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Cellular association of nanoparticles (NPs) in biological fluids is affected by proteins adsorbed onto the NP surface, forming a "protein corona", thereby impacting cellular bioactivity. Here we investigate, based on an extensive gold NPs protein corona dataset, the relationships between NP-cell association and protein corona fingerprints (PCFs) as well as NP physicochemical properties. Accordingly, quantitative structure-activity relationships (QSARs) were developed based on both linear and non-linear support vector regression (SVR) models making use of a sequential forward floating selection of descriptors. The SVR model with only 6 serum proteins and zeta potential had higher accuracy (R(2) = 0.895) relative to the linear model (R(2) = 0.850) with 11 PCFs. Considering the initial pool of 148 descriptors, the APOB, A1AT, ANT3, and PLMN serum proteins along with NP zeta potential were identified as most significant to correlating NP-cell association. The present study suggests that QSARs exploration of NP-cell association data, considering the role of both NP protein corona and physicochemical properties, can support the planning and interpretation of toxicity studies and guide the design of NPs for biomedical applications.

The facile and efficient one-step synthesis and the full characterization of novel π-electron rich macrocycles, calix-[n]tetrolarenes (n = 4, 5), are described. The tetramer and the much rarer sized pentamer were easily prepared by reaction of the commercially available, partially methylated 1,2,3,5-benzenetetrol with paraformaldehyde under TFA catalysis, with a total isolated yield of 73%. The reaction is solvent sensitive, and the number of methylated oxygens also affects the tetramer/pentamer distribution. The compounds formed may be considered as “chimeric” macrocycles of calixarene and pyrogallol[n]arene that may serve as new building blocks in host–guest and supramolecular chemistry.

Prediction of chemical bioactivity and physical properties has been one of the most important applications of statistical and more recently, machine learning and artificial intelligence methods in chemical sciences. This field of research, broadly known as Quantitative Structure-Activity Relationships (QSAR) modeling, has developed many important algorithms and has found a broad range of applications in physical organic and medicinal chemistry in the past 55+ years. This Perspective summarizes recent technological advances in QSAR modeling. Importantly, it also highlights the applicability of algorithms, modeling methods, and validation practices developed in QSAR to a wide range of research areas beyond traditional QSAR fields. These fields include nanotechnology, materials science, biomaterials, clinical informatics, and others. As modern research methods generate rapidly increasing amounts of data, knowledge of robust data-driven modelling methods is becoming essential for scientists in many disciplines both within and outside of chemical research. We hope that this contribution will serve to address this challenge.

Forward osmosis (FO) desalination was investigated via 2-D numerical model of the fully coupled hydrodynamics and mass transfer equations. The model was formulated for a detailed composite channel structure (feed and draw channels, membrane skin layer and porous support) being capable of describing co-current or counter current cross operation where the membrane skin faces the salt feed solution (SFF) or where the membrane skin faces the draw solution (SFD). Simulations based on existing experimental FO data confirmed that FO operation in a counter-current/SFD mode provides slight improvement with respect to water flux, and reduced cross migration of feed and draw solutes relative to the co-current mode of operation. Analysis of existing FO data also revealed the dependence of the intrinsic membrane water permeability and solute transport coefficients on draw solute concentration. Simulation results indicated significant cross membrane migration of feed and draw solutes for long (~1 m) relative to short (~10 cm) FO channels. Moreover, up to an order of magnitude decline of draw solute concentration difference (along the membrane) can be encountered at the draw channel exit region. Simulation results suggest that accurate assessment of FO performance in long channels is critical for full-scale plant design in order to minimize salt leakage, optimize recovery, and setting accurate inlet/outlet conditions to enable simulations of membrane elements in series.

Purpose To evaluate the ability of angular double-pulsed-field gradient (d-PFG) MR to provide microstructural information in complex phantoms and fixed nerves. Methods We modeled the signal in angular d-PFG MR experiments performed on phantoms of increasing complexity where the ground truth is known a priori. After analyzing the microstructural features of such phantoms the same methodology was used to study microstructural features in fixed nerves. Results We found that our modeling is able to determine with high accuracy and with very little prior knowledge the sizes and relative fractions of the restricted components as well as the fraction of the free diffusing water molecules. The same approach was used to study nerve microstructure. We found the apparent averaged axonal diameter (AAD) to be 2.3 ± 0.2 μm. However, here the results depended, to some extent, on the parameters used to collect the data and were affected by the diffusion time. Conclusion Modeling of the angular d-PFG MR signal provides a means to obtain accurate microstructural information in complex phantoms where the ground truth is known. This approach also seems to be suitable for obtaining microstructural features in fixed nerves. Magn Reson Med 74:25–32, 2015. © 2014 Wiley Periodicals, Inc.

Nanoparticles (NPs) have great potential to increase the diagnostic capacity of many imaging modalities. MRI is currently regarded as the method of choice for the imaging of deep tissues, and metal ions, such as calcium ions (Ca(2+)), are essential ingredients for life. Despite the tremendous importance of Ca(2+) for the well-being of living systems, the noninvasive determination of the changes in Ca(2+) levels in general, and extracellular Ca(2+) levels in particular, in deep tissues remains a challenge. Here, we describe the preparation and contrast mechanism of a flexible easy to prepare and selective superparamagnetic iron oxide (SPIO) NPs for the noninvasive determination of changes in extracellular Ca(2+) levels using conventional MRI. We show that SPIO NPs coated with monodisperse and purified alginate, having a specific molecular weight, provide a tool to selectively determine Ca(2+) concentrations in the range of 250 µm to 2.5 mm, even in the presence of competitive ions. The alginate-coated magnetic NPs (MNPs) aggregate in the presence of Ca(2+) , which, in turn, affects the T2 relaxation of the water protons in their vicinity. The new alginate-coated SPIO NP formulations, which have no effect on cell viability for 24 h, allow the detection of Ca(2+) levels secreted from ischemic cell cultures and the qualitative examination of the change in extracellular Ca(2+) levels in vivo. These results demonstrate that alginate-coated MNPs can be used, at least qualitatively, as a platform for the noninvasive MRI determination of extracellular Ca(2+) levels in myriad in vitro and in vivo biomedical applications.

A compartmental multimedia model was developed to enable evaluation of the dynamic environmental multimedia mass distribution and concentrations of engineered nanomaterials (ENMs). The approach considers the environment as a collection of compartments, linked via fundamental environmental intermedia transport processes. Model simulations for various environmental scenarios indicated that ENM accumulation in the sediment increased significantly with increased ENMs attachment to suspended solids in water. Atmospheric dry and wet depositions can be important pathways for ENMs input to the terrestrial environment in the absence of direct and distributed ENM release to soil. Increased ENM concentration in water due to atmospheric deposition (wet and dry) is expected as direct ENM release to water diminishes. However, for soluble ENMs dissolution can be the dominant pathway for suspended ENM removal from water even compared to advection. Mass accumulation in the multimedia environment for the evaluated ENMs (metal, metal oxides, carbon nanotubes (CNT), nanoclays) was mostly in the soil and sediment. The present modeling approach, as illustrated via different test cases, is suited for "what if" first tier analyses to assess the multimedia mass distribution of ENMs and associated potential exposure concentrations.

Testing for genetic abnormalities in epithelial growth factor receptor (EGFR), anaplastic lymphoma receptor tyrosine kinase (ALK), and potentially additional genes is a critical tool in the care of advanced NSCLC. There is conflicting evidence for the role of such tests in early NSCLC. We report a single-institute Sequenom testing for a wide range of mutations and their clinical correlations in early-resected NSCLC specimens.Early NSCLC paraffin-embedded, formalin-fixed (FFPE) specimens were collected, DNA extracted, and using Sequenom-based matrix-assisted laser desorption/ionization-time of flight analysis, mutations in 22 oncogenes and tumor suppressor genes were evaluated. Clinical data was collected retrospectively.The technique was found to be feasible. Thirty-six of 96 patients (37.5%) had any genetic abnormality identified, and 8 (8.3%) had 2 or more mutations. Kirsten rat sarcoma viral oncogene homolog (KRAS) and EGFR were the most common genes to appear mutated (15.6%); phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) was the gene to be found most commonly in tumors with co-mutations. Transversions were found mostly in KRAS gene mutations and to be nonprognostic. No difference in the spectrum of mutations was found between squamous-cell and non-squamous-cell lung cancers. Ever-smokers showed a trend for worse prognosis, with a similar spectrum of mutations.Sequenom-based mutation screen is feasible using FFPE samples. More than a third of the patients were found to harbor some genetic abnormality, and 8% were found to have more than a single mutated gene. Wide-range gene screens using large sample depositories are required for further insight into the important genes at play in early NSCLC.

Sensor fault detection and isolation (SFDI) approaches, based on support vector regression (SVR) plant sensor models and self-organizing-map (SOM) analysis, were investigated for application to reverse osmosis (RO) desalination plant operation. SFDI-SVR and SFDI-SOM were assessed using operational data from a small spiral-wound RO pilot plant and synthetic faulty data generated as perturbations relative to normal plant operational data. SFDI-SVR was achieved without false negative (FN) detections for sensor deviations of ≳|10%| and FN detections of, at the most, ≲|5%|, and for sensor deviations of ≳|4%| at sensor fault detection (FD) thresholds of up to ∼|4%|. False positive (FP) detections were almost invariant, with respect to sensor FD, being ≲|5%| for sensor deviations of ≳|5%|. Corrections of faulty sensor readings were within SVR model accuracy (AARE < 1%) for SFDI-SVR and ≲|5%| for SFDI-SOM. Although SFDI-SOM has lower detection accuracy, it requires a single overall plant model (or SOM), while providing pictorial representation of plant operation and depiction of faulty operational trajectories.

STUDY QUESTION: What are the effects of thin ovarian grafts compared with grafts of the standard thickness on follicle loss post-transplantation? SUMMARY ANSWER: Transplantation of reduced-thickness ovarian grafts led to intense activation and 'burn-out' a short time after transplantation resulting in significant folllicle loss. WHAT IS KNOWN ALREADY: Transplantation of fresh and frozen-thawed ovarian tissue has been proved successful, but techniques vary and are not optimised, often resulting in significant follicular loss. Follicle loss is mostly related to the freezing-thawing process and to post-transplantation hypoxia. STUDY DESIGN, SIZE, DURATION: Bovine ovarian tissue strips (n = 55) were prepared in two groups of conventional-thickness strips (1-2 mm) or thin strips (0.5-0.9 mm). Fresh or frozen-thawed samples were xenotransplanted into sterilized immune-deficient mice (n = 49). Non-transplanted conventional size fresh samples were used as controls (n = 6). Grafts from all study groups were recovered after 7 days for analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Morphometric differential counting of follicle classes was performed by two observers. Immunohistochemistry was conducted for proliferation (Ki67), cortical fibrosis (Masson tri-chrome) and blood-vessel density (CD31). Results were expressed as the mean number of dormant or growing follicle (GF) type per section or total follicle counts per graft. Blood-vessel density was calculated per mm(2). P-values

Identification of non-small cell lung carcinoma (NSCLC) patients at high-risk for recurrence after complete resection would potentially direct surveillance frequency and administration of adjuvant treatments. Genetic profiling of tumors could provide clinicians with information regarding recurrence risk. Conflicting evidence exists regarding EGFR, KRAS, and TP53 mutations as prognostic for recurrence. We aimed to test such mutations for prognostic significance in a cohort of early-resected NSCLC specimens. Formalin-fixed paraffin-embedded stage I NSCLC specimens resected in our institute during 1988–2008 were sampled. DNA was extracted and a panel of common EGFR, KRAS, and TP53 mutations was tested using a mass-spectrometry-based technique. Clinical data were extracted from patients’ files. A total of 96 NSCLC stage I patients were included in this study. EGFR mutation frequency of 15.6 %, KRAS mutation frequency of 15.6 %, and a TP53 mutation frequency of 6.2 % were found. A nonsignificant trend for longer relapse-free survival (RFS) was seen for patients with an EGFR mutation, and a nonsignificant trend for worse RFS was found for patients with a KRAS mutation. EGFR mutation and KRAS mutation were not found to be prognostic for RFS in our cohort of early NSCLC. Larger cohorts and a broader genetic screen for mutations are required.

Membrane mineral scaling in semi-batch RO (SBRO) and steady-state RO with partial recycle (SSRO-PR) were investigated experimentally in a spiral-wound pilot system with gypsum as a model scalant. Scaling in SSRO-PR operation, at a given level of solution supersaturation, was compared to SBRO operation at the equivalent time-averaged solution supersaturation, and also for operation at equivalent water recovery. Real-time tracking of mineral scaling revealed that SBRO was more prone to mineral scaling, in terms of both crystals formation rate and scaled membrane surface area, relative to SSRO-PR. The growth rates of crystals in both SBRO and SSRO-PR followed diffusional growth and were similar at the same level of solution supersaturation. However, the crystallization induction time was shorter and rate of crystal formation higher in SBRO relative to SSRO-PR. This behavior was consistent with the higher level of gypsum supersaturation reached in the SBRO filtration period when compared to SSRO-PR at either one of the above operational scenarios. For a given recovery, improved scale mitigation in SBRO via extended flushing to reset the “crystallization induction clock” may be feasible, but the tradeoff is an extended filtration period with a higher level of solution supersaturation.

Semi-batch reverse osmosis (SBRO) desalination was investigated via process modeling and experimentally using a spiral-wound SBRO pilot system. The salinity increase during SBRO filtration necessitates periodic flushing of the excess salinity buildup in the system. Accordingly, concentrate flushing efficacy and its impact on SBRO performance were investigated for multi-cycles of filtration and concentrate flushing. Progressive cycle-to-cycle concentrate salinity rise, due to incomplete (concentrate) flushing, was apparent leading to corresponding SEC increase, but a stable cycle-to-cycle operation was ultimately achieved. Flushing duration longer than the convective residence time improved concentrate flushing. However, for a given recovery, longer flushing required longer filtration. The analysis confirmed that the SEC for an ideal SBRO operation (i.e., complete flushing of excess concentrate salinity) is lower relative to SPRO. However, ideal operation is likely to be a challenge with practical SBRO systems as it would necessitate complete concentrate flushing over the course of one convective residence time. Indeed, experimental evaluation of SBRO demonstrated higher SEC relative to single-pass RO (SPRO). Clearly, experimental quantification of concentrate flushing efficacy is critical for establishing SBRO effectiveness. Irrespective of SEC considerations, both SBRO and SPRO with partial recycle offer the flexibility of desalting operation over a wide recovery range.

An experimental investigation was carried out to assess the removal efficiency of metal oxide nanoparticles from aqueous suspensions via sedimentation and the added benefit of membrane filtration. The study was conducted with aqueous suspensions of TiO2, ZnO, and CeO2 nanoparticles (NPs) of primary size of 10 nm–21 nm. The removal of NPs by gravitational settling was carried out with suspensions that were pretreated via pH adjustment and coagulant addition in order to increase the agglomerate size. Removal efficiencies were as high as 72.3–98.6% for the studied NPs with subsequent ultrafiltration of the remaining suspensions (post sedimentation) enabling essentially complete NP removal.

Relationships among fourteen different biological responses (including ten signaling pathway activities and four cytotoxicity effects) of murine macrophage (RAW264.7) and bronchial epithelial (BEAS-2B) cells exposed to six metal and metal oxide nanoparticles (NPs) were analyzed using both statistical and data mining approaches. Both the pathway activities and cytotoxicity effects were assessed using high-throughput screening (HTS) over an exposure period of up to 24 h and concentration range of 0.39-200 mg L(-1). HTS data were processed by outlier removal, normalization, and hit-identification (for significantly regulated cellular responses) to arrive at reliable multiparametric bioactivity profiles for the NPs. Association rule mining was then applied to the bioactivity profiles followed by a pruning process to remove redundant rules. The non-redundant association rules indicated that "significant regulation" of one or more cellular responses implies regulation of other (associated) cellular response types. Pairwise correlation analysis (via Pearson's χ(2) test) and self-organizing map clustering of the different cellular response types indicated consistency with the identified non-redundant association rules. Furthermore, in order to explore the potential use of association rules as a tool for data-driven hypothesis generation, specific pathway activity experiments were carried out for ZnO NPs. The experimental results confirmed the association rule identified for the p53 pathway and mitochondrial superoxide levels (via MitoSox reagent) and further revealed that blocking of the transcriptional activity of p53 lowered the MitoSox signal. The present approach of using association rule mining for data-driven hypothesis generation has important implications for streamlining multi-parameter HTS assays, improving the understanding of NP toxicity mechanisms, and selection of endpoints for the development of nanomaterial structure-activity relationships.

The biofouling propensity and cleaning effectiveness were evaluated for a new generation of polyamide thin-film composite (PA-TFC) membranes that are surface nano-structured (SNS) with terminally anchored hydrophilic polymer chains. The SNS-PA-TFC membranes were formed via surface graft polymerization onto the surface of polyamide base membranes previously activated via surface treatment with atmospheric pressure plasma. Poly(methacrylic acid) (PMMA) and polyacrylamide (PAAm) SNS-PA-TFC membranes were synthesized and evaluated with respect to their biofouling resistance using secondary wastewater from a municipal wastewater treatment (MWT) plant. Biofouling resistance and cleaning effectiveness were quantified via flux decline measurements in addition to imaging of the biofouled membranes before and after DI water and chemical (Na 2 ·EDTA) cleaning. Increased biofouling resistance was highest for the PMAA-SNS-PA-TFC membrane being a factor of 4.2 greater than for the commercial membrane of about the same salt rejection used in the MWT plant. Moreover, permeability recovery for the PMAA-SNS-PA-TFC membrane was higher by factors of up to ~1.2 relative to the reference commercial membrane upon cleaning with DI water and more aggressive chemical cleaning at high pressure. The present evaluation of the SNS-PA-TFC membranes suggests that biofouling resistance and cleaning effectiveness of RO membranes can be enhanced via hydrophilic brush layers.

q-Space diffusion MRI (QSI) was used to study the spinal cords of Long Evans shaker (les) rats, a model of dysmyelination, and their age-matched controls at different maturation stages. Diffusion was measured parallel and perpendicular to the fibers of the spinal cords of the two groups and at different diffusion times. The results showed that QSI is able to detect the dysmyelination process that occurs in this model in the different stages of the disease. The differences in the diffusion characteristics of the spinal cords of the two groups were found to be larger when the diffusion time was increased from 22 to 100 ms. We found that the radial mean displacement is a much better parameter than the QSI fractional anisotropy (FA) to document the differences between the two groups. We observed that the degree of myelination affects the diffusion characteristics of the tissues, but has a smaller effect on FA. All of the extracted diffusion parameters that are affected by the degree of myelination are affected in a diffusion time-dependent fashion, suggesting that the terms apparent anisotropy, apparent fractional anisotropy and even apparent root-mean-square displacement (rmsD) are more appropriate.

A novel model-based control system for the operation of a spiral-wound RO membrane desalination system was developed with a focus on maintaining energy-optimal operation. The control scheme utilized an operational model for spiral-wound RO desalting with a supervisory controller providing real-time updates of membrane permeability and the appropriate feed pressure set-points for maintaining the target permeate productivity at the lowest feasible specific energy consumption. System RO feed pressure and flow rates were controlled by a lower-level RO controller through adjustment of the RO high pressure feed pump, variable frequency drive, and RO concentrate valve. Seawater desalination tests with an RO plant, capable of permeate productivity up to 18 000 gallons/day, demonstrated effective self-adaptive energy-optimal operation, subject to feed salinity fluctuations, constraints imposed by the system’s physical limitations (i.e., minimum and maximum feasible operational pressures and flow rates), and the th...

Diffusion NMR is a powerful tool for gleaning microstructural information on opaque systems. In this work, the signal decay in single-pulsed-field gradient diffusion NMR experiments performed on a series of phantoms of increasing complexity, where the ground truth is known a priori, was modeled and used to identify microstructural features of these complex phantoms. We were able to demonstrate that, without assuming the number of components or compartments, the modeling can identify the number of restricted components, detect their sizes with an accuracy of a fraction of a micrometer, determine their relative populations, and identify and characterize free diffusion when present in addition to the components exhibiting restricted diffusion. After the accuracy of the modeling had been demonstrated, this same approach was used to study fixed nerves under different experimental conditions. It seems that this approach is able to characterize both the averaged axon diameter and the relative population of the different diffusing components in the neuronal tissues examined.

The brains of Long Evans shaker (les) rats, a model of dysmyelination, and their age- matched controls were studied by ex-vivo q-space diffusion imaging (QSI) and diffusion tensor imaging (DTI). The QSI and DTI indices were computed from the same acquisition. The les and the control brains were studied at different stages of maturation and disease progression. The mean displacement, the probability for zero displacement and kurtosis were computed from QSI data while the fractional anisotropy (FA) and the eigenvalues were computed from DTI. It was found that all QSI indices detect the les pathology, at all stages of maturation, while only some of the DTI indices could detect the les pathology. The QSI mean displacement was larger in the les group as compared with their age-matched controls while the probability for zero displacement and the kurtosis were both lower all indicating higher degree of restriction in the control brains. Since all the DTI eigenvalues were higher in the les brains as compared to controls, the less efficient DTI measure for discerning the les pathology was found to be the FA. Clearly, the most sensitive DTI parameter to the les pathology is λ3, i.e., the minimal diffusivity. Since the QSI and DTI data were obtained from the same acquisition, despite the somewhat higher SNR of the QSI data compared to the DTI data, it seems that the higher diagnostic capacity of the QSI data in this experimental model of dysmyelination, originates mainly from the higher diffusing weighting of the QSI data.

In recent years, enormous efforts have been made to translate nanotechnology innovations into medical practice. The main focuses were diagnosis and therapy with recent emphasis on multi-modal imaging. Since in many instance the sites for imaging and therapy are the same it became apparent that targeted magnetic nanoparticles (MNPs), which can be imaged, can also be used as a platform for theranostics applications. MNPs, which are characterized by high surface-to-volume ratios, are not only excellent scaffolds for loading targeting moieties, imaging tags and drugs, but can themselves be used to induce therapeutic effects making them the platform of choice for theranostics applications. In the current assay we will outline some of the recent progress in the synthesis and functionalization of MNPs, as well as their applications in multimodal imaging. The main body of the present essay, however, focuses on recent theranostic applications of such MNPs.

The feasibility of utilizing chemically-enhanced seeded precipitation (CESP) for primary reverse osmosis (PRO) concentrate demineralization was evaluated, via both experimental field tests and process analysis, to assess its potential use in enabling recovery enhancement via secondary RO (SRO) desalting. Field evaluations of batch CESP along with process simulations for desalting of agricultural drainage (AD) water (6700–14,400 mg/L TDS, SIg = ~ 0.9) have suggested that a PRO-CESP-SRO desalting approach is both technically and economically feasible to enable overall desalting recovery of about 83% and, with partial concentrate recycling, of up to 93%. In the CESP process, initial partial lime treatment provides adsorptive removal of residual antiscalant from the PRO concentrate. This enables subsequent concentrate desupersaturation (with respect to the major scaling salt calcium sulfate) to occur via seeded gypsum precipitation, unimpeded by residual antiscalant. The desupersaturated PRO concentrate (~ 34% reduction in SIg from ~ 1.7 to ~ 1.1) can then be further desalted in an SRO step up to the limit that is feasible with antiscalant dosing for scale control. When considering the cost of residual brine disposal, the cost of AD water desalination by PRO-CESP-SRO on the basis of desalted water volume is lower than RO by up to 39%.

The development of data-driven RO plant performance models was demonstrated using the support vector regression model building approach. Models of both steady state and unsteady state plant operation were developed based on a wide range of operational data obtained from a fully automated small spiral-wound RO pilot. Single output variable steady state plant models for flow rates and conductivities of the permeate and retentate streams were of high accuracy, with average absolute relative errors (AARE) of 0.70%–2.46%. Performance of a composite support vector regression (SVR) based model (for both streams) for flow rates and conductivities was of comparable accuracy to the single output variable models (AARE of 0.71%–2.54%). The temporal change in conductivity, as a result of transient system operation (induced by perturbation of either system pressure or flow rate), was described by SVR model, which utilizes a time forecasting approach, with performance level of less than 1% AARE for forecasting periods of 2 s to 3.5 min. The high level of performance obtained with the present modeling approach suggests that short-term performance forecasting models that are based on plant data, could be useful for advanced RO plant control algorithms, fault tolerant control and process optimization.

The development of classification nano-structure-activity Relationships (nano-SARs) of nanoparticle (NP) bioactivity is presented with the aim of demonstrating the integration of multiparametric toxicity/bioactivity assays to arrive at statistically meaningful class definitions (i.e., bioactivity/inactivity endpoints), as well as the implications of nano-SAR applicability domains and decision boundaries. Nano-SARs are constructed based on a dataset of 44 iron oxide core nanoparticles (NPs), used in molecular imaging and nano-sensing, containing bioactivity profiles for four cell types and four different assays. Class definitions are developed on the basis of 'hit' (i.e., significant bioactivity) identification analysis and self-organizing map based consensus clustering; these class definitions enable construction of nano-SARs of a high classification accuracy (>78%) with different NP descriptor combinations that include primary size, spin-lattice and spin-spin relaxivities, and zeta potentials. Analysis of the nano-SAR performance for different class definitions suggests that H4 (i.e., class with at least four hits) is a reasonable endpoint (from a 'regulatory' viewpoint) for keeping the level of false negatives (i.e., incorrect labeling of bioactive NPs as inactive) low. The establishment of a quantitative nano-SAR applicability domain is demonstrated, making use of a probability density with the H4 class definition and naive Bayesian classifier (NBC) model (with spin-lattice relaxivity and zeta potential as descriptors). Decision boundaries are determined for the above H4/NBC nano-SAR for different acceptance levels of false negative to false positive predictions, illustrating a practical approach that may assist in regulatory decision making with a consideration of reducing the likelihood of identifying bioactive NPs as being inactive.

This article discusses the remains of the

This article presents a new private Middle Assyrian letter that was sent by a woman to her husband. The letter is concerned with a liability borne by the husband. Of particular interest is an aphorism or popular saying which was drawn from the world of medicine, delivered by the woman at the close of the letter.

The technical feasibility of operating a spiral-wound RO plant in a cyclic mode of feed-flow reversal (FFR) was evaluated for brackish water desalting under conditions of high mineral scaling propensity. Scale-free and continuous permeate productivity was demonstrated, with calcium sulfate as the model scalant, in an automated spiral-wound RO pilot system in which FFR was triggered by scale detection in an external membrane monitor (MeMo). Real-time detection of mineral scaling in an external RO MeMo cell, receiving its feed from the concentrate of the RO plant tail element, enabled cyclic FFR operation in a self-adaptive mode accomplished by feed-back RO plant control in which permeate productivity was maintained. Membrane permeability was restored after each FFR cycle even with the initiation of membrane cleaning (i.e., via FFR) after a measurable level of scale formation in the MeMo and spiral-wound RO pilot. FFR cycle periods varied in length given the stochastic nature of crystal nucleation on the membranes in both the RO plant and in the MeMo RO cell. Scale-free FFR operation was demonstrated, without anticalant addition, with the RO plant operating (up to 81% recovery) such that the gypsum saturation index was up to 3.45 at the membrane surface of the tail element.

Biofilm formation, which frequently occurs in microbial infections and often reduces the efficacy of antibiotics, also perturbs many industrial and domestic processes. We found that a new class of water soluble pillar[5]arenes bearing phosphonium moieties (1, 2) and their respective ammonium analogues (3, 4) inhibit biofilm formation with IC50 values in the range of 0.67–1.66 μM. These compounds have no antimicrobial activity, do not damage red blood cell membranes, and do not affect mammalian cell viability in culture. Comparison of the antibiofilm activities of the phosphonium-decorated pillar[5]arene derivatives 1 and 2 with their respective ammonium counterparts 3 and 4 and their monomers 5 and 6, demonstrate that while positive charges, charge cooperativity and the pillararene platform are essential for the observed antibiofilm activity the nature of the charges is not.

Understanding the relationships between the physicochemical properties of engineered nanomaterials and their toxicity is critical for environmental and health risk analysis. However, this task is confounded by material diversity, heterogeneity of published data and limited sampling within individual studies. Here, we present an approach for analysing and extracting pertinent knowledge from published studies focusing on the cellular toxicity of cadmium-containing semiconductor quantum dots. From 307 publications, we obtain 1,741 cell viability-related data samples, each with 24 qualitative and quantitative attributes describing the material properties and experimental conditions. Using random forest regression models to analyse the data, we show that toxicity is closely correlated with quantum dot surface properties (including shell, ligand and surface modifications), diameter, assay type and exposure time. Our approach of integrating quantitative and categorical data provides a roadmap for interrogating the wide-ranging toxicity data in the literature and suggests that meta-analysis can help develop methods for predicting the toxicity of engineered nanomaterials. Literature data mining and knowledge extraction (known as meta-analysis) can be used to derive the relationships between toxicological outcome and the physicochemical properties of cadmium-containing quantum dots.

The main aim was to develop recommendations on eMental health interventions for the treatment of psychotic disorders. A systematic literature search on eMental health interventions was performed, and 24 articles about interventions in psychotic disorders were retrieved and systematically assessed for their quality. Studies were characterized by a large heterogeneity with regard to study type, sample sizes, interventions and outcome measures. Five graded recommendations were developed dealing with the feasibility of eMental health interventions, beneficial effects of psychoeducation, preliminary results of clinical efficacy, the need of moderation in peer support eMental health groups and the need to develop quality standards.

Because a variety of human-related activities, engineer-ed nanoparticles (ENMs) may be released to various environmental media and may cross environmental boundaries, and thus will be found in most media. Therefore, the potential environmental impacts of ENMs must be assessed from a multimedia perspective and with an integrated risk management approach that considers rapid developments and increasing use of new nanomaterials. Accordingly, this Account presents a rational process for the integration of in silico ENM toxicity and fate and transport analyses for environmental impact assessment. This approach requires knowledge of ENM toxicity and environmental exposure concentrations. Considering the large number of current different types of ENMs and that those numbers are likely to increase, there is an urgent need to accelerate the evaluation of their toxicity and the assessment of their potential distribution in the environment. Developments in high throughput screening (HTS) are now enabling the rapid generation of large data sets for ENM toxicity assessment. However, these analyses require the establishment of reliable toxicity metrics, especially when HTS includes data from multiple assays, cell lines, or organisms. Establishing toxicity metrics with HTS data requires advanced data processing techniques in order to clearly identify significant biological effects associated with exposure to ENMs. HTS data can form the basis for developing and validating in silico toxicity models (e.g., quantitative structure-activity relationships) and for generating data-driven hypotheses to aid in establishing and/or validating possible toxicity mechanisms. To correlate the toxicity of ENMs with their physicochemical properties, researchers will need to develop quantitative structure-activity relationships for nanomaterials (i.e., nano-SARs). However, as nano-SARs are applied in regulatory applications, researchers must consider their applicability and the acceptance level of false positive relative to false negative predictions and the reliability of toxicity data. To establish the environmental impact of ENMs identified as toxic, researchers will need to estimate the potential level of environmental exposure concentration of ENMs in the various media such as air, water, soil, and vegetation. When environmental monitoring data are not available, models of ENMs fate and transport (at various levels of complexity) serve as alternative approaches for estimating exposure concentrations. Risk management decisions regarding the manufacturing, use, and environmental regulations of ENMs would clearly benefit from both the assessment of potential ENMs exposure concentrations and suitable toxicity metrics. The decision process should consider the totality of available information: quantitative and qualitative data and the analysis of nanomaterials toxicity, and fate and transport behavior in the environment. Effective decision-making to address the potential impacts of nanomaterials will require considerations of the relevant environmental, ecological, technological, economic, and sociopolitical factors affecting the complete lifecycle of nanomaterials, while accounting for data and modeling uncertainties. Accordingly, researchers will need to establish standardized data management and analysis tools through nanoinformatics as a basis for the development of rational decision tools.

The influence of a pre-existing biofilm on RO membrane mineral scaling was evaluated using gypsum as a model scalant. The biofilm was established using microfiltered secondary treated wastewater effluent on-site in a wastewater treatment facility. Mineral scaling was then monitored via direct visual observation of crystal growth on the membrane surface in a transparent plate-and-frame RO cell. SEM imaging of the membrane surface and sectioned biofilm revealed gypsum crystals within the biofilm matrix, including the protrusion of crystal rods from within the biofilm. Both mineral scale surface coverage and crystal number density were greater in the presence of the biofilm. Moreover, individual mineral crystal growth rate within the biofilm was significantly higher relative to growth in the absence of a biofilm. Analyses of crystal growth and nucleation rates, within the biofilm and in its absence, suggest concentration polarization enhancement within the biofilm. The present study suggests that mineral scaling may not be restricted to tail elements in RO plants, but could also occur in lead elements where biofilms can enhance concentration polarization. Therefore, understanding of the coupling of biofouling and mineral scaling may be of particular significance to the operation and design of RO plants in water reuse applications.

An experimental study was carried out to demonstrate and quantify the feasibility of antiscalant (AS) removal from brackish water RO concentrate of high gypsum scaling propensity via lime treatment prior to seeded gypsum precipitation. Based on studies with model solutions, it was shown that sufficient AS removal (up to ∼90%) from RO concentrate is feasible via a lime treatment step (at a dose significantly lower than that required for conventional lime softening) to enable effective subsequent seeded gypsum precipitation. This two-step chemically-enhanced seeded precipitation (CESP) treatment of primary RO concentrate is suitable as an intermediate concentrate demineralization (ICD) stage for high recovery desalting employing secondary RO desalination. Analysis of gypsum precipitation and lime treatment kinetic data suggests that, after adequate CaCO 3 precipitation has been induced for effective AS scavenging, CaSO 4 desupersaturation can be achieved via seeded gypsum precipitation without retardation due to seed poisoning by AS. Also, the lime dose required to prevent seed poisoning during subsequent gypsum desupersaturation via seeded gypsum precipitation can be adequately assessed with a precipitation kinetics model that considers AS seed poisoning based on a Langmuir adsorption isotherm. The degree of AS removal after lime treatment increased linearly with the logarithm of the single lime dose additions. Staged lime dosing (i.e., multiple lime additions), however, removed a higher degree of AS relative to an equivalent single lime dose addition since a higher driving force for CaCO 3 precipitation could be maintained over the course of the lime treatment period.

The feasibility of removing calcium scale precursor ions from reverse osmosis (RO) concentrate by accelerated seeded precipitation (ASP) was investigated with the goal of increasing product water recovery and minimizing the volume of concentrate disposal from inland municipal wastewater desalination plants. Three seed materials were tested in laboratory trials — calcium carbonate, calcium sulfate and calcium phosphate. Calcium carbonate and calcium sulfate seed were not effective. The addition of calcium phosphate seed particles at 20 g L− 1 or phosphate ion in stoichiometric excess of the calcium concentration (250 mg L− 1 Ca = 6.25 mM Ca2+, 650 mg L− 1 HPO42− = 6.7 mM) decreased the calcium content in the RO concentrate to 10 mg L− 1. Evaluation of the accelerated seeded precipitation process using in-situ generated calcium phosphate seed at the pilot scale was performed on a 25 kL day− 1 pilot plant consisting of dissolved air flotation, ultrafiltration and reverse osmosis. The treated concentrate was filtered by a ceramic filtration system. Preliminary cost analyses indicate that high recovery RO using calcium phosphate precipitation can only be justified in inland situations where restrictions on concentrate disposal drive smaller evaporation pond storage volumes to offset the higher chemical and energy running costs.

Cet article examine les manuscrits de ‘Enlil et Namzitarra’ provenant d’Emar et d’Ugarit. Il propose notamment une nouvelle interpretation du discours sur le ‘theme de la vanite’ contenu dans cette composition soutenant que, contrairement a ce qui est affirme dans la litterature, le discours est prononce par Namzitarra et non par Enlil.

The JAK2V617F mutation has emerged in recent years as a diagnostic as well as treatment target in patients with polycythemia vera (PV). We analyzed JAK2V617F allele burden (JAK2(V617F)) in a Jewish population with PV. Results were correlated with disease symptoms and complications. Median JAK2(V617F) was 48% and 54% in patients of Ashkenazi and non-Ashkenazi origin, respectively (p =0.75). Higher JAK2(V617F) was seen in patients with imaging-proven splenomegaly (p =0.01). A correlation between JAK2(V617F) and the weekly hydoxyurea dose needed for disease control was found (p =0.043). In addition, a trend for higher allele burden in patients with longer disease duration (p =0.064) and those treated with cytoreductive drugs other than hydroxyurea (p =0.056) was noted. Higher JAK2(V617F) was seen in patients with transformation to myelofibosis (p =0.0001), but not in patients with vascular complications. JAK2(V617F) may assist in prognostic stratification of patients with PV.

Organophosphates are highly toxic substances, which cause severe brain damage. The hallmark of the brain injury is major convulsions. The goal of this study was to assess the spatial and temporal MR changes in the brain of paraoxon intoxicated rats. T2-weighted MRI and ¹H-MR-spectroscopy were conducted before intoxication, 3 h, 24 h, and 8 days postintoxication. T2 prolongation mainly in the thalami and cortex was evident as early as 3 h after intoxication (4-6% increase in T2 values, P 20% decrease, P 15%, P < 0.05). Animals who succumbed had extensive cortical edema, significant higher lactate levels and a significant decrease in NAA/creatine and NAA/choline levels compared to animals which survived the experiment. Organophosphates-induced brain damage is obvious on MR data already 3 h postintoxication. In vivo spectroscopic changes are more sensitive for assessing long-term injury than T2-weighted MR imaging. Early spectroscopic findings might be used as biomarkers for the severity of the intoxication and might predict early survival.

This paper argues that the peripheral recensions of theBallad of Early Rulersreflect Mesopotamian forerunners, and do not represent re-workings by the local scribes. The Ugarit recension is based on an Old Babylonian forerunner, and the Emar recension is based on a Middle Babylonian version that incorporated material from other scholarly sources. To support this contention, the Babylonian literary and scholarly background of the early rulers is discussed, and a reconstruction and analysis is offered of the Mari section of the Sumerian King List, in which two rulers of theBalladappear. The textual history of theBalladcontributes to the general debate regarding the origin, date of composition and transmission of Mesopotamian literature and its reception throughout scribal centers, not only in Ugarit and Emar, but also in Ḫattuša, Canaan and Egypt during the Late Bronze Age. A new copy of the Emar Ballad manuscript by Andrew George is offered at the end of this paper.

Conventional diffusion MRI methods are mostly capable of portraying microarchitectural elements such as fiber orientation in white matter from detection of diffusion anisotropy, which arises from the coherent organization of anisotropic compartments. Double-pulsed-field-gradient MR methods provide a means for obtaining microstructural information such as compartment shape and microscopic anisotropies even in scenarios where macroscopic organization is absent. Here, we apply angular double-pulsed-gradient-spin-echo MRI in the rat brain both ex vivo and in vivo for the first time. Robust angular dependencies are detected in the brain at long mixing time (t(m) ). In many pixels, the oscillations seem to originate from residual directors in randomly oriented media, i.e., from residual ensemble anisotropy, as corroborated by quantitative simulations. We then developed an analysis scheme that enables one to map of structural indices such as apparent eccentricity (aE) and residual phase (φ) that enables characterization of the rat brain in general, and especially the rat gray matter. We conclude that double-pulsed-gradient-spin-echo MRI may in principle become important in characterizing gray matter morphological features and pathologies in both basic and applied neurosciences.