Dyadic communication quality and family resilience in gynecologic cancer survivors: a study on the mediating role of perceived spousal support.

PURPOSE: To analyze the level of family resilience in Chinese gynecological cancer survivors and determine whether perceived spousal support plays a mediating role in the relationship between dyadic communication quality and family resilience, enhance the confidence of families in coping with the disease together, and thus promote psychosocial adaptation to cancer. METHODS: A total of 348 gynecologic cancer survivors were selected from a gynecologic ward in a public hospital in Shandong Province, China. All participants completed the Sociodemographic and Clinical Characteristics Questionnaire, Couples' Communication Quality Scale (CCQS), Perceived Social Support Scale (PSSS), and Family Hardiness Index (FHI). The mediating effect of perceived spousal support was estimated using the bootstrap method via IBM SPSS AMOS 21.0. RESULTS: The mean FHI score was 53.03 ± 9.34 points, showing moderate levels of family resilience. Family resilience was shown to be significantly positively associated with both perceived spousal support and dyadic communication quality (both p < 0.01). Furthermore, perceived spousal support was shown to partially mediate the relationship between communication quality and family resilience (ß = 0.141; 95% confidence interval: 0.063-0.243). CONCLUSION: The level of family resilience in survivors of gynecologic cancer needs to be further improved, and perceived spousal support partially mediates the relationship between dyadic communication quality and family resilience within this population. Therefore, dyadic communication quality and subjective perceived spousal support should be enhanced for gynecologic cancer survivors to increase their family resilience.

Influence of Grain Orientation and Grain Boundary Features on Local Stress State of Cu-8Al-11Mn Alloy Investigated Using Crystal Plasticity Finite Element Method.

Reducing the local stress in the vicinity of the grain boundaries is a favorable way to improve the super-elastic properties of super-elastic alloys. The crystal plasticity finite element method (CPFEM) was applied in this study to simulate the deformation behavior and local stress of a super-elastic Cu-8Al-11Mn (wt.%) alloy containing single grains with various orientations, columnar grains with different misorientation angles, and tri-crystals with distinct grain boundary morphologies. The results indicated that the stress distribution of single grains presented obvious orientation dependence during deformation. Uniformly distributed stress was observed in grains with orientations of 0° and 90° when more slip systems were activated during deformation. With the increase in the misorientation angles of columnar grains, the stresses in the vicinity of the grain boundaries increased, which was related to the difference in the shear stress of the slip systems in adjacent grains. When the difference in the shear stress of the slip systems in two adjacent grains was large, a local stress concentration formed in the vicinity of the grain boundary. Compared with the triple-junction grain boundaries, the local stresses of the straight and vertical grain boundaries were smaller, which was closely related to the number of activated slip systems on both sides of the grain boundary. The above results were obtained experimentally and could be used to design super-elastic alloys with high performance.

High-Throughput Nano-DESI Mass Spectrometry Imaging of Biological Tissues Using an Integrated Microfluidic Probe.

Nanospray desorption electrospray mass spectrometry imaging (nano-DESI MSI) enables quantitative mapping of hundreds of molecules in biological samples with minimal sample pretreatment. We have recently developed an integrated microfluidic probe (iMFP) for nano-DESI MSI. Herein, we describe an improved design of the iMFP for the high-throughput imaging of tissue sections. We increased the dimensions of the primary and spray channels and optimized the spray voltage and solvent flow rate to obtain a stable operation of the iMFP at both low and high scan rates. We observe that the sensitivity, molecular coverage, and spatial resolution obtained using the iMFP do not change to a significant extent as the scan rate increases. Using a scan rate of 0.4 mm/s, we obtained high-quality images of mouse uterine tissue sections (scan area: 3.2 mm × 2.3 mm) in only 9.5 min and of mouse brain tissue (scan area: 7.0 mm × 5.4 mm) in 21.7 min, which corresponds to a 10-15-fold improvement in the experimental throughput. We have also developed a quantitative metric for evaluating the quality of ion images obtained at different scan rates. Using this metric, we demonstrate that the quality of nano-DESI MSI data does not degrade substantially with an increase in the scan rate. The ability to image biological tissues with high throughput using iMFP-based nano-DESI MSI will substantially speed up tissue mapping efforts.

High-resolution imaging and identification of biomolecules using Nano-DESI coupled to ion mobility spectrometry.

Simultaneous spatial localization and structural characterization of molecules in complex biological samples currently represents an analytical challenge for mass spectrometry imaging (MSI) techniques. In this study, we describe a novel experimental platform, which substantially expands the capabilities and enhances the depth of chemical information obtained in high spatial resolution MSI experiments performed using nanospray desorption electrospray ionization (nano-DESI). Specifically, we designed and constructed a portable nano-DESI MSI platform and coupled it with a drift tube ion mobility (IM) spectrometer-mass spectrometer. We demonstrate imaging of drift time-separated ions with a high spatial resolution of better than ∼25 µm using uterine tissues on day 4 of pregnancy in mice. Collision cross-section measurements provide unique molecular descriptors of molecules observed in nano-DESI-IM-MSI necessary for their unambiguous identification by comparison with databases. Meanwhile, isomer-specific imaging reveals variations in the isomeric composition across the tissue. Furthermore, IM separation efficiently eliminates isobaric and isomeric interferences originating from solvent peaks, overlapping isotopic peaks of endogenous molecules extracted from the tissue, and products of in-source fragmentation, which is critical to obtaining accurate concentration gradients in the sample using MSI. The structural information provided by the IM separation substantially expands the molecular specificity of high-resolution MSI necessary for unraveling the complexity of biological systems.

Cannabinoid and planar cell polarity signaling converges to direct placentation.

Directed trophoblast migration toward the maternal mesometrial pole is critical for placentation and pregnancy success. Trophoblasts replace maternal arterial endothelial cells to increase blood supply to the placenta. Inferior trophoblast invasion results in pregnancy complications including preeclampsia, intrauterine growth restriction, miscarriage, and preterm delivery. The maternal chemotactic factors that direct trophoblast migration and the mechanism by which trophoblasts respond to these factors are not clearly understood. Here, we show that invasive trophoblasts deficient in Vangl2, a core planar cell polarity (PCP) component, fail to invade in maternal decidua, and this deficiency results in middle-gestational fetal demise. Previously, we have shown that tightly regulated endocannabinoids via G protein-coupled cannabinoid receptor CB1 are critical to the invasion of trophoblasts called spiral artery trophoblast giant cells (SpA-TGCs). We find that CB1 directly interacts with VANGL2. Trophoblast stem cells devoid of Cnr1 and/or Vangl2 show compromised cell migration. To study roles of VANGL2 and CB1 in trophoblast invasion in vivo, we conditionally deleted Cnr1 (coding CB1) and Vangl2 in progenitors of SpA-TGCs using trophoblast-specific protein alpha (Tpbpa)-Cre. We observed that signaling mediated by VANGL2 and CB1 restrains trophoblasts from random migration by keeping small GTPases quiescent. Our results show that organized PCP in trophoblasts is indispensable for their directed movement and that CB1 exerts its function by direct interaction with membrane proteins other than its canonical G protein-coupled receptor role.

Imaging and Analysis of Isomeric Unsaturated Lipids through Online Photochemical Derivatization of Carbon-Carbon Double Bonds*.

Unraveling the complexity of the lipidome requires the development of novel approaches for the structural characterization of lipid species with isomer-level discrimination. Herein, we introduce an online photochemical approach for lipid isomer identification through selective derivatization of double bonds by reaction with singlet oxygen. Lipid hydroperoxide products are generated promptly after laser irradiation. Fragmentation of these species in a mass spectrometer produces diagnostic fragments revealing the C=C locations in the unreacted lipids. This approach uses an inexpensive light source and photosensitizer making it easy to incorporate into any lipidomics workflow. We demonstrate the utility of this approach for the shotgun profiling of C=C locations in different lipid classes present in tissue extracts using electrospray ionization (ESI) and ambient imaging of lipid species differing only by the location of C=C bonds using nanospray desorption electrospray ionization (nano-DESI).

Pregnancy success in mice requires appropriate cannabinoid receptor signaling for primary decidua formation.

With implantation, mouse stromal cells begin to transform into epithelial-like cells surrounding the implantation chamber forming an avascular zone called the primary decidual zone (PDZ). In the mouse, the PDZ forms a transient, size-dependent permeable barrier to protect the embryo from maternal circulating harmful agents. The process of decidualization is critical for pregnancy maintenance in mice and humans. Mice deficient in cannabinoid receptors, CB1 and CB2, show compromised PDZ with dysregulated angiogenic factors, resulting in the retention of blood vessels and macrophages. This phenotype is replicated in Cnr1-/- but not in Cnr2-/-mice. In vitro decidualization models suggest that Cnr1 levels substantially increase in mouse and human decidualizing stromal cells, and that neutralization of CB1 signaling suppresses decidualization and misregulates angiogenic factors. Taken together, we propose that implantation quality depends on appropriate angiogenic events driven by the integration of CB2 in endothelial cells and CB1 in decidual cells.

Genome-wide identification of imprinted genes in pigs and their different imprinting status compared with other mammals.

Genomic imprinting often results in parent-of-origin specific differential expression of maternally and paternally inherited alleles and plays an essential role in mammalian development and growth. Mammalian genomic imprinting has primarily been studied in mice and humans, with only limited information available for pigs. To systematically characterize this phenomenon and evaluate imprinting status between different species, we investigated imprinted genes on a genome-wide scale in pig brain tissues. Specifically, we performed bioinformatics analysis of high-throughput sequencing results from parental genomes and offspring transcriptomes of hybrid crosses between Duroc and Diannan small-ear pigs. We identified 11 paternally and five maternally expressed imprinted genes in pigs with highly stringent selection criteria. Additionally, we found that the KCNQ1 and IGF2R genes, which are related to development, displayed a different imprinting status in pigs compared with that in mice and humans. This comprehensive research should help improve our knowledge on genomic imprinting in pigs and highlight the potential use of imprinted genes in the pig breeding field.

An Integrated Microfluidic Probe for Mass Spectrometry Imaging of Biological Samples*.

Ambient ionization based on liquid extraction is widely used in mass spectrometry imaging (MSI) of molecules in biological samples. The development of nanospray desorption electrospray ionization (nano-DESI) has enabled the robust imaging of tissue sections with high spatial resolution. However, the fabrication of the nano-DESI probe is challenging, which limits its dissemination to the broader scientific community. Herein, we describe the design and performance of an integrated microfluidic probe (iMFP) for nano-DESI MSI. The glass iMFP, fabricated using photolithography, wet etching, and polishing, shows comparable performance to the capillary-based nano-DESI MSI in terms of stability and sensitivity; a spatial resolution of better than 25 µm was obtained in these first proof-of-principle experiments. The iMFP is easy to operate and align in front of a mass spectrometer, which will facilitate broader use of liquid-extraction-based MSI in biological research, drug discovery, and clinical studies.

Determining population stratification and subgroup effects in association studies of rare genetic variants for nicotine dependence.

BACKGROUND: Rare variants (minor allele frequency < 1% or 5 %) can help researchers to deal with the confounding issue of 'missing heritability' and have a proven role in dissecting the etiology for human diseases and complex traits. METHODS: We extended the combined multivariate and collapsing (CMC) and weighted sum statistic (WSS) methods and accounted for the effects of population stratification and subgroup effects using stratified analyses by the principal component analysis, named here as 'str-CMC' and 'str-WSS'. To evaluate the validity of the extended methods, we analyzed the Genetic Architecture of Smoking and Smoking Cessation database, which includes African Americans and European Americans genotyped on Illumina Human Omni2.5, and we compared the results with those obtained with the sequence kernel association test (SKAT) and its modification, SKAT-O that included population stratification and subgroup effect as covariates. We utilized the Cochran-Mantel-Haenszel test to check for possible differences in single nucleotide polymorphism allele frequency between subgroups within a gene. We aimed to detect rare variants and considered population stratification and subgroup effects in the genomic region containing 39 acetylcholine receptor-related genes. RESULTS: The Cochran-Mantel-Haenszel test as applied to GABRG2 (P = 0.001) was significant. However, GABRG2 was detected both by str-CMC (P= 8.04E-06) and str-WSS (P= 0.046) in African Americans but not by SKAT or SKAT-O. CONCLUSIONS: Our results imply that if associated rare variants are only specific to a subgroup, a stratified analysis might be a better approach than a combined analysis.

Mice Missing Cnr1 and Cnr2 Show Implantation Defects.

Cannabinoid/endocannabinoid signaling is primarily mediated by cannabinoid receptor type 1 (CB1; encoded by Cnr1) and/or type 2 (CB2; encoded by Cnr2). Here, we show that Cnr1-/-Cnr2-/- mice are subfertile as a result of compromised implantation. Upon implantation, the epithelium is smooth and adhered to the blastocyst trophectoderm within the implantation chamber (crypt) in wild-type mice, whereas the epithelium in Cnr1-/-Cnr2-/- mice is ruffled, which compromises appropriate blastocyst-uterine interactions. The suboptimal implantation leads to higher incidence of pregnancy failure in Cnr1-/-Cnr2-/- mice. Histological analysis revealed heightened edema around the implantation chamber in these deleted females. With the use of a reporter mouse line, we observed that CB2 is present on endothelial cells of uterine blood vessels, and its absence leads to blood vessel leakage during implantation. These results suggest that appropriately regulated uterine edema is important to optimal implantation.

Ion-Induced Synthesis of Alginate Fibroid Hydrogel for Heavy Metal Ions Removal.

Design and synthesis of environmentally friendly adsorbents with high adsorption capacities are urgently needed to control pollution of water resources. In this work, a calcium ion-induced approach was used to synthesize sodium alginate fibroid hydrogel (AFH). The as-prepared AFH has certain mechanical strength, and the mechanical strength is enhanced especially after the adsorption of heavy metal ions, which is very convenient for the recovery. AFH exhibited excellent adsorption performances for Cu2+, Cd2+, and Pb2+ ions and displayed very high saturated adsorption capacities (Qe) of 315.92 mg·g-1 (Cu2+), 232.35 mg·g-1 (Cd2+), and 465.22 mg·g-1 (Pb2+) with optimized pH values (3.0-4.0) and temperature (303 K). The study of isotherms and kinetics indicated that adsorption processes of heavy metal ions fitted well with the pseudo-second-order kinetics model and the Langmuir model. Pb2+ was found to have the strongest competitiveness among the three heavy metal ions. Thus, AFH has great application prospects in the field of heavy metal ions removing from wastewater.

Genome wide analyses uncover allele-specific RNA editing in human and mouse.

RNA editing is one of the most common RNA level modifications that potentially generate amino acid changes similar to those resulting from genomic nonsynonymous mutations. However, unlike DNA level allele-specific modifications such as DNA methylation, it is currently unknown whether RNA editing displays allele-specificity across tissues and species. Here, we analyzed allele-specific RNA editing in human tissues and from brain tissues of heterozygous mice generated by crosses between divergent mouse strains and found a high proportion of overlap of allele-specific RNA editing sites between different samples. We identified three allele-specific RNA editing sites cause amino acid changes in coding regions of human and mouse genes, whereas their associated SNPs yielded synonymous differences. In vitro cellular experiments confirmed that sequences differing at a synonymous SNP can have differences in a linked allele-specific RNA editing site with nonsynonymous implications. Further, we demonstrate that allele-specific RNA editing is influenced by differences in local RNA secondary structure generated by SNPs. Our study provides new insights towards a better comprehension of the molecular mechanism that link SNPs with human diseases and traits.

Numerical simulation of non-dendritic structure formation in Mg-Al alloy solidified with ultrasonic field.

The formation of non-dendritic structure of Mg alloy solidified with ultrasonic treatment was investigated by numerical simulation and experiment. The models of nucleation and crystal growth involved the effects of ultrasonic cavitation and acoustic streaming were built. Based on the models, the grain refinement and the microstructure change from dendrite to non-dendritic structure of a Mg-Al alloy were numerically simulated by cellular automata method. The simulation and experimental results indicated that the ultrasonic cavitation strongly contributes to the grain refinement by improving nucleation, while the acoustic streaming is mainly responsible for the formation of non-dendritic structure.

A non-threshold region-specific method for detecting rare variants in complex diseases.

A region-specific method, NTR (non-threshold rare) variant detection method, was developed-it does not use the threshold for defining rare variants and accounts for directions of effects. NTR also considers linkage disequilibrium within the region and accommodates common and rare variants simultaneously. NTR weighs variants according to minor allele frequency and odds ratio to combine the effects of common and rare variants on disease occurrence into a single score and provides a test statistic to assess the significance of the score. In the simulations, under different effect sizes, the power of NTR increased as the effect size increased, and the type I error of our method was controlled well. Moreover, NTR was compared with several other existing methods, including the combined multivariate and collapsing method (CMC), weighted sum statistic method (WSS), sequence kernel association test (SKAT), and its modification, SKAT-O. NTR yields comparable or better power in simulations, especially when the effects of linkage disequilibrium between variants were at least moderate. In an analysis of diabetic nephropathy data, NTR detected more confirmed disease-related genes than the other aforementioned methods. NTR can thus be used as a complementary tool to help in dissecting the etiology of complex diseases.

Sustained Endocannabinoid Signaling Compromises Decidual Function and Promotes Inflammation-induced Preterm Birth.

Recent studies provide evidence that premature maternal decidual senescence resulting from heightened mTORC1 signaling is a cause of preterm birth (PTB). We show here that mice devoid of fatty acid amide hydrolase (FAAH) with elevated levels ofN-arachidonyl ethanolamide (anandamide), a major endocannabinoid lipid mediator, were more susceptible to PTB upon lipopolysaccharide (LPS) challenge. Anandamide is degraded by FAAH and primarily works by activating two G-protein-coupled receptors CB1 and CB2, encoded by Cnr1 and Cnr2, respectively. We found thatFaah(-/-)decidual cells progressively underwent premature senescence as marked by increased senescence-associated ß-galactosidase (SA-ß-Gal) staining and γH2AX-positive decidual cells. Interestingly, increased endocannabinoid signaling activated MAPK p38, but not p42/44 or mTORC1 signaling, inFaah(-/-)deciduae, and inhibition of p38 halted premature decidual senescence. We further showed that treatment of a long-acting anandamide in wild-type mice at midgestation triggered premature decidual senescence utilizing CB1, since administration of a CB1 antagonist greatly reduced the rate of PTB inFaah(-/-)females exposed to LPS. These results provide evidence that endocannabinoid signaling is critical in regulating decidual senescence and parturition timing. This study identifies a previously unidentified pathway in decidual senescence, which is independent of mTORC1 signaling.

Protective effect of the ω-3 polyunsaturated fatty acids on the schistosomiasis liver fibrosis in mice.

This study aims to observe the effect of ω-3 polyunsaturated fatty acids on initiation and elimination of the schistosomiasis inflammatory response and liver fibrosis. The mice infected with the cercariae of Schistosoma japonicum (20 ± cercarie per mice) were separated randomly into several groups. After 60 days, liver tissue samples of all mice were sectioned. Hematoxylin-eosin (HE) staining, Masson staining, the enzyme-linked immunosorbent assay (ELISA), and flow cytometry (FCM) were performed. Through HE and Masson staining, the size of egg (ovum) granuloma and the collagen deposited in mice's livers in ω-3 PUFAs and praziquantel mixed groups were less than that of model group and praziquantel treated group. The serum level of IL-13 and TNF-α were lower than that of model group and praziquantel treated group. The indicators of liver fibrosis, such as HA and LN in the group treated with ω-3 PUFAs and praziquantel before the release of soluble eggs antigen (SEA) into blood, were lower than that of model group and praziquantel treated group, respectively. The combined treatment of ω-3 polyunsaturated fatty acids and praziquantel conducted before the release of soluble eggs antigens into the blood decreases liver ovum granulomatous inflammation and fibrosis degree in the schistosomiasis. The mechanism of the ω-3 polyunsaturated fatty acid may be related to the adjustment of the anti-inflammatory and immune responses.

Muscle Segment Homeobox Genes Direct Embryonic Diapause by Limiting Inflammation in the Uterus.

Embryonic diapause is a reproductive strategy widespread in the animal kingdom. This phenomenon is defined by a temporary arrest in blastocyst growth and metabolic activity within a quiescent uterus without implantation until the environmental and maternal milieu become favorable for pregnancy to progress. We found that uterine Msx expression persists during diapause across species; their inactivation in the mouse uterus results in termination of diapause with the development of implantation-like responses ("pseudoimplantation") that ultimately succumbed to resorption. To understand the cause of this failure, we compared proteome profiles between floxed and Msx-deleted uteri. In deleted uteri, several functional networks, including transcription/translation, ubiquitin-proteasome, inflammation, and endoplasmic reticulum stress, were dysregulated. Computational modeling predicted intersection of these pathways on an enhanced inflammatory signature. Further studies showed that this signature was reflected in increased phosphorylated IκB levels and nuclear NFκB in deleted uteri. This was associated with enhanced proteasome activity and endoplasmic reticulum stress. Interestingly, treatment with anti-inflammatory glucocorticoid (dexamethasone) reduced the inflammatory signature with improvement of the diapause phenotype. These findings highlight an unexpected role of uterine Msx in limiting aberrant inflammatory responses to maintain embryonic diapause.

Entosis allows timely elimination of the luminal epithelial barrier for embryo implantation.

During implantation, uterine luminal epithelial (LE) cells first interact with the blastocyst trophectoderm. Within 30 hr after the initiation of attachment, LE cells surrounding the blastocyst in the implantation chamber (crypt) disappear, allowing trophoblast cells to make direct physical contact with the underneath stroma for successful implantation. The mechanism for the extraction of LE cells was thought to be mediated by apoptosis. Here, we show that LE cells in direct contact with the blastocyst are endocytosed by trophoblast cells by adopting the nonapoptotic cell-in-cell invasion process (entosis) in the absence of caspase 3 activation. Our in vivo observations were reinforced by the results of co-culture experiments with primary uterine epithelial cells with trophoblast stem cells or blastocysts showing internalization of epithelial cells by trophoblasts. We have identified entosis as a mechanism to remove LE cells by trophoblast cells in implantation, conferring a role for entosis in an important physiological process.

Cnr2 deficiency confers resistance to inflammation-induced preterm birth in mice.

Infection-induced inflammation, frequently associated with increased production of proinflammatory cytokines, is considered a significant contributor to preterm birth. A G protein-coupled cannabinoid receptor 2 (CB2), encoded by Cnr2, is expressed in various immune cells and was shown to modulate immune responses. We show here that Cnr2, but not Cnr1, deficient mice are resistant to lipopolysaccharide (LPS)-driven preterm birth and suppression of serum progesterone levels. After LPS challenge, Cnr2(-/-) mice exhibited increased serum levels of IL-10 with decreased IL-6 levels. These changes were associated with reduced LPS-induced Ptgs2 expression at the maternal-conceptus interface on day 16 of pregnancy. LPS stimulation of Cnr2(-/-) dendritic cells in vitro resulted in increased IL-10 with reduced IL-6 production and correlated with increased cAMP accumulation. Collectively, our results suggest that increased IL-10 production occurring via augmented cAMP accumulation represents a potential mechanism for the resistance of Cnr2(-/-) mice to LPS-induced preterm birth. These results may have clinical relevance, because currently, there are limited options to prevent preterm birth.