Exhaustion of cytotoxic effector natural killer (NK) and CD8
T cells have important functions in the establishment of persistent viral infections, but how exhaustion is induced during chronic ...hepatitis C virus (HCV) infection remains poorly defined. Here we show, using the humanized C/O
mice permissive for persistent HCV infection, that NK and CD8
T cells become sequentially exhausted shortly after their transient hepatic infiltration and activation in acute HCV infection. HCV infection upregulates Qa-1 expression in hepatocytes, which ligates NKG2A to induce NK cell exhaustion. Antibodies targeting NKG2A or Qa-1 prevents NK exhaustion and promotes NK-dependent HCV clearance. Moreover, reactivated NK cells provide sufficient IFN-γ that helps rejuvenate polyclonal HCV CD8
T cell response and clearance of HCV. Our data thus show that NKG2A serves as a critical checkpoint for HCV-induced NK exhaustion, and that NKG2A blockade sequentially boosts interdependent NK and CD8
T cell functions to prevent persistent HCV infection.
Clostridium butyricum TO-A, Enterococcus faecium T-110, and Bacillus subtilis TO-A are sold as oral probiotic preparations and reportedly exhibit many beneficial effects on the health of hosts, ...including humans and livestock. In this study, we compared the ability of these clinically applied probiotic bacteria with Escherichia coli OP50 in extending the lifespan of Caenorhabditis elegans. To compare the C. elegans lifespan-extending effects of the three bacteria, experiments were performed using a nematode growth medium containing a small amount of trypticase soy agar. The maximum lifespans of worms fed C. butyricum TO-A, E. faecium T-110, or B. subtilis TO-A increased by 11, 12, and 26%, respectively, compared with worms fed E. coli OP50. In addition, we conducted a metabolomic analysis of methanol extracts of B. subtilis TO-A cells, which exhibited the strongest lifespan-extending effect on C. elegans among the probiotic bacteria tested in this study. As a result, 59 candidate substances involved in extending the lifespan of C. elegans were identified in B. subtilis TO-A cells.
An environmentally benign protocol of chemoselective transfer hydrogenation of C=C and C=O bonds with alkanols under base‐free conditions is developed by this study, wherein the cobalt‐ bidentate ...phosphine catalyst precursor is commercially available and the active low‐valent Co species could be generated in‐situ. For the conjugation enones, the vinyl group is selectively reduced, whereas with nonconjugated alkenones, the selectivity is changed to the carbonyl group. Besides, ortho‐alkenyl‐benzaldehydes/imines are well tolerated, and the reduction solely occurs at the C=O/C=N site with this protocol.
Low‐cost and sustainable: An environmentally benign protocol of Co‐bidentate phosphine complex‐catalyzed chemoselective transfer hydrogenation of C=C and C=O bonds with equivalent alkanols under base‐free conditions was developed.
Transverse relaxation times (T2) and T2 spectrum for crude oil emulsions with different water content are obtained by low field nuclear magnetic resonance Carr-Purcell-Meiboom-Gill sequence and ...various methods to determine the water content are investigated. The results show that there are three methods to accurately determine the water content. When water content is greater than 20.0wt%, determination through T2 value of emulsions is fastest with the relative error below 2.5%. T2 spectrum show the characteristics of multiple peaks, and T2 value of the peaks originated from water are suitable for determination of water content for O/W emulsions. A method is developed and optimized to determine the water content by using the peak-area ratio in T2 spectrum, which is not limited by the water content and the form of emulsion.
The third-generation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), represented by osimertinib, has achieved remarkable clinical outcomes in the treatment of ...non-small-cell lung cancer (NSCLC) with EGFR mutation. However, resistance eventually emerges in most patients and the underlying molecular mechanisms remain to be fully understood. In this study, we generated an osimertinib-acquired resistant lung cancer model from a NSCLC cell line H1975 harboring EGFR L858R and T790M mutations. We found that the capacity of DNA damage repair was compromised in the osimertinib resistant cells, evidenced by increased levels of γH2AX and higher intensity of the comet tail after withdrawal from cisplatin. Pharmacological inhibiting the activity or genetic knockdown the expression of DNA-PK, a key kinase in DNA damage response (DDR), sensitized the resistant cells to osimertinib. Combination of osimertinib with the DNA-PK inhibitor, PI-103, or NU7441, synergistically suppressed the proliferation of the resistant cells. Mechanistically, we revealed that DNA-PK inhibitor in combination with osimertinib resulted in prolonged DNA damage and cell cycle arrest. These findings shed new light on the mechanisms of osimertinib resistance in the aspect of DNA repair, and provide a rationale for targeting DNA-PK as a therapeutic strategy to overcome osimertinib-acquired resistance in NSCLC.
A protocol for a CoII/N,N′,N′′‐trihydroxyisocyanuric acid (THICA)‐catalyzed aerobic oxidative esterification and amidation of aldehydes has been developed. Preliminary insight into the mechanism ...indicates that such an oxidative C−O/N cross‐coupling reaction proceeds by masking the aldehyde in a nucleophilic addition reaction with an alkoxy/amino source, thereby keeping the highly reactive formyl group from undesired oxidation. This protocol for the oxidative esterification and amidation of aldehydes proceeds through two different pathways that are characterized by the intrinsic nucleophilicity of the alkanol and amine substrates The former occurs in the presence of p‐CH3C6H4SO3H as a cocatalyst and orthoformates as the alkoxy sources, instead of alkanols, to efficiently afford the transient acetals. In contrast, the coupling of the more nucleophilic amines with aldehydes renders a readily accessible cross‐coupling reaction that occurs without any cocatalyst but is limited by the potential inhibition of THICA upon nucleophilic substitution by an amine. Consequently, only sterically hindered amines were tolerated in this catalytic system, whereas further condensation occurred in the presence of primary amines to lead to imines.
Through THICA and thin: A protocol for a CoII/N,N′,N′′‐trihydroxyisocyanuric acid (THICA) mediated aerobic oxidative esterification and amidation of aldehydes has been developed. A variety of esters and amides were obtained in moderate to excellent yields by using this one‐step approach.
Without use of any surfactant or oxidant, a series of Co3O4 catalysts have been prepared from cobalt nitrate aqueous solution via a very simple liquid-precipitation method with ammonium acid ...carbonate followed by calcination at various temperatures. The catalytic performance of the Co3O4 for CO oxidation has been studied with a continuous flowing laboratory microreactor system. The results show that the CO conversion of all the samples can reach 100% at ambient temperature. The catalyst calcined at 300 °C is able to maintain its activity for CO complete oxidation more than 500 min at 25 °C and about 240 min even at −78 °C. High reaction temperature results in a high catalytic stability, while the catalytic stability decreases with further increasing the reaction temperature. Characterizations with X-ray powder diffraction and transmission electron microscopy suggest that all the samples exist as a pure Co3O4 phase with the spinel structure, the samples are apt to aggregate and the specific surface area gradually decreases with increasing the calcination temperature, which directly leads to the decrease of catalytic stability. Furthermore, the amount of active oxygen species measured by CO titration experiments appears to be critical for catalytic performance.
In this paper, the Co
3
O
4
catalysts prepared by the liquid phase precipitation method were investigated with respect to their activity and stability in CO oxidation reaction. The Co
3
O
4
catalysts ...were comparatively investigated by thermal gravimetry analysis (TG-DTG), X-ray powder diffraction (XRD), N
2
adsorption, CO titration and O
2
-temperature program desorption (O
2
-TPD). The results of XRD show that all the catalysts exist as a pure Co
3
O
4
phase with the spinel structure. The high catalytic activity observed at ambient temperature is followed by a gradual decrease. The CO titration experiments show that the Co
3
O
4
catalysts possess active oxygen species. The total amount of active oxygen species and the specific surface area decrease with increasing calcination temperature. The O
2
-TPD results indicate that O
2
−
and O
−
are the possible active oxygen species.
This study aimed at comprehending the transversal relaxation time(T
2
) spectra and relaxation mechanism for O/W and W/O/W emulsions in NMR CPMG experiment. The T
2
relaxation model for O/W and W/O/W ...emulsions was established respectively. T
2
spectra of O/W emulsions with different water content and W/O/W emulsions with settling time in demulsification were analyzed based the relaxation models. The results show that the T
2
spectra characteristics of emulsions in NMR CPMG experiment are consistent with the prediction of relaxation models, which indicated that relaxation models were practical and contribute to the analysis of T
2
spectra for emulsions. Those study laid a foundation for analyzing the characters of single or double emulsions basing T
2
spectra.
We identify a B7 family molecule, B7-H4, by protein sequence analysis and comparative molecular modeling. While B7-H4 mRNA is widely distributed in mouse and human peripheral tissues, cell surface ...expression of B7-H4 protein is limited and shows an inducible pattern on hematopoietic cells. Putative receptor of B7-H4 can be upregulated on activated T cells. By arresting cell cycle, B7-H4 ligation of T cells has a profound inhibitory effect on the growth, cytokine secretion, and development of cytotoxicity. Administration of B7-H4Ig into mice impairs antigen-specific T cell responses whereas blockade of endogenous B7-H4 by specific monoclonal antibody promotes T cell responses. B7-H4 thus may participate in negative regulation of cell-mediated immunity in peripheral tissues.
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