Simultaneous High Ionic Conductivity and Lithium-Ion Transference Number in Single-Ion Conductor Network Polymer Enabling Fast-Charging Solid-State Lithium Battery.

Developing solid-state electrolyte with sufficient ionic conduction and flexible-intimate interface is vital to advance fast-charging solid-state lithium batteries. Solid polymer electrolyte yields the promise of interfacial compatibility, yet its critical bottleneck is how to simultaneously achieve high ionic conductivity and lithium-ion transference number. Herein, single-ion conducting network polymer electrolyte (SICNP) enabling fast charging is proposed to positively realize fast lithium-ion locomotion with both high ionic conductivity of 1.1 × 10-3 S cm-1 and lithium-ion transference number of 0.92 at room temperature. Experimental characterization and theoretical simulations demonstrate that the construction of polymer network structure for single-ion conductor not only facilitates fast hopping of lithium ions for boosting ionic kinetics, but also enables a high dissociation level of the negative charge for lithium-ion transference number close to unity. As a result, the solid-state lithium batteries constructed by coupling SICNP with lithium anodes and various cathodes (e.g., LiFePO4 , sulfur, and LiCoO2 ) display impressive high-rate cycling performance (e.g., 95% capacity retention at 5 C for 1000 cycles in LiFePO4 |SICNP|lithium cell) and fast-charging capability (e.g., being charged within 6 min and discharged over than 180 min in LiCoO2 |SICNP|lithium cell). Our study provides a prospective direction for solid-state electrolyte that meets the lithium-ion dynamics for practical fast-charging solid-state lithium batteries.

Efficient photoactivatable Dre recombinase for cell type-specific spatiotemporal control of genome engineering in the mouse.

Precise genetic engineering in specific cell types within an intact organism is intriguing yet challenging, especially in a spatiotemporal manner without the interference caused by chemical inducers. Here we engineered a photoactivatable Dre recombinase based on the identification of an optimal split site and demonstrated that it efficiently regulated transgene expression in mouse tissues spatiotemporally upon blue light illumination. Moreover, through a double-floxed inverted open reading frame strategy, we developed a Cre-activated light-inducible Dre (CALID) system. Taking advantage of well-defined cell-type-specific promoters or a well-established Cre transgenic mouse strain, we demonstrated that the CALID system was able to activate endogenous reporter expression for either bulk or sparse labeling of CaMKIIα-positive excitatory neurons and parvalbumin interneurons in the brain. This flexible and tunable system could be a powerful tool for the dissection and modulation of developmental and genetic complexity in a wide range of biological systems.

LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells.

The fourth member of the leucine-rich repeat-containing GPCR family (LGR4, frequently referred to as GPR48) and its cognate ligands, R-spondins (RSPOs) play crucial roles in the development of multiple organs as well as the survival of adult stem cells by activation of canonical Wnt signaling. Wnt/ß-catenin signaling acts to regulate breast cancer; however, the molecular mechanisms determining its spatiotemporal regulation are largely unknown. In this study, we identified LGR4 as a master controller of Wnt/ß-catenin signaling-mediated breast cancer tumorigenesis, metastasis, and cancer stem cell (CSC) maintenance. LGR4 expression in breast tumors correlated with poor prognosis. Either Lgr4 haploinsufficiency or mammary-specific deletion inhibited mouse mammary tumor virus (MMTV)- PyMT- and MMTV- Wnt1-driven mammary tumorigenesis and metastasis. Moreover, LGR4 down-regulation decreased in vitro migration and in vivo xenograft tumor growth and lung metastasis. Furthermore, Lgr4 deletion in MMTV- Wnt1 tumor cells or knockdown in human breast cancer cells decreased the number of functional CSCs by ∼90%. Canonical Wnt signaling was impaired in LGR4-deficient breast cancer cells, and LGR4 knockdown resulted in increased E-cadherin and decreased expression of N-cadherin and snail transcription factor -2 ( SNAI2) (also called SLUG), implicating LGR4 in regulation of epithelial-mesenchymal transition. Our findings support a crucial role of the Wnt signaling component LGR4 in breast cancer initiation, metastasis, and breast CSCs.-Yue, Z., Yuan, Z., Zeng, L., Wang, Y., Lai, L., Li, J., Sun, P., Xue, X., Qi, J., Yang, Z., Zheng, Y., Fang, Y., Li, D., Siwko, S., Li, Y., Luo, J., Liu, M. LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells.

Elevation of GPRC5A expression in colorectal cancer promotes tumor progression through VNN-1 induced oxidative stress.

The clearance of oxidative stress compounds is critical for the protection of the organism from malignancy, but how this key physiological process is regulated is not fully understood. Here, we found that the expression of GPRC5A, a well-characterized tumor suppressor in lung cancer, was elevated in colorectal cancer tissues in patients. In both cancer cell lines and a colitis-associated cancer model in mice, we found that GPRC5A deficiency reduced cell proliferation and increased cell apoptosis as well as inhibited tumorigenesis in vivo. Through RNA-Seq transcriptome analysis, we identified oxidative stress associated pathways were dysregulated. Moreover, in GPRC5A deficient cells and mouse tissues, the oxidative agents were reduced partially due to increased glutathione (GSH) level. Mechanistically, GPRC5A regulates NF-κB mediated Vanin-1 expression which is the predominant enzyme for cysteamine generation. Administration of cystamine (the disulfide form of cysteamine) in GPRC5A deficient cell lines inhibited γ-GCS activity, leading to reduction of GSH level and increase of cell growth. Taken together, our studies suggest that GPRC5a is a potential biomarker for colon cancer and promotes tumorigenesis through stimulation of Vanin-1 expression and oxidative stress in colitis associated cancer. This study revealed an unexpected oncogenic role of GPRC5A in colorectal cancer suggesting there are complicated functional and molecular mechanism differences of this gene in distinct tissues.

Repression of Mammalian Target of Rapamycin Complex 1 Inhibits Intestinal Regeneration in Acute Inflammatory Bowel Disease Models.

The mammalian target of rapamycin (mTOR) signaling pathway integrates environmental cues to regulate cell growth and survival through various mechanisms. However, how mTORC1 responds to acute inflammatory signals to regulate bowel regeneration is still obscure. In this study, we investigated the role of mTORC1 in acute inflammatory bowel disease. Inhibition of mTORC1 activity by rapamycin treatment or haploinsufficiency of Rheb through genetic modification in mice impaired intestinal cell proliferation and induced cell apoptosis, leading to high mortality in dextran sodium sulfate- and 2,4,6-trinitrobenzene sulfonic acid-induced colitis models. Through bone marrow transplantation, we found that mTORC1 in nonhematopoietic cells played a major role in protecting mice from colitis. Reactivation of mTORC1 activity by amino acids had a positive therapeutic effect in mTORC1-deficient Rheb(+/-) mice. Mechanistically, mTORC1 mediated IL-6-induced Stat3 activation in intestinal epithelial cells to stimulate the expression of downstream targets essential for cell proliferation and tissue regeneration. Therefore, mTORC1 signaling critically protects against inflammatory bowel disease through modulation of inflammation-induced Stat3 activity. As mTORC1 is an important therapeutic target for multiple diseases, our findings will have important implications for the clinical usage of mTORC1 inhibitors in patients with acute inflammatory bowel disease.

The association between circulating leukocytes and inflammatory bowel disease: a two-sample Mendelian randomization study.

Background: Inflammatory bowel disease (IBD) is a highly prevalent, recurrent, chronic intestinal inflammatory disease. Several observational studies have shown that circulating leukocytes are strongly associated with IBD. However, whether alterations in leukocytes are causally related to IBD remains uncertain. The present study explores this issue with the Mendelian randomization (MR) analysis method. Methods: The Genome wide association study (GWAS) statistical data related to circulating leukocytes and IBD were obtained from the Blood Cell Consortium and the IEU Qpen GWAS project, respectively. Inverse variance weighting (IVW) was used as the main MR analytical method, coupled with a series of sensitivity analyses to ensure the reliability of the results. Results: The results of IVW showed that increased monocyte count (especially CD14- CD16+ monocyte absolute counts) was negatively correlated with the risk of IBD and its main subtypes. Increased neutrophil count was positively associated with the risk of IBD and ulcerative colitis. Meanwhile, there was no causal relationship between basophil, eosinophil, lymphocyte counts and IBD risk. Conclusion: These results indicate that a causal relationship exists between circulating leukocytes and the risk of IBD and its subtypes, which confirms the important role that the leukocyte immune system plays in IBD. Our findings provide additional research directions for the clinical prevention and treatment of IBD.

Causality between various cytokines and asthma: a bidirectional two-sample Mendelian randomization analysis.

Background: Many studies have shown that cytokines play an important role in the pathogenesis of asthma, but their biological effects on asthma remain unclear. The Mendelian randomization (MR) method was used to evaluate the causal relationship between various cytokines [such as interleukins (ILs), interferons (IFNs), tumor necrosis factors (TNFs), colony-stimulating factors (CSFs), transforming growth factor (TGF), etc.,] and asthma. Methods: In this study, inverse variance weighting was used to evaluate the causal relationship between asthma and cytokines. In addition, the reliability of the results is ensured by multiple methods such as MR-Egger, weighted median, MR-Raps, MR-Presso, and RadialMR, as well as sensitivity analysis. Results: The results showed that none of the 11 cytokines was associated with the risk of asthma. In contrast, asthma can increase levels of IL-5 [odds ratio (OR) = 1.112, 95% confidence interval (CI): 1.009-1.224, P = 0.032] and IL-9 (OR = 1.111, 95% CI: 1.013-1.219, P = 0.025). Conclusion: Genetically predicted asthma was positively associated with elevated levels of IL-5 and IL-9, indicating the downstream effects of IL-5 and IL-9 on asthma. Medical treatments can thus be designed to target IL-5 and IL-9 to prevent asthma exacerbations.

Asthma and atopic dermatitis as risk factors for rheumatoid arthritis: a bidirectional mendelian randomization study.

BACKGROUND: Previous observational studies have shown an association between asthma, atopic dermatitis (AD) and rheumatoid arthritis (RA). However, the bidirectional cause-effect chain between asthma and AD and RA has not been proven yet. METHODS: We performed bidirectional two-sample Mendelian randomization (TSMR) and selected single nucleotide polymorphisms (SNPs) associated with asthma, AD, and RA as instrumental variables. All of the SNPs were obtained from the latest genome-wide association study in Europeans. Inverse variance weighted (IVW) was the main method used in MR analysis. MR-Egger, weighted model, simple model, and weighted median were used for quality control. The robustness of the results was tested by sensitivity analysis. RESULTS: Asthma was found to be the largest effect size for RA susceptibility using the IVW method (OR, 1.35;95%CI, 1.13-1.60; P, 0.001), followed by AD (OR, 1.10;95%CI, 1.02-1.19; P, 0.019). In contrast, there was no causal relationship between RA and asthma (IVW: P = 0.673) or AD (IVW: P = 0.342). No pleiotropy or heterogeneity was found in the sensitivity analysis. CONCLUSION: Findings from this study showed a causal relationship between genetic susceptibility to asthma or AD and increased risk of RA, but do not support a causal relationship between genetic susceptibility to RA and asthma or AD.

Tuning the Covalent Coupling Degree between the Cathode and Electrolyte for Optimized Interfacial Resistance in Solid-State Lithium Batteries.

The development of promising solid-state lithium batteries has been a challenging task mainly due to the poor interfacial contact and high interfacial resistance at the electrode/solid-state electrolyte (SSE) interface. Herein, we propose a strategy for introducing a class of covalent interactions with varying covalent coupling degrees at the cathode/SSE interface. This method significantly reduces interfacial impedances by strengthening the interactions between the cathode and SSE. By adjusting the covalent coupling degree from low to high, an optimal interfacial impedance of 33 Ω cm-2 was achieved, which is even lower than the interfacial impedance using liquid electrolytes (39 Ω cm-2). This work offers a fresh perspective on solving the interfacial contact problem in solid-state lithium batteries.