Blocking IL1RAP on cancer-associated fibroblasts in pancreatic ductal adenocarcinoma suppresses IL-1-induced neutrophil recruitment.

Background: Pancreatic ductal adenocarcinoma (PDAC) represents a major clinical challenge due to its tumor microenvironment, which exhibits immune-suppressive properties that facilitate cancer progression, metastasis, and therapy resistance. Interleukin 1 (IL-1) signaling has been implicated as a driver in this process. Mechanistically, both IL-1α and IL-1β bind to the IL-1 receptor type 1, forming a complex with IL-1-receptor accessory protein (IL1RAP), which triggers downstream signaling pathways.

Experimental observation of molecular-weight growth by the reactions of -benzyne with benzyl radicals.

The chemistry of -benzyne (-CH) is of fundamental importance due to its role as an essential molecular building block in molecular-weight growth reactions. Here, we report on an experimental investigation of the reaction of -CH with benzyl (CH) radicals in a well-controlled flash pyrolysis experiment using a resistively heated SiC microtubular reactor at temperatures of 800-1600 K and pressures near 30  torr. To this end, the reactants -CH and CH were pyrolytically generated from 1,2-diiodobenzene and benzyl bromide, respectively.

Tracking the reaction networks of acetaldehyde oxide and glyoxal oxide Criegee intermediates in the ozone-assisted oxidation reaction of crotonaldehyde.

The reaction of unsaturated compounds with ozone (O) is recognized to lead to the formation of Criegee intermediates (CIs), which play a key role in controlling the atmospheric budget of hydroxyl radicals and secondary organic aerosols. The reaction network of two CIs with different functionality, acetaldehyde oxide (CHCHOO) and glyoxal oxide (CHOCHOO) formed in the ozone-assisted oxidation reaction of crotanaldehyde (CA), is investigated over a temperature range between 390 K and 840 K in an atmospheric pressure jet-stirred reactor (JSR) at a residence time of 1.3 s, stoichiometry of 0.

Antibodies targeting the shared cytokine receptor IL-1 receptor accessory protein invoke distinct mechanisms to block all cytokine signaling.

Interleukin-1 (IL-1)-family cytokines are potent modulators of inflammation, coordinating a vast array of immunological responses across innate and adaptive immune systems. Dysregulated IL-1-family cytokine signaling, however, is involved in a multitude of adverse health effects, such as chronic inflammatory conditions, autoimmune diseases, and cancer. Within the IL-1 family of cytokines, six-IL-1α, IL-1β, IL-33, IL-36α, IL-36β, and IL-36γ-require the IL-1 receptor accessory protein (IL-1RAcP) as their shared co-receptor.

The photoionization of methoxymethanol: Fingerprinting a reactive C2 oxygenate in a complex reactive mixture.

Methoxymethanol (CH3OCH2OH) is a reactive C2 ether-alcohol that is formed by coupling events in both heterogeneous and homogeneous systems. It is found in complex reactive environments-for example those associated with catalytic reactors, combustion systems, and liquid-phase mixtures of oxygenates. Using tunable synchrotron-generated vacuum-ultraviolet photons between 10.

Time-resolved quantification of key species and mechanistic insights in low-temperature tetrahydrofuran oxidation.

We investigate the kinetics and report the time-resolved concentrations of key chemical species in the oxidation of tetrahydrofuran (THF) at 7500 torr and 450-675 K. Experiments are carried out using high-pressure multiplexed photoionization mass spectrometry (MPIMS) combined with tunable vacuum ultraviolet radiation from the Berkely Lab Advanced Light Source. Intermediates and products are quantified using reference photoionization (PI) cross sections, when available, and constrained by a global carbon balance tracking approach at all experimental temperatures simultaneously for the species without reference cross sections.

The glutaminase inhibitor CB-839 targets metabolic dependencies of JAK2-mutant hematopoiesis in MPN.

Hyperproliferation of myeloid and erythroid cells in myeloproliferative neoplasms (MPN) driven by the JAK2-V617F mutation is associated with altered metabolism. Given the central role of glutamine in anabolic and catabolic pathways, we examined the effects of pharmacologically inhibiting glutaminolysis, that is, the conversion of glutamine (Gln) to glutamate (Glu), using CB-839, a small molecular inhibitor of the enzyme glutaminase (GLS). We show that CB-839 strongly reduced the mitochondrial respiration rate of bone marrow cells from JAK2-V617F mutant (VF) mice, demonstrating a marked dependence of these cells on Gln-derived ATP production.

Gas-phase preparation of azulene (CH) and naphthalene (CH) the reaction of the resonantly stabilized fulvenallenyl and propargyl radicals.

Synthetic routes to the 10π Hückel aromatic azulene (CH) molecule, the simplest polycyclic aromatic hydrocarbon carrying an adjacent five- and seven-membered ring, have been of fundamental importance due to the role of azulene - a structural isomer of naphthalene - as an essential molecular building block of saddle-shaped carbonaceous nanostructures such as curved nanographenes and nanoribbons. Here, we report on the very first gas phase preparation of azulene by probing the gas-phase reaction between two resonantly stabilized radicals, fulvenallenyl and propargyl , in a molecular beam through isomer-resolved vacuum ultraviolet photoionization mass spectrometry. Augmented by electronic structure calculations, the novel Fulvenallenyl Addition Cyclization Aromatization (FACA) reaction mechanism affords a versatile concept for introducing the azulene moiety into polycyclic aromatic systems thus facilitating an understanding of barrierless molecular mass growth processes of saddle-shaped aromatics and eventually carbonaceous nanoparticles (soot, interstellar grains) in our universe.

Elucidating the photodissociation fingerprint and quantifying the determination of organic hydroperoxides in gas-phase autoxidation.

Hydroperoxides are formed in the atmospheric oxidation of volatile organic compounds, in the combustion autoxidation of fuel, in the cold environment of the interstellar medium, and also in some catalytic reactions. They play crucial roles in the formation and aging of secondary organic aerosols and in fuel autoignition. However, the concentration of organic hydroperoxides is seldom measured, and typical estimates have large uncertainties.

Plasma-Assisted Chemical-Looping Combustion: Low-Temperature Methane and Ethylene Oxidation with Nickel Oxide.

The chemical reaction network of low-temperature plasma-assisted oxidation of methane (CH) and ethylene (CH) with nickel oxide (NiO) was investigated in a heated plasma reactor through time-dependent species measurements by electron-ionization molecular beam mass spectrometry (EI-MBMS). Methane (ethylene) oxidation by NiO was explored in temperature ranges from 300-700 °C (300-500 °C) and 300-800 °C (300-600 °C) for the plasma and nonplasma conditions. Significant enhancement of methane oxidation was observed with plasma between 400 and 500 °C, where no oxidation was observed under nonplasma conditions.

A Comparative Study on the Combustion Chemistry of Two Bio-hybrid Fuels: 1,3-Dioxane and 1,3-Dioxolane.

Bio-hybrid fuels are a promising solution to accomplish a carbon-neutral and low-emission future for the transportation sector. Two potential candidates are the heterocyclic acetals 1,3-dioxane (CHO) and 1,3-dioxolane (CHO), which can be produced from the combination of biobased feedstocks, carbon dioxide, and renewable electricity. In this work, comprehensive experimental and numerical investigations of 1,3-dioxane and 1,3-dioxolane were performed to support their application in internal combustion engines.

Formation of Organic Acids and Carbonyl Compounds in n-Butane Oxidation via γ-Ketohydroperoxide Decomposition.

A crucial chain-branching step in autoignition is the decomposition of ketohydroperoxides (KHP) to form an oxy radical and OH. Other pathways compete with chain-branching, such as "Korcek" dissociation of γ-KHP to a carbonyl and an acid. Here we characterize the formation of a γ-KHP and its decomposition to formic acid+acetone products from observations of n-butane oxidation in two complementary experiments.

Near-Surface Gas-Phase Methoxymethanol Is Generated by Methanol Oxidation over Pd-Based Catalysts.

Catalytic conversion of alcohols underlies many commodity and fine chemical syntheses, but a complete mechanistic understanding is lacking. We examined catalytic oxidative conversion of methanol near atmospheric pressure using operando small-aperture molecular beam time-of-flight mass spectrometry, interrogating the gas phase 500 μm above Pd-based catalyst surfaces. In addition to a variety of stable C species, we detected methoxymethanol (CHOCHOH)─a rarely observed and reactive C oxygenate that has been proposed to be a critical intermediate in methyl formate production.

Identification of the acetaldehyde oxide Criegee intermediate reaction network in the ozone-assisted low-temperature oxidation of -2-butene.

Uni- and bi-molecular reactions involving Criegee intermediates (CIs) have been the focus of many studies due to the role these molecules play in atmospheric chemistry. The reactivity of CIs is known to strongly depend on their structure. The reaction network of the second simplest CI, acetaldehyde oxide (CHCHOO), is investigated in this work in an atmospheric pressure jet-stirred reactor (JSR) during the ozonolysis of -2-butene to explore the kinetic pathways relevant to atmospheric chemistry and low-temperature combustion.

Experimental Observation of Hydrocarbon Growth by Resonance-Stabilized Radical-Radical Chain Reaction.

Rapid molecular-weight growth of hydrocarbons occurs in flames, in industrial synthesis, and potentially in cold astrochemical environments. A variety of high- and low-temperature chemical mechanisms have been proposed and confirmed, but more facile pathways may be needed to explain observations. We provide laboratory confirmation in a controlled pyrolysis environment of a recently proposed mechanism, radical-radical chain reactions of resonance-stabilized species.

An Aromatic Universe-A Physical Chemistry Perspective.

This Perspective presents recent advances in our knowledge of the fundamental elementary mechanisms involved in the low- and high-temperature molecular mass growth processes to polycyclic aromatic hydrocarbons in combustion systems and in extraterrestrial environments (hydrocarbon-rich atmospheres of planets and their moons, cold molecular clouds, circumstellar envelopes). Molecular beam studies combined with electronic structure calculations extracted five key elementary mechanisms: Hydrogen Abstraction-Acetylene Addition, Hydrogen Abstraction-Vinylacetylene Addition, Phenyl Addition-DehydroCyclization, Radical-Radical Reactions, and Methylidyne Addition-Cyclization-Aromatization. These studies, summarized here, provide compelling evidence that key classes of aromatic molecules can be synthesized in extreme environments covering low temperatures in molecular clouds (10 K) and hydrocarbon-rich atmospheres of planets and their moons (35-150 K) to high-temperature environments like circumstellar envelopes of carbon-rich Asymptotic Giant Branch Stars stars and combustion systems at temperatures above 1400 K thus shedding light on the aromatic universe we live in.

Screening of DNA-Encoded Small Molecule Libraries inside a Living Cell.

DNA-encoded small molecule libraries (DELs) have facilitated the discovery of novel modulators of many different therapeutic protein targets. We report the first successful screening of a multimillion membered DEL inside a living cell. We demonstrate a novel method using oocytes from the South African clawed frog .

Elucidating the differences in oxidation of high-performance α- and β- diisobutylene biofuels via Synchrotron photoionization mass spectrometry.

Biofuels are a promising ecologically viable and renewable alternative to petroleum fuels, with the potential to reduce net greenhouse gas emissions. However, biomass sourced fuels are often produced as blends of hydrocarbons and their oxygenates. Such blending complicates the implementation of these fuels in combustion applications.

Extreme Low-Temperature Combustion Chemistry: Ozone-Initiated Oxidation of Methyl Hexanoate.

The accelerating chemical effect of ozone addition on the oxidation chemistry of methyl hexanoate [CH(CH)C(═O)OCH] was investigated over a temperature range from 460 to 940 K. Using an externally heated jet-stirred reactor at = 700 Torr (residence time τ = 1.3 s, stoichiometry φ = 0.

PEARL-seq: A Photoaffinity Platform for the Analysis of Small Molecule-RNA Interactions.

RNA is emerging as a valuable target for the development of novel therapeutic agents. The rational design of RNA-targeting small molecules, however, has been hampered by the relative lack of methods for the analysis of small molecule-RNA interactions. Here, we present our efforts to develop such a platform using photoaffinity labeling.

An overview of DNA-encoded libraries: A versatile tool for drug discovery.

DNA-encoded libraries (DELs) are collections of small molecules covalently attached to amplifiable DNA tags carrying unique information about the structure of each library member. A combinatorial approach is used to construct the libraries with iterative DNA encoding steps, facilitating tracking of the synthetic history of the attached compounds by DNA sequencing. Various screening protocols have been developed which allow protein target binders to be selected out of pools containing up to billions of different small molecules.