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The nuclear factor kappa beta (NFκB) signaling pathway plays an important role in liver homeostasis and cancer development. Tax1-binding protein 1 (Tax1BP1) is a regulator of the NFκB signaling pathway, but its role in the liver and hepatocellular carcinoma (HCC) is presently unknown. Here we investigated the role of Tax1BP1 in liver cells and murine models of HCC and liver fibrosis. We applied the diethylnitrosamine (DEN) model of experimental hepatocarcinogenesis in Tax1BP1+/+ and Tax1BP1−/− mice. The amount and subsets of non-parenchymal liver cells in in Tax1BP1+/+ and Tax1BP1−/− mice were determined and activation of NFκB and stress induced signaling pathways were assessed. Differential expression of mRNA and miRNA was determined. Tax1BP1−/− mice showed increased numbers of inflammatory cells in the liver. Furthermore, a sustained activation of the NFκB signaling pathway was found in hepatocytes as well as increased transcription of proinflammatory cytokines in isolated Kupffer cells from Tax1BP1−/− mice. Several differentially expressed mRNAs and miRNAs in livers of Tax1BP1−/− mice were found, which are regulators of inflammation or are involved in cancer development or progression. Furthermore, Tax1BP1−/− mice developed more HCCs than their Tax1BP1+/+ littermates. We conclude that Tax1BP1 protects from liver cancer development by limiting proinflammatory signaling.
This paper contributes to the clarification of the concept of “typicality” discussed in contemporary philosophy of physics by conceiving the nomological status of a typical behaviour such as that expressed in the Second Law of Thermodynamics as a “minutis rectis law”. A brief sketch of the discovery of “typicality” shows that there were ideas of typical behaviour not only in physics but also in sociology. On this basis and in analogy to the Second Law of Thermodynamics, it is shown that the nomological status of sociological laws such as Gresham’s Law can also be conceived as “minutis rectis laws”.
The current pandemic situation caused by the Betacoronavirus SARS-CoV-2 (SCoV2) highlights the need for coordinated research to combat COVID-19. A particularly important aspect is the development of medication. In addition to viral proteins, structured RNA elements represent a potent alternative as drug targets. The search for drugs that target RNA requires their high-resolution structural characterization. Using nuclear magnetic resonance (NMR) spectroscopy, a worldwide consortium of NMR researchers aims to characterize potential RNA drug targets of SCoV2. Here, we report the characterization of 15 conserved RNA elements located at the 5′ end, the ribosomal frameshift segment and the 3′-untranslated region (3′-UTR) of the SCoV2 genome, their large-scale production and NMR-based secondary structure determination. The NMR data are corroborated with secondary structure probing by DMS footprinting experiments. The close agreement of NMR secondary structure determination of isolated RNA elements with DMS footprinting and NMR performed on larger RNA regions shows that the secondary structure elements fold independently. The NMR data reported here provide the basis for NMR investigations of RNA function, RNA interactions with viral and host proteins and screening campaigns to identify potential RNA binders for pharmaceutical intervention.
Motivated by the question of whether and how wave–wave interactions should be implemented into atmospheric gravity-wave parametrizations, the modulation of triadic gravity-wave interactions by a slowly varying and vertically sheared mean flow is considered for a non-rotating Boussinesq fluid with constant stratification. An analysis using a multiple-scale WKBJ (Wentzel–Kramers–Brillouin–Jeffreys) expansion identifies two distinct scaling regimes, a linear off-resonance regime, and a nonlinear near-resonance regime. Simplifying the near-resonance interaction equations allows for the construction of a parametrization for the triadic energy exchange which has been implemented into a one-dimensional WKBJ ray-tracing code. Theory and numerical implementation are validated for test cases where two wave trains generate a third wave train while spectrally passing through resonance. In various settings, of interacting vertical wavenumbers, mean-flow shear, and initial wave amplitudes, the WKBJ simulations are generally in good agreement with wave-resolving simulations. Both stronger mean-flow shear and smaller wave amplitudes suppress the energy exchange among a resonantly interacting triad. Experiments with mean-flow shear as strong as in the vicinity of atmospheric jets suggest that internal gravity-wave dynamics are dominated in such regions by wave modulation. However, triadic gravity-wave interactions are likely to be relevant in weakly sheared regions of the atmosphere.
This article is directed towards addressing the employment related issues encountered by female workers in the gig economy in the EU. It revolves around analysing ‘the switch’ from the traditional labour market to the platform economy. It subsequently explains, by drawing comparisons, that the issues of gender inequality in the brick and mortar world are still prevalent in world of the digital platform. In fact, new challenges have emerged which are specifically related to the gig economy. Female workers are now affected by the inherent bias of algorithms. Moreover, due to the unequivocal propagation of ‘flexibility’ which is used as a weapon to glorify the gig economy; women are even more likely to be pushed into precarious work. The other prominent issues of gender inequality like the dynamics of intersectionality, the gender pay gap and hiring policies in traditional and digital platforms are also examined. Furthermore, the existing regulatory frameworks addressing these issues are discussed with the possibility of catering to the gender inequality issues in the gig economy through policy development. The article concludes with a reflection on the need for the EU to take immediate and efficacious policy measures in respect of female workers in the gig economy.
Sphingosine 1-phosphate (S1P) signaling influences numerous cell biological mechanisms such as differentiation, proliferation, survival, migration, and angiogenesis. Intriguingly, our current knowledge is based solely on the role of S1P with an 18-carbon long-chain base length, S1P d18:1. Depending on the composition of the first and rate-limiting enzyme of the sphingolipid de novo metabolism, the serine palmitoyltransferase, other chain lengths have been described in vivo. While cells are also able to produce S1P d20:1, its abundance and function remains elusive so far. Our experiments are highlighting the role of S1P d20:1 in the mouse central nervous system (CNS) and human glioblastoma. We show here that S1P d20:1 and its precursors are detectable in both healthy mouse CNS-tissue and human glioblastoma. On the functional level, we focused our work on one particular, well-characterized pathway, the induction of cyclooxygenase (COX)-2 expression via the S1P receptor 2 (S1P2). Intriguingly, S1P d20:1 only fairly induces COX-2 expression and can block the S1P d18:1-induced COX-2 expression mediated via S1P2 activation in the human glioblastoma cell line LN229. This data indicates that S1P d20:1 might act as an endogenous modulator of S1P signaling via a partial agonism at the S1P2 receptor. While our findings might stimulate further research on the relevance of long-chain base lengths in sphingolipid signaling, the metabolism of S1P d20:1 has to be considered as an integral part of S1P signaling pathways in vivo.
We derive the relation between cumulants of a conserved charge measured in a subvolume of a thermal system and the corresponding grand-canonical susceptibilities, taking into account exact global conservation of that charge. The derivation is presented for an arbitrary equation of state, with the assumption that the subvolume is sufficiently large to be close to the thermodynamic limit. Our framework – the subensemble acceptance method (SAM) – quantifies the effect of global conservation laws and is an important step toward a direct comparison between cumulants of conserved charges measured in central heavy ion collisions and theoretical calculations of grand-canonical susceptibilities, such as lattice QCD. As an example, we apply our formalism to net-baryon fluctuations at vanishing baryon chemical potentials as encountered in collisions at the LHC and RHIC.
We analyze the behavior of cumulants of conserved charges in a subvolume of a thermal system with exact global conservation laws by extending a recently developed subensemble acceptance method (SAM) [1] to multiple conserved charges. Explicit expressions for all diagonal and off-diagonal cumulants up to sixth order that relate them to the grand canonical susceptibilities are obtained. The derivation is presented for an arbitrary equation of state with an arbitrary number of different conserved charges. The global conservation effects cancel out in any ratio of two second order cumulants, in any ratio of two third order cumulants, as well as in a ratio of strongly intensive measures Σ and ∆ involving any two conserved charges, making all these quantities particularly suitable for theory-to-experiment comparisons in heavy-ion collisions. We also show that the same cancellation occurs in correlators of a conserved charge, like the electric charge, with any non-conserved quantity such as net proton or net kaon number. The main results of the SAM are illustrated in the framework of the hadron resonance gas model. We also elucidate how net-proton and net-Λ fluctuations are affected by conservation of electric charge and strangeness in addition to baryon number.
The production of light (anti-)(hyper-)nuclei in heavy-ion collisions at the LHC is considered in the framework of the Saha equation, making use of the analogy between the evolution of the early universe after the Big Bang and that of “Little Bangs” created in the lab. Assuming that disintegration and regeneration reactions involving light nuclei proceed in relative chemical equilibrium after the chemical freeze-out of hadrons, their abundances are determined through the famous cosmological Saha equation of primordial nucleosynthesis and show no exponential dependence on the temperature typical for the thermal model. A quantitative analysis, performed using the hadron resonance gas model in partial chemical equilibrium, shows agreement with experimental data of the ALICE collaboration on d, 3He, HΛ3, and 4He yields for a very broad range of temperatures at T≲155 MeV. The presented picture is supported by the observed suppression of resonance yields in central Pb–Pb collisions at the LHC. Keywords: Light (anti-)(hyper-)nuclei production, Saha equation, Partial chemical equilibrium.
We estimate the feeddown contributions from decays of unstable A=4 and A=5 nuclei to the final yields of protons, deuterons, tritons, 3He, and 4He produced in relativistic heavy-ion collisions at sNN>2.4 GeV, using the statistical model. The feeddown contribution effects do not exceed 5% at LHC and top RHIC energies due to the large penalty factors involved, but are substantial at intermediate collision energies. We observe large feeddown contributions for tritons, 3He, and 4He at sNN≲10 GeV, where they may account for as much as 70% of the final yield at the lower end of the collision energies considered. Sizable (>10%) effects for deuteron yields are observed at sNN≲4 GeV. The results suggest that the excited nuclei feeddown cannot be neglected in the ongoing and future analysis of light nuclei production at intermediate collision energies, including HADES and CBM experiments at FAIR, NICA at JINR, RHIC beam energy scan and fixed-target programmes, and NA61/SHINE at CERN. We further show that the freeze-out curve in the T-μB plane itself is affected significantly by the light nuclei at high baryochemical potential.
Background: Sepsis frequently occurs after major trauma and is closely associated with dysregulations in the inflammatory/complement and coagulation system. Thrombin-activatable fibrinolysis inhibitor (TAFI) plays a dual role as an anti-fibrinolytic and anti-inflammatory factor by downregulating complement anaphylatoxin C5a. The purpose of this study was to investigate the association between TAFI and C5a levels and the development of post-traumatic sepsis. Furthermore, the predictive potential of both TAFI and C5a to indicate sepsis occurrence in polytraumatized patients was assessed. Methods: Upon admission to the emergency department (ED) and daily for the subsequent ten days, circulating levels of TAFI and C5a were determined in 48 severely injured trauma patients (injury severity score (ISS) ≥ 16). Frequency matching according to the ISS in septic vs. non-septic patients was performed. Trauma and physiologic characteristics, as well as outcomes, were assessed. Statistical correlation analyses and cut-off values for predicting sepsis were calculated. Results: Fourteen patients developed sepsis, while 34 patients did not show any signs of sepsis (no sepsis). Overall injury severity, as well as demographic parameters, were comparable between both groups (ISS: 25.78 ± 2.36 no sepsis vs. 23.46 ± 2.79 sepsis). Septic patients had significantly increased C5a levels (21.62 ± 3.14 vs. 13.40 ± 1.29 ng/mL; p < 0.05) and reduced TAFI levels upon admission to the ED (40,951 ± 5637 vs. 61,865 ± 4370 ng/mL; p < 0.05) compared to the no sepsis group. Negative correlations between TAFI and C5a (p = 0.0104) and TAFI and lactate (p = 0.0423) and positive correlations between C5a and lactate (p = 0.0173), as well as C5a and the respiratory rate (p = 0.0266), were found. In addition, correlation analyses of both TAFI and C5a with the sequential (sepsis-related) organ failure assessment (SOFA) score have confirmed their potential as early sepsis biomarkers. Cut-off values for predicting sepsis were 54,857 ng/mL for TAFI with an area under the curve (AUC) of 0.7550 (p = 0.032) and 17 ng/mL for C5a with an AUC of 0.7286 (p = 0.034). Conclusion: The development of sepsis is associated with early decreased TAFI and increased C5a levels after major trauma. Both elevated C5a and decreased TAFI may serve as promising predictive factors for the development of sepsis after polytrauma.
Central Europe was affected by a compressional tectonic event in the Late Cretaceous, caused by the convergence of Iberia and Europe. Basement uplifts, inverted graben structures and newly formed marginal troughs are the main expressions of crustal shortening. Although the maximum activity occurred in a short period between 90 and 75 Ma, the exact timing of this event is still unclear. Dating of start and end of basin inversion is very different depending on the applied method. On the basis of borehole data, facies and thickness maps, the timing of basin re-organisation was reconstructed for several basins in Central Europe. The obtained data point to a synchronous start of basin inversion already at 95 Ma (Cenomanian), 5 Million years earlier than commonly assumed. The end of the Late Cretaceous compressional event is more difficult to pinpoint, because regional uplift and salt migration disturb the signal of shifting marginal troughs. Unconformities of Late Campanian to Paleogene age on inverted structures indicate slowly declining uplift rates.
Background: The vascular effects of training under blood flow restriction (BFR) in healthy persons can serve as a model for the exercise mechanism in lower extremity arterial disease (LEAD) patients. Both mechanisms are, inter alia, characterized by lower blood flow in the lower limbs. We aimed to describe and compare the underlying mechanism of exercise-induced effects of disease- and external application-BFR methods. Methods: We completed a narrative focus review after systematic literature research. We included only studies on healthy participants or those with LEAD. Both male and female adults were considered eligible. The target intervention was exercise with a reduced blood flow due to disease or external application. Results: We identified 416 publications. After the application of inclusion and exclusion criteria, 39 manuscripts were included in the vascular adaption part. Major mechanisms involving exercise-mediated benefits in treating LEAD included: inflammatory processes suppression, proinflammatory immune cells, improvement of endothelial function, remodeling of skeletal muscle, and additional vascularization (arteriogenesis). Mechanisms resulting from external BFR application included: increased release of anabolic growth factors, stimulated muscle protein synthesis, higher concentrations of heat shock proteins and nitric oxide synthase, lower levels in myostatin, and stimulation of S6K1. Conclusions: A main difference between the two comparators is the venous blood return, which is restricted in BFR but not in LEAD. Major similarities include the overall ischemic situation, the changes in microRNA (miRNA) expression, and the increased production of NOS with their associated arteriogenesis after training with BFR.
Although cyclophosphamide (CP) has been used successfully in the clinic for over 50 years, it has so far not been possible to elucidate the mechanism of action and to use it for improvement. This was not possible because the basis of the mechanism of action of CP, which was found by lucky coincidence, is apoptosis, the discovery of which was honored with the Nobel Prize only in 2002. Another reason was that results from cell culture experiments were used to elucidate the mechanism of action, ignoring the fact that in vivo metabolism differs from in vitro conditions. In vitro, toxic acrolein is formed during the formation of the cytotoxic metabolite phosphoreamidemustard (PAM), whereas in vivo proapoptotic hydroxypropanal (HPA) is formed. The CP metabolites formed in sequence 4-hydroxycyclophosphamide (OHCP) are the main cause of toxicity, aldophosphamide (ALDO) is the pharmacologically active metabolite and HPA amplifies the cytotoxic apoptosis initiated by DNA alkylation by PAM. It is shown that toxicity is drastically reduced but anti-tumor activity strongly increased by the formation of ALDO bypassing OHCP. Furthermore, it is shown that the anti-tumor activity against advanced solid P388 tumors that grow on CD2F1 mice is increased by orders of magnitude if DNA damage caused by a modified PAM is poorly repairable. View Full-Text
The events of 1968/69 initiated a dispute between Adorno and Marcuse over the (alleged) separation of theory and praxis. While Marcuse “stood at the barricades” Adorno sought recluse in the “ivory tower”. Marcuse and German students perceived Adorno’s move as departure from fundamental postulates of critical theory as laid down in Horkheimer’s 1937 essay. Adorno died amidst the process of clarifying his differences with Marcuse and thus the “unlimited discussions” between the two remain unfinished. This paper sets to examine how both Marcuse and Adorno remained dedicated to the unity of theory and praxis, albeit in different ways. I argue that Adorno did not separate theory and praxis; instead, he perceived the gap between critical theory and concrete historical situation. Adorno rejected simple and unreflective translation of theory into praxis. Hence his attempt to recalibrate critical theory. Marcuse’s and Adorno’s differences lie in their different evaluation of the student movement and this (mis)evaluation was context related. My second argument is that Marcuse/Adorno disagreement is partly caused by the absence of the two from the concrete historical context.
Some anaerobic bacteria use biotin-dependent Na+-translocating decarboxylases (Bdc) of β-keto acids or their thioester analogs as key enzymes in their energy metabolism. Glutaconyl-CoA decarboxylase (Gcd), a member of this protein family, drives the endergonic translocation of Na+ across the membrane with the exergonic decarboxylation of glutaconyl-CoA (ΔG0’ ≈−30 kJ/mol) to crotonyl-CoA. Here, we report on the molecular characterization of Gcd from Clostridium symbiosum based on native PAGE, size exclusion chromatography (SEC) and laser-induced liquid bead ion desorption mass spectrometry (LILBID-MS). The obtained molecular mass of ca. 400 kDa fits to the DNA sequence-derived mass of 379 kDa with a subunit composition of 4 GcdA (65 kDa), 2 GcdB (35 kDa), GcdC1 (15 kDa), GcdC2 (14 kDa), and 2 GcdD (10 kDa). Low-resolution structural information was achieved from preliminary electron microscopic (EM) measurements, which resulted in a 3D reconstruction model based on negative-stained particles. The Gcd structure is built up of a membrane-spanning base primarily composed of the GcdB dimer and a solvent-exposed head with the GcdA tetramer as major component. Both globular parts are bridged by a linker presumably built up of segments of GcdC1, GcdC2 and the 2 GcdDs. The structure of the highly mobile Gcd complex represents a template for the global architecture of the Bdc family.
Children with reading and/or spelling disorders have increased rates of behavioral and emotional problems and combinations of these. Some studies also find increased rates of attention-deficit/hyperactivity disorder (ADHD), conduct disorder, anxiety disorder, and depression. However, the comorbidities of, e.g., arithmetic disorders with ADHD, anxiety disorder, and depression have been addressed only rarely. The current study explored the probability of children with specific learning disorders (SLD) in reading, spelling, and/or arithmetic to also have anxiety disorder, depression, ADHD, and/or conduct disorder. The sample consisted of 3,014 German children from grades 3 and 4 (mean age 9;9 years) who completed tests assessing reading, spelling as well as arithmetic achievement and intelligence via a web-based application. Psychopathology was assessed using questionnaires filled in by the parents. In children with a SLD we found high rates of anxiety disorder (21%), depression (28%), ADHD (28%), and conduct disorder (22%). Children with SLD in multiple learning domains had a higher risk for psychopathology and had a broader spectrum of psychopathology than children with an isolated SLD. The results highlight the importance of screening for and diagnosing psychiatric comorbidities in children with SLD.
Purpose of Review: To review the latest developments and the current role of the cardiac magnetic resonance (CMR) in pericardial diseases and their complications.
Recent Findings: Cardiac Magnetic Resonance (CMR) has the ability to incorporate anatomy, physiology, and “virtual histology” strategies to achieve the most accurate diagnosis for even the most demanding, pericardial diseases.
Summary: Acute, chronic, recurrent, and constrictive pericarditis as well as pericarditis related complications, pericardial masses and congenital pericardial defects are commonly encountered in clinical practice with relatively significant morbidity and mortality. Owing to the challenging diagnosis, CMR imaging is often employed in confirming the diagnosis and elucidating the underling pathophysiology. In this review we outline the common CMR techniques and their expected diagnostic outcomes.
Introduction: The induced membrane technique for the treatment of large bone defects is a two-step procedure. In the first operation, a foreign body membrane is induced around a spacer, then, in the second step, several weeks or months later, the spacer is removed and the Membrane pocket is filled with autologous bone material. Induction of a functional biological membrane might be avoided by initially using a biological membrane. In this study, the effect of a human acellular dermis (hADM, Epiflex, DIZG gGmbH) was evaluated for the treatment of a large (5 mm), plate-stabilised femoral bone defect.
Material and Methods: In an established rat model, hADM was compared to the two-stage induced membrane technique and a bone defect without membrane cover. Syngeneous spongiosa from donor animals was used for defect filling in all groups. The group size in each case was n = 5, the induction time of the membrane was 3–4 weeks and the healing time after filling of the defect was 8 weeks.
Results: The ultimate loads were increased to levels comparable with native bone in both membrane groups (hADM: 63.2% ± 29.6% of the reference bone, p < 0.05 vs. no membrane, induced membrane: 52.1% ± 25.8% of the reference bone, p < 0.05 vs. no membrane) and were significantly higher than the control group without membrane (21.5%). The membrane groups were radiologically and histologically almost completely bridged by new bone formation, in contrast to the control Group where no closed osseous bridging could be observed.
Conclusion: The use of the human acellular dermis leads to equivalent healing results in comparison to the two-stage induced membrane technique. This could lead to a shortened therapy duration of large bone defects.
Integrity of dural closure after autologous platelet rich fibrin augmentation: an in vitro study
(2020)
Background: Watertight closure of the dura mater is fundamental in neurosurgery. Besides the classical suturing techniques, a variety of biomaterials have been proposed as sealants. Platelet rich fibrin (PRF) is an autologous biomaterial which can readily be obtained through low-speed centrifugation of patient’s own blood. It is rich in fibrin, growth factors, leucocytes and cytokines and has shown adhesive properties while promoting the physiological wound healing process. In this study, we investigated the effect of applying PRF in reinforcing the watertight dura mater closure. Methods: We created an in vitro testing device, where the watertight dura mater closure could be hydrostatically assessed. On 26 fresh harvested bovine dura maters, a standardised 20-mm incision was closed with a running suture, and the leak pressure was measured first without (primary leak pressure) and then with PRF augmentation (secondary leak pressure). The two groups of measurements have been statistically analysed with the Student’s paired t test. Results: The “running suture only group” had a leak pressure of 10.5 ± 1.2 cmH2O (mean ± SD) while the “PRF-augmented group” had a leak pressure of 47.2 ± 2.6 cm H2O. This difference was statistically significant (p < 0.001; paired t test). Conclusions: Autologous platelet rich fibrin augmentation reliably reinforced watertight closure of the dura mater to a > 4-fold increased leak pressure after failure of the initial standard running suture technique.