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Panose is iso-malto-oligosaccharide contained α-1,6 glycosidic bonds, and α-glucosidase is the key enzyme to produce panose. In this study, the α-glucosidase gene in deep-sea hydrothermal vents thermophilic archaea Thermococcus siculi HJ21 was synthesized, and cloned into the vector pET29a. Then expressed in Escherichia coli BL21 and purified by His Trap HP column. The molecular weight of α-glucosidase was determined by SDS-PAGE. The enzymatic properties and transglycosylation were also investigated. The results showed that the gene of α-glucosidase was 729 bp and encoded 242 amino acids. The molecular weight of α-glucosidase was about 27.2 kDa. Its optimal temperature and pH were 40 ℃ and 6.0 respectively. When the receptor was fructose, and the ratio of fructose and maltose was 1:9, the highest yield of panose could reached 79.1% after 10 h reaction. The results provide a basis for producing high-purity panose by α-glucosidase from archaea.

Abstract Radial diffusion (RD) induced by ULF waves can contribute to particle acceleration and scattering. Past global simulations that incorporate RD often use dipole magnetic fields, which could not realistically reveal the role of RD. To better understand the effects of RD and identify whether a background magnetic field model matters in understanding the ring current dynamics in response to RD, we simulate a storm event with different magnetic configurations using a global kinetic ring current model. Results indicate that RD can effectively diffuse protons of hundreds of keV to inner regions (L ∼ 3.5), especially in recovery phase. Comparisons with in‐situ observations demonstrate that simulations with TS05 overall capture both the intensity and variations of proton fluxes with the aid of RD, whereas that with a dipole field significantly overestimates low‐L region fluxes. This study implies adopting realistic magnetic fields is important for correctly interpreting the role of RD.

Abstract During the Earth's magnetic reversal, the dipole component of the magnetic field weakens, and the non‐dipole component becomes dominant, resulting in a far more complex magnetospheric topology than that of a dipole. In this study, we used a particle tracing technique to investigate the motion of ions within an irregular magnetosphere during the Matuyama‐Brunhes magnetic polarity reversal. Compared to the scenario in which the geomagnetic field is dominated by a dipole component, earthward‐moving particles can be hardly “trapped” in the inner magnetosphere when the geomagnetic field experiences the polarity reversal, and particles can directly precipitate into the Earth's atmosphere on a global scale. It suggests that under an irregular magnetospheric configuration, the traditional trapped region of particles (e.g., radiation belt or ring current) no longer exists.

We investigate the seasonal variations of ion precipitation, utilizing observations from the Mars Atmosphere and Volatile Evolution mission spanning from 2014 January 4 to 2023 February 14. Our analysis reveals that a diminishing pattern characterizes the transition from Mars season L _s 0°–180° to Mars season L _s 180°–360°, manifesting as a reduction in precipitating ion fluxes. Additionally, we discern a significant influence of the crustal magnetic field on the seasonal variations in precipitating ion fluxes. Intriguingly, within regions where the crustal magnetic field exhibits a strong quasi-horizontal orientation, opposite seasonal trends become evident. The underlying physical mechanism driving these seasonal variations in ion precipitation is probably attributed to the mass loading effect that may decelerate the solar wind and influence the magnetic pileup. A detailed investigation is further demanded in the future.

Electromagnetic ion cyclotron (EMIC) waves are widely believed to play an important role in influencing the radiation belt and ring current dynamics. Most studies have investigated the effects or characteristics of EMIC waves by assuming their left-handed polarization. However, recent studies have found that the reversal of polarization, which occurs at higher latitudes along the wave propagation path, can change the wave-induced pitch angle diffusion coefficients. Whether such a polarization reversal can influence the global ring current dynamics remains unknown. In this study, we investigate the ring current dynamics and proton precipitation loss in association with polarization-reversed EMIC waves by using the ring current–atmosphere interactions model (RAM). The results indicate that the polarization reversal of H-band EMIC waves can truly decrease the scattering rates of protons of 10 to 50 keV or >100 keV in comparison with the scenario in which the EMIC waves are considered purely left-handed polarized. Additionally, the global ring current intensity and proton precipitation may be slightly affected by the polarization reversal, especially during prestorm time and the recovery phase, but the effects are not large during the main phase. This is probably because the H-band EMIC waves contribute to the proton scattering loss primarily at E < 10 keV, an energy range that is not strongly affected by the polarization reversal.

Abstract Thanks to the gustatory system, humans can experience the flavors in foods and drinks while avoiding the intake of some harmful substances. Although great advances in the fields of biotechnology, microfluidics, and nanotechnologies have been made in recent years, this astonishing recognition system can hardly be replaced by any artificial sensors designed so far. Here, taste organoids are coupled with an extracellular potential sensor array to form a novel bioelectronic organoid and developed a taste organoids‐on‐a‐chip system (TOS) for highly mimicking the biological sense of taste ex vivo with high stability and repeatability. The taste organoids maintain key taste receptors expression after the third passage and high cell viability during 7 days of on‐chip culture. Most importantly, the TOS not only distinguishs sour, sweet, bitter, and salt stimuli with great specificity, but also recognizes varying concentrations of the stimuli through an analytical method based on the extraction of signal features and principal component analysis. It is hoped that this bioelectronic tongue can facilitate studies in food quality controls, disease modelling, and drug screening.

Aim: It has been found that the co-administration of nifedipine with apatinib could cause exposure changes of nifedipine in vivo. But, whether this pharmacokinetic drug-drug interaction (DDI) between nifedipine and apatinib could enhance the antihypertensive effect of nifedipine, causing sever changes of blood pressure was unknown. Therefore, the aim of the present study was to conduct the pharmacokinetic/pharmacodynamic (PK/PD) modelling to evaluate the effect of pharmacokinetic changes on the antihypertensive effect of nifedipine. Thus, the results could guide the co-administration of these two drugs in clinic.Methods: A physiologically-based pharmacokinetic (PBPK) model was first developed for nifedipine. The pharmacokinetic DDI between nifedipine and apatinib was evaluated. Then the verified PBPK models were linked to a PD model for investigating whether the exposure changes of nifedipine could cause severe changes in blood pressure. Furthermore, the changes in blood pressure caused by combination with apatinib were also assessed in patients with hepatic impairment via the PBPK/PD models.Results: The predicted area under plasma concentration-time profile (AUC), maximum concentration (Cmax), area under effect-time profile (AUE), and maximum reduction in systolic blood pressure (Rmax) are all within 0.5–2.0-fold of the observed data, indicating that the PBPK/PD models for nifedipine are successfully established. The increases of predicted AUC and Cmax of nifedipine in the presence of apatinib are 1.73 and 1.41-fold, respectively. Co-administration of nifedipine with apatinib could cause exposure changes of nifedipine in vivo. However, the predicted AUE and Rmax changes of nifedipine in the presence to the absence of apatinib in cancer patients as well as in patients with hepatic impairment are all within 1.25-fold. The results indicate that the exposure changes of nifedipine caused by combination of apatinib has little effect on the changes of systolic blood pressure both in cancer patients and patients with hepatic impairment.Conclusion: The pharmacokinetic changes of nifedipine caused by co-administration with apatinib has little impact on the antihypertensive effect of nifedipine. Apatinib is unlikely to cause severe pharmacodynamic DDI via inhibition of CYP3A4. It is suggested that nifedipine could be used in combination with apatinib without dose adjustment in clinic.

The interplanetary magnetic field (IMF) By component can cause asymmetric features in the magnetosphere-ionosphere system and influence the electromagnetic energy input. In this study, we use the Space Weather Modeling Framework (SWMF) to study the transient dynamics after a sudden change in the IMF By component exerts on the magnetosphere system. Simulation results reveal that under northward IMF conditions, an abrupt change of the IMF By from duskward to dawnward induces a dawnward geomagnetic field firstly in the cusp region and then in both the near-Earth and magnetotail regions. The signal of the new y-component of the geomagnetic field in the near-Earth region extends tailward while that in the magnetotail moves Earthward, leading the middle-tail region to react last. We investigate in detail the transitional change of the y-component of the geomagnetic field and compare it to the scenario under southward IMF conditions, and find that the latter case reacts in a much simpler manner and the responses are faster globally.

Abstract Background Nasopharyngeal carcinoma (NPC) is a malignant head and neck tumor, and more than 70% of new cases are in East and Southeast Asia. However, association between NPC and pseudogenes playing important roles in genesis of multiple tumor types is still not clear and needs to be investigated. Methods Using RNA-Sequencing (RNA-seq) technology, we analyzed pseudogene expression in 13 primary NPC and 6 recurrent NPC samples as well as their paracancerous counterparts. Quantitative PCR was used to validate the differentially expressed pseudogenes. Results We found 251 differentially expressed pseudogenes including 73 up-regulated and 178 down-regulated ones between primary NPC and paracancerous tissues. Enrichment analysis of gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were conducted to filter out the key pseudogenes. We reported that pseudogenes from cytochrome P450 (CYP) family, such as CYP2F2P, CYP2G1P, CYP4F24P, CYP2B7P and CYP2G2P were significantly down-regulated in NPC compared to paracancerous tissues, while IGHV1OR15–2, IGHV3–11, FCGR1CP and IGHV3–69-1 belonging to Fc gamma receptors were significantly up-regulated. CYP2B7P, CYP2F2P and CYP4F26P were enriched in arachidonic acid metabolism pathway. The qRT-PCR analysis validated the lower expression of pseudogenes CYP2F2P and CYP2B7P in NPC tissues and cell lines compared to paracancerous tissues and normal human nasopharyngeal epithelial cell line. CYP2B7P overexpression weakened migratory and invasive capacity of NPC cell line. Moreover, the expression pattern of those pseudogenes in recurrent NPC tissues was different from the primary NPC. Conclusion This study suggested the role of pseudogenes in tumorigenesis and progression, potentially functioning as therapeutic targets to NPC.

A particle-in-cell simulation of symmetric reconnection with zero guide field is carried out to understand the dynamics of ions along the separatrices. Through the investigation of ion velocity distributions at different moments and locations along the separatrices, a typical distribution is found: two counter-streaming populations in the perpendicular direction, with another two populations accelerated into distinct energy levels in the parallel direction. Backward tracing of ions reveals that the counter-streaming cores are mostly composed of ions initially located at the same side of the separatrix, while the other two accelerated populations in the parallel direction are composed of ions crossing through the neutral sheet. Through analysis of energy conversion of these populations, it is found that the ion energization along the separatrix is attributable primarily to the Hall electric field, while that in the region between the two separatrices is caused primarily by the induced reconnection electric field. For the counter-streaming population, the low-energy ions that cross the separatrix twice are affected by both Hall and reconnection electric fields, while the high-energy ions that directly enter the separatrix from the unperturbed plasma are energized mainly by the Hall electric field. For the two energized populations in the parallel direction, the ions with lower-energy are accelerated mainly by the in-plane electric field and the Hall electric field on the opposite side of the separatrix, whereas the ions with higher-energy not only experience the same energization process but also are constantly accelerated by the reconnection electric field.

A three-dimensional four species multi-fluid magnetohydrodynamic (MHD) model was constructed to simulate the solar wind global interaction with Mars. The model was augmented to consider production and loss of the significant ion species in the Martian ionosphere, i.e., H+, O2+, O+, CO2+, associated with chemical reactions among all species. An ideal dipole-like local crustal field model was used to simplify the empirically measured Martian crustal field. Results of this simulation suggest that the magnetic pile-up region (MPR) and the velocity profile in the meridian plane are asymmetric, which is due to the nature of the multi-fluid model to decouple individual ion velocity resulting in occurrence of plume flow in the northern Martian magnetotail. In the presence of dipole magnetic field model, boundary layers, such as bow shock (BS) and magnetic pile-up boundary (MPB), become protuberant. Moreover, the crustal field has an inhibiting effect on the flux of ions escaping from Mars, an effect that occurs primarily in the region between the terminator (SZA 90°) and the Sun–Mars line of the magnetotail (SZA 180°), partially around the terminator region. In contrast, near the tailward central line the crustal field has no significant impact on the escaping flux.

Abstract Based on the Whole Atmosphere Community Climate Model with thermosphere and ionosphere extension (WACCM‐X) model outputs and Thermosphere‐Ionosphere‐Mesosphere Energetics and Dynamics (TIMED)/Sounding of the Atmosphere using Broadband Emission Radiometry (SABER) observations, we examine the global structures and temporal variations, that is, climatological and meteorological characteristics, of the daily diurnal eastward propagating non‐migrating temperature tide with zonal wavenumber 3 component (DE3), which could drive the ionospheric longitudinal structure wavenumber 4 structure (WN4), from 2003 to 2012 within the ±45° latitudes in the Mesosphere and low thermosphere (MLT) region (with altitude of 75–108 km). For the climatological characteristics (i.e., long‐term variability such as inter‐ and intra‐annual variations), both the WACCM‐X model outputs and TIMED/SABER observations show that the DE3 tides have stronger amplitudes during boreal later summer and early autumn (July, August, and September), and show Quasi‐biennial oscillation phenomenon. Meanwhile, only the WACCM‐X model presents a weak peak of the DE3 in boreal winter (December, January, and February). As to the meteorological characteristics (i.e., short‐term variability such as day‐to‐day variations), it is found that: (a) the short‐term variabilities from both the model outputs and observations are stronger at low‐latitudes (100 km); (b) the two datasets display an obvious semi‐annual variation of the DE3 day‐to‐day variabilities with the monthly standard deviations larger during the solstices; (c) only from the WACCM‐X model outputs, the short‐term variability of the DE3 exhibit an annual variation with the monthly standard deviations larger in boreal winter, which is related to the small peak in the DE3 tidal amplitudes. Comparing the absolute amplitudes, the contribution of the wave phases play more important roles in the short‐term variation of the temperature DE3 tidal component from both the WACCM‐X model outputs and TIMED/SABER observations. Overall, the WACCM‐X model outputs can well reproduce the temporal variation of the non‐migrating tide DE3 in the MLT region, especially the day‐to‐day variability.

Aim: Apatinib is an orally administered vascular epidermal growth factor receptor (VEGFR)-tyrosine kinase inhibitors approved for the treatment of advanced gastric adenocarcinoma or gastric esophageal junction adenocarcinoma. Apatinib is predominantly metabolized by CYP3A4/5, followed by CYP2D6. The present study aimed to evaluate the potential drug–drug interaction (DDI) and drug–disease interaction (DDZI) risks of apatinib in Chinese volunteers.Methods: Modeling and simulation were conducted using Simcyp Simulator. The input parameters required for modeling were obtained from literature research or experiments. Then, the developed physiologically based pharmacokinetic (PBPK) models were applied to evaluate single-dose DDI potential in Chinese healthy volunteers with weak and moderate CYP3A inhibitors, strong CYP2D6 inhibitors, as well as CYP3A4 inducers. The DDZI potential was also predicted in patients with hepatic or renal impairment.Results: The developed PBPK models accurately assessed apatinib pharmacokinetics following single-dose administration in Chinese healthy volunteers and cancer patients. The DDI simulation showed 2–4-fold changes in apatinib exposures by moderate CYP3A4 inhibitors and CYP3A4 inducers. A moderate increase of apatinib exposure (1.25–2-fold) was found with strong CYP2D6 inhibitor. In the DDZI simulation with hepatic impairment, the AUC of apatinib was significantly increased by 2.25-fold and 3.04-fold for Child–Pugh B and Child–Pugh C, respectively, with slightly decreased Cmax by 1.54 and 1.67-fold, respectively.Conclusion: The PBPK models developed in the present study would be highly beneficial to quantitatively predict the pharmacokinetic changes of apatinib under different circumstances, which might be difficult to evaluate clinically, so as to avoid some risks in advance.

Aging is an important factor affecting function of smell, leading to the degeneration of mature olfactory sensory neurons and inducing the occurrence of smell loss. The mammalian olfactory epithelium (OE) can regenerate when subjected to chemical assaults. However, this capacity is not limitless. Inactivation of globose basal cells and failure to generate sensory neurons are the main obstacles to prevent the OE regeneration. Here, we found the significant attenuation in mature sensory neuronal generation and apparent transcriptional alternation in the OE from aged mice compared with young ones. The recruitment of leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5)-positive cells in injured OE was weakened in aged mice, and more Lgr5+ cells remained quiescence in aged OE postinjury. Lineage-traced progenies from Lgr5+ cells were significantly fewer in the OE with aging. Moreover, Notch activation enhanced the neuronal regeneration in aged OE, making the regenerative capacity of aged OE comparable with that of young animals after injury. The growth and morphology of three-dimensional (3D)-cultured organoids from the OE of young and aged mice varied and was modulated by small molecules regulating the Notch signaling pathway. Thus, we concluded that activation of Lgr5+ cells in injured OE was age dependent and Notch activation could enhance the capacity of neuronal generation from Lgr5+ cells in aged OE after injury.

Nasopharyngeal carcinoma (NPC) is a common malignant tumor in Southern China and Southeast Asia. In this study, we found that Leucine rich repeat containing G protein-coupled receptor 5 (Lgr5) was highly expressed in NPC tissues and marked NPC stem cells. Lgr5high tumors showed differential transcriptional landscape compared to Lgr5not high tumors. Lgr5 expression was associated with the clinicopathologic features in NPC and was able to regulate the stemness and viability of NPC cell line CNE1 and HNE1. Meanwhile, the migration, invasion and epithelial-mesenchymal transition (EMT) was modulated by Lgr5 via Wnt/β-catenin signaling pathway. Furthermore, Lgr5 could regulate the sensitivity of NPC cells to chemotherapy drugs. Xenografted tumors from Lgr5-overexpressed CNE1 cells showed stronger tumor forming capacity and higher expression level of stem cell markers. Thus, we characterized previously unidentified role of Lgr5 in NPC cells, potential serving as a NPC stem cell biomarker and a therapeutic target against NPC.

Atorvastatin and its lactone form metabolite are reported to be associated with statin-induced myopathy (SIM) such as myalgia and life-threatening rhabdomyolysis. Though the statin-induced rhabdomyolysis is not common during statin therapy, its incidence will significantly increase due to pharmacokinetic drug-drug interactions (DDIs) with inhibitor drugs which inhibit atorvastatin’s and its lactone’s metabolism and hepatic uptake. Thus, the quantitative analysis of DDIs of atorvastatin and its lactone with cytochrome P450 3A4 (CYP3A4) and organic anion-transporting polypeptide (OATP) inhibitors is of great importance. This study aimed to predict pharmacokinetic DDIs possibly causing atorvastatin-induced rhabdomyolysis using Physiologically Based Pharmacokinetic (PBPK) Modelling. Firstly, we refined the PBPK models of atorvastatin and atorvastatin lactone for predicting the DDIs with CYP3A4 and OATP inhibitors. Thereafter, we predicted the exposure changes of atorvastatin and atorvastatin lactone originating from the case reports of atorvastatin-induced rhabdomyolysis using the refined models. The simulation results show that pharmacokinetic DDIs of atorvastatin and its lactone with fluconazole, palbociclib diltiazem and cyclosporine are significant. Consequently, clinicians should be aware of necessary dose adjustment of atorvastatin being used with these four inhibitor drugs.