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Abstract No highly specific and sensitive biomarkers have been identified for early diagnosis of neural tube defects (NTDs). In this study, we used proteomics to identify novel proteins specific for NTDs. Our findings revealed three proteins showing differential expression during fetal development. In a rat model of NTDs, we used western blotting to quantify proteins in maternal serum exosomes on gestational days E18, E16, E14, and E12, in serum on E18 and E12, in neural tubes on E18 and E12, and in fetal neural exosomes on E18. The expression of coronin 1A and dynamin 2 was exosome-specific and associated with spina bifida aperta embryogenesis. Furthermore, coronin 1A and dynamin 2 were significantly downregulated in maternal serum exosomes (E12–E18), neural tubes, and fetal neural exosomes. Although downregulation was also observed in serum, the difference was not significant. Differentially expressed proteins were further analyzed in the serum exosomes of pregnant women during gestational weeks 12–40 using enzyme-linked immunosorbent assays. The findings revealed that coronin 1A and dynamin 2 showed potential diagnostic efficacy during gestational weeks 12–40, particularly during early gestation (12–18 weeks). Therefore, these two targets are used as candidate NTD screening and diagnostic biomarkers during early gestation. Key messages We used proteomics to identify novel proteins specific for NTDs. CORO1A and DNM2 showed exosome-specific expression and were associated with SBA. CORO1A and DNM2 were downregulated in maternal serum exosomes and FNEs. CORO1A and DNM2 showed good diagnostic efficacy for NTDs during early gestation. These two targets may have applications as NTD screening and diagnostic biomarkers.

Nonsyndromic cleft lip with palate (nsCLP) is a common congenital malformation; however, early prenatal diagnosis is challenging and pathogenesis remains unclear. The purpose of this study was to determine the diagnostic potential of miRNAs in plasma-derived exosomes and whole plasma of pregnant women to identify nsCLP and an underlying mechanism. Combined RNA sequencing analysis was performed on samples from plasma exosomes and whole plasma of pregnant women carrying normal fetuses or fetuses with nsCLP in an ongoing birth cohort, in addition to lip samples from nsCLP fetuses and healthy controls. Eight let-7 cluster miRNAs (hsa-let-7a-3p, hsa-let-7a-5p, hsa-let-7c-5p, hsa-let-7d-3p, hsa-let-7d-5p, hsa-let-7e-5p, hsa-let-7f-5p, and hsa-miR-98-5p) in plasma exosomes from pregnant women provided higher sensitivity/specificity for diagnosing fetal nsCLP than those in plasma. Area under the receiver operating characteristic curve value of the eight miRNAs from plasma exosomes was 0.992. Among them, hsa-let-7a-3p showed better diagnostic capability and was downregulated in nsCLP fetal lip tissues. Upstream and downstream target genes of hsa-let-7a-3p were screened and confirmed. Our work highlights the potential clinical application value of let-7 clusters in predicting nsCLP and associates as a new regulatory axis (EN2-LIN28A-hsa-let-7a-3p-HHIP-GLI2) with human nsCLP pathogenesis.

To improve the early detection of gastric cancer (GC), there is a growing need for novel and efficient biomarkers. We aimed to evaluate diagnostic value of thioredoxin reductase 1 (TXNRD1), which was found to be over expressed in various malignancies. We found that TXNRD1 has a higher expression level in GC tissues compared with adjacent normal tissues, and high TXNRD1 expression was significantly associated with poor outcomes of GC patients. Next, a total of 1446 cases were collected, with 896 cases in GC, 322 in benign gastric disease and 228 in healthy controls. We noticed plasma thioredoxin reductase (TrxR) level in GC [8.4 (7.1, 9.7) U/ml] was significantly higher than that in benign disease [6.1 (5.4, 7.2) U/ml] or healthy controls [3.7 (1.7, 5.6) U/ml]. Receiver operating characteristic analysis showed that the optimal cutoff value of TrxR activity for GC diagnosis was set at 5.75 U/ml with an area under the curve of 0.945. Moreover, a combined panel of TrxR and routine tumor markers could further elevate the diagnostic efficacy compared to a single biomarker. Finally, by measuring pre- and post-treatment TrxR activity and routine tumor markers, we found the change trend of them was broadly consistent, and plasma TrxR activity was significantly decreased in patients treated with platinum/fluorouracil-based therapy. Our findings recommend plasma TrxR activity combined with tumor markers as effective diagnostic tools for GC patients. As well, plasma TrxR has the potential to monitor therapeutic efficacy.

Congenital heart defects (CHDs) are one of the major causes of death in infants and young children, and heavy metal exposure during pregnancy is one of the possible risk factors. However, the effect of heavy metal exposure on CHDs is still controversial. We searched English (PubMed, Web of Science) and Chinese (CNKI and WanFang database) databases for relevant articles. The summarized effect sizes and 95% confidence intervals (CIs) were calculated by pooling estimates using the random-effects model. Egger's test was used to estimate publication bias. Heterogeneity among studies was indicated by p-values and I

Cancer cells typically experience higher oxidative stress than normal cells, such that elevating pro-oxidant levels can trigger cancer cell death. Although pre-exposure to mild oxidative agents will sensitize cancer cells to radiation, this pre-exposure may also activate the adaptive stress defense system in normal cells. Ascorbic acid is a prototype redox modulator that when infused intravenously appears to kill cancers without injury to normal tissues; however, the mechanisms involved remain elusive. In this study, we show how ascorbic acid kills cancer cells and sensitizes prostate cancer to radiation therapy while also conferring protection upon normal prostate epithelial cells against radiation-induced injury. We found that the NF-κB transcription factor RelB is a pivotal determinant in the differential radiosensitization effects of ascorbic acid in prostate cancer cells and normal prostate epithelial cells. Mechanistically, high reactive oxygen species concentrations suppress RelB in cancer cells. RelB suppression decreases expression of the sirtuin SIRT3 and the powerful antioxidant MnSOD, which in turn increases oxidative and metabolic stresses in prostate cancer cells. In contrast, ascorbic acid enhances RelB expression in normal cells, improving antioxidant and metabolic defenses against radiation injury. In addition to showing how RelB mediates the differential effects of ascorbic acid on cancer and normal tissue radiosensitivities, our work also provides a proof of concept for the existence of redox modulators that can improve the efficacy of radiotherapy while protecting against normal tissue injury in cancer settings. Cancer Res; 77(6); 1345–56. ©2017 AACR.

After treatment with AA, the expression of RelB, Bcl-xL, and Bax in PC3 and PZ cells was quantified by western blots by RT-PCR.

The subgroups of the animal experiment were analyzed using Kaplan-Meier survival curves with the log-rank test.

The effect of PEG-CAT on radiosensitization of AA in PC3 cells was determined by MTT assay.

Legends for Supplemental Table S1 and Supplemental Figures S1-S3.

Metal plates have always been the gold standard in the clinic for internal fracture fixation due to their high strength advantages. However, high elastic modulus can cause stress shielding and lead to bone embrittlement. This study used an electron beam melting method to prepare personalized porous Ti6Al4V (pTi) bone plates. Then, chemical vapor deposition (CVD) technology coats tantalum (Ta) metal on the pTi bone plates. The prepared porous Ta-coated bone plate has an elastic modulus similar to cortical bone, and no stress shielding occurred. In vitro experiments showed that compared with pTi plates, Ta coating significantly enhances the attachment and proliferation of cells on the surface of the scaffold. To better evaluate the function of the Ta-coated bone plate, animal experiments were conducted using a coat tibia fracture model. Our results showed that the Ta-coated bone plate could effectively fix the fracture. Both imaging and histological analysis showed that the Ta-coated bone plate had prominent indirect binding of callus formation. Histological results showed that new bone grew at the interface and formed good osseointegration with the host bone. Therefore, this study provides an alternative to bio-functional Ta-coated bone plates with improved osseointegration and osteogenic functions for orthopaedic applications., Graphical abstract Image 1, Highlights • Porous Ta coated bone plate has a low elastic modulus, which can avoid stress shielding. • Porous Ta coated bone plate has excellent biocompatibility and can be permanently implanted in the body. • Porous Ta coated bone plate has excellent osseointegration properties and can promote fracture healing.

Bladder cancer (BC) is one of the most common cancers in the world, with high morbidity and mortality. It is essential to develop a non-invasive, highly accurate, and simple method for BC diagnosis. This work proposed a fluorescent biosensor based on inorganic nanoflares combined with a DNAzyme walker for the simultaneous detection of BC exosomal microRNAs (miRNAs). This biosensor was constructed on the Au nanoparticle (AuNP) modified with the carbon dot (CD)-labeled substrates and DNAzyme strands (AuNP@CDs inorganic nanoflares-DNAzyme, APCD). In the presence of target miRNAs, DNAzyme was activated and then cleaved the CD-labeled substrates and automatically walked along the AuNP, allowing fluorescence recovery. Due to the structure and functional composition, the APCD biosensors demonstrated high sensitivity and specificity, with the reached limit of detection for a single miRNA at the femtomolar level and wide linear range from 50 fM to 10 nM. Furthermore, the simultaneous analysis of BC-related exosomal miR-133b and miR-135b in clinical serum specimens was achieved and consistent with qRT-PCR, suggesting it is a potential method for the diagnosis of BC and other cancers.

Implantable medical electronics (IMEs) are now becoming increasingly prevalent for diagnostic and therapeutic purposes. Despite extensive efforts, a primary challenge for IMEs is reliable wireless power and communication to provide well-controlled, therapeutically relevant effects. Ultrasonic energy transfer and communication (UETC) employing traveling ultrasound waves to transmit energy has emerged as a promising wireless strategy for IMEs. Nevertheless, conventional UETC systems are rigid, bulky, and based on toxic lead-based piezoelectric materials, raising efficiency and safety concerns. Here, we present a novel transcutaneous UETC system based on a two-dimensional flexible lead-free piezoelectric array (f-LFPA) that hybridizes high-performance (piezoelectric coefficient

The two monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), namely evolocumab and alirocumab, were first approved by the U.S. Food and Drug Administration (FDA) in 2015. PCSK9 inhibitor (PCSK9i) has served as a viable new therapeutic option to lower cholesterol levels and associated cardiovascular events. However, a better understanding of safety issue of PCSK9i is necessarily needed. We present here an increased risk of adverse pregnancy outcomes, including stillbirths and embryonic defects, particularly neural tube defects, following PCSK9i treatment harnessing a high-fat diet-based mouse model. Proteomics of PCSK9i-treated neural stem cells uncovered that PCSK9i may disrupt mitochondrial function via succinic dehydrogenase complex subunit A (SDHA), which is a key enzyme in the mitochondrial respiratory chain. Furthermore, PCSK9i-induced SDHA deficiency combines with high triglyceride to drive the production of reactive oxygen species and subsequent apoptosis during embryonic development, which may account for the occurrence of adverse pregnancy outcomes. Our findings reveal the existence of a hitherto unknown risk of PCSK9i in pregnant women, as well as novel gene-environment interaction.

Bladder cancer greatly endangers human health, and its early diagnosis is of vital importance. Exosomes, which contain proteins and nucleic acids related to their source cells, are expected to be an emerging biomarker for bladder cancer detection. Here, we propose a novel system for multiplexed analysis of bladder cancer-derived urine exosomes based on Janus magnetic microspheres as barcoded microcarriers. The microcarriers are constructed by droplet-templated coassembly of colloidal silica nanoparticles and magnetic nanoparticles under a magnetic field. The microcarriers possess one hemisphere with structural color and the other hemisphere with magneto-responsiveness. Benefiting from the unique structure, these Janus microcarriers could serve as barcodes and could move controllably in a sample solution, thus realizing the multiplex detection of exosomes with high sensitivity. Notably, the present platform is noninvasive since a urine specimen, as an ideal source of bladder cancer-derived exosomes, is employed as the sample solution. This feature, together with the good sensitivity, specificity, low sample consumption, and easy operation, indicates the great potential of the platform for bladder cancer diagnosis in clinical applications.

Fuzzy rough approximation operators are the underlying concepts in fuzzy rough set theory . There are at least two approaches to develop these primary concepts, i.e., the constructive approach and the axiomatic approach . Single axiomatic characterizations of fuzzy rough approximation operators have got tons of attention. In this paper, considering L being a GL-quantale, we will develop the theory of L -valued rough sets with an L -set as the basic universe of defining L -valued rough approximation operators. Adopting the idea of single axiomatic characterizations of fuzzy rough sets , we will present the axiomatic characterizations of L -valued upper and lower rough approximation operators on an L -set with respect to reflexive, symmetric, transitive L -valued relations on an L -set as well as their compositions. Choosing an L -set as the universe will break the rules that adopting Zadeh’s fuzzy sets as the universe. By these results, we will further provide a new framework of axiomatic research of fuzzy rough set theory.

The potential role of HIST1H2BN in prostate cancer remains unclear.To evaluate the carcinogenic role of HIST1H2BN in prostate cancer.The expression of HIST1H2BN in prostate cancer was analyzed using TCGA database and clinical samples. The roles and mechanisms of HIST1H2BN were investigated in DU145 and PC3 cells.HIST1H2BN was significantly upregulated in prostate cancer. HIST1H2BN knockdown inhibited cell proliferation, migration and EMT phenotype in prostate cancer cells. Downregulating HIST1H2BN diminished the expression and binding activity of NF-κB p65, then influenced the expression of MMP2 and MMP9. CONCLUSION : This is the first study to elaborate a HIST1H2BN-NF-κB-EMT regulatory axis in oncogenesis, indicating that HIST1H2BN might be potential therapeutic target for prostate cancer.

Spina bifida aperta (SBA) is one of the most common neural tube defects. Neural injury in SBA occurs in two stages involving failed neural tube closure and progressive degeneration through contact with the amniotic fluid. We previously suggested that intra-amniotic bone marrow-derived mesenchymal stem cell (BMSC) therapy for fetal rat SBA could achieve beneficial functional recovery through lesion-specific differentiation. The aim of this study is to examine whether the amniotic fluid microenvironment can be improved by intra-amniotic BMSC transplantation.The intra-amniotic BMSC injection was performed using in vivo rat fetal SBA models. The various cytokine expressions in rat amniotic fluid were screened by protein microassays. Intervention experiments were used to study the function of differentially expressed cytokines.A total of 32 cytokines showed significant upregulated expression in the BMSC-injected amniotic fluid. We focused on Activin A, NGF, BDNF, CNTF, and CXCR4. Intervention experiments showed that the upregulated Activin A, NGF, BDNF, and CNTF could inhibit apoptosis and promote synaptic development in fetal spinal cords. Inhibiting the activity of these factors weakened the anti-apoptotic and pro-differentiation effects of transplanted BMSCs. Inhibition of CXCR4 activity reduced the engraftment rate of BMSCs in SBA fetuses.BMSC transplantation can improve the amniotic fluid environment, and this is beneficial for SBA repair.

Piezocatalysis is regarded as a fascinating technology for water remediation and possible disease treatment. A high piezoelectric coefficient (

Gastric cancer (GC) is the third leading cause of cancer-associated mortality globally. Although the diagnosis and therapeutic strategies for GC have improved, the prognosis for advanced gastric cancer (AGC) remains poor. Hence, the present study sought to design a zebrafish model established by microinjecting human MGC-803 GC cell line for studying personalized molecular-targeted cancer therapy. Apatinib, a novel molecular-targeted agent, was evaluated for its in vivo efficacy through a comparison among the control groups (no treatment) and subject groups (treatment). Newly formed vessel length and tumor volume were measured in all of the groups for further study. The length of newly formed vessels was obviously shortened after apatinib treatment in the zebrafish model established in this study. Meanwhile, apatinib exhibited the best antitumor growth effect with dose and time dependence by suppressing AKT/GSK3α/β signaling, which may be the mechanism underlying the profound antitumor clinical effect of apatinib. The data indicated that apatinib therapy exerts an anti-angiogenesis effect and it can be recommended as a proper antitumor growth therapy for GC patients. Additionally, zebrafish models could be designed as a potential practical tool to explore new anti-GC cancer drugs.

Velocity vertical profiles in the bottom boundary layer are important to understand the oceanic circulation. The logarithmic vertical profile, u=Alnz+B, is the universal profile for the horizontal velocity in the boundary layer, in which two coefficients (A and B) need to be determined. The two coefficients are the functions of the friction velocity (u*) and the roughness length (z0), and they are calculated using u* and z0. However, the measurement of u* and z0 is a challenge. In the present study, an approach is developed to estimate the two coefficients (A and B) by using a series of flume laboratory experiments with flat boundary and regularly distributed cylinders as the rough boundaries. An acoustic doppler velocimeter (ADV) is used to measure the velocity vertical profiles of the steady flow. Using the measured velocity data, the regressed logarithmic profiles are obtained. Based on the series of the A and B values, the mathematical formula for A and B are statistically established as the function of the cylinder height, inflow velocity, and the water depth, which avoids the measurement of the friction velocity and the roughness length.

Breast cancer is the most common cause of malignancy and cancer-related morbidity and death worldwide that requests effective and safe chemotherapy. Evaluation of metallodrug-based anticancer agents and statins as chemotherapeutics with fewer side effects is a largely unexplored research field. Synthesis and characterization of the ruthenium-fluvastatin complex were achieved using multiple spectroscopic techniques and thus further examined to evaluate its chemotherapeutic prospects in both MDA-MB-231 and MCF-7 cancer lines and eventually in vivo models of DMBA-induced mammary carcinogenesis in rodents. Our studies indicate that the metal and ligand chelation was materialized by the ligand’s functional groups of carbonyl (=O) oxygen and hydroxyl (-OH), and the complex has been observed to be crystalline and able to chelate with CT-DNA. The complex was able to reduce cell proliferation and activate apoptotic events in breast carcinoma cell lines MCF-7 and MDA-MB-231. In addition, the complex was able to modify p53 expressions to interfere with apoptosis in the carcinoma of the breast, stimulated by the intrinsic apoptotic path assisted by Bcl2 and Bax in vivo, yet at the same point, controlling the PI3K/Akt/mTOR/VEGF pathway, as obtained from western blotting, correlates with the MMP9-regulated tumor mechanisms. Our research reveals that ruthenium-fluvastatin chemotherapy may disrupt, rescind, or interrupt breast carcinoma progression by modifying intrinsic apoptosis as well as the antiangiogenic cascade, thereby taking the role of a potential candidate in cancer therapy for the immediate future.

Exosomes, which play an important role in intercellular communication, are closely related to the pathogenesis of disease. However, their effective capture and multiplex screening are still challenging. Here, inspired by the unique structure of pollens, we present novel photonic crystal (PhC) barcodes with prickly surface by hydrothermal synthesis for multiplex exosome capturing and screening. These pollen-inspired PhC barcodes are imparted with extremely high specific surface area and excellent prickly surface nanostructures, which can improve the capture rate and detection sensitivity of exosomes. As the internal periodic structures are kept during the hydrothermal synthesis process, the pollen-inspired PhC barcodes exhibit obvious and stable structural colors for identification, which enables multiplex detection of exosomes. Thus, the pollen-inspired PhC barcodes can not only effectively capture and enrich cancer-related exosomes but also support multiplex screening of exosomes with high sensitivity. These features make the prickly PhC barcodes ideal for the analysis of exosomes in medical diagnosis.

Basic helix-loop-helix (bHLH) transcription factors play important roles in plant growth, development, metabolism, hormone signaling pathways, and responses to abiotic stresses. However, comprehensive genomic and functional analyses of bHLH genes have not yet been reported in desert euhalophytes. Suaeda aralocaspica, an annual C4 halophyte without Kranz anatomy, presents high photosynthetic efficiency in harsh natural habitats and is an ideal plant for identifying transcription factors involved in stress resistance. In this study, 83 bHLH genes in S. aralocaspica were identified and categorized into 21 subfamilies based on conserved motifs, gene structures, and phylogenetic analysis. Functional annotation enrichment revealed that the majority of SabHLHs were enriched in Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways involved in the response to stress conditions, as transcription factors. A number of cis-acting elements related to plant hormones and stress responses were also predicted in the promoter regions of SabHLHs, which were confirmed by expression analysis under various abiotic stress conditions (NaCl, mannitol, low temperature, ABA, GA3, MeJA, and SA); most were involved in tolerance to drought and salinity. SabHLH169 (076) protein localized in the nucleus was involved in transcriptional activity, and gene expression could be affected by different light qualities. This study is the first comprehensive analysis of the bHLH gene family in S. aralocaspica. These data will facilitate further characterization of their molecular functions in the adaptation of desert plants to abiotic stress.

Improving the level of national mental health and strengthening the construction of social psychological service system are the necessary and important ways to promote the implementation of the Healthy China strategy. However, the gap between the requirements of Healthy China strategy for social mental health service system and the current situation of mental health service in China is still widespread. Promoting the public to form an effective demand for psychological help and establishing a new mental health service model is the key to bridge this gap. Optimizing mental health literacy is an important starting point and breakthrough to solve this problem. At present, the research on mental health literacy is undergoing a transformation from the paradigm of psycho-epidemiology to the paradigm of psychology and sociology. Taking contemporary China as the background, the reconceptualization of mental health literacy and the exploration of the current situation of Chinese mental health literacy in the new era is one of the core task of current psychological path research. The significance of this study is mainly reflected in: (1) promote the formation of effective demand for help and improve the level of public mental health; (2) enhance cultural selfconfidence and construct the theory of mental health literacy of contemporary Chinese people; (3) guide the supply side structural reform of mental health services and promote mental health equity; (4) reduce the burden of mental illness and help build a well-off society in an all-round way; (5) help build a social and psychological service system.

Amniotic fluid-derived mesenchymal stromal cells (AFMSCs) present different features, depending on the isolation timing and culture conditions. The lack of uniform experimental standards hinders the comparison of results from different studies on AFMSCs. Moreover, understanding the molecular mechanisms that underlie the features of AFMSCs isolated at different embryonic developmental stages might allow the obtention of more viable and highly proliferative AFMSCs through genetic modification. We isolated AFMSCs from pregnant rats at embryonic day (E)12, E15, E18, and E21 and compared their cell proliferation capacity and transcriptome. The cell counting kit-8 assay and RNA sequencing revealed that E12 and E15 AFMSCs showed different characteristics from E18 and E21 AFMSCs. Therefore, AFMSCs were divided into two groups: early (E12 and E15) and late (E18 and E21) pregnancy-stage groups. Next, we screened the gene/microRNA pair Abca4/miR-351-3p that was related to cell proliferation. Abca4 knockdown/overexpression suggested that this gene represses the proliferation of AFMSCs, which is a newly discovered function of this gene. Finally, dual luciferase reporter gene assays confirmed that miR-351-3p targeted the coding sequence of Abca4 and regulated AFMSC proliferation. miR-351-3p promotes AFMSC proliferation via targeting the coding sequence of Abca4. Our findings provide a molecular foundation for further research for obtaining AFMSCs with a higher proliferation capacity. © AlphaMed Press 2021 SIGNIFICANCE STATEMENT: The authors observed that the early passage amniotic fluid-derived mesenchymal stromal cells (AFMSCs) display significantly higher proliferation capacity. Through the further investigation, the authors found out a novel role for ABCA4 in the regulation of AFMSC proliferation, which was with the decreased expression of Abca4, AFMSCs exhibited an increased proliferation. Further understanding of the mechanism by which ABCA4 affects cell proliferation would benefit the screening of other proliferation-related factors and its use in the supplementation of culture medium for AFMSCs, which in turn would allow the development of an optimal culture scheme and the obtention of a high number of highly proliferative AFMSC in vitro.

BackgroundAlthough retinitis pigmentosa (RP) is the most common type of hereditary retinal dystrophy, approximately 25%–45% of cases remain without a molecular diagnosis. von Willebrand factor A domain containing 8 (VWA8) encodes a mitochondrial matrix-targeted protein; its molecular function and pathogenic mechanism in RP remain unexplained.MethodsFamily members of patients with RP underwent ophthalmic examinations, and peripheral blood samples were collected for exome sequencing, ophthalmic targeted sequencing panel and Sanger sequencing. The importance ofVWA8in retinal development was demonstrated by a zebrafish knockdown model and cellular and molecular analysis.ResultsThis study recruited a Chinese family of 24 individuals with autosomal-dominant RP and conducted detailed ophthalmic examinations. Exome sequencing analysis of six patients revealed heterozygous variants inVWA8, namely, the missense variant c.3070G>A (p.Gly1024Arg) and nonsense c.4558C>T (p.Arg1520Ter). Furthermore,VWA8expression was significantly decreased both at the mRNA and protein levels. The phenotypes of zebrafish withVWA8knockdown are similar to those of clinical individuals harbouringVWA8variants. Moreover,VWA8defects led to severe mitochondrial damage, resulting in excessive mitophagy and the activation of apoptosis.ConclusionsVWA8plays a significant role in retinal development and visual function. This finding may provide new insights into RP pathogenesis and potential genes for molecular diagnosis and targeted therapy.

Lead‐free ferroelectric electrocaloric ceramics that could convert electrical energy into heat are the promising candidate for environment‐friendly cooling devices. For refrigeration devices, a large temperature change (ΔT) and good temperature stability are required, which are highly related to the phase structure and the applied electric field. In this work, a diffused ferroelectric–paraelectric (FP) phase transition is formed in (K, Na)NbO3 (KNN) by using appropriate composition engineering. The relaxor ferroelectrics in this work present both a large ΔT of 1.24 K and a high ΔT/ΔE of 0.19 K mm/kV. In addition, a wide temperature span exceeds 55 °C at the high electrocaloric effect (ECE) criterion (ΔT ≥ 0.5 K) could also be observed. This work not only opens a new strategy for obtaining high‐performance ceramics for refrigeration devices but also extends the application area of the KNN‐based lead‐free ferroelectrics from sensors, actuators and energy harvesting to solid‐state cooling applications.

Electrocaloric effect represents an environmentally friendly cooling alternative to replace the currently ubiquitous vapor-compression-based refrigeration. Previous studies have shown that large electrocaloric response is associated with the polarization change, which peaks around the phase transition temperature. However, there is only little focus on the effect of the detailed phase structure on the electrocaloric properties, particularly on the electrocaloric strength (ΔT/ΔE). For the first time, the correlation between ΔT/ΔE and the phase structure of perovskite ferroelectric materials was investigated, and a new frame to obtain optimized ΔT/ΔE related to the phase structure regulation was revealed. Given the simple and legible phase structure, BaTiO3-based ceramics are selected as a platform to reveal this relationship by employing both indirect and direct measurements. A striking variation of ΔT/ΔE and entropy change coefficient versus the electric field was first noticed at different phase structures: decreasing at the phase boundaries, whereas increasing in the pure phase regions, which could attribute to distinct entropy change mechanisms stemming from the discrepant energy profile at different phase structures. Beyond that, the maximum electrocaloric temperature change of ∼1 K and a large ΔT/ΔE of 0.48–0.25 × 10−6 K m V−1 were achieved under 5–40 kV cm−1. Also, a broad temperature span of 58 K with high ΔT/ΔE was maintained under 40 kV cm−1, and a desired electric field-stable ΔT/ΔE could be acquired. Our research provides a new paradigm for further designing and optimizing the electrocaloric performance of lead-free perovskite ferroelectrics.

The role of methyltransferase-like 3 (METTL3), which participates in catalyzing N-methyladenosine (m6A) RNA modification, in gastric cancer (GC) is unclear. Here, we found that METTL3 was overexpressed in human GC. Functionally, we verified that METTL3 promoted tumor cell proliferation and angiogenesis through a series of phenotypic experiments. Subsequently, ADAMTS9 was identified as the downstream effector of METTL3 in GC, which could be degraded by the YTHDF2-dependent pathway. Finally, the data suggested that METTL3 might facilitate GC progression through the ADAMTS9-mediated PI3K/AKT pathway. Our study unveiled the fundamental mechanisms of METTL3 in GC progression. The clinical value of METTL3 in GC deserves further exploration.

The Sharply increasing atmospheric nitrogen (N) deposition may substantially impact the N availability and photosynthetic capacity of terrestrial plants. Determining the trade-off relationship between within-leaf N sources and allocation is therefore critical for understanding the photosynthetic response to nitrogen deposition in grassland ecosystems. We conducted field experiments to examine the effects of inorganic nitrogen addition (sole NH4+, sole NO3– and mixed NH4+/NO3–: 50%/50%) on N assimilation and allocation by Leymus chinensis. The leaf N allocated to the photosynthetic apparatus (NPSN) and chlorophyll content per unit area (Chlarea) were significantly positively correlated with the photosynthetic N-use efficiency (PNUE). The sole NO3– treatment significantly increased the plant leaf PNUE and biomass by increasing the photosynthetic N allocation and Chlarea. Under the NO3 treatment, L. chinensis plants devoted more N to their bioenergetics and light-harvesting systems to increase electron transfer. Plants reduced the cell wall N allocation or increased their soluble protein concentrations to balance growth and defense under the NO3 treatment. In the sole NH4+ treatment, however, plants decreased their N allocation to photosynthetic components, but increased their N allocation to the cell wall and elsewhere. Our findings demonstrated that within-leaf N allocation optimization is a key adaptive mechanism by which plants maximize their PNUE and biomass under predicted future global changes.

Basic helix-loop-helix (bHLH) transcription factors play important roles in plant growth, development, metabolism, hormone signaling pathways, and responses to abiotic stresses. However, comprehensive genomic and functional analyses of

Bismuth ferrite-barium titanate (BF-BT) based ceramics have attracted extensive attention due to its excellent energy conversion. Recently it has been found that BF-BT based ceramics with large electrostrain are usually accompanied by a special domain configuration in which weak and strong piezoresponse domain grains coexist. In this work, we purposefully constructed the special domain configuration in the pseudocomposite ceramics of (1

Epidemiological studies show that obesity during pregnancy affects more than half of the pregnancies in the developed countries and is associated with obstetric problems and poor outcomes. Obesity tends to increase the incidence of complications. Furthermore, the resulting offspring are also adversely affected. However, the molecular mechanisms of obesity leading to poor pregnancy outcomes remain unclear. Omics methods are used for genetic diagnosis and marker discovery. The aim of this review was to summarize the maternal and fetal pathophysiological alterations induced by gestational obesity,identified using multi-omics detection techniques, and to generalize the biological functions and potential mechanisms of the differentially expressed molecules.

Neural tube defects (NTDs) are serious congenital malformations. In this study, we aimed to identify more specific and sensitive maternal serum biomarkers for noninvasive NTD screenings. We collected serum from 37 pregnant women carrying fetuses with NTDs and 38 pregnant women carrying normal fetuses. Isobaric tags for relative and absolute quantitation were conducted for differential proteomic analysis, and an enzyme-linked immunosorbent assay was used to validate the results. We then used a support vector machine (SVM) classifier to establish a disease prediction model for NTD diagnosis. We identified 113 differentially expressed proteins; of these, 23 were either up- or downregulated 1.5-fold or more, including five complement proteins (C1QA, C1S, C1R, C9, and C3); C3 and C9 were downregulated significantly in NTD groups. The accuracy rate of the SVM model of the complement factors (including C1QA, C1S, and C3) was 62.5%, with 60% sensitivity and 67% specificity, while the accuracy rate of the SVM model of alpha-fetoprotein (AFP, an established biomarker for NTDs) was 62.5%, with 75% sensitivity and 50% specificity. Combination of the complement factor and AFP data resulted in the SVM model accuracy of 75%, and receiver operating characteristic curve analysis showed 75% sensitivity and 75% specificity. These data suggest that a disease prediction model based on combined complement factor and AFP data could serve as a more accurate method of noninvasive prenatal NTD diagnosis.

Zn alloys are emerging as promising degradable biomedical materials due to their tailorable mechanical properties and moderate biodegradable rate, compared with conventional biodegradable metallic materials. Ag, as an effective antibacterial and reinforcing element, was incorporated into Zn-0.05Mg alloys. In the present work, the effects of the Ag addition on mechanical, cytotoxic, hemolytic, pyrogenic, histological behaviors of the animal were investigated. The compressive yielding strength is enhanced from 198 MPa for Zn-0.05Mg alloy up to 224 and 234 MPa for Zn-0.05Mg-0.5Ag and Zn-0.05Mg-1Ag alloys, respectively. When the compressive strain was 65%, the strength of the Zn-0.05Mg-1.0Ag alloy reached 833 MPa, which was much higher than that of 721 MPa for Zn-0.05Mg alloy. The relative growth rate (RGR) for the extracts of Zn-0.05Mg-1Ag alloy with the concentrations of 10, 50, and 100% after 5 days incubation reaches 98.5, 95.2, and 94.2%, which are higher than those in extracts of Zn-0.05Mg-0.5Ag alloy (98.2, 93.9, 92.1%). The hemolysis rate of the Zn-0.05Mg alloys with 0.5 and 1 wt% Ag is 2.46 and 2.28%, respectively. The variations of body weight and temperature, postinjection symptoms, pathological morphologies of the visceral organs demonstrate that the alloys are nontoxic according to the toxicity rating standards. Zn-0.05wt%Mg-(0.5, 1 wt%) Ag alloys are experimentally safe materials and promising for the future application as biodegradable medical devices.

Bladder cancer is a complex and highly prevalent disease associated with substantial morbidity and mortality rates. Detection and surveillance of biomarkers for bladder cancer are particularly critical in clinical diagnosis and prognostic monitoring. The current detection methods are limited to low sensitivity, low throughput, and high operational cost. In this paper, we present a multiplexed detection strategy for microRNA (miRNA) related to bladder cancer by utilizing photonic crystal (PhC) barcodes. PhC barcodes have characteristic reflective peaks generated by periodic orderly porous nanostructures, providing an ideal choice for encoding element. Besides, owing to the larger surface area provided by the structure, PhC barcodes is an effective platform for probes ligation and miRNAs detection. Compared with the planar microarrays, PhC barcodes avoid the problem of steric hindrance, making it express more efficient reaction and higher detection sensitivity. By introducing hybridization chain reaction (HCR), the detection efficiency of this strategy is greatly improved, making the rapid, accurate, high sensitivity quantification of miRNAs possible. The results indicated that the multiplexed detection strategy based on PhC barcodes can be applied to the clinical analysis of tumor markers.

The Sharply increasing atmospheric nitrogen (N) deposition may substantially impact the N availability and photosynthetic capacity of terrestrial plants. Determining the trade-off relationship between within-leaf N sources and allocation is therefore critical for understanding the photosynthetic response to nitrogen deposition in grassland ecosystems. We conducted field experiments to examine the effects of inorganic nitrogen addition (sole NH

A highly specific and sensitive biomarker in maternal serology analysis for early diagnosis of neural tube defects (NTDs) is yet to be determined. Proteomics was utilized to identify novel specific proteins for NTDs and it revealed three differentially expressed proteins in fetal development. In a rat model with NTDs, we quantified proteins in maternal serum exosomes using western blotting on gestational days E18, E16, E14, and E12; in serum on E18 and E12; in neural tubes on E18 and E12; and in fetal neural exosomes on E18. Coronin 1A and Dynamin 2 expressions were exosome-specific and associated with spina bifida aperta embryogenesis and were proved to be downregulated in maternal serum exosomes from E12 to E18, in neural tubes and fetal neural exosomes with statistical difference, and in serum with no difference. Differentially expressed proteins were further analyzed in the serum exosomes of pregnant women during gestational weeks 12–40 using ELISA. Coronin 1A and Dynamin 2 were demonstrated to possess good diagnostic efficacy during gestation weeks 12–40, particularly during early gestation (12–18 weeks), and may be used as potential NTD screening and diagnostic biomarkers during early gestation.

Background: The role of N6-methyladenosine medicated long non-coding RNAs (lncRNAs) is elusive in colorectal cancer (CRC). Materials and Methods: We identified m6A-associated lncRNAs by using the data gathered from The Cancer Genome Atlas (TCGA) and stratified CRC patients into different subgroups. Cox-regression analysis were performed to construct a m6A-associated lncRNA signature. And the role of this signature in prognosis and immune microenvironment was dissected subsequently. Finally, a gene set enrichment analysis (GSEA) were executed to predict the possible bio-mechanisms on the basis of the signature.Results: Three m6A-associated clusters were constructed from 866 differentially expressed lncRNAs. Cluster 2 had poor prognosis and low immune cell infiltration. A m6A-associated lncRNA signature consisting of 14 lncRNAs was constructed, and recognized as an independent prognostic indicator in CRC by using survival analysis and receiver operating characteristic (ROC) curves. The clinical features and immune cell infiltration status were significantly different in the patients stratified by risk score. Furthermore, GSEA showed that P53 pathway and Natural killer cell mediated cytotoxicity were more enriched in the low risk group.Conclusion: Our data revealed that m6A-associated lncRNAs could be potential prognostic and immunogenicity indicators in CRC.

Background Spina bifida aperta (SBA) is a relatively common clinical type of neural tube defect. Although prenatal fetal surgery has been proven to be an effective treatment for SBA, the recovery of neurological function remains unsatisfactory due to neuron deficiencies. Our previous results demonstrated that intra-amniotic transplanted bone marrow mesenchymal stem cells (BMSCs) could preserve neural function through lesion-specific engraftment and regeneration. To further optimize the role of BMSCs and improve the environment of defective spinal cords so as to make it more conducive to nerve repair, the intra-amniotic transplanted BMSCs were modified with brain-derived neurotrophic factor (BDNF-BMSCs), and the therapeutic potential of BDNF-BMSCs was verified in this study. Methods BMSCs were modified by adenovirus encoding a green fluorescent protein and brain-derived neurotrophic factor (Ad-GFP-BDNF) in vitro and then transplanted into the amniotic cavity of rat fetuses with spina bifida aperta which were induced by all-trans-retinoic acid on embryonic day 15. Immunofluorescence, western blot and real-time quantitative PCR were used to detect the expression of different neuron markers and apoptosis-related genes in the defective spinal cords. Lesion areas of the rat fetuses with spina bifida aperta were measured on embryonic day 20. The microenvironment changes after intra-amniotic BDNF-BMSCs transplantation were investigated by a protein array with 90 cytokines. Results We found that BDNF-BMSCs sustained the characteristic of directional migration, engrafted at the SBA lesion area, increased the expression of BDNF in the defective spinal cords, alleviated the apoptosis of spinal cord cells, differentiated into neurons and skin-like cells, reduced the area of skin lesions, and improved the amniotic fluid microenvironment. Moreover, the BDNF-modified BMSCs showed a better effect than pure BMSCs on the inhibition of apoptosis and promotion of neural differentiation. Conclusion These findings collectively indicate that intra-amniotic transplanted BDNF-BMSCs have an advantage of promoting the recovery of defective neural tissue of SBA fetuses.