An Inbred Ecosystem that Supports Medulloblastoma.

In a recent issue of Cell, Yao et al. use a unique genetic strategy to study sonic hedgehog-medulloblastoma. Their results reveal a complex network in the tumor microenvironment involving the trans-differentiation of cancer cells into astrocytes to fuel tumor growth.

Serpins promote cancer cell survival and vascular co-option in brain metastasis.

Brain metastasis is an ominous complication of cancer, yet most cancer cells that infiltrate the brain die of unknown causes. Here, we identify plasmin from the reactive brain stroma as a defense against metastatic invasion, and plasminogen activator (PA) inhibitory serpins in cancer cells as a shield against this defense. Plasmin suppresses brain metastasis in two ways: by converting membrane-bound astrocytic FasL into a paracrine death signal for cancer cells, and by inactivating the axon pathfinding molecule L1CAM, which metastatic cells express for spreading along brain capillaries and for metastatic outgrowth. Brain metastatic cells from lung cancer and breast cancer express high levels of anti-PA serpins, including neuroserpin and serpin B2, to prevent plasmin generation and its metastasis-suppressive effects. By protecting cancer cells from death signals and fostering vascular co-option, anti-PA serpins provide a unifying mechanism for the initiation of brain metastasis in lung and breast cancers.

Direct and indirect selenium speciation in biofortified wheat: A tale of two techniques.

Wheat can be biofortified with different inorganic selenium (Se) forms, selenite or selenate. The choice of Se source influences the physiological response of the plant and the Se metabolites produced. We looked at selenium uptake, distribution and metabolization in wheat exposed to selenite, selenate and a 1:1 molar mixture of both to determine the impact of each treatment on the Se speciation in roots, shoots, and grains. To achieve a comprehensive quantification of the Se species, the complementarity of high-performance liquid chromatography coupled with inductively coupled plasma mass spectrometry and X-ray absorption spectroscopy was exploited. This approach allowed the identification of the six main selenium species: selenomethionine, selenocysteine, selenocystine, selenite, selenate, and elemental selenium. The three treatments resulted in similar total selenium concentration in grains, 90-150 mg Se kg-1 , but produced different effects in the plant. Selenite enhanced root accumulation (66% of selenium) and induced the maximum toxicity, whereas selenate favored shoot translocation (46%). With the 1:1 mixture, selenium was distributed along the plant generating lower toxicity. Although all conditions resulted in >92% of organic selenium in the grain, selenate produced mainly C-Se-C forms, such as selenomethionine, while selenite (alone or in the mixture) enhanced the production of C-Se-Se-C forms, such as selenocystine, modifying the selenoamino acid composition. These results provide a better understanding of the metabolization of selenium species which is key to minimize plant toxicity and any concomitant effect that may arise due to Se-biofortification.

Efficient controlled release of cannabinoids loaded in γ-CD-MOFs and DPPC liposomes as novel delivery systems in oral health.

Olivetol (OLV), as a cannabidiol (CBD) analog, was incorporated in γ-cyclodextrin metal-organic frameworks (γ-CD-MOFs) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes as potential analgesic drug delivery systems (DDS) for dental hypersensitivity (DH) treatment. These DDS have been scarcely employed in oral health, being the first time in case of MOFs loaded with cannabinoids. In vitro experiments using bovine teeth were performed to verify if the drug is able to reach the dentin, where it can flow to the pulp tissues and exert its analgesic effect; enamel and dentin regions were analyzed by synchrotron radiation-based FTIR microspectroscopy. Principal component analysis (PCA) was used to process the spectroscopic data as a powerful chemometric tool, and it revealed a similar behavior in both regions. The studied DDS have been characterized by different techniques, and is was demonstrated that DDS is an efficient way to carry the drug through dental tissues without compromising their structure.

Validated method for polystyrene nanoplastic separation in aqueous matrices by asymmetric-flow field flow fraction coupled to MALS and UV-Vis detectors.

Plastics with nanosize (nanoplastics, NPLs) must be characterized, since they can be toxic or act as carriers of organic and inorganic pollutants, but there is a lack of reference materials and validated methods in the nanosize range. Therefore, this study has focused on the development and validation of a separation and size characterization methodology of polystyrene latex nanospheres, by using an asymmetric-flow field flow fraction system coupled to multi-angle light scattering and ultraviolet-visible detectors (AF4-MALS-UV). Hence, this work presents a fully validated methodology in the particle size range 30 to 490 nm, with bias between 95 and 109%, precision between 1 and 18%, LOD and LOQ below 0.2 and 0.3 µg respectively, except for 30-nm standard, for both detectors, and showing stable results for 100 analyses.

Effective Removal of Boron from Aqueous Solutions by Inorganic Adsorbents: A Review.

Increasing levels of boron in water exceeding acceptable thresholds have triggered concerns regarding environmental pollution and adverse health effects. In response, significant efforts are being made to develop new adsorbents for the removal of boron from contaminated water. Among the various materials proposed, inorganic adsorbents have emerged as promising materials due to their chemical, thermal, and mechanical stability. This review aims to comprehensively examine recent advances made in the development of inorganic adsorbents for the efficient removal of boron from water. Firstly, the adsorption performance of the most used adsorbents, such as magnesium, iron, aluminum, and individual and mixed oxides, are summarized. Subsequently, diverse functionalization methods aimed at enhancing boron adsorption capacity and selectivity are carefully analyzed. Lastly, challenges and future perspectives in this field are highlighted to guide the development of innovative high-performance adsorbents and adsorption systems, ultimately leading to a reduction in boron pollution.

Combination of Two Synchrotron Radiation-Based Techniques and Chemometrics to Study an Enhanced Natural Remineralization of Enamel.

The limitations to assess dental enamel remineralization have been overcome by a methodology resulting from the appropriate combination of synchrotron radiation-based techniques on both, infrared microspectroscopy and micro X-ray diffraction, with the help of specific data mining. Since amelogenin plays a key role in modulating the mineralization of tooth enamel, we propose a controlled ion release for fluorapatite structural ions (Ca2+, PO43-, and F-, also including Zn2+) by using weak acid and weak base ion-exchange resins in the presence of amelogenin to remineralize the surface of etched teeth. This combination provides the necessary ions for enamel remineralization and a guide for crystal growth due to the protein. Remineralized tooth samples were analyzed by applying the indicated methodology. The synchrotron data were treated using principal component analysis and multivariate curve resolution to analyze the mineral layer formed in the presence and absence of amelogenin. The remineralizing treatment created a fluorapatite layer free of carbonate impurities and with a similar orientation to that of the natural enamel thanks to amelogenin contribution.

Discriminating the origin of calcium oxalate monohydrate formation in kidney stones via synchrotron microdiffraction.

Nephrolithiasis is a multifactor disease that produces nephrolites in the kidneys. Calcium oxalate hydrate (dihydrated, COD, or monohydrated, COM) stones are the most common ones with more than sixty percent incidence worldwide. They are related to different pathologies, COD with hypercalciuria and COM with hyperoxaluria. COD is an unstable species and transforms into COM (herein named TRA to distinguish the origin of the monohydrated species). TRA and COM are chemically and crystallographically identical leading to misdiagnosis and recurrence increase. In the current study, the composition and crystalline structures of several calcium oxalate stones, classified by morpho-constitutional analysis, were examined by IR and synchrotron through-the-substrate micro-X-ray diffraction (tts-µXRD). Both IR and linear diffractogram studies were able to distinguish between the monohydrated and dihydrated phases but not between COM and TRA, as expected. The analysis of 2D diffraction patterns revealed that TRA showed a lower degree of crystallinity and less texture with respect to COM which can be used as a signature to distinguish between the two. This study confirms that despite the subtle differences between COM and TRA, the origin of the monohydrate oxalates can be unraveled using tts-µXRD. This valuable information should be taken into account in order to improve patients' diagnosis and reduce recurrence by considering and treating the origin of the formed stones.

Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer.

Brain metastasis represents a substantial source of morbidity and mortality in various cancers, and is characterized by high resistance to chemotherapy. Here we define the role of the most abundant cell type in the brain, the astrocyte, in promoting brain metastasis. We show that human and mouse breast and lung cancer cells express protocadherin 7 (PCDH7), which promotes the assembly of carcinoma-astrocyte gap junctions composed of connexin 43 (Cx43). Once engaged with the astrocyte gap-junctional network, brain metastatic cancer cells use these channels to transfer the second messenger cGAMP to astrocytes, activating the STING pathway and production of inflammatory cytokines such as interferon-α (IFNα) and tumour necrosis factor (TNF). As paracrine signals, these factors activate the STAT1 and NF-κB pathways in brain metastatic cells, thereby supporting tumour growth and chemoresistance. The orally bioavailable modulators of gap junctions meclofenamate and tonabersat break this paracrine loop, and we provide proof-of-principle that these drugs could be used to treat established brain metastasis.

The power of weak ion-exchange resins assisted by amelogenin for natural remineralization of dental enamel: an in vitro study.

This study aims to develop an innovative dental product to remineralize dental enamel by a proper combination of ion-exchange resins as controlled release of mineral ions that form dental enamel, in the presence of amelogenin to guide the appropriate crystal growth. The novel product proposed consists of a combination of ion-exchange resins (weak acid and weak base) individually loaded with the remineralizing ions: Ca2+, PO43- and F-, also including Zn2+ in a minor amount as antibacterial, together with the protein amelogenin. Such cocktail provides onsite controlled release of the ions necessary for enamel remineralization due to the weak character of the resins and at the same time, a guiding tool for related crystal growth by the indicated protein. Amelogenin protein is involved in the structural development of natural enamel and takes a key role in controlling the crystal growth morphology and alignment at the enamel surface. Bovine teeth were treated by applying the resins and protein together with artificial saliva. Treated teeth were evaluated with nanoindentation, scanning electron microscopy and energy-dispersive X-ray spectroscopy. The innovative material induces the dental remineralization creating a fluorapatite layer with a hardness equivalent to sound enamel, with the appropriate alignment of corresponding nanocrystals, being the fluorapatite more acid resistant than the original mineral. Our results suggest that the new product shows potential for promoting long-term remineralization leading to the inhibition of caries and protection of dental structures.

Decoupling the adsorption mechanisms of arsenate at molecular level on modified cube-shaped sponge loaded superparamagnetic iron oxide nanoparticles.

In this study, a commercial cube-shaped open-celled cellulose sponge adsorbent was modified by in-situ co-precipitation of superparamagnetic iron oxide nanoparticles (SPION) and used to remove As(V) from aqueous solutions. Fe K-edge X-ray absorption spectroscopy (XAS) and TEM identified maghemite as the main iron phase of the SPION nanoparticles with an average size 13 nm. Batch adsorption experiments at 800 mg/L showed a 63% increase of adsorption capacity when loading 2.6 wt.% mass fraction of SPION in the cube-sponge. Experimental determination of the adsorption thermodynamic parameters indicated that the As(V) adsorption on the composite material is a spontaneous and exothermic process. As K-edge XAS results confirmed that the adsorption enhancement on the composite can be attributed to the nanoparticles loaded. In addition, adsorbed As(V) did not get reduced to more toxic As(III) and formed a binuclear corner-sharing complex with SPION. The advantageous cube-shape of the sponge-loaded SPION composite together with its high affinity and good adsorption capacity for As(V), good regeneration capability and the enhanced-diffusion attributed to its open-celled structure make this adsorbent a good candidate for industrial applications.

Vascular co-option in brain metastasis.

Vascular co-option by brain metastasis-initiating cells has been demonstrated as a critical step in organ colonization. The physical interaction between the cancer cell and the endothelial cell is mediated by integrins and L1CAM and could be involved in aggressive growth but also latency and immune evasion. The key involvement of vascular co-option in brain metastasis has created an emerging field that aims to identify critical targets as well as effective inhibitors with the goal of preventing brain metastases.

Characterization of Calcium Oxalate Hydrates and the Transformation Process.

Calcium oxalate can be found in humans as kidney stones and in cultural heritage as films in two crystallographic species, dihydrate (COD/weddellite) and/or monohydrate (COM/whewellite). Due to its instability, COD is transformed into COM. Studying this crystalline conversion provides information about the origin of the monohydrated species, which will help in the assessment of prevention measurements to avoid their formation. In the present study, the synthesis of calcium oxalate hydrate microcrystals has been carefully performed to avoid mixture of phases in the final products; the long and short range order structure of both species have been studied by X-ray diffraction (XRD) and X-ray absorption spectroscopy (XAS), respectively. This structural information was considered in the density functional theory (DFT) computational study performed to assign the characteristic vibrational IR and Raman frequencies found. This detailed characterization allows an unambiguous assignment of the vibrations, thus providing the appropriate parameters required to monitor and characterize the transformation process.

Tooth whitening: From the established treatments to novel approaches to prevent side effects.

OBJECTIVE: The aim is to review the most important aspects about tooth whitening treatments, their side effects, and the new emerging approaches to overcome them. OVERVIEW: This review is focused on origin of tooth stains, the whitening systems and their chemistry, their side effects, and the new approaches. The search of bibliography of the period 1965-2018 has been analyzed. CONCLUSIONS: Tooth whitening has become one of the most requested dental treatments by the public. Tooth stains are classified according to their origin into two categories: intrinsic and extrinsic. The whitening systems are generally organized into two classes: in-office and at-home products. Most of the whitening systems use hydrogen peroxide as the active oxidative agent to degrade the organic compounds that cause stains. The concentration ranges depending on the treatment, and it may be applied directly or produced in a chemical reaction from carbamide peroxide that is more stable. Besides its popularity, tooth whitening still has some side effects being tooth hypersensitivity the most common. In order to decrease these side effects, new treatments are constantly in renewal processes. CLINICAL SIGNIFICANCE: Despite all the data and new strategies known about tooth whitening, there are many aspects that are not totally fully understood and methodologies that are not completely effective. Therefore, the development of effective, efficient, and long-lasting whitening treatments is still necessary.

Extracellular Albumin Covalently Sequesters Selenocompounds and Determines Cytotoxicity.

Selenocompounds (SeCs) are well-known nutrients and promising candidates for cancer therapy; however, treatment efficacy is very heterogeneous and the mechanism of action is not fully understood. Several SeCs have been reported to have albumin-binding ability, which is an important factor in determining the treatment efficacy of drugs. In the present investigation, we hypothesized that extracellular albumin might orchestrate SeCs efficacy. Four SeCs representing distinct categories were selected to investigate their cytotoxicity, cellular uptake, and species transformation. Concomitant treatment of albumin greatly decreased cytotoxicity and cellular uptake of SeCs. Using both X-ray absorption spectroscopy and hyphenated mass spectrometry, we confirmed the formation of macromolecular conjugates between SeCs and albumin. Although the conjugate was still internalized, possibly via albumin scavenger receptors expressed on the cell surface, the uptake was strongly inhibited by excess albumin. In summary, the present investigation established the importance of extracellular albumin binding in determining SeCs cytotoxicity. Due to the fact that albumin content is higher in humans and animals than in cell cultures, and varies among many patient categories, our results are believed to have high translational impact and clinical implications.

T lymphocytes facilitate brain metastasis of breast cancer by inducing Guanylate-Binding Protein 1 expression.

The discovery of genes and molecular pathways involved in the formation of brain metastasis would direct the development of therapeutic strategies to prevent this deadly complication of cancer. By comparing gene expression profiles of Estrogen Receptor negative (ER-) primary breast tumors between patients who developed metastasis to brain and to organs other than brain, we found that T lymphocytes promote the formation of brain metastases. To functionally test the ability of T cells to promote brain metastasis, we used an in vitro blood-brain barrier (BBB) model. By co-culturing T lymphocytes with breast cancer cells, we confirmed that T cells increase the ability of breast cancer cells to cross the BBB. Proteomics analysis of the tumor cells revealed Guanylate-Binding Protein 1 (GBP1) as a key T lymphocyte-induced protein that enables breast cancer cells to cross the BBB. The GBP1 gene appeared to be up-regulated in breast cancer of patients who developed brain metastasis. Silencing of GBP1 reduced the ability of breast cancer cells to cross the in vitro BBB model. In addition, the findings were confirmed in vivo in an immunocompetent syngeneic mouse model. Co-culturing of ErbB2 tumor cells with activated T cells induced a significant increase in Gbp1 expression by the cancer cells. Intracardial inoculation of the co-cultured tumor cells resulted in preferential seeding to brain. Moreover, intracerebral outgrowth of the tumor cells was demonstrated. The findings point to a role of T cells in the formation of brain metastases in ER- breast cancers, and provide potential targets for intervention to prevent the development of cerebral metastases.

Observation of Photon Droplets and Their Dynamics.

We present experimental evidence of photon droplets in an attractive (focusing) nonlocal nonlinear medium. Photon droplets are self-bound, finite-sized states of light that are robust to size and shape perturbations due to a balance of competing attractive and repulsive forces. It has recently been shown theoretically, via a multipole expansion of the nonlocal nonlinearity, that the self-bound state arises due to competition between the s-wave and d-wave nonlinear terms, together with diffraction. The theoretical photon droplet framework encompasses both a solitonlike stationary ground state and the nonsolitonlike dynamics that ensue when the system is displaced from equilibrium, i.e., driven into an excited state. We present numerics and experiments supporting the existence of these photon droplet states and measurements of the dynamical evolution of the photon droplet orbital angular momentum.

Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling.

Schizophrenia is a complex disorder that interferes with the function of several brain systems required for cognition and normal social behaviour. Although the most notable clinical aspects of the disease only become apparent during late adolescence or early adulthood, many lines of evidence suggest that schizophrenia is a neurodevelopmental disorder with a strong genetic component. Several independent studies have identified neuregulin 1 (NRG1) and its receptor ERBB4 as important risk genes for schizophrenia, although their precise role in the disease process remains unknown. Here we show that Nrg1 and ErbB4 signalling controls the development of inhibitory circuitries in the mammalian cerebral cortex by cell-autonomously regulating the connectivity of specific GABA (gamma-aminobutyric acid)-containing interneurons. In contrast to the prevalent view, which supports a role for these genes in the formation and function of excitatory synapses between pyramidal cells, we found that ErbB4 expression in the mouse neocortex and hippocampus is largely confined to certain classes of interneurons. In particular, ErbB4 is expressed by many parvalbumin-expressing chandelier and basket cells, where it localizes to axon terminals and postsynaptic densities receiving glutamatergic input. Gain- and loss-of-function experiments, both in vitro and in vivo, demonstrate that ErbB4 cell-autonomously promotes the formation of axo-axonic inhibitory synapses over pyramidal cells, and that this function is probably mediated by Nrg1. In addition, ErbB4 expression in GABA-containing interneurons regulates the formation of excitatory synapses onto the dendrites of these cells. By contrast, ErbB4 is dispensable for excitatory transmission between pyramidal neurons. Altogether, our results indicate that Nrg1 and ErbB4 signalling is required for the wiring of GABA-mediated circuits in the postnatal cortex, providing a new perspective to the involvement of these genes in the aetiology of schizophrenia.

Hollow fibre liquid phase micro-extraction by facilitated anionic exchange for the determination of flavonoids in faba beans (Vicia faba L.).

INTRODUCTION: Flavonoids are polyphenolic compounds found ubiquitously in foods of plant origin. They are commonly extracted from plant materials with ethanol, methanol, water, their combination or even with acidified extracting solutions. The disadvantages of these methods are the use of high quantity of organic solvent, the possible loss of analytes in the different steps and the laborious process of the techniques. In addition, the complexity of the phenolic mixtures present in plant materials requires a preliminary clean-up and fractionation of the crude extracts. OBJECTIVE: To develop a hollow fibre liquid phase micro-extraction (HF-LPME) method for a one step clean-up and pre-concentration of flavonoids. METHODOLOGY: Two flavonoids (catechin and rutin) has been extracted by HF-LPME and analysed by HPLC. The related driving force for the liquid membrane has been studied by means of facilitated and non-facilitated transport. Different ionic and non-ionic water insoluble compounds [trioctylamine (TOA), tributyl phosphate (TBP), trioctylphosphine oxide (TOPO) and methyltrioctylammonium chloride (aliquat 336)] were used as carriers. The liquid membrane was constituted by a solution of n-decanol in the presence or absence of carriers. RESULTS: Maximum enrichment factors were obtained with n-decanol/aliquat 336 (20%) as organic liquid membrane, sodium hydroxide (NaOH) (0.1 M) as donor solution, sodium chloride (NaCl) (2 M) as acceptor solution and 3 h as extraction time. Under these conditions, good results for validation parameters were obtained [for linearity, limit of detection (LOD), limit of quantitation (LOQ) and repeatability]. CONCLUSIONS: The developed method is simple, effective and has been successfully applied to determine catechin and rutin in ethanolic extracts of faba beans.