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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 415 records · Page 23
All sourcesNASA NTRSDOE OSTI
DOE OSTI2015

Quercetin reverses experimental pulmonary arterial hypertension by modulating the TrkA pathway

Pulmonary arterial hypertension (PAH) is characterized by excessive proliferation, resistance to apoptosis, and increased migration of pulmonary artery smooth muscle cells (PASMCs). We hypothesized that quercetin exerts protective effects against this disease; thus, a chronic hypoxia model of PAH was generated using male Sprague-Dawley rats, which were treated with quercetin. In this model, quercetin prevented the development of PAH, right ventricular hypertrophy, and vascular remodeling after exposure to hypoxia. Quercetin inhibited PASMC proliferation and increased the apoptosis of PASMCs in vivo. In vitro, quercetin significantly inhibited hypoxia-induced PASMC proliferation, arrested cells in G1/G0 and inhibited cell migration in a dose-dependent manner. Moreover, our results showed that quercetin increased cyclin D1 protein levels and decreased the protein expression of cyclin B1 and Cdc2. Additionally, quercetin altered the Bax/Bcl-2 ratio and reduced MMP2, MMP9, CXCR4, integrin β1, and integrin α5 expression. Using genome-wide microarray analysis, we found that factors regulating proliferation, apoptosis, cell cycle, and migration were related to the tyrosine receptor kinase A (TrkA) pathway. In addition, activation of the TrkA/AKT signaling cascade during hypoxia was inhibited by quercetin in a dose-dependent manner. Moreover, quercetin alone inhibited the TrkA/AKT signaling pathway, resulting in decreased PASMC migration, cell cycle arrest and the induction of apoptosis. Our data suggest that quercetin is a potential candidate for the treatment of hypoxia-induced PAH. - Graphical abstract: Graphical summary illustrating quercetin reversed hypoxia-induced PAH via modulating the TrkA signal cascade. - Highlights: • Quercetin ameliorate hypoxia-induced PAH and pulmonary arterial remodeling. • Quercetin reverses hypoxia-induced apoptosis resistance, cell cycle arrested and migration in PASMCs. • Quercetin alleviate experimental PAH partially by modulating the TrkA/AKT signaling pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

TIGIT overexpression diminishes the function of CD4 T cells and ameliorates the severity of rheumatoid arthritis in mouse models

Rheumatoid arthritis (RA) is an immune-mediated disease with a pathogenesis that involves CD4 T cell activation. Multiple immune regulatory molecules expressed on CD4{sup +} T cells were involved in RA pathogenesis. In this study, we investigated the role of T cell immunoglobulin and ITIM (immunoreceptor tyrosine-based inhibition motif) domain (TIGIT) in RA. The frequency of TIGIT-positive CD4{sup +} T cells in the synovial fluid (SF) of active RA patients was lower than that of inactive RA patients. And a negative correlation between RA disease activity and TIGIT expression was found. In CD4{sup +} T cells isolated from SF of active RA patients, TIGIT upregulation significantly decreased cell proliferation, as shown by MTT assay. TIGIT overexpression also significantly decreased the production of IFN-γ and IL-17, and increased that of IL-10, as determined by ELISA and qRT-PCR. In CD4{sup +} T cells isolated from SF of inactive RA patients, TIGIT was silenced by siRNA transfection. As expected, TIGIT knockdown resulted in an opposite effect on cell proliferation and the production of cytokines, including IFN-γ, IL-17 and IL-10. A RA mouse model was established using type II collagen induction. TIGIT was upregulated in RA mouse by lentivector infection. As expected, TIGIT overexpression in vivo significantly alleviated the disease severity and deceased the levels of anti-collagen II antibodies. TIGIT upregulation in the early stage was more effective to alleviate disease severity. Our data suggested the potential therapeutic role of TIGIT in RA patients. - Highlights: • TIGIT expression on SF CD4{sup +} T cells was decreased in active RA patients. • TIGIT overexpression diminished the function of CD4{sup +} T cells. • TIGIT-siRNA transfection promotes the function of CD4{sup +} T cells. • Mice with TIGIT overexpression were resistant to collagen induced RA.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

The novel HSP90 inhibitor NVP-AUY922 shows synergistic anti-leukemic activity with cytarabine in vivo

HSP90 is a molecular chaperone essential for stability, activity and intracellular sorting of many proteins, including oncoproteins, such as tyrosine kinases, transcription factors and cell cycle regulatory proteins. Therefore, inhibitors of HSP90 are being investigated for their potential as anti-cancer drugs. Here we show that the HSP90 inhibitor NVP-AUY922 induced degradation of the fusion oncoprotein FOP2-FGFR1 in a human acute myeloid leukemia (AML) cell line, KG-1a. Concordantly, downstream signaling cascades, such as STAT1, STAT3 and PLCγ were abrogated. At concentrations that caused FOP2-FGFR1 degradation and signaling abrogation, NVP-AUY922 treatment caused significant cell death and inhibition of proliferation of KG-1a cells in vitro. In an animal model for AML, NVP-AUY922 administrated alone showed no anti-leukemic activity. However, when NVP-AUY922 was administered in combination with cytarabine, the two compounds showed significant synergistic anti-leukemic activity in vivo. Thus NVP-AUY922 and cytarabine combination therapy might be a prospective strategy for AML treatment. - Highlights: • NVP-AUY922 induces degradation of the oncoprotein FOP2-FGFR1 in KG-1a leukemia cells. • NVP-AUY922 induces cell death and inhibition of proliferation of KG-1a cells. • NYP-AUY922 combined with cytarabine shows synergistic anti-leukemic activity in vivo.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Epidermal growth factor receptor signaling mediates aldosterone-induced profibrotic responses in kidney

Aldosterone has been recognized as a risk factor for the development of chronic kidney disease (CKD). Studies have indicated that enhanced activation of epidermal growth factor receptor (EGFR) is associated with the development and progression of renal fibrosis. But if EGFR is involved in aldosterone-induced renal fibrosis is less investigated. In the present study, we examined the effect of erlotinib, an inhibitor of EGFR tyrosine kinase activity, on the progression of aldosterone-induced renal profibrotic responses in a murine model underwent uninephrectomy. Erlotinib-treated rats exhibited relieved structural lesion comparing with rats treated with aldosterone alone, as characterized by glomerular hypertrophy, mesangial cell proliferation and expansion. Also, erlotinib inhibited the expression of TGF-β, α-SMA and mesangial matrix proteins such as collagen Ⅳ and fibronectin. In cultured mesangial cells, inhibition of EGFR also abrogated aldosterone-induced expression of extracellular matrix proteins, cell proliferation and migration. We also demonstrated that aldosterone induced the phosphorylation of EGFR through generation of ROS. And the activation of EGFR resulted in the phosphorylation of ERK1/2, leading to the activation of profibrotic pathways. Taken together, we concluded that aldosterone-mediated tissue fibrosis relies on ROS induced EGFR/ERK activation, highlighting EGFR as a potential therapeutic target for modulating renal fibrosis. - Highlights: • EGFR was involved in aldosterone-induced renal profibrotic responses. • Aldosterone-induced EGFR activation was mediated by MR-dependent ROS generation. • EGFR activated the MAPK/ERK1/2 signaling to promote renal fibrosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Protein Kinase G facilitates EGFR-mediated cell death in MDA-MB-468 cells

The Epidermal Growth Factor Receptor (EGFR) is a transmembrane receptor tyrosine kinase with critical implications in cell proliferation, migration, wound healing and the regulation of apoptosis. However, the EGFR has been shown to be hyper-expressed in a number of human malignancies. The MDA-MB-468 metastatic breast cell line is one example of this. This particular cell line hyper-expresses the EGFR and undergoes EGFR-mediated apoptosis in response to EGF ligand. The goal of this study was to identify the kinases that could be potential intermediates for the EGFR-mediated induction of apoptosis intracellularly. After identifying Cyclic GMP-dependent Protein Kinase G (PKG) as a plausible intermediate, we wanted to determine the temporal relationship of these two proteins in the induction of apoptosis. We observed a dose-dependent decrease in MDA-MB-468 cell viability, which was co-incident with increased PKG activity as measured by VASPSer239 phosphorylation. In addition, we observed a dose dependent decrease in cell viability, as well as an increase in apoptosis, in response to two different PKG agonists, 8-Bromo-cGMP and 8-pCPT-cGMP. MDA-MB-468 cells with reduced PKG activity had attenuated EGFR-mediated apoptosis. These findings indicate that PKG does not induce cell death via transphosphorylation of the EGFR. Instead, PKG activity occurs following EGFR activation. Together, these data indicate PKG as an intermediary in EGFR-mediated cell death, likely via apoptotic pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Melanogenesis inhibits respiration in B16-F10 melanoma cells whereas enhances mitochondrial cell content

Melanoma is a rare and aggressive skin tumor; the survival of patients diagnosed late is fairly low. This high mortality rate is due to the characteristics of the cells that allow them to be resistant to radiotherapy and conventional chemotherapy, besides of being able to evade the immune system. Melanin, the pigment responsible for skin, hair and eye color, seems to be involved in this resistance. The main function of melanin is to protect the cells against ultraviolet (UV) light by absorbing this radiation and reactive oxygen species (ROS) scavenging. But this pigment may have also a role as photosensitizer, because when it is irradiated with UVA light (320-400 nm), the generation of ROS was detected. Besides, the melanogenesis stimulation on B16-F10 cells resulted in cell cycle arrest, induction of a quiescent state, change in the expression of several proteins and alterations on ADP/ATP ratio. The present study aimed to investigate the influence of melanogenesis stimulation in mitochondrial function of B16-F10 melanoma cells. Therefore, we analyzed cells respiration, mitochondrial membrane potential (Δψ{sub m}) and mitochondria mass in B16-F10 melanoma cells stimulated with 0.4 mM L-tyrosine and 10 mM NH{sub 4}Cl. Our results showed that the induction of melanin synthesis was able to reduce significantly the oxygen consumption after 48 h of stimulation, without changes of mitochondrial membrane potential when compared to non-stimulated cells. Despite of respiration inhibition, the mitochondria mass was higher in cells with melanogenesis stimulation. We suggest that the stimulation in the melanin synthesis might be promoting the inhibition of electrons transport chain by some intermediate compound from the synthesis of the pigment and this effect could contribute to explain the entry in the quiescent state. - Highlights: • Melanoma pigmentation alters mitochondrial respiration. • Induction of melanin synthesis by 48 h do not change mitochondrial membrane potential. • Mitochondria mass was higher in cells with melanogenesis stimulation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Exosomes derived from imatinib-resistant chronic myeloid leukemia cells mediate a horizontal transfer of drug-resistant trait by delivering miR-365

Highlights: • Imatinib resistant CML cells-derived exosomes are internalized into sensitive CML cells. • Imatinib resistant CML cells-derived exosomes confer drug resistance trait to sensitive CML cells. • Exosomes mediate horizontal transfer of miR-365 between imatinib resistant CML cells and sensitive ones. • MiR-365 lowers chemosensitivity and apoptosis in imatinib-sensitive CML cells. Chronic myeloid leukemia (CML) is a malignant disorder of hematopoietic stem/progenitor cells. Majority of patients can be effectively treated with tyrosine kinase inhibitors (TKIs) such as imatinib, but a portion of patients will develop drug resistance. Accumulated evidences have identified exosomes in cancer as promoters of tumor progression. Herein, we found that exosomes derived from imatinib resistant CML cells can be internalized into sensitive CML cells and confer drug-resistance traits. We also demonstrated a significant higher level of miR-365 in exosomes derived from drug-resistant CML cells compared with those from sensitive ones using microarray and qRT-PCR. The imatinib sensitive CML cells transfected with pre-miR-365 displayed lower chemosensitivity and apoptosis rate compared with controls. We further confirmed that exosomal transfer of miR-365 induced drug resistance by inhibiting expression of pro-apoptosis protein in sensitive CML cells. In conclusion, our study reveals that exosomes mediate a horizontal transfer of drug-resistant trait in chronic myeloid leukemia cell by delivering miR-365.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

CS2164 exerts an antitumor effect against human Non-Hodgkin's lymphomas in vitro and in vivo

Non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of lymphoproliferative disorders. Mounting studies have suggested an involvement of angiogenesis signaling in NHLs progression and resistance to treatment. In this study, we investigated the cytotoxicity of CS2164, a novel receptor tyrosine kinase inhibitor selectively targeting VEGFR-2 and Aurora B in NHL cells. By in vitro culture system and in vivo xenograft model, we found that CS2164 significantly inhibited cell growth and abolished clonogenicity in NHL cells in a dose- and time-dependent manner. Meanwhile, CS2164 significantly induced NHL cells apoptosis and cell cycle arrest in G0/G1 phase. Moreover, CS2164 suppressed NHL cells growth and progression in an in vivo xenograft model. Mechanistically, CS2164-induced cytotoxicity was closely associated with inhibition of VEGFR2 and Aurora B as well as their downstream signaling cascades, including P38, ERK and H3 pathways. In conclusion, CS2164 exerts its cytotoxic effect via inhibition of proliferation and induction of apoptosis by modulating VEGFR2 and Aurora B signaling pathway, supporting a potential role for CS2164 in the treatment of NHLs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

HDAC inhibitor suppresses proliferation and tumorigenicity of drug-resistant chronic myeloid leukemia stem cells through regulation of hsa-miR-196a targeting BCR/ABL1

Highlights: • hsa-miR-196a mediates inhibition of CML stem cells. • Potentiate the anticancer effect of Imatinib mesylate by suberanilohydroxamic acid. • Synergism with Imatinib mesylate and suberanilohydroxamic acid reverses the tumor-promoting proteotranscriptomic profile. Failure to eradicate hematologic cancer stem cells (hCSCs) associated with resistance to tyrosine kinase inhibitors such as imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients is a clinical challenge that highlights the need for discovering and developing therapeutic strategies that target and eliminate these hCSCs. Herein, we document the essential role of the interplay between histone deacetylases (HDACs), the polycomb group proteins, pluripotency transcription factors and the cell cycle machinery in the viability, oncogenicity and therapy evasion of IM-resistant CD34+/CD38- CML stem cells (CML-SCs). Using the proteotranscriptomic analyses of wild type (WT), CD34+/CD38+ and CD34+/CD38− K562 or KU812 cells, we showed that CD34+/CD38− SC-enriched cells expressed significantly higher levels of CD44, CD133, SOX2, Nanog, OCT4, and c-Myc mRNA and/or protein, compared to the WT or CD34+/CD38+ cells. This overexpression of stemness factors in the CD34+/CD38− cells positively correlates with enhanced expression of HDACs 1–6, cyclins D1/D3, CDK 2, 4 and 6, while inversely correlating with p18, p21 and p27. Enhanced co-expression of MDR1, survivin, and Bcl-2 proteins, supposedly involved in IM-resistance and CML-SC survival, was detected in both CD34+/CD38− and CD34+/CD38+ cells. Importantly, we demonstrate that in synergism with IM, SAHA reverses the tumor-promoting proteotranscriptomic profile noted above and elicits marked inhibition of the CML-SCs by up-regulating hsa-miR-196a expression. This hsa-miR-196a-mediated SC-limiting effect of SAHA is dose-dependent, low-dosed, cell cycle-modulating and accompanied by leukemic SC apoptosis. Interestingly, this anti-SC therapeutic activity of SAHA in vitro was reproduced in vivo using the NOD-SCID mice models.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Role of α-Dystrobrevin in the differentiation process of HL-60 cells

Highlights: • α-Db is downexpressed in HL-60 cells induced into neutrophils with DMSO. • α-Db-1 knockdown prevented nuclei lobulation, increased lamin A/C, and syne1 expression. • α-Db-1 depletion augmented actin-F and the roughness of derived neutrophil membrane. The α-Dystrobrevin gene encodes at least five different protein isoforms, expressed in diverse tissues. The α-Dystrobrevin-1 isoform (α-Db-1) is a member of the cytoplasmic dystrophin-associated protein complex, which has a C-terminal extension comprising at least three tyrosine residues susceptible to phosphorylation in vivo. We previously described α-Db in stem-progenitor cells and blood neutrophils as playing a scaffolding role and, in association with kinesin and microtubules, α-Db promotes platelet-granule trafficking. Additionally, the microtubules must establish a balanced interaction with the lamina A/C network for appropriate nuclear morphology. Considering that the most outstanding feature during neutrophil differentiation is nuclei lobulation, we hypothesized that α-Db might possess a pivotal function during the neutrophil differentiation process. Western Blot (WB) and confocal microscope assays evidenced a differential pattern expression and a subcellular redistribution of α-Db in neutrophils derived from HL-60 cells. At the end of the differentiation process, we detected an important diminution in the expression of tubulin, kinesin, and α-Db-1. Knockdown of α-Db prevented nuclei lobulation, increased Lamin A/C and syne1 expression and augmented the roughness of derived neutrophil membrane and disturbed filopodia assembly. Our results suggest that HL-60 cells undergo extensive cytoskeletal reorganization including α-Db in order to possess lobulated nuclei when they further differentiate into neutrophils.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Protein kinase C mediated internalization of ErbB2 is independent of clathrin, ubiquitination and Hsp90 dissociation

Highlights: • PKC activation induces internalization but not degradation of ErbB2. • PKC-induced internalization of ErbB2 is independent of Hsp90 dissociation. • PKC-induced internalization of ErbB2 is independent of ErbB2 ubiquitination. • PKC-induced internalization of ErbB2 is clathrin independent. Overexpression of ErbB2 is frequent in cancer and understanding the mechanisms which regulate its expression is important. ErbB2 is considered endocytosis resistant. It has no identified ligand, but upon heterodimerization it is a potent mediator of proliferative signaling. A recent study established a role for protein kinase C (PKC) in internalization and recycling of ErbB2. We have now further investigated the molecular mechanisms involved in PKC-mediated downregulation of ErbB2. We confirm that PMA-induced PKC activation causes ErbB2 internalization, but while the Hsp90 inhibitor 17-AAG induced ErbB2 degradation, PMA had no such effect. When combined with 17-AAG, PMA had additive effect on ErbB2 internalization indicating that Hsp90 inhibition and PKC activation induce internalization by alternative mechanisms. We confirm that while 17-AAG-induced internalization was clathrin-mediated, PMA-induced internalization was clathrin independent. This difference may be explained by while both 17-AAG and PMA reduced the constitutive tyrosine phosphorylation of ErbB2, only 17-AAG induced Hsp90 dissociation, Hsp70 recruitment and ubiquitination of ErbB2. Importantly, since PMA induced internalization of ErbB2, but not dissociation of Hsp90, Hsp90 does not per se retain ErbB2 at the plasma membrane. The morphology of the compartment into which receptors are sorted upon PKC activation has not previously been identified. By immuno-electron microscopy, we show that PMA sorts ErbB2 into a complex tubulovesicular or cisternal organelle resembling a previously described endocytic recycling compartment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Modulation of Akt vs Stat3 activity by the focal adhesion kinase in non-neoplastic mouse fibroblasts

Adhesion of cells to each other and to the extracellular matrix (ECM) are both required for cellular functions. Cell-to-cell adhesion is mediated by cadherins and their engagement triggers the activation of Stat3, which offers a potent survival signal. Adhesion to the ECM on the other hand, activates FAK which attracts and activates Src, as well as receptor tyrosine kinases (RTKs), the PI3k/Akt and Ras/Erk pathways. However, the effect of cell density upon FAK and Akt activity has not been examined. We now demonstrate that, interestingly, despite being potent Stat3 activators, Src and RTKs are unable to activate Stat3 in sparsely growing (i.e., without cadherin engagement), non-neoplastic cells attached to the ECM. In contrast, cell aggregation (i.e., cadherin engagement in the absence of adhesion to a solid substratum) was found to activate both Stat3 and Akt. Pharmacologic or genetic reduction of FAK activity abolished Akt activity at low densities, indicating that FAK is an important activator of Akt in this setting. Notably, FAK knockout increased cellular sensitivity to the Stat3 inhibitor CPA7, while FAK reintroduction restored resistance to this drug. These findings suggest a complementary role of integrin/FAK/Akt and cadherin/Stat3-mediated pro-survival pathways, which may be of significance during neoplastic transformation and metastasis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

DYRK1A is required for maintenance of cancer stemness, contributing to tumorigenic potential in oral/oropharyngeal squamous cell carcinoma

Highlights: • DYRK1A is essential to maintain cancer stemness in OSCC. • DYRK1A regulates cancer stemness via FGF2 expression. • Levels of DYRK1A and FGF2 expression are positively correlated in OSCC cells. • DYRK1A-FGF2 is a novel molecular axis regulating cancer stemness in OSCC. DYRK1A, one of the dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs), plays an important role in various biological processes by regulating downstream targets via kinase-dependent and independent mechanisms. Here, we report a novel role of DYRK1A in maintaining tumor growth and stemness of oral/oropharyngeal squamous cell carcinoma (OSCC) cells. Deletion of DYRK1A from OSCC cells abrogated their in vivo tumorigenicity and self-renewal capacity, the key features of cancer stem-like cells (CSCs; also referred to as tumor-initiating cells). The DYRK1A deletion also induced the suppression of CSC populations and properties, such as migration ability and chemoresistance. Conversely, ectopic expression of DYRK1A in OSCC cells augmented their CSC phenotype. Among five DYRK members (DYRK1A, 1B, 2, 3, and 4), DYRK1A is the most dominantly expressed kinase, and its expression is upregulated in OSCC compared to normal oral epithelial cells. More importantly, DYRK1A was highly enriched in various CSC-enriched OSCC populations compared to their corresponding non-CSC populations, indicating its pivotal role in cancer progression and stemness. Further, our study revealed that fibroblast growth factor 2 (FGF2) is a key regulator in the DYRK1A-mediated CSC regulation. Functional studies demonstrated that the loss of DYRK1A inhibits CSC phenotype via reduction of FGF2. Overexpression of DYRK1A promotes CSC phenotype via upregulation of FGF2. Our study delineates a novel mechanism of cancer stemness regulation by DYRK1A-FGF2 axis in OSCC. Thus, inhibition of DYRK1A would lead to a potential novel therapeutic option for targeting CSCs in OSCC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Targeting HSPA8 inhibits proliferation via downregulating BCR-ABL and enhances chemosensitivity in imatinib-resistant chronic myeloid leukemia cells

The resistance to tyrosine kinase inhibitors is currently a major problem for chronic myeloid leukemia (CML) treatment and HSPA8 is highly expressed and a hallmark of poor prognosis in several human cancers. However, its role in imatinib-resistant CML (IR-CML) cells remains undetermined. Here, we determined HSPA8 was overexpressed in IR-CML cells and associated with imatinib resistance. HSPA8 ablation could downregulate BCR-ABL/STAT5 and BCR-ABL/AKT signaling pathways, dramatically induce proliferation inhibition, autophagy, G0/G1 phase cell cycle arrest but not apoptosis in IR-CML cells. Significantly, HSPA8 ablation enhanced the antitumor activity of imatinib via promoting apoptosis in vitro and vivo. These findings unraveled that HSPA8 ablation inhibits proliferation via downregulating BCR-ABL and enhances chemosensitivity of imatinib in IR-CML cells, which investigate the role and molecular mechanism of HSPA8 in IR-CML cells and suggest that HSPA8 may be a potential target for IR-CML treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Inhibition of beta-amyloid aggregation by fluorescent dye labels

The fluorescence decay of beta-amyloid's (Aβ) intrinsic fluorophore tyrosine has been used for sensing the oligomer formation of dye-labelled Aβ monomers and the results compared with previously studied oligomerization of the non-labelled Aβ peptides. It has been demonstrated that two different sized, covalently bound probes 7-diethylaminocoumarin-3-carbonyl and Hilyte Fluor 488 (HLF), alter the rate and character of oligomerization to different extents. The ability of HLF to inhibit formation of highly ordered structures containing beta-sheets was also shown. The implications of our findings for using fluorescence methods in amyloidosis research are discussed and the advantages of this auto-fluorescence approach highlighted.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Non-covalent interactions of nitrous oxide with aromatic compounds: Spectroscopic and computational evidence for the formation of 1:1 complexes

We present the first study of intermolecular interactions between nitrous oxide (N{sub 2}O) and three representative aromatic compounds (ACs): phenol, cresol, and toluene. The infrared spectroscopic experiments were performed in a Ne matrix and were supported by high-level quantum chemical calculations. Comparisons of the calculated and experimental vibrational spectra provide direct identification and characterization of the 1:1 N{sub 2}O-AC complexes. Our results show that N{sub 2}O is capable of forming non-covalently bonded complexes with ACs. Complex formation is dominated by dispersion forces, and the interaction energies are relatively low (about −3 kcal mol{sup −1}); however, the complexes are clearly detected by frequency shifts of the characteristic bands. These results suggest that N{sub 2}O can be bound to the amino-acid residues tyrosine or phenylalanine in the form of π complexes.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2014

Communication: Identification of daughter ions through their electronic spectroscopy at low temperature

We present experimental results on photofragmentation of cooled fragments issued from the photofragmentation of cold parent ions. The cooling of the daughter ions at a few K allows its characterization not only through its fragmentation pattern but also through its well resolved electronic spectroscopy. The proof of principle of the method is demonstrated on the photofragment resulting from C{sub α}–C{sub β} bond rupture in protonated tyrosine (TyrH{sup +}). The analysis of the daughter ion (m/z 108) photofragmentation spectrum is in agreement with the proposed mechanism implying a proton transfer to the phenyl ring as the first step of the fragmentation mechanism of TyrH{sup +}.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2014

Cold ion UV photofragmentation spectroscopy and dynamics (Invited)

Up to ten years ago, very little was known about the excited states of protonated amino acids isolated in the gas phase. From the experimental point of view, the study was hampered by the lack of ease of production of such species in sufficient density to apply photon-based techniques. With the development and widespread use of electrospray ionization sources coupled with modified or homebuilt mass spectrometers, there has been significant research into the spectroscopy of biomimetic and biologically relevant molecules. Besides, these species are floppy such that an efficient cooling is required to record clear spectroscopy. Warm protonated species display congested spectra. To extract precise spectroscopic information and avoid spectral congestion, the species need to be cooled down to less than 50 K. We present our latest results on the electronic spectroscopy of protonated phenylalanine and tyrosine on a large spectral domain (225-290 nm). These species are studied in a new simplified apparatus combining an electrospray ionization source, a cryogenically cooled quadrupole ion trap (∼10 K) and time-of-flight mass spectrometry. The role of proton transfer from the NH{sub 3}{sup +} moiety to the p-ring or to CO of the carboxylic acid group is evidenced by UV photofragment spectroscopy. This first step controls the fragmentation pathways, which strongly depend on the nature of the electronic excited states, i.e. ππ*, ππ*{sub CO} and πσ{sub NH3}.

74 ATOMIC AND MOLECULAR PHYSICS↗