Abstract only Background: Doxorubicin (DOX) is one of the most effective and commonly used chemotherapeutic agents for cancer. Clinical use of DOX is limited because of its serious dose-dependent ...cardiotoxicity. We recently demonstrated that oral intake of inorganic nitrate (NaNO3) protects against acute cardiotoxicity of DOX. The present study was designed to further elucidate if dietary supplementation of nitrite (NaNO2) also limits the cardiotoxic effects following chronic, multiple low-dose treatment of DOX. Methods & Results: Adult male CF-1 mice were divided into 4 groups (n=6/group): 1) Saline 0.2 ml, IP; 2) DOX 3 x weekly IP injection of 5 mg/kg DOX; cumulative dose = 15 mg/kg; 3) Nitrite - NaNO2 was added into drinking water at concentration of 50 mg/L for entire duration of 32 days; 4) Nitrite+DOX - mice received nitrite-enriched water 7 days before the first DOX injection and throughout the 32-day period. Five days after the last DOX injection, echocardiography and pressure-volume Millar microtip catheterization were performed to assess left ventricular (LV) contractile function and other hemodynamic indices. As shown in the Table below, LV systolic and diastolic function was significantly improved in Nitrite+DOX group as compared with DOX group. Oral nitrite intake augmented plasma level of nitrite, but not nitrate or sum of nitrate+nitrite (NOx). Further molecular studies revealed that nitrite intake enhanced cardiac activity of cGMP-dependent protein kinase (PKG) and reduced expression of endothelial nitric oxide synthase (eNOS) as compared with Saline or DOX (n=3/group). Conclusion: We have provided novel evidence showing that dietary nitrite supplementation reduces cardiotoxicity following chronic DOX treatment. The cardioprotective effect of nitrite may be mediated by the enhanced PKG signaling and the decreased expression of likely uncoupled eNOS in the heart. Nitrite could be a promising therapeutic agent in combating chronic DOX cardiotoxicity.
The existence of extracellular phosphoproteins has been acknowledged for over a century. However, research in this area has been undeveloped largely because the kinases that phosphorylate secreted ...proteins have escaped identification. Fam20C is a kinase that phosphorylates S-x-E/pS motifs on proteins in milk and in the extracellular matrix of bones and teeth. Here, we show that Fam20C generates the majority of the extracellular phosphoproteome. Using CRISPR/Cas9 genome editing, mass spectrometry, and biochemistry, we identify more than 100 secreted phosphoproteins as genuine Fam20C substrates. Further, we show that Fam20C exhibits broader substrate specificity than previously appreciated. Functional annotations of Fam20C substrates suggest roles for the kinase beyond biomineralization, including lipid homeostasis, wound healing, and cell migration and adhesion. Our results establish Fam20C as the major secretory pathway protein kinase and serve as a foundation for new areas of investigation into the role of secreted protein phosphorylation in human biology and disease.
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•Fam20C is unique among the known secretory pathway kinases•Fam20C generates the majority of the secreted phosphoproteome•Fam20C substrates are implicated in a broad spectrum of biological processes•Fam20C is crucial for proper adhesion, migration, and invasion of breast cancer cells
The kinases that catalyze the phosphorylation of secreted proteins have only recently been identified, with Fam20C being identified as the kinase responsible for generating the vast majority of the secreted phosphoproteome, including substrates thought to drive tumor cell migration.
In this paper we focus upon the electron injection dynamics in complete dye-sensitized nanocrystalline metal oxide solar cells (DSSCs). Electron injection dynamics are studied by transient absorption ...and emission studies of DSSCs and correlated with device photovoltaic performance and charge recombination dynamics. We find that the electron injection dynamics are dependent upon the composition of the redox electrolyte employed in the device. In a device with an electrolyte composition yielding optimum photovoltaic device efficiency, electron injection kinetics exhibit a half time of 150 ps. This half time is 20 times slower than that for control dye-sensitized films covered in inert organic liquids. This retardation is shown to result from the influence of the electrolyte upon the conduction band energetics of the TiO2 electrode. We conclude that optimum DSSC device performance is obtained when the charge separation kinetics are just fast enough to compete successfully with the dye excited-state decay. These conditions allow a high injection yield while minimizing interfacial charge recombination losses, thereby minimizing “kinetic redundancy” in the device. We show furthermore that the nonexponential nature of the injection dynamics can be simulated by a simple inhomogeneous disorder model and discuss the relevance of our findings to the optimization of both dye-sensitized and polymer based photovoltaic devices.
In this work, we present the synthesis and characterization of four conjugated polymers containing a novel chromophore for organic electronics based on an indigoid structure. These polymers exhibit ...extremely small band gaps of ~1.2 eV, impressive crystallinity, and extremely high n-type mobility exceeding 3 cm2 V s–1. The n-type charge carrier mobility can be correlated with the remarkably high crystallinity along the polymer backbone having a correlation length in excess of 20 nm. Theoretical analysis reveals that the novel polymers have highly rigid nonplanar geometries demonstrating that backbone planarity is not a prerequisite for either narrow band gap materials or ultrahigh mobilities. Moreover, the variation in backbone crystallinity is dependent on the choice of comonomer. OPV device efficiencies up to 4.1% and charge photogeneration up to 1000 nm are demonstrated, highlighting the potential of this novel chromophore class in high-performance organic electronics.
DNA-damaging agents are among the most frequently used anticancer drugs. However, they provide only modest benefit in most cancers. This may be attributed to a genome maintenance network, the DNA ...damage response (DDR), that recognizes and repairs damaged DNA. ATR is a major regulator of the DDR and an attractive anticancer target. Herein, we describe the discovery of a series of aminopyrazines with potent and selective ATR inhibition. Compound 45 inhibits ATR with a K i of 6 nM, shows >600-fold selectivity over related kinases ATM or DNA-PK, and blocks ATR signaling in cells with an IC50 of 0.42 μM. Using this compound, we show that ATR inhibition markedly enhances death induced by DNA-damaging agents in certain cancers but not normal cells. This differential response between cancer and normal cells highlights the great potential for ATR inhibition as a novel mechanism to dramatically increase the efficacy of many established drugs and ionizing radiation.
Optical excitation of RuII(2,2‘-bipyridyl-4,4‘dicarboxylate)2(NCS)2-sensitized nanocrystalline TiO2 films results in injection of an electron into the semiconductor. This paper addresses the kinetics ...of charge recombination which follows this charge separation reaction. These charge recombination kinetics were found to be strongly dependent upon excitation intensity, electrolyte composition, and the application of an electrical bias to the TiO2 film. For excitation intensities resulting in less than one excited dye molecule/TiO2 particle, the recombination kinetics were independent of excitation intensity. Increasing the excitation intensity above this level resulted in a rapid acceleration in the charge recombination kinetics. Similarly, for positive electrical potentials applied to the TiO2 electrode, the recombination kinetics were independent of applied potential. If the applied potential was more negative than a threshold potential V kin, a rapid acceleration of the charge recombination kinetics was again observed, for example from ∼1 ms at +0.1 V vs Ag/AgCl to ∼3 ps at −0.8 V (∼108 fold increase in the rate). Moreover, at a constant applied potential the charge recombination kinetics were found to be strongly dependent upon electrolyte composition (up to 106-fold change in rate). This strong dependence upon the electrolyte composition was found to be associated with shifts in the threshold potential V kin. Spectroelectrochemical measurements were used to monitor the shift in the trap/conduction band density of states induced by the electrolyte composition. A direct correlation was observed between the threshold voltage V kin observed from kinetic measurements, and the threshold voltage for electron occupation of conduction band/trap states of the TiO2 observed from spectroelectrochemical measurements. This direct correlation was observed for a wide range of electrolyte compositions including protic and aprotic solvents and the addition of Li+ ions and 4-tert-butylpyridine. We conclude that the charge recombination kinetics in such dye-sensitized films are strongly dependent upon the electron occupation in trap/conduction band states of the TiO2 film. This occupation may be modulated by variations in light intensity, applied electrical potential, and electrolyte composition. These results are discussed with relevance to the function of dye-sensitized photoelectrochemical devices.
The Collaborative Cross (CC) is a mouse recombinant inbred strain panel that is being developed as a resource for mammalian systems genetics. Here we describe an experiment that uses partially inbred ...CC lines to evaluate the genetic properties and utility of this emerging resource. Genome-wide analysis of the incipient strains reveals high genetic diversity, balanced allele frequencies, and dense, evenly distributed recombination sites-all ideal qualities for a systems genetics resource. We map discrete, complex, and biomolecular traits and contrast two quantitative trait locus (QTL) mapping approaches. Analysis based on inferred haplotypes improves power, reduces false discovery, and provides information to identify and prioritize candidate genes that is unique to multifounder crosses like the CC. The number of expression QTLs discovered here exceeds all previous efforts at eQTL mapping in mice, and we map local eQTL at 1-Mb resolution. We demonstrate that the genetic diversity of the CC, which derives from random mixing of eight founder strains, results in high phenotypic diversity and enhances our ability to map causative loci underlying complex disease-related traits.
In this phase 1 trial, inhibition of granulocyte-macrophage colony-stimulating factor (GM-CSF) was associated with clinically meaningful responses in 5 of 15 patients with relapsed or refractory ...chronic myelomonocytic leukemia (CMML). Preliminary data suggest that this approach may be tractable in CMML bearing activating NRAS mutations.
The response of the marine carbon cycle to changes in atmospheric CO2 concentrations will be determined, in part, by the relative response of calcifying and non-calcifying organisms to global change. ...Planktonic foraminifera are responsible for a quarter or more of global carbonate production, therefore understanding the sensitivity of calcification in these organisms to environmental change is critical. Despite this, there remains little consensus as to whether, or to what extent, chemical and physical factors affect foraminiferal calcification. To address this, we directly test the effect of multiple controls on calcification in culture experiments and core-top measurements of Globigerinoides ruber. We find that two factors, body size and the carbonate system, strongly influence calcification intensity in life, but that exposure to corrosive bottom waters can overprint this signal post mortem. Using a simple model for the addition of calcite through ontogeny, we show that variable body size between and within datasets could complicate studies that examine environmental controls on foraminiferal shell weight. In addition, we suggest that size could ultimately play a role in determining whether calcification will increase or decrease with acidification. Our models highlight that knowledge of the specific morphological and physiological mechanisms driving ontogenetic change in calcification in different species will be critical in predicting the response of foraminiferal calcification to future change in atmospheric pCO2.
Russelite bismuth tungstate (Bi2WO6) has been widely reported for the photocatalytic degradation and mineralization of a myriad of pollutants as well as organic compounds. These materials present ...perovskite-like structure with hierarchical morphologies, which confers excellent optoelectronic properties as potentials candidates for photocatalytic solar fuels production. Here, we propose the development of Bi2WO6/TiO2 heterojunctions for CO2 photoreduction, as a promising solution to produce fuels, alleviate global warming and tackle fossil fuel shortage. Our results show an improvement of the photocatalytic activity of the heterojunctions compared to the pristine semiconductors. Near Ambient Pressure X-ray Photoelectron Spectroscopy (NAP-XPS) experiments reveals a preferential CO2 adsorption over TiO2. On the other hand, transient absorption spectroscopy measurements show that the charge transfer pathway in Bi2WO6/TiO2 hybrids leads to longer-lived photogenerated carriers in spatially separated redox active sites, which favor the reduction of CO2 into highly electron demanding fuels and chemicals, such as CH4 and C2H6.
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•Bi2WO6 and a series of Bi2WO6/TiO2 heterostructures are active for light driven CO2 photoreduction with water as reductant.•Selectivity change towards CH4 for Bi2WO6/TiO2 heterostructures.•Prolonged lifetime of photogenerated carriers and enhanced charge transfer in hybrid heterostructures.
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