Robust and Adhesive Laminar Solid Electrolyte with Homogenous and Fast Li-Ion Conduction for High-Performance All-Solid-State Lithium Metal Battery.

Constructing composite solid electrolytes (CSEs) integrating the merits of inorganic and organic components is a promising approach to developing high-performance all-solid-state lithium metal batteries (ASSLMBs). CSEs are now capable of achieving homogeneous and fast Li-ion flux, but how to escape the trade-off between mechanical modulus and adhesion is still a challenge. Herein, a strategy to address this issue is proposed, that is, intercalating highly conductive, homogeneous, and viscous-fluid ionic conductors into robust coordination laminar framework to construct laminar solid electrolyte with homogeneous and fast Li-ion conduction (LSE-HFC). A 9 µm-thick LSH-HFC, in which poly(ethylene oxide)/succinonitrile is adsorbed by coordination laminar framework with metal-organic framework nanosheets as building blocks, is used here as an example to determine the validity. The Li-ion transfer mechanism is verified and works across the entire LSE-HFC, which facilitates homogeneous Li-ion flux and low migration energy barriers, endowing LSE-HFC with high ionic conductivity of 5.62 × 10-4 S cm-1 and Li-ion transference number of 0.78 at 25 °C. Combining the outstanding mechanical strength against punctures and the enhanced adhesion force with electrodes, LSE-HFC harvests uniform Li plating/stripping behavior. These enable the realization of high-energy-density ASSLMBs with excellent cycling stability when being assembled as LiFePO4/Li and LiNi0.6Mn0.2Co0.2O2/Li cells.

Hyperprogressive disease during PD-1 blockade in patients with advanced pancreatic cancer.

The occurrence of markedly accelerated tumor growth during immunotherapy is considered a new mode of progression called hyperprogressive disease (HPD) and its impact on pancreatic cancer (PC) patients receiving immunotherapy is unknown. In this study, we described and explored the incidence, prognosis and predictors of HPD in patients with advanced PC treated with programmed cell death-1 (PD-1) inhibitors. We retrospectively analyzed clinicopathological data from 104 patients with advanced pancreatic cancer who were treated with PD-1 inhibitors at our institution during 2015-2020 and identified 10 (9.6%) patients with HPD. Overall survival (OS) was significantly poorer in patients with HPD compared to patients with progressive disease (PD) (median OS: 5.6 vs. 3.6 months, p < .01). Clinicopathological factors associated with the occurrence of HPD included smoking, metastatic sites >2, liver metastasis, antibiotic therapy within 21 days before immunotherapy (Abx B21), hemoglobin (Hb) level <110 g/L, and PD-1 inhibitor treatment line >2. Subgroup analysis showed that high levels of CA19-9 at baseline were associated with the development of subsequent HPD (p = .024) and a worse prognosis (mOS:16.2 months vs. 6.1 months, p < .01). Our study demonstrated that HPD may occur in PC patients treated with PD-1 inhibitors and is associated with several clinicopathological characteristics and poor prognosis. The baseline tumor marker CA19-9 may be one of the early predictors of HPD development in PC patients receiving immunotherapy.

The CBL1/9-CIPK1 calcium sensor negatively regulates drought stress by phosphorylating the PYLs ABA receptor.

The stress hormone, Abscisic acid (ABA), is crucial for plants to respond to changes in their environment. It triggers changes in cytoplasmic Ca2+ levels, which activate plant responses to external stresses. However, how Ca2+ sensing and signaling feeds back into ABA signaling is not well understood. Here we reveal a calcium sensing module that negatively regulates drought stress via modulating ABA receptor PYLs. Mutants cbl1/9 and cipk1 exhibit hypersensitivity to ABA and drought resilience. Furthermore, CIPK1 is shown to interact with and phosphorylate 7 of 14 ABA receptors at the evolutionarily conserved site corresponding to PYL4 Ser129, thereby suppressing their activities and promoting PP2C activities under normal conditions. Under drought stress, ABA impedes PYLs phosphorylation by CIPK1 to respond to ABA signaling and survive in unfavorable environment. These findings provide insights into a previously unknown negative regulatory mechanism of the ABA signaling pathway, which is mediated by CBL1/9-CIPK1-PYLs, resulting in plants that are more sensitive to drought stress. This discovery expands our knowledge about the interplay between Ca2+ signaling and ABA signaling.

Plasma membrane-associated calcium signaling regulates arsenate tolerance in Arabidopsis.

Arsenate [As(V)] is a metalloid with heavy metal properties and is widespread in many environments. Dietary intake of food derived from arsenate-contaminated plants constitutes a major fraction of the potentially health-threatening human exposure to arsenic. However, the mechanisms underlying how plants respond to arsenate stress and regulate the function of relevant transporters are poorly understood. Here, we observed that As(V) stress induces a significant Ca2+ signal in Arabidopsis (Arabidopsis thaliana) roots. We then identified a calcium-dependent protein kinase, CALCIUM-DEPENDENT PROTEIN KINASE 23 (CPK23), that interacts with the plasma membrane As(V)/Pi transporter PHOSPHATE TRANSPORTER 1;1 (PHT1;1) in vitro and in vivo. cpk23 mutants displayed a sensitive phenotype under As(V) stress, while transgenic Arabidopsis plants with constitutively active CPK23 showed a tolerant phenotype. Furthermore, CPK23 phosphorylated the C-terminal domain of PHT1;1, primarily at Ser514 and Ser520. Multiple experiments on PHT1;1 variants demonstrated that PHT1;1S514 phosphorylation is essential for PHT1;1 function and localization under As(V) stress. In summary, we revealed that plasma-membrane-associated calcium signaling regulates As(V) tolerance. These results provide insight for crop bioengineering to specifically address arsenate pollution in soils.

A composite indicator of derived neutrophil-lymphocyte ratio and lactate dehydrogenase correlates with outcomes in pancreatic carcinoma patients treated with PD-1 inhibitors.

Background: There are currently no established biomarkers that can predict whether advanced pancreatic carcinoma (PC) patients would benefit from immune checkpoint inhibitors (ICIs). Our study investigated whether the pretreatment composite biomarker of derived neutrophil-lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) can be used as a reliable prognostic factor for the survival of PC patients receiving PD-1 inhibitor therapy. Methods: Patients with advanced PC treated with PD-1 inhibitors at a single center from September 2015 to September 2020 were included. The high levels of dNLR (≥3) and LDH (≥250 U/L) were considered to be risk factors. Based on these two risk factors, patients in this study were categorized into two risk groups: the good dNLR-LDH group, without risk factors, and the intermediate/poor dNLR-LDH group, with one to two risk factors. Overall survival (OS) and progression-free survival (PFS) served as this study's primary and secondary endpoints. Cox regression models were used to identify independent prognostic factors for survival benefit. Results: There were 98 patients in our study. The good group included 61 (62.2%) patients and the intermediate/poor group included 37 (37.8%). The overall patients with PC who received immunotherapy had a median OS of 12.1 months, and the good dNLR-LDH group had a significantly longer OS compared with the intermediate/poor dNLR-LDH group (44.2 vs. 6.4 months; p < 0.010); median PFS was 3.7 and 2.5 months (p = 0.010). The number of metastatic sites >2 and immunotherapy as third-line or later was associated with worse PFS, and the line of immunotherapy and the dNLR-LDH indicator were independent prognostic factors for OS, according to multivariate analysis. Conclusion: The pretreatment composite biomarker of dNLR and LDH can be used as a prognostic biomarker in patients with advanced PC treated with PD-1 inhibitors.

Polymerase η Recruits DHX9 Helicase to Promote Replication across Guanine Quadruplex Structures.

DNA polymerase η (Pol η) catalyzes accurate bypass of ultraviolet light-induced cyclobutane pyrimidine dimers, and it also functions in several other related processes, including bypassing DNA with unusual structures. Here, we performed unbiased proteome-wide profiling of Pol η-interacting proteins by using two independent approaches, i.e., proximity labeling and affinity pull-down followed by LC-MS/MS analysis. We identified several helicases, including DHX9, as novel Pol η-interacting proteins. Additionally, ChIP-Seq analysis showed that Pol η is enriched at guanine quadruplex (G4) structure sites in chromatin. Moreover, Pol η promotes the recruitment of DHX9 to G4 structure loci in chromatin and facilitates DHX9-mediated unwinding of G4 structures. Deficiency in Pol η or DHX9 leads to attenuated replication across G4 regions in genomic DNA. Together, we unveiled the interaction between Pol η and DHX9 and demonstrated that the interaction promotes the replicative bypass of G4 structures in chromatin.

A water-soluble fluorescent probe for real-time visualization of γ-glutamyl transpeptidase activity in living cells.

γ-glutamyl transpeptidase (GGT) is a kind of cell-surface enzyme that is overexpressed in many cancer cells. It is of great significance to develop an ideal tool for the diagnosis of GGT-rich cancer cells. Here, we reported a simple-structured but effective imaging probe for the detection of GGT activity. In the presence of GGT, the γ-glutamyl linkage could be cleaved specifically to produce amino-substituted product, resulting in significant fluorescence enhancement at 578 nm. Moreover, we successfully employed the probe to monitor GGT activity in HepG2 cells. We envisaged that such a simple but effective imaging tool could improve the practical applications for bioimaging.

NT-seq: a chemical-based sequencing method for genomic methylome profiling.

DNA methylation plays vital roles in both prokaryotes and eukaryotes. There are three forms of DNA methylation in prokaryotes: N6-methyladenine (6mA), N4-methylcytosine (4mC), and 5-methylcytosine (5mC). Although many sequencing methods have been developed to sequence specific types of methylation, few technologies can be used for efficiently mapping multiple types of methylation. Here, we present NT-seq for mapping all three types of methylation simultaneously. NT-seq reliably detects all known methylation motifs in two bacterial genomes and can be used for identifying de novo methylation motifs. NT-seq provides a simple and efficient solution for detecting multiple types of DNA methylation.

Characteristics of human oral microbiome and its non-invasive diagnostic value in chronic kidney disease.

BACKGROUND: Morbidity of chronic kidney disease (CKD) is increased, with many complications and high mortality rates. The characteristics of oral microbiome in CKD patients have not been reported. This study aims to analyze the oral microbiome, and to demonstrate the potential of microbiome as noninvasive biomarkers for CKD patients. METHODS: The study collected 253 oral samples from different regions of China (Central China and East China) prospectively and finally 235 samples completed Miseq sequencing, including 103 samples from CKD patients and 132 healthy controls (HCs). RESULTS: Compared with HCs (n=88), the oral microbial diversity in CKD patients (n=44) was increased. Fourteen genera including Streptococcus, Actinomyces and Leptotrichia were enriched, while six genera including Prevotella and Haemophilus were decreased in CKD patients. Moreover, 49 predicted microbial gene functions including arginine metabolism and tryptophan metabolism increased, while 55 functions including Ribosome and DNA repair recombination proteins decreased. Furthermore, correlation analysis demonstrated that 38 operational taxonomic units (OTUs) were closely related to 5 clinical indicators of CKD. Notably, 7 optimal biomarkers were identified using random forest model, and the classifier model respectively reached an area under the curve (AUC) of 0.9917 and 0.8026 in the discovery and validation phase, achieving a cross-region validation. CONCLUSIONS: We first illustrated the characteristics of the oral microbiome of patients with CKD, identified the potential of oral microbial makers as noninvasive tools for the diagnosis of CKD and achieved cross-region validation.

KIF21A regulates breast cancer aggressiveness and is prognostic of patient survival and tumor recurrence.

PURPOSE: Invasion of carcinoma cells into surrounding tissue affects breast cancer staging, influences choice of treatment, and impacts on patient outcome. KIF21A is a member of the kinesin superfamily that has been well-studied in congenital extraocular muscle fibrosis. However, its biological relevance in breast cancer is unknown. This study investigated the functional roles of KIF21A in this malignancy and examined its expression pattern in breast cancer tissue. METHODS: The function of KIF21A in breast carcinoma was studied in vitro by silencing its expression in breast cancer cells and examining the changes in cellular activities. Immunohistochemical staining of breast cancer tissue microarrays was performed to determine the expression patterns of KIF21A. RESULTS: Knocking down the expression of KIF21A using siRNA in MDA-MB-231 and MCF7 human breast cancer cells resulted in significant decreases in tumor cell migration and invasiveness. This was associated with reduced Patched 1 expression and F-actin microfilaments. Additionally, the number of focal adhesion kinase- and paxillin-associated focal adhesions was increased. Immunohistochemical staining of breast cancer tissue microarrays showed that KIF21A was expressed in both the cytoplasmic and nuclear compartments of carcinoma cells. Predominance of cytoplasmic KIF21A was significantly associated with larger tumors and high grade cancer, and prognostic of cause-specific overall patient survival and breast cancer recurrence. CONCLUSION: The data demonstrates that KIF21A is an important regulator of breast cancer aggressiveness and may be useful in refining prognostication of this malignant disease.

Preparing Two-Dimensional Ordered Li0.33 La0.557 TiO3 Crystal in Interlayer Channel of Thin Laminar Inorganic Solid-State Electrolyte towards Ultrafast Li+ Transfer.

Inorganic superionic conductor holds great promise for high-performance all-solid-state lithium batteries. However, the ionic conductivity of traditional inorganic solid electrolytes (ISEs) is always unsatisfactory owing to the grain boundary resistance and large thickness. Here, a 13 µm-thick laminar framework with ≈1.3 nm interlayer channels is fabricated by self-assembling rigid, hydrophilic vermiculite (Vr) nanosheets. Then, Li0.33 La0.557 TiO3 (LLTO) precursors are impregnated in interlayer channels and afterwards in situ sintered to large-size, oriented, and defect-free LLTO crystal. We demonstrate that the confinement effect permits ordered arrangement of LLTO crystal along the c-axis (the fastest Li+ transfer direction), permitting the resultant 15 µm-thick Vr-LLTO electrolyte an ionic conductivity of 8.22×10-5  S cm-1 and conductance of 87.2 mS at 30 °C. These values are several times' higher than that of traditional LLTO-based electrolytes. Moreover, Vr-LLTO electrolyte has a compressive modulus of 1.24 GPa. Excellent cycling performance is demonstrated with all-solid-state Li/LiFePO4 battery.

GTPase ROP6 negatively modulates phosphate deficiency through inhibition of PHT1;1 and PHT1;4 in Arabidopsis thaliana.

Phosphorus, an essential macroelement for plant growth and development, is a major limiting factor for sustainable crop yield. The Rho of plant (ROP) GTPase is involved in regulating multiple signal transduction processes in plants, but potentially including the phosphate deficiency signaling pathway remains unknown. Here, we identified that the rop6 mutant exhibited a dramatic tolerant phenotype under Pi-deficient conditions, with higher phosphate accumulation and lower anthocyanin content. In contrast, the rop6 mutant was more sensitive to arsenate (As(V)) toxicity, the analog of Pi. Immunoblot analysis displayed that the ROP6 protein was rapidly degraded through ubiquitin/26S proteasome pathway under Pi-deficient conditions. In addition, pull-down assay using GST-RIC1 demonstrated that the ROP6 activity was decreased obviously under Pi-deficient conditions. Strikingly, protein-protein interaction and two-voltage clamping assays demonstrated that ROP6 physically interacted with and inhibited the key phosphate uptake transporters PHT1;1 and PHT1;4 in vitro and in vivo. Moreover, genetic analysis showed that ROP6 functioned upstream of PHT1;1 and PHT1;4. Thus, we conclude that GTPase ROP6 modulates the uptake of phosphate by inhibiting the activities of PHT1;1 and PHT1;4 in Arabidopsis.

The Effect of Artemisinin-Based Drugs vs Non-artemisinin-based Drugs on Gametophyte Carrying in the Body After the Treatment of Uncomplicated Falciparum Malaria: A Systematic Review and Meta-analysis.

The WHO recommends Artemisinin-based combination therapy (ACTs) as the first-line treatment for malaria. This meta-analysis aims to analyze the effects of artemisinin and its derivatives as well as non-artemisinin drugs on the gametophytes in the host during the treatment of falciparum malaria. Fourteen studies were included in this analysis, and the artemisinin combination drugs involved were: artemether-lumefantrine (AL), artemisinin (AST), artemether-benflumetol (AB), dihydroartemisinin-piperaquine + trimethoprim + primaquine (CV8), amodiaquine + sulfadoxine-pyrimethamine (ASP), pyronaridine-phosphate + dihydroartemisinin (PP-DHA), dihydroartemisinin (DHA), and mefloquine + artesunate (MA), with 1702 patients. The control intervention measures involved the following: sulfadoxine-pyrimethamine (SP), mefloquine (MQ), atovaquone-proguanil (AT-PG), chloroquine + sulfadoxine-pyrimethamine (C-SP), quinine (Q), pyronaridine-phosphate (PP), pyronaridine (PN), and mefloquine + primaquine (MP), with 833 patients. The effect of ACTs was more obvious (OR = 0.37, 95%CI: 0.22-0.62, p < 0.05). In the control group of second malaria attacks, the difference between the two groups was not statistically significant (RD = 1.16, 95%CI: 0.81-1.66, p < 0.05); there was no significant difference in treatment failure during follow-up (RD = -0.01, 95%CI: 0.04-0.03, p < 0.05). There were also very few serious adverse events in both groups. ACTs showed good therapeutic effects in preventing gametocythemia but did not control the recrudescence rate and overall cure, which indicated the effectiveness of the combination of antimalarial drugs. Further research is required to explore which compatibility method is most conducive to the development of clinical malaria control.

Alterations of the Human Gut Microbiome in Chronic Kidney Disease.

Gut microbiota make up the largest microecosystem in the human body and are closely related to chronic metabolic diseases. Herein, 520 fecal samples are collected from different regions of China, the gut microbiome in chronic kidney disease (CKD) is characterized, and CKD classifiers based on microbial markers are constructed. Compared with healthy controls (HC, n = 210), gut microbial diversity is significantly decreased in CKD (n = 110), and the microbial community is remarkably distinguished from HC. Genera Klebsiella and Enterobacteriaceae are enriched, while Blautia and Roseburia are reduced in CKD. Fifty predicted microbial functions including tryptophan and phenylalanine metabolisms increase, while 36 functions including arginine and proline metabolisms decrease in CKD. Notably, five optimal microbial markers are identified using the random forest model. The area under the curve (AUC) reaches 0.9887 in the discovery cohort and 0.9512 in the validation cohort (49 CKD vs 63 HC). Importantly, the AUC reaches 0.8986 in the extra diagnosis cohort from Hangzhou. Moreover, Thalassospira and Akkermansia are increased with CKD progression. Thirteen operational taxonomy units are correlated with six clinical indicators of CKD. In conclusion, this study comprehensively characterizes gut microbiome in non-dialysis CKD and demonstrates the potential of microbial markers as non-invasive diagnostic tools for CKD in different regions of China.

Effects of tristetraprolin on doxorubicin (adriamycin)-induced experimental kidney injury through inhibiting IL-13/STAT6 signal pathway.

To study the effects of Tristetraprolin (TTP) on Doxorubicin (DOX)-induced experimental kidney injury (KI). DOX was used to induce kidney injury in Balb/c male mice (in vivo) and in human kidney proximal tubular epithelial cell line (HK-2) and normal rat kidney epithelial cell line (NRK-52E) (in vitro). Body weight of experimental mice were recorded daily. Histological changes were observed using hematoxylin-eosin (HE) staining, and levels of blood urea nitrogen, serum creatinine and serum cystatin C in KI mice, and MDA, LDH and SOD in cells were detected using the corresponding kits. Meanwhile, the 2, 7-dichlorodihydrofluorescein diacetate (DCF-DA) fluorescent staining was used to assess intracellular levels of reactive oxygen species (ROS). TTP and Kim-1 expressions were measured by immunohistochemistry and western blot. The TNF-α, IL-1ß and IL-6 levels were evaluated by ELISA. Expressions of IL-13, STAT6, p-STAT6, Bcl-2, Bax, cleaved-caspase3 were detected using western blot, respectively. Cell Counting Kit-8 (CCK-8) was conducted for analyzing cell viability, and cells apoptosis were assessed by DAPI staining and flow cytometry. DOX treatment decreased body weight and aggravated renal injury without changes in water and food intake. DOX significantly reduced TTP expression, stimulated IL-13/STAT6 pathway and elevated the levels of several factors related to renal injury, including inflammatory response, oxidative stress and cell apoptosis, which were significantly restored by the treatment of overexpression TTP in vitro. Overexpression of TTP significantly reduces DOX-induced adverse outcomes so as to prevent renal injury. Inhibition of IL-13/STAT6 pathway may be the functional mechanism under TTP in experimental KI.