CXCR4-targeted and MMP-responsive iron oxide nanoparticles for enhanced magnetic resonance imaging

MRI offers high spatial resolution with excellent tissue penetration but it has limited sensitivity and the commonly administered contrast agents lack specificity. In this study, two sets of iron oxide nanoparticles (IONPs) were synthesized that were designed to selectively undergo copper-free click conjugation upon sensing of matrix metalloproteinase (MMP) enzymes, thereby leading to a self-assembled superparamagnetic nanocluster network with T2 signal enhancement properties. For this purpose, IONPs with bioorthogonal azide and alkyne surfaces masked by polyethylene glycol (PEG) layers tethered to CXCR4-targeted peptide ligands were synthesized and characterized. The IONPs were tested in vitro and T2 signal enhancements of around 160 % were measured when the IONPs were incubated with cells expressing MMP2/9 and CXCR4. Simultaneous systemic administration of the bioorthogonal IONPs in tumor-bearing mice demonstrated the signal-enhancing ability of these ‘smart’ self-assembling nanomaterials

Understanding and representing atmospheric convection across scales: recommendations from the meeting held at Dartington Hall, Devon, UK, 28–30 January 2013

As weather and climate models move toward higher resolution, there is growing excitement about potential future improvements in the understanding and prediction of atmospheric convection and its interaction with larger-scale phenomena. A meeting in January 2013 in Dartington, Devon was convened to address the best way to maximise these improvements, specifically in a UK context but with international relevance. Specific recommendations included increased convective-scale observations, high-resolution virtual laboratories, and a system of parameterization test beds with a range of complexities. The main recommendation was to facilitate the development of physically based convective parameterizations that are scale-aware, non-local, non-equilibrium, and stochastic

A sex-specific microRNA-96/5HT1B Axis influences development of pulmonary hypertension

Rationale: Females are predisposed to pulmonary arterial hypertension (PAH); evidence suggests that serotonin, mutations in the bone morphogenetic protein receptor (BMPR) II gene, and estrogens influence development of PAH. The 5-hydroxytryptamine 1B receptor (5-HT1BR) mediates human pulmonary artery smooth muscle cell (hPASMC) proliferation. Objectives: We aimed to determine whether selected microRNAs (miRNAs) expressed in PASMCs are influenced by sex, BMPR-II mutations, and estrogens, and contribute to PASMC proliferation in PAH. Methods: Expression levels of miRNAs targeting genes related to PAH, estrogen, and serotonin were determined by quantitative RT-PCR in hPASMCs and mouse PASMCs harboring a heterozygous mutation in BMPR-II (BMPR-IIR899X+/− PASMCs). miRNA-96 targets 5-HT1BR and was selected for further investigation. miRNA target validation was confirmed by luciferase reporter assay. Precursor miRNA-96 was transfected into hPASMCs to examine effects on proliferation and 5-HT1BR expression. The effect of a miRNA-96 mimic on the development of hypoxic pulmonary hypertension in mice was also assessed. Measurements and Main Results: miRNA-96 expression was reduced in BMPR-IIR899X+/− PASMCs from female mice and hPASMCs from female patients with PAH; this was associated with increased 5-HT1BR expression and serotonin-mediated proliferation. 5-HT1BR was validated as a target for miRNA-96. Transfection of precursor miRNA-96 into hPASMCs reduced 5-HT1BR expression and inhibited serotonin-induced proliferation. Restoration of miRNA-96 expression in pulmonary arteries in vivo via administration of an miRNA-96 mimic reduced the development of hypoxia-induced pulmonary hypertension in the mouse. Conclusions: Increased 5-HT1BR expression may be a consequence of decreased miRNA-96 expression in female patient PASMCs, and this may contribute to the development of PAH

Coordinated Monitoring of the Eccentric O-star Binary Iota Orionis: The X-ray Analysis

We analyse two ASCA observations of the highly eccentric O9III + B1III binary Iota Orionis obtained at periastron and apastron. Based on the assumption of a strong colliding winds shock between the stellar components, we expected to see significant variation in the X-ray emission between these phases. The observations proved otherwise: the X-ray luminosities and spectral distributions were remarkably similar. The only noteworthy feature was the hint of a proximity effect during periastron passage, supported also in the optical. We discuss the accuracy of our results, and also analyse archival ROSAT observations. We investigate why we do not see a clear colliding winds signature. A simple model shows that the wind attenuation to the expected position of the shock apex is negligible throughout the orbit, which poses the puzzling question of why the expected 1/D variation (ie. a factor of 7.5) in the intrinsic luminosity is not seen in the data. Two scenarios are proposed: either the colliding winds emission is unexpectedly weak such that intrinsic shocks in the winds dominate the emission, or, alternatively, that the emission observed is colliding winds emission but in a more complex form than we would naively expect. Complex hydrodynamical models are then analyzed. Despite strongly phase-variable emission from the models, both were consistent with the observations. We find that if the mass-loss rates of the stars are low then intrinsic wind shocks could dominate the emission. However, when we assume higher mass-loss rates of the stars, we find that the observed emission could also be consistent with a purely colliding winds origin. To distinguish between the different models X-ray observations with improved phase coverage will be necessary.Comment: 18 pages, 14 figures, uses mn.st

Rhodium(II) Proximity-Labeling Identifies a Novel Target Site on STAT3 for Inhibitors with Potent Anti-Leukemia Activity

Nearly 40 % of children with acute myeloid leukemia (AML) suffer relapse arising from chemoresistance, often involving upregulation of the oncoprotein STAT3 (signal transducer and activator of transcription 3). Herein, rhodium(II)-catalyzed, proximity-driven modification identifies the STAT3 coiled-coil domain (CCD) as a novel ligand-binding site, and we describe a new naphthalene sulfonamide inhibitor that targets the CCD, blocks STAT3 function, and halts its disease-promoting effects in vitro, in tumor growth models, and in a leukemia mouse model, validating this new therapeutic target for resistant AML

The Basic Competencies of Biological Experimentation: Concept-Skill Statements

This biological experimentation competencies map is a model created by members of the ACE-Bio Network of seven areas a competent biologist calls in when doing experimentation in biology. Each competency is represented by a summary word on a uniquely colored segment of the model. For presentation convenience, the seven major areas within experimentation in biology are mapped onto tables in a linear manner. However, this is not meant to convey a particular order that one must follow during experimentation. The areas are given equal weight and flexible order of their use throughout the process of experimentation. This work is meant to provide a framework for ACE Bio Network participants and other instructors or academic leaders in the biological sciences to study implementation of experimentation activities and assessments across diverse institutional and curricular contexts. In addition to the document in pdf format, another link provides the file in MSWord format so that users can easily modify it to guide assessment of student learning about experimentation, undergraduate biology instruction, curriculum development, professional faculty development, program evaluation, or review of research literature in a way that is appropriate to their own context

A School-Based Environmental Intervention to Reduce Smoking among High School Students: The Acadiana Coalition of Teens against Tobacco (ACTT)

A school-based environmental program to reduce adolescent smoking was conducted in 20 schools (10 intervention; 10 control) in south central Louisiana. The 9th grade cohort (n = 4,763; mean age = 15.4 yrs; 51% female; 61% Caucasian; 30-day smoking prevalence at baseline = 25%) was followed over four years for 30-day smoking prevalence with the school as the unit of analysis. Although prevalence decreased in intervention schools and increased in control schools in Year 2 the significant difference between the two groups at baseline was not overcome by the intervention and increases in prevalence were observed in both groups in Years 3 and 4. The higher the percentage of white students in a school the higher the prevalence rates regardless of intervention/control status. Boys’ and girls’ smoking rates were similar. These outcome data, student feedback and process evaluation provide a basis for continuing to create more innovative adolescent tobacco control programs