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During the operation of proton exchange membrane fuel cell (PEMFC), about half of the energy is dissipated as heat. To enhance the energy efficiency of fuel cell electric vehicle (FCEV), we hereby propose a waste heat recovery system for low-temperature energy harvesting of FCEV. A comprehensive fluid-thermal-electrical multiphysics model is established to predict the performance of the proposed thermoelectric generator (TEG) system. Subsequently, a practical prototype of TEG system is developed. Transient and steady-state experimental results from the prototype validated the feasibility and power generation efficiency of the TEG system. At a temperature difference of 40°C, the highest open circuit voltage and power output of each TEG are 6.2V and 0.33W respectively, the results affirmatively demonstrate that the TEG system can recover the low temperature waste heat from PEMFC, thus providing valuable guidance for the design of the future PEMFC thermal management system in FCEV.
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Antineoplásicos , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Diseño Asistido por Computadora , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/farmacología , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , N-Metiltransferasa de Histona-Lisina/metabolismo , Estructura Molecular , Relación Estructura-Actividad , Mutaciones Letales Sintéticas , Metionina Adenosiltransferasa/antagonistas & inhibidores , Metionina Adenosiltransferasa/química , Metionina Adenosiltransferasa/metabolismoRESUMEN
Objective: This study investigated the efficacy of different concentrations of Cholesterol-loaded cyclodextrin (CLC) on cryopreservation in boar sperm quality. Methods: In this study, we treated boar sperm with different concentrations of CLC before freezing and analyzed the sperm cholesterol concentration, plasma membrane, acrosome integrity rate and total motility rate before and after freeze-thawing. We also investigated the levels of reactive oxygen species (ROS), malondialdehyde (MDA), ATP, and structural- and oxidative-damage related proteins in all groups after thawing. Results: The results revealed that the cholesterol concentration of the CLC-treated groups was higher than that of the control group, both before freezing and after thawing (p < 0.05). The plasma membrane integrity rate, acrosome integrity rate, and total motility rate of sperm were also enhanced after thawing in the CLC-treated group (all p < 0.05). Moreover, ROS and MDA production and ATP loss were reduced in CLC-treated sperm during freezing and thawing (p < 0.05). Finally, CLC pretreatment partially prevented the consumption of various proteins involved in metabolism including CAPZB, HSP90AA1 and PGAM2 (p < 0.05). Conclusion: CLC treatment increased cholesterol concentration and decreased structural injury and oxidative damage during boar sperm freezing and thawing, improving the efficacy of sperm cryopreservation in boar.
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The water resources carrying capacity (WRCC) is a complex and comprehensive system that is jointly influenced by water resources, society, the economy and the ecological environment. Previous WRCC studies have primarily focused on estimating the overall level of regional WRCC. Few studies have explored the interactions among the various elements in the WRCC system and their influence on the WRCC evolution. Therefore, the purpose of this paper is, on the one hand, to explore the dynamic interactive relationships within the WRCC system from the perspectives of water resources, society, the economy and the ecological environment using a coupling coordination degree model and a panel vector autoregressive (PVAR) model, and on the other hand, to determine the evolutionary driving mechanism of the WRCC using the geographically and temporally weighted regression (GTWR) model to improve the regional WRCC. Taking 21 cities in Guangdong Province as an example, the results show that (1) the coupling coordination degree among the four WRCC subsystems in Guangdong Province shows an overall upward trend from 2009 to 2020, and the coordination between water resources utilization and other subsystems needs to be further strengthened. (2) The economic subsystem is the core of the WRCC system with reinforcing effects on both water resources and social subsystems but significant inhibitory effects on the ecological environment subsystem. Notably, the development of the ecological environment plays a crucial role in promoting social and economic development. (3) From 2009 to 2020, the development of the WRCC in Guangdong Province is initially driven by social and economic development, followed by economic development and ecological environmental protection, and then mainly by ecological environmental protection, which gradually becomes the primary driving force. This study provides a new entry point for studying the regional WRCC and formulating targeted measures for enhancing the regional WRCC.
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PARP7 has been recently identified as an effective drug target due to its specific role in tumor generation and immune function recovery. Herin, we report the discovery of compound 8, which contained a tricyclic fused ring, as a highly selective PARP7 inhibitor against other PARPs. In particular, compound 8 strongly inhibits PARP7 with an IC50 of 0.11 nM, and suppresses the proliferation of NCI-H1373 lung cancer cells with an IC50 of 2.5 nM. Compound 8 exhibits a favorable pharmacokinetic profile with a bioavailability of 104 % in mice, and 78 % in dogs. Importantly, daily treatment of 30 mg/kg of 8 induced 81.6 % tumor suppression in NCI-H1373 lung xenograft mice tumor models, which is significantly better than the clinical candidate, RBN-2397. These intriguing features highlight the promising advantages of 8 as an antitumor agent.
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Antineoplásicos , Neoplasias , Humanos , Ratones , Animales , Perros , Disponibilidad Biológica , Antineoplásicos/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Línea Celular Tumoral , Proliferación CelularRESUMEN
Clinical researches have shown that epidermal growth factor receptor (EGFR) is a key target for treatment of non-small cell lung cancer (NSCLC). Many EGFR inhibitors were successfully developed as ani-tumor drugs to treat NSCLC patients. Unfortunately, drug resistances were found in clinic. To overcome C797S mutation in EGFR, a novel series of 4-arylamine substituted pyrimidine derivatives were designed and synthesized under the principle of structure-based drug design. Interestingly, compounds 6e and 9i demonstrated the best anti-proliferative activity against A549, NCI-H1975, and HCC827 cells. In particular, the IC50 values against HCC827 cells reached to 24.6 nM and 31.6 nM, which were much lower than human normal cells 2BS and LO2. Furthermore, compounds 6e and 9i showed extraordinary activity against EGFR19del/T790M/C797S (IC50 = 16.06 nM and 37.95 nM) and EGFRL858R/T790M/C797S (IC50 = 11.81 nM and 26.68 nM), which were potent than Osimertinib (IC50 = 52.28 nM and 157.60 nM). Further studies have shown that compounds 6e and 9i could pertain inhibition of HCC827 colony formation, and arrest HCC827 cells at G2/M phase. Moreover, the most promising compound 6e could inhibit the migration of HCC827 cells, induce HCC827 cells apoptosis, and significantly inhibit the phosphorylation of EGFR, AKT and Erk1/2. In vivo xenograft mouse model with HCC827 cells, compound 6e resulted in remarkable tumor regression without obvious toxicity. In addition, molecular docking studies suggested that compound 6e could firmly combine with T790M-mutant, T790 M/C797S-mutant, and L858R/T790 M/C797S-mutant EGFR kinases as ATP-competitive inhibitor.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Animales , Humanos , Ratones , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular , Resistencia a Antineoplásicos , Receptores ErbB , Neoplasias Pulmonares/patología , Simulación del Acoplamiento Molecular , Mutación , Inhibidores de Proteínas Quinasas , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Aminas/químicaRESUMEN
Small molecules capable of modulating methionine adenosyltransferase 2A (MAT2A) are of significant interest in precise cancer therapeutics. Herein, we raised the hole-electron Coulombic attraction as a reliable molecular descriptor for predicting the reactive oxygen generation capacity of MAT2A inhibitors, based on which we discovered compound H3 as a sonically activated degrader of MAT2A. Upon sonication, H3 can generate reactive oxygen species to specifically degrade cellular MAT2A via rapid oxidative reactions. Combination of H3 and sonication induced 87% MAT2A depletion in human colon cancer cells, thus elevating its antiproliferation effects by 8-folds. In vivo, H3 had a favorable pharmacokinetic profile (bioavailability = 77%) and ADME properties. Owing to the MAT2A degradation merits, H3 at a dosage of 10 mg/kg induced 31% tumor regression in xenograft colon tumor models. The significantly boosted antitumor potency can potentially alleviate the toxicity of high-dose MAT2A inhibitors to normal cells and tissues, especially to the liver.
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Neoplasias Hepáticas , Metionina Adenosiltransferasa , Humanos , Metionina Adenosiltransferasa/metabolismo , Electrones , Neoplasias Hepáticas/metabolismo , S-Adenosilmetionina/metabolismo , MetioninaRESUMEN
PARP7 has emerged as a promising anti-tumor target due to its crucial roles in nucleic acid sensing and immune regulation. Herein, we explored the structural-activity relationship of tricyclic PARP7 inhibitors containing a hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine motif. The effects of the chirality of the fused rings, the group conjugated to the fused rings, and the size of the linker on PARP7 inhibition were fully investigated. Our work leads to the discovery of an extremely potent and orally-bioavailable PARP7 inhibitor, namely 18 (PARP7 inhibition IC50 = 0.56 nM), for efficacious treatment of lung cancer in vivo. Notably, 18 showed acceptable bioavailability in ICR mice (F = 33.9%) and Beagle dogs (F = 45.2%). Further investigation of ADME-T properties suggested that 18 has the potential to be developed as a candidate drug molecule for PARP7-sensitive tumors.
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Relación Estructura-Actividad , Ratones , Animales , Perros , Ratones Endogámicos ICR , Disponibilidad BiológicaRESUMEN
Diamond tools play a vital role in precision machining. However, the adhesive wear restricts their application when Fe-based workpieces are cut by diamond tools. Thus, it is significant to theoretically explain the interface binding mechanism between the diamond and Fe alloy matrix. In this study, the adhesion and friction behaviors of a γ-Fe/diamond (denoted as Fe/C) heterogeneous contact interface were investigated employing density functional theory (DFT). The results show that the transfer of the Fe atom to C atom occurs when the interaction energy for a given configuration is larger than the separation energy of the corresponding Fe surface layers. The energy barriers of the Fe/C(100), (110) and (111) sliding interfaces along the minimum energy path are 1.45, 0.48 and 0.42 J m-2, respectively, indicating that the Fe/C(111) interface is the easiest to slide. Furthermore, the friction potential barrier increases with an increase in the load (1-5 nN) according to the potential energy curves. Moreover, the friction coefficient of the Fe/C interface is larger than 0.2 and provides a theoretical minimum friction coefficient for the Fe/C sliding interface.
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The patterns of biogeographic distribution and assembly processes of microbiota are of vital importance for understanding ecological adaptation and functioning maintenance. However, the role of morphological characteristics in microbial assembly is still poorly ascertained. Here, by integrating high-throughput sequencing and robust extrapolation of traits, we investigated taxonomic and phylogenetic turnovers of various cyanobacterial morphotypes in biocrusts to evaluate the contributions of deterministic and stochastic processes across a large scale of drylands in northwestern China. The results showed that the non-heterocystous filamentous category dominated biocrusts in the arid ecosystem and exhibited strong tolerance against environmental fluctuations. Despite the significant distance-decay relationship of ß-diversity detected in all categories, both species composition and phylogenetic turnover rates of coccoid cyanobacteria were higher than non-heterocystous filamentous and heterocystous morphotypes. Moreover, the assembly of cyanobacteria was driven by different ecological processes that the entire community and non-heterocystous filamentous morphotype were governed by deterministic processes, while stochasticity prevailed in heterocystous and coccoid cyanobacteria. Nonetheless, aridity can modulate the balance between determinism and stochasticity and prompt a shifting threshold among morphotypes. Our findings provide a unique perspective to understanding the critical role of microbial morphology in community assembly and facilitate the prediction of biodiversity loss under climate change.
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Cianobacterias , Microbiota , Ecosistema , Filogenia , Microbiología del Suelo , Cianobacterias/genética , BiodiversidadRESUMEN
KRAS mutations (G12C, G12D, etc.) are implicated in the oncogenesis and progression of many deadliest cancers. Son of sevenless homolog 1 (SOS1) is a crucial regulator of KRAS to modulate KRAS from inactive to active states. We previously discovered tetra-cyclic quinazolines as an improved scaffold for inhibiting SOS1-KRAS interaction. In this work, we report the design of tetra-cyclic phthalazine derivatives for selectively inhibiting SOS1 against EGFR. The lead compound 6c displayed remarkable activity to inhibit the proliferation of KRAS(G12C)-mutant pancreas cells. 6c showed a favorable pharmacokinetic profile in vivo, with a bioavailability of 65.8% and exhibited potent tumor suppression in pancreas tumor xenograft models. These intriguing results suggested that 6c has the potential to be developed as a drug candidate for KRAS-driven tumors.
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Proteínas Proto-Oncogénicas p21(ras) , Proteína SOS1 , Humanos , Proteína SOS1/genética , Proteína SOS1/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Mutación , Quinazolinas/farmacología , Receptores ErbB/genéticaRESUMEN
Sonodynamic therapy (SDT) has been recognized as a spatial-temporal and noninvasive modality for the treatment of deep-seated tumors. However, current sonosensitizers suffer from low sonodynamic efficacy. Herein, we reported the design of nuclear factor kappa B (NF-κB) targeting sonosensitizers (TR1, TR2, and TR3) by integrating a resveratrol motif into a conjugated electron donor-acceptor (triphenylamine benzothiazole) skeleton. Among these sonosensitizers, TR2 with two resveratrol units in one molecule was the most potent for inhibiting NF-κB signaling. Owing to the synergy of high sonodynamic efficacy and NF-κB activation inhibition, TR2 displayed a remarkable sonocytotoxicity to MCF-7 breast cancer cells. Xenograft mice studies demonstrated that TR2 had excellent anticancer potency and biosafety. This study thus opens up a new avenue for the development of efficient organic sonosensitizers for cancer ablation.
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Neoplasias de la Mama , Neoplasias , Terapia por Ultrasonido , Humanos , Ratones , Animales , Femenino , FN-kappa B , Resveratrol/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias/terapia , Células MCF-7RESUMEN
Inhibition of methionine adenosyltransferase 2A (MAT2A) in cancers with a deletion of methylthioadenosine phosphorylase (MTAP) gene leads to synthetic lethality, thus receiving significant interest in the field of precise cancer treatment. Herein, we report the discovery of a tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine fragment which occupies the MAT2A allosteric pocket. The lead compound 8 exhibited extremely high potency to inhibit MAT2A enzymatic activity (IC50 = 18 nM) and proliferation of MTAP-null cancer cells (IC50 = 52 nM). 8 had a favorable pharmacokinetic profile with a bioavailability of 116% in mice. More importantly, introducing an amide motif (28) to the core structure raised the plasma drug exposure from 11â¯718 to 41â¯192 ng·h·mL-1. 28 displayed a significantly better in vivo potency than AG-270, which is being evaluated in clinical trails, and induced -52% tumor regression in a xenograft MTAP-depleted colon tumor model.
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Neoplasias del Colon , Metionina Adenosiltransferasa , Humanos , Ratones , Animales , Metionina Adenosiltransferasa/metabolismo , Disponibilidad Biológica , MetioninaRESUMEN
In this paper, according to the C(111) surface and Ti(112Ì 0) surface relative positions, three stacking interface models were constructed by the first-principles method, and they were defined as 1st-C(111)/Ti(112Ì 0), 2nd-C(111)/Ti(112Ì 0), and 4th-C(111)/Ti(112Ì 0), respectively. After calculation, the work of interfacial adhesion of the 1st-C(111)/Ti(112Ì 0), 2nd-C(111)/Ti(112Ì 0), and 4th-C(111)/Ti(112Ì 0) interface models is found to be 9.689, 10.246, and 9.714 J/m2, respectively, and their interface energies are observed to be 1.064, 0.507, and 1.039 J/m2, respectively. Moreover, the electronic characteristics of C(111)/Ti(112Ì 0) interfaces are dominated by polar covalent bonds, supplemented by certain metallicity. When the strain reaches 13, 15, and 12%, respectively, the maximum tensile stress values of 1st-C(111)/Ti(112Ì 0), 2nd-C(111)/Ti(112Ì 0), and 4th-C(111)/Ti(112Ì 0) interface models are observed to be 16.207, 19.183, and 17.393 GPa, respectively. After all C(111)/Ti(112Ì 0) interfaces fracture under tension, the Ti atoms of the Ti(112Ì 0) surface are transferred to the C(111) surface, indicating that the strength of Ti-C bonds at the interface is higher than the strength of Ti-Ti bonds inside the Ti(112Ì 0) surface. The maximum value of the sliding potential energy surface is 1.709 J/m2; the maximum value of the potential energy curve is 0.445 J/m2; and the ideal shear strength of the C(111)/Ti(112Ì 0) interface is 0.386 GPa. In summary, the interfacial adhesion property of the 2nd-C(111)/Ti(112Ì 0) interface is better than those of 1st-C(111)/Ti(112Ì 0) and 4th-C(111)/Ti(112Ì 0) interfaces.
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KRAS mutations (G12C, G12D, etc.) are implicated in the oncogenesis and progression of many refractory cancers. Son of sevenless homolog 1 (SOS1) is a key regulator of KRAS to modulate KRAS from inactive to active states. Herein, we disclosed efficacy-improving tetra-cyclic quinazoline derivatives as an enhanced scaffold for inhibiting the SOS1-KRAS interaction. Compound 37, which conjugated 1-carbonitrile-cyclopropane to tetra-cyclic quinazoline, showed a twofold higher oral drug exposure and 2.5-fold longer half-life than BI-3406 in CD-1 mouse plasma. In a Mia-paca-2 xenograft model, 37 administrated alone inhibited tumor growth by 71%. Preclinical investigations demonstrated that 37 had a limited inhibition of CYP and hERG. Overall, our studies showed that 37 was a promising drug candidate for treatment of KRAS-driven cancer.
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Carcinoma , Proteína SOS1 , Humanos , Animales , Ratones , Quinazolinas , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
This paper proposes a new laser parameter measuring method based on cone-arranged fibers to further improve the measurable spot size, allowable incident angle range, and spatial sampling resolution. This method takes a conical array composed of flexible fibers to sample and shrink the cross-section spot of the laser beam, facilitating low-distortion shooting with a charge-coupled diode (CCD) camera, and adopts homogenized processing and algorithm analysis to correct the spot. This method is experimentally proven to achieve high-accuracy measurements with a decimeter-level spot-receiving surface, millimeter-level resolution, and high tolerance in order to incite skew angle. Comparing the measured spot under normal incidence with the real one, the root mean square error (RMSE) of their power in the bucket (PIB) curves is less than 1%. When the incident angle change is between -8° and 8°, the RMSE is less than 2% and the measurement error of total power is less than 5% based on the premise that the fiber's numerical aperture (NA) is 0.22. The possibility of further optimizing the measurement method by changing the fiber parameters and array design is also reported.
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By using the differential scintillation method suggested and described in this work, vibrations of unmanned aircraft vehicle platforms can be eliminated. Therefore, airborne beacons have great potential applications in turbulence measurements along an arbitrary atmospheric path. The experiment with a constant beacon shows that the retrieved results of the differential scintillation method have good consistency with the scintillation index inversion method. Additionally, a similar verification was carried out between a simulative airborne beacon and a constant beacon; the differential scintillation method indicated more consistent results than the scintillation index inversion method, and its retrieved results of different beacons were in good agreement with a correlation coefficient close to 1, reaching 0.994. In verification experiments over a slant path, the retrieved results of the differential scintillation method showed good statistical properties when an airborne beacon was measured under various weather conditions. The results indicated that the new, to the best of our knowledge, proposed differential scintillation method is a reliable and feasible technique for eliminating stability issues in the measurements of airborne beacons.
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The interaction between son of sevenless 1 (SOS1) gene and Kirsten rat sarcoma viral oncogene (KRAS) is crucial for activating signals of proliferation and survival in a range of cancers. We previously discovered compound 40a with a tetracyclic quinazoline pharmacophore as a potent orally bioavailable SOS1 inhibitor. Herein, we disclosed the discovery of compound 13c, which substituted the third ring with the seven-membered ring, as a clinical drug candidate for suppressing KRAS-driven tumors. 13c strongly disrupted the protein-protein interaction between SOS1 and KRAS with low IC50 values of 3.9 nM (biochemical) and 21 nM (cellular). 13c showed a favorable pharmacokinetic profile with a bioavailability of 86.8% in beagles and exhibited 83.0% tumor suppression in Mia-paca-2 pancreas xenograft mice tumor models. 13c exhibited a weak time-dependent CY3A4P inhibition than BI-3406, thereby reducing the risk of drug-drug interaction in drug combination. Toxicological investigations revealed that 13c had a lower risk of sudden cardiac death than BI-3406. Overall, 13c has been under evaluation in preclinical trials.
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Carcinoma , Neoplasias Pancreáticas , Animales , Perros , Humanos , Ratones , Isótopos de Carbono , Núcleo Familiar , Neoplasias Pancreáticas/tratamiento farmacológico , Proteínas Proto-Oncogénicas p21(ras)/genética , Quinazolinas/uso terapéutico , Proteína SOS1/metabolismoRESUMEN
Water scarcity and water pollution problems are becoming increasingly serious in many regions of the world due to rapid socioeconomic development. Water resources environmental carrying capacity (WRECC), which embodies the attributes of social, economic, resource and environmental aspects, is usually considered as a significant metric to guide regional sustainable development. Most existing studies on WRECC mainly focus on conceptual discussions and evaluation methods, lacking a systematic insight into the theoretical connotations of WRECC and neglecting the interaction mechanisms within the WRECC system. Therefore, this study aims to propose a new WRECC evaluation method based on support and pressure theory to deeply reveal the state change and driving mechanisms of WRECC. Firstly, a WRECC evaluation system incorporating support and pressure is constructed and the WRECC performance is determined by both the support index and pressure index. Subsequently, the catastrophe progression method and the obstacle degree model are introduced to quantify the WRECC and identify the primary influencing factors. Lastly, the feasibility and validity of this methodology are verified through an empirical application in the Guangdong-Hong Kong-Macao Greater Bay Area (GBA). The results indicate that the WRECC of the GBA presents an upward trend from 2010 to 2019, shifting from a low-value load state to a low-value surplus state. Moreover, the WRECC performance varies significantly among cities in the GBA, especially for edge cities that generally exhibit higher support, pressure and WRECC indices than central cities. In addition, common obstacles that affect WRECC are total water resources, water resources per capita, water consumption per hectare for agriculture and proportion of the tertiary industry. Furthermore, this study reveals that the coupling relationship between support and pressure develops towards a positive direction, and water environment protection and economic development are the main drivers of WRECC development. This new proposed methodology can provide a theoretical reference for investigating regional WRECC and formulating appropriate sustainable development strategies.
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Conservación de los Recursos Naturales , Recursos Hídricos , China , Ciudades , Hong Kong , Macao , AguaRESUMEN
The major challenges of photothermal therapy (PTT) toward clinical application are the severe skin injury and inflammation response associated with high power laser irradiation. Herein, polydopamine nanoparticles (PDA-EST and PDA-RAL) targeted to estrogen receptor α (ERα) for efficient ablation of breast tumor under a low irradiation density of 0.1 W cm-2 are reported. These nanoparticles are capable of recruiting ERα on their surface and induce a complete ERα degradation via localized heat. Owing to the ERα targetability, PDA-EST and PDA-RAL strongly suppress the proliferation of breast cancer cells without causing significant inflammation. This work provides a generalized method for enhancing PTT efficacy under low irradiation density.