Adenine Nucleotide Translocase 1 Expression is Coupled to the HSP27-Mediated TLR4 Signaling in Cardiomyocytes

The cardiac-specific overexpression of the adenine nucleotide translocase 1 (ANT1) has cardioprotective effects in various experimental heart disease models. Here, we analyzed the link between ANT1 expression and heat shock protein 27 (HSP27)-mediated toll-like receptor 4 (TLR4) signaling, which represents a novel communication pathway between mitochondria and the extracellular environment. The interaction between ANT1 and HSP27 was identified by co-immunoprecipitation from neonatal rat cardiomyocytes. ANT1 transgenic (ANT1-TG) cardiomyocytes demonstrated elevated HSP27 expression levels. Increased levels of HSP27 were released from the ANT1-TG cardiomyocytes under both normoxic and hypoxic conditions. Extracellular HSP27 stimulated TLR4 signaling via protein kinase B (AKT). The HSP27-mediated activation of the TLR4 pathway was more pronounced in ANT1-TG cardiomyocytes than in wild-type (WT) cardiomyocytes. HSP27-specific antibodies inhibited TLR4 activation and the expression of HSP27. Inhibition of the HSP27-mediated TLR4 signaling pathway with the TLR4 inhibitor oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) reduced the mitochondrial membrane potential (∆ψm) and increased caspase 3/7 activity, which are both markers for cell stress. Conversely, treating cardiomyocytes with recombinant HSP27 protein stimulated TLR4 signaling, induced HSP27 and ANT1 expression, and stabilized the mitochondrial membrane potential. The activation of HSP27 signaling was verified in ischemic ANT1-TG heart tissue, where it correlated with ANT1 expression and the tightness of the inner mitochondrial membrane. Our study shows a new mechanism by which ANT1 is part of the cardioprotective HSP27-mediated TLR4 signaling

Spatiotemporal dynamics of nektonic biodiversity and vegetation shifts during the Smithian–Spathian transition: conodont and palynomorph insights from Svalbard

The Smithian–Spathian transition (~249.2 Ma) is marked by profound environmental changes, carbon cycle perturbations, and the stepwise loss of nektonic biodiversity (ammonoids and conodonts). While biotic and abiotic changes have been intensely studied for the palaeosubtropics and palaeotropics, the global spatio-temporal pattern, including mid- to higher latitudes, remains unresolved. In this study, we present conodont and palynomorph data from the Lower Triassic Vikinghøgda Formation in the Stensiöfjellet section, Svalbard. Conodont samples from this sequence generally yielded relatively few specimens with one exception in the basal Vendomdalen Member, which proved exceptionally abundant and diverse. Most conodont samples of the Lusitaniadalen Member are typically dominated by middle to late Smithian segminiplanate forms, such as Scythogondolella spp. This exceptional horizon in the basal Vendomdalen Member, associated with the cosmopolitan ammonoid Bajarunia, indicates an earliest Spathian age. This sample presents the first-ever recorded conodont fauna from the earliest Spathian in the Boreal realm and associates segminiplanate with numerous segminate forms. The presence of an abundant and diverse segminate conodont fauna in northern mid-latitudes during the Early Triassic suggests that temperature was not the main regulator for their distribution, as opposed to segminiplanate forms, which were apparently more restricted to colder waters. Palynomorphs are poorly preserved but allow the discrimination of three assemblages. Association 1 is lycophyte spore dominated, and associations 2 and 3 are both dominated by bisaccate pollen. The change from lycophyte-dominated to a gymnosperm-dominated vegetation occurs just above the Wasatchites beds. A comparison with the records from the southern palaeosubtropics indicates that the vegetation shift was synchronous and coincided with the onset of a cooling episode, commencing in the latest Smithian. □ Intra-Triassic extinction, palaeoclimate, palaeoenvironment, conodonts, palynomorphs, Svalbard. Marc Leu ✉ [[email protected]], Elke Schneebeli-Hermann [[email protected]] and Hugo Bucher [[email protected]] Department of Palaeontology, University of Zurich, Karl Schmid-Strasse 4, 8006 Zurich, Switzerland; Øyvind Hammer [oyvind. [email protected]] and Franz-Josef Lindemann [[email protected]], Natural History Museum, University of Oslo, Pb. 1172 Blindern, 0318 Oslo, Norway; manuscript received on 04/08/2023; manuscript accepted on 28/02/2024; manuscript published on 20/06/2024 in Lethaia 57(2)

Quantifying Economic Dependency

In this paper we compare several types of economic dependency ratios for a selection of European countries. These dependency ratios take into account not only the demographic structure of the population, but also the differences in age-specific economic behaviour such as labour market activity, income and consumption as well as age-specific public transfers. In selected simulations where we combine patterns of age-specific economic behaviour and transfers with population projections, we show that in all countries population ageing would lead to a pronounced increase in dependency ratios if present age-specific patterns were not to change. Our analysis of cross-country differences in economic dependency demonstrates that these differences are driven by both differences in age-specific economic behaviour and in the age composition of the populations. The choice of which dependency ratio to use in a specific policy context is determined by the nature of the question to be answered. The comparison of our various dependency ratios across countries gives insights into which strategies might be effective in mitigating the expected increase in economic dependency due to demographic change

Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver

Activation of the constitutive androstane receptor (CAR) may induce adaptive but also adverse effects in rodent liver, including the induction of drug-metabolizing enzymes, transient hepatocellular proliferation, and promotion of liver tumor growth. Human relevance of CAR-related adverse hepatic effects is controversially debated. Here, we used the chimeric FRG-KO mouse model with livers largely repopulated by human hepatocytes, in order to study human hepatocytes and their response to treatment with the model CAR activator phenobarbital (PB) in vivo. Mice received an intraperitoneal injection with 50 mg/kg body weight PB or saline, and were sacrificed after 72–144 h. Non-repopulated FRG-KO mice were used as additional control. Comprehensive proteomics datasets were generated by merging data obtained by targeted as well as non-targeted proteomics approaches. For the first time, a novel proteomics workflow was established to comparatively analyze the effects of PB on human and murine proteins within one sample. Analysis of merged proteome data sets and bioinformatics data mining revealed comparable responses in murine and human hepatocytes with respect to nuclear receptor activation and induction of xenobiotic metabolism. By contrast, activation of MYC, a key regulator of proliferation, was predicted only for mouse but not human hepatocytes. Analyses of 5-bromo-2′-deoxyuridine incorporation confirmed this finding. In summary, this study for the first time presents a comprehensive proteomic analysis of CAR-dependent effects in human and mouse hepatocytes from humanized FRG-KO mice. The data support the hypothesis that PB does induce adaptive metabolic responses, but not hepatocellular proliferation in human hepatocytes in vivo.publishedVersio

Proteomic analysis in valvular cardiomyopathy: aortic regurgitation vs. aortic stenosis

Left ventricular (LV) reverse remodeling after aortic valve (AV) surgery is less predictable in chronic aortic regurgitation (AR) than in aortic stenosis (AS). We aimed to disclose specific LV myocardial protein signatures possibly contributing to differential disease progression. Global protein profiling of LV myocardial samples excised from the subaortic interventricular septum in patients with isolated AR or AS undergoing AV surgery was performed using liquid chromatography–electrospray ionization–tandem mass spectrometry. Based on label-free quantitation protein intensities, a logistic regression model was calculated and adjusted for age, sex and protein concentration. Web-based functional enrichment analyses of phenotype-associated proteins were performed utilizing g:Profiler and STRING. Data are available via ProteomeXchange with identifier PXD039662. Lysates from 38 patients, including 25 AR and 13 AS samples, were analyzed. AR patients presented with significantly larger LV diameters and volumes (end-diastolic diameter: 61 (12) vs. 48 (13) mm, p < 0.001; end-diastolic volume: 180.0 (74.6) vs. 92.3 (78.4), p = 0.001). A total of 171 proteins were associated with patient phenotype: 117 were positively associated with AR and the enrichment of intracellular compartment proteins (i.e., assigned to carbohydrate and nucleotide metabolism, protein biosynthesis and the proteasome) was detected. Additionally, 54 were positively associated with AS and the enrichment of extracellular compartment proteins (i.e., assigned to the immune and hematopoietic system) was observed. In summary, functional enrichment analysis revealed specific AR- and AS-associated signatures of LV myocardial proteins

Effect of Experimental Thyrotoxicosis onto Blood Coagulation: A Proteomics Study

Background: Hyperthyroidism is known to induce a hypercoagulable state. It stimulates plasma levels of procoagulative factors and reduces fibrinolytic activity. So far most of the data have been derived from patients with endogenous hyperthyroidism with a wide variability in the underlying pathogenesis and severity of the disease. Objectives: In this study we experimentally induced thyrotoxicosis in healthy volunteers to explore the effects of thyroxine excess on the plasma proteome. Using a shotgun proteomics approach, the abundance of plasma proteins was monitored before, during and after thyrotoxicosis. Methods: Sixteen healthy male subjects were sampled at baseline, 4 and 8 weeks under 250 µg/day thyroxine p.o., as well as 4 and 8 weeks after stopping the application. Plasma proteins were analyzed after depletion of 6 high-abundance proteins (MARS6) by LC-ESI-MS/MS mass spectrometry. Mass spectrometric raw data were processed using a label-free, intensity-based workflow. Subsequently, the linear dependence between protein abundances and fT4 levels were calculated using a Pearson correlation. Results: All subjects developed biochemical thyrotoxicosis, and this effect was reversed within the first 4 weeks of follow-up. None of the volunteers noticed any subjective symptoms. Levels of 10 proteins involved in the coagulation cascade specifically correlated with fT4, supporting an influence of thyroid hormone levels on blood coagulation even at nonpathological levels. Conclusions: The results suggest that experimental thyrotoxicosis exerts selective and specific thyroxine-induced effects on coagulation markers. Our study design allows assessment of thyroid hormone effects on plasma protein levels without secondary effects of other diseases or therapies

Biotransformation of biphenyl by the filamentous fungus <i>Talaromyces helicus</i>

The filamentous fungus Talaromyces helicus, isolated from oil-contaminated sludge, oxidizes biphenyl via 4-hydroxybiphenyl to the dihydroxylated derivatives 4,4′-dihydroxybiphenyl and 3,4-dihydroxybiphenyl, which, to a certain extent, are converted to glycosyl conjugates. The sugar moiety of the conjugate formed from 4,4′-dihydroxybiphenyl was identified as glucose. Further metabolites: 2-hydroxybiphenyl, 2,5-dihydroxylated biphenyl, and the ring cleavage product 4-phenyl-2-pyrone-6-carboxylic acid accumulated only in traces. From these results the main pathway for biotransformation of biphenyl in T. helicus could be proposed to be the excretion of dihydroxylated derivatives (>75%) and their glucosyl conjugates (<25%).Instituto de Botánica "Dr. Carlos Spegazzini

Palaeoenvironmental variability and carbon cycle perturbations during the Smithian-Spathian (Early Triassic) in Central Spitsbergen

The Early Triassic Smithian and Spathian time intervals are characterized by perturbations in the global carbon cycle, fluctuations in sea surface temperature, high turnover rates of marine nekton, and a change in terrestrial vegetation. Despite the importance of this time interval, comprehensive multiproxy investigations from Early Triassic high and middle latitude regions remain scarce due to the difficulty in accessing sections. The objective of this study is to increase our understanding of regional and local palaeoenvironmental and carbon cycle perturbations from a middle Smithian to late Spathian middle latitude section from Central Spitsbergen. Geochemical analyses show an increase in phosphorus and nitrogen just at and above the Smithian–Spathian boundary (SSB). High primary productivity led to increasingly anoxic conditions in bottom waters during the middle and late Spathian, enhancing the preservation of organic matter in the sediments. Anoxic conditions restrain phosphorus remineralization, allowing it to be recycled within the water column. This increase in anoxia is consistent with observations in other Arctic basins, demonstrating larger regional similarities in palaeoenvironmental conditions. The fluctuations in isostatic and eustatic sea levels affected organic carbon sequestration by regulating organic matter mineral interactions via the control of grain size within the sediment. This study demonstrates that local organic carbon sequestration in the Barents Sea shelf during the Spathian was influenced by a multitude of factors, including sedimentology, redox conditions, nutrient availability, and primary productivity. □ Vikinghøgda Formation, bulk rock geochemistry, particulate organic matter, extinction recovery, carbon isotopes, Stensiöfjellet Franziska R. Blattmann ✉ [[email protected]], Zoneibe A.S. Luz [[email protected]] and Torsten W. Vennemann [[email protected]], Institute of Earth Surface Dynamics, University of Lausanne, Quartier UNIL-Mouline, 1015 Lausanne, Switzerland; Elke Schneebeli-Hermann [[email protected]] and Hugo F.R. Bucher [[email protected]], Department of Palaeontology, University of Zürich, Karl-Schmid-Strasse 4, 8006 Zürich, Switzerland; Thierry Adatte [[email protected]], Institute of Earth Sciences, University of Lausanne, Quartier UNIL-Mouline, CH-1015 Lausanne, Switzerland; Christian Vérard [[email protected]], Section of Earth and Environmental Sciences, University of Geneva, Rue des Maraîchers 13, CH-1205 Geneva, Switzerland; Øyvind Hammer [[email protected]], Natural History Museum, University of Oslo, Pb. 1172 Blindern, 0318 Oslo, Norway; manuscript received on 08/08/2023; manuscript accepted on 02/02/2024; manuscript published on 20/06/2024 in Lethaia 57(2)

Plasma proteome and metabolome characterization of an experimental human thyrotoxicosis model.

BACKGROUND: Determinations of thyrotropin (TSH) and free thyroxine (FT4) represent the gold standard in evaluation of thyroid function. To screen for novel peripheral biomarkers of thyroid function and to characterize FT4-associated physiological signatures in human plasma we used an untargeted OMICS approach in a thyrotoxicosis model. METHODS: A sample of 16 healthy young men were treated with levothyroxine for 8 weeks and plasma was sampled before the intake was started as well as at two points during treatment and after its completion, respectively. Mass spectrometry-derived metabolite and protein levels were related to FT4 serum concentrations using mixed-effect linear regression models in a robust setting. To compile a molecular signature discriminating between thyrotoxicosis and euthyroidism, a random forest was trained and validated in a two-stage cross-validation procedure. RESULTS: Despite the absence of obvious clinical symptoms, mass spectrometry analyses detected 65 metabolites and 63 proteins exhibiting significant associations with serum FT4. A subset of 15 molecules allowed a robust and good prediction of thyroid hormone function (AUC = 0.86) without prior information on TSH or FT4. Main FT4-associated signatures indicated increased resting energy expenditure, augmented defense against systemic oxidative stress, decreased lipoprotein particle levels, and increased levels of complement system proteins and coagulation factors. Further association findings question the reliability of kidney function assessment under hyperthyroid conditions and suggest a link between hyperthyroidism and cardiovascular diseases via increased dimethylarginine levels. CONCLUSION: Our results emphasize the power of untargeted OMICs approaches to detect novel pathways of thyroid hormone action. Furthermore, beyond TSH and FT4, we demonstrated the potential of such analyses to identify new molecular signatures for diagnosis and treatment of thyroid disorders. This study was registered at the German Clinical Trials Register (DRKS) [DRKS00011275] on the 16th of November 2016

A global Staphylococcus aureus proteome resource applied to the in vivo characterization of host-pathogen interactions.

Data-independent acquisition mass spectrometry promises higher performance in terms of quantification and reproducibility compared to data-dependent acquisition mass spectrometry methods. To enable high-accuracy quantification of Staphylococcus aureus proteins, we have developed a global ion library for data-independent acquisition approaches employing high-resolution time of flight or Orbitrap instruments for this human pathogen. We applied this ion library resource to investigate the time-resolved adaptation of S. aureus to the intracellular niche in human bronchial epithelial cells and in a murine pneumonia model. In epithelial cells, abundance changes for more than 400 S. aureus proteins were quantified, revealing, e.g., the precise temporal regulation of the SigB-dependent stress response and differential regulation of translation, fermentation, and amino acid biosynthesis. Using an in vivo murine pneumonia model, our data-independent acquisition quantification analysis revealed for the first time the in vivo proteome adaptation of S. aureus. From approximately 2.15 × 1