The unimolecular decomposition of dimethoxymethane: channel switching as a function of temperature and pressure

Branching ratios of competing unimolecular reactions often exhibit a complicated temperature and pressure dependence that makes modelling of complex reaction systems in the gas phase difficult. In particular, the competition between steps proceeding via tight and loose transition states is known to present a problem. A recent example from the field of combustion chemistry is the unimolecular decomposition of CH$_3$OCH$_2$OCH$_3$ (DMM), which is discussed as an alternative fuel accessible from sustainable sources. It is shown by a detailed master equation analysis with energy- and angular-momentum-resolved specific rate coefficients from RRKM theory and from the simplified statistical adiabatic channel model, how channel switching of DMM depends on temperature and pressure, and under which experimental conditions which channels prevail. The necessary molecular and energy data were obtained from quantum-chemical calculations at the CCSD(F12*)(T*)/cc-pVQZ-F12//B2PLYP-D3/def2-TZVPP level of theory. A parameterization describing the channel branching over extended ranges of temperature and pressure is derived, and the model is used to simulate shock tube experiments with detection by atomic resonance absorption spectroscopy and time-of-flight mass spectrometry. The agreement between the simulated and experimental concentration–time profiles is very good. The temperature and pressure dependence of the channel branching is rationalized, and the data are presented in a form that can be readily implemented into DMM combustion models

High glucose‐induced oxidative stress and mitochondrial dysfunction in neurons

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154474/1/fsb2fasebj16131027com.pd

Kinetics of the Reactions of Hydroxyl Radicals with Furan and its Alkylated Derivatives 2-Methyl Furan and 2,5-Dimethyl Furan

Furans are promising second generation biofuels with comparable energy densities to conventional fossil fuels. Combustion of furans is initiated and controlled to a large part by reactions with OH radicals, the kinetics of which are critical to understand the processes occurring under conditions relevant to low-temperature combustion. The reactions of OH radicals with furan (OH + F, R1), 2-methyl furan (OH + 2-MF, R2), and 2,5-dimethyl furan (OH + 2,5-DMF, R3) have been studied in this work over the temperature range 294 to 668 K at pressures between 5 mbar and 10 bar using laser flash photolysis coupled with laser-induced fluorescence (LIF) spectroscopy to generate and monitor OH radicals under pseudo-first-order conditions. Measurements at p ≤ 200 mbar were made in N2, using H2O2 or (CH3)3COOH radical precursors, while those at p ≥ 2 bar were made in He, using HNO3 as the radical precursor. The kinetics of the reactions R1-R3 were observed to display a negative dependence on temperature over the range investigated, indicating the dominance of addition reactions under such conditions, with no significant dependence on pressure observed. Master equation calculations are in good agreement with the observed kinetics, and a combined parameterisation of addition channels and abstraction channels for R1-R3 is provided on the basis of this work and previous shock tube measurements at higher temperatures. This work significantly extends the temperature range previously investigated for R1 and represents the first temperature-dependent measurements of R2 and R3 at temperatures relevant for atmospheric chemistry and low-temperature combustion

The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis.

Ferroptosis is a form of regulated cell death that is caused by the iron-dependent peroxidation of lipids1,2. The glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols3,4. Ferroptosis has previously been implicated in the cell death that underlies several degenerative conditions2, and induction of ferroptosis by the inhibition of GPX4 has emerged as a therapeutic strategy to trigger cancer cell death5. However, sensitivity to GPX4 inhibitors varies greatly across cancer cell lines6, which suggests that additional factors govern resistance to ferroptosis. Here, using a synthetic lethal CRISPR-Cas9 screen, we identify ferroptosis suppressor protein 1 (FSP1) (previously known as apoptosis-inducing factor mitochondrial 2 (AIFM2)) as a potent ferroptosis-resistance factor. Our data indicate that myristoylation recruits FSP1 to the plasma membrane where it functions as an oxidoreductase that reduces coenzyme Q10 (CoQ) (also known as ubiquinone-10), which acts as a lipophilic radical-trapping antioxidant that halts the propagation of lipid peroxides. We further find that FSP1 expression positively correlates with ferroptosis resistance across hundreds of cancer cell lines, and that FSP1 mediates resistance to ferroptosis in lung cancer cells in culture and in mouse tumour xenografts. Thus, our data identify FSP1 as a key component of a non-mitochondrial CoQ antioxidant system that acts in parallel to the canonical glutathione-based GPX4 pathway. These findings define a ferroptosis suppression pathway and indicate that pharmacological inhibition of FSP1 may provide an effective strategy to sensitize cancer cells to ferroptosis-inducing chemotherapeutic agents

Temperature-Dependent, Site-Specific Rate Coefficients for the Reaction of OH (OD) with Methyl Formate Isotopologues via Experimental and Theoretical Studies

Methyl esters are an important component of combustion and atmospheric systems. Reaction with the OH radical plays an important role in the removal of the simplest methyl ester, methyl formate (MF, CH₃OCHO). In this paper, the overall rate coefficients for the reactions of OH and OD with MF isotopologues, studied under pseudo-first-order conditions, are reported using two different laser flash photolysis systems with the decay of OH monitored by laser-induced fluorescence. The room-temperature rate coefficient for OH + MF, (1.95 ± 0.34) × 10⁻¹³ cm³ molecule⁻¹ s⁻¹, is in good agreement with the literature. The rate coefficient exhibits curved Arrhenius behavior, and our results bridge the gap between previous low-temperature and shock tube studies. In combination with the literature, the rate coefficient for the reaction of OH with MF between 230 and 1400 K can be parametrized as kOH+MF = (3.2 × 10⁻¹³) × (T/300 K)².³ × exp(−141.4 K/T) cm³ molecule⁻¹ s⁻¹ with an overall estimated uncertainty of ∼30%. The reactions of OD with MF isotopologues show a small enhancement (inverse secondary isotope effect) compared to the respective OH reactions. The reaction of OH/OD with MF shows a normal primary isotope effect, a decrease in the rate coefficient when MF is partially or fully deuterated. Experimental studies have been supported by ab initio calculations at the CCSD(T)-F12/aug-cc-pVTZ//M06-2X/6-31+G** level of theory. The calculated, zero-point-corrected, barrier heights for abstraction at the methyl and formate sites are 1.3 and 6.0 kJ mol⁻¹, respectively, and the ab initio predictions of kinetic isotope effects are in agreement with experiment. Fitting the experimental isotopologue data refines these barriers to 0.9 ± 0.6 and 4.1 ± 0.9 kJ mol⁻¹. The branching ratio is approximately 50:50 at 300 K. Between 300 and 500 K, abstraction via the higher-energy, higher-entropy formate transition state becomes more favored (60:40). However, experiment and calculations suggest that as the temperature increases further, with higher energy, less constrained conformers of the methyl transition state become more significant. The implications of the experimental and theoretical results for the mechanisms of MF atmospheric oxidation and low-temperature combustion are discussed

Parkinson's Disease DJ-1 L166P Alters rRNA Biogenesis by Exclusion of TTRAP from the Nucleolus and Sequestration into Cytoplasmic Aggregates via TRAF6

Mutations in PARK7/DJ-1 gene are associated to autosomal recessive early onset forms of Parkinson's disease (PD). Although large gene deletions have been linked to a loss-of-function phenotype, the pathogenic mechanism of missense mutations is less clear. The L166P mutation causes misfolding of DJ-1 protein and its degradation. L166P protein may also accumulate into insoluble cytoplasmic aggregates with a mechanism facilitated by the E3 ligase TNF receptor associated factor 6 (TRAF6). Upon proteasome impairment L166P activates the JNK/p38 MAPK apoptotic pathway by its interaction with TRAF and TNF Receptor Associated Protein (TTRAP). When proteasome activity is blocked in the presence of wild-type DJ-1, TTRAP forms aggregates that are localized to the cytoplasm or associated to nucleolar cavities, where it is required for a correct rRNA biogenesis. In this study we show that in post-mortem brains of sporadic PD patients TTRAP is associated to the nucleolus and to Lewy Bodies, cytoplasmic aggregates considered the hallmark of the disease. In SH-SY5Y neuroblastoma cells, misfolded mutant DJ-1 L166P alters rRNA biogenesis inhibiting TTRAP localization to the nucleolus and enhancing its recruitment into cytoplasmic aggregates with a mechanism that depends in part on TRAF6 activity. This work suggests that TTRAP plays a role in the molecular mechanisms of both sporadic and familial PD. Furthermore, it unveils the existence of an interplay between cytoplasmic and nucleolar aggregates that impacts rRNA biogenesis and involves TRAF6

Lactic Acid Induces Aberrant Amyloid Precursor Protein Processing by Promoting Its Interaction with Endoplasmic Reticulum Chaperone Proteins

Lactic acid, a natural by-product of glycolysis, is produced at excess levels in response to impaired mitochondrial function, high-energy demand, and low oxygen availability. The enzyme involved in the production of β-amyloid peptide (Aβ) of Alzheimer's disease, BACE1, functions optimally at lower pH, which led us to investigate a potential role of lactic acid in the processing of amyloid precursor protein (APP).Lactic acid increased levels of Aβ40 and 42, as measured by ELISA, in culture medium of human neuroblastoma cells (SH-SY5Y), whereas it decreased APP metabolites, such as sAPPα. In cell lysates, APP levels were increased and APP was found to interact with ER-chaperones in a perinuclear region, as determined by co-immunoprecipitation and fluorescence microscopy studies. Lactic acid had only a very modest effect on cellular pH, did increase the levels of ER chaperones Grp78 and Grp94 and led to APP aggregate formation reminiscent of aggresomes.These findings suggest that sustained elevations in lactic acid levels could be a risk factor in amyloidogenesis related to Alzheimer's disease through enhanced APP interaction with ER chaperone proteins and aberrant APP processing leading to increased generation of amyloid peptides and APP aggregates

Modification of small ubiquitin-related modifier 2 (SUMO2) by phosphoubiquitin in HEK293T cells

Additional complexity in the post-translational modification of proteins by ubiquitin is achieved by ubiquitin phosphorylation, for example within PINK1-parkin mediated mitophagy. We performed a preliminary proteomic analysis to identify proteins differentially modified by ubiquitin in HEK293T, compared to phosphomimetic ubiquitin (Ser65Asp), and identified small ubiquitin-related modifier 2 (SUMO2) as a candidate. By transfecting SUMO2 and its C-terminal–GG deletion mutant, along with phosphomimetic ubiquitin, we confirm that ubiquitin modifies SUMO2, rather than vice versa. Further investigations revealed that transfected SUMO2 can also be conjugated by endogenous phospho-Ser65-(poly)ubiquitin in HEK293T cells, pointing to a previously unappreciated level of complexity in SUMO2 modification, and that unanchored (substrate-free) polyubiquitin chains may also be subject to phosphorylation