Polar domain structural evolution under electric field and temperature in the (Bi0.5 Na0.5)TiO3 -0.06BaTiO3 piezoceramics

Lead‐free bismuth sodium titanate and related compounds are of great interest as promising candidates for piezoelectric applications. However, the full understanding of this family of materials is still a challenge partly because of their structural complexity and different behaviors with or without the application of an external electric field. Here, piezoresponse force microscopy is used to gain insight into the mesoscopic‐scale domain structure of the morphotropic phase boundary (MPB) composition of (1‐x)Bi0.5Na0.5TiO3‐xBaTiO3 solid solution at x = 0.06 (abbreviated as BNT‐6BT). The evolution of the domains with the changes of the electric field and temperature has been thoroughly examined in conjunction with the crystal structure analysis and dielectric studies. It is found that ferroelectric domains with size of hundreds of nanometers are embedded in a relaxor state without visible domains on a mesoscopic scale, which are considered to contribute to the tetragonal and cubic phases in the material, respectively. Temperature‐independent domain configuration is observed in the unpoled sample from room temperature to 200°C. While, temperature‐dependent domain configuration is observed in the poled sample. The homogenously poled state breaks into the mixed domain configuration containing polydomain structure and invisible state around the so‐called depoling temperature. The structural changes on different length scales are also discussed. This work provides an in‐depth understanding of the structural and domain changes under an electric field and the temperature‐dependent domain evolution in both unpoled and poled states in the BNT‐BT solid solution of the MPB composition

Cuproptosis-related risk score predicts prognosis and characterizes the tumor microenvironment in colon adenocarcinoma

IntroductionCuproptosis is a novel copper-dependent regulatory cell death (RCD), which is closely related to the occurrence and development of multiple cancers. However, the potential role of cuproptosis-related genes (CRGs) in the tumor microenvironment (TME) of colon adenocarcinoma (COAD) remains unclear.MethodsTranscriptome, somatic mutation, somatic copy number alteration and the corresponding clinicopathological data of COAD were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus database (GEO). Difference, survival and correlation analyses were conducted to evaluate the characteristics of CRGs in COAD patients. Consensus unsupervised clustering analysis of CRGs expression profile was used to classify patients into different cuproptosis molecular and gene subtypes. TME characteristics of different molecular subtypes were investigated by using Gene set variation analysis (GSVA) and single sample gene set enrichment analysis (ssGSEA). Next, CRG Risk scoring system was constructed by applying logistic least absolute shrinkage and selection operator (LASSO) cox regression analysis and multivariate cox analysis. Real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) were used to exam the expression of key Risk scoring genes.ResultsOur study indicated that CRGs had relatively common genetic and transcriptional variations in COAD tissues. We identified three cuproptosis molecular subtypes and three gene subtypes based on CRGs expression profile and prognostic differentially expressed genes (DEGs) expression profile, and found that changes in multilayer CRGs were closely related to the clinical characteristics, overall survival (OS), different signaling pathways, and immune cell infiltration of TME. CRG Risk scoring system was constructed according to the expression of 7 key cuproptosis-related risk genes (GLS, NOX1, HOXC6, TNNT1, GLS, HOXC6 and PLA2G12B). RT-qPCR and IHC indicated that the expression of GLS, NOX1, HOXC6, TNNT1 and PLA2G12B were up-regulated in tumor tissues, compared with those in normal tissues, and all of GLS, HOXC6, NOX1 and PLA2G12B were closely related with patient survival. In addition, high CRG risk scores were significantly associated with high microsatellite instability (MSI-H), tumor mutation burden (TMB), cancer stem cell (CSC) indices, stromal and immune scores in TME, drug susceptibility, as well as patient survival. Finally, a highly accurate nomogram was constructed to promote the clinical application of the CRG Risk scoring system.DiscussionOur comprehensive analysis showed that CRGs were greatly associated with TME, clinicopathological characteristics, and prognosis of patient with COAD. These findings may promote our understanding of CRGs in COAD, providing new insights for physicians to predict prognosis and develop more precise and individualized therapy strategies

Gestational Folic Acid Administration Alleviated Maternal Postpartum Emotional and Cognitive Dysfunction in Mice

Gestational folic acid (FA) supplementation has been widely recognized for its benefits in preventing offspring defects, but its effect on postpartum females has not yet been adequately assessed. The occurrence of emotional and cognitive dysfunction is common in postpartum women, and its treatment remains limited. Considering the promising results of FA in various psychiatric disorders both in human and redents, we tested the effect of gestational FA administration on postpartum psychiatric behavioral phenotypes and the implicated brain-related mechanisms in a murine model. FA was administered orally in both the hormone-stimulated-pregnancy (HSP) model and pregnant mice at doses of 1 and 5 mg/kg. Postpartum behavioral results showed that the disorders of cognitive performance, depressive, and anxiety-related behaviors were all alleviated in the 5 mg/kg FA group. However, the general development of their offspring remained unaffected. Immunofluorescence and immunoblot results revealed that FA pretreatment significantly activated the maternal hippocampal BDNF-related pathway. Morphological studies have confirmed that FA promotes hippocampal neurogenesis. Moreover, synaptic plasticity and synaptic transmission are enhanced. All of these hippocampal changes play critical roles in rescuing neuronal function and behaviors. Thus, our data suggest that gestational FA administration has a therapeutic effect that improves cognition and reduces depression and anxiety in a murine postpartum model. This may be developed as a preventive and adjuvant therapeutic option for pregnant women

A single amino acid substitution confers enhanced methylation activity of mammalian Dnmt3b on chromatin DNA

Dnmt3a and Dnmt3b are paralogous enzymes responsible for de novo DNA methylation but with distinguished biological functions. In mice, disruption of Dnmt3b but not Dnmt3a causes global DNA hypomethylation, especially in repetitive sequences, which comprise the large majority of methylated DNA in the genome. By measuring DNA methylation activity of Dnmt3a and Dnmt3b homologues from five species, we found that mammalian Dnmt3b possessed significantly higher methylation activity on chromatin DNA than Dnmt3a and non-mammalian Dnmt3b. Sequence comparison and mutagenesis experiments identified a single amino acid substitution (I662N) in mammalian Dnmt3b as being crucial for its high chromatin DNA methylation activity. Further mechanistic studies demonstrated this substitution markedly enhanced the binding of Dnmt3b to nucleosomes and hence increased the chromatin DNA methylation activity. Moreover, this substitution was crucial for Dnmt3b to efficiently methylate repetitive sequences, which increased dramatically in mammalian genomes. Consistent with our observation that Dnmt3b evolved more rapidly than Dnmt3a during the emergence of mammals, these results demonstrated that the I662N substitution in mammalian Dnmt3b conferred enhanced chromatin DNA methylation activity and contributed to functional adaptation in the epigenetic system

A genome-wide association study of marginal zone lymphoma shows association to the HLA region

Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P - 3.95 x 10(-15)) and HLA-B (rs2922994, P - 2.43 x 10(-9)) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility

Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes

Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22–1.82, P-value = 8.5 × 10−5]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93–3.51, P-value = 4.0 × 10−10). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk

Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of three new genome-wide association studies (GWAS) and one prior scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of nine promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; $P=2.33x10^{-21}$), rs2523607 at 6p21.33 (HLA-B; $2.40x10^{-10}$), rs79480871 at 2p23.3 (NCOA1; $P=4.23x10^{-8}$), and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; $P=9.98x10^{-13}$ and $P=3.63x10^{-11}$, respectively). These data provide substantial new evidence for genetic susceptibility to this B-cell malignancy, and point towards pathways involved in immune recognition and immune function in the pathogenesis of DLBCL

Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10(-11)), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10(-8)) and 3q28 (rs9815073, LPP, P=3.62 × 10(-8)), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10(-11)) in the combined analysis. We find suggestive evidence (P<5 × 10(-7)) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10(-8)) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10(-7)). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility