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BACKGROUND: Treatment with regorafenib, a multiple-kinase inhibitor, to manage metastatic colorectal cancers (mCRCs) shows a modest improvement in overall survival but is associated with severe toxicities. Thus, to reduce regorafenib-induced toxicity, we used regorafenib at low concentration along with a dual JAK/HDAC small-molecule inhibitor (JAK/HDACi) to leverage the advantages of both JAK and HDAC inhibition to enhance antitumor activity. The therapeutic efficacy and safety of the combination treatment was evaluated with CRC models. METHODS: The cytotoxicity of JAK/HDACi, regorafenib, and their combination were tested with normal colonic and CRC cells exhibiting various genetic backgrounds. Kinomic, ATAC-seq, RNA-seq, cell cycle, and apoptosis analyses were performed to evaluate the cellular functions/molecular alterations affected by the combination. Efficacy of the combination was assessed using patient-derived xenograft (PDX) and experimental metastasis models of CRC. To evaluate the interplay between tumor, its microenvironment, and modulation of immune response, MC38 syngeneic mice were utilized. RESULTS: The combination therapy decreased cell viability; phosphorylation of JAKs, STAT3, EGFR, and other key kinases; and inhibited deacetylation of histone H3K9, H4K8, and alpha tubulin proteins. It induced cell cycle arrest at G0-G1 phase and apoptosis of CRC cells. Whole transcriptomic analysis showed that combination treatment modulated molecules involved in apoptosis, extracellular matrix-receptor interaction, and focal adhesion pathways. It synergistically reduces PDX tumor growth and experimental metastasis, and, in a syngeneic mouse model, the treatment enhances the antitumor immune response as evidenced by higher infiltration of CD45 and cytotoxic cells. Pharmacokinetic studies showed that combination increased the bioavailability of regorafenib. CONCLUSIONS: The combination treatment was more effective than with regorafenib or JAK/HDACi alone, and had minimal toxicity. A clinical trial to evaluate this combination for treatment of mCRCs is warranted.
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Neoplasias Colorrectales , Inhibidores de Histona Desacetilasas , Compuestos de Fenilurea , Piridinas , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Humanos , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/administración & dosificación , Animales , Ratones , Piridinas/farmacología , Piridinas/administración & dosificación , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Inhibidores de Histona Desacetilasas/administración & dosificación , Metástasis de la Neoplasia , Proliferación Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Sinergismo Farmacológico , Línea Celular Tumoral , Femenino , Apoptosis/efectos de los fármacos , Inhibidores de las Cinasas Janus/farmacología , Inhibidores de las Cinasas Janus/administración & dosificación , Inhibidores de las Cinasas Janus/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Endometriosis, an incurable gynecological disease that causes abnormal growth of uterine-like tissue outside the uterine cavity, leads to pelvic pain and infertility in millions of individuals. Endometriosis can be treated with medicine and surgery, but recurrence and comorbidities impair quality of life. In recent years, nanoparticle (NP)-based therapy has drawn global attention, notably in medicine. Studies have shown that NPs could revolutionize conventional therapeutics and imaging. Researchers aim to enhance the prognosis of endometriosis patients with less invasive and more effective NP-based treatments. This study evaluates this potential paradigm shift in endometriosis management, exploring NP-based systems for improved treatments and diagnostics. Insights into nanotechnology applications, including gene therapy, photothermal therapy, immunotherapy, and magnetic hyperthermia, offering a theoretical reference for the clinical use of nanotechnology in endometriosis treatment, are discussed in this review.
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The main aim of this article is to highlight the clinical features indicating gastric perforation in neonates so that prompt surgery can provide a good outcome for an otherwise fatal condition. Data was collected retrospectively from all neonates who presented to our tertiary care institute with subsequent diagnosis of gastric perforation from January 2020 to December 2023 (three years). Simple statistical analysis involving sums, means, averages, and percentages was used. Five neonates were operated over a period of three years with a diagnosis of gastric perforation. Two of them were spontaneous. Of the remaining three, each one was associated with malrotation, prematurity, and COVID-19. All five cases could be diagnosed with the finding of free gas in the peritoneum on the abdominal radiograph. Overall mortality was 60% (three of five neonates). Neonatal gastric perforation typically occurs in the first week of life, specifically within the second to seventh day. Symptom onset is usually sudden, with abdominal distension as the first sign, with acidic contents causing severe peritonitis and rapid progression to sepsis and shock. Early diagnosis with subsequent timely resuscitation and surgical repair is crucial to good outcomes. Massive pneumoperitoneum on abdominal radiographs with typical signs in a neonate should raise suspicion of gastric perforation, especially in the first week of life.
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Orthocarboxylic acidsâorganic molecules carrying three hydroxyl groups at the same carbon atomâhave been distinguished as vital reactive intermediates by the atmospheric science and physical (organic) chemistry communities as transients in the atmospheric aerosol cycle. Predicted short lifetimes and their tendency to dehydrate to a carboxylic acid, free orthocarboxylic acids, signify one of the most elusive classes of organic reactive intermediates, with even the simplest representative methanetriol (CH(OH)3)âhistorically known as orthoformic acidânot previously been detected experimentally. Here, we report the first synthesis of the previously elusive methanetriol molecule in low-temperature mixed methanol (CH3OH) and molecular oxygen (O2) ices subjected to energetic irradiation. Supported by electronic structure calculations, methanetriol was identified in the gas phase upon sublimation via isomer-selective photoionization reflectron time-of-flight mass spectrometry combined with isotopic substitution studies and the detection of photoionization fragments. The first synthesis and detection of methanetriol (CH(OH)3) reveals its gas-phase stability as supported by a significant barrier hindering unimolecular decomposition. These findings progress our fundamental understanding of the chemistry and chemical bonding of methanetriol, hydroxyperoxymethane (CH3OOOH), and hydroxyperoxymethanol (CH2(OH)OOH), which are all prototype molecules in the oxidation chemistry of the atmosphere.
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A large body of evidence has shown a direct link between arsenic exposure and drug resistance to Leishmania parasites against antimonial preparations in visceral leishmaniasis (VL) hyper-endemic regions, especially in India and its sub-continent. However, the implicated roles of arsenic on the VL host, pathophysiological changes, and immune function have not yet been clarified, particularly at the reported concentration of arsenic in the VL hyper-endemic area of Bihar, India. Herein, we exposed the mouse VL model to arsenic (0.5 mg/L to 2 mg/L) through their drinking water and analyzed its effect on T cells proliferation, Th1/Th2-mediators, MAPK signaling cascade, and parasite load in preclinical models. Coherently, the parasite count in Giemsa stained spleen imprint has been investigated and found significant positive associations with levels of arsenic exposure. The liver and kidney function tests (AST, ALT, ALP, BUN, Creatinine, Urea, etc.) are apparent to hepatonephric toxicity in arsenic exposed VL mice compared to unexposed. This observation appears to be consistent with the up-regulated expression of immune regulatory Th2 mediators (IL-4, IL-10, TGF-ß) and down-regulated expression of Th1 mediators (IL-12, IFN-γ, TNF-α) with a suppressed leishmanicidal function of macrophage (ROS, NO, iNOS). We also established that arsenic exposure modulated the host ERK-1/2 and p38 MAPK signaling cascade, limited T lymphocyte proliferation, and a lower IgG2a/IgG1 ratio to favor the Leishmania parasite survival inside the host. This study suggests that the contorted Th1-subtype and exacerbated Th2-subtype immune responses are involved in the increased susceptibility and pathogenesis of Leishmania parasite among subjects/individuals regularly exposed to arsenic.
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Arsénico , Agua Potable , Leishmania donovani , Leishmaniasis Visceral , Humanos , Animales , Ratones , Leishmaniasis Visceral/parasitología , Arsénico/toxicidad , Progresión de la EnfermedadRESUMEN
The relationship between diabetes mellitus (DM) and high serum uric acid is complex and controversial. Many epidemiological studies have reported a positive association, whereas others have reported an inverse association or none. In the pathogenesis of DM it is the intracellular urate that is more important than the extracellular and dissociation between the two is possible. Evidence suggests that high serum uric acid induces insulin resistance and beta cell failure in animal models. Reduction of intracellular uric acid can be achieved by dietary measures such as reducing fructose and salt intake, and uric acid-lowering drugs. We suggest that in the Western diet, these elements play a crucial role in pathogenesis of DM. To determine the precise and exact interrelationship between intracellular and extracellular uric acid, well-designed studies are required. Besides this, clinical trials are needed to determine whether intracellular and extracellular urate reduction will provide benefit in prevention and treatment of DM and complications associated with it.
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Diabetes Mellitus , Resistencia a la Insulina , Animales , Humanos , Ácido Úrico , Diabetes Mellitus/tratamiento farmacológicoRESUMEN
INTRODUCTION: The prevalence of hyperuricemia (HU) and hypouricemia (Hypo-U) is highly variable in different parts of India and there is a lack of data from the Eastern part of Uttar Pradesh. We designed this study in order to know the exact prevalence of HU and Hypo-U. MATERIALS AND METHODS: This is a cross-sectional study conducted in Varanasi. Data were collected from newly onset diabetic patients over a period of 1 year. RESULTS: Among the 312 diabetic patients, 12.5 and 19.23% were found to have HU and Hypo-U, respectively. Hypouricemic diabetic patients are phenotypically different. They are characterized by the female sex, higher glycated hemoglobin A1c (GlyHbA1c), higher estimated glomerular filtration rate (eGFR), lower body mass index (BMI), and less insulin resistance. CONCLUSION: The prevalence of HU and Hypo-U is high in newly-onset diabetic patients. Hypouricemic diabetic patients are phenotypically different. Hence routine screening of uric acid is essential for proper diagnosis and appropriate treatment of hypouricemic diabetic patients.
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Diabetes Mellitus Tipo 2 , Hiperuricemia , Humanos , Femenino , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Ácido Úrico , Estudios Transversales , Hiperuricemia/epidemiología , Prevalencia , Factores de RiesgoRESUMEN
Nickel (Ni)-catalyzed growth of a single- or rotated-graphene layer is a well-established process above 800 K. In this report, a Au-catalyzed, low-temperature, and facile route at 500 K for graphene formation is described. The substantially lower temperature is enabled by the presence of a surface alloy of Au atoms embedded within Ni(111), which catalyzes the outward segregation of carbon atoms buried in the Ni bulk at temperatures as low as 400-450 K. The resulting surface-bound carbon in turn coalesces into graphene above 450-500 K. Control experiments on a Ni(111) surface show no evidence of carbon segregation or graphene formation at these temperatures. Graphene is identified by its out-of-plane optical phonon mode at 750 cm-1 and its longitudinal/transverse optical phonon modes at 1470 cm-1 while surface carbon is identified by its C-Ni stretch mode at 540 cm-1, as probed by high-resolution electron energy-loss spectroscopy. Dispersion measurements of the phonon modes confirm the presence of graphene. Graphene formation is observed to be maximum at 0.4 ML Au coverage. The results of these systematic molecular-level investigations open the door to graphene synthesis at the low temperatures required for integration with complementary metal-oxide-semiconductor processes.
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Although pyridinic-nitrogen (pyri-N) doped graphene is highly active for the oxygen reduction reaction (ORR) of fuel cells in alkaline media, the activity critically decreases under acidic conditions. We report on how to prevent the deactivation based on the mechanistic understanding that O 2 + p y r i - N H + + e - â O 2 , a + p y r i - N H ${{{\rm O}}_{2}+{\rm p}{\rm y}{\rm r}{\rm i}{\rm { -}}{\rm N}{{\rm H}}^{+}+{{\rm e}}^{-}{\to }_{\ }^{{\rm \ }}{{\rm O}}_{2,{\rm a}}+{\rm p}{\rm y}{\rm r}{\rm i}{\rm { -}}{\rm N}{\rm H}}$ governs the ORR kinetics. First, we considered that the deactivation is due to the hydration of pyri-NH+ , leading to a lower shift of the redox potential. Introducing the hydrophobic cavity prevented the hydration of pyri-NH+ but inhibited the proton transport. We then increased proton conductivity in the hydrophobic cavity by introducing SiO2 particles coated with ionic liquid polymer/Nafion® which kept the high onset potentials with an increased current density even in acidic media.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a human coronavirus (HCoV) that has created a pandemic situation worldwide as COVID-19. This virus can invade human cells via angiotensin-converting enzyme 2 (ACE2) receptor-based mechanisms, affecting the human respiratory tract. However, several reports of neurological symptoms suggest a neuroinvasive development of coronavirus. SARS-CoV-2 can damage the brain via several routes, along with direct neural cell infection with the coronavirus. The chronic inflammatory reactions surge the brain with proinflammatory elements, damaging the neural cells, causing brain ischemia associated with other health issues. SARS-CoV-2 exhibited neuropsychiatric and neurological manifestations, including cognitive impairment, depression, dizziness, delirium, and disturbed sleep. These symptoms show nervous tissue damage that enhances the occurrence of neurodegenerative disorders and aids dementia. SARS-CoV-2 has been seen in brain necropsy and isolated from the cerebrospinal fluid of COVID-19 patients. The associated inflammatory reaction in some COVID-19 patients has increased proinflammatory cytokines, which have been investigated as a prognostic factor. Therefore, the immunogenic changes observed in Parkinson's and Alzheimer's patients include their pathogenetic role. Inflammatory events have been an important pathophysiological feature of neurodegenerative diseases (NDs) such as Parkinson's and Alzheimer's. The neuroinflammation observed in AD has exacerbated the Aß burden and tau hyperphosphorylation. The resident microglia and other immune cells are responsible for the enhanced burden of Aß and subsequently mediate tau phosphorylation and ultimately disease progression. Similarly, neuroinflammation also plays a key role in the progression of PD. Several studies have demonstrated an interplay between neuroinflammation and pathogenic mechanisms of PD. The dynamic proinflammation stage guides the accumulation of α-synuclein and neurodegenerative progression. Besides, few viruses may have a role as stimulators and generate a cross-autoimmune response for α-synuclein. Hence, neurological complications in patients suffering from COVID-19 cannot be ruled out. In this review article, our primary focus is on discussing the neuroinvasive effect of the SARS-CoV-2 virus, its impact on the blood-brain barrier, and ultimately its impact on the people affected with neurodegenerative disorders such as Parkinson's and Alzheimer's.
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Enfermedad de Alzheimer , COVID-19 , Enfermedad de Parkinson , Enfermedad de Alzheimer/complicaciones , COVID-19/complicaciones , Humanos , Enfermedad de Parkinson/complicaciones , Peptidil-Dipeptidasa A , SARS-CoV-2 , alfa-SinucleínaRESUMEN
Electro-catalytic activity of Pt in the oxygen reduction reaction (ORR) depends strongly on its morphology. For an understanding of how morphology affects the catalytic properties of Pt, the investigation of Pt materials having well-defined morphologies is required. However, the challenges remain in rational and facile synthesis of Pt particles with tuneable well-defined morphology. A promising approach for the controlled synthesis of Pt particles is 'self-assembly of building blocks'. Here, we report a unique synthesis method to control Pt morphology by using a self-assembly route, where nanoflower, nanowire, nanosheet and nanotube morphologies of Pt particles have been produced in a controlled manner. In the growth mechanism, Pt nanoparticles (5-11 nm) are rapidly prepared by using NaBH4 as a reductant, followed by their agglomeration promoted by adding 1,2-ethylenediamine. The morphology of the resulting Pt particles can be easily controlled by tuning hydrophobic/hydrophilic interactions by the addition of isopropanol and H2O. Of the Pt particles prepared using this method, Pt nanotubes show the highest ORR catalytic activity in an acid electrolyte with an onset potential of 1.02 V vs. RHE.
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The Strecker Synthesis of (a)chiral α-amino acids from simple organic compounds, such as ammonia (NH3), aldehydes (RCHO), and hydrogen cyanide (HCN) has been recognized as a viable route to amino acids on primordial earth. However, preparation and isolation of the simplest hemiaminal intermediate - the aminomethanol (NH2CH2OH)- formed in the Strecker Synthesis to even the simplest amino acid glycine (H2NCH2COOH) has been elusive. Here, we report the identification of aminomethanol prepared in low-temperature methylamine (CH3NH2) - oxygen (O2) ices upon exposure to energetic electrons. Isomer-selective photoionization time-of-flight mass spectrometry (PI-ReTOF-MS) facilitated the gas phase detection of aminomethanol during the temperature program desorption (TPD) phase of the reaction products. The preparation and observation of the key transient aminomethanol changes our perception of the synthetic pathways to amino acids and the unexpected kinetic stability in extreme environments.
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Geminal diols-organic molecules carrying two hydroxyl groups at the same carbon atom-have been recognized as key reactive intermediates by the physical (organic) chemistry and atmospheric science communities as fundamental transients in the aerosol cycle and in the atmospheric ozonolysis reaction sequence. Anticipating short lifetimes and their tendency to fragment to water plus the aldehyde or ketone, free geminal diols represent one of the most elusive classes of organic reactive intermediates. Here, we afford an exceptional glance into the preparation of the previously elusive methanediol [CH2(OH)2] transient-the simplest geminal diol-via energetic processing of low-temperature methanol-oxygen ices. Methanediol was identified in the gas phase upon sublimation via isomer-selective photoionization reflectron time-of-flight mass spectrometry combined with isotopic substitution studies. Electronic structure calculations reveal that methanediol is formed via excited state dynamics through insertion of electronically excited atomic oxygen into a carbon-hydrogen bond of the methyl group of methanol followed by stabilization in the icy matrix. The first preparation and detection of methanediol demonstrates its gas-phase stability as supported by a significant barrier hindering unimolecular decomposition to formaldehyde and water. These findings advance our perception of the fundamental chemistry and chemical bonding of geminal diols and signify their role as an efficient sink of aldehydes and ketones in atmospheric environments eventually coupling the atmospheric chemistry of geminal diols and Criegee intermediates.
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Enols have emerged as critical reactive intermediates in combustion processes and in fundamental molecular mass growth processes in the interstellar medium, but the elementary reaction pathways to enols in extreme environments, such as during the decomposition of molecular energetic materials, are still elusive. Here, we report on the original identification of the enol and keto isomers of oxy-s-triazine, as well as its deoxygenated derivative 1,3,5-triazine, formed in the photodecomposition processes of 1,3,5-trinitro-1,3,5-triazinane (RDX)-a molecular energetic material. The identification was facilitated by exploiting isomer-selective tunable photoionization reflectron time-of-flight mass spectrometry (PI-ReTOF-MS) in conjunction with quantum chemical calculations. The present study reports the first experimental evidence of an enol intermediate in the dissociation domain of a nitramine-based energetic material. Our investigations suggest that the enols like 1,3,5-triazine-2-ol could be the source of hydroxyl radicals, and their inclusion in the theoretical models is important to understand the unprecedented chemistry of explosive materials.
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The surface mineralogy of dwarf planet Ceres is rich in ammonium (NH4+) bearing phyllosilicates. However, the origin and formation mechanisms of ammoniated phyllosilicates on Ceres's surface are still elusive. Here we report on laboratory simulation experiments under astrophysical conditions mimicking Ceres' physical and chemical environments with the goal to better understand the source of ammoniated minerals on Ceres' surface. We observe that thermally driven proton exchange reactions between phyllosilicates and ammonia (NH3) could trigger at low temperature leading to the genesis of ammoniated-minerals. Our study revealed the thermal (300 K) and radiation stability of ammoniated-phyllosilicates over a timescale of at least some 500 million years. The present experimental investigations corroborate the possibility that Ceres formed at a location where ammonia ices on the surface would have been stable. However, the possibility of Ceres' origin near to its current location by accreting ammonia-rich material cannot be excluded.
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We present the first formation of the previously elusive phosphine imide (HN[double bond, length as m-dash]PH3) along with its phosphinous amide (H2N-PH2) isomer via exposure of phosphine (PH3) and ammonia (NH3) ices to ionizing radiation. Our approach may be extended to prepare, separate, and detect highly reactive compounds such as intermediates of Wittig reactions.
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The introduction of pyridinic nitrogen (pyri-N) into carbon-based electrocatalysts for the oxygen reduction reaction is considered to create new active sites. Herein, the role of pyri-N in such catalysts was investigated from a mechanistic viewpoint using carbon black (CB)-supported pyri-N-containing molecules as model catalysts; the highest activity was observed for 1,10-phenanthroline/CB. X-ray photoemission spectroscopy showed that in acidic electrolytes, both pyri-N atoms of 1,10-phenanthroline could be protonated to form pyridinium ions (pyri-NH+ ). In O2 -saturated electrolytes, one of the pyri-NH+ species was reduced to pyri-NH upon the application of a potential; no such reduction was observed in N2 -saturated electrolytes. This behavior was ascribed to electrochemical reduction of pyri-NH+ occurring simultaneously with the thermal adsorption of O2 , as supported by DFT calculations. According to these calculations, the coupled reduction was promoted by hydrophobic environments.
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The hitherto elusive oxaziridine molecule (cyclo-H2CONH) - an optically active, high energy isomer of nitrosomethane (CH3NO) - is prepared in processed methane-nitrogen monoxide ices and detected upon sublimation in the gas phase. Electronic structure calculations reveal likely routes via addition of carbene (CH2) to the nitrogen-oxygen double bond of nitrosyl hydride (HNO). Our findings provide a fundamental framework to explore the preparation and stability of racemic oxaziridines exploited in chiral substrate-controlled diastereoselective preparation such as Sharpless asymmetric epoxidation, thus advancing our fundamental understanding of the preparation and chemical bonding of strained rings in small organic molecules.
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Energetic materials such as 1,3,5-trinitro-1,3,5-triazinane (RDX) are known to photodissociate when exposed to UV light. However, the fundamental photochemical process(es) that initiate the decomposition of RDX is (are) still debatable. In this study we investigate the photodissociation of solid-phase RDX at four distinct UV wavelengths (254 nm (4.88 eV), 236 nm (5.25 eV), 222 nm (5.58 eV), 206 nm (6.02 eV)) exploiting a surface science machine at 5 K. We also conducted dose-dependent studies at the highest and lowest photon energy of 206 nm (6.02 eV) and 254 nm (4.88 eV). The products were monitored online and in situ via infrared spectroscopy. During the temperature-programmed desorption phase, the subliming products were detected with a reflectron time-of-flight mass spectrometer coupled with soft-photoionization at 10.49 eV (PI-ReTOF-MS). Infrared spectroscopy revealed the formation of small molecules including nitrogen monoxide (NO), nitrogen monoxide dimer ([NO]2), dinitrogen trioxide (N2O3), carbon dioxide (CO2), carbon monoxide (CO), dinitrogen monoxide (N2O), water (H2O), and nitrite group (-ONO) while ReTOF-MS identified 32 cyclic and acyclic products. Among these, 11 products such as nitryl isocyanate (CN2O3), 5-nitro-1,3,5-triazinan-2-one (C3H6N4O3) and 1,5-dinitro-1,3,5-triazinan-2-one (C3H5N5O5) were detected for the first time in photodecomposition of RDX. Dose-dependent in combination with wavelength-dependent photolysis experiments aid to identify key primary and secondary products as well as distinguished pathways that are more preferred at lower and higher photon energies. Our experiments reveled that N-NO2 bond fission and nitro-nitrite isomerization are the initial steps in the UV photolysis of RDX. Reaction mechanisms are derived by comparing the experimental findings with previous electronic structure calculations to rationalize the origin of the observed products. The present study can assist in understanding the complex chemistry behind the photodissociation of electronically excited RDX molecule, thus bringing us closer to unraveling the decomposition mechanisms of nitramine-based explosives.
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Although the chemistry of phosphorus and nitrogen has fascinated chemists for more than 350 years, the Hückel aromatic cyclotriphosphazene (P3N3, 2) molecule-a key molecular building block in phosphorus chemistry-has remained elusive. Here, we report a facile, versatile pathway producing cyclotriphosphazene and its Dewar benzene-type isomer (P3N3, 5) in ammonia-phosphine ices at 5 K exposed to ionizing radiation. Both isomers were detected in the gas phase upon sublimation via photoionization reflectron time-of-flight mass spectrometry and discriminated via isomer-selective photochemistry. Our findings provide a fundamental framework to explore the preparation of inorganic, isovalent species of benzene (C6H6) by formally replacing the CâH moieties alternatingly through phosphorus and nitrogen atoms, thus advancing our perception of the chemical bonding of phosphorus systems.