Hydrogen Peroxide and Amyotrophic Lateral Sclerosis: From Biochemistry to Pathophysiology

Free radicals are unstable chemical reactive species produced during Redox dyshomeostasis (RDH) inside living cells and are implicated in the pathogenesis of various neurodegenerative diseases. One of the most complicated and life-threatening motor neurodegenerative diseases (MND) is amyotrophic lateral sclerosis (ALS) because of the poor understanding of its pathophysiology and absence of an effective treatment for its cure. During the last 25 years, researchers around the globe have focused their interest on copper/zinc superoxide dismutase (Cu/Zn SOD, SOD1) protein after the landmark discovery of mutant SOD1 (mSOD1) gene as a risk factor for ALS. Substantial evidence suggests that toxic gain of function due to redox disturbance caused by reactive oxygen species (ROS) changes the biophysical properties of native SOD1 protein thus, instigating its fibrillization and misfolding. These abnormal misfolding aggregates or inclusions of SOD1 play a role in the pathogenesis of both forms of ALS, i.e., Sporadic ALS (sALS) and familial ALS (fALS). However, what leads to a decrease in the stability and misfolding of SOD1 is still in question and our scientific knowledge is scarce. A large number of studies have been conducted in this area to explore the biochemical mechanistic pathway of SOD1 aggregation. Several studies, over the past two decades, have shown that the SOD1-catalyzed biochemical reaction product hydrogen peroxide (H2O2) at a pathological concentration act as a substrate to trigger the misfolding trajectories and toxicity of SOD1 in the pathogenesis of ALS. These toxic aggregates of SOD1 also cause aberrant localization of TAR-DNA binding protein 43 (TDP-43), which is characteristic of neuronal cytoplasmic inclusions (NCI) found in ALS. Here in this review, we present the evidence implicating the pivotal role of H2O2 in modulating the toxicity of SOD1 in the pathophysiology of the incurable and highly complex disease ALS. Also, highlighting the role of H2O2 in ALS, we believe will encourage scientists to target pathological concentrations of H2O2 thereby halting the misfolding of SOD1.

Regulating the Electron Localization of Metallic Bismuth for Boosting CO2 Electroreduction

Electrochemical reduction of CO2 to formate is economically attractive but improving the reaction selectivity and activity remains challenging. Herein, we introduce boron (B) atoms to modify the local electronic structure of bismuth with positive valence sites for boosting conversion of CO2 into formate with high activity and selectivity in a wide potential window. By combining experimental and computational investigations, our study indicates that B dopant differentiates the proton participations of rate-determining steps in CO2 reduction and in the competing hydrogen evolution. By comparing the experimental observations with the density functional theory, the dominant mechanistic pathway of B promoted formate generation and the B concentration modulated effects on the catalytic property of Bi are unravelled. This comprehensive study offers deep mechanistic insights into the reaction pathway at an atomic and molecular level and provides an effective strategy for the rational design of highly active and selective electrocatalysts for efficient CO2 conversion.

The Essential Functional Interplay of the Catalytic Groups in Acid Phosphatase

Cooperative interplay between the functional devices of a preorganized active site is fundamental to enzyme catalysis. A deepened understanding of this phenomenon is central to elucidating the remarkable efficiency of natural enzymes, and provides an essential benchmark for enzyme design and engineering. Here, we study the functional interconnectedness of the catalytic nucleophile (His18) in an acid phosphatase by analyzing the consequences of its replacement with aspartate. We present crystallographic, biochemical and computational evidence for a conserved mechanistic pathway via a phospho-enzyme intermediate on Asp18. Linear free-energy relationships for phosphoryl transfer from phosphomonoester substrates to His18/Asp18 provide evidence for cooperative interplay between the nucleophilic and general-acid catalytic groups in the wildtype enzyme, and its substantial loss in the H18D variant. As an isolated factor of phosphatase efficiency, the advantage of a histidine compared to an aspartate nucleophile is around 10^4-fold. Cooperativity with the catalytic acid adds ≥10^2-fold to that advantage. Empirical valence bond simulations of phosphoryl transfer from glucose 1-phosphate to His and Asp in the enzyme explain the loss of activity of the Asp18 enzyme through a combination of impaired substrate positioning in the Michaelis complex, as well as a shift from early to late protonation of the leaving group in the H18D variant. The evidence presented furthermore suggests that the cooperative nature of catalysis distinguishes the enzymatic reaction from the corresponding reaction in solution and is enabled by the electrostatic preorganization of the active site. Our results reveal sophisticated discrimination in multifunctional catalysis of a highly proficient phosphatase active site.

Exploring pleiotropic effects of lipid modifiers on coagulation and hemostasis with genetics

Background: Statins have long been suspected to have pleiotropic effects via thrombotic factors. Randomized controlled trials are too limited to be definitive. We examined the associations of genetically mimicking effects of statins, PCSK9 inhibitors and alternative lipid targets (in genes LDLR, APOC3, and LPL) on key indicators of coagulation system function, i.e., prothrombin time (PT) and activated partial thromboplastin time (aPTT). Methods: We assessed the effect of established genetic mimics of effects of lipid modifiers and alternative lipid treatment targets on PT (n=58,110) and aPTT (n=37,767), all transformed to z-scores, using Mendelian randomization taking advantage of Biobank Japan. Ischemic heart disease (IHD) was a control outcome. Results: Genetically mimicked effects of statins increased PT by 0.31 standard deviation (SD) per SD increase in LDL (95% confidence interval (CI) 0.10 to 0.51) based on rs12916 but did not affect aPTT. Genetically mimicking effects of targeting LDLR increased PT based on rs688 (0.33 SD per SD increase in TG, 95% CI 0.03 to 0.63) but did not affect aPTT. Genetically mimicking effects of PCSK9 inhibitors or targeting APOC3, or LPL had no effect on PT or aPTT. Genetically mimicking effects of statins, PCSK9 inhibitors and alternative lipid targets reduced risk of IHD in Biobank Japan. Conclusion: Statins, and possibly targeting LDLR, may also act via a coagulation cascade factor, likely specific to the extrinsic or common pathway. Further elucidation of the mechanistic pathway may facilitate development of new interventions and inform use of statins particularly in relation to use of other anticoagulants.

Digenic Inheritance: Evidence and Gaps in Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder characterized by the inability to properly terminate an immune response. Familial HLH (FHLH) and related immune dysregulation syndromes are associated with mutations in the genes PRF1, UNC13D, STX11, STXBP2, LYST, AP3B1, and RAB27A, all of which are required for the assembly, exocytosis, and function of cytotoxic granules within CD8+ T cells and natural killer (NK) cells. Loss-of-function mutations in these genes render the cytotoxicity pathway ineffective, thereby failing to eradicate immune stimuli, such as infectious pathogens or malignant cells. The resulting persistent immune system stimulation drives hypercytokinemia, ultimately leading to severe tissue inflammation and end-organ damage. Traditionally, a diagnosis of FHLH requires the identification of biallelic loss-of-function mutations in one of these degranulation pathway genes. However, this narrow definition fails to encompass patients with other genetic mechanisms underlying degranulation pathway dysfunction. In particular, mounting clinical evidence supports a potential digenic mode of inheritance of FHLH in which single loss-of-function mutations in two different degranulation pathway genes cooperate to impair pathway activity. Here, we review the functions of the FHLH-associated genes within the degranulation pathway and summarize clinical evidence supporting a model in which cumulative defects along this mechanistic pathway may underlie HLH.

Visualizing compassion: Episodic simulation as contemplative practice

Contemplative interventions designed to cultivate compassion are receiving increasing empirical attention. Accumulating evidence suggests that these interventions bolster prosocial motivation and warmth towards others. Less is known about how these practices impact compassion in everyday life. Here we consider one mechanistic pathway through which compassion practices may impact perception and action in the world: simulation. Evidence suggests that vividly imagining a situation simulates that experience in the brain as if it were, to a degree, actually happening. Thus, we hypothesize that simulation during imagery-based contemplative practices can construct sensorimotor patterns in the brain that prime an individual to act compassionately in the world. We first present evidence across multiple literatures in Psychology that motivates this hypothesis, including the neuroscience of mental imagery and the emerging literature on prosocial episodic simulation. Then, we examine the specific contemplative practices in compassion-based interventions that may construct such simulations. We conclude with future directions for investigating how compassion-based interventions may shape prosocial perception and action in everyday life.

Triflic Anhydride (Tf2O)-Activated Transformation of Amides, Sulfoxides and Phosphorus Oxides via Nucleophilic Trapping

Trifluoromethanesulfonic anhydride (Tf2O) has found a wide range of applications in synthetic organic chemistry as a strong electrophilic activator leading to the transient generation of a triflate intermediate. This versatile triflate intermediate undergoes nucleophilic trapping with diverse nucleophiles to yield novel compounds. In this review, we describe the features and applications of triflic anhydride in organic synthesis reported in the past decade, especially in amide, sulfoxide, and phosphorus oxide chemistry through electrophilic activation. A plausible mechanistic pathway of each important reaction is also discussed.

Process Intensification of Methane Production via Catalytic Hydrogenation in the Presence of Ni-CeO2/Cr2O3 Using a Micro-Channel Reactor

A slight amount of Cr2O3 segregation in 40 wt% NiO/Ce0.5Cr0.5O2 was presented at the surface. The best catalytic performance towards the reaction was achieved at 74% of CO2 conversion and 100% CH4 selectivity at 310 °C, the reactant (H2/CO2) feed molar ratio was 4, and the WHSV was 56,500 mlN·h−1·g−1cat. The mechanistic pathway was proposed through carbonates and formates as a mediator during CO2 and H2 interaction. Activation energy was estimated at 4.85 kJ/mol, when the orders of the reaction were ranging from 0.33 to 1.07 for nth-order, and 0.40 to 0.53 for mth-order.

Role of Maternal Microbiota and Nutrition in Early-Life Neurodevelopmental Disorders

The rise in the prevalence of obesity and other related metabolic diseases has been paralleled by an increase in the frequency of neurodevelopmental problems, which has raised the likelihood of a link between these two phenomena. In this scenario, maternal microbiota is a possible linking mechanistic pathway. According to the “Developmental Origins of Health and Disease” paradigm, environmental exposures (in utero and early life) can permanently alter the body’s structure, physiology, and metabolism, increasing illness risk and/or speeding up disease progression in offspring, adults, and even generations. Nutritional exposure during early developmental stages may induce susceptibility to the later development of human diseases via interactions in the microbiome, including alterations in brain function and behavior of offspring, as explained by the gut–brain axis theory. This review provides an overview of the implications of maternal nutrition on neurodevelopmental disorders and the establishment and maturation of gut microbiota in the offspring.