Soft nanoimprinted titanium dioxide (TiO2) substrates decorated with methylammonium lead halide perovskite (MAPbI3) crystals were fabricated by controlling the perovskite precursor concentration and ...volume during spin coat processing combined with the use of hydrophobic TiO2 templates. The patterned growth was demonstrated with different perovskite crystallization methods. We investigated and successfully demonstrated the controlled assembly of two MAPbI3 nanomaterials, one a nanocomposite formed between the perovskite and a hole conducting polymer poly(2,5-bis(N-methyl-N-hexylamino)phenylene vinylene) (BAMPPV), and a second formed from perovskite crystals using common solution based MAPbI3 growth methods (1-step and 2-step processing). Both types of MAPbI3 crystals were fabricated on hydrophobic TiO2 nanotemplates composed of nanowells or grating patterns. Patterned areas as large as 100 m × 100 m were achieved. We examined and characterized the substrates using atomic force microscopy, scanning electron microscopy, x-ray diffraction, and energy dispersive spectroscopy. We present the optical properties (i.e. fluorescence and transmission) of soft nanoimprinted nanowells decorated with perovskites demonstrating the successful synthesis of MAPbI3 perovskite nanocrystals. As an example of their use, we demonstrate a two terminal device and show photocurrent response of a perovskite patterned micro-grating. Our method is a nondestructive approach to nanopatterning perovskites, and produces patterned arrays that maintain their photo-electric properties. The results presented herein suggests an attractive route to developing nanopatterned and small area perovskite substrates for applications in photovoltaics, x-ray sensing/detection, image sensor arrays, and others.
Thorough preclinical target validation is essential for the success of drug discovery efforts. In this study, we combined chemical and genetic perturbants, including the development of a novel ...selective maternal embryonic leucine zipper kinase (MELK) inhibitor HTH-01-091, CRISPR/Cas9-mediated MELK knockout, a novel chemical-induced protein degradation strategy, RNA interference and CRISPR interference to validate MELK as a therapeutic target in basal-like breast cancers (BBC). In common culture conditions, we found that small molecule inhibition, genetic deletion, or acute depletion of MELK did not significantly affect cellular growth. This discrepancy to previous findings illuminated selectivity issues of the widely used MELK inhibitor OTSSP167, and potential off-target effects of MELK-targeting short hairpins. The different genetic and chemical tools developed here allow for the identification and validation of any causal roles MELK may play in cancer biology, which will be required to guide future MELK drug discovery efforts. Furthermore, our study provides a general framework for preclinical target validation.
In this paper laboratory work is documented establishing iodide ion chemical ionization mass spectrometry (I- CIMS) as a sensitive method for the unambiguous detection of peroxynitric acid (HO2NO2; ...PNA). A dynamic calibration source for HO2NO2, HO2, and HONO was developed and calibrated using a novel total NOy cavity ring-down spectroscopy (CaRDS) detector. Photochemical sources of these species were used for the calibration and validation of the I- CIMS instrument for detection of HO2NO2. Ambient observations of HO2NO2 using I- CIMS during the 2013 and 2014 Uintah Basin Wintertime Ozone Study (UBWOS) are presented. Strong inversions leading to a build-up of many primary and secondary pollutants as well as low temperatures drove daytime HO2NO2 as high as 1.5 ppbv during the 2013 study. A comparison of HO2NO2 observations to mixing ratios predicted using a chemical box model describing an ozone formation event observed during the 2013 wintertime shows agreement in the daily maxima HO2NO2 mixing ratio, but a differences of several hours in the timing of the observed maxima. Observations of vertical gradients suggest that the ground snow surface potentially serves as both a net sink and source of HO2NO2 depending on the time of day. Sensitivity tests using a chemical box model indicate that the lifetime of HO2NO2 with respect to deposition has a non-negligible impact on ozone production rates on the order of 10 %.
Malignant rhabdoid tumors (MRTs) are aggressive pediatric cancers arising in brain, kidney and soft tissues, which are characterized by loss of the tumor suppressor SNF5/SMARCB1. MRTs are poorly ...responsive to chemotherapy and thus a high unmet clinical need exists for novel therapies for MRT patients. SNF5 is a core subunit of the SWI/SNF chromatin remodeling complex which affects gene expression by nucleosome remodeling. Here, we report that loss of SNF5 function correlates with increased expression of fibroblast growth factor receptors (FGFRs) in MRT cell lines and primary tumors and that re-expression of SNF5 in MRT cells causes a marked repression of FGFR expression. Conversely, siRNA-mediated impairment of SWI/SNF function leads to elevated levels of FGFR2 in human fibroblasts. In vivo, treatment with NVP-BGJ398, a selective FGFR inhibitor, blocks progression of a murine MRT model. Hence, we identify FGFR signaling as an aberrantly activated oncogenic pathway in MRTs and propose pharmacological inhibition of FGFRs as a potential novel clinical therapy for MRTs.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
While P-glycoprotein (PGP, ABCB1) is known to play an important role in drug exclusion at the blood brain barrier (BBB), less is known about the contribution of other members in the ATP-binding ...cassette (ABC) transporter family to BBB drug efflux, or whether these transporters are expressed differently in humans and in mammalian species of pharmacological interest. We used quantitative real-time PCR to determine mRNA expression levels for the majority of ABC family members in brain and in isolated brain microvessel endothelial capillary cells (BMEC) from human, rat, mouse, pig and cow. We confirmed BBB expression of several well-characterized ABC family members that are implicated in xenobiotic exclusion from the brain, including ABCB1 (PGP), ABCG2 (BCRP), ABCC1 (MRP1), ABCC4 (MRP4), and ABCC5 (MRP5). In addition, we detected high expression and enrichment in BMEC of several less well-characterized ABC transporters in one or more species, including ABCA2-4, ABCB4, ABCB6-8, ABCB10, ABCC3, ABCC6, ABCC10, and ABCE1. We also uncovered species differences in the expression of a number of transporters, including ABCG2 and ABCC4. This study identifies several additional ABC family members that may contribute to xenobiotic efflux at the human BBB, and compares the expression of a broad array of efflux transporters between human and four other species relevant to pharmacological research.
Human epidermal growth factor receptor-2 (HER2) amplification/overexpression (HER2+) frequently co-occurs with PI3K pathway activation in breast tumors. PI3K signaling is most often activated by ...PIK3CA mutation or PTEN loss, which frequently results in sensitivity to p110α or p110β inhibitors, respectively. To examine the p110 isoform dependence in HER2+, PTEN-deficient tumors, we generated genetic mouse models of breast tumors driven by concurrent Her2 activation and Pten loss coupled with deletion of p110α or p110β. Ablation of p110α, but not p110β, significantly impaired the development of Her2+/Pten-null tumors in mice. We further show that p110α primarily mediates oncogenic signaling in HER2+/PTEN-deficient human cancers while p110β conditionally mediates PI3K/AKT signaling only upon HER2 inhibition. Combined HER2 and p110α inhibition effectively reduced PI3K/AKT signaling and growth of cancer cells both in vitro and in vivo. Addition of the p110β inhibitor to dual HER2 and p110α inhibition induced tumor regression in a xenograft model of HER2+/PTEN-deficient human cancers. Together, our data suggest that combined inhibition of HER2 and p110α/β may serve as a potent and durable therapeutic regimen for the treatment of HER2+, PTEN-deficient breast tumors.
In lieu of comprehensive instrumental seismic monitoring, short historical records, and limited fault trench investigations for many seismically active areas, the sedimentary record provides ...important archives of seismicity in the form of preserved horizons of soft-sediment deformation features, termed seismites. Here we report on extensive seismites in the Late Quaternary-Recent (≤ ~ 28,000 years BP) alluvial and lacustrine strata of the Rukwa Rift Basin, a segment of the Western Branch of the East African Rift System. We document examples of the most highly deformed sediments in shallow, subsurface strata close to the regional capital of Mbeya, Tanzania. This includes a remarkable, clastic 'megablock complex' that preserves remobilized sediment below vertically displaced blocks of intact strata (megablocks), some in excess of 20 m-wide. Documentation of these seismites expands the database of seismogenic sedimentary structures, and attests to large magnitude, Late Pleistocene-Recent earthquakes along the Western Branch of the East African Rift System. Understanding how seismicity deforms near-surface sediments is critical for predicting and preparing for modern seismic hazards, especially along the East African Rift and other tectonically active, developing regions.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We have developed a thermal dissociation–chemical ionization mass spectrometry (TD‐CIMS) technique for fast measurements of a series of peroxyacyl nitrates and dinitrogen pentoxide. Thermally ...generated acylperoxy radicals react with I− to produce a carboxylate ion that is unique for each parent species. NO3 resulting from the decomposition of N2O5 reacts with I− to form NO3−. The measurement technique was verified for PAN and PPN during an informal comparison with a gas chromatograph (GC) equipped with an electron capture detector (ECD) in Boulder, Colorado, during October 2002. Good agreement was obtained between the two instruments with R2 = 0.91 for PAN (n = 657) and R2 = 0.89 for PPN (n = 655). Detection limits of 7 pptv and 4 pptv were determined for PAN and PPN, respectively, for a 1 s integration period and a signal‐to‐noise ratio of 3. The TD‐CIMS simultaneously detected ambient PiBN and N2O5 + NO3 in addition to PAN and PPN during the intercomparison period. We estimate a detection limit of 3 pptv in 1 s for PiBN. PnBN would be detected at the same mass, so we cannot rule out a contribution from PnBN to our PiBN estimate. Sensitivity to MPAN was found to be lower than to PAN in laboratory experiments, but a detection limit of 10 pptv can still be achieved by integrating for 15 s. Assuming the same sensitivity as for PAN, the detection limit for the sum of N2O5 and NO3 was estimated to be 12 pptv in 1 s. The fast time response of the TD‐CIMS combined with a sensitivity and limit of detection comparable to the GC/ECD make this a promising technique for PAN flux measurements by eddy covariance. PAN uptake by different types of vegetation could be important input for global and regional ozone models, and PAN deposition to snow is of interest in polar regions.
The reactivity of water at Ag(111), Zn(0001) and Cu(111) surfaces studied by X-ray photoelectron and high resolution electron spectroscopies at low temperatures (80–295 K) is reviewed. Emphasis is ...given to the coadsorption approach in revealing mechanisms for oxygen–water reactions with comparisons made with previous studies and the models proposed for ammonia–oxygen reactions at metal surfaces. Transient dioxygen–water precursor states result in facile and extensive surface hydroxylation with implications for catalytic oxidation. The orientation of the hydroxyl states with respect to the surface normal are sensitive to the oxygen–water ratio and for high oxygen ratios (200:1) an unreactive oxide overlayer forms at Cu(111) and Zn(0001). The significance of weakly adsorbed complexes, dioxygen–water and carbon dioxide–water, is discussed and, provided they are not kinetically controlled, are models for reactions at high pressures and temperatures with insights to the mechanisms of “real” catalytic reactions. Although scanning tunnelling microscopy has revealed “complex and unpredictable” water structures at low temperatures at metal surfaces, their reactivity and surface dynamics have received less attention.
Graphical Abstract
The assessment of parenting has been problematic due to theoretical disagreement, concerns over generalisability, and problems with the psychometric properties of current parenting measures. The aim ...of this study was to develop a comprehensive, psychometrically sound self-report parenting measure for use with parents of preadolescent children, and to use this empirical scale development process to identify the core dimensions of contemporary parenting behaviour. Following item generation and parent review, 846 parents completed an online survey comprising 116 parenting items. Exploratory and confirmatory factor analyses supported a six factor parenting model, comprising Emotional Warmth, Punitive Discipline, Anxious Intrusiveness, Autonomy Support, Permissive Discipline and Democratic Discipline. This measure will allow for the comprehensive and consistent assessment of parenting in future research and practice.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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