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A high level of PD-L1 in cancer cells promotes tumor immune escape and inhibits tumor immunotherapy. Although PD-L1 gene expression is upregulated by multiple pathways, its gene transcriptional repression is still unclear. Here we found that loss of PPARα, one of the peroxisome-proliferator-activated receptors (PPARs) family members, promoted colorectal tumor immune escape. Mechanistically, PPARα directly bound to the PD-L1 promoter resulting in its gene transcriptional repression, which in turn increased T cell activity, and PPARα agonist enhanced this event. However, ERK induced PPARα-S12 phosphorylation leading to blockade of PPARα-mediated PD-L1 transcriptional repression, and the combination of ERK inhibitor with PPARα agonist significantly inhibited tumor immune escape. These findings suggest that the ERK-PPARα pathway inhibited PD-L1 gene transcriptional repression and promoted colorectal tumor immune escape.
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Antígeno B7-H1 , Neoplasias Colorrectales , PPAR alfa , Escape del Tumor , PPAR alfa/metabolismo , PPAR alfa/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Humanos , Fosforilación , Animales , Ratones , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Sistema de Señalización de MAP QuinasasRESUMEN
Using gas phase Fourier-transform microwave spectroscopy complemented by theoretical analysis, this study delivers a comprehensive depiction of the physical origin of the 'n â π* interaction' between CO2 and acrolein, one of the most reactive aldehydes. Three distinct isomers of the acrolein-CO2 complex, linked through a Câ¯O tetrel bond (or n â π* interaction) and a C-Hâ¯O hydrogen bond, have been unambiguously identified in the pulsed jet. Relative intensity measurements allowed estimation on the population ratio of the three isomers to be T1/T2/C1 ≈ 25/5/1. Advanced theoretical analyses were employed to elucidate the intricacies of the noncovalent interactions within the examined complex. This study not only sheds light on the molecular underpinnings of n â π* interactions but also paves the way for future exploration in carbon dioxide capture and utilization, leveraging the fundamental principles uncovered in the study of acrolein-carbon dioxide interactions.
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Chromones are a class of naturally occurring compounds, renowned for their diverse biological activities with significant relevance in medicine and biochemistry. This study marks the first analysis of rotational spectra of both the chromone monomer and its monohydrate through Fourier transform microwave spectroscopy. The observation of nine mono-substituted 13C isotopologues facilitated a semi-experimental determination of the equilibrium structure of the chromone monomer. In the case of chromone monohydrate, two distinct isomers were identified, each characterized by a combination of O-Hâ¯O and C-Hâ¯O hydrogen bonds involving the chromone's carbonyl group. This study further delved into intermolecular non-covalent interactions, employing different theoretical approaches. The relative population ratio of the two identified isomers was estimated to be about 2:1 within the supersonic jet.
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Cromonas , Cromonas/química , Enlace de Hidrógeno , Conformación Molecular , Análisis Espectral/métodos , Microondas , Estructura MolecularRESUMEN
The rotational spectrum of an acrolein-formaldehyde complex has been characterized using pulsed jet Fourier transform microwave spectroscopy complemented with quantum chemical calculations. One isomer has been observed in pulsed jets, which is stabilized by a dominant O=Câ¯O tetrel bond (n â π* interaction) and a secondary C-Hâ¯O hydrogen bond. Splittings arising from the internal rotation of formaldehyde around its C2v axis were also observed, from which its V2 barrier was evaluated. It seems that when V2 equals or exceeds 4.61 kJ mol-1, no splitting of the spectral lines of the rotational spectrum was observed. The nature of the non-covalent interactions of the target complex is elucidated through natural bond orbital analysis. These findings contribute to a deeper understanding on the non-covalent interactions within the dimeric complex formed by two aldehydes.
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Ethanolamine hydrates containing from one to seven water molecules were identified via rotational spectroscopy with the aid of accurate quantum chemical methods considering anharmonic vibrational corrections. Ethanolamine undergoes significant conformational changes upon hydration to form energetically favorable hydrogen bond networks. The final structures strongly resemble the pure (H2O)3-9 complexes reported before when replacing two water molecules by ethanolamine. The 14N nuclear quadrupole coupling constants of all the ethanolamine hydrates have been determined and show a remarkable correlation with the strength of hydrogen bonds involving the amino group. After addition of the seventh water molecule, both hydrogen atoms of the amino group actively contribute to hydrogen bond formation, reinforcing the network and introducing approximately 21-27 % ionicity towards the formation of protonated amine. These findings highlight the critical role of microhydration in altering the electronic environment of ethanolamine, enhancing our understanding of amine hydration dynamics.
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This study delves into driving forces behind the formation of a hetero ternary cluster consisting of volatile organic compounds from industrial or combustion sources, specifically cyclopentene, alongside greenhouse gases like carbon dioxide, and water vapor. While substantial progress has been made in understanding binary complexes, the structural intricacies of hetero ternary clusters remain largely uncharted. Our research characterized the cyclopentene-CO2-H2O hetero ternary cluster utilizing Fourier transform microwave spectroscopy. The observed isomer in the pulsed jet has CO2 and H2O aligning above the cyclopentene ring, with water undergoing an internal rotation approximately about its C2 symmetry axis. Theoretical analyses support these observations, identifying an O-H···π hydrogen bond and a secondary C···O tetrel bond within this cluster. This study marks a critical step towards comprehending the molecular dynamics and interactions of VOCs, greenhouse gases, and water in the atmosphere, paving the way for further investigations into their roles in climate dynamics and air quality.
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Blockade of the programmed death 1 (PD-1)/ programmed death ligand 1 (PD-L1) immune checkpoint could increase antitumor immunotherapy for multiple types of cancer, but the response rate of patients is about 10%-40%. Peroxisome proliferator activated receptor γ (PPARγ) plays an important role in regulating cell metabolism, inflammation, immunity, and cancer progression, while the mechanism of PPARγ on cancer cell immune escape is still unclear. Here we found that PPARγ expression exhibits a positive correlation with activation of T cells in non-small-cell lung cancer (NSCLC) by clinical analysis. Deficiency of PPARγ promoted immune escape of NSCLC by inhibiting T-cell activity, which was associated with increased PD-L1 protein level. Further analysis showed that PPARγ reduced PD-L1 expression independent of its transcriptional activity. PPARγ contains the microtubule-associated protein 1A/1B-light chain 3 (LC3) interacting region motif, which acts as an autophagy receptor for PPARγ binding to LC3, leading to degradation of PD-L1 in lysosomes, which in turn suppresses NSCLC tumor growth by increasing T-cell activity. These findings suggest that PPARγ inhibits the tumor immune escape of NSCLC by inducing PD-L1 autophagic degradation.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Antígeno B7-H1 , PPAR gamma , Escape del TumorRESUMEN
A novel instrument based on broadband cavity-enhanced absorption spectroscopy has been developed using a supercontinuum broadband light source, which showcases its ability in simultaneous measurements of the concentration of NO2 and the extinction of particulate matter. Side-by-side intercomparison was carried out with the reference NOx analyzer for NO2 and OPC-N2 particle counter for particulate matter, which shows a good linear correlation with r2 > 0.90. The measurement limits (1σ) of the developed instrument were experimentally determined to be 230 pptv in 40 s for NO2 and 1.24 Mm-1 for the extinction of particulate matter in 15 s. This work provides a promising method in simultaneously monitoring atmospheric gaseous compounds and particulate matter, which would further advance our understanding on gas-particle heterogeneous interactions in the context of climate change and air quality.
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The pure rotational spectra of 1-phenylethanol and its monohydrate were measured by using a pulsed jet Fourier transform microwave spectrometer. One conformer of the 1-phenylethanol monomer with the trans form was observed in the pulsed jet. The experimental values of rotational constants of ten isotopologues, including eight mono-substituted 13 C and one D isotopologues, allow an accurate structure determination of the skeleton of 1-phenylethanol. For its monohydrate, only one isomer has been observed, of which 1-phenylethanol adopts the trans form and binds with water through an O-Hâ â â Ow and an Ow -Hâ â â π hydrogen bond. Each rotational transition displays a doublet with a relative intensity ratio of 1 : 3, due to a hindered internal rotation of water around its C2 axis. This study provides the information on accurate geometry of 1-phenylethanol (PE) and large amplitude motion of water in the PE monohydrate.
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The rotational spectrum of the isoprene-maleic anhydride complex has been investigated by pulsed jet Fourier transform microwave spectroscopy and interpreted with complementary quantum chemical calculations. Theoretical predictions have yielded four plausible isomers, all residing within an energy window of 12 kJ mol-1. However, two distinct isomers characterized by a π-π stacked configuration have been experimentally observed in pulsed jets, which have differed in the orientation of isoprene over maleic anhydride. The relative population ratio of the two detected isomers has been estimated to be NI/NII ≈ 3/1 from rigorous measurements of the relative intensity on a set of µc-type transitions. Remarkably, this study underscores the pivotal role played by the interaction between the CîC bonding orbital (π) of isoprene and the CîC antibonding orbital (π*) of maleic anhydride in stabilizing the target complex.
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The rotational spectra of maleic anhydride-(H2O)1-3 have been investigated for the first time by using pulsed jet Fourier transform microwave spectroscopy with complementary computational analyses. The experimental evidence points out that water tends to self-aggregate with hydrogen bonds and form homodromic cycles. Differences in bond lengths and charge distribution between the two carbonyl sites have been observed upon stepwise hydrations, which might further introduce a selectivity on the nucleophilic attack sites of hydrolysis. This study provides an important insight into the incipient solvation process (microsolvation) of maleic anhydride in water by understanding the cooperation and rearrangement of intermolecular hydrogen bonds in its stepwise hydrates.
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Rotational spectra of the 4-fluoroacetophenone monomer and its monohydrate were investigated by Fourier transform microwave spectroscopy complemented with quantum chemical calculations. One conformer of 4-fluoroacetophenone and two isomers of 4-fluoroacetophenone-H2O have been observed in the pulsed jets. The observation of all mono-substituted 13C isotopologues in natural abundance allows an accurate structural determination of the 4-fluoroacetophenone monomer. Both detected isomers of 4-fluoroacetophenone-H2O are stabilized by a dominant O-Hâ¯O and a secondary C-Hâ¯O hydrogen bond. The fluorination effects on the geometries, intermolecular non-covalent interactions and V3 barrier of the methyl internal rotation were analysed. The relative population ratio of the two observed isomers for 4-fluoroacetophenone-H2O was also estimated to be NI/NII ≈ 7/1.
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Rotational spectroscopy represents an invaluable tool for several applications: from the identification of new molecules in interstellar objects to the characterization of van der Waals complexes, but also for the determination of very accurate molecular structures and for conformational analyses. In this work, we used high-resolution rotational spectroscopic techniques in combination with high-level quantum-chemical calculations to address all these aspects for two isomers of cyanofuran, namely 2-furonitrile and 3-furonitrile. In particular, we have recorded and analyzed the rotational spectra of both of them from 6 to 320 GHz; rotational transitions belonging to several singly-substituted isotopologues have been identified as well. The rotational constants derived in this way have been used in conjunction with computed rotation-vibration interaction constants in order to derive a semi-experimental equilibrium structure for both isomers. Moreover, we observed the rotational spectra of four different intermolecular adducts formed by furonitrile and water, whose identification has been supported by a conformational analysis and a theoretical spectroscopic characterization. A semi-experimental determination of the intermolecular parameters has been achieved for all of them and the results have been compared with those obtained for the analogous system formed by benzonitrile and water.
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The rotational spectrum of the phenyl isothiocyanate-CO2 complex was investigated by pulsed-jet Fourier transform microwave spectroscopy complemented by quantum chemical calculations. Only one isomer, with CO2 almost in the plane of phenyl isothiocyanate, has been detected in the pulsed jet, of which the spectrum displays a quadrupole coupling hyperfine structure due to the presence of a 14N nucleus (I = 1). This structure is nearly equal to the lowest energy geometry obtained by B3LYP-D3(BJ)/6-311++G(d,p), which has been dominated by a C···S tetrel bond (n â π* interaction) and one secondary C-H···O hydrogen bond (n â σ* interaction). Molecular electrostatic potential and natural bond orbital analysis were used to characterize the noncovalent interactions of the complex. The results from this study would lay the groundwork for the design and advancement of materials that exhibit high efficiency in capturing CO2.
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The rotational spectrum of acetoin (3-hydroxy-2-butanone) was measured by using Fourier transform microwave spectroscopy with the aid of quantum chemical calculations. Only one conformer of acetoin was detected in the pulsed jet, whose spectrum featured the splittings raised from the internal rotation of the methyl top linking to the CâO group. Based on the spectroscopic result, radio-astronomical searches for acetoin were carried out toward the massive star-forming region Sgr B2(N) using the Shanghai Tianma 65 m and IRAM 30 m radio telescopes. No lines belonging to acetoin were detected toward Sgr B2(N). Its upper limit of column density was calculated.
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Peroxisome proliferator-activated receptor δ (PPARδ) is a nuclear receptor transcription factor that plays an important role in the regulation of metabolism, inflammation, and cancer. In addition, the nutrient-sensing kinase 5'AMP-activated protein kinase (AMPK) is a critical regulator of cellular energy in coordination with PPARδ. However, the molecular mechanism of the AMPK/PPARδ pathway on cancer progression is still unclear. Here, we found that activated AMPK induced PPARδ-S50 phosphorylation in cancer cells, whereas the PPARδ/S50A (nonphosphorylation mimic) mutant reversed this event. Further analysis showed that the PPARδ/S50E (phosphorylation mimic) but not the PPARδ/S50A mutant increased PPARδ protein stability, which led to reduced p62/SQSTM1-mediated degradation of misfolded PPARδ. Furthermore, PPARδ-S50 phosphorylation decreased PPARδ transcription activity and alleviated PPARδ-mediated uptake of glucose and glutamine in cancer cells. Soft agar and xenograft tumor model analysis showed that the PPARδ/S50E mutant but not the PPARδ/S50A mutant inhibited colon cancer cell proliferation and tumor growth, which was associated with inhibition of Glut1 and SLC1A5 transporter protein expression. These findings reveal a new mechanism of AMPK-induced PPARδ-S50 phosphorylation, accumulation of misfolded PPARδ protein, and inhibition of PPARδ transcription activity contributing to the suppression of colon tumor formation.
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Adenilato Quinasa/metabolismo , Proliferación Celular , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Glucosa/metabolismo , Glutamina/metabolismo , PPAR gamma/metabolismo , Animales , Línea Celular Tumoral , Femenino , Xenoinjertos , Humanos , Ratones Desnudos , FosforilaciónRESUMEN
The rotational spectra of 4-hydroxy-2-butanone and its monohydrate were investigated by Fourier transform microwave spectroscopy complemented by quantum chemical calculations. One conformer of 4-hydroxy-2-butanone, with the intramolecular O-Hâ¯O hydrogen bond, has been observed in the pulsed jet. Rotational spectra of the six isotopologues (including four 13C and one 18O mono-substitution species) in natural abundance were measured and assigned, enabling the accurate structural determination of the molecular skeleton. The most stable isomer of its monohydrate, in which water inserts into the intramolecular hydrogen bond and serves the dual role of being a proton donor and acceptor, was also detected. The rotational spectra of HOD, DOH, D2O and H218O isotopologues were also measured allowing the accurate evaluation of the parameters of the intermolecular hydrogen bonds. This rotational spectroscopic investigation demonstrates that upon complexation, the weak intramolecular hydrogen bond in the monomer is replaced by two strong intermolecular O-Hâ¯O hydrogen bonds, leading to a change in the orientation of the -OH group of 4-hydroxy-2-butanone.
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Butanonas/química , Microondas , Agua , Enlace de Hidrógeno , Espectroscopía de Resonancia Magnética , Imágenes de Microonda , Espectroscopía Infrarroja por Transformada de Fourier , Agua/químicaRESUMEN
The structures and non-covalent interactions at play in the 3-oxetanone homodimer have been investigated using a pulsed jet Fourier transform microwave spectrometer supplemented with quantum chemical calculations. Two isomers were identified in the pulsed jet. With the analyses of non-covalent intermolecular interactions including the quantum theory of atoms, Johnson's non-covalent interactions and natural bond orbital, the observed global minimum is stabilized by a combination of one sp2-Câ¯O tetrel bond and a network of multiple C-Hâ¯O weak hydrogen bonds. The second isomer is characterized by carbonyl-carbonyl interactions, with the formation of one sp2- and one sp3-Câ¯O tetrel bond. The conformational population of the two observed isomers in the supersonic expansion was estimated to be NCE1/NCC1 ≈ 7/5.
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Two configurations of the furan-CF3Cl complex have been observed by high-resolution rotational spectroscopy. One is characterized by a dominant Cl lone pairâ¯π*aromatic interaction and the other is stabilized by a C-Cl···π-CîC- halogen bond. This is the first rotational spectroscopic evidence, to the best of our knowledge, that shows how a complexation with a partner like CF3Cl (the weak lone pair belt of Cl, to be more specific) can modulate both the aromatic π* and diene π characters of a heteroaromatic molecule in the formation of non-covalent interactions. The results emphasize the partner molecules' role in modulating the π electron structure and will not only deepen our understanding on non-covalent interactions but also lead to better designs of heteroaromatic-based drugs and materials.
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Electrones , Halógenos , Halógenos/química , Rotación , Análisis EspectralRESUMEN
Rotational spectra of the 2-ethynylpyridine monomer and its monohydrate have been characterized by pulsed jet Fourier transform microwave spectroscopy complemented with quantum chemical calculations. The measurements of rotational transitions of the 2-ethynylpyridine monomer and its eight monosubstituted isotopologues (15N and 13C) in natural abundances allow an accurate structural description of the skeleton of 2-ethynylpyridine. For the monohydrate, only the most stable isomer, stabilized by an O-H···N and a secondary C-H···O hydrogen bonds, has been observed in the supersonic jet. Johnson's noncovalent interaction and quantum theory of atoms in molecules analyses have been performed and compared with results for several ortho-substituted pyridine derivatives to elucidate the general trend in their binding energies.