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Bargaining with a bank
(2018)
This paper examines bargaining as a mechanism to resolve information problems. To guide the analysis, I develop a parsimonious model of a credit negotiation between a bank and firms with varying levels of impatience. In equilibrium, impatient firms accept the bank’s offer immediately, while patient firms wait and negotiate price adjustments. I test the empirical predictions using a hand-collected dataset on credit line negotiations. Firms signing the bank’s offer right away draw down their line of credit after origination and default more than late signers. Late signers negotiate price adjustments more frequently, and, consistent with the model, these adjustments predict better ex post performance.
We show that time-varying volatility of volatility is a significant risk factor which affects the cross-section and the time-series of index and VIX option returns, beyond volatility risk itself. Volatility and volatility-of-volatility measures, identified model-free from the option price data as the VIX and VVIX indices, respectively, are only weakly related to each other. Delta-hedged index and VIX option returns are negative on average, and are more negative for strategies which are more exposed to volatility and volatility-of-volatility risks. Volatility and volatility of volatility significantly and negatively predict future delta-hedged option payoffs. The evidence is consistent with a no-arbitrage model featuring time-varying market volatility and volatility-of-volatility factors, both of which have negative market price of risk.
This paper studies the distributional consequences of a systematic variation in expenditure shares and prices. Using European Union Household Budget Surveys and Harmonized Index of Consumer Prices data, we construct household-specific price indices and reveal the existence of a pro-rich inflation in Europe. Particularly, over the period 2001-15, the consumption bundles of the poorest deciles in 25 European countries have, on average, become 10.5 percentage points more expensive than those of the richest decile. We find that ignoring the differential inflation across the distribution underestimates the change in the Gini (based on consumption expenditure) by up to 0.03 points. Cross-country heterogeneity in this change is large enough to alter the inequality ranking of numerous countries. The average inflation effect we detect is almost as large as the change in the standard Gini measure over the period of interest.
The paper analyses the contagion channels of the European financial system through the stochastic block model (SBM). The model groups homogeneous connectivity patterns among the financial institutions and describes the shock transmission mechanisms of the financial networks in a compact way. We analyse the global financial crisis and European sovereign debt crisis and show that the network exhibits a strong community structure with two main blocks acting as shock spreader and receiver, respectively. Moreover, we provide evidence of the prominent role played by insurances in the spread of systemic risk in both crises. Finally, we demonstrate that policy interventions focused on institutions with inter-community linkages (community bridges) are more effective than the ones based on the classical connectedness measures and represents consequently, a better early warning indicator in predicting future financial losses.
The increase in alternative working arrangements has sparked a debate over the positive impact of increased flexibility against the negative impact of decreased financial security. We study the prevalence and determinants of intermediated work in order to document the relative importance of the arguments for and against this recent labor market trend. We link data on individual participation and losses from a Federal Trade Commission settlement with a Multi-Level Marketing firm with detailed county-level information. Participation is greater in middle-income areas and in areas where female labor market non-participation is higher, suggesting that flexibility offers real benefits. However, losses from MLM participation are higher in areas with lower education levels and higher income inequality, suggesting that the downsides of alternative work are particularly high in certain demographics. Our results illustrate that the advantages and disadvantages of alternative work arrangements accrue to different groups.
We develop a simple theoretical model to motivate testable hypotheses about how peer-to-peer (P2P) platforms compete with banks for loans. The model predicts that (i) P2P lending grows when some banks are faced with exogenously higher regulatory costs; (ii) P2P loans are riskier than bank loans; and (iii) the risk-adjusted interest rates on P2P loans are lower than those on bank loans. We confront these predictions with data on P2P lending and the consumer bank credit market in Germany and find empirical support. Overall, our analysis indicates the P2P lenders are bottom fishing when regulatory shocks create a competitive disadvantage for some banks.
In contrast to the popularity of financial education interventions worldwide, studies on the economic effects of those interventions report mixed results. With a focus on the effect on disadvantaged groups, we review both the theoretical and empirical findings in order to understand why this discrepancy exists. The survey first highlights that it is necessary to distinguish between the concepts of, and the relationships between, financial education, financial literacy and financial behavior to identify the true effects of financial education. The review addresses possible biases caused by third factors such as numeracy. Next, we review theories on financial literacy which make clear that the effect of financial education interventions is heterogeneous across the population. Last, we look closely at main empirical studies on financial education targeted at the migrants/immigrants, the low-income earners and the young, and compare their methodologies. There seems to be a positive effect on short-term financial knowledge and awareness of the young, but there is no proven evidence on long-term behavior after being grown up. Studies on financial behavior of migrants and immigrants show almost no effect of financial education.
This paper investigates the effect of the conventional and unconventional (e.g. Quantitative Easing - QE) monetary policy intervention on the insurance industry. We first analyze the impact on the stock performances of 166 (re)insurers from the last QE programme launched by the European Central Bank (ECB) by constructing an event study around the announcement date. Then we enlarge the scope by looking at the monetary policy surprise effects on the same sample of (re)insurers over a timeframe of 12 years, also extending the analysis to the Credit Default Swaps (CDS) market. In the second part of the paper by building a set of balance sheet-based indices, we identify the characteristics of (re)insurers that determine sensitivity to monetary policy actions. Our evidences suggest that a single intervention extrapolated from the comprehensive strategy cannot be utilized to estimate the effect of monetary policy intervention on the market. With respect to the impact of monetary policies, we show how the effect of interventions changes over time. Expansionary monetary policy interventions, when generating an instantaneous reduction of interest rates, generated movement in stock prices in the same direction till September 2010. This effect turned positive during the European sovereign debt crisis. However, the effect faded away in 2014-2015. The pattern is confirmed by the impact on the CDS market. With regard to the determinants of these effects, our analysis suggests that sensitivity is mainly driven by asset allocation and in particular by exposure to fixed income assets.
his paper studies heterogeneity in the reaction to rank feedback. In a laboratory experiment, individuals take part in a series of dynamic real-effort contests with intermediate feedback. To solve the identification problem in estimating the causal effect of rank feedback on subsequent effort provision we implement a random multiplier in the first round of each contest. The realization of this multiplier then serves as a valid instrument for rank feedback. While rank feedback has a robust effect on subsequent effort provision on average, an explicit analysis of between-subject heterogeneity reveals that a substantial fraction of participants in fact react entirely opposite than the aggregated results indicate. We further show that this heterogeneity has consequences for overall outcomes, thereby arguing that heterogeneous sensitivities to rank feedback could have implications for the design of various policies in education and organizations.
Purpose: Anastomotic leakage is a major surgical complication following esophagectomy and gastric pull-up. Specific risk factors such as celiac trunk (TC) stenosis and high calcification score of the aorta have been identified, but no data are available on their relative prognostic values. This retrospective study aimed to compare and evaluate calcification score versus stenosis quantification with regards to prognostic impact on anastomotic leakage.
Patients and methods: Preoperative contrast-enhanced computed tomography scans of 164 consecutive patients with primary esophageal cancer were evaluated by two radiologists to apply a calcification score (0–3 scale) assessing the aorta, the celiac axis and the right and left postceliac arteries. Concurrently, the presence and degree of stenosis of TC and superior mesenteric artery were recorded for stenosis quantification.
Results: Anastomotic leakage was noted in 14/164 patients and 12/14 showed stenosis of TC (n=11). The presence of TC stenosis was found to have a significant impact on anastomotic healing (p=0.004). The odds ratio for the prediction of anastomotic leakage by the degree of stenosis was 1.04 (95% CI, 1.02–1.07). Ten of 14 patients had aortic calcification scores of 1 or 2, but calcification scores of the aorta, the celiac axis and the right and left postceliac arteries did not correlate with the corresponding TC stenosis values and showed no influence on patient outcome as defined by the occurrence of anastomotic insufficiency (p=0.565, 0.855, 0.518 and 1.000, respectively). Inter-reader reliability of computed tomography analysis and absolute agreement on calcium scoring was mostly over 90%. No significant differences in preoperative comorbidities and patient characteristics were found between those with and without anastomotic leakage.
Conclusion: Measurement of TC stenosis in preoperative contrast-enhanced computed tomography scans proved to be more reliable than calcification scores in predicting anastomotic leakage and should, therefore, be used in the risk assessment of patients undergoing esophagectomy and gastric pull-up.
Purpose: All-ceramic restorations required extensive tooth preparation. The purpose of this in vitro study was to investigate a minimally invasive preparation and thickness of monolithic zirconia crowns, which would provide sufficient mechanical endurance and strength.
Materials and methods: Crowns with thickness of 0.2 mm (group 0.2, n=32) or of 0.5 mm (group 0.5, n=32) were milled from zirconia and fixed with resin-based adhesives (groups 0.2A, 0.5A) or zinc phosphate cements (groups 0.2C, 0.5C). Half of the samples in each subgroup (n=8) underwent thermal cycling and mechanical loading (TCML)(TC: 5℃ and 55℃, 2×3,000 cycles, 2 min/cycle; ML: 50 N, 1.2×106 cycles), while the other samples were stored in water (37℃/24 h). Survival rates were compared (Kaplan-Maier). The specimens surviving TCML were loaded to fracture and the maximal fracture force was determined (ANOVA; Bonferroni; α=.05). The fracture mode was analyzed.
Results: In both 0.5 groups, all crowns survived TCML, and the comparison of fracture strength among crowns with and without TCML showed no significant difference (P=.628). Four crowns in group 0.2A and all of the crowns in group 0.2C failed during TCML. The fracture strength after 24 hours of the cemented 0.2 mm-thick crowns was significantly lower than that of adhesive bonded crowns. All cemented crowns provided fracture in the crown, while about 80% of the adhesively bonded crowns fractured through crown and die.
Conclusion: 0.5 mm thick monolithic crowns possessed sufficient strength to endure physiologic performance, regardless of the type of cementation. Fracture strength of the 0.2 mm cemented crowns was too low for clinical application.
With a notional amount outstanding of more than USD 500 trillion, the market for OTC derivatives is of vital importance for global financial stability. A growing proportion of these contracts are cleared via central counterparties (CCPs), which means that CCPs are gaining in importance as critical financial market infrastructures. At the same time, there is growing concern that a new "too big to fail" problem could arise, as the CCP industry is highly concentrated due to economies of scale. From a European perspective, it should be noted that the clearing of euro-denominated OTC derivatives mainly takes place in London, hence outside the EU in the foreseeable future. For some time there has been a controversial discussion as to whether this can remain the case post Brexit.
CCPs, which clear a significant proportion of euro OTC derivatives and are systemically relevant from an EU perspective, should be subject to direct supervision by EU authorities and should be established in the EU. This would represent an important building block for a future Capital Markets Union in Europe, as regulatory or supervisory arbitrage in favour of systemically important third- ountry CCPs could be prevented. In addition, if a systemically relevant CCP handling a considerable portion of the euro OTC derivatives business were to run into serious difficulties, this may impact ECB monetary policy. This applies both to demand for central bank money and to the transmission of monetary policy measures, which can be significantly impaired, particularly in the event that the repo market or payment systems are disrupted. It is therefore essential for the ECB to be closely involved in the supervision of CCPs. Against this background, the draft amendment of EMIR (European Market Infrastructure Regulation) presented on 13 June 2017 is a step in the right direction. In addition, there is an urgent need to introduce a recovery and resolution mechanism for CCPs in the EU to complement the existing single resolution mechanism (SRM) for banks in the eurozone. Only then can the diverse interdependencies between banks and CCPs be adequately taken into account in the recovery and resolution programmes required in a financial crisis.
Mannan-induced Nos2 in macrophages enhances IL-17–driven psoriatic arthritis by innate lymphocytes
(2018)
Previous identification of the inducible nitric oxide synthase (NOS2) gene as a risk allele for psoriasis (Ps) and psoriatic arthritis (PsA) suggests a possible pathogenic role of nitric oxide (NO). Using a mouse model of mannan-induced Ps and PsA (MIP), where macrophages play a regulatory role by releasing reactive oxygen species (ROS), we found that NO was detectable before disease onset in mice, independent of a functional nicotinamide adenine dinucleotide phosphate oxidase 2 complex. MIP was suppressed by either deletion of Nos2 or inhibition of NO synthases with NG-nitro-L-arginine methyl ester, demonstrating that Nos2-derived NO is pathogenic. NOS2 expression was also up-regulated in lipopolysaccharide- and interferon-γ–stimulated monocyte subsets from patients with PsA compared to healthy controls. Nos2-dependent interleukin-1α (IL-1α) release from skin macrophages was essential for arthritis development by promoting IL-17 production of innate lymphoid cells. We conclude that Nos2-derived NO by tissue macrophages promotes MIP, in contrast to the protective effect by ROS.
Selective BRAF inhibitors such as vemurafenib have become a treatment option in patients with Langerhans cell Histiocytosis (LCH). To date, only 14 patients receiving vemurafenib for LCH have been reported. Although vemurafenib can stabilize the clinical condition of these patients, it does not seem to cure the patients, and it is unknown, when and how to stop vemurafenib treatment. We present a girl with severe multisystem LCH who responded only to vemurafenib. After 8 months of treatment, vemurafenib was tapered and replaced by prednisone and vinblastine, a strategy which has not been described to date. Despite chemotherapy, early relapse occurred, but remission was achieved by re-institution of vemurafenib. Further investigation needs to address the optimal duration of vemurafenib therapy in LCH and whether and which chemotherapeutic regimen may prevent disease relapse after cessation of vemurafenib.
Human papilloma virus (HPV) infection is linked to cervical cancer, which represents the world's fourth most common cancer in women. So far, no detailed map of the worldwide HPV research architecture has been constructed. Hence, this study focuses on the chronological development and geographical distribution of the global HPV-specific publications and evaluates citation-based parameters as well as socioeconomic features of the publishing countries.
In total, 29,330 HPV-related publications were identified. The US was the leading country with 12,270 publications. Only high-income-countries were found in the ranking of the fifteen most active countries with Germany, France, and Japan among the top five. Analysis of HPV research activity in relation to the economic strength demonstrated a lead position of Finland and Sweden with an average of 2248.78 and 1924.67 HPV-related publications per GDP in 1000 bn US-$, respectively. The most active upper-middle-income country was Mexico (416.78 HPV-related publications per GDP in 1000 bn US-$). India as lower-middle-income country reached a value of 279.78 HPV-related publications per GDP in 1000 bn US-$. Collaboration analysis pointed to the US as the center of the 4517 international HPV collaborations.
The worldwide HPV-research landscape is dominated by North American and Western European countries. By contrast, a high prevalence of HPV-related cervical cancer is documented for low-income countries. Hence, HPV-related public health interventions and prevention research specifically tailored to these countries needs to be fostered by monetary support and international collaborations.
Background: Sphingolipids are versatile signaling molecules derived from membrane lipids of eukaryotic cells. Ceramides regulate cellular processes such as proliferation, differentiation and apoptosis and are involved in cellular stress responses. Experimental evidence suggests a pivotal role of sphingolipids in the pathogenesis of cardiovascular diseases, including ischemic stroke. A neuroprotective effect has been shown for beta-adrenergic antagonists in rodent stroke models and supported by observational clinical data. However, the exact underlying pathophysiological mechanisms are still under investigation. We aimed to examine the influence of propranolol on the ceramide metabolism in the stroke-affected brain.
Methods: Mice were subjected to 60 or 180 min transient middle cerebral artery occlusion (tMCAO) and infarct size, functional neurological deficits, glucose tolerance, and brain ceramide levels were assessed after 12, 24, and 72 h to evaluate whether the latter two processes occur in a similar time frame. Next, we assessed the effects of propranolol (10 mg/kg bw) at 0, 4 and 8 h after tMCAO and FTY720 (fingolimod; 1 mg/kg) on infarct size, functional outcome, immune cell counts and brain ceramide levels at 24 h after 60 min tMCAO.
Results: We found a temporal coincidence between stroke-associated impaired glucose tolerance and brain ceramide accumulation. Whereas propranolol reduced ischemic lesion size, improved functional outcome and reduced brain ceramide accumulation without an effect on circulating immune cells, FTY720 showed the known neuroprotective effect and strong reduction of circulating immune cells without affecting brain ceramide accumulation.
Conclusions: Propranolol ameliorates both stroke-associated impairment of glucose tolerance and brain ceramide accumulation which are temporally linked, strengthening the evidence for a role of the sympathetic nervous system in regulating post-stroke glucose metabolism and its metabolic consequences in the brain.
5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) is an established pharmacological activator of AMP-activated protein kinase (AMPK). Both, AICAR and AMPK were reported to attenuate inflammation. However, AICAR is known for many AMPK-independent effects, although the mechanisms remain incompletely understood. Here we report a potent suppression of lipopolysaccharide (LPS)-induced inflammatory gene expression by AICAR in primary human macrophages, which occurred independently of its conversion to AMPK-activating 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl monophosphate. Although AICAR did not interfere with activation of cytosolic signalling cascades and nuclear translocation of nuclear factor - κB (NFκB) by LPS, it prevented the recruitment of NFκB and RNA polymerase II to target gene promoters. AICAR also inhibited signal transducer and activator of transcription 3 (STAT3)-dependent induction of interleukin (IL) IL-6 and IL-10 targets, while leaving STAT6 and HIF1α-dependent gene expression in IL-4 and dimethyloxalylgylcine-treated macrophages intact. This points to a transcription factor-specific mode of action. Attenuated gene expression correlated with impaired NFκB and STAT3, but not HIF-binding in electrophoretic mobility shift assays in vitro. Conclusively, AICAR interferes with DNA binding of NFκB and STAT3 to modulate inflammatory responses.
Inducible gene expression is an important tool in molecular biology research to study protein function. Most frequently, the antibiotic doxycycline is used for regulation of so-called tetracycline (Tet)-inducible systems. In contrast to stable gene overexpression, these systems allow investigation of acute and reversible effects of cellular protein induction. Recent reports have already called for caution when using Tet-inducible systems as the employed antibiotics can disturb mitochondrial function and alter cellular metabolism by interfering with mitochondrial translation. Reprogramming of energy metabolism has lately been recognized as an important emerging hallmark of cancer and is a central focus of cancer research. Therefore, the scope of this study was to systematically analyze dose-dependent metabolic effects of doxycycline on a panel of glioma cell lines with concomitant monitoring of gene expression from Tet-inducible systems. We report that doxycycline doses commonly used with inducible expression systems (0.01–1 µg/mL) substantially alter cellular metabolism: Mitochondrial protein synthesis was inhibited accompanied by reduced oxygen and increased glucose consumption. Furthermore, doxycycline protected human glioma cells from hypoxia-induced cell death. An impairment of cell growth was only detectable with higher doxycycline doses (10 µg/mL). Our findings describe settings where doxycycline exerts effects on eukaryotic cellular metabolism, limiting the employment of Tet-inducible systems.
Sphingosine kinase (SK) catalyses the formation of sphingosine 1-phosphate (S1P), which acts as a key regulator of inflammatory and fibrotic reactions, mainly via S1P receptor activation. Here, we show that in the human renal proximal tubular epithelial cell line HK2, the profibrotic mediator transforming growth factor β (TGFβ) induces SK-1 mRNA and protein expression, and in parallel, it also upregulates the expression of the fibrotic markers connective tissue growth factor (CTGF) and fibronectin. Stable downregulation of SK-1 by RNAi resulted in the increased expression of CTGF, suggesting a suppressive effect of SK-1-derived intracellular S1P in the fibrotic process, which is lost when SK-1 is downregulated. In a further approach, the S1P transporter Spns2, which is known to export S1P and thereby reduces intracellular S1P levels, was stably downregulated in HK2 cells by RNAi. This treatment decreased TGFβ-induced CTGF and fibronectin expression, and it abolished the strong induction of the monocyte chemotactic protein 1 (MCP-1) by the pro-inflammatory cytokines tumor necrosis factor (TNF)α and interleukin (IL)-1β. Moreover, it enhanced the expression of aquaporin 1, which is an important water channel that is expressed in the proximal tubules, and reverted aquaporin 1 downregulation induced by IL-1β/TNFα. On the other hand, overexpression of a Spns2-GFP construct increased S1P secretion and it resulted in enhanced TGFβ-induced CTGF expression. In summary, our data demonstrate that in human renal proximal tubular epithelial cells, SK-1 downregulation accelerates an inflammatory and fibrotic reaction, whereas Spns2 downregulation has an opposite effect. We conclude that Spns2 represents a promising new target for the treatment of tubulointerstitial inflammation and fibrosis.
Due to its remote and isolated location, Antarctica is home to a unique diversity of species. The harsh conditions have shaped a primarily highly adapted endemic fauna. This includes the notothenioid family Channichthyidae. Their exceptional physiological adaptations have made this family of icefish the focus of many studies. However, studies on their ecology, especially on their parasite fauna, are comparatively rare. Parasites, directly linked to the food chain, can function as biological indicators and provide valuable information on host ecology (e.g., trophic interactions) even in remote habitats with limited accessibility, such as the Southern Ocean. In the present study, channichthyid fish (Champsocephalus gunnari: n = 25, Chaenodraco wilsoni: n = 33, Neopagetopsis ionah: n = 3, Pagetopsis macropterus: n = 4, Pseudochaenichthys georgianus: n = 15) were collected off South Shetland Island, Elephant Island, and the tip of the Antarctic Peninsula (CCAML statistical subarea 48.1). The parasite fauna consisted of 14 genera and 15 species, belonging to the six taxonomic groups including Digenea (four species), Nematoda (four), Cestoda (two), Acanthocephala (one), Hirudinea (three), and Copepoda (one). The stomach contents were less diverse with only Crustacea (Euphausiacea, Amphipoda) recovered from all examined fishes. Overall, 15 new parasite-host records could be established, and possibly a undescribed genotype or even species might exist among the nematodes.
Biological invasions have been associated with niche changes; however, their occurrence is still debated. We assess whether climatic niches between native and non-native ranges have changed during the invasion process using two globally spread mosquitoes as model species, Aedes albopictus and Aedes aegypti. Considering the different time spans since their invasions (>300 vs. 30–40 years), niche changes were expected to be more likely for Ae. aegypti than for Ae. albopictus. We used temperature and precipitation variables as descriptors for the realized climatic niches and different niche metrics to detect niche dynamics in the native and non-native ranges. High niche stability, therefore, no niche expansion but niche conservatism was revealed for both species. High niche unfilling for Ae. albopictus indicates a great potential for further expansion. Highest niche occupancies in non-native ranges occurred either under more temperate (North America, Europe) or tropical conditions (South America, Africa). Aedes aegypti has been able to fill its native climatic niche in the non-native ranges, with very low unfilling. Our results challenge the assumption of rapid evolutionary change of climatic niches as a requirement for global invasions but support the use of native range-based niche models to project future invasion risk on a large scale.
Borrelia burgdorferi sensu lato (Bbsl), the causative agent of Lyme disease, establishes an initial infection in the host’s skin following a tick bite, and then disseminates to distant organs, leading to multisystem manifestations. Tick-to-vertebrate host transmission requires that Bbsl survives during blood feeding. Complement is an important innate host defense in blood and interstitial fluid. Bbsl produces a polymorphic surface protein, CspA, that binds to a complement regulator, Factor H (FH) to block complement activation in vitro. However, the role that CspA plays in the Bbsl enzootic cycle remains unclear. In this study, we demonstrated that different CspA variants promote spirochete binding to FH to inactivate complement and promote serum resistance in a host-specific manner. Utilizing a tick-to-mouse transmission model, we observed that a cspA-knockout B. burgdorferi is eliminated from nymphal ticks in the first 24 hours of feeding and is unable to be transmitted to naïve mice. Conversely, ectopically producing CspA derived from B. burgdorferi or B. afzelii, but not B. garinii in a cspA-knockout strain restored spirochete survival in fed nymphs and tick-to-mouse transmission. Furthermore, a CspA point mutant, CspA-L246D that was defective in FH-binding, failed to survive in fed nymphs and at the inoculation site or bloodstream in mice. We also allowed those spirochete-infected nymphs to feed on C3-/- mice that lacked functional complement. The cspA-knockout B. burgdorferi or this mutant strain complemented with cspA variants or cspA-L246D was found at similar levels as wild type B. burgdorferi in the fed nymphs and mouse tissues. These novel findings suggest that the FH-binding activity of CspA protects spirochetes from complement-mediated killing in fed nymphal ticks, which ultimately allows Bbsl transmission to mammalian hosts.
SAFE Newsletter : 2018, Q1
(2018)
Epithelial-to-mesenchymal transition (EMT) is supposed to be responsible for increased invasion and metastases in epithelial cancer cells. The activation of EMT genes has further been proposed to be important in the process of malignant transformation of primary CNS tumors. Since the cellular source and clinical impact of EMT factors in primary CNS tumors still remain unclear, we aimed at deciphering their distribution in vivo and clinico-pathological relevance in human gliomas.
We investigated 350 glioma patients for the expression of the key EMT factors SLUG and TWIST by immunohistochemistry and immunofluorescence related to morpho-genetic alterations such as EGFR-amplification, IDH-1 (R132H) mutation and 1p/19q LOH. Furthermore, transcriptional cluster and survival analyses were performed.
Our data illustrate that SLUG and TWIST are overexpressed in gliomas showing vascular proliferation such as pilocytic astrocytomas and glioblastomas. EMT factors are exclusively expressed by non-neoplastic pericytes/vessel-associated mural cells (VAMCs). They are not associated with patient survival but correlate with pericytic/VAMC genes in glioblastoma cluster analysis.
In summary, the upregulation of EMT genes in pilocytic astrocytomas and glioblastomas reflects the level of activation of pericytes/VAMCs in newly formed blood vessels. Our results underscore that the negative prognostic potential of the EMT signature in the group of diffuse gliomas of WHO grade II-IV does most likely not derive from glioma cells but rather reflects the degree of proliferating mural cells thereby constituting a potential target for future alternative treatment approaches.
The spindle assembly checkpoint (SAC) acts as a molecular safeguard in ensuring faithful chromosome transmission during mitosis, which is regulated by a complex interplay between phosphatases and kinases including PLK1. Adenomatous polyposis coli (APC) germline mutations cause aneuploidy and are responsible for familial adenomatous polyposis (FAP). Here we study the role of PLK1 in colon cancer cells with chromosomal instability promoted by APC truncation (APC-ΔC). The expression of APC-ΔC in colon cells reduces the accumulation of mitotic cells upon PLK1 inhibition, accelerates mitotic exit and increases the survival of cells with enhanced chromosomal abnormalities. The inhibition of PLK1 in mitotic, APC-∆C-expressing cells reduces the kinetochore levels of Aurora B and hampers the recruitment of SAC component suggesting a compromised mitotic checkpoint. Furthermore, Plk1 inhibition (RNAi, pharmacological compounds) promotes the development of adenomatous polyps in two independent ApcMin/+ mouse models. High PLK1 expression increases the survival of colon cancer patients expressing a truncated APC significantly.
Division of labor and task specialization explain the success of human and insect societies. Social insect colonies are characterized by division of labor, with workers specializing in brood care early and foraging later in life. Theory posits that this task switching requires shifts in responsiveness to task-related cues, yet experimental evidence is weak. Here, we show that a Vitellogenin (Vg) ortholog identified in an RNAseq study on the ant T. longispinosus is involved in this process: using phylogenetic analyses of Vg and Vg-like genes, we firstly show that this candidate gene does not cluster with the intensively studied honey bee Vg but falls into a separate Vg-like A cluster. Secondly, an experimental knockdown of Vg-like A in the fat body caused a reduction in brood care and an increase in nestmate care in young ant workers. Nestmate care is normally exhibited by older workers. We demonstrate experimentally that this task switch is at least partly based on Vg-like A–associated shifts in responsiveness from brood to worker cues. We thus reveal a novel mechanism leading to early behavioral maturation via changes in social cue responsiveness mediated by Vg-like A and associated pathways, which proximately play a role in regulating division of labor.
Objectives: The aim of this multicenter retrospective study was to investigate safety and efficacy of direct acting antiviral (DAA) treatment in the rare subgroup of patients with HCV/HIV-coinfection and advanced liver cirrhosis on the liver transplant waiting list or after liver transplantation, respectively.
Methods: When contacting 54 German liver centers (including all 23 German liver transplant centers), 12 HCV/HIV-coinfected patients on antiretroviral combination therapy were reported having received additional DAA therapy while being on the waiting list for liver transplantation (patient characteristics: Child-Pugh A (n = 6), B (n = 5), C (n = 1); MELD range 7–21; HCC (n = 2); HCV genotype 1a (n = 8), 1b (n = 2), 4 (n = 2)). Furthermore, 2 HCV/HIV-coinfected patients were denoted having received DAA therapy after liver transplantation (characteristics: HCV genotype 1a (n = 1), 4 (n = 1)).
Results: Applied DAA regimens were SOF/DAC (n = 7), SOF/LDV/RBV (n = 3), SOF/RBV (n = 3), PTV/r/OBV/DSV (n = 1), or PTV/r/OBV/DSV/RBV (n = 1), respectively. All patients achieved SVR 12, in the end. In one patient, HCV relapse occurred after 24 weeks of SOF/DAC therapy; subsequent treatment with 12 weeks PTV/r/OBV/DSV achieved SVR 12. One patient underwent liver transplantation while on DAA treatment. Analysis of liver function revealed either stable parameters or even significant improvement during DAA therapy and in follow-up. MELD scores were found to improve in 9/13 therapies in patients on the waiting list for liver transplantation; in only 2 patients a moderate increase of MELD scores persisted at the end of follow-up.
Conclusion: DAA treatment was safe and highly effective in this nation-wide cohort of patients with HCV/HIV-coinfection awaiting liver transplantation or being transplanted.
Purpose: Stereotactic radiosurgery (SRS) is an established primary treatment for newly diagnosed brain metastases with high local control rates. However, data about local re-irradiation in case of local failure after SRS (re-SRS) are rare. We evaluated the feasibility, efficacy and patient selection characteristics in treating locally recurrent metastases with a second course of SRS.
Methods: We retrospectively evaluated patients with brain metastases treated with re-SRS for local tumor progression between 2011 and 2017. Patient and treatment characteristics as well as rates of tumor control, survival and toxicity were analyzed.
Results: Overall, 32 locally recurrent brain metastases in 31 patients were irradiated with re-SRS. Median age at re-SRS was 64.9 years. The primary histology was breast cancer and non-small-cellular lung cancer (NSCLC) in respectively 10 cases (31.3%), in 5 cases malignant melanoma (15.6%). In the first SRS-course 19 metastases (59.4%) and in the re-SRS-course 29 metastases (90.6%) were treated with CyberKnife® and the others with Gamma Knife. Median planning target volume (PTV) for re-SRS was 2.5 cm3 (range, 0.1–37.5 cm3) and median dose prescribed to the PTV was 19 Gy (range, 12–28 Gy) in 1–5 fractions to the median 69% isodose (range, 53–80%). The 1-year overall survival rate was 61.7% and the 1-year local control rate was 79.5%. The overall rate of radiological radio-necrosis was 16.1% and four patients (12.9%) experienced grade ≥ 3 toxicities.
Conclusions: A second course of SRS for locally recurrent brain metastases after prior local SRS appears to be feasible with acceptable toxicity and can be considered as salvage treatment option for selected patients with high performance status. Furthermore, this is the first study utilizing robotic radiosurgery for this indication, as an additional option for frameless fractionated treatment.
Indication for combined cardiac surgery and orthotopic liver transplantation is rare and patients are at high risks. Individual surgical strategy must be developed since a general standard of such procedure does not exist. We report the case of a 45-year-old woman who underwent simultaneously modified Bentall procedure and orthotopic liver transplantation. Underlying diseases were end-stage polycystic liver, aneurysm of the ascending aorta, and severe aortic regurgitation. To avoid prolonged bypass times, both teams worked simultaneously. During cardiac reperfusion, time inferior vena cava stayed ligated while the cyst liver was explanted.
Background. The placement of an implant in a previously infected site is an important etiologic factor contributing to implant failure. The aim of this case report is to present the management of retrograde peri-implantitis (RPI) in a first maxillary molar site, 2 years after the implant placement. The RPI was treated using an air-abrasive device, Er,Cr:YSGG laser, and guided bone regeneration (GBR).
Case Description. A 65-year-old Caucasian male presented with a draining fistula associated with an implant at tooth #3. Tooth #3 revealed periapical radiolucency two years before the implant placement. Tooth #3 was extracted, and a ridge preservation procedure was performed followed by implant rehabilitation. A periapical radiograph (PA) showed lack of bone density around the implant apex. The site was decontaminated with an air-abrasive device and Er,Cr:YSGG laser, and GBR was performed. The patient was seen every two weeks until suture removal, followed by monthly visits for 12 months. The periapical X-rays, from 6 to 13 months postoperatively, showed increased bone density around the implant apex, with no signs of residual clinical or radiographic pathology and probing depths ≤4 mm.
Conclusions. The etiology of RPI in this case was the placement of an implant in a previously infected site. The use of an air-abrasive device, Er,Cr:YSGG, and GBR was utilized to treat this case of RPI. The site was monitored for 13 months, and increased radiographic bone density was noted.
Learning, memory consolidation, and retrieval are processes known to be modulated by the circadian (circa: about; dies: day) system. The circadian regulation of memory performance is evolutionarily conserved, independent of the type and complexity of the learning paradigm tested, and not specific to crepuscular, nocturnal, or diurnal organisms. In mammals, long-term memory (LTM) formation is tightly coupled to de novo gene expression of plasticity-related proteins and posttranslational modifications and relies on intact cAMP/protein kinase A (PKA)/protein kinase C (PKC)/mitogen-activated protein kinase (MAPK)/cyclic adenosine monophosphate response element-binding protein (CREB) signaling. These memory-essential signaling components cycle rhythmically in the hippocampus across the day and night and are clearly molded by an intricate interplay between the circadian system and memory. Important components of the circadian timing mechanism and its plasticity are members of the Period clock gene family (Per1, Per2). Interestingly, Per1 is rhythmically expressed in mouse hippocampus. Observations suggest important and largely unexplored roles of the clock gene protein PER1 in synaptic plasticity and in the daytime-dependent modulation of learning and memory. Here, we review the latest findings on the role of the clock gene Period 1 (Per1) as a candidate molecular and mechanistic blueprint for gating the daytime dependency of memory processing.
Modification of SMN2 exon 7 (E7) splicing is a validated therapeutic strategy against spinal muscular atrophy (SMA). However, a target-based approach to identify small-molecule E7 splicing modifiers has not been attempted, which could reveal novel therapies with improved mechanistic insight. Here, we chose as a target the stem-loop RNA structure TSL2, which overlaps with the 5′ splicing site of E7. A small-molecule TSL2-binding compound, homocarbonyltopsentin (PK4C9), was identified that increases E7 splicing to therapeutic levels and rescues downstream molecular alterations in SMA cells. High-resolution NMR combined with molecular modelling revealed that PK4C9 binds to pentaloop conformations of TSL2 and promotes a shift to triloop conformations that display enhanced E7 splicing. Collectively, our study validates TSL2 as a target for small-molecule drug discovery in SMA, identifies a novel mechanism of action for an E7 splicing modifier, and sets a precedent for other splicing-mediated diseases where RNA structure could be similarly targeted.
The use of cardiac troponins (cTn) is the gold standard for diagnosing myocardial infarction. Independent of myocardial infarction (MI), however, sex, age and kidney function affect cTn levels. Here we developed a method to adjust cTnI levels for age, sex, and renal function, maintaining a unified cut-off value such as the 99th percentile. A total of 4587 individuals enrolled in a prospective longitudinal study were used to develop a model for adjustment of cTn. cTnI levels correlated with age and estimated glomerular filtration rate (eGFR) in males/females with rage = 0.436/0.518 and with reGFR = −0.142/−0.207. For adjustment, these variables served as covariates in a linear regression model with cTnI as dependent variable. This adjustment model was then applied to a real-world cohort of 1789 patients with suspected acute MI (AMI) (N = 407). Adjusting cTnI showed no relevant loss of diagnostic information, as evidenced by comparable areas under the receiver operator characteristic curves, to identify AMI in males and females for adjusted and unadjusted cTnI. In specific patients groups such as in elderly females, adjusting cTnI improved specificity for AMI compared with unadjusted cTnI. Specificity was also improved in patients with renal dysfunction by using the adjusted cTnI values. Thus, the adjustments improved the diagnostic ability of cTnI to identify AMI in elderly patients and in patients with renal dysfunction. Interpretation of cTnI values in complex emergency cases is facilitated by our method, which maintains a single diagnostic cut-off value in all patients.
The tumor vasculature differs from normal blood vessels in morphology, composition and stability. Here, we describe a novel tumor vessel-disrupting mechanism. In an HT1080/mouse xenograft tumor model rhodocetin-αβ was highly effective in disrupting the tumor endothelial barrier. Mechanistically, rhodocetin-αβ triggered MET signaling via neuropilin-1. As both neuropilin-1 and MET were only lumen-exposed in a subset of abnormal tumor vessels, but not in normal vessels, the prime target of rhodocetin-αβ were these abnormal tumor vessels. Consequently, cells lining such tumor vessels became increasingly motile which compromised the vessel wall tightness. After this initial leakage, rhodocetin-αβ could leave the bloodstream and reach the as yet inaccessible neuropilin-1 on the basolateral side of endothelial cells and thus disrupt nearby vessels. Due to the specific neuropilin-1/MET co-distribution on cells lining such abnormal tumor vessels in contrast to normal endothelial cells, rhodocetin-αβ formed the necessary trimeric signaling complex of rhodocetin-αβ-MET-neuropilin-1 only in these abnormal tumor vessels. This selective attack of tumor vessels, sparing endothelial cell-lined vessels of normal tissues, suggests that the neuropilin-1-MET signaling axis may be a promising drugable target for anti-tumor therapy, and that rhodocetin-αβ may serve as a lead structure to develop novel anti-tumor drugs that target such vessels.
The etiology of many diseases results from the dysregulation of inflammation. Understanding the molecular mechanisms controlling the inflammatory response is essential to formulate therapeutic strategies for the treatment of inflammatory conditions. In fact, substantial research has unveiled important aspects of the inflammatory machinery, both at the cellular and molecular levels. Recently, sphingolipids (Sph) have emerged as signaling molecules that regulate many cell functions, and ample evidence emphasizes their role in the regulation of inflammatory responses. ...
B lymphocytes are key players in humoral immunity, expressing diverse surface immunoglobulin receptors directed against specific antigenic epitopes. The development and profile of distinct subpopulations have gained awareness in the setting of primary immunodeficiency disorders, primary or secondary autoimmunity and as therapeutic targets of specific antibodies in various diseases. The major B cell subpopulations in peripheral blood include naïve (CD19+ or CD20+IgD+CD27−), non-switched memory (CD19+ or CD20+IgD+CD27+) and switched memory B cells (CD19+ or CD20+IgD−CD27+). Furthermore, less common B cell subpopulations have also been described as having a role in the suppressive capacity of B cells to maintain self-tolerance. Data on reference values for B cell subpopulations are limited and only available for older age groups, neglecting the continuous process of human B cell development in children and adolescents. This study was designed to establish an exponential regression model to produce continuous reference values for main B cell subpopulations to reflect the dynamic maturation of the human immune system in healthy children.
An iridium(III/IV/V) redox series featuring a terminal imido complex with triplet ground state
(2018)
The iridium(III/IV/V) imido redox series [Ir(NtBu){N(CHCHPtBu2)2}]0/+/2+ was synthesized and examined spectroscopically, magnetically, crystallographically and computationally. The monocationic iridium(IV) imide exhibits an electronic doublet ground state with considerable ‘imidyl’ character as a result of covalent Ir–NtBu bonding. Reduction gives the neutral imide [Ir(NtBu){N(CHCHPtBu2)2}] as the first example of an iridium complex with a triplet ground state. Its reactivity with respect to nitrene transfer to selected electrophiles (CO2) and nucleophiles (PMe3), respectively, is reported.
Organoboranes are among the most versatile and widely used reagents in synthetic chemistry. A significant further expansion of their application spectrum would be achievable if boron-containing reactive intermediates capable of inserting into C–H bonds or performing nucleophilic substitution reactions were readily available. However, current progress in the field is still hampered by a lack of universal design concepts and mechanistic understanding. Herein we report that the doubly arylene-bridged diborane(6) 1H2 and its B[double bond, length as m-dash]B-bonded formal deprotonation product Li2[1] can activate the particularly inert C(sp3)–H bonds of added H3CLi and H3CCl, respectively. The first case involves the attack of [H3C]− on a Lewis-acidic boron center, whereas the second case follows a polarity-inverted pathway with nucleophilic attack of the B[double bond, length as m-dash]B double bond on H3CCl. Mechanistic details were elucidated by means of deuterium-labeled reagents, a radical clock, α,ω-dihaloalkane substrates, the experimental identification of key intermediates, and quantum-chemical calculations. It turned out that both systems, H3CLi/1H2 and H3CCl/Li2[1], ultimately funnel into the same reaction pathway, which likely proceeds past a borylene-type intermediate and requires the cooperative interaction of both boron atoms.
Quercetin is a flavonoid that is ubiquitously found in vegetables and fruits. Like other flavonoids, it is active in balancing cellular reactive oxygen species (ROS) levels and has a cyto-protective function. Previously, a link between ROS balancing, aging, and the activity of O-methyltransferases was reported in different organisms including the aging model Podospora anserina. Here we describe a role of the S-adenosylmethionine-dependent O-methyltransferase PaMTH1 in quercetin-induced lifespan extension. We found that effects of quercetin treatment depend on the methylation state of the flavonoid. Specifically, we observed that quercetin treatment increases the lifespan of the wild type but not of the PaMth1 deletion mutant. The lifespan increasing effect is not associated with effects of quercetin on mitochondrial respiration or ROS levels but linked to the induction of the PaMth1 gene. Overall, our data demonstrate a novel role of O-methyltransferase in quercetin-induced longevity and identify the underlying pathway as part of a network of longevity assurance pathways with the perspective to intervene into mechanisms of biological aging.
Purpose: DINO and DACOTA were prospective, noninterventional studies assessing the health status and quality of life of patients with COPD newly treated with roflumilast 500 µg once-daily add-on therapy.
Patients and methods: Patients were evaluated over 6 months. Clinical COPD questionnaire (CCQ) and COPD assessment test (CAT) scores were recorded at baseline and after 3 and 6 months. In DACOTA, post-bronchodilator FEV1 was recorded at each time point.
Results: Of 5,462 and 3,645 patients recruited into DINO and DACOTA, respectively, 3,274 patients in DINO and 916 patients in DACOTA completed the 6-month visit. Almost all patients had severe or very severe airway obstruction; mean baseline CCQ total score was 3.9 in DINO and 3.7 in DACOTA. Overall, 33.8% of patients in DACOTA and 30.6% in DINO discontinued treatment prematurely. Significant and clinically relevant improvements in CCQ total scores were observed in both studies (mean change from baseline of 1.36 in DINO and 0.91 in DACOTA at Month 6 [all P<0.001]). Changes in CAT total score from baseline to Month 6 indicated that the average clinical impact of COPD was reduced from a severe (score: 21–30) to a moderate (score: 11–20) impairment. In DACOTA, mean change in post-bronchodilator FEV1 was 202 mL (P<0.001). Diarrhea, nausea, and weight decrease were the most frequently reported adverse drug reactions.
Conclusion: In real-life clinical practice, roflumilast treatment as an add-on therapy is associated with clinically relevant improvements in health status and quality of life.
In this thesis we introduce the imaginary projection of (multivariate) polynomials as the projection of their variety onto its imaginary part, I(f) = { Im(z_1, ... , z_n) : f(z_1, ... , z_n) = 0 }. This induces a geometric viewpoint to stability, since a polynomial f is stable if and only if its imaginary projection does not intersect the positive orthant. Accordingly, the thesis is mainly motivated by the theory of stable polynomials.
Interested in the number and structure of components of the complement of imaginary projections, we show as a key result that there are only finitely many components which are all convex. This offers a connection to the theory of amoebas and coamoebas as well as to the theory of hyperbolic polynomials.
For hyperbolic polynomials, we show that hyperbolicity cones coincide with components of the complement of imaginary projections, which provides a strong structural relationship between these two sets. Based on this, we prove a tight upper bound for the number of hyperbolicity cones and, respectively, for the number of components of the complement in the case of homogeneous polynomials. Beside this, we investigate various aspects of imaginary projections and compute imaginary projections of several classes explicitly.
Finally, we initiate the study of a conic generalization of stability by considering polynomials whose roots have no imaginary part in the interior of a given real, n-dimensional, proper cone K. This appears to be very natural, since many statements known for univariate and multivariate stable polynomials can be transferred to the conic situation, like the Hermite-Biehler Theorem and the Hermite-Kakeya-Obreschkoff Theorem. When considering K to be the cone of positive semidefinite matrices, we prove a criterion for conic stability of determinantal polynomials.
The endoplasmic-reticulum-associated protein degradation pathway ensures quality control of newly synthesized soluble and membrane proteins of the secretory pathway. Proteins failing to fold into their native structure are processed in a multistep process and finally ubiquitinated and degraded by the proteasome in order to protect the cell from proteotoxic stress. My thesis covers structural as well as functional studies of various protein components that constitute the protein complexes that are responsible for this process.
One sub-project addressed the mechanism of glycan recognition by Yos9 as part of the ERAD substrate selection. NMR solution structures of the mannose-6-phosphate homology (MRH) domain of Yos9 both in a free and glycan bound conformation reveal a gripping movement of loop regions upon binding of correctly processed glycan structures.
The main projects focused on revealing the mechanism of efficient ubiquitin chain assembly by the ERAD ubiquitination machinery. This included the investigation of the role of the ERAD components Cue1 and Ubc7 in processive ubiquitin chain formation, how ubiquitin chain conformations change during elongation, how the conformation of a chain is impacted by interacting proteins and finally understand the activity regulation of the ERAD E2 enzyme Ubc7 by its cognate RING E3 ligases. Nuclear magnetic resonance (NMR) analysis and fluorescence-based ubiquitination assays show that the CUE domain of Cue1 contributes with its proximal binding preference as well as with its position dependent accelerating effect to efficient ubiquitin chain formation. This is required to efficiently drive degradation of substrates. Specific ubiquitin binding events dictate and coordinate the spatial arrangement of the E2 enzyme relative to the distal tip of a chain. This process can be further accelerated by RING E3 ligases that promote Ubc7 activity by more than ~20 fold via inducing allosteric changes around the catalytic cysteine. My results additionally suggest a model where Ubc7 dimerization results in proximity induced activation of the E2. This data ensures rapid diubiquitin formation that is followed by a CUE domain assisted chain elongation mechanism where Cue1 acts in an E4 like fashion.
How ubiquitin binding events can modulate the conformations of a ubiquitin chain were investigated by pulsed electron-electron double resonance (PELDOR) spectroscopy combined with molecular modeling. This shows that K48-linked diubiquitin samples a broad conformational space which can be modulated in distinct ways. The CUE domain of Cue1 uses conformational selection of pre-populated open conformations to support ubiquitin chain elongation. In contrast, deubiquitinating enzymes shift the conformational distribution to weakly or even non-populated conformations to allow cleavage of the isopeptide bond that connects adjacent ubiquitins. Ubiquitin chain elongation increases the sampled conformational space and suggests that this high conformational flexibility might contribute to efficient proteasomal recognition.
Background: Does the dogma of nephron sparing surgery (NSS) still stand for large renal masses? Available studies dealing with that issue are considerably biased often mixing imperative with elective indications for NSS and also including less malignant variants or even benign renal tumors. Here, we analyzed the oncological long-term outcomes of patients undergoing elective NSS or radical tumor nephrectomy (RN) for non-endophytic, large (≥7cm) clear cell renal carcinoma (ccRCC).
Methods: Prospectively acquired, clinical databases from two academic high-volume centers were screened for patients from 1980 to 2010. The query was strictly limited to patients with elective indications. Surgical complications were retrospectively assessed and classified using the Clavien-Dindo-classification system (CDS). Overall survival (OS) and cancer specific survival (CSS) were analyzed using the Kaplan-Meier-method and the log-rank test.
Results: Out of in total 8664 patients in the databases, 123 patients were identified (elective NSS (n = 18) or elective RN (n = 105)) for ≥7cm ccRCC. The median follow-up over all was 102 months (range 3–367 months). Compared to the RN group, the NSS group had a significantly longer median OS (p = 0.014) and median CSS (p = 0.04).
Conclusions: In large renal masses, NSS can be performed safely with acceptable complication rates. In terms of long-term OS and CSS, NSS was at least not inferior to RN. Our findings suggest that NSS should also be performed in patients presenting with renal tumors ≥7cm whenever technically feasible. Limitations include its retrospective nature and the limited availability of data concerning long-term development of renal function in the two groups.
Consistent individual differences in behavioral tendencies (animal personality) can affect individual mate choice decisions. We asked whether personality traits affect male and female mate choice decisions similarly and whether potential personality effects are consistent across different mate choice situations. Using western mosquitofish (Gambusia affinis) as our study organism, we characterized focal individuals (males and females) twice for boldness, activity, and sociability/shoaling and found high and significant behavioral repeatability. Additionally, each focal individual was tested in two different dichotomous mate choice tests in which it could choose between computer-animated stimulus fish of the opposite sex that differed in body size and activity levels, respectively. Personality had different effects on female and male mate choice: females that were larger than average showed stronger preferences for large-bodied males with increasing levels of boldness/activity (i.e., towards more proactive personality types). Males that were larger than average and had higher shoaling tendencies showed stronger preferences for actively swimming females. Size-dependent effects of personality on the strength of preferences for distinct phenotypes of potential mating partners may reflect effects of age/experience (especially in females) and social dominance (especially in males). Previous studies found evidence for assortative mate choice based on personality types or hypothesized the existence of behavioral syndromes of individuals’ choosiness across mate choice criteria, possibly including other personality traits. Our present study exemplifies that far more complex patterns of personality-dependent mate choice can emerge in natural systems.
Cdc2-like kinases (CLKs) represent a family of serine-threonine kinases involved in the regulation of splicing by phosphorylation of SR-proteins and other splicing factors. Although compounds acting against CLKs have been described, only a few show selectivity against dual-specificity tyrosine phosphorylation regulated-kinases (DYRKs). We here report a novel CLK inhibitor family based on a 6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one core scaffold. Within the series, 3-(3-chlorophenyl)-6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one (KuWal151) was identified as inhibitor of CLK1, CLK2 and CLK4 with a high selectivity margin towards DYRK kinases. The compound displayed a potent antiproliferative activity in an array of cultured cancer cell lines. The X-ray structure analyses of three members of the new compound class co-crystallized with CLK proteins corroborated a molecular binding mode predicted by docking studies.
Understanding the spatial and temporal dynamics of species assemblages is a main challenge in ecology. The mechanisms that shape species assemblages and their temporal fluctuations along tropical elevational gradients are particularly poorly understood. Here, we examined the spatio-temporal dynamics of bird assemblages along an elevational gradient in Ecuador. We conducted bird point counts at three elevations (1000, 2000 and 3000 m) on 18 1-ha plots and repeated the sampling eight times over two years (216 hours in total). For each plot, we obtained data of monthly temperatures and precipitation and recorded the overall resource availability (i.e., the sum of flower, fruit, and invertebrate resources). As expected, bird richness decreased from low to high elevations. Moreover, we found a significant decrease in bird abundance and richness and an increase in evenness between the most and least humid season at each of the three elevations. Climatic factors were more closely related to these temporal fluctuations than local resource availability. While temperature had significant positive effects on the abundance of birds at mid and high elevations, precipitation negatively affected bird abundance at low and mid elevations. Our study highlights that bird assemblages along tropical elevational gradients can show pronounced seasonal fluctuations. In particular, low temperatures and high precipitation seem to impose important constraints on birds. We conclude that potential changes in climate, due to global warming, are likely to affect the spatio-temporal dynamics of bird assemblages along tropical elevational gradients.
Background: Glaucoma is a neurodegenerative disease, leading to thinning of the retinal nerve fibre layer (RNFL). The exact influence of ocular, cardiovascular, morphometric, lifestyle and cognitive factors on RNFL thickness (RNFLT) is unknown and was analysed in a subgroup of the Gutenberg Health Study (GHS).
Methods: Global peripapillary RNFLT was measured in 3224 eyes of 1973 subjects (49% female) using spectral-domain optical coherence tomography (SD-OCT). The association of age, sex, ocular, cardiovascular, morphometric, lifestyle and cognitive factors on RNFLT was analysed using Pearson correlation coefficient and fitting a linear mixed model.
Results: In the univariable analysis highest correlations were found for axial length (r = -0.27), spherical equivalent (r = 0.24), and glaucoma (r = -0.15) (p<0.0001, respectively). Other significant correlations with RNFLT were found for age, sex, intraocular pressure, systemic hypertension and systolic blood pressure, previous eye surgery, cholesterol, homocysteine, history of coronary artery disease, history of myocardial infarction, apnoea, diabetes and alcohol intake, p<0.05, respectively. Body length, body weight, BMI, diastolic blood pressure, blood glucose, HbA1c, history of apoplexy, cognitive function, peripheral artery disease, tinnitus, migraine, nicotine intake, central corneal thickness, and pseudophakia were not significantly correlated with RNFLT. The regression model revealed a significant relationship between RNFLT and age in decades (p<0.02), spherical equivalent (p<0.0001), axial length (p<0.0001), glaucoma (p<0.0001), tinnitus (p = 0.04), apnoea (p = 0.047), homocysteine (p = 0.05) and alcohol intake >10g/d for women and >20g/d for men (p = 0.02). Glaucoma, apnoea, higher homocysteine, higher alcohol intake and higher axial length as well as age were related to decreased RNFLT while higher spherical equivalent or history for tinnitus were related to thicker RNFL.
Conclusion: RNFLT is related to age, ocular parameters and lifestyle factors. Considering these parameters in normative databases could improve the evaluation of peripapillary RNFLT. It is necessary to evaluate if a reduction of alcohol intake as well as the therapy of apnea or high homocysteine levels could positively influence RNFLT.
Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract infection in early childhood. Underlying pathomechanisms of elevated pulmonary morbidity in later infancy are largely unknown. We found that RSV‐infected H441 cells showed increased mRNA expression of connective tissue growth factor (CTGF), a key factor in airway remodeling. Additional dexamethasone treatment led to further elevated mRNA levels, indicating additive effects. Caffeine treatment prevented RSV‐mediated increase in CTGF mRNA. RSV may be involved in airway remodeling processes by increasing CTGF mRNA expression. Caffeine might abrogate these negative effects and thereby help to restore lung homeostasis.
Extracellular vesicles (EVs) are increasingly recognized as important mediators of intercellular communication. In this study, we aimed to further characterize the role of macrophage-derived EVs in immune responses against hepatitis C virus (HCV) and the potential of polyunsaturated fatty acids (PUFAs) to modulate this modality of innate immunity. To this end, EVs were isolated from interferon-stimulated macrophage cultures or from serum of patients with acute or chronic hepatitis C. EVs were characterized by electron microscopy, flow cytometry, RNA-sequencing, and Western blot analysis. The effect of EVs on replication of HCV was assessed in coculture models. Functional analyses were performed to assess the impact of PUFAs on EV-mediated antiviral immunity. We found that macrophages secreted various cytokines shortly after stimulation with type I and II IFN, which orchestrated a fast but short-lasting antiviral state. This rapid innate immune answer was followed by the production of macrophage-derived EVs, which induced a late, but long-lasting inhibitory effect on HCV replication. Of note, exposure of macrophages to PUFAs, which are important regulators of immune responses, dampened EV-mediated antiviral immune responses. Finally, EVs from patients with hepatitis C exhibited long-lasting antiviral activities during IFN therapy as well. The antiviral effect of EVs from Caucasian and Japanese patients differed, which may be explained by different nutritional uptake of PUFAs. In conclusion, our data indicate that macrophage-derived EVs mediate long-lasting inhibitory effects on HCV replication, which may bridge the time until efficient adaptive immune responses are established, and which can be blunted by PUFAs.
Background/Aims: Signaling of Gs protein-coupled receptors (GsPCRs) is accomplished by stimulation of adenylyl cyclase, causing an increase of the intracellular cAMP concentration, activation of the intracellular cAMP effectors protein kinase A (PKA) and Epac, and an efflux of cAMP, the function of which is still unclear.
Methods: Activation of adenylyl cyclase by GsPCR agonists or cholera toxin was monitored by measurement of the intracellular cAMP concentration by ELISA, anti-phospho-PKA substrate motif phosphorylation by immunoblotting, and an Epac-FRET assay in the presence and absence of adenosine receptor antagonists or ecto-nucleotide phosphodiesterase/pyrophosphatase2 (eNPP2) inhibitors. The production of AMP from cAMP by recombinant eNPP2 was measured by HPLC. Extracellular adenosine was determined by LC-MS/MS, extracellular ATP by luciferase and LC-MS/MS. The expression of eNPP isoenzymes 1-3 was examined by RT-PCR. The expression of multidrug resistance protein 4 was suppressed by siRNA.
Results: Here we show that the activation of GsPCRs and the GsPCRs-independent activation of Gs proteins and adenylyl cyclase by cholera toxin induce stimulation of cell surface adenosine receptors (A2A or A2B adenosine receptors). In PC12 cells stimulation of adenylyl cyclase by GsPCR or cholera toxin caused activation of A2A adenosine receptors by an autocrine signaling pathway involving cAMP efflux through multidrug resistance protein 4 and hydrolysis of released cAMP to AMP by eNPP2. In contrast, in PC3 cells cholera toxin- and GsPCR-induced stimulation of adenylyl cyclase resulted in the activation of A2B adenosine receptors.
Conclusion: Our findings show that stimulation of adenylyl cyclase causes a remarkable activation of cell surface adenosine receptors.