Individual Particle Morphology and Acidity

The morphological characterization of particles during the Pittsburgh Air Quality Study (PAQS) suggests that particle shape and physical state depends on their acidity. The aerosol shape parameters measured by Computer-Controlled Scanning Electron Microscopy (CCSEM) are statistically different in periods when atmospheric particles are neutral and when they are acidic. High concentrations of particles smaller than 500 nm with high sulfur content and liquid appearance or signs of a previous liquid state before partial or total recrystallization are present on filters collected in days with high aerosol acidity. By contrast, in winter and summer periods in which the aerosol was neutral, the shape parameter values are similar and suggest that the particles have been dried out. These direct observations support the hypothesis that during summer acidic periods in the Eastern United States the particles may contain some water even at low relative humidity both in the atmosphere and on filters.     

Single Charging of Nanoparticles by UV Photoionization at High Flow Rates

The feasibility of UV photoionization for single unipolar charging of nanoparticles at flow rates up to 100 l· min ^?1 is demonstrated. The charging level of the aerosol particles can be varied by adjusting the intensity of the UV radiation. The suitability of a UV photocharger followed by a DMA to deliver monodisperse nanoparticles at high aerosol flow rates has been assessed experimentally in comparison to a radioactive bipolar charger ( ⁸⁵ Kr, 10 mCi). Monodisperse aerosols with particle sizes in the range of 5 to 25 nm and number concentrations between 10 ⁴ and 10 ⁵ cm ^?3 have been obtained at flow rates up to 100 l· min ^?1 with the two aerosol chargers. In terms of output particle concentration, the UV photoionizer performs better than the radioactive ionizer with increasing aerosol flow rate. Aerosol charging in the UV photoionizer is described by means of a photoelectric charging model that relies on an empirical parameter and of a diffusion charging model based on the Fuchs theory. The UV photocharger behaved as a quasi-unipolar charger for polydisperse aerosols with particles sizes less than 30 nm and number concentrations ～10 ⁷ cm ^?3 . Much reduced diffusion charging was observed in the experiments, with respect to the calculations, likely due to ion losses onto the walls caused by unsteady electric fields in the irradiation region.     

Tracking the Interplay between Bound Peptide and the Lid Domain of DnaK,Using Molecular Dynamics

Hsp70 chaperones consist of two functional domains: the 44 kDa Nucleotide Binding Domain (NBD), that binds and hydrolyses ATP, and the 26 kDa Substrate Binding Domain (SBD), which binds unfolded proteins and reactivates them, utilizing energy obtained from nucleotide hydrolysis. The structure of the SBD of the bacterial Hsp70, DnaK, consists of two sub-domains: A β-sandwich part containing the hydrophobic cavity to which the hepta-peptide NRLLLTG (NR) is bound, and a segment made of 5 α-helices, called the “lid” that caps the top of the β-sandwich domain. In the present study we used the Escherichia coli Hsp70, DnaK, as a model for Hsp70 proteins, focusing on its SBD domain, examining the changes in the lid conformation. We deliberately decoupled the NBD from the SBD, limiting the study to the structure of the SBD section, with an emphasis on the interaction between the charges of the peptide with the residues located in the lid. Molecular dynamics simulations of the complex revealed significant mobility within the lid structure; as the structure was released from the forces operating during the crystallization process, the two terminal helices established a contact with the positive charge at the tip of the peptide. This contact is manifested only in the presence of electrostatic attraction. The observed internal motions within the lid provide a molecular role for the function of this sub-domain during the reaction cycle of Hsp 70 chaperones.     

Neuropsychopharmacology of Emerging Drugs of Abuse: meta- and para-Halogen-Ring-Substituted α-PVP (“flakka”) Derivatives

Changes in the molecular structure of synthetic cathinones has led to an increase in the number of novel emerging drugs in the illicit drug market at an unprecedented rate. Unfortunately, little is known about the neuropsychopharmacology of recently emerged halogen-substituted α-PVP derivatives. Thus, the aim of this study was to investigate the role of para- and meta-halogen (F-, Cl-, and Br-) substitutions on the in vitro, in silico, and in vivo effects of α-pyrrolidinopentiophenone (α-PVP) derivatives. HEK293 cells expressing the human dopamine or serotonin transporter (hDAT and hSERT) were used for the uptake inhibition and transporter affinity assays. Molecular docking was used to model the interaction mechanism against DAT. Swiss CD-1 mice were used for the horizontal locomotor activity, open field test, and conditioned place preference paradigm. All compounds demonstrated potent DA uptake inhibition and higher DAT selectivity than cocaine. Meta-substituted cathinones showed higher DAT/SERT ratios than their para- analogs, which correlates with an increased psychostimulant effect in vivo and with different meta- and para-in silico interactions at DAT. Moreover, all compounds induced rewarding and acute anxiogenic effects in mice. In conclusion, the present study demonstrates the role of meta- and para-halogen substitutions in the mechanism of action and provides the first evidence of the rewarding and anxiety-like properties of halogenated α-PVP derivatives.     

Direct <Emphasis Type="SmallCaps">d</Emphasis>-Glucose Oxidation over Noble Metal Nanoparticles Introduced on Polymer and Inorganic Supports

In the present work, nanocatalysts prepared on inorganic supports (zeolites) were investigated in d-glucose oxidation and compared to systems supported on polymer (hypercrosslinked polystyrene (HPS)) previously described. Catalytic activities and selectivities were measured under various reaction conditions. The selectivity of d-glucose oxidation and activity of both Pd-containing zeolites and HPS-Ru were similar (99.7% and TOF 0.013–0.014 mol/(mol Me s)). Physicochemical analysis X-ray photoelectron spectroscopy, liquid nitrogen physisorption, diffuse reflectance infrared Fourier transform spectroscopy of adsorbed CO for metal sites evaluation, CD₃CN for acid sites evaluation showed that Pd species were in oxidic form, while Ru species were in oxidic and reduced form. The catalytic activity decreased when acidic sites were present in Pd-containing zeolites.     

Synthesis,Structural Analysis,and Biological Evaluation of Thioxoquinazoline Derivatives as Phosphodiesterase 7 Inhibitors

PDE7 inhibitors regulate pro‐inflammatory and immune T‐cell functions, and are a potentially novel class of drugs particularly useful for treatment of a wide variety of immune and inflammatory disorders. Structural optimization of thioxoquinazoline derivatives led to new compounds with very interesting profiles as PDE7 or PDE7/PDE4 dual inhibitors, which may be further developed as new drugs for inflammatory and neurological diseases.

     

Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and Cardiomyocytes

Fibrosis is a hallmark of adverse cardiac remodeling, which promotes heart failure, but it is also an essential repair mechanism to prevent cardiac rupture, signifying the importance of appropriate regulation of this process. In the remodeling heart, cardiac fibroblasts (CFs) differentiate into myofibroblasts (MyoFB), which are the key mediators of the fibrotic response. Additionally, cardiomyocytes are involved by providing pro-fibrotic cues. Nuclear receptor Nur77 is known to reduce cardiac hypertrophy and associated fibrosis; however, the exact function of Nur77 in the fibrotic response is yet unknown. Here, we show that Nur77-deficient mice exhibit severe myocardial wall thinning, rupture and reduced collagen fiber density after myocardial infarction and chronic isoproterenol (ISO) infusion. Upon Nur77 knockdown in cultured rat CFs, expression of MyoFB markers and extracellular matrix proteins is reduced after stimulation with ISO or transforming growth factor–β (TGF-β). Accordingly, Nur77-depleted CFs produce less collagen and exhibit diminished proliferation and wound closure capacity. Interestingly, Nur77 knockdown in neonatal rat cardiomyocytes results in increased paracrine induction of MyoFB differentiation, which was blocked by TGF-β receptor antagonism. Taken together, Nur77-mediated regulation involves CF-intrinsic promotion of CF-to-MyoFB transition and inhibition of cardiomyocyte-driven paracrine TGF-β-mediated MyoFB differentiation. As such, Nur77 provides distinct, cell-specific regulation of cardiac fibrosis.     

Strategies to Apply Water-Deficit Stress: Similarities and Disparities at the Whole Plant Metabolism Level in Medicago truncatula

Water-deficit stresses such as drought and salinity are the most important factors limiting crop productivity. Hence, understanding the plant responses to these stresses is key for the improvement of their tolerance and yield. In this study M. truncatula plants were subjected to 250 mM NaCl as well as reduced irrigation (No-W) and 250 g/L polyethylene glycol (PEG)-6000 to induce salinity and drought stress, respectively, provoking a drop to −1.7 MPa in leaf water potential. The whole plant physiology and metabolism was explored by characterizing the stress responses at root, phloem sap and leaf organ level. PEG treatment led to some typical responses of plants to drought stress, but in addition to PEG uptake, an important impairment of nutrient uptake and a different regulation of carbon metabolism could be observed compared to No-W plants. No-W plants showed an important redistribution of antioxidants and assimilates to the root tissue, with a distinctive increase in root proline degradation and alkaline invertase activity. On the contrary, salinity provoked an increase in leaf starch and isocitrate dehydrogenase activity, suggesting key roles in the plant response to this stress. Overall, results suggest higher protection of salt-stressed shoots and non-irrigated roots through different mechanisms, including the regulation of proline and carbon metabolism, while discarding PEG as safe mimicker of drought. This raises the need to understand the effect at the whole plant level of the different strategies employed to apply water-deficit stress.