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The miRNA biogenesis is tightly regulated to avoid dysfunction and consequent disease development. Here, we describe modulation of miRNA processing as a novel noncanonical function of the 5-lipoxygenase (5-LO) enzyme in monocytic cells. In differentiated Mono Mac 6 (MM6) cells, we found an in situ interaction of 5-LO with Dicer, a key enzyme in miRNA biogenesis. RNA sequencing of small noncoding RNAs revealed a functional impact, knockout of 5-LO altered the expression profile of several miRNAs. Effects of 5-LO could be observed at two levels. qPCR analyses thus indicated that (a) 5-LO promotes the transcription of the evolutionarily conserved miR-99b/let-7e/miR-125a cluster and (b) the 5-LO-Dicer interaction downregulates the processing of pre-let-7e, resulting in an increase in miR-125a and miR-99b levels by 5-LO without concomitant changes in let-7e levels in differentiated MM6 cells. Our observations suggest that 5-LO regulates the miRNA profile by modulating the Dicer-mediated processing of distinct pre-miRNAs. 5-LO inhibits the formation of let-7e which is a well-known inducer of cell differentiation, but promotes the generation of miR-99b and miR-125a known to induce cell proliferation and the maintenance of leukemic stem cell functions.
The term fatigue is not only used to describe a sleepy state with a lack of drive, as observed in patients with chronic physical illnesses, but also a state with an inhibition of drive and central nervous system (CNS) hyperarousal, as frequently observed in patients with major depression. An electroencephalogram (EEG)-based algorithm has been developed to objectively assess CNS arousal and to disentangle these pathophysiologically heterogeneous forms of fatigue. The aim of this study was to test the hypothesis that fatigued patients with CNS hyperarousal score higher on depressive symptoms than those without this neurophysiological pattern. Methods: Subjects with fatigue (Multidimensional Fatigue Inventory sum-score > 40) in the context of cancer, neuroinflammatory, or autoimmune diseases were drawn from the 60+ cohort of the Leipzig Research Center for Civilization Diseases. CNS arousal was assessed by automatic EEG-vigilance stage classification using the Vigilance Algorithm Leipzig (VIGALL 2.1) based on 20 min EEG recordings at rest with eyes closed. Depression was assessed by the Inventory of Depressive Symptomatology (IDS-SR). Results: Sixty participants (33 female; median age: 67.5 years) were included in the analysis. As hypothesized, fatigued patients with CNS hyperarousal had higher IDS-SR scores than those without hyperarousal (F1,58 = 18.34; p < 0.0001, η2 = 0.240). Conclusion: hyperaroused fatigue in patients with chronic physical illness may be a sign of comorbid depression.
Development of treatment strategies of chronic inflammatory disorders relies on on-going progress in drug discovery approaches and related molecular biologics. This study presents a gene reporter-based approach of phenotypic screening for anti-inflammatory compounds in the context of rheumatoid arthritis (RA).
CEBPD gene, used as the target gene for the screening readout, encodes CCAAT/enhancer binding protein delta (C/EBPδ) transcription factor (TF). Structural and regulatory characteristics of CEBPD gene as well as function of C/EBPδ TF in the context of inflammation satisfied assay requirements. C/EBPδ TF acts as a key regula-tor of inflammatory gene transcription in macrophages (Mϕ) and is observed to con-tribute to disease development in both a rodent model of RA and RA patient biopsies.
Despite well-described pro-inflammatory effects of C/EBPδ TF, it functions as a cell context-specific signal integrator showing also an anti-inflammatory activity. Conse-quently, both activation and inhibition of CEBPD alike may display a desired anti-inflammatory effect. The aim of this study was to develop a high-throughput screening assay for
CEBPD-modulating compounds and confirm hit compounds’ anti-inflammatory effects via gene expression analysis.
Generation and characterization of a multi-gene-reporter cassette 1.0 encoding enzy-matic secreted alkaline phosphatase (SEAP) gene reporter was a priority during the assay development. Chemiluminescent SEAP assay demonstrating high assay sensitivi-ty, broad linear range, high reproducibility and repeatability was chosen to monitor activity of the defined CEBPD promoter (CEBPD::SEAP). PMA-differentiated and M1-polarized THP-1-derived Mϕ stably expressing multi-gene-reporter cassette 1.0 were used as the assay’s cellular system. mRNA expression of both reporter CEBPD::SEAP and endogenous CEBPD mirrored each other in response to a LPS and IFN-g-triggered inflammatory stimulus (M1 treatment), even though the defined CEBPD promoter re-gion, utilized in the assay, contained only the most proximal and known regulatory se-quences. SEAP chemiluminescence in the reporter cells´ supernatant reliably correlat-ed with the M1 treatment-induced CEBPD::SEAP gene expression. The final screening protocol was developed for semi-automatic screening in the 384-well format.
In total, 2054 compounds from LOPAC®1280 and ENZO®774 libraries were screened twice
using the enzymatic SEAP readout with subsequent analysis of 18 selected compounds: nine with the highest and nine with the lowest signals, further characterized by qPCR. Gene expression levels of endogenous CEBPD, CEBPD::SEAP reporter as well as, IL-6,
IL-1β, and CCL2 as inflammatory markers were quantified. qPCR assays failed to corre-late to SEAP readout in 15 compounds within three standard deviations (SDs) from sol-vent control: nine low signal and six high signal compounds. Demonstrating both assay sensitivity and specificity, a correlation between qPCR gene expression and SEAP readout was observed for three hit compounds with signals above three SDs: BET inhib-itors (BETi) GSK 1210151A and Ro 11-1464 as well as an HDAC inhibitor (HDACi) vori-nostat. The control compound trichostatin A (TSA) that reproducibly upregulated SEAP readout is also an HDAC inhibitor with a similar structure to vorinostat and was there-fore included in the anti-inflammatory phenotype analysis.
The observed suppression of IL-6, IL-1ß, and CCL2 gene expression by hit compounds suggested their anti-inflammatory effect in THP-1 reporter Mϕ. mRNA expression of
IL-6 and CCL2 was suppressed by HDACi and BETi at both 4 and 24 hours, while BETi reduced IL-1β mRNA expression 24 hour time point. BETi significantly upregulated gene expression of both reporter CEBPD::SEAP and endogenous CEBPD, 4 hours after M1 treatment. At the same time point, HDACi completely abolished the mRNA expres-sion of the endogenous CEBPD, while simultaneously upregulating mRNA expression of the reporter CEBPD::SEAP. The use of the most proximal 300 base pairs region of en-dogenous CEBPD promoter, making the upstream regulatory elements unavailable in the assay, may account for differential expression levels of SEAP and C/EBPδ TF. This observation corroborated the need to include a longer and more extensive CEBPD´s gene regulatory area. Thus, an improved multi-gene-reporter cassette 2.0 was gener-ated to be used on the basis of a bacterial artificial chromosome (BAC) covering CE-BPD´s genomic area of about 200,000 base pairs.
The generated screening assay is flexible, reliable, and sensitive displaying potential for drug discovery and drug repurposing. The pharmacological modulation of CEBPD gene expression, first reported for GSK 1210151A, Ro 11-1464, and vorinostat, contrib-utes to the understanding of inflammatory responses in Mϕ and may have RA thera-peutic applications.
In the context of data science, data projection and clustering are common procedures. The chosen analysis method is crucial to avoid faulty pattern recognition. It is therefore necessary to know the properties and especially the limitations of projection and clustering algorithms. This report describes a collection of datasets that are grouped together in the Fundamental Clustering and Projection Suite (FCPS). The FCPS contains 10 datasets with the names "Atom", "Chainlink", "EngyTime", "Golfball", "Hepta", "Lsun", "Target", "Tetra", "TwoDiamonds", and "WingNut". Common clustering methods occasionally identified non-existent clusters or assigned data points to the wrong clusters in the FCPS suite. Likewise, common data projection methods could only partially reproduce the data structure correctly on a two-dimensional plane. In conclusion, the FCPS dataset collection addresses general challenges for clustering and projection algorithms such as lack of linear separability, different or small inner class spacing, classes defined by data density rather than data spacing, no cluster structure at all, outliers, or classes that are in contact. This report describes a collection of datasets that are grouped together in the Fundamental Clustering and Projection Suite (FCPS). It is designed to address specific problems of structure discovery in high-dimensional spaces.
Analysing the composition of ambient ultrafine particles (UFP) is a challenging task due to the low mass and chemical complexity of small particles, yet it is a prerequisite for the identification ofparticle sources and the assessment of potential health risks. Here, we show the molecular characterization of UFP, based on cascade impactor (Nano-MOUDI) 10samples that were collected at an air quality monitoring station nearby one of Europe`s largest airports in Frankfurt, Germany. At this station, particle-size-distribution measurements show enhanced number concentration of particles smaller than 50nm during airport operating hours. We sampled the lower UFP fraction (0.010-0.018 μm; 0.018-0.032 μm; 0.032-0.056 μm) when the air masses arrived from the airport. We developed an optimized filter extraction procedure, used ultra-high performance liquid chromatography (UHPLC) for compound separation, and a heated electrospray ionization (HESI) source with an 15Orbitrap high-resolution mass spectrometer (HRMS) as a detector for organic compounds. A non-target screening detected ~200 organic compounds in the UFP fraction with sample-to-blank ratios larger than five. We identified the largest signals as homologous series of pentaerythritol esters (PEE) and trimethylolpropane esters (TMPE), which are base stocks of aircraft lubrication oils. We unambiguously attribute the majority of detected compounds to jet engine lubrication oils by matching retention times, high-resolution/accurate mass (HR/AM) measurements, and comparing MS/MS fragmentation patterns between both ambient samples and commercially available jet oils. For each UFP stage, we created molecular fingerprints to visualize the complex chemical composition ofthe organic fraction and their average carbon oxidation state. These graphs underline the presence of the homologous series of PEE and TMPE, and the appearance of jet oil additives (e.g. tricresyl phosphate (TCP)). Targeted screening on TCP confirmed the absence of the harmful tri-orthoisomer, while we identified a thermal transformation product of TMPE-based lubrication oil (trimethylolpropane phosphate (TMP-P)). Even though a quantitative determination of the identified compounds is limited, the presented method enables the qualitative detection of molecular markers for jet engine lubricants in UFP and thus strongly improves the source apportionment of UFP near airports.
Simple Summary: Therapeutic antibodies are an integral part of treatment regimens for metastasized colorectal cancer. In KRAS wildtype tumors both bevacizumab and cetuximab are active. While bevacizumab has previously been shown to induce tumor hypoxia, we here report that EGFR inhibition by cetuximab protects colon cancer cells from hypoxia-induced cell death. This effect appears to be responsible for the inferior efficacy of a treatment sequence of bevacizumab followed by cetuximab versus an inverse sequence that we observed in a colorectal cancer mouse model. It also offers a mechanistic explanation for effects observed in clinical trials such as underadditive or even detrimental effects when combining bevacizumab and cetuximab (CAIRO2 trial) and the superior efficacy of first line cetuximab (FIRE-3 trial) under chemotherapy backbones in colorectal cancer.
Abstract: Monoclonal antibodies like cetuximab, targeting the epidermal growth factor receptor (EGFR), and bevacizumab, targeting the vascular endothelial growth factor (VEGF), are an integral part of treatment regimens for metastasized colorectal cancer. However, inhibition of the EGFR has been shown to protect human glioma cells from cell death under hypoxic conditions. In colon carcinoma cells, the consequences of EGFR blockade in hypoxia (e.g., induced by bevacizumab) have not been evaluated yet. LIM1215 and SW948 colon carcinoma and LNT-229 glioblastoma cells were treated with cetuximab, PD153035, and erlotinib and analyzed for cell density and viability. The sequential administration of either cetuximab followed by bevacizumab (CET->BEV) or bevacizumab followed by cetuximab (BEV->CET) was investigated in a LIM1215 (KRAS wildtype) and SW948 (KRAS mutant) xenograft mouse model. In vitro, cetuximab protected from hypoxia. In the LIM1215 model, a survival benefit with cetuximab and bevacizumab monotherapy was observed, but only the sequence CET->BEV showed an additional benefit. This effect was confirmed in the SW948 model. Our observations support the hypothesis that bevacizumab modulates the tumor microenvironment (e.g., by inducing hypoxia) where cetuximab could trigger protective effects when administered later on. The sequence CET->BEV therefore seems to be superior as possible mutual adverse effects are bypassed.
Background & Aims: Phosphodiesterase‐5 inhibitors (PDE‐5‐I) are used for treatment of erectile dysfunction (ED), which is common in patients with cirrhosis. They may improve portal hypertension (PH), but contradictory data on efficacy and side‐effects have been reported. Non‐selective beta blockers (NSBB) reduce portal pressure, but might aggravate ED. Thus, we evaluated the combination of PDE‐5‐I with NSBB and its impact on PH and ED in experimental cirrhosis.
Methods: ED was assessed in cirrhotic patients (n = 86) using standardized questionnaire. Experimental cirrhosis was induced by bile‐duct‐ligation or carbon‐tetrachloride intoxication in rats. Corpus cavernosum pressure – a surrogate of ED ‐, as well as systemic and portal haemodynamics, were measured in vivo and in situ after acute administration of udenafil alone or in combination with propranolol. mRNA and protein levels of PDE‐5 signalling were analysed using PCR and western Blot.
Results: ED in humans was related to severity of liver disease and to NSBB treatment. PDE‐5 was mainly expressed in hepatic stellate cells and upregulated in human and experimental cirrhosis. Propranolol reduced corpus cavernosum pressure in cirrhotic rats and it was restored by udenafil. Even though udenafil treatment improved PH, it led to a reduction of mean arterial pressure. The combination of udenafil and propranolol reduced portal pressure and hepatic resistance without systemic side‐effects.
Conclusions: ED is common with advanced cirrhosis and concomitant NSBB treatment. The combination of PDE‐5‐I and NSBB improves ED and PH in experimental cirrhosis.
Background: Recently, RBFOX1, a gene encoding an RNA binding protein, has consistently been associated with aggressive and antisocial behavior. Several loci in the gene have been nominally associated with aggression in genome-wide association studies, the risk alleles being more frequent in the general population. We have hence examined the association of four RBFOX1 single nucleotide polymorphisms, previously found related to aggressive traits, with aggressiveness, personality, and alcohol use disorder in birth cohort representative samples.
Methods: We used both birth cohorts of the Estonian Children Personality Behavior and Health Study (ECPBHS; original n = 1,238). Aggressiveness was assessed using the Buss–Perry Aggression Questionnaire and the Lifetime History of Aggressiveness structured interview at age 25 (younger cohort) or 33 (older cohort). Big Five personality at age 25 was measured with self-reports and the lifetime occurrence of alcohol use disorder assessed with the MINI interview. RBFOX1 polymorphisms rs809682, rs8062784, rs12921846, and rs6500744 were genotyped in all participants. Given the restricted size of the sample, correction for multiple comparisons was not applied.
Results: Aggressiveness was not significantly associated with the RBFOX1 genotype. RBFOX1 rs8062784 was associated with neuroticism and rs809682 with extraversion. Two out of four analyzed RBFOX1 variants, rs8062784 and rs12921846, were associated with the occurrence of alcohol use disorder.
Conclusions: In the birth cohort representative sample of the ECPBHS, no association of RBFOX1 with aggressiveness was found, but RBFOX1 variants affected basic personality traits and the prevalence of alcohol use disorder. Future studies on RBFOX1 should consider the moderating role of personality and alcohol use patterns in aggressiveness.
The aging process is characterized by a chronic, low‐grade inflammatory state, termed “inflammaging.” It has been suggested that macrophage activation plays a key role in the induction and maintenance of this state. In the present study, we aimed to elucidate the mechanisms responsible for aging‐associated changes in the myeloid compartment of mice. The aging phenotype, characterized by elevated cytokine production, was associated with a dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis and diminished serum corticosteroid levels. In particular, the concentration of corticosterone, the major active glucocorticoid in rodents, was decreased. This could be explained by an impaired expression and activity of 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1), an enzyme that determines the extent of cellular glucocorticoid responses by reducing the corticosteroids cortisone/11‐dehydrocorticosterone to their active forms cortisol/corticosterone, in aged macrophages and peripheral leukocytes. These changes were accompanied by a downregulation of the glucocorticoid receptor target gene glucocorticoid‐induced leucine zipper (GILZ) in vitro and in vivo. Since GILZ plays a central role in macrophage activation, we hypothesized that the loss of GILZ contributed to the process of macroph‐aging. The phenotype of macrophages from aged mice was indeed mimicked in young GILZ knockout mice. In summary, the current study provides insight into the role of glucocorticoid metabolism and GILZ regulation during aging.
Background: Previous studies have demonstrated that CF (Cystic Fibrosis) prognosis is dependent of three major parameters: FEV1 (Forced Expiratory Pressure in one second), BMI (Body Mass Index) and need of intravenous antibiotic therapy. The CF centres of Frankfurt, Germany, and Moscow, Russia, care for cystic fibrosis patients. We decided to investigate and compare both centers from 1990 to 2015. No comparable study has been published so far.
Method: German patient data was collected from the national cystic fibrosis database “Muko.web”. Missing values were extracted from the Hospital Information System. Russian patient data were taken directly from the medical records in Moscow. In a descriptive statistical analysis with Bias and R Studio the values were compared.
Result: A total of 428 patients from Moscow (217 male, 211 female; 348 (81,3%) were P. aeruginosa positive) and 159 patients from Frankfurt (92 male, 67 female; 137 (86,2%) with P. aeruginosa positive) were compared with regard to P. aeruginosa positivity, BMI, FEV1 and need of intravenous antibiotic therapy. CF patients in Moscow stratified by age groups had lower BMI than CF patients in Frankfurt (age 16-18: p=0,003; age 19-22: p=0,004; age 23-29: p<0,001; age 30-35: p<0,001; age 36-66: p=0,024). In a matching pairs analysis including 100 patients from Frankfurt and 100 patients from Moscow for the year 2015 FEV1 was significantly lower in Moscow patients (p<0,001).
Conclusion: BMI, FEV1 and need of intravenous therapy have significant impact on survival and on quality of life of CF patients. A lower BMI and a lower FEV1 result in a worse survival and determine the prognosis. This study showed a significant difference in prognostic parameters between Frankfurt and Moscow in the crosssectional analysis for the year 2015. A further study should evaluate this difference to show whether this difference will be found over a longer period of time.
Stored and cooled highly-charged ions offer unprecedented capabilities for precision studies in realm of atomic-, nuclear-structure and astrophysics. In context of the latter, after the successful investigation of the cross section of 96Ru(p,γ) in 2009, in 2016 the first measurement of the 124Xe(p,γ)125Cs reaction was performed at the Experimental Storage Ring (ESR) at GSI.
Stored and cooled, highly-charged ions offer unprecedented capabilities for precision studies in the realm of atomic, nuclear structure and astrophysics[1]. After the successful investigation of the 96Ru(p,7)97Rh reaction cross section in 2009[2], the first measurement of the 124Xe(p,7)125Cs reaction cross section has been performed with decelerated, fully-ionized 124Xe ions in 2016 at the Experimental Storage Ring (ESR) of GSI[3]. Using a Double Sided Silicon Strip Detector, introduced directly into the ultra-high vacuum environment of a storage ring, the 125Cs proton-capture products have been successfully detected. The cross section has been measured at 5 different energies between 5.5AMeV and 8AMeV, on the high energy tail of the Gamow-window for hot, explosive scenarios such as supernovae and X-ray binaries. The elastic scattering on the H2 gas jet target is the major source of background to count the (p,7) events. Monte Carlo simulations show that an additional slit system in the ESR in combination with the energy information of the Si detector will enable background free measurements of the proton-capture products. The corresponding hardware is being prepared and will increase the sensitivity of the method tremendously.
The paper investigates the different productivity domains (Rainer 2005) of two Italian event denoting suffixes, -mento and -zione. These suffixes share the same eventive semantics, they are both productive and thus can be seen as rivals in the formation of event nominalizations. The aim is to obtain a better understanding of the constraints that play a role in the selection of one affix over the other. By means of a logistic regression model the contribution of different features of the base verb is investigated. The analysis is conducted on a dataset of 678 nominalizations extracted from a section of Midia, a diachronic balanced corpus explicitly built for morphological research (Gaeta 2017). Results show that the frequency, the inflectional class and the number of characters of the base verb as well as the presence of the prefix a- significantly contribute to the definition of the different domains, only partially confirming previous findings.
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.
This essay restages Arendt's 'Auseinandersetzung' with Heidegger regarding 'political beginnings'. Sketching Heidegger's exceptionalist account of 'new beginnings' and Arendt's dispute with him in relation to the tension between the spheres of 'philosophy' and 'politics', I trace her position about 'political founding'. I claim that Arendt invites us to recognize the 'principle of an-archy' innate to 'political beginnings', which cannot be absorbed by exceptionalist invocations of the 'history of Being'.
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.
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.
Abiinae is the second-largest subfamily in Cimbicidae, a small family of true sawflies (Tenthredinoidea). The subfamily is adequately defined, but the generic classification has been unstable. Currently, only two genera are regarded as valid: Abia Leach, 1817 and Allabia Semenov & Gussakovskij, 1937. We evaluate the generic classification of Abiinae in a phylogenetic context. A total of 32 species (out of 57 described for the subfamily), including the type species of Allabia, Allabia infernalis (Semenov, 1896), are scored for 150 adult morphological characters. Results show some resolution, but only few clades can be circumscribed by consistent character combinations. Most of the characters that have previously been used to define genera are not congruent; consequently, most suggested genus definitions appear to be random character state combinations and few natural groups can be identified. For these reasons, we treat Allabia syn. nov. as a junior synonym of Abia and make the following additional taxonomic changes: Abia infernalis Semenov, 1896 comb. rev. and Abia malaisei (Semenov & Gussakovskij, 1937) syn. nov. For the purpose of long-term stability of the classification of Abiinae, we recommend recognizing only one genus, Abia, within the subfamily.
The paper presents new odonatological data from the formerly unstudied islands Patnanungan and Jomalig as well from the northeastern part of Polillo, The Philippines. Four species are new for the PolilloIsland group, including one new taxon Anax parthenope julius – for The Philippines. Currently, 78 odonate taxa are known from the Polillogroup.
This paper presents the faunistic results of three short field excursions conducted in spring and early summer of 2018 in Kosovo, considering dragonfly fauna one of the most understudied countries of Europe. This study presents first systematic dragonfly research in Kosovo. Within a total of 13 field days between end of April and end of June 2018, 60 sites were surveyed and 44 dragonfly species were found. Significant results include the first documented report of 15 species for Kosovo. New data on several other species with a broader European concern or generally rare on the West Balkan peninsula, i.e. Coenagrion ornatum, Anax ephippiger, Caliaeschna microstigma, Cordulegaster heros, C. bidentata, Somatochlora flavomaculata, and Sympetrum flaveolum, are also presented. The overview of all visited sites is included. Altogether, 47 dragonfly species are now reported for Kosovo.
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.
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.
In this paper the primary types of Centris bees described by the British entomologist Theodore Dru Alison Cockerell deposited in the Natural History Museum (London) and the Oxford University Museum of Natural History (Oxford) in the United Kingdom, as well as in the United States National Museum (Washington), American Museum of Natural History (New York), the Academy of Natural Sciences of Drexel University (Philadelphia), and in the California Academy of Sciences (San Francisco) in the United States were studied. To stabilize the application of the name C. lepeletieri (= C. haemorrhoidalis (Fabricius)), a lectotype is designated. The study of the primary types allow proposing the revalidation of C. cisnerosi nom. rev. from the synonymy of C. agilis Smith, C. nitida geminata nom. rev. from C. facialis Mocsáry, C. rufulina nom. rev. from C. varia (Erichson), C. semilabrosa nom. rev. from C. terminata Smith and C. triangulifera nom. rev. from C. labrosa Friese. Centris bakeri syn. nov., C. bimaculata carrikeri syn. nov., C. fusciventris matoensis syn. nov., C. heterodonta syn. nov. and C. elegans grenadensis syn. nov. are proposed as a new junior synonyms of C. varia, C. claripennis Friese nom. rev., C. caurensis, C. dentata Smith and C. elegans Smith, respectively. Centris ruae is withdrawn from the synonymy of C. transversa Pérez and proposed as a new junior synonym of C. nitida Smith. In addition, a lectotype for C. buchholzi Herbst (= C. wilmattae) is designated. Information on the repository of the lectotype of C. lepeletieri and images of most primary types studied here are also provided.
In this paper, the species of Centris of the “hyptidis group” are revisited, proposing to recognize them as members of Anisoctenodes subgen. nov., a new subgenus supported by morphological and molecular data. The species included in this new taxon are C. hyptidis Ducke, 1908 (type-species), C. hyptidoides Roig-Alsina, 2000, C. thelyopsis Vivallo & Melo, 2009 and C. anisitsi (Schrottky, 1908), transferring this latter from Centris (Xanthemisia) Moure, 1945. An updated key, information on the type depository, a distribution map, photographs of both sexes as well as of the diagnostic characters of the new subgenus are also provided.
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.
Xenorhabdus and Photorhabdus are bacterial genera that live in symbiosis with entomopathogenic nematodes of the genera Steinernema and Heterorhabditis, respectively. These nematodes infect insect larvae through the trachea and then enter the hemocoel. Once inside the hemocoel, the nematodes release the bacteria through their intestine. Thereafter, the bacteria become active and kill the larvae within 48 h. During this process, the immune system of the insect host is compromised by molecules produced and secreted by the bacteria. This illustrates that the bacteria possess not only a large arsenal of biological weaponry such as antibiotics and fungicides but also lipases, proteases, etc. Therefore, they are not only able to kill the insect but also protect the cadaver from other food competitors.
During the past decades, a large number of natural products have been identified from Xenorhabdus and Photorhabdus. However, the targets and functions for many of these biological molecules are still unknown. Therefore, the goal of the doctoral thesis is to elucidate the modes of action of these natural products from Xenorhabdus and Photorhabdus with the main focus on non-ribosomal peptides (NRPs). The work can be divided into two parts. Initially, it starts with the synthesis of natural compounds and various chemically modified derivatives. Besides that, a number of peptides were synthesized for other projects to either verify their structures or quantify the amount produced by the bacteria. Then, secondary analysis methods are applied and provide additional insight into the modes of action of these compounds.
During the thesis, I carried out peptide synthesis either manually or with an automatic synthesizer system from Biotage. Here, the Fmoc-protecting group strategy was preferred in most cases. Natural products, such as silathride, xenoautoxin, phenylethylamide, tryptamide, rhabdopeptide, 3-hydroxyoctanoic acid, and PAX, were produced during this process. Furthermore, new peptide derivatives derived from synthetic NRPS approaches using the XU concept or SYNZIP were generated as standards.
Most of these natural compounds were experimentally verified by MIC tests (broth microdilution, plate diffusion) to be biologically active. For example, silathride, phenylethylamide, and tryptamide showed quorum quenching effects when tested against Chromobacterium violaceum. Initial results from collaborators (PD Dr. Nadja Hellmann/Mainz) showed that tryptamide and phenylethylamide interact with membrane or membrane proteins.
(R)-3-hydroxyoctanoic acid was synthesized to verify the molecule structure of phototemtide A, a cyclic lipopeptide with antiprotozoal activity. The rhabdopeptides are another class, which showed remarkable antiprotozoal effects. However, their mode of action was unknown. These compounds are relatively short peptide sequences, which contain hydrophobic residues, such as valine, leucine, or phenylalanine. Moreover, they possess N methylation, resulting in a rod-shaped highly hydrophobic structure. In this work, I synthesized eight new derivatives of rhabdopeptides for photo-affinity labeling (PAL). These molecules should react covalently under UV-light irradiation with the biological target of the peptides. In addition, these derivatives can be enriched in a pull-down assay using click chemistry. Afterward, analytic methods such as mass detection (proteome analysis) can be applied to elucidate the protein targets.
The PAX peptides derivatives are well-known to have anti-microbial activities and believed to be secreted into the environment by the producing bacteria. However, I found that the majority of these peptides are located in the cell pellet fraction and not in the supernatant. This has been shown through quantification using HPLC MS. New PAX derivatives were synthesized, which carry a moiety suitable for covalent modification using click-chemistry, therefore being functionalizable with a fluorescence dye. In collaboration with Dr. Christoph Spahn (Prof. Dr. Mike Heilemann group), we used confocal, as well as super-resolution microscopy, in particular, single-molecule localization microscopy (SMLM) to investigate the spatial distribution of clickable PAX molecules and revealed that they localize at the bacterial membrane. Furthermore, bioactivity assays revealed that the promotor exchanged X. doucetiae PAX mutants, which do not produce PAX molecules without chemical induction (hereby termed as pax-), were more susceptible to several insect AMPs tested. Based on these findings, a new dual mechanism of action for PAX was proposed. Besides the previously shown antimicrobial activity, these molecules with a positive net charge of +5 (pH = 7) would bind to the negatively charged bacterial surface. Hereby, the surface charge (typically negative) would be inversed resulting in a protective effect for Xenorhabdus against other positively charged AMPs. Furthermore, PAX was investigated as AMP against E. coli to study its antimicrobial mechanism of action. Here, the results show that PAX can disrupt the E. coli membrane at higher concentrations (> 30 µg/ml), enter the cytosol, and lead to reorganization of subcellular structures, such as the nucleoid during this process.
Another aspect of secondary analysis is the application of proteomic analysis. Therefore, I induced X. nematophila, X. szentirmaii, and P. luminescens with insect lysate. These samples were analyzed using HPLC-MS/MS (Q Exactive) together with a database approach (Maxquant/Andromeda). The results showed that in all strains the lipid degradation and the glyoxylate pathway were induced. This is in line with the given insect lysate diet, which mostly contained lipids. Moreover, several interesting unknown peptides and proteins were also upregulated and might get into the focus of future research.
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
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.
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: 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.
Ongoing climate change is a major threat to biodiversity and impacts on species distributions and abundances are already evident. Heterogenous responses of species due to varying abiotic tolerances and dispersal abilities have the potential to further amplify or ameliorate these impacts through changes in species assemblages. Here we investigate the impacts of climate change on terrestrial bird distributions and, subsequently, on species richness as well as on different aspects of phylogenetic diversity of species assemblages across the globe. We go beyond previous work by disentangling the potential impacts on assemblage phylogenetic diversity of species gains vs. losses under climate change and compare the projected impacts to randomized assemblage changes.
We show that climate change might not only affect species numbers and composition of global species assemblages but could also have profound impacts on assemblage phylogenetic diversity, which, across extensive areas, differ significantly from random changes. Both the projected impacts on phylogenetic diversity and on phylogenetic structure vary greatly across the globe. Projected increases in the evolutionary history contained within species assemblages, associated with either increasing phylogenetic diversification or clustering, are most frequent at high northern latitudes. By contrast, projected declines in evolutionary history, associated with increasing phylogenetic over-dispersion or homogenisation, are projected across all continents.
The projected widespread changes in the phylogenetic structure of species assemblages show that changes in species richness do not fully reflect the potential threat from climate change to ecosystems. Our results indicate that the most severe changes to the phylogenetic diversity and structure of species assemblages are likely to be caused by species range shifts rather than range reductions and extinctions. Our findings highlight the importance of considering diverse measures in climate impact assessments and the value of integrating species-specific responses into assessments of entire community changes.
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.
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 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.
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.
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.
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.