structures and cerebellum in 19,862 healthy White-British UK Biobank participants by multivariate genome-wide association study on the first 49 eigenvalues each. Controlling for surface and volume, we identified 80 unique variants influencing the shapes of one or several structures, with the highest yield (37 variants) for brain stem. The previously known influence of several of these loci on basic morphology, such as volume, is thus shown to also influence complex shape. Known associations of observed loci with blood pressure, neurodegeneration, alcohol consumption, and mental disorders hint at preclinical stages of these conditions potentially mediating the genetic effect on brain morphology. Significant correlations between LBS of several brain structures and the polygenic risks of hypertension, ischemic stroke, and schizophrenia evince brain shapes as early biomarkers.
AU  - Primus, S.A.
AU  - Hoffstaedter, F.*
AU  - Raimondo, F.*
AU  - Eickhoff, S.B.*
AU  - Winkelmann, J.
AU  - Oexle, K.
AU  - Patil, K.R.*
C1  - 74917
C2  - 57655
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Beyond volume: Unraveling the genetics of human brain geometry.
JO  - Sci. Adv.
VL  - 11
IS  - 24
PB  - Amer Assoc Advancement Science
PY  - 2025
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Telomere length regulation is essential for genome stability as short telomeres can trigger cellular senescence and apoptosis constituting an integral aspect of biological aging. Telomere biology disorders (TBDs) such as dyskeratosis congenita (DC) are rare, inherited diseases with known mutations in at least 16 different genes encoding components of the telomere maintenance complexes. The precise role of TEN1, part of the CST complex (CTC1, STN1, and TEN1), and the consequences of its loss of function in vivo are not yet known. We investigated the first viable murine model of Ten1 deficiency created by CRISPR-Cas9-mediated exon 3 deletion. Ten1 homozygous knockout mice present with telomere attrition, short life span, skin hyperpigmentation, aplastic anemia, and cerebellar hypoplasia. Molecular analyses revealed a reduction of proliferating cells, increased apoptosis, and stem cell depletion with activation of the p53/p21 signaling pathway. Our data demonstrate that Ten1 deficiency causes telomere shortening and associates with accelerated aging.
AU  - Sanz-Moreno, A.
AU  - Becker, L.
AU  - Xie, K.*
AU  - da Silva Buttkus, P.
AU  - Dragano, N.R.V.
AU  - Aguilar-Pimentel, J.A.
AU  - Amarie, O.V.
AU  - Calzada-Wack, J.
AU  - Kraiger, M.
AU  - Leuchtenberger, S.
AU  - Seisenberger, C.
AU  - Marschall, S.
AU  - Rathkolb, B.
AU  - Scifo, E.*
AU  - Liu, T.*
AU  - Thanabalasingam, A.*
AU  - Sanchez-Vazquez, R.*
AU  - Martinez, P.*
AU  - Blasco, M.A.*
AU  - Savage, S.A.*
AU  - Fuchs, H.
AU  - Ehninger, D.*
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
C1  - 74054
C2  - 57054
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Loss of Ten1 in mice induces telomere shortening and models human dyskeratosis congenita.
JO  - Sci. Adv.
VL  - 11
IS  - 15
PB  - Amer Assoc Advancement Science
PY  - 2025
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Blood glucose is lower in mountain dwellers living under low partial oxygen pressure. We show that obese mice maintained under hypoxia exhibit a delayed but distinct decrease in blood glucose with improved insulin sensitivity, which is independent of changes in body weight. This effect of hypoxia is mediated by erythropoiesis and is a direct result of the rising hematocrit, which could be due to erythrocytes acting as carriers of glucose units in the blood. Glucose lowering by the red cell mass is evidenced by a prompt decrease in glycemia in mice receiving a blood transfusion. Furthermore, life under hypoxia as well as treatment with erythropoietin reduce glycemia also in mice expressing the erythropoietin receptor exclusively in hematopoietic cells, which contrasts with previous assumptions attributing metabolic actions of erythropoietin to direct action on nonhematopoietic tissues. Our results provide a rationale for associations between hematocrit and blood glucose in humans under anti-anemic therapy, polycythemia, smoking, and high-altitude exposure.
AU  - Scherer, T.*
AU  - Metz, M.*
AU  - Beghini, M.*
AU  - Bilban, M.*
AU  - Gensthaler, L.*
AU  - Luca, A.C.*
AU  - Kaplanian, M.*
AU  - Abu Eid, S.*
AU  - Koldyka, O.*
AU  - Hackl, M.T.*
AU  - Dürr, S.*
AU  - Rivelles, E.*
AU  - Schönecker, S.S.*
AU  - Pöltl, L.*
AU  - Kaya, A.*
AU  - Chami, R.*
AU  - Nusko, L.*
AU  - Tschare, C.*
AU  - Ablaza, K.*
AU  - Höbler, A.L.*
AU  - Klimek, P.*
AU  - Leutner, M.*
AU  - Yamamoto, M.*
AU  - Suzuki, N.*
AU  - Stemmer, K.
AU  - Zeyda, M.*
AU  - Steinacher, D.*
AU  - Nics, L.*
AU  - Müller, A.M.S.*
AU  - Helbich, T.H.*
AU  - Moriggl, R.*
AU  - Kautzky-Willer, A.*
AU  - Windberger, U.*
AU  - Prager, G.*
AU  - Fürnsinn, C.*
C1  - 74124
C2  - 57312
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - A direct effect of the hematocrit on blood glucose: Evidence from hypoxia- and erythropoietin-treated mice.
JO  - Sci. Adv.
VL  - 11
IS  - 16
PB  - Amer Assoc Advancement Science
PY  - 2025
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - The centrosome is a microtubule orchestrator, nucleating and anchoring microtubules that grow radially and exert forces on cargos. At the same time, mechanical stresses from the microenvironment and cellular shape changes compress and bend microtubules. Yet, centrosomes are membraneless organelles, raising the question of how centrosomes withstand mechanical forces. Here, we discover that centrosomes can deform and even fracture. We reveal that centrosomes experience deformations during navigational pathfinding within motile cells. Coherence of the centrosome is maintained by Dyrk3 and cNAP1, preventing fracturing by forces. While cells can compensate for the depletion of centriolar-based centrosomes, the fracturing of centrosomes impedes cellular function by generating coexisting microtubule organizing centers that compete during path navigation and thereby cause cellular entanglement in the microenvironment. Our findings show that cells actively maintain the integrity of the centrosome to withstand mechanical forces. These results suggest that centrosome stability preservation is fundamental, given that almost all cells in multicellular organisms experience forces.
AU  - Schmitt, M.T.*
AU  - Kroll, J.*
AU  - Ruiz-Fernandez, M.J.A.*
AU  - Hauschild, R.*
AU  - Ghosh, S.*
AU  - Kameritsch, P.*
AU  - Merrin, J.*
AU  - Schmid, J.*
AU  - Stefanowski, K.*
AU  - Thomae, A.W.*
AU  - Cheng, J.*
AU  - Öztan, G.N.*
AU  - Konopka, P.*
AU  - Camargo Ortega, G.
AU  - Penz, T.*
AU  - Bach, L.*
AU  - Baumjohann, D.*
AU  - Bock, C.*
AU  - Straub, T.*
AU  - Meissner, F.*
AU  - Kiermaier, E.*
AU  - Renkawitz, J.*
C1  - 74195
C2  - 57364
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Protecting centrosomes from fracturing enables efficient cell navigation.
JO  - Sci. Adv.
VL  - 11
IS  - 17
PB  - Amer Assoc Advancement Science
PY  - 2025
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Histone variants with metabolite-binding macrodomains provide a poorly understood link between chromatin composition and metabolism. To address their contribution to physiological health, we generated and analyzed mice individually lacking the histone variants macroH2A1.1, macroH2A1.2, or macroH2A2. We identified several histopathologic changes in the kidney as isoform-specific phenotype of complete macroH2A1.1 loss affecting male and female animals. Kidney alterations were barely associated with organ-intrinsic gene expression changes but strongly correlated with a systemic shift in nutrient metabolization and alterations in NAD+ (nicotinamide adenine dinucleotide, oxidized form) metabolism. Reduced lipid oxidation and increased glycolysis were found in male and female mice lacking macroH2A1.1 but not macroH2A1.2 or macroH2A2. Male macroH2A1.1-deficient mice also had better glucose tolerance and altered hepatic gene expression. Replacing chow by ketogenic diet overrode the macroH2A1.1-dependent metabolic phenotype and prevented kidney abnormalities. Together, our results indicate that macroH2A1.1 controls nutrient metabolization and links macroH2A1.1 levels to secondary changes in the kidney.
AU  - Winkler, R.*
AU  - Comas-Armangue, G.
AU  - Corujo, D.*
AU  - Sanz-Moreno, A.
AU  - Calzada-Wack, J.
AU  - Bhattacharya, S.A.*
AU  - Rathkolb, B.
AU  - Dragano, N.R.V.
AU  - Qiao, C.X.*
AU  - Chiodi, V.*
AU  - Filipescu, D.*
AU  - Park, D.H.*
AU  - Domenici, M.R.*
AU  - Kirigin Callaú, V.*
AU  - Gerlini, R.
AU  - Rozman, J.
AU  - Klein-Rodewald, T.
AU  - Aguilar-Pimentel, J.A.
AU  - Becker, L.
AU  - Seisenberger, C.
AU  - Marschall, S.
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Bernstein, E.*
AU  - Vinciguerra, M.*
AU  - Oberdoerffer, P.*
AU  - Hrabě de Angelis, M.
AU  - Teperino, R.
AU  - Buschbeck, M.*
C1  - 75848
C2  - 58142
TI  - Loss of histone macroH2A1.1 causes kidney abnormalities secondary to a change in nutrient metabolization.
JO  - Sci. Adv.
VL  - 11
IS  - 43
PY  - 2025
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Marine sediments are highly bioactive habitats, where sulfate-reducing bacteria contribute substantially to seabed carbon cycling by oxidizing ~77 Tmol Corg year-1. This remarkable activity is largely attributable to the deltaproteobacterial family Desulfobacteraceae of complete oxidizers (to CO2), which our biogeography focused meta-analysis verified as cosmopolitan. However, the catabolic/regulatory networks underlying this ecophysiological feat at the thermodynamic limit are essentially unknown. Integrating cultivation-based (80 conditions) proteogenomics of six representative Desulfobacteraceae spp., we identify molecular commonalities explaining the family's environmental relevance and success. Desulfobacteraceae genomes are specifically enriched in substrate uptake, degradation capacities, and regulatory functions including fine-tuned sulfate uptake. Conserved gene arrangements and shared regulatory patterns translate into strikingly similar (sub-)proteome profiles. From 319 proteins, we constructed a meta-network for catabolizing 35 substrates. Therefrom, we defined a Desulfobacteraceae characteristic gene subset, which we found prevalent in metagenomes of organic-rich, marine sediments. These genes are promising targets to advance our mechanistic understanding of Desulfobacteraceae-driven biogeochemical processes in marine sediments and beyond.
AU  - Wöhlbrand, L.*
AU  - Dörries, M.*
AU  - Siani, R.
AU  - Medrano-Soto, A.*
AU  - Schnaars, V.*
AU  - Schumacher, J.*
AU  - Hilbers, C.*
AU  - Thies, D.*
AU  - Kube, M.*
AU  - Reinhardt, R.*
AU  - Schloter, M.
AU  - Saier, M.H.*
AU  - Winklhofer, M.*
AU  - Rabus, R.*
C1  - 73595
C2  - 57128
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Key role of Desulfobacteraceae in C/S cycles of marine sediments is based on congeneric catabolic-regulatory networks.
JO  - Sci. Adv.
VL  - 11
IS  - 10
PB  - Amer Assoc Advancement Science
PY  - 2025
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Mitochondrial fusion and fission accompany adaptive responses to stress and altered metabolic demands. Inner membrane fusion and cristae morphogenesis depends on optic atrophy 1 (Opa1), which is expressed in different isoforms and is cleaved from a membrane-bound, long to a soluble, short form. Here, we have analyzed the physiological role of Opa1 isoforms and Opa1 processing by generating mouse lines expressing only one cleavable Opa1 isoform or a non-cleavable variant thereof. Our results show that expression of a single cleavable or non-cleavable Opa1 isoform preserves embryonic development and the health of adult mice. Opa1 processing is dispensable under metabolic and thermal stress but prolongs life span and protects against mitochondrial cardiomyopathy in OXPHOS-deficient Cox10-/- mice. Mechanistically, loss of Opa1 processing disturbs the balance between mitochondrial biogenesis and mitophagy, suppressing cardiac hypertrophic growth in Cox10-/- hearts. Our results highlight the critical regulatory role of Opa1 processing, mitochondrial dynamics, and metabolism for cardiac hypertrophy.
AU  - Ahola, S.*
AU  - Pazurek, L.A.*
AU  - Mayer, F.*
AU  - Lampe, P.*
AU  - Hermans, S.*
AU  - Becker, L.
AU  - Amarie, O.V.
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
AU  - Riedel, D.*
AU  - Nolte, H.*
AU  - Langer, T.*
C1  - 71394
C2  - 56105
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Opa1 processing is dispensable in mouse development but is protective in mitochondrial cardiomyopathy.
JO  - Sci. Adv.
VL  - 10
IS  - 31
PB  - Amer Assoc Advancement Science
PY  - 2024
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Type 2 diabetes (T2D) and obesity are strongly associated with low natriuretic peptide (NP) plasma levels and a down-regulation of NP guanylyl cyclase receptor-A (GCA) in skeletal muscle and adipose tissue. However, no study has so far provided evidence for a causal link between atrial NP (ANP)/GCA deficiency and T2D pathogenesis. Here, we show that both systemic and skeletal muscle ANP/GCA deficiencies in mice promote metabolic disturbances and prediabetes. Skeletal muscle insulin resistance is further associated with altered mitochondrial function and impaired endurance running capacity. ANP/GCA-deficient mice exhibit increased proton leak and reduced content of mitochondrial oxidative phosphorylation proteins. We further show that GCA is related to several metabolic traits in T2D and positively correlates with markers of oxidative capacity in human skeletal muscle. Together, these results indicate that ANP/GCA signaling controls muscle mitochondrial integrity and oxidative capacity in vivo and plays a causal role in the development of prediabetes.
AU  - Carper, D.*
AU  - Lac, M.*
AU  - Coue, M.*
AU  - Labour, A.*
AU  - Märtens, A.*
AU  - Banda, J.A.A.*
AU  - Mazeyrie, L.*
AU  - Mechta, M.*
AU  - Ingerslev, L.R.*
AU  - Elhadad, M.A.
AU  - Petit, J.V.*
AU  - Maslo, C.*
AU  - Monbrun, L.*
AU  - Del Carmine, P.*
AU  - Sainte-Marie, Y.*
AU  - Bourlier, V.*
AU  - Laurens, C.*
AU  - Mithieux, G.*
AU  - Joanisse, D.R.*
AU  - Coudray, C.*
AU  - Feillet-Coudray, C.*
AU  - Montastier, E.*
AU  - Viguerie, N.*
AU  - Tavernier, G.*
AU  - Waldenberger, M.
AU  - Peters, A.
AU  - Wang-Sattler, R.
AU  - Adamski, J.
AU  - Suhre, K.*
AU  - Gieger, C.
AU  - Kastenmüller, G.
AU  - Illig, T.*
AU  - Lichtinghagen, R.*
AU  - Seissler, J.*
AU  - Mounier, R.*
AU  - Hiller, K.*
AU  - Jordan, J.*
AU  - Barrès, R.*
AU  - Kuhn, M.*
AU  - Pesta, D.*
AU  - Moro, C.*
C1  - 71967
C2  - 56299
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Loss of atrial natriuretic peptide signaling causes insulin resistance, mitochondrial dysfunction, and low endurance capacity.
JO  - Sci. Adv.
VL  - 10
IS  - 41
PB  - Amer Assoc Advancement Science
PY  - 2024
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Cortical neurogenesis follows a simple lineage: apical radial glia cells (RGCs) generate basal progenitors, and these produce neurons. How this occurs in species with expanded germinal zones and a folded cortex, such as human, remains unclear. We used single-cell RNA sequencing from individual cortical germinal zones in ferret and barcoded lineage tracking to determine the molecular diversity of progenitor cells and their lineages. We identified multiple RGC classes that initiate parallel lineages, converging onto a common class of newborn neuron. Parallel RGC classes and transcriptomic trajectories were repeated across germinal zones and conserved in ferret and human, but not in mouse. Neurons followed parallel differentiation trajectories in the gyrus and sulcus, with different expressions of human cortical malformation genes. Progenitor cell lineage multiplicity is conserved in the folded mammalian cerebral cortex.
AU  - Del-Valle-Anton, L.*
AU  - Amin, S.A.*
AU  - Cimino, D.
AU  - Neuhaus, F.*
AU  - Dvoretskova, E.*
AU  - Fernandez, V.*
AU  - Babal, Y.K.*
AU  - Garcia-Frigola, C.*
AU  - Prieto-Colomina, A.*
AU  - Murcia-Ramón, R.*
AU  - Nomura, Y.*
AU  - Cárdenas, A.*
AU  - Feng, C.*
AU  - Moreno-Bravo, J.A.*
AU  - Götz, M.
AU  - Mayer, C.*
AU  - Borrell, V.*
C1  - 70386
C2  - 55552
TI  - Multiple parallel cell lineages in the developing mammalian cerebral cortex.
JO  - Sci. Adv.
VL  - 10
IS  - 13
PY  - 2024
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Coordination of cellular activity through Ca2+ enables β cells to secrete precise quantities of insulin. To explore how the Ca2+ response is orchestrated in space and time, we implement optogenetic systems to probe the role of individual β cells in the glucose response. By targeted β cell activation/inactivation in zebrafish, we reveal a hierarchy of cells, each with a different level of influence over islet-wide Ca2+ dynamics. First-responder β cells lie at the top of the hierarchy, essential for initiating the first-phase Ca2+ response. Silencing first responders impairs the Ca2+ response to glucose. Conversely, selective activation of first responders demonstrates their increased capability to raise pan-islet Ca2+ levels compared to followers. By photolabeling and transcriptionally profiling β cells that differ in their thresholds to a glucose-stimulated Ca2+ response, we highlight vitamin B6 production as a signature pathway of first responders. We further define an evolutionarily conserved requirement for vitamin B6 in enabling the Ca2+ response to glucose in mammalian systems.
AU  - Delgadillo-Silva, L.F.
AU  - Tasöz, E.
AU  - Singh, S.P.*
AU  - Chawla, P.*
AU  - Georgiadou, E.*
AU  - Gompf, A.*
AU  - Rutter, G.A.*
AU  - Ninov, N.
C1  - 70918
C2  - 55823
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Optogenetic β cell interrogation in vivo reveals a functional hierarchy directing the Ca2+ response to glucose supported by vitamin B6.
JO  - Sci. Adv.
VL  - 10
IS  - 26
PB  - Amer Assoc Advancement Science
PY  - 2024
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Circular RNAs (circRNAs) are a large class of noncoding RNAs. Despite the identification of thousands of circular transcripts, the biological significance of most of them remains unexplored, partly because of the lack of effective methods for generating loss-of-function animal models. In this study, we focused on circTulp4, an abundant circRNA derived from the Tulp4 gene that is enriched in the brain and synaptic compartments. By creating a circTulp4-deficient mouse model, in which we mutated the splice acceptor site responsible for generating circTulp4 without affecting the linear mRNA or protein levels, we were able to conduct a comprehensive phenotypic analysis. Our results demonstrate that circTulp4 is critical in regulating neuronal and brain physiology, modulating the strength of excitatory neurotransmission and sensitivity to aversive stimuli. This study provides evidence that circRNAs can regulate biologically relevant functions in neurons, with modulatory effects at multiple levels of the phenotype, establishing a proof of principle for the regulatory role of circRNAs in neural processes.
AU  - Giusti, S.A.*
AU  - Pino, N.S.
AU  - Pannunzio, C.*
AU  - Ogando, M.B.*
AU  - Armando, N.G.*
AU  - Garrett, L.
AU  - Zimprich, A.
AU  - Becker, L.
AU  - Gimeno, M.L.*
AU  - Lukin, J.*
AU  - Merino, F.L.*
AU  - Pardi, M.B.*
AU  - Pedroncini, O.*
AU  - Di Mauro, G.C.*
AU  - Gailus-Durner, V.
AU  - Fuchs, H.
AU  - Hrabě de Angelis, M.
AU  - Patop, I.L.*
AU  - Turck, C.W.*
AU  - Deussing, J.M.*
AU  - Vogt Weisenhorn, D.M.
AU  - Jahn, O.*
AU  - Kadener, S.*
AU  - Hölter, S.M.
AU  - Brose, N.*
AU  - Giesert, F.
AU  - Wurst, W.
AU  - Marin-Burgin, A.*
AU  - Refojo, D.*
C1  - 70751
C2  - 55624
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - A brain-enriched circular RNA controls excitatory neurotransmission and restricts sensitivity to aversive stimuli.
JO  - Sci. Adv.
VL  - 10
IS  - 21
PB  - Amer Assoc Advancement Science
PY  - 2024
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Endothelial cells (ECs) are highly plastic, capable of differentiating into various cell types. Endothelial-to-mesenchymal transition (EndMT) is crucial during embryonic development and contributes substantially to vascular dysfunction in many cardiovascular diseases (CVDs). While targeting EndMT holds therapeutic promise, understanding its mechanisms and modulating its pathways remain challenging. Using single-cell RNA sequencing on three in vitro EndMT models, we identified conserved gene signatures. We validated original regulators in vitro and in vivo during embryonic heart development and peripheral artery disease. EndMT induction led to global expression changes in all EC subtypes rather than in mesenchymal clusters. We identified mitochondrial calcium uptake as a key driver of EndMT; inhibiting mitochondrial calcium uniporter (MCU) prevented EndMT in vitro, and conditional Mcu deletion in ECs blocked mesenchymal activation in a hind limb ischemia model. Tissues from patients with critical limb ischemia with EndMT features exhibited significantly elevated endothelial MCU. These findings highlight MCU as a regulator of EndMT and a potential therapeutic target.
AU  - Lebas, M.*
AU  - Chinigò, G.*
AU  - Courmont, E.*
AU  - Bettaieb, L.*
AU  - Machmouchi, A.*
AU  - Goveia, J.*
AU  - Beatovic, A.*
AU  - Van Kerckhove, J.*
AU  - Robil, C.*
AU  - Angulo, F.S.*
AU  - Vedelago, M.*
AU  - Errerd, A.*
AU  - Treps, L.*
AU  - Gao, V.*
AU  - Delgado De La Herran, H.C.
AU  - Mayeuf-Louchart, A.*
AU  - L'homme, L.*
AU  - Chamlali, M.*
AU  - Dejos, C.*
AU  - Gouyer, V.*
AU  - Garikipati, V.N.S.*
AU  - Tomar, D.*
AU  - Yin, H.*
AU  - Fukui, H.*
AU  - Vinckier, S.*
AU  - Stolte, A.*
AU  - Conradi, L.C.*
AU  - Infanti, F.*
AU  - Lemonnier, L.*
AU  - Zeisberg, E.M.*
AU  - Luo, Y.*
AU  - Lin, L.*
AU  - Desseyn, J.L.*
AU  - Pickering, J.W.*
AU  - Kishore, R.*
AU  - Madesh, M.*
AU  - Dombrowicz, D.*
AU  - Perocchi, F.
AU  - Staels, B.*
AU  - Pla, A.F.*
AU  - Gkika, D.*
AU  - Cantelmo, A.R.*
C1  - 71442
C2  - 56175
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Integrated single-cell RNA-seq analysis reveals mitochondrial calcium signaling as a modulator of endothelial-to-mesenchymal transition.
JO  - Sci. Adv.
VL  - 10
IS  - 32
PB  - Amer Assoc Advancement Science
PY  - 2024
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Defects in adipocyte lipolysis drive multiple aspects of cardiometabolic disease, but the transcriptional framework controlling this process has not been established. To address this, we performed a targeted perturbation screen in primary human adipocytes. Our analyses identified 37 transcriptional regulators of lipid mobilization, which we classified as (i) transcription factors, (ii) histone chaperones, and (iii) mRNA processing proteins. On the basis of its strong relationship with multiple readouts of lipolysis in patient samples, we performed mechanistic studies on one hit, ZNF189, which encodes the zinc finger protein 189. Using mass spectrometry and chromatin profiling techniques, we show that ZNF189 interacts with the tripartite motif family member TRIM28 and represses the transcription of an adipocyte-specific isoform of phosphodiesterase 1B (PDE1B2). The regulation of lipid mobilization by ZNF189 requires PDE1B2, and the overexpression of PDE1B2 is sufficient to attenuate hormone-stimulated lipolysis. Thus, our work identifies the ZNF189-PDE1B2 axis as a determinant of human adipocyte lipolysis and highlights a link between chromatin architecture and lipid mobilization.
AU  - Ludzki, A.C.*
AU  - Hansen, M.*
AU  - Zareifi, D.*
AU  - Jalkanen, J.*
AU  - Huang, Z.*
AU  - Omar-Hmeadi, M.*
AU  - Renzi, G.*
AU  - Klingelhuber, F.
AU  - Boland, S.*
AU  - Ambaw, Y.A.*
AU  - Wang, N.*
AU  - Damdimopoulos, A.E.*
AU  - Liu, J.*
AU  - Jernberg, T.*
AU  - Petrus, P.*
AU  - Arner, P.*
AU  - Krahmer, N.
AU  - Fan, R.*
AU  - Treuter, E.*
AU  - Gao, H.*
AU  - Rydén, M.*
AU  - Mejhert, N.*
C1  - 69010
C2  - 55187
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Transcriptional determinants of lipid mobilization in human adipocytes.
JO  - Sci. Adv.
VL  - 10
IS  - 1
PB  - Amer Assoc Advancement Science
PY  - 2024
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Coxsackievirus B (CVB) infection of pancreatic β cells is associated with β cell autoimmunity and type 1 diabetes. We investigated how CVB affects human β cells and anti-CVB T cell responses. β cells were efficiently infected by CVB in vitro, down-regulated human leukocyte antigen (HLA) class I, and presented few, selected HLA-bound viral peptides. Circulating CD8+ T cells from CVB-seropositive individuals recognized a fraction of these peptides; only another subfraction was targeted by effector/memory T cells that expressed exhaustion marker PD-1. T cells recognizing a CVB epitope cross-reacted with β cell antigen GAD. Infected β cells, which formed filopodia to propagate infection, were more efficiently killed by CVB than by CVB-reactive T cells. Our in vitro and ex vivo data highlight limited CD8+ T cell responses to CVB, supporting the rationale for CVB vaccination trials for type 1 diabetes prevention. CD8+ T cells recognizing structural and nonstructural CVB epitopes provide biomarkers to differentially follow response to infection and vaccination.
AU  - Vecchio, F.*
AU  - Carré, A.*
AU  - Korenkov, D.*
AU  - Zhou, Z.*
AU  - Apaolaza Gallegos, S.P.
AU  - Tuomela, S.*
AU  - Burgos-Morales, O.*
AU  - Snowhite, I.*
AU  - Perez-Hernandez, J.*
AU  - Brandao, B.*
AU  - Afonso, G.*
AU  - Halliez, C.*
AU  - Kaddis, J.*
AU  - Kent, S.C.*
AU  - Nakayama, M.*
AU  - Richardson, S.J.*
AU  - Vinh, J.*
AU  - Verdier, Y.*
AU  - Laiho, J.*
AU  - Scharfmann, R.*
AU  - Solimena, M.
AU  - Marinicova, Z.
AU  - Bismuth, E.*
AU  - Lucidarme, N.*
AU  - Sánchez, J.*
AU  - Bustamante, C.*
AU  - Gomez, P.*
AU  - Buus, S.*
AU  - You, S.H.*
AU  - Pugliese, A.*
AU  - Hyoty, H.*
AU  - Rodriguez-Calvo, T.
AU  - Flodstrom-Tullberg, M.*
AU  - Mallone, R.*
C1  - 70180
C2  - 55445
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Coxsackievirus infection induces direct pancreatic β cell killing but poor antiviral CD8+ T cell responses.
JO  - Sci. Adv.
VL  - 10
IS  - 10
PB  - Amer Assoc Advancement Science
PY  - 2024
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Small interfering RNAs (siRNAs) are widely used in biomedical research and in clinical trials. Here, we demonstrate that siRNA treatment is commonly associated with significant sensitization to ferroptosis, independently of the target protein knockdown. Genetically targeting mitochondrial antiviral-signaling protein (MAVS) reversed the siRNA-mediated sensitizing effect, but no activation of canonical MAVS signaling, which involves phosphorylation of IkBα and interferon regulatory transcription factor 3 (IRF3), was observed. In contrast, MAVS mediated a noncanonical signal resulting in a prominent increase in mitochondrial ROS levels, and increase in the BACH1/pNRF2 transcription factor ratio and GPX4 up-regulation, which was associated with a 50% decrease in intracellular glutathione levels. We conclude that siRNAs commonly sensitize to ferroptosis and may severely compromise the conclusions drawn from silencing approaches in biomedical research. Finally, as ferroptosis contributes to a variety of pathophysiological processes, we cannot exclude side effects in human siRNA-based therapeutical concepts that should be clinically tested.
AU  - von Mässenhausen, A.*
AU  - Schlecht, M.N.*
AU  - Beer, K.*
AU  - Maremonti, F.*
AU  - Tonnus, W.*
AU  - Belavgeni, A.*
AU  - Gavali, S.*
AU  - Flade, K.*
AU  - Riley, J.S.*
AU  - Zamora Gonzalez, N.*
AU  - Brucker, A.J.*
AU  - Becker, J.N.*
AU  - Tmava, M.*
AU  - Meyer, C.*
AU  - Peitzsch, M.*
AU  - Hugo, C.*
AU  - Gembardt, F.*
AU  - Angeli, J.P.F.*
AU  - Bornstein, S.R.
AU  - Tait, S.W.G.*
AU  - Linkermann, A.*
C1  - 70241
C2  - 55458
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Treatment with siRNAs is commonly associated with GPX4 up-regulation and target knockdown-independent sensitization to ferroptosis.
JO  - Sci. Adv.
VL  - 10
IS  - 11
PB  - Amer Assoc Advancement Science
PY  - 2024
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Rapid live-cell hyperspectral imaging at large fields of view (FOVs) and high cell confluency remains challenging for conventional vibrational spectroscopy-based microscopy technologies. At the same time, imaging at high cell confluency and large FOVs is important for proper cell function and statistical significance of measurements, respectively. Here, we introduce phase-shifting mid-infrared optothermal microscopy (PSOM), which interprets molecular-vibrational information as the optical path difference induced by mid-infrared absorption and can take snapshot vibrational images over broad excitation areas at high live-cell confluency. By means of phase-shifting, PSOM suppresses noise to a quarter of current optothermal microscopy modalities to allow capturing live-cell vibrational images at FOVs up to 50 times larger than state of the art. PSOM also reduces illumination power flux density (PFD) down to four orders of magnitude lower than other conventional vibrational microscopy methods, such as coherent anti-Stokes Raman scattering (CARS), thus considerably decreasing the risk of cell photodamage.
AU  - Yuan, T.
AU  - Riobo, L.
AU  - Gasparin, F.
AU  - Ntziachristos, V.
AU  - Pleitez, M.A.
C1  - 70051
C2  - 55384
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Phase-shifting optothermal microscopy enables live-cell mid-infrared hyperspectral imaging of large cell populations at high confluency.
JO  - Sci. Adv.
VL  - 10
IS  - 8
PB  - Amer Assoc Advancement Science
PY  - 2024
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Various cellular sources hamper interpretation of positron emission tomography (PET) biomarkers in the tumor microenvironment (TME). We developed an approach of immunomagnetic cell sorting after in vivo radiotracer injection (scRadiotracing) with three-dimensional (3D) histology to dissect the cellular allocation of PET signals in the TME. In mice with implanted glioblastoma, translocator protein (TSPO) radiotracer uptake per tumor cell was higher compared to tumor-associated microglia/macrophages (TAMs), validated by protein levels. Translation of in vitro scRadiotracing to patients with glioma immediately after tumor resection confirmed higher single-cell TSPO tracer uptake of tumor cells compared to immune cells. Across species, cellular radiotracer uptake explained the heterogeneity of individual TSPO-PET signals. In consideration of cellular tracer uptake and cell type abundance, tumor cells were the main contributor to TSPO enrichment in glioblastoma; however, proteomics identified potential PET targets highly specific for TAMs. Combining cellular tracer uptake measures with 3D histology facilitates precise allocation of PET signals and serves to validate emerging novel TAM-specific radioligands.
AU  - Bartos, L.M.*
AU  - Kirchleitner, S.V.*
AU  - Kolabas, Z.I.
AU  - Quach, S.*
AU  - Beck, A.*
AU  - Lorenz, J.*
AU  - Blobner, J.*
AU  - Mueller, S.A.*
AU  - Ulukaya, S.
AU  - Höher, L.
AU  - Horvath, I.
AU  - Wind-Mark, K.*
AU  - Holzgreve, A.*
AU  - Ruf, V.C.*
AU  - Gold, L.*
AU  - Kunze, L.H.*
AU  - Kunte, S.T.*
AU  - Beumers, P.*
AU  - Park, H.E.*
AU  - Antons, M.*
AU  - Zatcepin, A.*
AU  - Briel, N.*
AU  - Hoermann, L.*
AU  - Schaefer, R.*
AU  - Messerer, D.*
AU  - Bartenstein, P.*
AU  - Riemenschneider, M.J.*
AU  - Lindner, S.*
AU  - Ziegler, S.*
AU  - Herms, J.*
AU  - Lichtenthaler, S.F.*
AU  - Ertürk, A.
AU  - Tonn, J.C.*
AU  - von Baumgarten, L.*
AU  - Albert, N.L.*
AU  - Brendel, M.*
C1  - 68691
C2  - 54900
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Deciphering sources of PET signals in the tumor microenvironment of glioblastoma at cellular resolution.
JO  - Sci. Adv.
VL  - 9
IS  - 43
PB  - Amer Assoc Advancement Science
PY  - 2023
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - This research addresses the assessment of adipose tissue (AT) and spatial distribution of visceral (VAT) and subcutaneous fat (SAT) in the trunk from standardized magnetic resonance imaging at 3 T, thereby demonstrating the feasibility of deep learning (DL)-based image segmentation in a large population-based cohort in Germany (five sites). Volume and distribution of AT play an essential role in the pathogenesis of insulin resistance, a risk factor of developing metabolic/cardiovascular diseases. Cross-validated training of the DL-segmentation model led to a mean Dice similarity coefficient of >0.94, corresponding to a mean absolute volume deviation of about 22 ml. SAT is significantly increased in women compared to men, whereas VAT is increased in males. Spatial distribution shows age- and body mass index-related displacements. DL-based image segmentation provides robust and fast quantification of AT (≈15 s per dataset versus 3 to 4 hours for manual processing) and assessment of its spatial distribution from magnetic resonance images in large cohort studies.
AU  - Haueise, T.
AU  - Schick, F.
AU  - Stefan, N.
AU  - Schlett, C.L.*
AU  - Weiss, J.B.*
AU  - Nattenmüller, J.*
AU  - Göbel-Guéniot, K.*
AU  - Norajitra, T.*
AU  - Nonnenmacher, T.*
AU  - Kauczor, H.U.*
AU  - Maier-Hein, K.H.*
AU  - Niendorf, T.*
AU  - Pischon, T.*
AU  - Jöckel, K.H.*
AU  - Umutlu, L.*
AU  - Peters, A.
AU  - Rospleszcz, S.
AU  - Kröncke, T.*
AU  - Hosten, N.*
AU  - Völzke, H.*
AU  - Krist, L.*
AU  - Willich, S.N.*
AU  - Bamberg, F.*
AU  - Machann, J.
C1  - 67809
C2  - 54287
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Analysis of volume and topography of adipose tissue in the trunk: Results of MRI of 11,141 participants in the German National Cohort.
JO  - Sci. Adv.
VL  - 9
IS  - 19
PB  - Amer Assoc Advancement Science
PY  - 2023
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Interleukins are secreted proteins that regulate immune responses. Among these, the interleukin 12 (IL-12) family holds a central position in inflammatory and infectious diseases. Each family member consists of an α and a β subunit that together form a composite cytokine. Within the IL-12 family, IL-35 remains particularly ill-characterized on a molecular level despite its key role in autoimmune diseases and cancer. Here we show that both IL-35 subunits, IL-12α and EBI3, mutually promote their secretion from cells but are not necessarily secreted as a heterodimer. Our data demonstrate that IL-12α and EBI3 are stable proteins in isolation that act as anti-inflammatory molecules. Both reduce secretion of proinflammatory cytokines and induce the development of regulatory T cells. Together, our study reveals IL-12α and EBI3, the subunits of IL-35, to be functionally active anti-inflammatory immune molecules on their own. This extends our understanding of the human cytokine repertoire as a basis for immunotherapeutic approaches.
AU  - Hildenbrand, K.*
AU  - Bohnacker, S.
AU  - Menon, P.R.*
AU  - Kerle, A.*
AU  - Prodjinotho, U.F.*
AU  - Hartung, F.
AU  - Strasser, P.C.*
AU  - Catici, D.A.M.*
AU  - Rührnößl, F.*
AU  - Haslbeck, M.*
AU  - Schumann, K.*
AU  - Müller, S.I.*
AU  - da Costa, C.P.*
AU  - Esser-von Bieren, J.
AU  - Feige, M.J.*
C1  - 68698
C2  - 54907
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Human interleukin-12α and EBI3 are cytokines with anti-inflammatory functions.
JO  - Sci. Adv.
VL  - 9
IS  - 43
PB  - Amer Assoc Advancement Science
PY  - 2023
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Adverse events in early life can modulate the response to additional stressors later in life and increase the risk of developing psychiatric disorders. The underlying molecular mechanisms responsible for these effects remain unclear. Here, we uncover that early life adversity (ELA) in mice leads to social subordination. Using single-cell RNA sequencing (scRNA-seq), we identified cell type-specific changes in the transcriptional state of glutamatergic and GABAergic neurons in the ventral hippocampus of ELA mice after exposure to acute social stress in adulthood. These findings were reflected by an alteration in excitatory and inhibitory synaptic transmission induced by ELA in response to acute social stress. Finally, enhancing the inhibitory network function through transient diazepam treatment during an early developmental sensitive period reversed the ELA-induced social subordination. Collectively, this study significantly advances our understanding of the molecular, physiological, and behavioral alterations induced by ELA, uncovering a previously unknown cell type-specific vulnerability to ELA.
AU  - Kos, A.*
AU  - Lopez, J.P.*
AU  - Bordes, J.*
AU  - De Donno, C.
AU  - Dine, J.*
AU  - Brivio, E.*
AU  - Karamihalev, S.*
AU  - Luecken, M.
AU  - Almeida-Correa, S.*
AU  - Gasperoni, S.*
AU  - Dick, A.*
AU  - Miranda, L.*
AU  - Büttner, M.
AU  - Stoffel, R.*
AU  - Flachskamm, C.*
AU  - Theis, F.J.
AU  - Schmidt, M.V.*
AU  - Chen, A.*
C1  - 68882
C2  - 53740
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Early life adversity shapes social subordination and cell type-specific transcriptomic patterning in the ventral hippocampus.
JO  - Sci. Adv.
VL  - 9
IS  - 48
PB  - Amer Assoc Advancement Science
PY  - 2023
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - The proposed mechanisms of sleep-dependent memory consolidation involve the overnight regulation of neural activity at both synaptic and whole-network levels. Now, there is a lack of in vivo data in humans elucidating if, and how, sleep and its varied stages balance neural activity, and if such recalibration benefits memory. We combined electrophysiology with in vivo two-photon calcium imaging in rodents as well as intracranial and scalp electroencephalography (EEG) in humans to reveal a key role for non-oscillatory brain activity during rapid eye movement (REM) sleep to mediate sleep-dependent recalibration of neural population dynamics. The extent of this REM sleep recalibration predicted the success of overnight memory consolidation, expressly the modulation of hippocampal-neocortical activity, favoring remembering rather than forgetting. The findings describe a non-oscillatory mechanism how human REM sleep modulates neural population activity to enhance long-term memory.
AU  - Lendner, J.D.*
AU  - Niethard, N.*
AU  - Mander, B.A.*
AU  - van Schalkwijk, F.J.*
AU  - Schuh-Hofer, S.*
AU  - Schmidt, H.*
AU  - Knight, R.T.*
AU  - Born, J.
AU  - Walker, M.P.*
AU  - Lin, J.J.*
AU  - Helfrich, R.F.*
C1  - 67952
C2  - 54430
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Human REM sleep recalibrates neural activity in support of memory formation.
JO  - Sci. Adv.
VL  - 9
IS  - 34
PB  - Amer Assoc Advancement Science
PY  - 2023
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - How the multiple facets of soil fungal diversity vary worldwide remains virtually unknown, hindering the management of this essential species-rich group. By sequencing high-resolution DNA markers in over 4000 topsoil samples from natural and human-altered ecosystems across all continents, we illustrate the distributions and drivers of different levels of taxonomic and phylogenetic diversity of fungi and their ecological groups. We show the impact of precipitation and temperature interactions on local fungal species richness (alpha diversity) across different climates. Our findings reveal how temperature drives fungal compositional turnover (beta diversity) and phylogenetic diversity, linking them with regional species richness (gamma diversity). We integrate fungi into the principles of global biodiversity distribution and present detailed maps for biodiversity conservation and modeling of global ecological processes.
AU  - Mikryukov, V.*
AU  - Dulya, O.*
AU  - Zizka, A.*
AU  - Bahram, M.*
AU  - Hagh-Doust, N.*
AU  - Anslan, S.*
AU  - Prylutskyi, O.*
AU  - Delgado-Baquerizo, M.*
AU  - Maestre, F.T.*
AU  - Nilsson, H.*
AU  - Pärn, J.*
AU  - Öpik, M.*
AU  - Moora, M.*
AU  - Zobel, M.*
AU  - Espenberg, M.*
AU  - Mander, A.P.*
AU  - Khalid, A.N.*
AU  - Corrales, A.*
AU  - Agan, A.*
AU  - Vasco-Palacios, A.M.*
AU  - Saitta, A.*
AU  - Rinaldi, A.C.*
AU  - Verbeken, A.*
AU  - Sulistyo, B.P.*
AU  - Tamgnoue, B.*
AU  - Furneaux, B.*
AU  - Duarte Ritter, C.*
AU  - Nyamukondiwa, C.*
AU  - Sharp, C.*
AU  - Marin, C.*
AU  - Gohar, D.*
AU  - Klavina, D.*
AU  - Sharmah, D.*
AU  - Dai, D.Q.*
AU  - Nouhra, E.*
AU  - Biersma, E.M.*
AU  - Rahn, E.*
AU  - Cameron, E.K.*
AU  - De Crop, E.*
AU  - Otsing, E.*
AU  - Davydov, E.A.*
AU  - Albornoz, F.E.*
AU  - Brearley, F.Q.*
AU  - Buegger, F.
AU  - Zahn, G.*
AU  - Bonito, G.*
AU  - Hiiesalu, I.*
AU  - Barrio, I.C.*
AU  - Heilmann-Clausen, J.*
AU  - Ankuda, J.*
AU  - Doležal, J.*
AU  - Kupagme, J.Y.*
AU  - Maciá-Vicente, J.G.*
AU  - Djeugap Fovo, J.*
AU  - Geml, J.*
AU  - Alatalo, J.M.*
AU  - Alvarez-Manjarrez, J.*
AU  - Poldmaa, K.*
AU  - Runnel, K.*
AU  - Adamson, K.*
AU  - Bråthen, K.A.*
AU  - Pritsch, K.
AU  - Tchan Issifou, K.*
AU  - Armolaitis, K.*
AU  - Hyde, K.D.*
AU  - Newsham, K.K.*
AU  - Panksep, K.*
AU  - Lateef, A.A.*
AU  - Hansson, L.*
AU  - Lamit, L.J.*
AU  - Saba, M.*
AU  - Tuomi, M.*
AU  - Gryzenhout, M.*
AU  - Bauters, M.*
AU  - Piepenbring, M.*
AU  - Wijayawardene, N.N.*
AU  - Yorou, N.S.*
AU  - Kurina, O.*
AU  - Mortimer, P.E.*
AU  - Meidl, P.*
AU  - Kohout, P.*
AU  - Puusepp, R.*
AU  - Drenkhan, R.*
AU  - Garibay-Orijel, R.*
AU  - Godoy, R.*
AU  - Alkahtani, S.*
AU  - Rahimlou, S.*
AU  - Dudov, S.V.*
AU  - Polme, S.*
AU  - Ghosh, S.*
AU  - Mundra, S.*
AU  - Ahmed, T.*
AU  - Netherway, T.*
AU  - Henkel, T.*
AU  - Roslin, T.*
AU  - Nteziryayo, V.*
AU  - Fedosov, V.E.*
AU  - Onipchenko, V.G.*
AU  - Yasanthika, W.A.E.*
AU  - Lim, Y.H.*
AU  - Van Nuland, M.*
AU  - Soudzilovskaia, N.A.*
AU  - Antonelli, A.*
AU  - Koljalg, U.*
AU  - Abarenkov, K.*
AU  - Tedersoo, L.*
C1  - 68895
C2  - 53748
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Connecting the multiple dimensions of global soil fungal diversity.
JO  - Sci. Adv.
VL  - 9
IS  - 48
PB  - Amer Assoc Advancement Science
PY  - 2023
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - We report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4). MAP4K4 has been implicated in many signaling pathways including c-Jun N-terminal and RAS kinases and is currently under investigation as a druggable target for multiple disorders. Using several zebrafish models, we demonstrate that these human variants are either loss-of-function or dominant-negative alleles and show that decreasing Map4k4 activity causes developmental defects. Furthermore, MAP4K4 can restrain hyperactive RAS signaling in early embryonic stages. Together, our data demonstrate that MAP4K4 negatively regulates RAS signaling in the early embryo and that variants identified in affected humans abrogate its function, establishing MAP4K4 as a causal locus for individuals with syndromic neurodevelopmental differences.
AU  - Patterson, V.*
AU  - Ullah, F.*
AU  - Bryant, L.*
AU  - Griffin, J.N.*
AU  - Sidhu, A.*
AU  - Saliganan, S.*
AU  - Blaile, M.*
AU  - Saenz, M.S.*
AU  - Smith, R.*
AU  - Ellingwood, S.*
AU  - Grange, D.K.*
AU  - Hu, X.*
AU  - Mireguli, M.*
AU  - Luo, Y.*
AU  - Shen, Y.*
AU  - Mulhern, M.*
AU  - Zackai, E.*
AU  - Ritter, A.*
AU  - Izumi, K.*
AU  - Hoefele, J.*
AU  - Wagner, M.
AU  - Riedhammer, K.M.*
AU  - Seitz, B.*
AU  - Robin, N.H.*
AU  - Goodloe, D.*
AU  - Mignot, C.*
AU  - Keren, B.*
AU  - Cox, H.*
AU  - Jarvis, J.*
AU  - Hempel, M.*
AU  - Gibson, C.F.*
AU  - Tran Mau-Them, F.*
AU  - Vitobello, A.*
AU  - Bruel, A.L.*
AU  - Sorlin, A.*
AU  - Mehta, S.*
AU  - Raymond, F.L.*
AU  - Gilmore, K.*
AU  - Powell, B.C.*
AU  - Weck, K.*
AU  - Li, C.*
AU  - Vulto-van Silfhout, A.T.*
AU  - Giacomini, T.*
AU  - Mancardi, M.M.*
AU  - Accogli, A.*
AU  - Salpietro, V.*
AU  - Zara, F.*
AU  - Vora, N.L.*
AU  - Davis, E.E.*
AU  - Burdine, R.*
AU  - Bhoj, E.*
C1  - 67781
C2  - 54259
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish.
JO  - Sci. Adv.
VL  - 9
IS  - 17
PB  - Amer Assoc Advancement Science
PY  - 2023
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Obesity and type 2 diabetes (T2D) are growing health challenges with unmet treatment needs. Traf2- and NCK-interacting protein kinase (TNIK) is a recently identified obesity- and T2D-associated gene with unknown functions. We show that TNIK governs lipid and glucose homeostasis in Drosophila and mice. Loss of the Drosophila ortholog of TNIK, misshapen, altered the metabolite profiles and impaired de novo lipogenesis in high sugar-fed larvae. Tnik knockout mice exhibited hyperlocomotor activity and were protected against diet-induced fat expansion, insulin resistance, and hepatic steatosis. The improved lipid profile of Tnik knockout mice was accompanied by enhanced skeletal muscle and adipose tissue insulin-stimulated glucose uptake and glucose and lipid handling. Using the T2D Knowledge Portal and the UK Biobank, we observed associations of TNIK variants with blood glucose, HbA1c, body mass index, body fat percentage, and feeding behavior. These results define an untapped paradigm of TNIK-controlled glucose and lipid metabolism.
AU  - Pham, T.C.P.*
AU  - Dollet, L.*
AU  - Ali, M.S.*
AU  - Raun, S.H.*
AU  - Møller, L.L.V.*
AU  - Jafari, A.*
AU  - Ditzel, N.*
AU  - Andersen, N.R.*
AU  - Fritzen, A.M.*
AU  - Gerhart-Hines, Z.*
AU  - Kiens, B.*
AU  - Suomalainen, A.*
AU  - Simpson, S.J.*
AU  - Salling Olsen, M.*
AU  - Kieser, A.
AU  - Schjerling, P.*
AU  - Nieminen, A.I.*
AU  - Richter, E.A.*
AU  - Havula, E.*
AU  - Sylow, L.*
C1  - 68014
C2  - 54492
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - TNIK is a conserved regulator of glucose and lipid metabolism in obesity.
JO  - Sci. Adv.
VL  - 9
IS  - 32
PB  - Amer Assoc Advancement Science
PY  - 2023
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Prolonged cytopenias after chimeric antigen receptor (CAR) T cell therapy are a significant clinical problem and the underlying pathophysiology remains poorly understood. Here, we investigated how (CAR) T cell expansion dynamics and serum proteomics affect neutrophil recovery phenotypes after CD19-directed CAR T cell therapy. Survival favored patients with "intermittent" neutrophil recovery (e.g., recurrent neutrophil dips) compared to either "quick" or "aplastic" recovery. While intermittent patients displayed increased CAR T cell expansion, aplastic patients exhibited an unfavorable relationship between expansion and tumor burden. Proteomics of patient serum collected at baseline and in the first month after CAR-T therapy revealed higher markers of endothelial dysfunction, inflammatory cytokines, macrophage activation, and T cell suppression in the aplastic phenotype group. Prolonged neutrophil aplasia thus occurs in patients with systemic immune dysregulation at baseline with subsequently impaired CAR-T expansion and myeloid-related inflammatory changes. The association between neutrophil recovery and survival outcomes highlights critical interactions between host hematopoiesis and the immune state stimulated by CAR-T infusion.
AU  - Rejeski, K.*
AU  - Perez, A.*
AU  - Iacoboni, G.*
AU  - Blumenberg, V.*
AU  - Bücklein, V.L.*
AU  - Völkl, S.*
AU  - Penack, O.*
AU  - Albanyan, O.*
AU  - Stock, S.*
AU  - Müller, F.*
AU  - Karschnia, P.*
AU  - Petrera, A.
AU  - Reid, K.*
AU  - Faramand, R.*
AU  - Davila, M.L.*
AU  - Modi, K.*
AU  - Dean, E.A.*
AU  - Bachmeier, C.*
AU  - von Bergwelt-Baildon, M.*
AU  - Locke, F.L.*
AU  - Bethge, W.*
AU  - Bullinger, L.*
AU  - Mackensen, A.*
AU  - Barba, P.*
AU  - Jain, M.D.*
AU  - Subklewe, M.*
C1  - 68225
C2  - 54770
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Severe hematotoxicity after CD19 CAR-T therapy is associated with suppressive immune dysregulation and limited CAR-T expansion.
JO  - Sci. Adv.
VL  - 9
IS  - 38
PB  - Amer Assoc Advancement Science
PY  - 2023
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - We report a huge organic diversity in the Tissint Mars meteorite and the sampling of several mineralogical lithologies, which revealed that the organic molecules were nonuniformly distributed in functionality and abundance. The range of organics in Tissint meteorite were abundant C3-7 aliphatic branched carboxylic acids and aldehydes, olefins, and polyaromatics with and without heteroatoms in a homologous oxidation structural continuum. Organomagnesium compounds were extremely abundant in olivine macrocrystals and in the melt veins, reflecting specific organo-synsthesis processes in close interaction with the magnesium silicates and temperature stresses, as previously observed. The diverse chemistry and abundance in complex molecules reveal heterogeneity in organic speciation within the minerals grown in the martian mantle and crust that may have evolved over geological time.
AU  - Schmitt-Kopplin, P.
AU  - Matzka, M.
AU  - Ruf, A.*
AU  - Ménez, B.*
AU  - Chennaoui Aoudjehane, H.*
AU  - Harir, M.
AU  - Lucio, M.
AU  - Hertzog, J.
AU  - Hertkorn, N.
AU  - Gougeon, R.D.*
AU  - Hoffmann, V.*
AU  - Hinman, N.W.*
AU  - Ferrière, L.*
AU  - Greshake, A.*
AU  - Gabelica, Z.*
AU  - Trif, L.*
AU  - Steele, A.*
C1  - 67214
C2  - 54225
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Complex carbonaceous matter in Tissint martian meteorites give insights into the diversity of organic geochemistry on Mars.
JO  - Sci. Adv.
VL  - 9
IS  - 2
PB  - Amer Assoc Advancement Science
PY  - 2023
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Immune checkpoint inhibitors (ICIs) enhance anticancer immunity by releasing repressive signals into tumor microenvironments (TMEs). To be effective, ICIs require preexisting immunologically "hot" niches for tumor antigen presentation and lymphocyte recruitment. How the mutational landscape of cancer cells shapes these immunological niches remains poorly defined. We found in human and murine colorectal cancer (CRC) models that the superior antitumor immune response of mismatch repair (MMR)-deficient CRC required tumor cell-intrinsic activation of cGAS-STING signaling triggered by genomic instability. Subsequently, we synthetically enforced STING signaling in CRC cells with intact MMR signaling using constitutively active STING variants. Even in MMR-proficient CRC, genetically encoded gain-of-function STING was sufficient to induce cancer cell-intrinsic interferon signaling, local activation of antigen-presenting cells, recruitment of effector lymphocytes, and sensitization of previously "cold" TMEs to ICI therapy in vivo. Thus, our results introduce a rational strategy for modulating cancer cell-intrinsic programs via engineered STING enforcement to sensitize resistant tumors to ICI responsiveness.
AU  - Vornholz, L.*
AU  - Isay, S.E.*
AU  - Kurgyis, Z.*
AU  - Strobl, D.C.
AU  - Loll, P.*
AU  - Mosa, M.H.*
AU  - Luecken, M.
AU  - Sterr, M.
AU  - Lickert, H.
AU  - Winter, C.*
AU  - Greten, F.R.*
AU  - Farin, H.F.*
AU  - Theis, F.J.
AU  - Ruland, J.*
C1  - 67724
C2  - 54032
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Synthetic enforcement of STING signaling in cancer cells appropriates the immune microenvironment for checkpoint inhibitor therapy.
JO  - Sci. Adv.
VL  - 9
IS  - 11
PB  - Amer Assoc Advancement Science
PY  - 2023
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Corticosteroids regulate vital processes, including stress responses, systemic metabolism, and blood pressure. Here, we show that corticosteroid synthesis is related to the polyunsaturated fatty acid (PUFA) content of mitochondrial phospholipids in adrenocortical cells. Inhibition of the rate-limiting enzyme of PUFA synthesis, fatty acid desaturase 2 (FADS2), leads to perturbations in the mitochondrial lipidome and diminishes steroidogenesis. Consistently, the adrenocortical mitochondria of Fads2-/- mice fed a diet with low PUFA concentration are structurally impaired and corticoid levels are decreased. On the contrary, FADS2 expression is elevated in the adrenal cortex of obese mice, and plasma corticosterone is increased, which can be counteracted by dietary supplementation with the FADS2 inhibitor SC-26192 or icosapent ethyl, an eicosapentaenoic acid ethyl ester. In humans, FADS2 expression is elevated in aldosterone-producing adenomas compared to non-active adenomas or nontumorous adrenocortical tissue and correlates with expression of steroidogenic genes. Our data demonstrate that FADS2-mediated PUFA synthesis determines adrenocortical steroidogenesis in health and disease.
AU  - Witt, A.*
AU  - Mateska, I.*
AU  - Palladini, A.
AU  - Sinha, A.*
AU  - Wölk, M.*
AU  - Harauma, A.*
AU  - Bechmann, N.*
AU  - Pamporaki, C.*
AU  - Dahl, A.*
AU  - Rothe, M.*
AU  - Kopaliani, I.*
AU  - Adolf, C.*
AU  - Riester, A.*
AU  - Wielockx, B.*
AU  - Bornstein, S.R.*
AU  - Kroiss, M.*
AU  - Peitzsch, M.*
AU  - Moriguchi, T.*
AU  - Fedorova, M.*
AU  - Grzybek, M.
AU  - Chavakis, T.*
AU  - Mirtschink, P.*
AU  - Alexaki, V.I.*
C1  - 68078
C2  - 54556
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Fatty acid desaturase 2 determines the lipidomic landscape and steroidogenic function of the adrenal gland.
JO  - Sci. Adv.
VL  - 9
IS  - 29
PB  - Amer Assoc Advancement Science
PY  - 2023
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - An adaptive stress response involves various mediators and circuits orchestrating a complex interplay of physiological, emotional, and behavioral adjustments. We identified a population of corticotropin-releasing hormone (CRH) neurons in the lateral part of the interstitial nucleus of the anterior commissure (IPACL), a subdivision of the extended amygdala, which exclusively innervate the substantia nigra (SN). Specific stimulation of this circuit elicits hyperactivation of the hypothalamic-pituitary-adrenal axis, locomotor activation, and avoidance behavior contingent on CRH receptor type 1 (CRHR1) located at axon terminals in the SN, which originate from external globus pallidus (GPe) neurons. The neuronal activity prompting the observed behavior is shaped by IPACLCRH and GPeCRHR1 neurons coalescing in the SN. These results delineate a previously unidentified tripartite CRH circuit functionally connecting extended amygdala and basal ganglia nuclei to drive locomotor activation and avoidance behavior.
AU  - Chang, S.*
AU  - Fermani, F.*
AU  - Lao, C.L.*
AU  - Huang, L.
AU  - Jakovcevski, M.*
AU  - Di Giaimo, R.*
AU  - Gagliardi, M.*
AU  - Menegaz, D.*
AU  - Hennrich, A.A.*
AU  - Ziller, M.J.*
AU  - Eder, M.*
AU  - Klein, R.*
AU  - Cai, N.
AU  - Deussing, J.M.*
C1  - 66764
C2  - 53298
TI  - Tripartite extended amygdala-basal ganglia CRH circuit drives locomotor activation and avoidance behavior.
JO  - Sci. Adv.
VL  - 8
IS  - 46
PY  - 2022
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Maladaptive insulin signaling is a key feature in the pathogenesis of severe metabolic disorders, including obesity and diabetes. Enhancing insulin sensitivity represents a major goal in the treatment of patients affected by diabetes. Here, we identify transforming growth factor-β1 stimulated clone 22 D4 (TSC22D4) as a novel interaction partner for protein kinase B/Akt1, a critical mediator of insulin/phosphatidylinositol 3-kinase signaling pathway. While energy deprivation and oxidative stress promote the TSC22D4-Akt1 interaction, refeeding mice or exposing cells to glucose and insulin impairs this interaction, which relies on an intrinsically disordered region (D2 domain) within TSC22D4. Functionally, the interaction with TSC22D4 reduces basal phosphorylation of Akt and its downstream targets during starvation, thereby promoting insulin sensitivity. Genetic, liver-specific reconstitution experiments in mice demonstrate that the interaction between TSC22D4 and Akt1 improves glucose handling and insulin sensitivity. Overall, our findings postulate a model whereby TSC22D4 acts as an environmental sensor and interacts with Akt1 to regulate insulin signaling and glucose metabolism.
AU  - Demir, S.
AU  - Wolff, G.
AU  - Wieder, A.
AU  - Maida, A.
AU  - Bühler, L.
AU  - Brune, M.
AU  - Hautzinger, O.
AU  - Feuchtinger, A.
AU  - Poth, T.*
AU  - Szendroedi, J.
AU  - Herzig, S.
AU  - Ekim Üstünel, B.
C1  - 66470
C2  - 52828
TI  - TSC22D4 interacts with Akt1 to regulate glucose metabolism.
JO  - Sci. Adv.
VL  - 8
IS  - 42
PY  - 2022
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Cell transplantation is a promising approach for the reconstruction of neuronal circuits after brain damage. Transplanted neurons integrate with remarkable specificity into circuitries of the mouse cerebral cortex affected by neuronal ablation. However, it remains unclear how neurons perform in a local environment undergoing reactive gliosis, inflammation, macrophage infiltration, and scar formation, as in traumatic brain injury (TBI). To elucidate this, we transplanted cells from the embryonic mouse cerebral cortex into TBI-injured, inflamed-only, or intact cortex of adult mice. Brain-wide quantitative monosynaptic rabies virus (RABV) tracing unraveled graft inputs from correct regions across the brain in all conditions, with pronounced quantitative differences: scarce in intact and inflamed brain versus exuberant after TBI. In the latter, the initial overshoot is followed by pruning, with only a few input neurons persisting at 3 months. Proteomic profiling identifies candidate molecules for regulation of the synaptic yield, a pivotal parameter to tailor for functional restoration of neuronal circuits.
AU  - Grade, S.
AU  - Thomas, J.
AU  - Zarb, Y.
AU  - Thorwirth, M.
AU  - Conzelmann, K.K.*
AU  - Hauck, S.M.
AU  - Götz, M.
C1  - 65443
C2  - 52300
TI  - Brain injury environment critically influences the connectivity of transplanted neurons.
JO  - Sci. Adv.
VL  - 8
IS  - 23
PY  - 2022
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - The mediobasal hypothalamus (MBH) is the central region in the physiological response to metabolic stress. The FK506-binding protein 51 (FKBP51) is a major modulator of the stress response and has recently emerged as a scaffolder regulating metabolic and autophagy pathways. However, the detailed protein-protein interactions linking FKBP51 to autophagy upon metabolic challenges remain elusive. We performed mass spectrometry-based metabolomics of FKBP51 knockout (KO) cells revealing an increased amino acid and polyamine metabolism. We identified FKBP51 as a central nexus for the recruitment of the LKB1/AMPK complex to WIPI4 and TSC2 to WIPI3, thereby regulating the balance between autophagy and mTOR signaling in response to metabolic challenges. Furthermore, we demonstrated that MBH FKBP51 deletion strongly induces obesity, while its overexpression protects against high-fat diet (HFD)-induced obesity. Our study provides an important novel regulatory function of MBH FKBP51 within the stress-adapted autophagy response to metabolic challenges.
AU  - Häusl, A.S.*
AU  - Bajaj, T.*
AU  - Brix, L.M.*
AU  - Pöhlmann, M.L.*
AU  - Hafner, K.*
AU  - de Angelis, M.
AU  - Nagler, J.
AU  - Dethloff, F.*
AU  - Balsevich, G.*
AU  - Schramm, K.-W.
AU  - Giavalisco, P.*
AU  - Chen, A.*
AU  - Schmidt, M.V.*
AU  - Gassen, N.C.*
C1  - 64579
C2  - 51943
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Mediobasal hypothalamic FKBP51 acts as a molecular switch linking autophagy to whole-body metabolism.
JO  - Sci. Adv.
VL  - 8
IS  - 10
PB  - Amer Assoc Advancement Science
PY  - 2022
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Alternative splicing plays key roles for cell type-specific regulation of protein function. It is controlled by cis-regulatory RNA elements that are recognized by RNA binding proteins (RBPs). The MALT1 paracaspase is a key factor of signaling pathways that mediate innate and adaptive immune responses. Alternative splicing of MALT1 is critical for controlling optimal T cell activation. We demonstrate that MALT1 splicing depends on RNA structural elements that sequester the splice sites of the alternatively spliced exon7. The RBPs hnRNP U and hnRNP L bind competitively to stem-loop RNA structures that involve the 5' and 3' splice sites flanking exon7. While hnRNP U stabilizes RNA stem-loop conformations that maintain exon7 skipping, hnRNP L disrupts these RNA elements to facilitate recruitment of the essential splicing factor U2AF2, thereby promoting exon7 inclusion. Our data represent a paradigm for the control of splice site selection by differential RBP binding and modulation of pre-mRNA structure.
AU  - Jones, A.
AU  - Grass, C.
AU  - Meininger, I.
AU  - Geerlof, A.
AU  - Klostermann, M.*
AU  - Zarnack, K.*
AU  - Krappmann, D.
AU  - Sattler, M.
C1  - 65858
C2  - 52945
TI  - Modulation of pre-mRNA structure by hnRNP proteins regulates alternative splicing of MALT1.
JO  - Sci. Adv.
VL  - 8
IS  - 31
PY  - 2022
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Transplantation is a clinically relevant approach for brain repair, but much remains to be understood about influences of the disease environment on transplant connectivity. To explore the effect of amyloid pathology in Alzheimer's disease (AD) and aging, we examined graft connectivity using monosynaptic rabies virus tracing in APP/PS1 mice and in 16- to 18-month-old wild-type (WT) mice. Transplanted neurons differentiated within 4 weeks and integrated well into the host visual cortex, receiving input from the appropriate brain regions for this area. Unexpectedly, we found a prominent several-fold increase in local inputs, in both amyloid-loaded and aged environments. State-of-the-art deep proteome analysis using mass spectrometry highlights complement system activation as a common denominator of environments promoting excessive local input connectivity. These data therefore reveal the key role of the host pathology in shaping the input connectome, calling for caution in extrapolating results from one pathological condition to another.
AU  - Thomas, J.
AU  - Martinez-Reza, M.F.
AU  - Thorwirth, M.
AU  - Zarb, Y.
AU  - Conzelmann, K.K.*
AU  - Hauck, S.M.
AU  - Grade, S.
AU  - Götz, M.
C1  - 65442
C2  - 52299
TI  - Excessive local host-graft connectivity in aging and amyloid-loaded brain.
JO  - Sci. Adv.
VL  - 8
IS  - 23
PY  - 2022
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Dexamethasone is widely used as an immunosuppressive therapy and recently as COVID-19 treatment. Here, we demonstrate that dexamethasone sensitizes to ferroptosis, a form of iron-catalyzed necrosis, previously suggested to contribute to diseases such as acute kidney injury, myocardial infarction, and stroke, all of which are triggered by glutathione (GSH) depletion. GSH levels were significantly decreased by dexamethasone. Mechanistically, we identified that dexamethasone up-regulated the GSH metabolism regulating protein dipeptidase-1 (DPEP1) in a glucocorticoid receptor (GR)-dependent manner. DPEP1 knockdown reversed the phenotype of dexamethasone-induced ferroptosis sensitization. Ferroptosis inhibitors, the DPEP1 inhibitor cilastatin, or genetic DPEP1 inactivation reversed the dexamethasone-induced increase in tubular necrosis in freshly isolated renal tubules. Our data indicate that dexamethasone sensitizes to ferroptosis by a GR-mediated increase in DPEP1 expression and GSH depletion. Together, we identified a previously unknown mechanism of glucocorticoid-mediated sensitization to ferroptosis bearing clinical and therapeutic implications.
AU  - von Mässenhausen, A.*
AU  - Zamora Gonzalez, N.*
AU  - Maremonti, F.*
AU  - Belavgeni, A.*
AU  - Tonnus, W.*
AU  - Meyer, C.*
AU  - Beer, K.*
AU  - Hannani, M.T.*
AU  - Lau, A.*
AU  - Peitzsch, M.*
AU  - Hoppenz, P.*
AU  - Locke, S.*
AU  - Chavakis, T.*
AU  - Kramann, R.*
AU  - Muruve, D.A.*
AU  - Hugo, C.*
AU  - Bornstein, S.R.
AU  - Linkermann, A.*
C1  - 64253
C2  - 51933
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor-induced dipeptidase-1 expression and glutathione depletion.
JO  - Sci. Adv.
VL  - 8
IS  - 5
PB  - Amer Assoc Advancement Science
PY  - 2022
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Currently, there is no pharmacological treatment targeting defective tissue repair in chronic disease. Here, we used a transcriptomics-guided drug target discovery strategy using gene signatures of smoking-associated chronic obstructive pulmonary disease (COPD) and from mice chronically exposed to cigarette smoke, identifying druggable targets expressed in alveolar epithelial progenitors, of which we screened the function in lung organoids. We found several drug targets with regenerative potential, of which EP and IP prostanoid receptor ligands had the most profound therapeutic potential in restoring cigarette smoke-induced defects in alveolar epithelial progenitors in vitro and in vivo. Mechanistically, we found, using single-cell RNA sequencing analysis, that circadian clock and cell cycle/apoptosis signaling pathways were differentially expressed in alveolar epithelial progenitor cells in patients with COPD and in a relevant model of COPD, which was prevented by prostaglandin E2 or prostacyclin mimetics. We conclude that specific targeting of EP and IP receptors offers therapeutic potential for injury to repair in COPD.
AU  - Wu, X.*
AU  - Bos, I.S.T.*
AU  - Conlon, T.M.
AU  - Ansari, M.
AU  - Verschut, V.*
AU  - van der Koog, L.*
AU  - Verkleij, L.A.*
AU  - D'Ambrosi, A.*
AU  - Matveyenko, A.*
AU  - Schiller, H. B.
AU  - Königshoff, M.*
AU  - Schmidt, M.*
AU  - Kistemaker, L.E.M.*
AU  - Yildirim, A.Ö.
AU  - Gosens, R.*
C1  - 64686
C2  - 51944
TI  - A transcriptomics-guided drug target discovery strategy identifies receptor ligands for lung regeneration.
JO  - Sci. Adv.
VL  - 8
IS  - 12
PY  - 2022
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Previous results indicate the presence of an interferon (IFN) signature in type 1 diabetes (T1D), capable of inducing chronic inflammation and compromising b cell function. Here, we determined the expression of the IFN response markers MxA, PKR, and HLA-I in the islets of autoantibody-positive and T1D donors. We found that these markers can be coexpressed in the same islet, are more abundant in insulin-containing islets, are highly expressed in islets with insulitis, and their expression levels are correlated with the presence of the enteroviral protein VP1. The expression of these markers was associated with down-regulation of multiple genes in the insulin secretion pathway. The coexistence of an IFN response and a microbial stress response is likely to prime islets for immune destruction. This study highlights the importance of therapeutic interventions aimed at eliminating potentially persistent infections and diminishing inflammation in individuals with T1D.
AU  - Apaolaza Gallegos, S.P.
AU  - Balcacean, D.
AU  - Zapardiel-Gonzalo, J.
AU  - Nelson, G.*
AU  - Lenchik, N.*
AU  - Akhbari, P.*
AU  - Gerling, I.*
AU  - Richardson, S.J.*
AU  - Rodriguez-Calvo, T.
C1  - 61480
C2  - 50284
TI  - Islet expression of type I interferon response sensors is associated with immune infiltration and viral infection in type 1 diabetes.
JO  - Sci. Adv.
VL  - 7
IS  - 9
PY  - 2021
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - CAR T cell therapy remains ineffective in solid tumors, due largely to poor infiltration and T cell suppression at the tumor site. T regulatory (Treg) cells suppress the immune response via inhibitory factors such as transforming growth factor–β (TGF-β). Treg cells expressing the C-C chemokine receptor 8 (CCR8) have been associated with poor prognosis in solid tumors. We postulated that CCR8 could be exploited to redirect effector T cells to the tumor site while a dominant-negative TGF-β receptor 2 (DNR) can simultaneously shield them from TGF-β. We identified that CCL1 from activated T cells potentiates a feedback loop for CCR8+ T cell recruitment to the tumor site. This sustained and improved infiltration of engineered T cells synergized with TGF-β shielding for improved therapeutic efficacy. Our results demonstrate that addition of CCR8 and DNR into CAR T cells can render them effective in solid tumors.
AU  - Cadilha, B.L.*
AU  - Benmebarek, M.R.*
AU  - Dorman, K.*
AU  - Oner, A.*
AU  - Lorenzini, T.*
AU  - Obeck, H.*
AU  - Vänttinen, M.*
AU  - Pilato, M.D.*
AU  - Pruessmann, J.N.*
AU  - Stoiber, S.*
AU  - Huynh, D.*
AU  - Märkl, F.*
AU  - Seifert, M.*
AU  - Manske, K.*
AU  - Suarez-Gosalvez, J.*
AU  - Zeng, Y.*
AU  - Lesch, S.*
AU  - Karches, C.H.*
AU  - Heise, C.*
AU  - Gottschlich, A.*
AU  - Thomas, M.
AU  - Marr, C.
AU  - Zhang, J.*
AU  - Pandey, D.*
AU  - Feuchtinger, T.*
AU  - Subklewe, M.*
AU  - Mempel, T.R.*
AU  - Endres, S.*
AU  - Kobold, S.
C1  - 62252
C2  - 50716
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Combined tumor-directed recruitment and protection from immune suppression enable CAR T cell efficacy in solid tumors.
JO  - Sci. Adv.
VL  - 7
IS  - 24
PB  - Amer Assoc Advancement Science
PY  - 2021
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Fibrogenic processes instigate fatal chronic diseases leading to organ 
      failure and death. Underlying biological processes involve induced 
      massive deposition of extracellular matrix (ECM) by aberrant 
      fibroblasts. We subjected diseased primary human lung fibroblasts to an 
      advanced three-dimensional phenotypic high-content assay and screened a 
      repurposing drug library of small molecules for inhibiting ECM 
      deposition. Fibrotic Pattern Detection by Artificial Intelligence 
      identified tranilast as an effective inhibitor. Structure-activity 
      relationship studies confirmed N-(2-butoxyphenyl)-3-(phenyl)acrylamides
       (N23Ps) as a novel and highly potent compound class. N23Ps suppressed 
      myofibroblast transdifferentiation, ECM deposition, cellular 
      contractility, and altered cell shapes, thus advocating a unique mode of
       action. Mechanistically, transcriptomics identified SMURF2 as a 
      potential therapeutic target network. Antifibrotic activity of N23Ps was
       verified by proteomics in a human ex vivo tissue fibrosis disease 
      model, suppressing profibrotic markers SERPINE1 and CXCL8. Conclusively,
       N23Ps are a novel class of highly potent compounds inhibiting organ 
      fibrosis in patients.
AU  - Gerckens, M.
AU  - Schorpp, K.K.
AU  - Pelizza, F.*
AU  - Wögrath, M.
AU  - Reichau, K.
AU  - Ma, H.
AU  - Dworsky, A.-M.
AU  - Sengupta, A.
AU  - Stoleriu, M.-G.
AU  - Heinzelmann, K.
AU  - Merl-Pham, J.
AU  - Irmler, M.
AU  - Alsafadi, H.N.
AU  - Trenkenschuh, E.*
AU  - Sarnova, L.*
AU  - Jirouskova, M.*
AU  - Frieß, W.*
AU  - Hauck, S.M.
AU  - Beckers, J.
AU  - Kneidinger, N.
AU  - Behr, J.
AU  - Hilgendorff, A.
AU  - Hadian, K.
AU  - Lindner, M.
AU  - Königshoff, M.
AU  - Eickelberg, O.*
AU  - Gregor, M.*
AU  - Plettenburg, O.
AU  - Yildirim, A.Ö.
AU  - Burgstaller, G.
C1  - 63884
C2  - 51641
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics.
JO  - Sci. Adv.
VL  - 7
IS  - 52
PB  - Amer Assoc Advancement Science
PY  - 2021
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - The mammalian circadian clock, expressed throughout the brain and body, 
      controls daily metabolic homeostasis. Clock function in peripheral 
      tissues is required, but not sufficient, for this task. Because of the 
      lack of specialized animal models, it is unclear how tissue clocks 
      interact with extrinsic signals to drive molecular oscillations. Here, 
      we isolated the interaction between feeding and the liver clock by 
      reconstituting Bmal1 exclusively in hepatocytes (Liver-RE), in otherwise
       clock-less mice, and controlling timing of food intake. We found that 
      the cooperative action of BMAL1 and the transcription factor CEBPB 
      regulates daily liver metabolic transcriptional programs. Functionally, 
      the liver clock and feeding rhythm are sufficient to drive temporal 
      carbohydrate homeostasis. By contrast, liver rhythms tied to redox and 
      lipid metabolism required communication with the skeletal muscle clock, 
      demonstrating peripheral clock cross-talk. Our results highlight how the
       inner workings of the clock system rely on communicating signals to 
      maintain daily metabolism.
AU  - Greco, C.M.*
AU  - Koronowski, K.B.*
AU  - Smith, J.G.*
AU  - Shi, J.*
AU  - Kunderfranco, P.*
AU  - Carriero, R.*
AU  - Chen, S.*
AU  - Samad, M.*
AU  - Welz, P.S.*
AU  - Zinna, V.M.*
AU  - Mortimer, T.*
AU  - Chun, S.K.*
AU  - Shimaji, K.*
AU  - Sato, T.*
AU  - Petrus, P.*
AU  - Kumar, A.*
AU  - Vaca-Dempere, M.*
AU  - Deryagian, O.*
AU  - Van, C.*
AU  - Monroy Kuhn, J.M.
AU  - Lutter, D.
AU  - Seldin, M.M.*
AU  - Masri, S.*
AU  - Li, W.*
AU  - Baldi, P.*
AU  - Dyar, K.A.
AU  - Muñoz-Cánoves, P.*
AU  - Benitah, S.A.*
AU  - Sassone-Corsi, P.*
C1  - 63123
C2  - 51155
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Integration of feeding behavior by the liver circadian clock reveals network dependency of metabolic rhythms.
JO  - Sci. Adv.
VL  - 7
IS  - 39
PB  - Amer Assoc Advancement Science
PY  - 2021
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Nitrous oxide is a powerful greenhouse gas whose atmospheric growth rate has accelerated over the past decade. Most anthropogenic N2O emissions result from soil N fertilization, which is converted to N2O via oxic nitrification and anoxic denitrification pathways. Drought-affected soils are expected to be well oxygenated; however, using high-resolution isotopic measurements, we found that denitrifying pathways dominated N2O emissions during a severe drought applied to managed grassland. This was due to a reversible, drought-induced enrichment in nitrogen-bearing organic matter on soil microaggregates and suggested a strong role for chemo- or codenitrification. Throughout rewetting, denitrification dominated emissions, despite high variability in fluxes. Total N2O flux and denitrification contribution were significantly higher during rewetting than for control plots at the same soil moisture range. The observed feedbacks between precipitation changes induced by climate change and N2O emission pathways are sufficient to account for the accelerating N2O growth rate observed over the past decade.
AU  - Harris, E.*
AU  - Díaz-Pinés, E.*
AU  - Stoll, E.*
AU  - Schloter, M.
AU  - Schulz, S.
AU  - Duffner, C.
AU  - Li, K.*
AU  - Moore, K.L.*
AU  - Ingrisch, J.*
AU  - Reinthaler, D.*
AU  - Zechmeister-Boltenstern, S.*
AU  - Glatzel, S.*
AU  - Brüggemann, N.*
AU  - Bahn, M.*
C1  - 61340
C2  - 50169
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Denitrifying pathways dominate nitrous oxide emissions from managed grassland during drought and rewetting.
JO  - Sci. Adv.
VL  - 7
IS  - 6
PB  - Amer Assoc Advancement Science
PY  - 2021
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Despite its importance in regulating cellular or tissue function, electrical conductivity can only be visualized in tissue indirectly as voltage potentials using fluorescent techniques, or directly with radio waves. These either requires invasive procedures like genetic modification or suffers from limited resolution. Here, we introduce radio-frequency thermoacoustic mesoscopy (RThAM) for the noninvasive imaging of conductivity by exploiting the direct absorption of near-field ultrashort radio-frequency pulses to stimulate the emission of broadband ultrasound waves. Detection of ultrasound rather than radio waves enables micrometer-scale resolutions, over several millimeters of tissue depth. We confirm an imaging resolution of <30 μm in phantoms and demonstrate microscopic imaging of conductivity correlating to physical structures in 1- and 512-cell zebrafish embryos, as well as larvae. These results support RThAM as a promising method for high-resolution, label-free assessment of conductivity in tissues.
AU  - Huang, Y.
AU  - Omar, M.
AU  - Tian, W.
AU  - López-Schier, H.
AU  - Westmeyer, G.G.
AU  - Chmyrov, A.
AU  - Sergiadis, G.
AU  - Ntziachristos, V.
C1  - 62034
C2  - 50579
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Noninvasive visualization of electrical conductivity in tissues at the micrometer scale.
JO  - Sci. Adv.
VL  - 7
IS  - 20
PB  - Amer Assoc Advancement Science
PY  - 2021
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Increase in the size of human neocortex―acquired in evolution―accounts 
      for the unique cognitive capacity of humans. This expansion reflects the
       evolutionarily enhanced proliferative ability of basal progenitors 
      (BPs), including the basal radial glia and basal intermediate 
      progenitors (bIPs) in mammalian cortex, which may have been acquired 
      through epigenetic alterations in BPs. However, how the epigenome in BPs
       differs across species is not known. Here, we report that histone H3 
      acetylation is a key epigenetic regulation in bIP amplification and 
      cortical expansion. Through epigenetic profiling of sorted bIPs, we show
       that histone H3 lysine 9 acetylation (H3K9ac) is low in murine bIPs and
       high in human bIPs. Elevated H3K9ac preferentially increases bIP 
      proliferation, increasing the size and folding of the normally smooth 
      mouse neocortex. H3K9ac drives bIP amplification by increasing 
      expression of the evolutionarily regulated gene, Trnp1, in developing cortex. Our findings demonstrate a previously unknown mechanism that controls cortical architecture.
AU  - Kerimoglu, C.*
AU  - Pham, L.*
AU  - Tonchev, A.B.*
AU  - Sakib, M.S.*
AU  - Xie, Y.*
AU  - Sokpor, G.*
AU  - Ulmke, P.A.*
AU  - Kaurani, L.*
AU  - Abbas, E.*
AU  - Nguyen, H.T.*
AU  - Rosenbusch, J.*
AU  - Michurina, A.*
AU  - Capece, V.*
AU  - Angelova, M.*
AU  - Maricic, N.*
AU  - Brand-Saberi, B.*
AU  - Esgleas Izquierdo, M.
AU  - Albert, M.*
AU  - Minkov, R.*
AU  - Kovachev, E.*
AU  - Teichmann, U.*
AU  - Seong, R.H.*
AU  - Huttner, W.B.*
AU  - Nguyen, H.P.*
AU  - Stoykova, A.*
AU  - Staiger, J.F.*
AU  - Fischer, A.*
AU  - Tuoc, T.*
C1  - 63052
C2  - 51157
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - H3 acetylation selectively promotes basal progenitor proliferation and neocortex expansion.
JO  - Sci. Adv.
VL  - 7
IS  - 38
PB  - Amer Assoc Advancement Science
PY  - 2021
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Variants in FTO have the strongest association with obesity; however, it is still unclear how those noncoding variants mechanistically affect whole-body physiology. We engineered a deletion of the rs1421085 conserved cis-regulatory module (CRM) in mice and confirmed in vivo that the CRM modulates Irx3 and Irx5 gene expression and mitochondrial function in adipocytes. The CRM affects molecular and cellular phenotypes in an adipose depot-dependent manner and affects organismal phenotypes that are relevant for obesity, including decreased high-fat diet-induced weight gain, decreased whole-body fat mass, and decreased skin fat thickness. Last, we connected the CRM to a genetically determined effect on steroid patterns in males that was dependent on nutritional challenge and conserved across mice and humans. Together, our data establish cross-species conservation of the rs1421085 regulatory circuitry at the molecular, cellular, metabolic, and organismal level, revealing previously unknown contextual dependence of the variant's action.
AU  - Laber, S.*
AU  - Forcisi, S.
AU  - Bentley, L.*
AU  - Petzold, J.*
AU  - Moritz, F.
AU  - Smirnov, K.
AU  - Al Sadat, L.*
AU  - Williamson, I.*
AU  - Strobel, S.*
AU  - Agnew, T.*
AU  - Sengupta, S.*
AU  - Nicol, T.*
AU  - Grallert, H.
AU  - Heier, M.
AU  - Honecker, J.*
AU  - Mianne, J.*
AU  - Teboul, L.*
AU  - Dumbell, R.*
AU  - Long, H.*
AU  - Simon, M.*
AU  - Lindgren, C.*
AU  - Bickmore, W.A.*
AU  - Hauner, H.*
AU  - Schmitt-Kopplin, P.
AU  - Claussnitzer, M.*
AU  - Cox, R.D.*
C1  - 62612
C2  - 50890
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Linking the FTO obesity rs1421085 variant circuitry to cellular, metabolic, and organismal phenotypes in vivo.
JO  - Sci. Adv.
VL  - 7
IS  - 30
PB  - Amer Assoc Advancement Science
PY  - 2021
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Circadian rhythm synchronizes each body function with the environment and regulates physiology. Disruption of normal circadian rhythm alters organismal physiology and increases disease risk. Recent epidemiological data and studies in model organisms have shown that maternal circadian disruption is important for offspring health and adult phenotypes. Less is known about the role of paternal circadian rhythm for offspring health. Here, we disrupted circadian rhythm in male mice by night-restricted feeding and showed that paternal circadian disruption at conception is important for offspring feeding behavior, metabolic health, and oscillatory transcription. Mechanistically, our data suggest that the effect of paternal circadian disruption is not transferred to the offspring via the germ cells but initiated by corticosterone-based parental communication at conception and programmed during in utero development through a state of fetal growth restriction. These findings indicate paternal circadian health at conception as a newly identified determinant of offspring phenotypes.
AU  - Lassi, M.
AU  - Tomar, A.
AU  - Comas-Armangue, G.
AU  - Vogtmann, R.*
AU  - Dijkstra, D.J.*
AU  - Corujo, D.*
AU  - Gerlini, R.
AU  - Darr, J.
AU  - Scheid, F.
AU  - Rozman, J.
AU  - Aguilar-Pimentel, J.A.
AU  - Koren, O.*
AU  - Buschbeck, M.*
AU  - Fuchs, H.
AU  - Marschall, S.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
AU  - Plösch, T.*
AU  - Gellhaus, A.*
AU  - Teperino, R.
C1  - 62143
C2  - 50469
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Disruption of paternal circadian rhythm affects metabolic health in male offspring via nongerm cell factors.
JO  - Sci. Adv.
VL  - 7
IS  - 22
PB  - Amer Assoc Advancement Science
PY  - 2021
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Hsp90 is a molecular chaperone that interacts with a specific set of 
      client proteins and assists their folding. The underlying molecular 
      mechanisms, involving dynamic transitions between open and closed 
      conformations, are still enigmatic. Combining nuclear magnetic 
      resonance, small-angle x-ray scattering, and biochemical experiments, we
       have identified a key intermediate state of Hsp90 induced by adenosine 
      triphosphate (ATP) binding, in which rotation of the Hsp90 N-terminal 
      domain (NTD) yields a domain arrangement poised for closing. This 
      ATP-stabilized NTD rotation is allosterically communicated across the 
      full Hsp90 dimer, affecting distant client sites. By analyzing the 
      interactions of four distinct clients, i.e., steroid hormone receptors 
      (glucocorticoid receptor and mineralocorticoid receptor), p53, and Tau, 
      we show that client-specific interactions with Hsp90 select and enhance 
      the NTD-rotated state and promote closing of the full-length Hsp90 
      dimer. The p23 co-chaperone shifts the population of Hsp90 toward the 
      closed state, thereby enhancing client interaction and processing.
AU  - Lopez, A.
AU  - Dahiya, V.*
AU  - Delhommel, F.
AU  - Freiburger, L.
AU  - Stehle, R.*
AU  - Asami, S.*
AU  - Rutz, D.*
AU  - Blair, L.*
AU  - Buchner, J.*
AU  - Sattler, M.
C1  - 63904
C2  - 51733
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Client binding shifts the populations of dynamic Hsp90 conformations through an allosteric network.
JO  - Sci. Adv.
VL  - 7
IS  - 51
PB  - Amer Assoc Advancement Science
PY  - 2021
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Chronic activation and dysregulation of the neuroendocrine stress response have severe physiological and psychological consequences, including the development of metabolic and stress-related psychiatric disorders. We provide the first unbiased, cell type-specific, molecular characterization of all three components of the hypothalamic-pituitary- adrenal axis, under baseline and chronic stress conditions. Among others, we identified a previously unreported subpopulation of Abcb1b+ cells involved in stress adaptation in the adrenal gland. We validated our findings in a mouse stress model, adrenal tissues from patients with Cushing's syndrome, adrenocortical cell lines, and peripheral cortisol and genotyping data from depressed patients. This extensive dataset provides a valuable resource for researchers and clinicians interested in the organism's nervous and endocrine responses to stress and the interplay between these tissues. Our findings raise the possibility that modulating ABCB1 function may be important in the development of treatment strategies for patients suffering from metabolic and stress-related psychiatric disorders.
AU  - Lopez, J.P.*
AU  - Brivio, E.*
AU  - Santambrogio, A.*
AU  - De Donno, C.
AU  - Kos, A.*
AU  - Peters, M.*
AU  - Rost, N.*
AU  - Czamara, D.*
AU  - Brückl, T.M.*
AU  - Roeh, S.*
AU  - Pöhlmann, M.L.*
AU  - Engelhardt, C.*
AU  - Ressle, A.*
AU  - Stoffel, R.*
AU  - Tontsch, A.*
AU  - Villamizar, J.M.*
AU  - Reincke, M.*
AU  - Riester, A.*
AU  - Sbiera, S.*
AU  - Fassnacht, M.*
AU  - Mayberg, H.S.*
AU  - Craighead, W.E.*
AU  - Dunlop, B.W.*
AU  - Nemeroff, C.B.*
AU  - Schmidt, M.V.*
AU  - Binder, E.B.*
AU  - Theis, F.J.
AU  - Beuschlein, F.*
AU  - Andoniadou, C.L.*
AU  - Chen, A.*
C1  - 61143
C2  - 50066
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Single-cell molecular profiling of all three components of the HPA axis reveals adrenal ABCB1 as a regulator of stress adaptation.
JO  - Sci. Adv.
VL  - 7
IS  - 5
PB  - Amer Assoc Advancement Science
PY  - 2021
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - [Figure: see text].
AU  - Tošner, Z.*
AU  - Brandl, M.J.*
AU  - Blahut, J.*
AU  - Glaser, S.J.*
AU  - Reif, B.
C1  - 63276
C2  - 51295
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Maximizing efficiency of dipolar recoupling in solid-state NMR using optimal control sequences.
JO  - Sci. Adv.
VL  - 7
IS  - 42
PB  - Amer Assoc Advancement Science
PY  - 2021
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Preproinsulin (PPI) is presumably a crucial islet autoantigen found in patients with type 1 diabetes (T1D) but is also recognized by CD8(+) T cells from healthy individuals. We quantified PPI-specific CD8(+) T cells within different areas of the human pancreas from nondiabetic controls, autoantibody-positive donors, and donors with T1D to investigate their role in diabetes development. This spatial cellular quantitation revealed unusually high frequencies of autoreactive CD8(+) T cells supporting the hypothesis that PPI is indeed a key autoantigen. To our surprise, PPI-specific CD8(+) T cells were already abundantly present in the nondiabetic pancreas, thus questioning the dogma that T1D is caused by defective thymic deletion or systemic immune dysregulation. During T1D development, these cells accumulated in and around islets, indicating that an islet-specific trigger such as up-regulation of major histocompatibility complex class I might be essential to unmask beta cells to the immune system.
AU  - Bender, C.*
AU  - Rodriguez-Calvo, T.
AU  - Amirian, N.*
AU  - Coppieters, K.T.*
AU  - Von Herrath, M.G.*
C1  - 60381
C2  - 49317
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - The healthy exocrine pancreas contains preproinsulin-specific CD8 T cells that attack islets in type 1 diabetes.
JO  - Sci. Adv.
VL  - 6
IS  - 42
PB  - Amer Assoc Advancement Science
PY  - 2020
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.
AU  - Bryant, L.*
AU  - Li, D.*
AU  - Cox, S.G.*
AU  - Marchione, D.*
AU  - Joiner, E.F.*
AU  - Wilson, K.*
AU  - Janssen, K.*
AU  - Lee, P.*
AU  - March, M.E.*
AU  - Nair, D.*
AU  - Sherr, E.*
AU  - Fregeau, B.*
AU  - Wierenga, K.J.*
AU  - Wadley, A.*
AU  - Mancini, G.M.S.*
AU  - Powell-Hamilton, N.*
AU  - van de Kamp, J.M.*
AU  - Grebe, T.*
AU  - Dean, J.*
AU  - Ross, A.*
AU  - Crawford, H.P.*
AU  - Powis, Z.*
AU  - Cho, M.T.*
AU  - Willing, M.C.*
AU  - Manwaring, L.*
AU  - Schot, R.*
AU  - Nava, C.*
AU  - Afenjar, A.*
AU  - Lessel, D.*
AU  - Wagner, M.
AU  - Klopstock, T.*
AU  - Winkelmann, J.
AU  - Catarino, C.B.*
AU  - Retterer, K.*
AU  - Schuette, J.L.*
AU  - Innis, J.W.*
AU  - Pizzino, A.*
AU  - Lüttgen, S.*
AU  - Denecke, J.*
AU  - Strom, T.M.
AU  - Monaghan, K.G.*
AU  - Yuan, Z.F.*
AU  - Dubbs, H.*
AU  - Bend, R.*
AU  - Lee, J.A.*
AU  - Lyons, M.J.*
AU  - Hoefele, J.*
AU  - Günthner, R.*
AU  - Reutter, H.*
AU  - Keren, B.*
AU  - Radtke, K.*
AU  - Sherbini, O.*
AU  - Mrokse, C.*
AU  - Helbig, K.L.*
AU  - Odent, S.*
AU  - Cogné, B.*
AU  - Mercier, S.*
AU  - Bézieau, S.*
AU  - Besnard, T.*
AU  - Küry, S.*
AU  - Redon, R.*
AU  - Reinson, K.*
AU  - Wojcik, M.H.*
AU  - Õunap, K.*
AU  - Ilves, P.*
AU  - Innes, A.M.*
AU  - Kernohan, K.D.*
AU  - Costain, G.*
AU  - Meyn, M.S.*
AU  - Chitayat, D.*
AU  - Zackai, E.*
AU  - Lehman, A.*
AU  - Kitson, H.*
AU  - Martin, M.G.*
AU  - Martinez-Agosto, J.A.*
AU  - Nelson, S.F.*
AU  - Palmer, C.G.S.*
AU  - Papp, J.C.*
AU  - Parker, N.H.*
AU  - Sinsheimer, J.S.*
AU  - Vilain, E.*
AU  - Wan, J.*
AU  - Yoon, A.J.*
AU  - Zheng, A.*
AU  - Brimble, E.*
AU  - Ferrero, G.B.*
AU  - Radio, F.C.*
AU  - Carli, D.*
AU  - Barresi, S.*
AU  - Brusco, A.*
AU  - Tartaglia, M.*
AU  - Thomas, J.M.*
AU  - Umana, L.*
AU  - Weiss, M.M.*
AU  - Gotway, G.*
AU  - Stuurman, K.E.*
AU  - Thompson, M.L.*
AU  - McWalter, K.*
AU  - Stumpel, C.T.R.M.*
AU  - Stevens, S.J.C.*
AU  - Stegmann, A.P.A.*
AU  - Tveten, K.*
AU  - Vøllo, A.*
AU  - Prescott, T.*
AU  - Fagerberg, C.*
AU  - Laulund, L.W.*
AU  - Larsen, M.J.*
AU  - Byler, M.*
AU  - Lebel, R.R.*
AU  - Hurst, A.C.*
AU  - Schrier Vergano, S.A.*
AU  - Norman, J.*
AU  - Mercimek-Andrews, S.*
AU  - Neira, J.*
AU  - Van Allen, M.I.*
AU  - Longo, N.*
AU  - Sellars, E.*
AU  - Louie, R.J.*
AU  - Cathey, S.S.*
AU  - Brokamp, E.*
AU  - Heron, D.*
AU  - Snyder, M.*
AU  - Vanderver, A.*
AU  - Simon, C.*
AU  - de la Cruz, X.*
AU  - Padilla, N.*
AU  - Crump, J.G.*
AU  - Chung, W.*
AU  - Garcia, B.*
AU  - Hakonarson, H.H.*
AU  - Bhoj, E.J.*
C1  - 60727
C2  - 49573
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients.
JO  - Sci. Adv.
VL  - 6
IS  - 49
PB  - Amer Assoc Advancement Science
PY  - 2020
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Recently, covalent modifications of RNA, such as methylation, have emerged as key regulators of all aspects of RNA biology and have been implicated in numerous diseases, for instance, cancer. Here, we undertook a combination of in vitro and in vivo screens to test 78 potential methyltransferases for their roles in hepatocellular carcinoma (HCC) cell proliferation. We identified methyltransferase-like protein 6 (METTL6) as a crucial regulator of tumor cell growth. We show that METTL6 is a bona fide transfer RNA (tRNA) methyltransferase, catalyzing the formation of 3-methylcytidine at C32 of specific serine tRNA isoacceptors. Deletion of Mettl6 in mouse stem cells results in changes in ribosome occupancy and RNA levels, as well as impaired pluripotency. In mice, Mettl6 knockout results in reduced energy expenditure. We reveal a previously unknown pathway in the maintenance of translation efficiency with a role in maintaining stem cell self-renewal, as well as impacting tumor cell growth profoundly.
AU  - Ignatova, V.V.
AU  - Kaiser, S.*
AU  - Ho, J.S.Y.*
AU  - Bing, X.*
AU  - Stolz, P.*
AU  - Tan, Y.X.*
AU  - Lee, C.L.*
AU  - Gay, F.P.H.*
AU  - Lastres, P.R.
AU  - Gerlini, R.
AU  - Rathkolb, B.
AU  - Aguilar-Pimentel, J.A.
AU  - Sanz-Moreno, A.
AU  - Klein-Rodewald, T.
AU  - Calzada-Wack, J.
AU  - Ibragimov, E.
AU  - Valenta, M.
AU  - Lukauskas, S.
AU  - Pavesi, A.*
AU  - Marschall, S.
AU  - Leuchtenberger, S.
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
AU  - Bultmann, S.*
AU  - Rando, O.J.*
AU  - Guccione, E.*
AU  - Kellner, S.M.*
AU  - Schneider, R.
C1  - 60370
C2  - 49180
TI  - METTL6 is a tRNA m3C methyltransferase that regulates pluripotency and tumor cell growth.
JO  - Sci. Adv.
VL  - 6
IS  - 35
PY  - 2020
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Polyubiquitin chains are flexible multidomain proteins, whose conformational dynamics enable them to regulate multiple biological pathways. Their dynamic is determined by the linkage between ubiquitins and by the number of ubiquitin units. Characterizing polyubiquitin behavior as a function of their length is hampered because of increasing system size and conformational variability. Here, we introduce a new approach to efficiently integrating small- angle x-ray scattering with simulations allowing us to accurately characterize the dynamics of linear di-, tri-, and tetraubiquitin in the free state as well as of diubiquitin in complex with NEMO, a central regulator in the NF-kappa B pathway. Our results show that the behavior of the diubiquitin subunits is independent of the presence of additional ubiquitin modules and that the dynamics of polyubiquitins with different lengths follow a simple model. Together with experimental data from multiple biophysical techniques, we then rationalize the 2:1 NEMO:polyubiquitin binding.
AU  - Jussupow, A.*
AU  - Messias, A.C.
AU  - Stehle, R.
AU  - Geerlof, A.
AU  - Solbak, S.M.Ø.*
AU  - Paissoni, C.*
AU  - Bach, A.*
AU  - Sattler, M.
AU  - Camilloni, C.*
C1  - 60378
C2  - 49319
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - The dynamics of linear polyubiquitin.
JO  - Sci. Adv.
VL  - 6
IS  - 42
PB  - Amer Assoc Advancement Science
PY  - 2020
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - The ninefold radial arrangement of microtubule triplets (MTTs) is the hallmark of the centriole, a conserved organelle crucial for the formation of centrosomes and cilia. Although strong cohesion between MTTs is critical to resist forces applied by ciliary beating and the mitotic spindle, how the centriole maintains its structural integrity is not known. Using cryo-electron tomography and subtomogram averaging of centrioles from four evolutionarily distant species, we found that MTTs are bound together by a helical inner scaffold covering similar to 70% of the centriole length that maintains MTTs cohesion under compressive forces. Ultrastructure Expansion Microscopy (U-ExM) indicated that POC5, POC1B, FAM161A, and Centrin-2 localize to the scaffold structure along the inner wall of the centriole MTTs. Moreover, we established that these four proteins interact with each other to form a complex that binds microtubules. Together, our results provide a structural and molecular basis for centriole cohesion and geometry.
AU  - Le Guennec, M.*
AU  - Klena, N.*
AU  - Gambarotto, D.*
AU  - Laporte, M.H.*
AU  - Tassin, A.M.*
AU  - van den Hoek, H.*
AU  - Erdmann, P.S.*
AU  - Schaffer, M.*
AU  - Kovacik, L.*
AU  - Borgers, S.*
AU  - Goldie, K.N.*
AU  - Stahlberg, H.*
AU  - Bornens, M.*
AU  - Azimzadeh, J.*
AU  - Engel, B.D.
AU  - Hamel, V.*
AU  - Guichard, P.*
C1  - 58669
C2  - 48232
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - A helical inner scaffold provides a structural basis for centriole cohesion.
JO  - Sci. Adv.
VL  - 6
IS  - 7
PB  - Amer Assoc Advancement Science
PY  - 2020
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - We introduce two photochromic proteins for cell-specific in vivo optoacoustic (OA) imaging with signal unmixing in the temporal domain. We show highly sensitive, multiplexed visualization of T lymphocytes, bacteria, and tumors in the mouse body and brain. We developed machine learning-based software for commercial imaging systems for temporal unmixed OA imaging, enabling its routine use in life sciences.
AU  - Mishra, K.
AU  - Stankevych, M.
AU  - Fuenzalida Werner, J.P.
AU  - Grassmann, S.*
AU  - Gujrati, V.
AU  - Huang, Y.
AU  - Klemm, U.
AU  - Buchholz, V.R.*
AU  - Ntziachristos, V.
AU  - Stiel, A.-C.
C1  - 59416
C2  - 48804
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Multiplexed whole-animal imaging with reversibly switchable optoacoustic proteins.
JO  - Sci. Adv.
VL  - 6
IS  - 24
PB  - Amer Assoc Advancement Science
PY  - 2020
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Tumor-associated macrophages (TAMs) influence lung tumor development by inducing immunosuppression. Transcriptome analysis of TAMs isolated from human lung tumor tissues revealed an up-regulation of the Wnt/beta-catenin pathway. These findings were reproduced in a newly developed in vitro "trained" TAM model. Pharmacological and macrophage-specific genetic ablation of beta-catenin reprogrammed M2-like TAMs to M1-like TAMs both in vitro and in various in vivo models, which was linked with the suppression of primary and metastatic lung tumor growth. An in-depth analysis of the underlying signaling events revealed that beta-catenin-mediated transcriptional activation of FOS-like antigen 2 (FOSL2) and repression of the AT-rich interaction domain 5A (ARID5A) drive gene regulatory switch from M1-like TAMs to M2-like TAMs. Moreover, we found that high expressions of beta-catenin and FOSL2 correlated with poor prognosis in patients with lung cancer. In conclusion, beta-catenin drives a transcriptional switch in the lung tumor microenvironment, thereby promoting tumor progression and metastasis.
AU  - Sarode, P.*
AU  - Zheng, X.*
AU  - Giotopoulou, G.A.
AU  - Weigert, A.*
AU  - Kuenne, C.*
AU  - Günther, S.*
AU  - Friedrich, A.*
AU  - Gattenlöhner, S.*
AU  - Stiewe, T.*
AU  - Brüne, B.*
AU  - Grimminger, F.*
AU  - Stathopoulos, G.T.
AU  - Pullamsetti, S.S.*
AU  - Seeger, W.*
AU  - Savai, R.*
C1  - 59462
C2  - 48836
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Reprogramming of tumor-associated macrophages by targeting β-catenin/FOSL2/ARID5A signaling: A potential treatment of lung cancer.
JO  - Sci. Adv.
VL  - 6
IS  - 23
PB  - Amer Assoc Advancement Science
PY  - 2020
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.
AU  - Couto Alves, A.*
AU  - De Silva, N.M.G.*
AU  - Karhunen, V.*
AU  - Sovio, U.*
AU  - Das, S.*
AU  - Rob Taal, H.*
AU  - Warrington, N.M.*
AU  - Lewin, A.M.*
AU  - Kaakinen, M.*
AU  - Cousminer, D.L.*
AU  - Thiering, E.
AU  - Timpson, N.J.*
AU  - Bond, T.A.*
AU  - Lowry, E.*
AU  - Brown, C.D.*
AU  - Lindi, V.*
AU  - Bradfield, J.P.*
AU  - Geller, F.*
AU  - Speed, D.*
AU  - Coin, L.J.M.*
AU  - Loh, M.*
AU  - Barton, S.J.*
AU  - Beilin, L.J.*
AU  - Bisgaard, H.*
AU  - Bønnelykke, K.*
AU  - Alili, R.*
AU  - Hatoum, I.J.*
AU  - Schramm, K.
AU  - Cartwright, R.*
AU  - Charles, M.A.*
AU  - Salerno, V.*
AU  - Clément, K.*
AU  - Claringbould, A.A.J.*
AU  - van Duijn, C.M.*
AU  - Moltchanova, E.*
AU  - Eriksson, J.G.*
AU  - Elks, C.*
AU  - Feenstra, B.*
AU  - Flexeder, C.
AU  - Franks, S.*
AU  - Frayling, T.M.*
AU  - Freathy, R.M.*
AU  - Elliott, P.*
AU  - Widén, E.*
AU  - Hakonarson, H.*
AU  - Hattersley, A.T.*
AU  - Rodriguez, A.*
AU  - Banterle, M.*
AU  - Heinrich, J.
AU  - Heude, B.*
AU  - Holloway, J.W.*
AU  - Hofman, A.*
AU  - Hyppönen, E.*
AU  - Inskip, H.*
AU  - Kaplan, L.M.*
AU  - Hedman, A.K.*
AU  - Läärä, E.*
AU  - Prokisch, H.
AU  - Grallert, H.
AU  - Lakka, T.A.*
AU  - Lawlor, D.A.*
AU  - Melbye, M.*
AU  - Ahluwalia, T.S.*
AU  - Marinelli, M.*
AU  - Millwood, I.Y.*
AU  - Palmer, L.J.*
AU  - Pennell, C.E.*
AU  - Perry, J.R.*
AU  - Ring, S.M.*
AU  - Savolainen, M.J.*
AU  - Rivadeneira, F.*
AU  - Standl, M.
AU  - Sunyer, J.*
AU  - Tiesler, C.M.
AU  - Uitterlinden, A.G.*
AU  - Schierding, W.*
AU  - Sullivan, O.M.*
AU  - Prokopenko, I.*
AU  - Herzig, K.H.*
AU  - Smith, G.D.*
AU  - O'Reilly, P.*
AU  - Felix, J.F.*
AU  - Buxton, J.L.*
AU  - Blakemore, A.I.F.*
AU  - Ong, K.K.*
AU  - Jaddoe, V.W.V.*
AU  - Grant, S.F.A.*
AU  - Sebert, S.*
AU  - McCarthy, M.I.*
C1  - 57202
C2  - 47609
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI.
JO  - Sci. Adv.
VL  - 5
IS  - 9
PB  - Amer Assoc Advancement Science
PY  - 2019
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Carcinoma cells undergo epithelial-mesenchymal transition (EMT); however, contributions of EMT heterogeneity to disease progression remain a matter of debate. Here, we addressed the EMT status of ex vivo cultured circulating and disseminated tumor cells (CTCs/DTCs) in a syngeneic mouse model of metastatic breast cancer (MBC). Epithelial-type CTCs with a restricted mesenchymal transition had the strongest lung metastases formation ability, whereas mesenchymal-type CTCs showed limited metastatic ability. EpCAM expression served as a surrogate marker to evaluate the EMT heterogeneity of clinical samples from MBC, including metastases, CTCs, and DTCs. The proportion of epithelial-type CTCs, and especially DTCs, correlated with distant metastases and poorer outcome of patients with MBC. This study fosters our understanding of EMT in metastasis and underpins heterogeneous EMT phenotypes as important parameters for tumor prognosis and treatment. We further suggest that EpCAM-dependent CTC isolation systems will underestimate CTC numbers but will quantify clinically relevant metastatic cells.
AU  - Liu, X.*
AU  - Li, J.*
AU  - Cadilha, B.L.*
AU  - Markota, A.*
AU  - Voigt, C.*
AU  - Huang, Z.*
AU  - Lin, P.P.*
AU  - Wang, D.D.*
AU  - Dai, J.*
AU  - Kranz, G.*
AU  - Krandick, A.*
AU  - Libl, D.*
AU  - Zitzelsberger, H.
AU  - Zagorski, I.
AU  - Braselmann, H.
AU  - Pan, M.*
AU  - Zhu, S.*
AU  - Huang, Y.*
AU  - Niedermeyer, S.*
AU  - Reichel, C.A.*
AU  - Uhl, B.*
AU  - Briukhovetska, D.*
AU  - Suárez, J.*
AU  - Kobold, S.*
AU  - Gires, O.
AU  - Wang, H.*
C1  - 56377
C2  - 46998
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Epithelial-type systemic breast carcinoma cells with a restricted mesenchymal transition are a major source of metastasis.
JO  - Sci. Adv.
VL  - 5
IS  - 6
PB  - Amer Assoc Advancement Science
PY  - 2019
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Amyloid-beta (A beta) aggregation and neuroinflammation are consistent features in Alzheimer's disease (AD) and strong candidates for the initiation of neurodegeneration. S100B is one of the most abundant proinflammatory proteins that is chronically up-regulated in AD and is found associated with senile plaques. This recognized biomarker for brain distress may, thus, play roles in amyloid aggregation which remain to be determined. We report a novel role for the neuronal S100B protein as suppressor of A beta 42 aggregation and toxicity. We determined the structural details of the interaction between monomeric A beta 42 and S100B, which is favored by calcium binding to S100B, possibly involving conformational switching of disordered A beta 42 into an alpha-helical conformer, which locks aggregation. From nuclear magnetic resonance experiments, we show that this dynamic interaction occurs at a promiscuous peptide-binding region within the interfacial cleft of the S100B homodimer. This physical interaction is coupled to a functional role in the inhibition of A beta 42 aggregation and toxicity and is tuned by calcium binding to S100B. S100B delays the onset of A beta 42 aggregation by interacting with A beta 42 monomers inhibiting primary nucleation, and the calcium-bound state substantially affects secondary nucleation by inhibiting fibril surface-catalyzed reactions through S100B binding to growing A beta 42 oligomers and fibrils. S100B protects cells from A beta 42-mediated toxicity, rescuing cell viability and decreasing apoptosis induced by A beta 42 in cell cultures. Together, our findings suggest that molecular targeting of S100B could be translated into development of novel approaches to ameliorate AD neurodegeneration.
AU  - Cristóvão, J.S.*
AU  - Morris, V.K.
AU  - Cardoso, I.*
AU  - Leal, S.S.*
AU  - Martínez, J.*
AU  - Botelho, H.M.*
AU  - Göbl, C.
AU  - David, R.*
AU  - Kierdorf, K.*
AU  - Alemi, M.*
AU  - Madl, T.
AU  - Fritz, G.*
AU  - Reif, B.
AU  - Gomes, C.M.*
C1  - 53963
C2  - 45160
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - The neuronal S100B protein is a calcium-tuned suppressor of amyloid-beta aggregation.
JO  - Sci. Adv.
VL  - 4
IS  - 6
PB  - Amer Assoc Advancement Science
PY  - 2018
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Wheat is an important staple grain for humankind globally because of its end-use quality and nutritional properties and its adaptability to diverse climates. For a small proportion of the population, specific wheat proteins can trigger adverse immune responses and clinical manifestations such as celiac disease, wheat allergy, baker's asthma, and wheat-dependent exercise-induced anaphylaxis (WDEIA). Establishing the content and distribution of the immunostimulatory regions in wheat has been hampered by the complexity of the wheat genome and the lack of complete genome sequence information. We provide novel insights into the wheat grain proteins based on a comprehensive analysis and annotation of the wheat prolamin Pfam clan grain proteins and other non-prolamin allergens implicated in these disorders using the new International Wheat Genome Sequencing Consortium bread wheat reference genome sequence, RefSeq v1.0. Celiac disease and WDEIA genes are primarily expressed in the starchy endosperm and show wide variation in protein- and transcript-level expression in response to temperature stress. Nonspecific lipid transfer proteins and a-amylase trypsin inhibitor gene families, implicated in baker's asthma, are primarily expressed in the aleurone layer and transfer cells of grains and are more sensitive to cold temperature. The study establishes a new reference map for immunostimulatory wheat proteins and provides a fresh basis for selecting wheat lines and developing diagnostics for products with more favorable consumer attributes.
AU  - Juhász, A.*
AU  - Belova, T.*
AU  - Florides, C.G.*
AU  - Maulis, C.*
AU  - Fischer, I.
AU  - Gell, G.*
AU  - Birinyi, Z.*
AU  - Ong, J.*
AU  - Keeble-Gagnère, G.*
AU  - Maharajan, A.*
AU  - Ma, W.*
AU  - Gibson, P.*
AU  - Jia, J.*
AU  - Lang, D.
AU  - Mayer, K.F.X.
AU  - Spannagl, M.
AU  - Tye-Din, J.A.*
AU  - Appels, R.*
AU  - Olsen, O.A.*
C1  - 54167
C2  - 45380
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Genome mapping of seed-borne allergens and immunoresponsive proteins in wheat.
JO  - Sci. Adv.
VL  - 4
IS  - 8
PB  - Amer Assoc Advancement Science
PY  - 2018
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Mitochondrial uncoupling protein 1 (UCP1) is essential for nonshivering thermogenesis in brown adipose tissue and is widely accepted to have played a key thermoregulatory role in small-bodied and neonatal placental mammals that enabled the exploitation of cold environments. We map ucp1 sequences from 133 mammals onto a species tree constructed from a similar to 51-kb sequence alignment and show that inactivating mutations have occurred in at least 8 of the 18 traditional placental orders, thereby challenging the physiological importance of UCP1 across Placentalia. Selection and timetree analyses further reveal that ucp1 inactivations temporally correspond with strong secondary reductions in metabolic intensity in xenarthrans and pangolins, or in six other lineages coincided with a similar to 30 million-year episode of global cooling in the Paleogene that promoted sharp increases in body mass and cladogenesis evident in the fossil record. Our findings also demonstrate that members of various lineages (for example, cetaceans, horses, woolly mammoths, Steller's sea cows) evolved extreme cold hardiness in the absence of UCP1-mediated thermogenesis. Finally, we identify ucp1 inactivation as a historical contingency that is linked to the current low species diversity of clades lacking functional UCP1, thus providing the first evidence for species selection related to the presence or absence of a single gene product.
AU  - Gaudry, M.J.*
AU  - Jastroch, M.
AU  - Treberg, J.R.*
AU  - Hofreiter, M.*
AU  - Paijmans, J.L.A.*
AU  - Starrett, J.*
AU  - Wales, N.*
AU  - Signore, A.V.*
AU  - Springer, M.S.*
AU  - Campbell, K.L.*
C1  - 52085
C2  - 43717
CY  - Washington
TI  - Inactivation of thermogenic UCP1 as a historical contingency in multiple placental mammal clades.
JO  - Sci. Adv.
VL  - 3
IS  - 7
PB  - Amer Assoc Advancement Science
PY  - 2017
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - Nature has evolved an astonishingly modular architecture of covalently linked protein domains with diverse functionalities to enable complex cellular networks that are critical for cell survival. The coupling of sensory modules with enzymatic effectors allows direct allosteric regulation of cellular signaling molecules in response to diverse stimuli. We present molecular details of red light-sensing bacteriophytochromes linked to cyclic dimeric guanosine monophosphate-producing diguanylyl cyclases. Elucidation of the first crystal structure of a full-length phytochrome with its enzymatic effector, in combination with the characterization of light-induced changes in conformational dynamics, reveals how allosteric light regulation is fine-tuned by the architecture and composition of the coiled-coil sensor-effector linker and also the central helical spine. We anticipate that consideration of molecular principles of sensor-effector coupling, going beyond the length of the characteristic linker, and the appreciation of dynamically driven allostery will open up new directions for the design of novel red light-regulated optogenetic tools.
AU  - Gourinchas, G.*
AU  - Etzl, S.*
AU  - Göbl, C.
AU  - Vide, U.*
AU  - Madl, T.
AU  - Winkler, A.S.*
C1  - 50687
C2  - 42832
TI  - Long-range allosteric signaling in red light-regulated diguanylyl cyclases.
JO  - Sci. Adv.
VL  - 3
IS  - 3
PY  - 2017
SN  - 2375-2548
ER  - 

TY  - JOUR
AB  - We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.
AU  - Andlauer, T.F.*
AU  - Buck, D.*
AU  - Antony, G.*
AU  - Bayas, A.*
AU  - Bechmann, L.*
AU  - Berthele, A.*
AU  - Chan, A.*
AU  - Gasperi, C.*
AU  - Gold, R.*
AU  - Graetz, C.*
AU  - Haas, J.*
AU  - Hecker, M.*
AU  - Infante-Duarte, C.*
AU  - Knop, M.*
AU  - Kümpfel, T.*
AU  - Limmroth, V.*
AU  - Linker, R.A.*
AU  - Loleit, V.*
AU  - Luessi, F.*
AU  - Meuth, S.G.*
AU  - Mühlau, M.*
AU  - Nischwitz, S.*
AU  - Paul, F.*
AU  - Pütz, M.*
AU  - Ruck, T.*
AU  - Salmen, A.*
AU  - Stangel, M.*
AU  - Stellmann, J.P.*
AU  - Stürner, K.H.*
AU  - Tackenberg, B.*
AU  - Then Bergh, F.*
AU  - Tumani, H.*
AU  - Warnke, C.*
AU  - Weber, F.*
AU  - Wiendl, H.*
AU  - Wildemann, B.*
AU  - Zettl, U.K.*
AU  - Ziemann, U.*
AU  - Zipp, F.*
AU  - Knauer-Arloth, J.
AU  - Weber, P.*
AU  - Radivojkov-Blagojevic, M.
AU  - Scheinhardt, M.O.*
AU  - Dankowski, T.*
AU  - Bettecken, T.*
AU  - Lichtner, P.
AU  - Czamara, D.*
AU  - Carrillo-Roa, T.*
AU  - Binder, E.B.*
AU  - Berger, K.*
AU  - Bertram, L.*
AU  - Franke, A.*
AU  - Gieger, C.
AU  - Herms, S.*
AU  - Homuth, G.*
AU  - Ising, M.*
AU  - Jöckel, K.-H.*
AU  - Kacprowski, T.*
AU  - Kloiber, S.*
AU  - Laudes, M.*
AU  - Lieb, W.*
AU  - Lill, C.M.*
AU  - Lucae, S.*
AU  - Meitinger, T.
AU  - Moebus, S.*
AU  - Müller-Nurasyid, M.
AU  - Nöthen, M.M.*
AU  - Petersmann, A.*
AU  - Rawal, R.
AU  - Schminke, U.*
AU  - Strauch, K.
AU  - Völzke, H.*
AU  - Waldenberger, M.
AU  - Wellmann, J.*
AU  - Porcu, E.*
AU  - Mulas, A.*
AU  - Pitzalis, M.*
AU  - Sidore, C.*
AU  - Zara, I.*
AU  - Cucca, F.*
AU  - Zoledziewska, M.*
AU  - Ziegler, A.*
AU  - Hemmer, B.*
AU  - Müller-Myhsok, B.*
C1  - 49034
C2  - 41564
TI  - Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.
JO  - Sci. Adv.
VL  - 2
IS  - 6
PY  - 2016
SN  - 2375-2548
ER  -