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Research Square Jun 2024Human manganese superoxide dismutase (MnSOD) plays a crucial role in controlling levels of reactive oxygen species (ROS) by converting superoxide (O ) to molecular...
Human manganese superoxide dismutase (MnSOD) plays a crucial role in controlling levels of reactive oxygen species (ROS) by converting superoxide (O ) to molecular oxygen (O ) and hydrogen peroxide (H O ) with proton-coupled electron transfers (PCETs). The reactivity of human MnSOD is determined by the state of a key catalytic residue, Tyr34, that becomes post-translationally inactivated by nitration in various diseases associated with mitochondrial dysfunction. We previously reported that Tyr34 has an unusual pK due to its proximity to the Mn metal and undergoes cyclic deprotonation and protonation events to promote the electron transfers of MnSOD. To shed light on the role of Tyr34 MnSOD catalysis, we performed neutron diffraction, X-ray spectroscopy, and quantum chemistry calculations of Tyr34Phe MnSOD in various enzymatic states. The data identifies the contributions of Tyr34 in MnSOD activity that support mitochondrial function and presents a thorough characterization of how a single tyrosine modulates PCET catalysis.
PubMed: 38946943
DOI: 10.21203/rs.3.rs-4494128/v1 -
World Journal of Gastroenterology Jun 2024In this editorial, we respond to a review article by Nabi , in which the authors discussed gastroesophageal reflux (GER) following peroral endoscopic myotomy (POEM)....
In this editorial, we respond to a review article by Nabi , in which the authors discussed gastroesophageal reflux (GER) following peroral endoscopic myotomy (POEM). POEM is presently the primary therapeutic option for achalasia, which is both safe and effective. A few adverse effects were documented after POEM, including GER. The diagnostic criteria were not clear enough because approximately 60% of patients have a long acid exposure time, while only 10% experience reflux symptoms. Multiple predictors of high disease incidence have been identified, including old age, female sex, obesity, and a baseline lower esophageal sphincter pressure of less than 45 mmHg. Some technical steps during the procedure, such as a lengthy or full-thickness myotomy, may further enhance the risk. Proton pump inhibitors are currently the first line of treatment. Emerging voices are increasingly advocating for the routine combining of POEM with an endoscopic fundoplication method, such as peroral endoscopic fundoplication or transoral incisionless fundoplication. However, more research is necessary to determine the safety and effectiveness of these procedures in the long term for patients who have undergone them.
Topics: Humans; Esophageal Achalasia; Esophageal Sphincter, Lower; Esophagoscopy; Fundoplication; Gastroesophageal Reflux; Myotomy; Natural Orifice Endoscopic Surgery; Proton Pump Inhibitors; Risk Factors; Treatment Outcome
PubMed: 38946871
DOI: 10.3748/wjg.v30.i23.2947 -
Nature Communications Jun 2024Transition metal-catalyzed asymmetric hydrogenation is one of the most efficient methods for the preparation of chiral α-substituted propionic acids. However, research...
Transition metal-catalyzed asymmetric hydrogenation is one of the most efficient methods for the preparation of chiral α-substituted propionic acids. However, research on this method, employing cleaner earth-abundant metal catalysts, is still insufficient in both academic and industrial contexts. Herein, we report an efficient nickel-catalyzed asymmetric hydrogenation of α-substituted acrylic acids affording the corresponding chiral α-substituted propionic acids with up to 99.4% ee (enantiomeric excess) and 10,000 S/C (substrate/catalyst). In particular, this method can be used to obtain (R)-dihydroartemisinic acid with 99.8:0.2 dr (diastereomeric ratio) and 5000 S/C, which is an essential intermediate for the preparation of the antimalarial drug Artemisinin. The reaction mechanism has been investigated via experiments and DFT (Density Functional Theory) calculations, which indicate that the protonolysis of the C-Ni bond of the key intermediate via an intramolecular proton transfer from the carboxylic acid group of the substrate, is the rate-determining step.
PubMed: 38942809
DOI: 10.1038/s41467-024-49801-0 -
Radiotherapy and Oncology : Journal of... Jun 2024As no guidelines for pencil beam scanning (PBS) proton therapy (PT) of paediatric posterior fossa (PF) tumours exist to date, this study investigated planning techniques...
BACKGROUND AND PURPOSE
As no guidelines for pencil beam scanning (PBS) proton therapy (PT) of paediatric posterior fossa (PF) tumours exist to date, this study investigated planning techniques across European PT centres, with special considerations for brainstem and spinal cord sparing.
MATERIALS AND METHODS
A survey and a treatment planning comparison were initiated across nineteen European PBS-PT centres treating paediatric patients. The survey assessed all aspects of the treatment chain, including but not limited to delineations, dose constraints and treatment planning. Each centre planned two PF tumour cases for focal irradiation, according to their own clinical practice but based on common delineations. The prescription dose was 54 Gy(RBE) for Case 1 and 59.4 Gy(RBE) for Case 2. For both cases, planning strategies and relevant dose metrics were compared.
RESULTS
Seventeen (89 %) centres answered the survey, and sixteen (80 %) participated in the treatment planning comparison. In the survey, thirteen (68 %) centres reported using the European Particle Therapy Network definition for brainstem delineation. In the treatment planning study, while most centres used three beam directions, their configurations varied widely across centres. Large variations were also seen in brainstem doses, with a brainstem near maximum dose (D2%) ranging from 52.7 Gy(RBE) to 55.7 Gy(RBE) (Case 1), and from 56.8 Gy(RBE) to 60.9 Gy(RBE) (Case 2).
CONCLUSION
This study assessed the European PBS-PT planning of paediatric PF tumours. Agreement was achieved in e.g. delineation-practice, while wider variations were observed in planning approach and consequently dose to organs at risk. Collaboration between centres is still ongoing, striving towards common guidelines.
PubMed: 38942120
DOI: 10.1016/j.radonc.2024.110414 -
Ultrasonics Sonochemistry Jun 2024Ultrasonic technology has a significant degassing effect and can increase the efficiency of hydrogen production in the proton exchange membrane electrolysis of water....
Ultrasonic technology has a significant degassing effect and can increase the efficiency of hydrogen production in the proton exchange membrane electrolysis of water. However, further research is needed to understand its influence mechanism on hydrogen bubbles. In this work, a kinetic analysis is performed to investigate the principle of hydrogen production and the kinetic behaviour of hydrogen bubble evolution by applying the ultrasonic amplification technique under static and flow dynamics in the proton exchange membrane electrolysis cell. The evolution of hydrogen bubbles in the static and in the flow dynamic of the aqueous electrolyte solution under ultrasound was characterised by imaging. The results show that the aqueous electrolyte solution in the flow state reduces the size of hydrogen bubbles and increases the detachment speed compared to the static state, which promotes the process of hydrogen bubble evolution, and that the thermal effect of ultrasound on the temperature of the aqueous electrolyte solution in the flow state is very small compared to the static state and can be ignored. Ultrasound has different effects on the different stages of hydrogen bubble evolution. In the nucleation stage, the ultrasonic cavitation effect increases the highly reactive radicals such as •OH, H•, etc., and the mechanical vibration effect of ultrasound increases the nucleation sites, which are denser and more evenly distributed. In the growth phase, the ultrasonic cavitation effect and the mechanical vibration effect promote the breaking of hydrogen bonds of water molecules and improve mass transport, which promotes the growth of hydrogen bubbles, and the fluctuating energy of positive and negative ultrasound promotes the growth of hydrogen bubbles with the vibration speed. In the detachment phase, the radius of the hydrogen bubbles is influenced by the ultrasound. The radius of the hydrogen bubbles changes with the positive and negative ultrasonic pressure, the radius of the hydrogen bubbles at negative ultrasonic pressure increases, the positive ultrasonic pressure decreases, the changing effect of the radius of the hydrogen bubbles favours the detachment of the hydrogen bubbles. In the polymerisation phase, the ultrasound leads to increased polymerisation of the fine bubble streams. Ultrasound contributes to the hydrogen production effect of proton exchange membrane water electrolysis in actual operation.
PubMed: 38941702
DOI: 10.1016/j.ultsonch.2024.106968 -
Journal of Magnetic Resonance (San... Jun 2024Hyperpolarized water in dissolution dynamic nuclear polarization (dDNP) experiments has emerged as a promising method for enhancing nuclear magnetic resonance (NMR)...
Hyperpolarized water in dissolution dynamic nuclear polarization (dDNP) experiments has emerged as a promising method for enhancing nuclear magnetic resonance (NMR) signals, particularly in studies of proteins and peptides. Herein, we focus on the application of "proton exchange-doubly relayed" nuclear Overhauser effects (NOE) from hyperpolarized water to achieve positive signal enhancement of methyl groups in the side chain of an alanine-glycine peptide. In particular, we show a cascade hyperpolarization transfer. Initial proton exchange between solvent and amide introduces hyperpolarization into the peptide. Subsequently, intermolecular NOE relays the hyperpolarization first to Ala-H and then in a second step to the Ala-CH moiety. Both NOEs have negative signs. Hence, the twice-relayed NOE pathway leads to a positive signal enhancement of the methyl group with respect to the thermal equilibrium magnetization. This effect might indicate a way towards hyperpolarized water-based signal enhancement for methyl groups, which are often used for NMR studies of large proteins in solution.
PubMed: 38941676
DOI: 10.1016/j.jmr.2024.107727 -
JACC. Advances Jan 2024Proton pump inhibitors (PPIs) and histamine type 2-receptor blockers (H2Bs) are commonly used for stress ulcer prophylaxis among patients requiring invasive mechanical...
BACKGROUND
Proton pump inhibitors (PPIs) and histamine type 2-receptor blockers (H2Bs) are commonly used for stress ulcer prophylaxis among patients requiring invasive mechanical ventilation (IMV). Recent studies suggest an increased mortality associated with PPIs compared to H2Bs, but these studies poorly represent patients with cardiovascular disease or acute myocardial infarction (AMI).
OBJECTIVES
The aim of this study was to compare outcomes related to stress ulcer prophylaxis with PPIs compared to H2Bs in patients with AMI requiring IMV.
METHODS
We queried the Vizient Clinical Data Base for adults aged ≥18 years admitted between October 2015 and December 2019 with a primary diagnosis of AMI and requiring IMV. Using multivariable logistic regression, we assessed for the association between stress ulcer prophylaxis and in-hospital mortality.
RESULTS
Including 11,252 patients with AMI requiring IMV, 66.7% (n = 7,504) received PPIs and 33.3% (n = 3,748) received H2Bs. Age, sex, and the proportion of patients presenting with ST-segment elevation myocardial infarction or cardiogenic shock were similar between groups (all, > 0.05). Compared to PPIs, patients receiving H2Bs had a lower mortality (41.5% vs 43.5%, = 0.047), which was not statistically significant after multivariate adjustment (odds ratio 0.97; 95% confidence interval: 0.89-1.06, = 0.49). In unadjusted and adjusted analyses, H2Bs use was associated with fewer ventilator days, less ventilator-associated pneumonia, and lower hospitalization cost but similar infections.
CONCLUSIONS
Among patients with AMI requiring IMV in this observation cohort study, there was no difference in mortality among patients receiving H2Bs vs PPIs for stress ulcer prophylaxis despite fewer ventilator days and lower ventilator-associated pneumonia in those receiving H2Bs.
PubMed: 38939822
DOI: 10.1016/j.jacadv.2023.100750 -
ACG Case Reports Journal Jul 2024Transcatheter arterial radioembolization (TARE) is a common locoregional treatment for hepatocellular carcinoma. It is associated with peptic ulcer disease in up to 5%...
Transcatheter arterial radioembolization (TARE) is a common locoregional treatment for hepatocellular carcinoma. It is associated with peptic ulcer disease in up to 5% of patients. A 70-year-old man with Roux-en-Y gastric bypass and liver cirrhosis with hepatocellular carcinoma treated with TARE 6 months earlier was evaluated for continued melena and was found to have an ulcer in the excluded stomach. This was successfully treated with liquid proton pump inhibitor through gastrostomy tube to the excluded stomach. This represents a unique case of successful management of TARE-induced peptic ulcer disease in the excluded stomach of a Roux-en-Y gastric bypass patient.
PubMed: 38939352
DOI: 10.14309/crj.0000000000001399 -
Chemical Science Jun 2024Study of alternating DNA GC sequences by different time-resolved spectroscopies has provided fundamental information on the interaction between UV light and DNA, a...
Study of alternating DNA GC sequences by different time-resolved spectroscopies has provided fundamental information on the interaction between UV light and DNA, a process of great biological importance. Multiple decay paths have been identified, but their interplay is still poorly understood. Here, we characterize the photophysics of GC-DNA by integrating different computational approaches, to study molecular models including up to 6 bases described at a full quantum mechanical level. Quantum dynamical simulations, exploiting a nonadiabatic linear vibronic coupling (LVC) model, coupled with molecular dynamics sampling of the initial structures of a (GC) DNA duplex, provide new insights into the photophysics in the sub-picosecond time-regime. They indicate a substantial population transfer, within 50 fs, from the spectroscopic states towards G → C charge transfer states involving two stacked bases (CT), thus explaining the ultrafast disappearance of fluorescence. This picture is consistent with that provided by quantum mechanical geometry optimizations, using time dependent-density functional theory and a polarizable continuum model, which we use to parametrize the LVC model and to map the main excited state deactivation pathways. For the first time, the infrared and excited state absorption signatures of the various states along these pathways are comprehensively mapped. The computational models suggest that the main deactivation pathways, which, according to experiment, lead to ground state recovery on the 10-50 ps time scale, involve CT followed by interstrand proton transfer from the neutral G to C. Our calculations indicate that CT is populated to a larger extent and more rapidly in GC than in CG steps and suggest the likely involvement of monomer-like and interstrand charge transfer decay routes for isolated and less stacked CG steps. These findings underscore the importance of the DNA sequence and thermal fluctuations for the dynamics. They will also aid the interpretation of experimental results on other sequences.
PubMed: 38939156
DOI: 10.1039/d4sc00910j -
Chemical Science Jun 2024The scission and homologation of CO is a fundamental process in the Fischer-Tropsch reaction. However, given the heterogeneous nature of the catalyst and forcing...
The scission and homologation of CO is a fundamental process in the Fischer-Tropsch reaction. However, given the heterogeneous nature of the catalyst and forcing reaction conditions, it is difficult to determine the intermediates of this reaction. Here we report detailed mechanistic insight into the scission/homologation of CO by two-coordinate iron terphenyl complexes. Mechanistic investigations, conducted using monitoring and reaction sampling techniques (IR, NMR, EPR and Mössbauer spectroscopy) and structural characterisation of isolable species, identify a number of proposed intermediates. Crystallographic and IR spectroscopic data reveal a series of migratory insertion reactions from 1 to 4. Further studies past the formation of 4 suggest that ketene complexes are formed en route to squaraine 2 and iron carboxylate 3, with a number of ketene containing structures being isolated, in addition to the formation of unbound, protonated ketene (8). The synthetic and mechanistic studies are supported by DFT calculations.
PubMed: 38939136
DOI: 10.1039/d4sc01286k