Rapid strain improvement through optimized evolution in the cytostat

Acetate is present in lignocellulosic hydrolysates at growth inhibiting concentrations. Industrial processes based on such feedstock require strains that are tolerant of this and other inhibitors present. We investigated the effect of acetate on Saccharomyces cerevisiae and show that elevated acetate concentrations result in a decreased specific growth rate, an accumulation of cells in the G1 phase of the cell cycle, and an increased cell size. With the cytostat cultivation technology under previously derived optimal operating conditions, several acetate resistant mutants were enriched and isolated in the shortest possible time. In each case, the isolation time was less than 5 days. The independently isolated mutant strains have increased specific growth rates under conditions of high acetate concentrations, high ethanol concentrations, and high temperature. In the presence of high acetate concentrations, the isolated mutants produce ethanol at higher rates and titers than the parental strain and a commercial ethanol producing strain that has been analyzed for comparison. Whole genome microarray analysis revealed gene amplifications in each mutant. In one case, the LPP1 gene, coding for lipid phosphate phosphatase, was amplified. Two mutants contained amplified ENA1, ENA2, and ENA5 genes, which code for P‐type ATPase sodium pumps. LPP1 was overexpressed on a plasmid, and the growth data at elevated acetate concentrations suggest that LPP1 likely contributes to the phenotype of acetate tolerance. A diploid cross of the two mutants with the amplified ENA genes grew faster than either individual haploid parent strain when 20 g/L acetate was supplemented to the medium, which suggests that these genes contribute to acetate tolerance in a gene dosage dependent manner. Biotechnol. Bioeng. 2009;103: 500–512. © 2009 Wiley Periodicals, Inc.     

Flexible Ion‐Conducting Composite Membranes for Lithium Batteries

The use of metallic lithium anodes enables higher energy density and higher specific capacity Li‐based batteries. However, it is essential to suppress lithium dendrite growth during electrodeposition. Li‐ion‐conducting ceramics (LICC) can mechanically suppress dendritic growth but are too fragile and also have low Li‐ion conductivity. Here, a simple, versatile, and scalable procedure for fabricating flexible Li‐ion‐conducting composite membranes composed of a single layer of LICC particles firmly embedded in a polymer matrix with their top and bottom surfaces exposed to allow for ionic transport is described. The membranes are thin (<100 μm) and possess high Li‐ion conductance at thicknesses where LICC disks are mechanically unstable. It is demonstrated that these membranes suppress Li dendrite growth even when the shear modulus of the matrix is lower than that of lithium. It is anticipated that these membranes enable the use of metallic lithium anodes in conventional and solid‐state Li‐ion batteries as well as in future Li? S and Li? O₂ batteries.     

Impact of the Quality of Bowel Cleansing on the Efficacy of Colonic Cancer Screening: A Prospective,Randomized, Blinded Study

Objectives

Efficacy of two low volume bowel cleansing preparations, polyethylene glycol plus ascorbate (PEG+Asc) and sodium picosulfate/magnesium citrate (NaPic/MgCit), were compared for polyp and adenoma detection rate (PDR and ADR) and overall cleansing ability. Primary endpoint was PDR (the number of patients with ≥1 polypoid or flat lesion recorded by the colonoscopist).

Methods

Diagnostic, surveillance or screening colonoscopy patients were enrolled into this investigator-blinded, multi-center Phase IV study and randomized 1:1 to receive PEG+Asc (administered the evening before and the morning of colonoscopy, per label) or NaPic/MgCit (administered in the morning and afternoon the day before colonoscopy, per label). The blinded colonoscopist documented any lesion and assessed cleansing quality (Harefield Cleansing Scale).

Results

Of 394 patients who completed the study, 393 (PEG+Asc, N=200; NaPic/MgCit, N=193) had a colonoscopy. Overall PDR for PEG+Asc versus NaPic/MgCit was 51.5% versus 44.0%, p=0.139. PDR and ADR on the right side of the bowel were significantly higher with PEG+Asc versus NaPic/MgCit (PDR: 56[28.0%] versus 32[16.6%], p=0.007; ADR: 42[21.0%] versus 23[11.9%], p=0.015), as was detection of flat lesions (43[21.5%] versus 25[13.0%], p=0.025). Cleansing quality was better with PEG+Asc than NaPic/MgCit (98.5% versus 57.5% considered successful cleansing). Overall, there were 132 treatment-emergent adverse events (93 versus 39 for PEG+Asc and NaPic/MgCit, respectively). These were mainly mild abdominal symptoms, all of which were reported for higher proportions of patients in the PEG+Asc than NaPic/MgCit group. Twice as many patients in the NaPic/MgCit versus the PEG+Asc group reported tolerance of cleansing solution as ‘very good’.

Conclusions

Compared with NaPic/MgCit, PEG+Asc may be more efficacious for overall cleansing ability, and subsequent detection of right-sided and flat lesions. This is likely attributable to the different administration schedules of the two bowel cleansing preparations, which may positively impact the detection and prevention of colorectal cancer, thereby improving mortality rates.

Trial Registration

ClinicalTrials.gov NCT01689792.     

Midregional-proAtrial Natriuretic Peptide and High Sensitive Troponin T Strongly Predict Adverse Outcome in Patients Undergoing Percutaneous Repair of Mitral Valve Regurgitation

Background

It is not known whether biomarkers of hemodynamic stress, myocardial necrosis, and renal function might predict adverse outcome in patients undergoing percutaneous repair of severe mitral valve insufficiency. Thus, we aimed to assess the predictive value of various established and emerging biomarkers for major adverse cardiovascular events (MACE) in these patients.

Methods

Thirty-four patients with symptomatic severe mitral valve insufficiency with a mean STS-Score for mortality of 12.6% and a mean logistic EuroSCORE of 19.7% undergoing MitraClip therapy were prospectively included in this study. Plasma concentrations of mid regional-proatrial natriuretic peptide (MR-proANP), Cystatin C, high-sensitive C-reactive protein (hsCRP), high-sensitive troponin T (hsTnT), N-terminal B-type natriuretic peptide (NT-proBNP), galectin-3, and soluble ST-2 (interleukin 1 receptor-like 1) were measured directly before procedure. MACE was defined as cardiovascular death and hospitalization for heart failure (HF).

Results

During a median follow-up of 211 days (interquartile range 133 to 333 days), 9 patients (26.5%) experienced MACE (death: 7 patients, rehospitalization for HF: 2 patients). Thirty day MACE-rate was 5.9% (death: 2 patients, no rehospitalization for HF). Baseline concentrations of hsTnT (Median 92.6 vs 25.2 ng/L), NT-proBNP (Median 11251 vs 1974 pg/mL) and MR-proANP (Median 755.6 vs 318.3 pmol/L, all p<0.001) were clearly higher in those experiencing an event vs event-free patients, while other clinical variables including STS-Score and logistic EuroSCORE did not differ significantly. In Kaplan-Meier analyses, NT-proBNP and in particular hsTnT and MR-proANP above the median discriminated between those experiencing an event vs event-free patients. This was further corroborated by C-statistics where areas under the ROC curve for prediction of MACE using the respective median values were 0.960 for MR-proANP, 0.907 for NT-proBNP, and 0.822 for hsTnT.

Conclusions

MR-proANP and hsTnT strongly predict cardiovascular death and rehospitalization for HF in patients undergoing percutaneous repair of mitral valve insufficiency. Both markers might be useful components in new scoring systems to better predict short- and potentially long-term mortality and morbidity after MitraClip procedure.     

Landscape-Scale Controls on Aboveground Forest Carbon Stocks on the Osa Peninsula,Costa Rica

Tropical forests store large amounts of carbon in tree biomass, although the environmental controls on forest carbon stocks remain poorly resolved. Emerging airborne remote sensing techniques offer a powerful approach to understand how aboveground carbon density (ACD) varies across tropical landscapes. In this study, we evaluate the accuracy of the Carnegie Airborne Observatory (CAO) Light Detection and Ranging (LiDAR) system to detect top-of-canopy tree height (TCH) and ACD across the Osa Peninsula, Costa Rica. LiDAR and field-estimated TCH and ACD were highly correlated across a wide range of forest ages and types. Top-of-canopy height (TCH) reached 67 m, and ACD surpassed 225 Mg C ha^-1, indicating both that airborne CAO LiDAR-based estimates of ACD are accurate in tall, high-biomass forests and that the Osa Peninsula harbors some of the most carbon-rich forests in the Neotropics. We also examined the relative influence of lithologic, topoedaphic and climatic factors on regional patterns in ACD, which are known to influence ACD by regulating forest productivity and turnover. Analyses revealed a spatially nested set of factors controlling ACD patterns, with geologic variation explaining up to 16% of the mapped ACD variation at the regional scale, while local variation in topographic slope explained an additional 18%. Lithologic and topoedaphic factors also explained more ACD variation at 30-m than at 100-m spatial resolution, suggesting that environmental filtering depends on the spatial scale of terrain variation. Our result indicate that patterns in ACD are partially controlled by spatial variation in geologic history and geomorphic processes underpinning topographic diversity across landscapes. ACD also exhibited spatial autocorrelation, which may reflect biological processes that influence ACD, such as the assembly of species or phenotypes across the landscape, but additional research is needed to resolve how abiotic and biotic factors contribute to ACD variation across high biomass, high diversity tropical landscapes.     

Individually Adapted Imagery Improves Brain-Computer Interface Performance in End-Users with Disability

Brain-computer interfaces (BCIs) translate oscillatory electroencephalogram (EEG) patterns into action. Different mental activities modulate spontaneous EEG rhythms in various ways. Non-stationarity and inherent variability of EEG signals, however, make reliable recognition of modulated EEG patterns challenging. Able-bodied individuals who use a BCI for the first time achieve - on average - binary classification performance of about 75%. Performance in users with central nervous system (CNS) tissue damage is typically lower. User training generally enhances reliability of EEG pattern generation and thus also robustness of pattern recognition. In this study, we investigated the impact of mental tasks on binary classification performance in BCI users with central nervous system (CNS) tissue damage such as persons with stroke or spinal cord injury (SCI). Motor imagery (MI), that is the kinesthetic imagination of movement (e.g. squeezing a rubber ball with the right hand), is the "gold standard" and mainly used to modulate EEG patterns. Based on our recent results in able-bodied users, we hypothesized that pair-wise combination of "brain-teaser" (e.g. mental subtraction and mental word association) and "dynamic imagery" (e.g. hand and feet MI) tasks significantly increases classification performance of induced EEG patterns in the selected end-user group. Within-day (How stable is the classification within a day?) and between-day (How well does a model trained on day one perform on unseen data of day two?) analysis of variability of mental task pair classification in nine individuals confirmed the hypothesis. We found that the use of the classical MI task pair hand vs. feed leads to significantly lower classification accuracy - in average up to 15% less - in most users with stroke or SCI. User-specific selection of task pairs was again essential to enhance performance. We expect that the gained evidence will significantly contribute to make imagery-based BCI technology become accessible to a larger population of users including individuals with special needs due to CNS damage.     

Interdisciplinarity and Impact: Distinct Effects of Variety,Balance, and Disparity

Interdisciplinary research is increasingly recognized as the solution to today’s challenging scientific and societal problems, but the relationship between interdisciplinary research and scientific impact is still unclear. This paper studies the association between the degree of interdisciplinarity and the number of citations at the paper level. Different from previous studies compositing various aspects of interdisciplinarity into a single indicator, we use factor analysis to uncover distinct dimensions of interdisciplinarity corresponding to variety, balance, and disparity. We estimate Poisson models with journal fixed effects and robust standard errors to analyze the divergent relationships between these three factors and citations. We find that long-term (13-year) citations (1) increase at an increasing rate with variety, (2) decrease with balance, and (3) increase at a decreasing rate with disparity. Furthermore, interdisciplinarity also affects the process of citation accumulation: (1) although variety and disparity have positive effects on long-term citations, they have negative effects on short-term (3-year) citations, and (2) although balance has a negative effect on long-term citations, its negative effect is insignificant in the short run. These findings have important implications for interdisciplinary research and science policy.     

Perioperative Chemotherapy in Gastroesophageal Cancer. A Retrospective Monocenter Evaluation of 42 Cases

Background

Perioperative chemotherapy increases the overall and progression-free survival of patients suffering from resectable adenocarcinomas of the lower esophagus, gastroesophageal junction and stomach (GEC). Comparing different chemotherapy regimens platin-based protocols with 5-fluorouracil (5-FU)/calcium folinate (CF) or oral fluoropyrimidines were favorable in terms of efficacy and side-effects. However, there is no consensus which regimen is the most efficacious.

Methods

42 consecutive patients with resectable GEC (UICC II and III) were treated with 3 pre- and postoperative chemotherapy cycles each consisting of epirubicin, oxaliplatin and capecitabine (EOX). We analyzed the overall survival, progression-free survival and toxicity retrospectively in comparison to published data.

Results

The median overall survival in our cohort was 29 months and the progression-free survival was 17 months. The most frequent grade 3 and 4 toxicities during preoperative chemotherapy were diarrhea (16.7%), leukocytopenia (9.5%) and nausea (9.5%); overall 38.1% of our patients suffered from grade 3 or 4 toxicity. Surgery was carried out in 83% of our patients, 69% of those achieved R0 resection.

Conclusion

Comparing our data with the results of previously published randomized trials EOX is at least non-inferior with regard to overall survival, progression-free survival and toxicity. In conclusion, EOX is an appropriate perioperative therapy for patients with resectable GEC.