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Halophilic archaea cultivated from surface sterilized middle-late Eocene rock salt are polyploid
(2014)
Live bacteria and archaea have been isolated from several rock salt deposits of up to hundreds of millions of years of age from all around the world. A key factor affecting their longevity is the ability to keep their genomic DNA intact, for which efficient repair mechanisms are needed. Polyploid microbes are known to have an increased resistance towards mutations and DNA damage, and it has been suggested that microbes from deeply buried rock salt would carry several copies of their genomes. Here, cultivable halophilic microbes were isolated from a surface sterilized middle-late Eocene (38–41 million years ago) rock salt sample, drilled from the depth of 800 m at Yunying salt mine, China. Eight unique isolates were obtained, which represented two haloarchaeal genera, Halobacterium and Halolamina. We used real-time PCR to show that our isolates are polyploid, with genome copy numbers of 11–14 genomes per cell in exponential growth phase. The ploidy level was slightly downregulated in stationary growth phase, but the cells still had an average genome copy number of 6–8. The polyploidy of halophilic archaea living in ancient rock salt might be a factor explaining how these organisms are able to overcome the challenge of prolonged survival during their entombment.
We examine both the degree and the structural stability of inflation persistence at different quantiles of the conditional inflation distribution. Previous research focused exclusively on persistence at the conditional mean of the inflation rate. As economic theory provides reasons for inflation persistence to differ across conditional quantiles, this is a potentially severe constraint. Conventional studies of inflation persistence cannot identify changes in persistence at selected quantiles that leave persistence at the median of the distribution unchanged. Based on post-war US data we indeed find robust evidence for a structural break in persistence at all quantiles of the inflation process in the early 1980s. While prior to the 1980s inflation was not mean reverting, quantile autoregression based unit root tests suggest that since the end of the Volcker disinflation the unit root can be rejected at every quantile of the conditional inflation distribution.
Background: Emergency ultrasound is gaining importance in medical education. Widespread teaching methods are frontal presentations and hands-on training. The primary goal of our study was to evaluate the impact of frontal presentations (PS) by analysis of retained knowledge rate (RKR) and learning load (LL).
Methods: Our study was conducted during four introductory courses in emergency ultrasound covering Extended Focused Assessment with Sonography for Trauma (E-FAST) and Focused Echocardiography Evaluation in Life Support (FEEL). Standardized PS (length of 10 to 50 min) were presented by experienced trainers, who were asked to provide keywords, key messages, and images and assign a score to each. Group 1 consisted of 11 medical students with no prior ultrasound experience, and group 2 consisted of 80 physicians. Each group was audience to seven to eight standard PS and requested to answer a free text questionnaire after 0 h, 2.5 h, 24 h, and 14 days.
Results: In group 1, 168/176 questionnaires were analyzed, and 161/202 were analyzed in group 2. RKR in group 1 was 32.5%, 15%, 16%, and 12% at 0 h, 2.5 h, 24 h, and 2 weeks. The physicians' RKR were 23%, 20.5%, and 22.4% after 0, 2.5, and 24 h of a respective PS. The LL was 1.6/min for students and 1.2/min for physicians. There was no difference in RKR when comparing PS with higher and lower LL for both groups; shorter or case-based PS were associated with a higher RKR (p < 0.01).
Conclusions: Our study provides evidence that only a limited amount of information can be processed at a time. Only 12% of knowledge is retained after 2 weeks. Presentations of short duration can increase the retained knowledge rate. Therefore, frontal presentations and classroom-based ultrasound training and teaching should be adapted.
Background: Various kinase inhibitors are known to be ATP-binding cassette (ABC) transporter substrates and resistance acquisition to kinase inhibitors has been associated to increased ABC transporter expression. Here, we investigated the role of the ABC transporters ABCB1, ABCC1, and ABCG2 during melanoma cell resistance acquisition to the V600-mutant BRAF inhibitors PLX4032 (vemurafenib) and PLX4720. PLX4032 had previously been shown to interfere with ABCB1 and ABCG2. PLX4720 had been demonstrated to interact with ABCB1 but to a lower extent than PLX4032.
Findings: PLX4032 and PLX4720 affected ABCC1- and ABCG2-mediated drug transport in a similar fashion. In a panel of 16 V600E BRAF-mutated melanoma cell lines consisting of four parental cell lines and their sub-lines with acquired resistance to PLX4032, PLX4720, vincristine (cytotoxic ABCB1 and ABCC1 substrate), or mitoxantrone (cytotoxic ABCG2 substrate), we detected enhanced ABC transporter expression in 4/4 cytotoxic ABC transporter substrate-resistant, 3/4 PLX4720-resistant, and 1/4 PLX4032-resistant melanoma cell lines.
Conclusion: PLX4032 has the potential to induce ABC transporter expression but this potential is lower than that of PLX4720 or cytotoxic ABC transporter substrates. Since ABC transporters confer multi-drug resistance, this is of relevance for the design of next-line therapies.
Introduction: Over the last years, electronic cigarettes (ECs) have become more popular, particularly in individuals who want to give up smoking tobacco. The aim of the present study was to assess the influence of the different e-smoking liquids on the viability and proliferation of human periodontal ligament fibroblasts.
Method and materials: For this study six test solutions with components from ECs were selected: lime-, hazelnut- and menthol-flavored liquids, nicotine, propylene glycol, and PBS as control group. The fibroblasts were incubated up to 96 h with the different liquids, and cell viability was measured by using the PrestoBlue® reagent, the ATP detection and the migration assay. Fluorescence staining was carried out to visualize cell growth and morphology. Data were statistically analyzed by two-tailed one-way ANOVA.
Results: The cell viability assay showed that the proliferation rates of the cells incubated with nicotine or the various flavored liquids of the e-cigarettes were reduced in comparison to the controls, though not all reductions were statistically significant. After an incubation of 96 h with the menthol-flavored liquid the fibroblasts were statistically significant reduced (p < 0.001). Similar results were found for the detection of ATP in fibroblasts; the incubation with menthol-flavored liquids (p < 0.001) led to a statistically significant reduction. The cell visualization tests confirmed these findings.
Conclusion: Within its limits, the present in vitro study demonstrated that menthol additives of e-smoking have a harmful effect on human periodontal ligament fibroblasts. This might indicate that menthol additives should be avoided for e-cigarettes.
Background: Targeted therapies have improved therapeutic options of treating renal cell carcinoma (RCC). However, drug response is temporary due to resistance development.
Methods: Functional and molecular changes in RCC Caki-1 cells, after acquired resistance to the mammalian target of rapamycin (mTOR)-inhibitor everolimus (Cakires), were investigated with and without additional application of the histone deacetylase (HDAC)-inhibitor valproic acid (VPA). Cell growth was evaluated by MTT assay, cell cycle progression and apoptosis by flow cytometry. Target molecules of everolimus and VPA, apoptotic and cell cycle regulating proteins were investigated by western blotting. siRNA blockade was performed to evaluate the functional relevance of the proteins.
Results: Everolimus resistance was accompanied by significant increases in the percentage of G2/M-phase cells and in the IC50. Akt and p70S6K, targets of everolimus, were activated in Cakires compared to drug sensitive cells. The most prominent change in Cakires cells was an increase in the cell cycle activating proteins cdk2 and cyclin A. Knock-down of cdk2 and cyclin A caused significant growth inhibition in the Cakires cells. The HDAC-inhibitor, VPA, counteracted everolimus resistance in Cakires, evidenced by a significant decrease in tumor growth and cdk2/cyclin A.
Conclusion: It is concluded that non-response to everolimus is characterized by increased cdk2/cyclin A, driving RCC cells into the G2/M-phase. VPA hinders everolimus non-response by diminishing cdk2/cyclin A. Therefore, treatment with HDAC-inhibitors might be an option for patients with advanced renal cell carcinoma and acquired everolimus resistance.
Background: To report an unplanned interim analysis of a prospective, one-armed, single center phase I/II trial (NCT01566123).
Methods: Between 2007 and 2013, 27 patients (pts) with primary/recurrent retroperitoneal sarcomas (size > 5 cm, M0, at least marginally resectable) were enrolled. The protocol attempted neoadjuvant IMRT using an integrated boost with doses of 45-50 Gy to PTV and 50-56 Gy to GTV in 25 fractions, followed by surgery and IOERT (10-12 Gy). Primary endpoint was 5-year-LC, secondary endpoints included PFS, OS, resectability, and acute/late toxicity. The majority of patients showed high grade lesions (FNCLCC G1:18%, G2:52%, G3:30%), predominantly liposarcomas (70%). Median tumor size was 15 cm (6-31).
Results: Median follow-up was 33 months (5-75). Neoadjuvant IMRT was performed as planned (median dose 50 Gy, 26-55) in all except 2 pts (93%). Gross total resection was feasible in all except one patient. Final margin status was R0 in 6 (22%) and R1 in 20 pts (74%). Contiguous-organ resection was needed in all grossly resected patients. IOERT was performed in 23 pts (85%) with a median dose of 12 Gy (10-20 Gy).We observed 7 local recurrences, transferring into estimated 3- and 5-year-LC rates of 72%. Two were located outside the EBRT area and two were observed after more than 5 years. Locally recurrent situation had a significantly negative impact on local control. Distant failure was found in 8 pts, resulting in 3- and 5-year-DC rates of 63%. Patients with leiomyosarcoma had a significantly increased risk of distant failure. Estimated 3- and 5-year-rates were 40% for PFS and 74% for OS. Severe acute toxicity (grade 3) was present in 4 pts (15%). Severe postoperative complications were found in 9 pts (33%), of whom 2 finally died after multiple re-interventions. Severe late toxicity (grade 3) was scored in 6% of surviving patients after 1 year and none after 2 years.
Conclusion: Combination of neoadjuvant IMRT, surgery and IOERT is feasible with acceptable toxicity and yields good results in terms of LC and OS in patients with high-risk retroperitoneal sarcomas. Long term follow-up seems mandatory given the observation of late recurrences. Accrual of patients will be continued with extended follow-up.
Background: Evaluation of automated attenuation-based tube potential selection and its impact on image quality and radiation dose in CT (computed tomography) examinations for cancer staging.
Methods: A total of 110 (59 men, 51 women) patients underwent chest-abdomen-pelvis CT examinations; 55 using a fixed tube potential of 120 kV/current of 210 Reference mAs (using CareDose4D), and 55 using automated attenuation-based tube potential selection (CAREkV) also using a current of 210 Reference mAs. This evaluation was performed as a single-centre, observer-blinded retrospective analysis. Image quality was assessed by two readers in consensus. Attenuation, image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were measured or calculated for objective image evaluation. For the evaluation of radiation exposure, dose-length-product (DLP) values were compared and Size-specific dose estimates (SSDE) values were calculated.
Results: Diagnostic image quality was obtained from all patients. The median DLP (703.5 mGy · cm, range 390–2203 mGy · cm) was 7.9% lower when using the algorithm compared with the standard 120 kV protocol (median 756 mGy · cm, range 345–2267 mGy · cm). A reduction in potential to 100 kV occurred in 32 cases; therefore, these patients received significantly lower radiation exposure compared with the 120 kV protocol.
Conclusion: Automated attenuation-based tube potential selection produces good diagnostic image quality in chest-abdomen-pelvis CT and reduces the patient’s overall radiation dose by 7.9% compared to the standard 120 kV protocol.
Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
The European Central Bank (ECB) has finalized its comprehensive assessment of the solvency of the largest banks in the euro area and on October 26 disclosed the results of this assessment. In the present paper, Acharya and Steffen compare the outcomes of the ECB's assessment to their own benchmark stress tests conducted for 39 publically listed financial institutions that are also included in the ECB's regulatory review. The authors identify a negative correlation between their benchmark estimates for capital shortfalls and the regulatory capital shortfall, but a positive correlation between their benchmark estimates for losses under stress both in the banking book and in the trading book. They conclude that the regulatory stress test outcomes are potentially heavily affected by discretion of national regulators in measuring what is capital, and especially the use of risk-weighted assets in calculating the prudential capital requirement.