Structural Elucidation of a Metagenomic Urethanase and Its Engineering Towards Enhanced Hydrolysis Profiles.

While plastics like polyethylene terephthalate can already be degraded efficiently by the activity of hydrolases, other synthetic polymers like polyurethanes (PUs) and polyamides (PAs) largely resist biodegradation. In this study, we solved the first crystal structure of the metagenomic urethanase UMG-SP-1, identified highly flexible loop regions to comprise active site residues, and targeted a total of 20 potential hot spots by site-saturation mutagenesis. Engineering campaigns yielded variants with single mutations, exhibiting almost 3- and 8-fold improved activity against highly stable N-aryl urethane and amide bonds, respectively. Furthermore, we demonstrated the release of the corresponding monomers from a thermoplastic polyester-PU and a PA (nylon 6) by the activity of a single, metagenome-derived urethanase after short incubation times. Thereby, we expanded the hydrolysis profile of UMG-SP-1 beyond the reported low-molecular weight carbamates. Together, these findings promise advanced strategies for the bio-based degradation and recycling of plastic materials and waste, aiding efforts to establish a circular economy for synthetic polymers.

Ultrasound supports clinical decision-making in determining the Sanders' skeletal maturity score of the hand.

PURPOSE: The Sanders Scoring System has revolutionized the way we assess the remaining growth potential of the skeleton. However, because it involves radiation exposure, it must be used with caution in children. The purpose of the study was to evaluate whether the Sanders skeletal maturity score (SMS) could be accurately determined using ultrasound (U). METHODS: We took radiographs (R) of the hand and performed U of the thumb and index finger in 115 patients between six and 19 years of age who were undergoing treatment for scoliosis or limb deformities. Paediatric orthopaedic surgeons, a paediatrician, and a paediatric radiologist were evaluated the blinded images. Those classified images are based on the SMS and the Thumb Ossification Composite Index (TOCI). RESULTS: Intrarater reliability was high for SMS and slightly weaker for TOCI, but still significant. Interrater reliability was clear for R and weaker for U in both staging systems. Ultimately, SMS 3 and 7 achieved the highest percentage of concordance (P) of 71.7% and 66.0%, respectively, when U was performed. Combining the clinically relevant groups of SMS 3&4 and SMS 7&8 also significantly increased peak scores (SMS 3 and 4 P = 76.7%; SMS 7 and 8 P = 79.7%). The probabilities of peak scores were significantly weaker when the TOCI score was examined. CONCLUSION: Our study shows that U can be used effectively especially to measure stages 3 and 4 and stages 7 and 8 of SMS. The U method is easy to use and therefore may offer advantages in clinical practice without the need for radiation exposure.

Wounding Triggers Wax Biosynthesis in Arabidopsis Leaves in an Abscisic Acid and Jasmonoyl-Isoleucine Dependent Manner.

Wounding caused by insects or abiotic factors such as wind and hail can cause severe stress for plants. Intrigued by the observation that wounding induces expression of genes involved in surface wax synthesis in a jasmonoyl-isoleucine (JA-Ile)-independent manner, the role of wax biosynthesis and respective genes upon wounding was investigated. Wax, a lipid-based barrier, protects plants both from environmental threats as well as from an uncontrolled loss of water. Its biosynthesis is described to be regulated by abscisic acid (ABA), whereas the main wound-signal is the hormone JA-Ile. We show in this study, that genes coding for enzymes of surface wax synthesis are induced upon wounding in Arabidopsis thaliana leaves in a JA-Ile-independent but ABA-dependent manner. Furthermore, the ABA-dependent transcription factor MYB96 is a key regulator of wax biosynthesis upon wounding. On the metabolite level, wound-induced wax accumulation is strongly reduced in JA-Ile-deficient plants, but this induction is only slightly decreased in ABA-reduced plants. To further analyze the ABA-dependent wound response, we conducted wounding experiments in high humidity. They show that high humidity prevents the wound-induced wax accumulation in A. thaliana leaves. Together the data presented in this study show that wound-induced wax accumulation is JA-Ile-dependent on the metabolite level, but the expression of genes coding for enzymes of wax synthesis is regulated by ABA.

Novel thiazolopyridine derivatives of diflapolin as dual sEH/FLAP inhibitors with improved solubility.

Inflammatory responses are orchestrated by a plethora of lipid mediators, and perturbations of their biosynthesis or degradation hinder resolution and lead to uncontrolled inflammation, which contributes to diverse pathologies. Small molecules that induce a switch from pro-inflammatory to anti-inflammatory lipid mediators are considered valuable for the treatment of chronic inflammatory diseases. Commonly used non-steroidal anti-inflammatory drugs (NSAIDs) are afflicted with side effects caused by the inhibition of beneficial prostanoid formation and redirection of arachidonic acid (AA) into alternative pathways. Multi-target inhibitors like diflapolin, the first dual inhibitor of soluble epoxide hydrolase (sEH) and 5-lipoxygenase-activating protein (FLAP), promise improved efficacy and safety but are confronted by poor solubility and bioavailability. Four series of derivatives bearing isomeric thiazolopyridines as bioisosteric replacement of the benzothiazole core and two series additionally containing mono- or diaza-isosteres of the phenylene spacer were designed and synthesized to improve solubility. The combination of thiazolo[5,4-b]pyridine, a pyridinylen spacer and a 3,5-Cl2-substituted terminal phenyl ring (46a) enhances solubility and FLAP antagonism, while preserving sEH inhibition. Moreover, the thiazolo[4,5-c]pyridine derivative 41b, although being a less potent sEH/FLAP inhibitor, additionally decreases thromboxane production in activated human peripheral blood mononuclear cells. We conclude that the introduction of nitrogen, depending on the position, not only enhances solubility and FLAP antagonism (46a), but also represents a valid strategy to expand the scope of application towards inhibition of thromboxane biosynthesis.

Modulation of the 5-Lipoxygenase Pathway by Chalcogen-Containing Inhibitors of Leukotriene A4 Hydrolase.

The 5-lipoxygenase (5-LOX) pathway gives rise to bioactive inflammatory lipid mediators, such as leukotrienes (LTs). 5-LOX carries out the oxygenation of arachidonic acid to the 5-hydroperoxy derivative and then to the leukotriene A4 epoxide which is converted to a chemotactic leukotriene B4 (LTB4) by leukotriene A4 hydrolase (LTA4H). In addition, LTA4H possesses aminopeptidase activity to cleave the N-terminal proline of a pro-inflammatory tripeptide, prolyl-glycyl-proline (PGP). Based on the structural characteristics of LTA4H, it is possible to selectively inhibit the epoxide hydrolase activity while sparing the inactivating, peptidolytic, cleavage of PGP. In the current study, chalcogen-containing compounds, 4-(4-benzylphenyl) thiazol-2-amine (ARM1) and its selenazole (TTSe) and oxazole (TTO) derivatives were characterized regarding their inhibitory and binding properties. All three compounds selectively inhibit the epoxide hydrolase activity of LTA4H at low micromolar concentrations, while sparing the aminopeptidase activity. These inhibitors also block the 5-LOX activity in leukocytes and have distinct inhibition constants with recombinant 5-LOX. Furthermore, high-resolution structures of LTA4H with inhibitors were determined and potential binding sites to 5-LOX were proposed. In conclusion, we present chalcogen-containing inhibitors which differentially target essential steps in the biosynthetic route for LTB4 and can potentially be used as modulators of inflammatory response by the 5-LOX pathway.

Job Quality in the Late Career in Sweden, Japan and the United States.

Increasing numbers of older workers continue to work after being eligible to claim a state pension, yet little is known about the quality of these jobs. We examine how psychosocial and physical job quality as well as job satisfaction vary over the late career in three contrasting national settings: Sweden, Japan and the United States. Analyses using random effects modelling drew on data from the Swedish Longitudinal Occupational Survey of Health (n = 13,936-15,520), Japanese Study of Ageing and Retirement (n = 3704) and the Health and Retirement Study (n = 6239 and 8002). Age was modelled with spline functions in which two knots were placed at ages indicating eligibility for pensions claiming or mandatory retirement. In each country, post-pensionable-age jobs were generally less stressful, freer and more satisfying than jobs held by younger workers, results that held irrespective of gender or education level.

Development of SFC-MS Method for Quantification of Eicosanoids Biosynthesized in Primary Human Blood Cells.

Eicosanoids are lipid mediators generated from arachidonic acid with pro- and anti-inflammatory properties. Despite these lipid mediators being known for decades, quantitative determination in biological samples is still challenging due to low abundance, instability, the existence of regio- and stereoisomers, and a wide polarity range that hampers chromatographic separation. In this study, we developed a supercritical fluid chromatography mass spectrometry (SFC-MS) platform for the quantification of relevant eicosanoids. Application of a chiral amylose-based column and modifier combination of 2-propanol/acetonitrile offered separation and sufficient resolution of 11 eicosanoids (5-, 12-, 15-HETE, PGB1, LTB4, t-LTB4, 20-OH-LTB4, PGE2, PGD2, PGF2α, TxB2) with baseline separation of isobaric analytes within 12 min. The method was validated in terms of range (78-2500 ng/mL), linearity, accuracy, precision, and recovery according to EMA guidelines. Finally, we confirmed the method's applicability by quantifying eicosanoid levels in human primary blood cells. In conclusion, we present a validated SFC-MS method for the determination of relevant eicosanoids in biological samples with a wide range of polarity while maintaining baseline separation of isobars, which allows coupling to a single quadrupole mass detector.

Identification of 2,4-Dinitro-Biphenyl-Based Compounds as MAPEG Inhibitors.

We identified 2,4-dinitro-biphenyl-based compounds as new inhibitors of leukotriene C4 synthase (LTC4 S) and 5-lipoxygenase-activating protein (FLAP), both members of the "Membrane Associated Proteins in Eicosanoid and Glutathione metabolism" (MAPEG) family involved in the biosynthesis of pro-inflammatory eicosanoids. By molecular docking we evaluated the putative binding against the targets of interest, and by applying cell-free and cell-based assays we assessed the inhibition of LTC4 S and FLAP by the small molecules at low micromolar concentrations. The present results integrate the previously observed inhibitory profile of the tested compounds against another MAPEG member, i. e., microsomal prostaglandin E2 synthase (mPGES)-1, suggesting that the 2,4-dinitro-biphenyl scaffold is a suitable molecular platform for a multitargeting approach to modulate pro-inflammatory mediators in inflammation and cancer treatment.

PEP7 acts as a peptide ligand for the receptor kinase SIRK1 to regulate aquaporin-mediated water influx and lateral root growth.

Plant receptors constitute a large protein family that regulates various aspects of development and responses to external cues. Functional characterization of this protein family and the identification of their ligands remain major challenges in plant biology. Previously, we identified plasma membrane-intrinsic sucrose-induced receptor kinase 1 (SIRK1) and Qian Shou kinase 1 (QSK1) as receptor/co-receptor pair involved in the regulation of aquaporins in response to osmotic conditions induced by sucrose. In this study, we identified a member of the elicitor peptide (PEP) family, namely PEP7, as the specific ligand of th receptor kinase SIRK1. PEP7 binds to the extracellular domain of SIRK1 with a binding constant of 1.44 ± 0.79 µM and is secreted to the apoplasm specifically in response to sucrose treatment. Stabilization of a signaling complex involving SIRK1, QSK1, and aquaporins as substrates is mediated by alterations in the external sucrose concentration or by PEP7 application. Moreover, the presence of PEP7 induces the phosphorylation of aquaporins in vivo and enhances water influx into protoplasts. Disturbed water influx, in turn, led to delayed lateral root development in the pep7 mutant. The loss-of-function mutant of SIRK1 is not responsive to external PEP7 treatment regarding kinase activity, aquaporin phosphorylation, water influx activity, and lateral root development. Taken together, our data indicate that the PEP7/SIRK1/QSK1 complex represents a crucial perception and response module that mediates sucrose-controlled water flux in plants and lateral root development.

Changes in Secondary Healthcare Use Over Retirement Transition: Examining Social Differences With Swedish Register Data.

Background: Despite its relevance for healthcare expenditures and public health, few studies have examined how secondary healthcare use changes during the retirement transition. We therefore use Swedish register data to examine whether retirement is associated with intensified secondary healthcare use overall and for specific subgroups based on gender and education. Methods: The sample was all individuals registered in Sweden who retired from paid work in 2010. We used Generalised Estimating Equations models to analyse changes in two indicators of secondary healthcare use, namely specialist visits and hospitalisation, from 3 years prior to 5 years after retirement. Results: Retirement is not associated with changes in specialist visits or hospitalisation per se. Three years before retirement, women were more likely to visit a specialist but less likely to be hospitalised than men; these gender differences disappeared approximately 1 year before retirement. Women with high education were more likely to visit a specialist than women with low education across the entire retirement transition, particularly post-retirement. Significant differences with regard to specialist visits between male educational groups only emerged 12 months after retirement. There were no educational differences with regard to hospitalisation. Conclusions: We conclude that secondary healthcare use in Sweden does not generally change with retirement. However, over the course of retirement gender differences in secondary healthcare use tend to decrease and within-gender educational differences tend to increase. We interpret the results as reflecting the role of labour market institutions in contributing to gender differences but repressing educational differences in secondary healthcare use.

Development of healthcare use across contemporary retirement pathways: results from a register based cohort study.

AIM: We aimed to understand the interplay between retirement pathways and healthcare use in the postponed and structurally changing context of retirement. METHODS: Based on Swedish register data on income and healthcare use, we applied combined sequence and cluster analysis to identify typical pathways into retirement and analysed their relation to healthcare use developments. RESULTS: We detected five distinct pathways into retirement. Level of healthcare use was significantly higher for the pathway via disability pensions. We saw an overall increase in healthcare use across the retirement process that was related to age rather than to the different pathways. CONCLUSIONS: Level of healthcare use at the beginning of the retirement process may be related to selection into different pathways of retirement. We did not find clear evidence across several healthcare measures that different pathways lead to different developments in healthcare use.

Sphingolipid-Induced Programmed Cell Death is a Salicylic Acid and EDS1-Dependent Phenotype in Arabidopsis Fatty Acid Hydroxylase (Fah1, Fah2) and Ceramide Synthase (Loh2) Triple Mutants.

Ceramides (Cers) and long-chain bases (LCBs) are plant sphingolipids involved in the induction of plant programmed cell death (PCD). The fatty acid hydroxylase mutant fah1 fah2 exhibits high Cer levels and moderately elevated LCB levels. Salicylic acid glucoside level is increased in this mutant, but no cell death can be detected by trypan blue staining. To determine the effect of Cers with different chain lengths, fah1 fah2 was crossed with ceramide synthase mutants longevity assurance gene one homologue1-3 (loh1, loh2 and loh3). Surprisingly, only triple mutants with loh2 show cell death detected by trypan blue staining under the selected conditions. Sphingolipid profiling revealed that the greatest differences between the triple mutant plants are in the LCB and LCB-phosphate (LCB-P) fraction. fah1 fah2 loh2 plants accumulate LCB d18:0, LCB t18:0 and LCB-P d18:0. Crossing fah1 fah2 loh2 with the salicylic acid (SA) synthesis mutant sid2-2 and with the SA signaling mutants enhanced disease susceptibility 1-2 (eds1-2) and phytoalexin deficient 4-1 (pad4-1) revealed that lesions are SA- and EDS1-dependent. These quadruple mutants also confirm that there may be a feedback loop between SA and sphingolipid metabolism as they accumulated less Cers and LCBs. In conclusion, PCD in fah1 fah2 loh2 is a SA- and EDS1-dependent phenotype, which is likely due to accumulation of LCBs.

The indirubin derivative 6-bromoindirubin-3'-glycerol-oxime ether (6BIGOE) potently modulates inflammatory cytokine and prostaglandin release from human monocytes through GSK-3 interference.

Indirubin is a natural bis-indole alkaloid contained as active ingredient in the traditional Chinese remedy Danggui Longhui Wan. Indirubin and its 3'-oxime derivatives exhibit anti-cancer and anti-inflammatory properties and they inhibit glycogen synthase kinase (GSK)-3 in cell-free assays where 6-bromoindirubin-3'-oxime (6BIO) is among the most potent analogs. Here, we reveal 6-bromoindirubin-3'-glycerol-oxime ether (6BIGOE) as highly potent derivative able to inhibit pro-inflammatory cytokine, chemokine and prostaglandin (PG) release in human primary monocytes while increasing anti-inflammatory interleukin (IL)-10 levels. 6BIGOE suppressed lipopolysaccharide (LPS)-induced IL-1ß and PGE2 release with IC50 of 0.008 and 0.02 µM, respectively, being ≥ 12-fold more potent than 6BIO. The effects of 6BIGOE are mediated via intracellular inhibition of GSK-3, where 6BIGOE again surpassed the effectiveness of 6BIO despite the higher potency of the latter in cell-free GSK-3 activity assays. Side-by-side comparison of 6BIGOE (0.1 µM) with the selective GSK-3 inhibitor SB216763 (5 µM) revealed congruent properties such as enrichment of ß-catenin and suppression of cyclooxygenase (COX)-2 protein levels due to GSK-3 inhibition. Metabololipidomics using ultra-performance liquid chromatography-tandem mass spectrometry showed that 6BIGOE selectively decreases pro-inflammatory COX-derived product formation without marked modulation of other lipid mediators. In summary, 6BIGOE is a highly potent indirubin derivative in the cellular context that favorably modulates pro- and anti-inflammatory cytokines as well as COX-2-derived PG via interference with GSK-3.

Disruption of Arabidopsis neutral ceramidases 1 and 2 results in specific sphingolipid imbalances triggering different phytohormone-dependent plant cell death programmes.

Sphingolipids act as regulators of programmed cell death (PCD) and the plant defence response. The homeostasis between long-chain base (LCB) and ceramide (Cer) seems to play an important role in executions of PCD. Therefore, deciphering the role of neutral ceramidases (NCER) is crucial to identify the sphingolipid compounds that trigger and execute PCD. We performed comprehensive sphingolipid and phytohormone analyses of Arabidopsis ncer mutants, combined with gene expression profiling and microscopic analyses. While ncer1 exhibited early leaf senescence (developmentally controlled PCD - dPCD) and an increase in hydroxyceramides, ncer2 showed spontaneous cell death (pathogen-triggered PCD-like - pPCD) accompanied by an increase in LCB t18:0 at 35 d, respectively. Loss of NCER1 function resulted in accumulation of jasmonoyl-isoleucine (JA-Ile) in the leaves, whereas disruption of NCER2 was accompanied by higher levels of salicylic acid (SA) and increased sensitivity to Fumonisin B1 (FB1 ). All mutants were also found to activate plant defence pathways. These data strongly suggest that NCER1 hydrolyses ceramides whereas NCER2 functions as a ceramide synthase. Our results reveal an important role of NCER in the regulation of both dPCD and pPCD via a tight connection between the phytohormone and sphingolipid levels in these two processes.

Bioactivity and Mode of Action of Bacterial Tetramic Acids.

Microbially produced 3-acyltetramic acids display a diverse range of biological activities. The pyreudiones are new members of this class that were isolated from bacteria of the genus Pseudomonas. Here, we performed a structure-activity relationship study and determined their mode of action. An efficient biomimetic synthesis was developed to synthesize pyreudione A. Pyreudiones and synthetic analogs thereof were tested for their amoebicidal, antibacterial, antiproliferative, and cytotoxic activities. The length of the alkyl side chain and the nature of the amino acid residues within the tetramic acid moiety strongly affected activity, in particular against mycobacteria. The mode of action was shown to correlate with the ability of pyreudiones to act as protonophores. Removal of the acidic proton by methylation of pyreudione A resulted in a loss of bioactivity.

Melleolides impact fungal translation via elongation factor 2.

Melleolides from the honey mushroom Armillaria mellea represent a structurally diverse group of polyketide-sesquiterpene hybrids. Among various bioactivites, melleolides show antifungal effects against Aspergillus and other fungi. This bioactivity depends on a Δ2,4-double bond present in dihydroarmillylorsellinate (DAO) or arnamial, for example. Yet, the mode of action of Δ2,4-unsaturated, antifungal melleolides has been unknown. Here, we report on the molecular target of DAO in the fungus Aspergillus nidulans. Using a combination of synthetic chemistry to create a DAO-labelled probe, protein pulldown assays, MALDI-TOF-based peptide analysis and western blotting, we identify the eukaryotic translation elongation factor 2 (eEF2) as a binding partner of DAO. We confirm the inhibition of protein biosynthesis in vivo with an engineered A. nidulans strain producing the red fluorescent protein mCherry. Our work suggests a binding site dissimilar from that of the protein biosynthesis inhibitor sordarin, and highlights translational elongation as a valid antifungal drug target.

Gliotoxin from Aspergillus fumigatus Abrogates Leukotriene B4 Formation through Inhibition of Leukotriene A4 Hydrolase.

The epidithiodioxopiperazine gliotoxin is a virulence factor of Aspergillus fumigatus, the most important airborne fungal pathogen of humans. Gliotoxin suppresses innate immunity in invasive aspergillosis, particularly by compromising neutrophils, but the underlying molecular mechanisms remain elusive. Neutrophils are the first responders among innate immune cells recruited to sites of infection by the chemoattractant leukotriene (LT)B4 that is biosynthesized by 5-lipoxygenase and LTA4 hydrolase (LTA4H). Here, we identified gliotoxin as inhibitor of LTA4H that selectively abrogates LTB4 formation in human leukocytes and in distinct animal models. Gliotoxin failed to inhibit the formation of other eicosanoids and the aminopeptidase activity of the bifunctional LTA4H. Suppression of LTB4 formation by gliotoxin required the cellular environment and/or reducing conditions, and only the reduced form of gliotoxin inhibited LTA4H activity. Conclusively, gliotoxin suppresses the biosynthesis of the potent neutrophil chemoattractant LTB4 by direct interference with LTA4H thereby impairing neutrophil functions in invasive aspergillosis.

Invisible Scars or Open Wounds? The Role of Mid-career Income for the Gender Pension Gap in Sweden.

This study investigates the importance of mid-career income for the gender pension gap and psychological scarring effects of low income earlier in life. More specifically we analyse whether women's typically less stable mid-life careers also affect outcomes in late careers and in retirement. Swedish income register data from 1990, 2009, and 2015 was linked to the "HEalth, Ageing, and Retirement Transitions in Sweden" survey. The gender pension gap of 966 retirees and worries about pension income of 2,723 older workers between the age of 60 and 66 years were investigated. Blinder-Oaxaca decompositions were applied to analyse the gender pension gap and linear regressions were used for the analysis of financial worries. Results show that gender differences in mid-career income play a stronger role for the gender pension gap than late career income. Mid-career income is furthermore related to higher worries about pension income and accounts for observed gender differences. Our findings demonstrate that gender gaps in mid-career income can be regarded as an open wound with visible negative effects in older ages. The reformed pension system in Sweden may potentially contribute to an even greater gender gap in pensions.

Melleolides from Honey Mushroom Inhibit 5-Lipoxygenase via Cys159.

5-Lipoxygenase (5-LO) initiates the biosynthesis of pro-inflammatory leukotrienes from arachidonic acid, which requires the nuclear membrane-bound 5-LO-activating protein (FLAP) for substrate transfer. Here, we identified human 5-LO as a molecular target of melleolides from honey mushroom (Armillaria mellea). Melleolides inhibit 5-LO via an α,ß-unsaturated aldehyde serving as Michael acceptor for surface cysteines at the substrate entrance that are revealed as molecular determinants for 5-LO activity. Experiments with 5-LO mutants, where select cysteines had been replaced by serine, indicated that the investigated melleolides suppress 5-LO product formation via two distinct modes of action: (1) by direct interference with 5-LO activity involving two or more of the cysteines 159, 300, 416, and 418, and (2) by preventing 5-LO/FLAP assemblies involving selectively Cys159 in 5-LO. Interestingly, replacement of Cys159 by serine prevented 5-LO/FLAP assemblies as well, implying Cys159 as determinant for 5-LO/FLAP complex formation at the nuclear membrane required for leukotriene biosynthesis.

[Change of retirement transition in the political paradigm shift in Europe : Late career and retirement transitions in Germany, Austria, Sweden and Estonia]. / Wandel von Ruhestandsübergängen im politischen Paradigmenwechsel Europas : Späte Erwerbsphase und Rentenübergang in Deutschland, Österreich, Schweden und Estland.

BACKGROUND: In the last two decades labor market participation for older employees has undergone a gradual political paradigm shift in many European countries from a policy of early retirement to one of extending working lives and active aging. OBJECTIVE: This study investigated if this political paradigm shift is causing new social inequalities in retirement transition due to restricted financial possibilities for early retirement. MATERIAL AND METHODS: Data were derived from the European Union Labor Force Survey from the years 2006 and 2012 and selected European countries (Germany, Austria, Sweden and Estonia) were analyzed. RESULTS: Associations between the specific implementation of the policy of active aging, the freedom of choice in retirement timing and retirement transition were found. It seems that voluntary retirement transitions are highest in those countries where the labor market and social policies are most coherent and aimed at supporting older workers' employability. CONCLUSION: The reduction of early retirement incentives should be supported by active labor market policies and a policy of extensive age-independent further training measures in order to minimize social inequalities.