Activated Platelets Autocrine 5-Hydroxytryptophan Aggravates Sepsis-Induced Acute Lung Injury by Promoting Neutrophils Extracellular Traps Formation

Excessive neutrophil extracellular trap (NET) formation is an important contributor to sepsis-induced acute lung injury (ALI). Recent reports indicate that platelets can induce neutrophil extracellular trap formation. However, the specific mechanism remains unclear. Tph1 gene, which encodes the rate-limiting enzyme for peripheral 5-hydroxytryptophan (5-HT) synthesis, was knocked out in mice to simulate peripheral 5-HT deficiency. Cecal ligation and puncture (CLP) surgery was performed to induce sepsis. We found that peripheral 5-HT deficiency reduced NET formation in lung tissues, alleviated sepsis-induced lung inflammatory injury, and reduced the mortality rate of CLP mice. In addition, peripheral 5-HT deficiency was shown to reduce the accumulation of platelets and NETs in the lung of septic mice. We found that platelets from wild-type (WT), but not Tph1 knockout (Tph1−/−), mice promote lipopolysaccharide (LPS)-induced NET formation. Exogenous 5-HT intervention increased LPS-induced NET formation when Tph1−/− platelets were co-cultured with WT neutrophils. Therefore, our study uncovers a mechanism by which peripheral 5-HT aggravated sepsis-induced ALI by promoting NET formation in the lung of septic mice.

Unconventional mechanism and selectivity of the Pd-catalyzed C–H bond lactonization in aromatic carboxylic acid

The search for more effective and highly selective C–H bond oxidation of accessible hydrocarbons and biomolecules is a greatly attractive research mission. The elucidating of mechanism and controlling factors will, undoubtedly, help to broaden scope of these synthetic protocols, and enable discovery of more efficient, environmentally benign, and highly practical new C–H oxidation reactions. Here, we reveal the stepwise intramolecular SN2 nucleophilic substitution mechanism with the rate-limiting C–O bond formation step for the Pd(II)-catalyzed C(sp3)–H lactonization in aromatic 2,6-dimethylbenzoic acid. We show that for this reaction, the direct C–O reductive elimination from both Pd(II) and Pd(IV) (oxidized by O2 oxidant) intermediates is unfavorable. Critical factors controlling the outcome of this reaction are the presence of the η3-(π-benzylic)–Pd and K+–O(carboxylic) interactions. The controlling factors of the benzylic vs ortho site-selectivity of this reaction are the: (a) difference in the strains of the generated lactone rings; (b) difference in the strengths of the η3-(π-benzylic)–Pd and η2-(π-phenyl)–Pd interactions, and (c) more pronounced electrostatic interaction between the nucleophilic oxygen and K+ cation in the ortho-C–H activation transition state. The presented data indicate the utmost importance of base, substrate, and ligand in the selective C(sp3)–H bond lactonization in the presence of C(sp2)–H.

A Four-Step Enzymatic Cascade for Efficient Production of L-Phenylglycine from Biobased L-Phenylalanine

Enantiopure amino acids are of particular interest in the agrochemical and pharmaceutical industries. Here, we reported a multi-enzyme cascade for efficient production of L-phenylglycine (L-Phg) from biobased L-phenylalanine (L-Phe). We first attempted to engineer Escherichia coli for expressing L-amino acid deaminase (LAAD) from Proteus mirabilis, hydroxymandelate synthase (HmaS) from Amycolatopsis orientalis, (S)-mandelate dehydrogenase (SMDH) from Pseudomonas putida, the endogenous aminotransferase (AT) encoded by ilvE and L-glutamate dehydrogenase (GluDH) from E. coli. However, 10 mM L-Phe only afforded the synthesis of 7.21 mM L-Phg. The accumulation of benzoylformic acid suggested that the transamination step might be rate-limiting. We next used leucine dehydrogenase (LeuDH) from Bacillus cereus to bypass the use of L-glutamate as amine donor, and 40 mM L-Phe gave 39.97 mM (6.04 g/L) L-Phg, reaching 99.9% conversion. In summary, this work demonstrated a concise four-step enzymatic cascade for the L-Phg synthesis from biobased L-Phe, with a potential for future industrial applications.

Physiological Perspectives on Molecular Mechanisms and Regulation of Vesicular Glutamate Transport: Lessons From Calyx of Held Synapses

Accumulation of glutamate, the primary excitatory neurotransmitter in the mammalian central nervous system, into presynaptic synaptic vesicles (SVs) depends upon three vesicular glutamate transporters (VGLUTs). Since VGLUTs are driven by a proton electrochemical gradient across the SV membrane generated by vacuolar-type H+-ATPases (V-ATPases), the rate of glutamate transport into SVs, as well as the amount of glutamate in SVs at equilibrium, are influenced by activities of both VGLUTs and V-ATPase. Despite emerging evidence that suggests various factors influencing glutamate transport by VGLUTs in vitro, little has been reported in physiological or pathological contexts to date. Historically, this was partially due to a lack of appropriate methods to monitor glutamate loading into SVs in living synapses. Furthermore, whether or not glutamate refilling of SVs can be rate-limiting for synaptic transmission is not well understood, primarily due to a lack of knowledge concerning the time required for vesicle reuse and refilling during repetitive stimulation. In this review, we first introduce a unique electrophysiological method to monitor glutamate refilling by VGLUTs in a giant model synapse from the calyx of Held in rodent brainstem slices, and we discuss the advantages and limitations of the method. We then introduce the current understanding of factors that potentially alter the amount and rate of glutamate refilling of SVs in this synapse, and discuss open questions from physiological viewpoints.

Enhanced Catalytic Activity of Boron Nitride Nanotubes by Encapsulation of Nickel Wire Toward O2 Activation and CO Oxidation: A Theoretical Study

Perfect boron nitride (BN) nanotubes are chemically inert, and hardly considered as catalysts. Nevertheless, metal wire encapsulated BN nanotubes show extraordinarily high chemical activity. We report nickel (Ni) nanowire encapsulated BN(8.0) and BN(9.0) nanotubes toward O2 activation and CO oxidization on the basis of first-principles calculations. Our results suggest that Ni wire encapsulated BN(8.0) and BN(9.0) nanotubes can easily adsorb and activate O2 molecules to form peroxo or superoxo species exothermically. Meanwhile, superoxo species are ready to react with CO molecules forming OCOO intermediate state and finally yielding CO2 molecules. Meanwhile, the rate-limiting step barrier is only 0.637 eV, implying excellent performance for CO oxidation on Ni nanowire encapsulated BN nanotubes. Furthermore, encapsulation of nickel wire improves the catalytic activity of BN nanotubes by facilitating electron transfer from Ni wire to BN nanotubes, which facilitates the adsorption of highly electronegative O2 molecules and subsequent CO oxidation. This study provides a practical and efficient strategy for activating O2 on a metal encapsulated BN nanotube toward CO oxidation.

A review of late-stage tungsten fuzz growth

Tungsten will be used as the plasma-facing divertor material in the International Thermonuclear Experimental Reactor (ITER) fusion reactor. Under high temperatures and high ion fluxes, a ‘fuzz’ nanostructure forms on the tungsten surface with dramatically different properties and could contaminate the plasma. Although simulations and experimental observations have provided understanding of the initial fuzz formation process, there is debate over whether tungsten or helium migration is rate-limiting during late-stage growth, and the mechanisms by which tungsten and helium migrations occur. Here, the proposed mechanisms are considered in turn. It is concluded that tungsten migration occurs by adatom diffusion along the fuzz surface. Continual helium migration through the porous fuzz to the tungsten bulk is also required for fuzz growth, for continued bubble growth and rupture. Helium likely migrates due to ballistic penetration, although diffusion may contribute. It is difficult to determine the limiting process, which may switch from helium penetration to tungsten adatom diffusion above a threshold flux. Areas for further research to clarify the mechanisms are then considered. A greater understanding of the fuzz formation mechanism is key to the successful design of plasma-facing tungsten components, and may have applications in forming porous tungsten catalysts.

Perspective—Electrochemistry in Understanding and Designing Electrochemical Energy Storage Systems

The number of publications in electrochemical energy storage has increased exponentially in the past decades, focusing mostly on materials science. The electrochemical process controlling the observed overall performances is often not well discussed. This article highlights the importance of understanding rate-limiting steps in the electrochemical process which change dynamically at different conditions and scales. Applying electrochemistry to identify and overcome those rate-limiting steps in the electrochemical devices is the pre-requisite to discover effective solutions and design different batteries to further advance electrochemical energy storage systems for a broad range of various applications.

Recognized and Emerging Features of Erythropoietic and X-Linked Protoporphyria

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are inherited disorders resulting from defects in two different enzymes of the heme biosynthetic pathway, i.e., ferrochelatase (FECH) and delta-aminolevulinic acid synthase-2 (ALAS2), respectively. The ubiquitous FECH catalyzes the insertion of iron into the protoporphyrin ring to generate the final product, heme. After hemoglobinization, FECH can utilize other metals like zinc to bind the remainder of the protoporphyrin molecules, leading to the formation of zinc protoporphyrin. Therefore, FECH deficiency in EPP limits the formation of both heme and zinc protoporphyrin molecules. The erythroid-specific ALAS2 catalyses the synthesis of delta-aminolevulinic acid (ALA), from the union of glycine and succinyl-coenzyme A, in the first step of the pathway in the erythron. In XLP, ALAS2 activity increases, resulting in the amplified formation of ALA, and iron becomes the rate-limiting factor for heme synthesis in the erythroid tissue. Both EPP and XLP lead to the systemic accumulation of protoporphyrin IX (PPIX) in blood, erythrocytes, and tissues causing the major symptom of cutaneous photosensitivity and several other less recognized signs that need to be considered. Although significant advances have been made in our understanding of EPP and XLP in recent years, a complete understanding of the factors governing the variability in clinical expression and the severity (progression) of the disease remains elusive. The present review provides an overview of both well-established facts and the latest findings regarding these rare diseases.

Cancer types with high numbers of driver events are largely preventable

There is a long-standing debate on whether cancer is predominantly driven by extrinsic risk factors such as smoking, or by intrinsic processes such as errors in DNA replication. We have previously shown that the number of rate-limiting driver events per tumor can be estimated from the age distribution of cancer incidence using the gamma/Erlang probability distribution. Here, we show that this number strongly correlates with the proportion of cancer cases attributable to modifiable risk factors for all cancer types except the ones inducible by infection or ultraviolet radiation. The correlation was confirmed for three countries, three corresponding incidence databases and risk estimation studies, as well as for both sexes: USA, males (r = 0.80, P = 0.002), females (r = 0.81, P = 0.0003); England, males (r = 0.90, P < 0.0001), females (r = 0.67, P = 0.002); Australia, males (r = 0.90, P = 0.0004), females (r = 0.68, P = 0.01). Hence, this study suggests that the more driver events a cancer type requires, the more of its cases are due to preventable anthropogenic risk factors.