Determination of Hepatocellular Carcinoma and Characterization of Hepatic Focal Lesions with Adaptive Multi-Exponential Intravoxel Incoherent Motion Model

PURPOSE: To distinguish hepatocellular carcinoma (HCC) from other types of hepatic lesions with the adaptive multi-exponential IVIM model. METHODS: 94 hepatic focal lesions, including 38 HCC, 16 metastasis, 12 focal nodular hyperplasia, 13 cholangiocarcinoma, and 15 hemangioma, were examined in this study. Diffusion-weighted images were acquired with 13 b values (b?=?0, 3, …, 500 s/mm²) to measure the adaptive multi-exponential IVIM parameters, namely, pure diffusion coefficient (D), diffusion fraction (f_d), pseudo-diffusion coefficient (D_i*) and perfusion-related diffusion fraction (f_i) of the ith perfusion component. Comparison of the parameters of and their diagnostic performance was determined using Mann-Whitney U test, independent-sample t test, one-way analysis of variance, Z test and receiver-operating characteristic analysis. RESULTS: D, D₁* and D₂* presented significantly difference between HCCs and other hepatic lesions, whereas f_d, f₁ and f₂ did not show statistical differences. In the differential diagnosis of HCCs from other hepatic lesions, D₂* (AUC, 0.927) provided best diagnostic performance among all parameters. Additionally, the number of exponential terms in the model was also an important indicator for distinguishing HCCs from other hepatic lesions. In the benign and malignant analysis, D gave the greatest AUC values, 0.895 or 0.853, for differentiation between malignant and benign lesions with three or two exponential terms. Most parameters were not significantly different between hypovascular and hypervascular lesions. For multiple comparisons, significant differences of D, D₁* or D₂* were found between certain lesion types. CONCLUSION: The adaptive multi-exponential IVIM model was useful and reliable to distinguish HCC from other hepatic lesions.     

Antagonism between elevated CO2, nighttime warming,and summer drought reduces the robustness of PSII performance to freezing events

Plant responses to warming, elevated CO₂, and changes in summer precipitation patterns involve complex interactions. In this study we aim to reveal the single factor responses and their interactive effects on photosystem II (PSII) performance during an autumn-to-winter period. The study was carried out in the CLIMAITE multifactor experiment, which includes the combined impact of elevated CO₂ (free air carbon enrichment; CO₂), warming (passive nighttime warming; T) and summer drought (rain-excluding curtains; D) in a temperate heath ecosystem. PSII performance was probed by the effective quantum yield in light, F_v′/F_m′, using the pulse amplitude methodology, and the total performance index, PI_total, which integrate changes of the chlorophyll-a fluorescence transient including the maximal quantum yield in darkness, F_v/F_m.Decreasing temperature during autumn linearly reduced PI_total, both in the wavy hair-grass, Deschampsia flexuosa, and in the evergreen dwarf shrub common heather, Calluna vulgaris, and following freezing events the PI_total and F_v′/F_m′ were reduced even more. Contrary to expected, indirect effects of the previous summer drought reduced PSII performance before freezing events, particularly in Calluna. In combinations with elevated CO₂ interactive effects with drought, D × CO₂ and warming, T × D × CO₂, were negatively skewed and caused the reduction of PSII performance in both species after occurrence of freezing events. Neither passive nighttime warming nor elevated CO₂ as single factors reduced PSII performance via incomplete cold hardening as hypothesized. Instead, the passive nighttime warming strongly increased PSII performance, especially after freezing events, and when combined with elevated CO₂ a strongly skewed positive T × CO₂ interactive effect was seen. This indicates that these plants take advantage of the longer growing season induced by the warming in elevated CO₂ until a winter frost period becomes permanent. However, if previously exposed to summer drought this positive effect reverses via interactive D × CO₂ and T × D × CO₂ effects immediately after freezing events, causing the full combination of TDCO₂ not to differ from the control.In a future warmer climate with high CO₂ and summer drought, the occurrence of freezing events thus seem highly decisive for reducing PSII performance in the autumn-to-winter period. Such a reduced robustness of PSII performance may be highly decisive for the magnitude of the late season photosynthetic carbon uptake and reduce the growing season length in these temperate heath plants.     

Optimization of intravascular shear stress assessment in vivo

The advent of microelectromechanical systems (MEMS) sensors has enabled real-time wall shear stress (WSS) measurements with high spatial and temporal resolution in a 3-D bifurcation model. To optimize intravascular shear stress assessment, we evaluated the feasibility of catheter/coaxial wire-based MEMS sensors in the abdominal aorta of the New Zealand white (NZW) rabbits. Theoretical and computational fluid dynamics (CFD) analyses were performed. Fluoroscope and angiogram provided the geometry of aorta, and the Doppler ultrasound system provided the pulsatile flow velocity for the boundary conditions. The physical parameters governing the shear stress assessment in NZW rabbits included (1) the position and distance from which the MEMS sensors were mounted to the terminal end of coaxial wire or the entrance length, (L_e), (2) diameter ratios of aorta to the coaxial wire (D_aorta /D_{coaxial wire}=1.5–9.5), and (3) the range of Reynolds numbers (116–1550). At an aortic diameter of 2.4 mm and a maximum Reynolds number of 212 (a mean Reynolds number of 64.2), the time-averaged shear stress (τ_ave) was computed to be 10.06 dyn cm^?2 with a systolic peak at 33.18 dyn cm^?2. In the presence of a coaxial wire (D_aorta /D_{coaxial wire}=6 and L_e=1.18 cm), the τ_ave value increased to 15.54 dyn cm^?2 with a systolic peak at 51.25 dyn cm^?2. Real-time intravascular shear stress assessment by the MEMS sensor revealed an τ_ave value of 11.92 dyn cm^?2 with a systolic peak at 47.04 dyn cm^?2. The difference between CFD and experimental τ_ave was 18.5%. These findings provided important insights into packaging the MEMS sensors to optimize in vivo shear stress assessment.     

A Multi-Variate framework to assess reliability and discrimination power of Bayesian estimation of Intravoxel Incoherent Motion parameters

PurposeTo propose a multivariate multi-step framework for a systematic assessment of the estimation reliability and discriminability of Intravoxel Incoherent Motion (IVIM) model parameters.MethodsMonte-Carlo simulations were generated on a range of SNRs and in different IVIM combinations considering: i) a dense discretization with 24 b-values; ii) a discretization with 9 b-values. A state-of-the-art Bayesian fitting method was adopted. The framework assessed: i) the best model between mono- and bi-exponential, through the BIC index; ii) the fitting accuracy; iii) the power in discriminating two different IVIM parameters distributions of estimated coefficients, using a multivariate test. Exemplificative oncologic cases were also presented.ResultsThe bi-exponential fitting was reliable for perfusion fraction higher than 5%, with high accuracy in D estimation, acceptable error for f, but high uncertainty in D*. The discrimination of two distributions is generally feasible if differences in D values (at least 0.3 x10^-3 mm²/s) are present; in the case of similar D values, a minimal difference of 5% in f can be discriminated just in case of balanced sample size and dense b-values discretization, whereas the impact of D* is quite negligible. These results were also supported by clinical examples.ConclusionsIVIM model is generally accurate in estimating diffusion, but uncertainties related to perfusion estimation are not negligible and compromise the discrimination power when different populations should be differentiated. The proposed framework should be adopted as interpretative guidelines to better understand when IVIM model applied on real data can provide reliable findings.     

Sewage treatment in a combined up-flow anaerobic sludge blanket (UASB)–down-flow hanging sponge (DHS) system

The performance of up-flow anaerobic sludge blanket (UASB) in combination with down-flow hanging sponge (DHS) system for sewage treatment at an average wastewater temperature of 15 °C has been investigated for 6 months. The results showed that a combined system operated at a total HRT of 10.7 h and total SRT of 88 days represents a cost effective sewage treatment process. The average COD_total and BOD_5 total concentrations measured in the final effluent of the total system (UASB + DHS) amounted to 43 and 3.0 mg/l, respectively, corresponding to the overall removal efficiency of 90% for COD_total and 98% for BOD_5 total. The total process provided a final effluent containing a low concentration of 12 mg/l for TSS.Eighty-six percent of ammonia was eliminated at space loading rate of 1.6 kg COD/m³ d and HRT of 2.7 h. The calculated nitrification rate of the DHS system according to the nitrate and nitrite production amounted to 0.18 kg/m³ d. The removal of F. coliform in the UASB reactor only amounted to 0.86 log₁₀. On the other hand, the F. coliform concentration dropped substantially, i.e. by 2.6 log₁₀ in the DHS system resulting only 2.7 × 10³/100 ml in the final effluent.The calculated average sludge production for UASB operated at an HRT of 8.0 h amounted to 30 g TSS/d, corresponding to sludge yield coefficient of 0.2 g TSS/g total COD removed, while it was indeed very low only 6.0 g TSS/d corresponding to sludge yield coefficient of 0.09 g TSS/g total COD removed, for DHS system.The DHS profile results revealed that in the first and second segment of DHS system, the COD_total, BOD_5 total and TSS was eliminated, followed by the oxidation of ammonia in the next segments.     

Log-relative growth: A new dendrochronological approach to study diameter growth in Cedrela odorata and Juglans neotropica,Central Forest,Peru

Many studies regarding growth in diameter at breast height (D) in trees suffer from several problems, including heteroscedasticity, temporal autocorrelation and very low statistical adjustments. In growth ring studies, growth models are sometimes omitted, presenting only a mean curve or smoothings, while studies that use models often do not address the above mentioned problems. For these reasons, this paper proposes a new approach to the classical modeling of D = f(t), where t is age (years), using the logarithmic transformation of the relative growth rate ln(1/D)(dD/dt) = ln f(D, A),where A is the asymptote of D based on the differential growth rate model of von Bertalanffy. High statistically significant adjustments for Cedrela odorata (ME = 65%, model efficiency, ME, an analogous to R² but for non-linear regressions), and Juglans neotropica (ME = 78%) were obtained and met all regression assumptions. These equations were integrated to obtain D = f(t) for both species, followed by self and independent validation. Based on these equations, different life history and silviculture traits were calculated for both species. This procedure does not appear to have been previously used in the study of tree growth.     

Correlation of the Apparent Diffusion Coefficient (ADC) with the Standardized Uptake Value (SUV) in Lymph Node Metastases of Non-Small Cell Lung Cancer (NSCLC) Patients Using Hybrid 18F-FDG PET/MRI

ObjectiveTo compare the apparent diffusion coefficient (ADC) in lymph node metastases of non-small cell lung cancer (NSCLC) patients with standardized uptake values (SUV) derived from combined 18F-fluoro-deoxy-glucose-positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI).ResultsA total of 146 suspicious lymph nodes were found in 25 patients. One hundred lymph nodes were eligible for final analysis. Ninety-one lymph nodes were classified as malignant and 9 as benign according to the reference standard. In malignant lesions, mean SUV_max was 9.1 ± 3.8 and mean SUV_mean was 6.0 ± 2.5 while mean ADC_mean was 877.0 ± 128.6 x10^-5 mm²/s in PET/MRI. For all malignant lymph nodes, a weak, inverse correlation between SUV_max and ADC_mean as well as SUV_mean and ADC_mean (r = -0.30, p<0.05 and r = -0.36, p<0.05) existed.ConclusionThe present data show a weak inverse correlation between increased glucose-metabolism and cellularity in lymph node metastases of NSCLC patients. 18F-FDG-PET and DWI thus may offer complementary information for the evaluation of treatment response in lymph node metastases of NSCLC.     

Partitioning of latent heat flux at a northern peatland

The partitioning of latent heat flux (Q_E) to vascular plant and moss surface components was assessed for a Sphagnum-dominated bog with a hummock–hollow surface having a sparse canopy of low shrubs. Results from porometry and eddy covariance measurements of Q_E showed evaporation from the moss surface ranged from greater than 50% of total Q_E early in the growing season to less than 20% after a dry period toward the end of the growing season. Both soil moisture and vapour pressure deficit (D_a) affected this partitioning with drier moss and peat, lower water table, and smaller D_a all reducing moss Q_E. Daily maximum moss Q_E ranged from greater than 200 W m⁻² early in the growing season to less than 100 W m⁻² during a dry period. In contrast, vascular contribution to total Q_E increased over the season from a daily maximum of about 150 W m⁻² to 250 W m⁻² due to increase in leaf area by leaf replacement and emergence and to drying of the moss surface. Porometry results showed average daily maximum conductance from bog shrubs was near 8 mm s⁻¹. These conductance values were smaller than those reported for vascular plants from more nutrient-rich wetlands. The effect of increases in D_a on vascular Q_E were moderated by decreases in stomatal conductance. At constant available energy, vascular leaf conductance was reduced by as much as 2 mm s⁻¹ and moss surface conductance was enhanced by up to 3 mm s⁻¹ by large D_a. Considering vascular and non-vascular water transport characteristics and frequency of water table position and given the observed variations of Q_E partitioning with water table location and moss and peat water content, it is suggested that modelling efforts focus on how dry hummocks and wet hollows each contribute to Q_E, especially as related to D_a and soil moisture dynamics.     

Effect of 1,25 dihydroxyvitamin D3 on intracellular IFN-γ and TNF-α positive T cell subsets in pulmonary tuberculosis

We studied the immunomodulatory effect of 1,25(OH)₂D₃ on single cell expression of IFN-γ and TNF-α cytokines in T cell subsets of pulmonary tuberculosis (PTB) patients (n = 22) and normal healthy subjects (n = 22). Peripheral blood mononuclear cells (PBMCs) were cultured with live Mycobacterium tuberculosis (MTB) with or without 1,25(OH)₂D₃ (10^?7 M) for 48 h. T cell subsets positive for IFN-γ and TNF-α were enumerated by flow cytometry and the culture supernatants were assayed for both the cytokines using ELISA. In both NHS and PTB patients, a significantly reduced percentage of IFN-γ and TNF-α expressing CD3+, CD3+CD4+ and CD3+CD8+ T cells were observed in cultures stimulated with live MTB and treated with 1,25(OH)₂D₃ compared to cultures without 1,25(OH)₂D₃ (NHS; CD3+ IFN-γ+: p < 0.0001; CD3+TNF-α +: p = 0.0292 and PTB; CD3+ IFN-γ+: p = 0.0292; CD3+ TNF-α +: p = 0.0028). The levels of IFN-γ and TNF-α in the culture supernatants of 1,25(OH)₂D₃ treated cultures were also found to be significantly decreased in both groups (NHS; IFN-γ: p = 0.0001; TNF-α: p < 0.0001) and (PTB; IFN-γ: p < 0.0001; TNF-α: p < 0.0001). A positive correlation was observed between IFN-γ and TNF-α expressing CD3+CD8+ T cells in MTB stimulated cultures treated with or without 1,25(OH)₂D₃ in NHS (p = 0.0001; p = 0.001, respectively) and PTB patients (p = 0.002; p = 0.005, respectively). The present study revealed the suppressive effect of 1,25(OH)₂D₃ on single cell expression of IFN-γ and TNF-α by CD3+CD4+ and CD3+CD8+ T cells in pulmonary tuberculosis. This suppressive effect of 1,25(OH)₂D₃ on proinflammatory and Th1 cytokine positive cells might have a role in reducing inflammation at the site of infection.     

Pyrrolidine analogs of GZ-793A: Synthesis and evaluation as inhibitors of the vesicular monoamine transporter-2 (VMAT2)

Central heterocyclic ring size reduction from piperidinyl to pyrrolidinyl in the vesicular monoamine transporter-2 (VMAT2) inhibitor GZ-793A and its analogs resulted in novel N-propane-1,2(R)-diol analogs 11a–i. These compounds were evaluated for their affinity for the dihydrotetrabenazine (DTBZ) binding site on VMAT2 and for their ability to inhibit vesicular dopamine (DA) uptake. The 4-difluoromethoxyphenethyl analog 11f was the most potent inhibitor of [³H]-DTBZ binding (K_i = 560 nM), with 15-fold greater affinity for this site than GZ-793A (K_i = 8.29 μM). Analog 11f also showed similar potency of inhibition of [³H]-DA uptake into vesicles (K_i = 45 nM) compared to that for GZ-793A (K_i = 29 nM). Thus, 11f represents a new water-soluble inhibitor of VMAT function.     

Target Binding to S100B Reduces Dynamic Properties and Increases Ca2 +-Binding Affinity for Wild Type and EF-Hand Mutant Proteins

Mutations in the second EF-hand (D61N, D63N, D65N, and E72A) of S100B were used to study its Ca^2 + binding and dynamic properties in the absence and presence of a bound target, TRTK-12. With ^D63NS100B as an exception (^D63NK_D = 50 ± 9 μM), Ca^2 + binding to EF2-hand mutants were reduced by more than 8-fold in the absence of TRTK-12 (^D61NK_D = 412 ± 67 μM, ^D65NK_D = 968 ± 171 μM, and ^E72AK_D = 471 ± 133 μM), when compared to wild-type protein (^WTK_D = 56 ± 9 μM). For the TRTK-12 complexes, the Ca^2 +-binding affinity to wild type (^WT + TRTKK_D = 12 ± 10 μM) and the EF2 mutants was increased by 5- to 14-fold versus in the absence of target (^{D61N + TRTK}K_D = 29 ± 1.2 μM, ^{D63N + TRTK}K_D = 10 ± 2.2 μM, ^{D65N + TRTK}K_D = 73 ± 4.4 μM, and ^{E72A + TRTK}K_D = 18 ± 3.7 μM). In addition, R_ex, as measured using relaxation dispersion for side‐chain ¹⁵N resonances of Asn63 (^D63NS100B), was reduced upon TRTK-12 binding when measured by NMR. Likewise, backbone motions on multiple timescales (picoseconds to milliseconds) throughout wild type, ^D61NS100B, ^D63NS100B, and ^D65NS100B were lowered upon binding TRTK-12. However, the X-ray structures of Ca^2 +-bound (2.0 Å) and TRTK-bound (1.2 Å) ^D63NS100B showed no change in Ca^2 + coordination; thus, these and analogous structural data for the wild-type protein could not be used to explain how target binding increased Ca^2 +-binding affinity in solution. Therefore, a model for how S100B–TRTK‐12 complex formation increases Ca^2 + binding is discussed, which considers changes in protein dynamics upon binding the target TRTK-12.     

Polysaccharide of nectarine gum exudate: Comparison with that of peach gum

The gum exudate polysaccharide from the trunk of nectarine (PPNEC) was compared with that of peach, being composed of Ara, Xyl, Man, Gal, and uronic acids in 37:13:2:42:6 molar ratio and had M_w 3.93 × 10⁶ g mol^?1, compared with 5.61 × 10⁶ g mol^?1 for peach gum polysaccharide. Methylation analysis of PPNEC indicated a highly branched structure with relatively high amounts of di- (16%) and tri-O-substituted (9%) Galp units and nonreducing end-units of Araf (26%) and Xylp (17%). Combination with ¹³C NMR data, showed the presence of α-l-Araf (nonreducing end, 3-O-, 5-O-, and 2,5-di-O-subst.), β-l-Arap (4-O- and 2,4-di-O-subst.), β-d-Galp (3-O-, 2,3-di-O-, 3,6-di-O-, and 3,4,6-tri-O-subst.), and α- and/or β-d-Xylp nonreducing end-units. A signal appeared from 4-O-Me-α-d-GlcpA units. PPNEC had structures similar to those of polysaccharide from peach tree gum, although in different proportions and with a lower M_w.     

Measurement of 25-OH-vitamin D in human serum using liquid chromatography tandem-mass spectrometry with comparison to radioimmunoassay and automated immunoassay

The plasma 25-OH vitamin D concentration is a reliable biomarker for vitamin D status but assay's variability makes adequate monitoring of vitamin D status difficult. We employed isotope-dilution liquid chromatography (LC) tandem-mass spectrometry (MS/MS) for the measurement of both 25-OH vitamin D₃ and 25-OH vitamin D₂ in human serum. Hexadeuterium labelled 25-OH vitamin D₃ internal standard (IS) was added to calibrators (prepared in phosphate-buffered saline with 60 g/L albumin), controls or patient sera and 25-OH vitamin D metabolites were released from vitamin D binding protein by adding sodium hydroxide prior to protein precipitation by acetonitrile/methanol (9:1, v/v). Subsequent off-line solid-phase extraction was followed by chromatographic separation on a C-18 column using a water/methanol/ammonium acetate gradient. Detection was by Atmospheric Pressure Electrospray Ionisation (AP-EI) followed by selected reaction monitoring. We compared the LC-MS/MS assay to the DiaSorin radioimmunoassay (RIA) and a recently re-standardised version of an automated electrochemiluminescent immunoassay (ECLIA) from Roche Diagnostics. We also analysed external quality control samples from the International Vitamin D External Quality Assessment Scheme (DEQAS) for comparison with other participating laboratories using LC-MS. The method was linear from 5 to at least 550 nmol/L with intra- and interday CV's ≤6% for both 25-OH vitamin D₃ and 25-OH vitamin D₂. Recoveries ranged between 94.9 and 106.9% for 25-OH vitamin D₃ and 82.7 and 100.3% for 25-OH vitamin D₂. Our results for the DEQAS serum pools averaged ?7.2% from the overall LC-MS method mean. The DiaSorin RIA agreed well with the LC-MS/MS method (r² = 0.90; average bias 1.61 nmol/L), the Roche ECLIA considerably disagreed (r² = 0.58; bias 10.13 nmol/L). This LC-MS/MS method is reliable and robust for the measurement of both 25-OH vitamin D₃ and 25-OH vitamin D₂ in human serum.     

A study on multidimensional time series model of individual age’s measurement in Castanopsis kawakamii population

Studies on disclosing characteristics and endangered mechanisms of Castanopsis kawakamii population ecology have already become an urgent task of protecting C. kawakamii population. The establishment of the standard life table is one of an important work study on C. kawakamii population ecology, and determining individual ages of the plant is necessary for studying age structures and population dynamics of C. kawakamii. There are three main methods of determining individual age of forest population: (1) by annual ring of tree, (2) by individual growth phase, and (3) by DBH and height of tree. However, the three methods have their shortcomings, such as low precision, worse serviceability, high difficulty for operation and so on. In this paper, a new method for determining plant individual ages more accurately is presented on the basis of the method aboU_t “annual ring–time series”. Based on the stem analysis, the multidimensional time series model of diameter growth at breast height in C. kawakamii population was established by U_tilizing the analY_tical method of multidimensional time series: Y_t = 1.325034Y_t-1 ? 0.4711007Y_t-2 ? 284.5648U_t + 569.4783U_t?1 ? 284.8745U_t?2, where Y_t, Y_t-1, Y_t-2 represent diameter growth in C. kawakamii population at t, t ? 10 and t ? 20 years respectively, and U_t, U_t?1, U_t?2 represent individual age in C. kawakamii population at t, t ? 10 and t ? 20 years respectively, the model coefficient correlation is 0.9994. Based on this model CAR(2), the total increment of individual DBH in C. kawakamii population are simulated and regressively verified at different ages. The mean simulating precision of this model was 98.84%, the maximum relative error was 2.56%, bU_t the next was 2.47% and the minimum relative error was 0.07%, showing that this model was suitable for estimating breast-height diameter of C. kawakamii plant. Using the multidimensional time series model, diameter growth of C. kawakamii population for longer time series was estimated in order to gain data for establishing the relationship model of individual age, diameter growth and to increase its precision in determining individual age is by tree ring analysis. A combination method of determining individual age of C. kawakamii population by integrating annual ring data with its diameter using multidimensional time series model, which can improve precision of individual ages in C. kawakami, was produced: A = 9.966671944 + 1.146011591D + 0.041059628D² ? 0.000211907D³, where A and D represent individual age and diameter at breast height respectively in C. kawakamii population, the model coefficient correlation is 0.9998. The combination model, which shows that the regression relationship is significant and the model can exactly predict the individual age of population, is a valuable tool for determining individual ages in endangered plants.     

8-Substituted 1,3-dimethyltetrahydropyrazino[2,1-f]purinediones: Water-soluble adenosine receptor antagonists and monoamine oxidase B inhibitors

Multitarget approaches, i.e., addressing two or more targets simultaneously with a therapeutic agent, are hypothesized to offer additive therapeutic benefit for the treatment of neurodegenerative diseases. Validated targets for the treatment of Parkinson’s disease are, among others, the A_2A adenosine receptor (AR) and the enzyme monoamine oxidase B (MAO-B). Additional blockade of brain A₁ ARs may also be beneficial. We recently described 8-benzyl-substituted tetrahydropyrazino[2,1-f]purinediones as a new lead structure for the development of such multi-target drugs. We have now designed a new series of tetrahydropyrazino[2,1-f]purinediones to extensively explore their structure–activity-relationships. Several compounds blocked human and rat A₁ and A_2AARs at similar concentrations representing dual A₁/A_2A antagonists with high selectivity versus the other AR subtypes. Among the best dual A₁/A_2AAR antagonists were 8-(3-(4-chlorophenyl)propyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (41, K_i human A₁: 65.5 nM, A_2A: 230 nM; K_i rat A₁: 352 nM, A_2A: 316 nM) and 1,3-dimethyl-8-((2-(thiophen-2-yl)thiazol-4-yl)methyl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (57, K_i human A₁: 642 nM, A_2A: 203 nM; K_i rat A₁: 166 nM, A_2A: 121 nM). Compound 57 was found to be well water-soluble (0.7 mg/mL) at a physiological pH value of 7.4. One of the new compounds showed triple-target inhibition: (R)-1,3-dimethyl-8-(2,1,3,4-tetrahydronaphthalen-1-yl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (49) was about equipotent at A₁ and A_2AARs and at MAO-B (K_i human A₁: 393 nM, human A_2A: 595 nM, IC₅₀ human MAO-B: 210 nM) thus allowing future in vivo explorations of the intended multi-target approach.     

Evaluation of biocomposite-based supports for immobilized-cell xylitol production compared with a free-cell system

This study was conducted to evaluate the importance of aeration in free and immobilized cell systems in an aerated bioreactor for xylitol production from an oat hull hemicellulosic hydrolysate using an integrated process. The aeration rate (AR) or oxygen mass transfer coefficient (k_La) demonstrated a significant role in controlling cell (Candida guilliermondii FTI 20037) regeneration and bioconversion performance in free and immobilized cell systems. In the free cell system, an aeration rate of 1.25 vvm corresponding to k_La of 15.8 1/h resulted in maximum values of product yield (Y_p/s: 0.87 g/g), productivity (Q_p: 0.57 g/l/h), and final xylitol concentration (P_f: 55 g/l) from the hydrolysate with a 74.5 g/l xylose concentration. However, in the aerated immobilized cell system, maximum and almost similar results (almost P_f: 54 g/l, Q_p: 0.57 g/l/h and Y_p/s: 0.84 g/g) were obtained with aeration rates from 1.25 to 1.5 vvm using composites based on polypropylene (PP) and partially delignified fiber (PDF). Composites based on acid treated fiber (ATF) containing a high amount of lignin showed some inhibitory impact on xylose uptake and xylitol formation (P_f: 47 g/l and Q_p < 0.49 g/l/h) with the optimal aeration rate of 1.5 vvm in the initial cycle of the bioconversion; this inhibition impact could be resolved in the next consecutive cycles. The surface modifier polyethyleneimine (PEI) slightly enhanced cell retention in the immobilized form on the ATF-based cell support. This investigation helps fill in the knowledge gaps existing on the integrated processing of the lignocellulosic biomass for xylitol bioproduction and biorefinery industry; however, more scale-up studies are recommended for commercialization.     

Inhibition kinetics of a commercial mixed culture by ammonium sulfate

The inhibitory effect of ammonium sulfate on a commercial mixed culture, used in biological waste-water treatment was studied under aerobic batch conditions. Several mathematical models of enzyme and growth kinetics including a death factor were analyzed through nonlinear regression to find the best fit to corresponding data of inhibition. The best fit model was found to be the generalized Monod type with a death factor having the biokinetic parameters; μ_max 0.681 h⁻¹, K_s 0.224 g dm⁻³, K_i 56240 g dm⁻³, K 0.055 g dm⁻³ and k_d 0.052 h⁻¹ to represent the experimental data accurately. The low saturation coefficient value along with high maximum specific growth rate and inhibition coefficient denotes the competitive characteristics of commercial mixed cultures in the biological treatment of high ammonium polluted waste waters.     

The role of apparent diffusion coefficient values in characterization of solid focal liver lesions:a prospective and comparative clinical study

We evaluated and compared the diagnostic accuracy(DA) of apparent diffusion coefficient(ADC) values with that of lesion-to-liver ADC ratios in the characterization of solid focal liver lesions(FLLs).This prospective study was approved by the Institutional Human Ethics Board,after waiving written informed consent.Diffusion-weighted imaging and other routine magnetic resonance imaging were performed on 142 consecutive patients with suspected liver disease.The mean ADC values and lesion-to-liver ADC ratios were compared between benign and malignant solid FLLs.Receiver operating characteristic analysis was performed.The study participants included 46 patients(28 men,18 women;mean age,52.5 years) with 57 solid FLLs(32 malignant and 25 benign FLLs).The mean ADC values and ADC ratios of benign solid FLLs were significantly higher than those of malignant lesions(P0.01).The difference between the area under the receiver operating characteristic curve of the ADC values(0.699) and ADC ratios(0.752) was not significant.Our study suggests that the DA of the ADC ratio is not significantly higher than that of ADC in characterizing solid FLLs.     

Regionally diverse mitochondrial calcium signaling regulates spontaneous pacing in developing cardiomyocytes

The quintessential property of developing cardiomyocytes is their ability to beat spontaneously. The mechanisms underlying spontaneous beating in developing cardiomyocytes are thought to resemble those of adult heart, but have not been directly tested. Contributions of sarcoplasmic and mitochondrial Ca²⁺-signaling vs. I_f-channel in initiating spontaneous beating were tested in human induced Pluripotent Stem cell-derived cardiomyocytes (hiPS-CM) and rat Neonatal cardiomyocytes (rN-CM). Whole-cell and perforated-patch voltage-clamping and 2-D confocal imaging showed: (1) both cell types beat spontaneously (60–140/min, at 24 °C); (2) holding potentials between −70 and 0 mV had no significant effects on spontaneous pacing, but suppressed action potential formation; (3) spontaneous pacing at −50 mV activated cytosolic Ca²⁺-transients, accompanied by in-phase inward current oscillations that were suppressed by Na⁺-Ca²⁺-exchanger (NCX)- and ryanodine receptor (RyR2)-blockers, but not by Ca²⁺- and I_f-channels blockers; (4) spreading fluorescence images of cytosolic Ca²⁺-transients emanated repeatedly from preferred central cellular locations during spontaneous beating; (5) mitochondrial un-coupler, FCCP at non-depolarizing concentrations (∼50 nM), reversibly suppressed spontaneous pacing; (6) genetically encoded mitochondrial Ca²⁺-biosensor (mitycam-E31Q) detected regionally diverse, and FCCP-sensitive mitochondrial Ca²⁺-uptake and release signals activating during I_NCX oscillations; (7) I_f-channel was absent in rN-CM, but activated only negative to −80 mV in hiPS-CM; nevertheless blockers of I_f-channel failed to alter spontaneous pacing.