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Abstract Combined molecular, physicochemical and chemical properties of electrophilic warheads can be applied to create covalent drugs with diverse facets. Here we study these properties in fluorinated diketones (FDKs) and their multicomponent equilibrium systems in the presence of protic nucleophiles, revealing the potential of the CF2(CO)2 group to act as a multifaceted warhead for reversible covalent drugs. The equilibria compositions of various FDKs in water/octanol contain up to nine species. A simultaneous direct species-specific 19F-NMR-based log P determination of these complex equilibria systems was achieved and revealed in some cases lipophilic to hydrophilic shifts, indicating possible adaptation to different environments. This was also demonstrated in 19F-MAS-NMR-based water-membrane partitioning measurements. An interpretation of the results is suggested by the aid of a DFT study and 19F-DOSY-NMR spectroscopy. In dilute solutions, a model FDK reacted with protected cysteine to form two hemi-thioketal regioisomers, indicating possible flexible regio-reactivity of CF2(CO)2 warheads toward cysteine residues.

Thin-film composite (TFC) polyamide (PA) RO membrane modified with a layer of tethered poly(acrylic acid) (PAA) chains displayed intrinsic rejections of nitrate, boron, As(III), and As(V) of 98.0%, 90.7%, 96%, and 99.6%, respectively. The solute permeability coefficients for nitrate, boron, As(III), and As(V) by the SNS-PAA-PA membrane were lower by 31–38%, 49–63%, 57–72% and 87–93% relative to tested commercial membranes. The above results indicate that the SNS-PAA-PA membrane should be suitable for purification of brackish source water contaminated with nitrate, boron, As(III), and As(V) to levels 1219 ppm, 2 ppm, 95 ppb, and 948 ppb, respectively. The study results suggest that there is merit in further exploration of the potential of the present approach for enhancing RO membranes performance for targeted solute removal.

Abstract An uncharged, water‐soluble per‐ethylene‐glycol pillar[5]arene derivative (1) was synthesized and its aggregation mode, host‐guest chemistry in water and extraction ability was explored. Compound 1 is a liquid at room temperature; in water, limited self‐aggregation occurred at high concentrations as deduced from diffusion NMR and dynamic light scattering. Compound 1 forms pseudo‐rotaxane‐like 1 : 1 host‐guest complexes with 1,ω‐di‐substituted alkanes with association constants on the order of 103–104 m−1. Interestingly, NMR experiments showed that the guest location relative to the host ring system differs among the different complexes. In proof‐of‐concept experiments, compound 1 was shown to extract structurally related organic compounds from benzene into water with significant selectivity. Compound 1, which is a liquid at room temperature and has only limited interactions with its side arms, can, in principle, be regarded as a complement to or as a kind of type I porous liquid.

Abstract FMR1 premutation (55–200 CGG repeats) results in fragile X-associated primary ovarian insufficiency (FXPOI). We evaluated expression levels of folliculogenesis-related mediators, follicle-stimulating hormone (FSH) receptor and anti-Mullerian hormone (AMH), to gain insights into the mechanisms underlying the reduced ovarian function. Mural granulosa cells (MGCs) were collected from FMR1 premutation carriers and noncarriers undergoing IVF treatments. At baseline, MGCs of carriers demonstrated significantly higher mRNA expression levels of AMH (3.5 ± 2.2, n = 12 and 0.97 ± 0.5, n = 17, respectively; p = 0.0003) and FSH receptor (5.6 ± 2.8 and 2.7 ± 2.8, respectively; p = 0.02) and higher AMH protein expression on immunostaining. Accordingly, FMR1 premutation-transfected COV434 cells exhibited higher AMH protein expression than COV434 cells transfected with 20 CGG repeats. We conclude that FMR1 premutation may lead to dysregulation of AMH expression levels, probably due to a compensatory mechanism. Elucidating the pathophysiology of FXPOI may help in early detection of ovarian dysfunction and tailoring IVF treatments to FMR1 premutation carriers.

Nanotechnology has enabled the discovery of a multitude of novel materials exhibiting unique physicochemical (PChem) properties compared to their bulk analogues. These properties have led to a rapidly increasing range of commercial applications; this, however, may come at a cost, if an association to long-term health and environmental risks is discovered or even just perceived. Many nanomaterials (NMs) have not yet had their potential adverse biological effects fully assessed, due to costs and time constraints associated with the experimental assessment, frequently involving animals. Here, the available NM libraries are analyzed for their suitability for integration with novel nanoinformatics approaches and for the development of NM specific Integrated Approaches to Testing and Assessment (IATA) for human and environmental risk assessment, all within the NanoSolveIT cloud-platform. These established and well-characterized NM libraries (e.g. NanoMILE, NanoSolutions, NANoREG, NanoFASE, caLIBRAte, NanoTEST and the Nanomaterial Registry (>2000 NMs)) contain physicochemical characterization data as well as data for several relevant biological endpoints, assessed in part using harmonized Organisation for Economic Co-operation and Development (OECD) methods and test guidelines. Integration of such extensive NM information sources with the latest nanoinformatics methods will allow NanoSolveIT to model the relationships between NM structure (morphology), properties and their adverse effects and to predict the effects of other NMs for which less data is available. The project specifically addresses the needs of regulatory agencies and industry to effectively and rapidly evaluate the exposure, NM hazard and risk from nanomaterials and nano-enabled products, enabling implementation of computational ‘safe-by-design’ approaches to facilitate NM commercialization.

The gypsum and calcite scaling propensities of the thin-film composite polyamide (PA-TFC) reverse osmosis (RO) membrane, modified with a tethered surface layer of polyacrylic acid (PAA) chains, was evaluated and compared to the scaling of selected commercial RO membranes. The tethered PAA layer was synthesized onto a commercial polyamide membrane (i.e., base-PA) via atmospheric pressure plasma-induced graft polymerization (APPIGP). The PAA nano-structured (SNS) base-PA membrane (SNS-PAA-PA) was scaled to a lesser degree, as quantified by a lower permeate flux decline and surface imaging, relative to the tested commercial membranes (Dow SW30, Toray SWRO, and BWRO). The cleaning of gypsum-scaled membranes with D.I. water flushing achieved 100% water permeability recovery for both the SNS-PAA-PA and Dow SW30 membranes, relative to 92–98% permeability restoration for the Toray membranes. The calcium carbonate scaling of SNS-PAA-PA membranes was also lower relative to the commercial membranes, but permeability recovery after D.I. water cleaning was somewhat lower (94%) but consistent with the level of surface scale coverage. In contrast, the calcite and gypsum-scaled membrane areas of the commercial membranes post-cleaning were significantly higher than for the SNS-PAA-PA membrane but with 100% permeability recovery, suggesting the potential for membrane damage when mineral scaling is severe.

In this paper we present a new method for automatic transliteration and segmentation of Unicode cuneiform glyphs using Natural Language Processing (NLP) techniques. Cuneiform is one of the earliest known writing system in the world, which documents millennia of human civilizations in the ancient Near East. Hundreds of thousands of cuneiform texts were found in the nineteenth and twentieth centuries CE, most of which are written in Akkadian. However, there are still tens of thousands of texts to be published. We use models based on machine learning algorithms such as recurrent neural networks (RNN) with an accuracy reaching up to 97% for automatically transliterating and segmenting standard Unicode cuneiform glyphs into words. Therefore, our method and results form a major step towards creating a human-machine interface for creating digitized editions. Our code, Akkademia, is made publicly available for use via a web application, a python package, and a github repository.

The potential environmental impact of nanomaterials is a critical concern and the ability to assess these potential impacts is top priority for the progress of sustainable nanotechnology. Risk assessment tools are needed to enable decision makers to rapidly assess the potential risks that may be imposed by engineered nanomaterials (ENMs), particularly when confronted by the reality of limited hazard or exposure data. In this review, we examine a range of available risk assessment frameworks considering the contexts in which different stakeholders may need to assess the potential environmental impacts of ENMs. Assessment frameworks and tools that are suitable for the different decision analysis scenarios are then identified. In addition, we identify the gaps that currently exist between the needs of decision makers, for a range of decision scenarios, and the abilities of present frameworks and tools to meet those needs.

The data presented are supplementary to an article [Kim et al., 2019] on synthesis and surface characterization of tethered polyacrylic acid (PAA) layers on polysulfone (PSf) film/membrane surfaces via atmospheric pressure plasma-induced graft polymerization (APPIGP). Data on surface characterization of the synthesized tethered PAA layers includes: AFM topographic surface images and height distributions of surface features, dry layer thickness, chain rupture length distributions determined via AFM based force spectroscopy (AFM-FS), in addition to measurements of water contact angles. Fouling propensity data for ultrafiltration of alginic acid as a model foulant are also provided for native and PAA grafted PSf ultrafiltration (UF) membranes.

Introduction: Fragile X syndrome (FXS) is a common form of X-linked intellectual and developmental disability with a prevalence of 1/4000–5000 in males and 1/6000–8000 in females. Most cases of the syndrome result from expansion of a premutation (55–200 CGGs) to a full mutation (>200 CGGs) repeat located in the 5′ untranslated region of the fragile X mental retardation (FMR1) gene. The risk for full mutation expansions increases dramatically with increasing numbers of CGG repeats. Recent studies, however, revealed AGG interruptions within the repeat area function as a “protective factor” decreasing the risk of intergenerational expansion.Materials and Methods: This study was conducted to validate the relevance of AGG analysis for the ethnically diverse Israeli population. To increase the accuracy of our results, we combined results from Israel with those from the New York State Institute for Basic Research in Developmental Disabilities (IBR). To the best of our knowledge this is the largest cohort of different ethnicities to examine risks of unstable transmissions and full mutation expansions among FMR1 premutation carriers.Results: The combined data included 1471 transmissions of maternal premutation alleles: 369 (25.1%) stable and 1,102 (74.9%) unstable transmissions. Full mutation expansions were identified in 20.6% (303/1471) of transmissions. A total of 97.4% (388/397) of transmissions from alleles with no AGGs were unstable, 79.6% (513/644) in alleles with 1 AGG and 46.7% (201/430) in alleles with 2 or more AGGs. The same trend was seen with full mutation expansions where 40% (159/397) of alleles with no AGGs expanded to a full mutation, 20.2% (130/644) for alleles with 1 AGG and only 3.2% (14/430) in alleles with 2 AGGs or more. None of the alleles with 3 or more AGGs expanded to full mutations.Conclusion: We recommend that risk estimates for FMR1 premutation carriers be based on AGG interruptions as well as repeat size in Israel and worldwide.

Abnormalities in the X-linked FMR1 gene are associated with a constellation of disorders, which have broad and profound implications for the person first diagnosed, and extended family members of all ages. The rare and pleiotropic nature of the associated disorders, both common and not, place great burdens on (1) the affected families, (2) their care providers and clinicians, and (3) investigators striving to conduct research on the conditions. Fragile X syndrome, occurring more severely in males, is the leading genetic cause of intellectual disability. Fragile X associated tremor and ataxia syndrome (FXTAS) is a neurodegenerative disorder seen more often in older men. Fragile X associated primary ovarian insufficiency (FXPOI) is a chronic disorder characterized by oligo/amenorrhea and hypergonadotropic hypogonadism before age 40 years. There may be significant morbidity due to: (1) depression and anxiety related to the loss of reproductive hormones and infertility; (2) reduced bone mineral density; and (3) increased risk of cardiovascular disease related to estrogen deficiency. Here we report the case of a young woman who never established regular menses and yet experienced a 5-year diagnostic odyssey before establishing a diagnosis of FXPOI despite a known family history of fragile X syndrome and early menopause. Also, despite having clearly documented FXPOI the woman conceived spontaneously and delivered two healthy children. We review the pathophysiology and management of FXPOI. As a rare disease, the diagnosis of FXPOI presents special challenges. Connecting patients and community health providers with investigators who have the requisite knowledge and expertise about the FMR1 gene and FXPOI would facilitate both patient care and research. There is a need for an international natural history study on FXPOI. The effort should be coordinated by a global virtual center, which takes full advantage of mobile device communication systems.

The impact of ZnO and TiO2 manufactured nanoparticles (MNPs) on soil bacterial communities for different exposure periods and MNP doses was explored via data visualization techniques. Interrelationships between MNP treatments and responses of bacterial taxa were illustrated by bipartite graphs, allowing fast identification of important soil bacterial taxa that are susceptible to MNPs. Contribution biplots with subcompositional coherence property were generated via log-ratio analysis (LRA), which jointly display the treatment distribution and the variance (contribution) of bacterial taxa. The LRA contribution biplots and nonmetric multi-dimensional scaling (NMDS) of the dataset, along with hierarchical clustering, demonstrated that high doses of ZnO and TiO2 MNPs caused significant compositional changes in soil bacterial communities. The suitability of family level for MNP taxonomic impact assessment was demonstrated by both the LRA biplots and simplified NMDSs with quantification provided by the distance correlation between MNP impacts summarized at different taxonomic levels. The present study demonstrates that visual exploration could potentially assist in knowledge discovery and interpretation of data on soil bacterial communities exposed to MNPs and thus evaluate the potential for environmental impacts.

An integrated simulation tool was developed for assessing the potential release and environmental distribution of nanomaterials (RedNano) based on a life cycle assessment approach and multimedia compartmental modeling coupled with mechanistic intermedia transport processes. The RedNano simulation tool and its web-based software implementation enables rapid “what-if?” scenario analysis, in order to assess the response of an environmental system to various release scenarios of engineered nanomaterials (ENMs). It also allows for the investigation of the impact of geographical and meteorological parameters on ENM distribution in the environment, comparison of the impact of ENM production and potential releases on different regions, and estimation of source release rates based on monitored ENM concentrations. Moreover, the RedNano simulation tool is suitable for research, academic, and regulatory purposes. Specifically, it has been used in environmental multimedia impact assessment courses at both the undergraduate and graduate levels. The RedNano simulation tool can also serve as a decision support tool to rapidly and critically assess the potential environmental implications of ENMs and thus ensure that nanotechnology is developed in a productive and environmentally responsible manner.

Calmodulin lysine methyl transferase (CaM KMT) is ubiquitously expressed and highly conserved from plants to vertebrates. CaM is frequently trimethylated at Lys-115, however, the role of CaM methylation in vertebrates has not been studied. CaM KMT was found to be homozygously deleted in the 2P21 deletion syndrome that includes 4 genes. These patients present with cystinuria, severe intellectual disabilities, hypotonia, mitochondrial disease and facial dysmorphism. Two siblings with deletion of three of the genes included in the 2P21 deletion syndrome presented with cystinuria, hypotonia, a mild/moderate mental retardation and a respiratory chain complex IV deficiency. To be able to attribute the functional significance of the methylation of CaM in the mouse and the contribution of CaM KMT to the clinical presentation of the 2p21deletion patients, we produced a mouse model lacking only CaM KMT with deletion borders as in the human 2p21deletion syndrome. No compensatory activity for CaM methylation was found. Impairment of complexes I and IV, and less significantly III, of the mitochondrial respiratory chain was more pronounced in the brain than in muscle. CaM KMT is essential for normal body growth and somatosensory development, as well as for the proper functioning of the adult mouse brain. Developmental delay was demonstrated for somatosensory function and for complex behavior, which involved both basal motor function and motivation. The mutant mice also had deficits in motor learning, complex coordination and learning of aversive stimuli. The mouse model contributes to the evaluation of the role of methylated CaM. CaM methylation appears to have a role in growth, muscle strength, somatosensory development and brain function. The current study has clinical implications for human patients. Patients presenting slow growth and muscle weakness that could result from a mitochondrial impairment and mental retardation should be considered for sequence analysis of the CaM KMT gene.

High-throughput genomic mutation screening for primary tumors has characteristically been expensive, labor-intensive, and inadequate to detect low levels of mutation in a background of wild-type signal. We present a new, combined PCR and colorimetric approach that is inexpensive, simple, and can detect the presence of 1% mutation in a background of wild-type. We compared manual dideoxy sequencing of p53 for eight lung cancer samples to a novel assay combining a primer extension step and an enzymatic colorimetric step in a 96-well plate with covalently attached oligonucleotide sequences. For every sample, we were able to detect the presence or absence of the specific mutation with a statistically significant difference between the sample optical density (OD) and the background OD, with a sensitivity and specificity of 100%. This assay is straightforward, accurate, inexpensive, and allows for rapid, high-throughput analysis of samples, making it ideal for genomic mutation or polymorphism screening studies in both clinical and research settings.

AimTo assess the role of mRNA accumulation in granulosa cells as the cause of low ovarian response among FMR1 premutation carriers undergoing pre-implantation genetic diagnosis (PGD).DesignCase control study in an academic IVF unit. Twenty-one consecutive FMR1 premutation carriers and 15 control women were included. After oocyte retrieval the granulosa cells mRNA levels of FMR1 was measured using RT-PCR.ResultsIn FMR1 premutation carriers, there was a significant non-linear association between the number of CGG repeats and the number of retrieved oocytes (pConclusionWe suggest that there is a no-linear association between the number of CGG repeats and ovarian function, resulting from an increased granulosa cells FMR1 mRNA accumulation in FMR1 carriers in the mid-range (80-120 repeats).

A phenotype recognition model was developed for high throughput screening (HTS) of engineered Nano-Materials (eNMs) toxicity using zebrafish embryo developmental response classified, from automatically captured images and without manual manipulation of zebrafish positioning, by three basic phenotypes (i.e., hatched, unhatched, and dead). The recognition model was built with a set of vectorial descriptors providing image color and texture information. The best performing model was attained with three image descriptors (color histogram, representative color, and color layout) identified as most suitable from an initial pool of six descriptors. This model had an average recognition accuracy of 97.40±0.95% in a 10-fold cross-validation and 93.75% in a stress test of low quality zebrafish images. The present work has shown that a phenotyping model can be developed with accurate recognition ability suitable for zebrafish-based HTS assays. Although the present methodology was successfully demonstrated for only three basic zebrafish embryonic phenotypes, it can be readily adapted to incorporate more subtle phenotypes.

BackgroundNeural stem cells are currently being investigated as potential therapies for neurodegenerative diseases, stroke, and trauma. However, concerns have been raised over the safety of this experimental therapeutic approach, including, for example, whether there is the potential for tumors to develop from transplanted stem cells.Methods and findingsA boy with ataxia telangiectasia (AT) was treated with intracerebellar and intrathecal injection of human fetal neural stem cells. Four years after the first treatment he was diagnosed with a multifocal brain tumor. The biopsied tumor was diagnosed as a glioneuronal neoplasm. We compared the tumor cells and the patient's peripheral blood cells by fluorescent in situ hybridization using X and Y chromosome probes, by PCR for the amelogenin gene X- and Y-specific alleles, by MassArray for the ATM patient specific mutation and for several SNPs, by PCR for polymorphic microsatellites, and by human leukocyte antigen (HLA) typing. Molecular and cytogenetic studies showed that the tumor was of nonhost origin suggesting it was derived from the transplanted neural stem cells. Microsatellite and HLA analysis demonstrated that the tumor is derived from at least two donors.ConclusionsThis is the first report of a human brain tumor complicating neural stem cell therapy. The findings here suggest that neuronal stem/progenitor cells may be involved in gliomagenesis and provide the first example of a donor-derived brain tumor. Further work is urgently needed to assess the safety of these therapies.

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. [ABSTRACT FROM AUTHOR]

A new class of surface-structured RO membranes was developed with a hydrophilic brush layer of terminally anchored polymer chains resulting in fouling resistant membranes of low mineral scaling propensity and high permeability. The approach is based on free-radical graft polymerization of a suitable monomer, onto the active polyamide (PA) layer of a thin film composite (PA-TFC) membrane, post-surface activation with an impinging atmospheric pressure plasma source. Two types of nano-structured (SNS) RO membranes (SNS-PA-TFC) were synthesized based on methacrylic acid (MAA-SNS-PA-TFC) and acrylamide (AA-SNS-PA-TFC) graft polymerization. The poly(methacrylic acid) and poly(acrylamide) brush layers, on the PA surface, resulted in RO membranes of significantly lower mineral scaling propensity, evaluated with respect to the mineral scalant calcium sulfate dihydrate, compared with commercial RO membrane (LFC1) of about the same salt rejection (∼95%) and surface roughness (∼70 nm). Direct membrane surface imaging indicated that the rate of nucleation and thus mineral scaling were reduced owing to the polymer brush layer. Fouling resistance of the SNS-PA-TFC membranes was also demonstrated with respect to model foulants (the protein BSA and alginic acid). The MAA-SNS-PA-TFC and AA-SNS-PA-TFC membranes had a negatively charged and near neutral surfaces, respectively, with water contact angles somewhat lower for the former and higher for the latter membranes relative to the LFC1 membrane. The AA-SNS-PA-TFC membrane displayed lower mineral scaling propensity than the MAA based membrane, although its alginic acid fouling resistance was inferior, despite its lower surface roughness (25–33 nm) relative to the MAA-SNS-PA-RFC (∼60–80 nm) and LFC1 (∼73 nm) membranes. [ABSTRACT FROM AUTHOR]

Polymer layer growth by free radical graft polymerization (FRGP) and controlled nitroxide-mediated graft polymerization (NMGP) of polystyrene was achieved by atmospheric pressure hydrogen plasma surface activation of silicon. Kinetic polystyrene layer growth by atmospheric pressure plasma-induced FRGP (APPI-FRGP) exhibited a maximum surface-grafted layer thickness (125 Å after 20 h) at an initial monomer concentration of [M] 0= 2.62 M at 85 °C. Increasing both the reaction temperature ( T= 100 °C) and initial monomer concentration ([M] 0= 4.36 M) led to an increased initial film growth rate but a reduced polymer layer thickness, due to uncontrolled thermal initiation and polymer grafting from solution. Controlled atmospheric pressure plasma-induced NMGP (APPI-NMGP), using 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), exhibited a linear increase in grafted polystyrene layer growth with time due to controlled surface graft polymerization as well as reduced uncontrolled solution polymerization and polymer grafting, resulting in a polymer layer thickness of 285 Å after 60 h at [TEMPO] = 10 mM, [M] 0= 4.36 M, and T= 120 °C. Atomic force microscopy (AFM) surface analysis demonstrated that polystyrene-grafted surfaces created by APPI-NMGP exhibited a high surface density of spatially homogeneous polymer features with a low root-mean-square (RMS) surface roughness ( Rrms= 0.36 nm), similar to that of the native silicon surface ( Rrms= 0.21 nm). In contrast, polymer films created by APPI-FRGP at [M] 0= 2.62 M demonstrated an increase in polymer film surface roughness observed at reaction temperatures of 85 °C ( Rrms= 0.55 nm) and 100 °C ( Rrms= 1.70 nm). The present study concluded that the current approach to APPI controlled radical polymerization may be used to achieve a grafted polymer layer with a lower surface roughness and a higher fractional coverage of surface-grafted polymers compared to both conventional FRGP and APPI-FRGP. [ABSTRACT FROM AUTHOR]

We followed the self-assembly of C-alkyl-resorcin4arene (1a,1b) in the presence of tetraethylammonium salts (2). The X-ray structure of C-ethyl-resorcin4arene (1c) in the presence of TEABr (2b), showed a dimer encapsulating one guest. However, diffusion measurements reveal that two molecules of tetraethylammonium are encapsulated within the hexameric capsule of 1a,bin chloroform, regardless of the anion. Most importantly, the anion affects the role of water in the self-assembly and the nature of the formed capsules. [ABSTRACT FROM AUTHOR]

Abstract  Although magnetic resonance imaging (MRI) is one of the most important imaging modalities of the central nervous system (CNS), one of the main drawbacks of MRI is its limited specificity. This can potentially be partially alleviated by target-specific contrast agents. In the present paper we describe a simple high yield synthesis of two such gadolinium-based spiperone targeted MRI contrast agents, 1a and 1b. The R1 relaxivities of 1a and 1b were evaluated and found to be 5.94 and 8.31 mM−1 s−1, respectively at 9.4T, while their R2 relaxivities at the same magnetic field were found to be 18.05 and 22.60 mM−1 s−1, respectively. In addition and very importantly compound 1a, which is a gadolinium-based, spiperone-targeted MRI contrast agent, was found to preserve some of the spiperone affinity toward the dopamine D2 receptor. Compounds 1a and 1b thus represent potential agents for in vitro dopamine receptor imaging using MRI in experimental models. [ABSTRACT FROM AUTHOR]

The effect of hydration repulsion on the agglomeration of nanoparticles in aqueous suspensions was investigated via the description of agglomeration by the Smoluchowski coagulation equation using constant number Monte–Carlo simulation making use of the classical DLVO theory extended to include the hydration repulsion energy. Evaluation of experimental DLS measurements for TiO2, CeO2, SiO2, and α-Fe2O3 (hematite) at high IS (up to 900 mM) or low |ζ-potential| (≥1.35 mV) demonstrated that hydration repulsion energy can be above electrostatic repulsion energy such that the increased overall repulsion energy can significantly lower the agglomerate diameter relative to the classical DLVO prediction. While the classical DLVO theory, which is reasonably applicable for agglomeration of NPs of high |ζ-potential| (∼>35 mV) in suspensions of low IS (∼<1 mM), it can overpredict agglomerate sizes by up to a factor of 5 at high IS or low |ζ-potential|. Given the potential important role of hydration repulsion over a range of relevant conditions, there is merit in quantifying this repulsion energy over a wide range of conditions as part of overall characterization of NP suspensions. Such information would be of relevance to improved understanding of NP agglomeration in aqueous suspensions and its correlation with NP physicochemical and solution properties. [ABSTRACT FROM AUTHOR]

The transcription factor forkhead box P3 (FOXP3 in humans; Foxp3 in mice) controls the development and function of regulatory T cells (Treg). In mice, CD4+CD25− T cells do not express Foxp3 following TCR activation. Whether FOXP3 is a common activation-induced molecule in human T cells—hence not Treg restricted—is currently a controversial issue. As FOXP3 can significantly modulate the function of T cells, understanding the mode (and regulation) of FOXP3 expression in human T cells is vital. Here we show that in conventional CD4+CD25− T cells, the induction of FOXP3 expression following TCR activation is both restricted to a fraction of the progeny and transient. Moreover, FOXP3 expression in vivo is particularly infrequent in activated effector CD4+ T cells that accumulate within inflamed joints. We next demonstrate that the repression of FOXP3 transcription in resting conventional human CD25− T cells is linked to complete methylation of an evolutionarily conserved intronic CpG island. The dense methylation pattern is furthermore inherited after activation by progeny. This intronic CpG island, on the other hand, is frequently unmethylated in CD4+CD25+ T cells. Importantly, blocking maintenance DNA methylation, by pharmacological inhibition of DNA methyltransferase-1, induced significant and stable activation-dependent FOXP3 expression in cycling conventional T cells, which was further amplified by co-treatment with transforming growth factor β. In contrast to natural Treg, such induced CD4+FOXP3+ T cells could produce pro-inflammatory cytokines upon activation. These results indicate that DNA methylation normally restricts FOXP3 transcription in conventional human T cells. [ABSTRACT FROM AUTHOR]