Characterization of alternative splicing events and prognostic signatures in gastric cancer.

BACKGROUND: Accumulating evidences indicate that the specific alternative splicing (AS) events are linked to the occurrence and prognosis of gastric cancer (GC). Nevertheless, the impact of AS is still unclear and needed to further elucidation. METHODS: The expression profile of GC and normal samples were downloaded from TCGA. AS events were achieved from SpliceSeq database. Cox regression together with LASSO analysis were employed to identify survival-associated AS events (SASEs) and calculate risk scores. PPI and pathway enrichment analysis were implemented to determine the function and pathways of these genes. Kaplan-Meier (K-M) analysis and Receiver Operating Characteristic Curves were used to evaluate the clinical significance of genes of SASEs. Q-PCR were applied to validate the hub genes on the survival prognosis in 47 GC samples. Drug sensitivity and immune cell infiltration analysis were conducted. RESULTS: In total, 48 140 AS events in 10 610 genes from 361 GC and 31 normal samples were analyzed. Through univariate Cox regression, 855 SASEs in 763 genes were screened out. Further, these SASEs were analyzed by PPI and 17 hub genes were identified. Meanwhile, using Lasso and multivariate Cox regression analysis, 135 SASEs in 132 genes related to 7 AS forms were further screened and a GC prognostic model was constructed. K-M curves indicates that high-risk group has poorer prognosis. And the nomogram analysis on the basis of the multivariate Cox analysis was disclosed the interrelationships between 7 AS forms and clinical parameters in the model. Five key genes were then screened out by PPI analysis and Differential Expression Gene analysis based on TCGA and Combined-dataset, namely STAT3, RAD51B, SOCS2, POLE2 and TSR1. The expression levels of AS in STAT3, RAD51B, SOCS2, POLE2 and TSR1 were all significantly correlated with survival by qPCR verification. Nineteen drugs were sensitized to high-risk patients and eight immune cells showed significantly different infiltration between the STAD and normal groups. CONCLUSIONS: In this research, the prognostic model constructed by SASEs can be applied to predict the prognosis of GC patients and the selected key genes are expected to become new biomarkers and therapeutical targets for GC treatment.

A new mechanism of thyroid hormone receptor ß agonists ameliorating nonalcoholic steatohepatitis by inhibiting intestinal lipid absorption via remodeling bile acid profiles.

Excessive dietary calories lead to systemic metabolic disorders, disturb hepatic lipid metabolism, and aggravate nonalcoholic steatohepatitis (NASH). Bile acids (BAs) play key roles in regulating nutrition absorption and systemic energy homeostasis. Resmetirom is a selective thyroid hormone receptor ß (THRß) agonist and the first approved drug for NASH treatment. It is well known that the THRß activation could promote intrahepatic lipid catabolism and improve mitochondrial function, however, its effects on intestinal lipid absorption and BA compositions remain unknown. In the present study, the choline-deficient, L-amino acid defined, high-fat diet (CDAHFD) and high-fat diet plus CCl4 (HFD+CCl4)-induced NASH mice were used to evaluate the effects of resmetirom on lipid and BA composition. We showed that resmetirom administration (10 mg·kg-1·d-1, i.g.) significantly altered hepatic lipid composition, especially reduced the C18:2 fatty acyl chain-containing triglyceride (TG) and phosphatidylcholine (PC) in the two NASH mouse models, suggesting that THRß activation inhibited intestinal lipid absorption since C18:2 fatty acid could be obtained only from diet. Targeted analysis of BAs showed that resmetirom treatment markedly reduced the hepatic and intestinal 12-OH to non-12-OH BAs ratio by suppressing cytochrome P450 8B1 (CYP8B1) expression in both NASH mouse models. The direct inhibition by resmetirom on intestinal lipid absorption was further verified by the BODIPY gavage and the oral fat tolerance test. In addition, disturbance of the altered BA profiles by exogenous cholic acid (CA) supplementation abolished the inhibitory effects of resmetirom on intestinal lipid absorption in both normal and CDAHFD-fed mice, suggesting that resmetirom inhibited intestinal lipid absorption by reducing 12-OH BAs content. In conclusion, we discovered a novel mechanism of THRß agonists on NASH treatment by inhibiting intestinal lipid absorption through remodeling BAs composition, which highlights the multiple regulation of THRß activation on lipid metabolism and extends the current knowledge on the action mechanisms of THRß agonists in NASH treatment.

Blood cell parameters and risk of nonalcoholic fatty liver disease: a comprehensive Mendelian randomization study.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is on the rise globally, and past research suggests a significant association with various blood cell components. Our goal is to explore the potential correlation between whole blood cell indices and NAFLD risk using Mendelian randomization (MR). METHODS: We analyzed data from 4,198 participants in the 2017-2018 National Health and Nutrition Examination Survey to investigate the link between blood cell indicators and NAFLD. Using various methods like weighted quantile sum and multivariate logistic regression, we assessed the association. Additionally, two-sample Mendelian randomization were employed to infer causality for 36 blood cell indicators and NAFLD. RESULTS: Multivariate logistic regression identified 10 NAFLD risk factors. Weighted quantile sum revealed a positive correlation (p = 6.03e-07) between total blood cell indices and NAFLD, with hemoglobin and lymphocyte counts as key contributors. Restricted cubic spline analysis found five indicators with significant nonlinear correlations to NAFLD. Mendelian randomization showed a notable association between reticulocyte counts and NAFLD using the inverse-variance weighted method. CONCLUSIONS: Hematological markers pose an independent NAFLD risk, with a positive causal link found for reticulocyte count. These results emphasize the importance of monitoring NAFLD and investigating specific underlying mechanisms further.

Melanin-like nanoparticles alleviate ischemia-reperfusion injury in the kidney by scavenging reactive oxygen species and inhibiting ferroptosis.

Kidney transplantation is essential for patients with end-stage renal disease; however, ischemia-reperfusion injury (IRI) during transplantation can lead to acute kidney damage and compromise survival. Recent studies have reported that antiferroptotic agents may be a potential therapeutic strategy, by reducing production of reactive oxygen species (ROS). Therefore, we constructed rutin-loaded polydopamine nanoparticles (PEG-PDA@rutin NPs, referred to as PPR NPs) to eliminate ROS resulting from IRI. Physicochemical characterization showed that the PPR NPs were ∼100 nm spherical particles with good ROS scavenging ability. Notably, PPR NPs could effectively enter lipopolysaccharide (LPS)-treated renal tubular cells, then polydopamine (PDA) released rutin to eliminate ROS, repair mitochondria, and suppress ferroptosis. Furthermore, in vivo imaging revealed that PPR NPs efficiently accumulated in the kidneys after IRI and effectively protected against IRI damage. In conclusion, PPR NPs demonstrated an excellent ability to eliminate ROS, suppress ferroptosis, and protect kidneys from IRI.

Low-voltage stimulated denitrification performance of high-salinity wastewater using halotolerant microorganisms.

Nitrate is a common contaminant in high-salinity wastewater, which has adverse effects on both the environment and human health. However, conventional biological treatment exhibits poor denitrification performance due to the high-salinity shock. In this study, an innovative approach using an electrostimulating microbial reactor (EMR) was explored to address this challenge. With a low-voltage input of 1.2 V, the EMR reached nitrate removal kinetic parameter (kNO3-N) of 0.0166-0.0808 h-1 under high-salinities (1.5 %-6.5 %), which was higher than that of the microbial reactor (MR) (0.0125-0.0478 h-1). The mechanisms analysis revealed that low-voltage significantly enhanced microbial salt-in strategy and promoted the secretion of extracellular polymeric substances. Halotolerant denitrification microorganisms (Pseudomonas and Nitratireductor) were also enriched in EMR. Moreover, the EMR achieved a NO3-N removal efficiency of 73.64 % in treating high-salinity wastewater (salinity 4.69 %) over 18-cycles, whereas the MR only reached 54.67 %. In summary, this study offers an innovative solution for denitrification of high-salinity wastewater.

Dynamic prediction of goal location by coordinated representation of prefrontal-hippocampal theta sequences.

Prefrontal (PFC) and hippocampal (HPC) sequences of neuronal firing modulated by theta rhythms could represent upcoming choices during spatial memory-guided decision-making. How the PFC-HPC network dynamically coordinates theta sequences to predict specific goal locations and how it is interrupted in memory impairments induced by amyloid beta (Aß) remain unclear. Here, we detected theta sequences of firing activities of PFC neurons and HPC place cells during goal-directed spatial memory tasks. We found that PFC ensembles exhibited predictive representation of the specific goal location since the starting phase of memory retrieval, earlier than the hippocampus. High predictive accuracy of PFC theta sequences existed during successful memory retrieval and positively correlated with memory performance. Coordinated PFC-HPC sequences showed PFC-dominant prediction of goal locations during successful memory retrieval. Furthermore, we found that theta sequences of both regions still existed under Aß accumulation, whereas their predictive representation of goal locations was weakened with disrupted spatial representation of HPC place cells and PFC neurons. These findings highlight the essential role of coordinated PFC-HPC sequences in successful memory retrieval of a precise goal location.

Optimizing heat source distribution in sintering molds: Integrating response surface model with sequential quadratic programming.

The sintering mold imposes strict requirements for temperature uniformity. The mold geometric parameters and the power configuration of heating elements exert substantial influence. In this paper, we introduce an optimization approach that combines response surface models with the sequential quadratic programming algorithm to optimize the geometric parameters and heating power configuration of a heating system for sintering mold. The response surface models of the maximum temperature difference, maximum temperature, and minimum temperature of the sintering area are constructed utilizing the central composite design method. The model's reliability is rigorously confirmed through variance analysis, residual analysis, and generalization capability validation. The models demonstrate remarkable predictive accuracy within the design space. A nonlinear constrained optimization model is established based on the response surface models, and the optimal parameters are obtained after 9 iterations using the sequential quadratic programming algorithm. Under the optimal parameters, the maximum temperature difference is maintained at less than 5 °C, confirming exceptional temperature uniformity. We conduct parameter analysis based on standardized effects to determine the main influencing factors of temperature uniformity, revealing that the distance between adjacent heating rods and the power density of the inner heating rods exert significant influence. Enhanced temperature uniformity can be achieved by adopting a larger distance between heating rods and configuring the power density of the heating rods to a relatively modest level. This work introduces a practical approach to optimize the heating systems for sintering molds, with potential applications in various industrial mold optimization.

One-Stone-for-Two-Birds Strategy for VSe2 to Enable High Capacity and Long-Life Zinc Storage.

Based on a specific zinc storage mechanism and excellent electronic conductivity, transition metal dichalcogenides, represented by vanadium diselenide, are widely used in aqueous zinc-ion battery (AZIB) energy storage systems. However, most vanadium diselenide cathode materials are presently limited by low specific capacity and poor cycling life. Herein, a simple hydrothermal process has been proposed for obtaining a vanadium diselenide cathode for an AZIB. The interaction of defects and crystal planes enhances zinc storage capacity and reduces the migration energy barrier. Moreover, abundant lamellar structure greatly increases reaction sites and alleviates volume expansion during the electrochemical process. Thus, the as-obtained vanadium diselenide AZIB exhibits an excellent reversible specific capacity of 377 mAh g-1 at 1 A g-1, and ultralong cycle stability of 291 mAh g-1 after 3200 cycles, with a nearly negligible capacity loss. This one-stone-for-two-birds strategy would be expected to be applied to large-scale synthesis of a high-performance zinc-ion battery cathode in the future.

Interference Suppression Algorithm Based on Short Time Fractional Fourier Transform.

Narrowband interference and wideband interference are both common jamming signals against synthetic aperture radar, which can degrade the signal severely. To suppress interference effectively, an interference suppression method based on short-time fractional Fourier transform (STFrFT) is proposed. After transforming the signal into the time-frequency domain through STFrFT, an adaptive gain coefficient is determined for the instantaneous frequency spectrum at every certain time. The gain coefficient can be preserved while suppressing the interference. Finally, we obtain the useful signal by inverse STFrFT. The simulation and performance analysis show the effectiveness and validity of the proposed algorithm for measured data.

N-MYC regulates cell survival via eIF4G1 in inv(16) acute myeloid leukemia.

N-MYC (encoded by MYCN) is a critical regulator of hematopoietic stem cell function. While the role of N-MYC deregulation is well established in neuroblastoma, the importance of N-MYC deregulation in leukemogenesis remains elusive. Here, we demonstrate that N-MYC is overexpressed in acute myeloid leukemia (AML) cells with chromosome inversion inv(16) and contributes to the survival and maintenance of inv(16) leukemia. We identified a previously unknown MYCN enhancer, active in multiple AML subtypes, essential for MYCN mRNA levels and survival in inv(16) AML cells. We also identified eukaryotic translation initiation factor 4 gamma 1 (eIF4G1) as a key N-MYC target that sustains leukemic survival in inv(16) AML cells. The oncogenic role of eIF4G1 in AML has not been reported before. Our results reveal a mechanism whereby N-MYC drives a leukemic transcriptional program and provides a rationale for the therapeutic targeting of the N-MYC/eIF4G1 axis in myeloid leukemia.

Cohesin loss and MLL-AF9 are not synthetic lethal in murine hematopoietic stem and progenitor cells.

Objective As cohesin mutations are rarely found in MLL-rearranged acute myeloid leukemias, we investigated the potential synthetic lethality between cohesin mutations and MLL-AF9 using murine hematopoietic stem and progenitor cells. Results Contrary to our hypothesis, a complete loss of Stag2 or haploinsufficiency of Smc3 were well tolerated in MLL-AF9-expressing hematopoietic stem and progenitor cells. Minimal effect of cohesin subunit loss on the in vitro self-renewal of MLL-AF9-expressing cells was observed. Despite the differing mutational landscapes of cohesin-mutated and MLL fusion AMLs, previous studies showed that cohesin and MLL fusion mutations similarly drive abnormal self-renewal through HOXA gene upregulation. The utilization of a similar mechanism suggests that little selective pressure exists for the acquisition of cohesin mutations in AMLs expressing MLL fusions, explaining their lack of co-occurrence. Our results emphasize the importance of using genetic models to test suspected synthetic lethality and suggest that a lack of co-occurrence may instead point to a common mechanism of action between two mutations.

Circ_0079471 Regulates the Proliferation, Migration, Invasion and Apoptosis of Osteosarcoma Cells by Mediating miR-485-3p and TRIP6.

BACKGROUND: Circular RNAs (circRNAs) are a special class of non-coding RNA molecules that show a closed circular structure and have been implicated in both tumour formation and oncogenesis. OBJECTIVE: This study aimed to learn more about how circ_0079471 functions in osteosarcomas (OSs). METHOD: Quantitative real-time polymerase chain reaction was used to detect the expression levels of thyroid hormone receptor-interacting protein 6 (TRIP6), miR-485-3p and circ_0079471. Methyl-thiazolyl-tetrazolium and flow cytometry were used to track cell growth and cell-cycle progression, and the research explored wound healing (migration) and invasion using Transwell plates. Western blotting was used to determine the protein expression of TRIP6, proliferating cell nuclear antigen and cyclin D1, and a dual-luciferase assay revealed the target relationship. RESULT: A xenograft experiment evaluated the in vivo effects of circ_0079471 on OS, and the results revealed the high expression of circ_0079471 in OS tissue and cells. The proliferation, cell-cycle migration and invasion of cells were reduced after circ_0079471 knockdown in OS cells; however, the effects of this knockdown were reversed when TRIP6 was overexpressed in the OS cells. The function of circ_0079471 was also achieved by in vivo miR-485-3p sponging. The upregulation of miR-485-3p and the downregulation of TRIP6 partly resulted in circ_0079471 downregulation, which subsequently inhibited OS progression. CONCLUSION: According to these results, circ_0079471 influences the development of OS by regulating miR-485-3p and TRIP6.

Electrochemical sensing fibers for wearable health monitoring devices.

Real-time monitoring of health conditions is an emerging strong issue in health care, internet information, and other strongly evolving areas. Wearable electronics are versatile platforms for non-invasive sensing. Among a variety of wearable device principles, fiber electronics represent cutting-edge development of flexible electronics. Enabled by electrochemical sensing, fiber electronics have found a wide range of applications, providing new opportunities for real-time monitoring of health conditions by daily wearing, and electrochemical fiber sensors as explored in the present report are a promising emerging field. In consideration of the key challenges and corresponding solutions for electrochemical sensing fibers, we offer here a timely and comprehensive review. We discuss the principles and advantages of electrochemical sensing fibers and fabrics. Our review also highlights the importance of electrochemical sensing fibers in the fabrication of "smart" fabric designs, focusing on strategies to address key issues in fiber-based electrochemical sensors, and we provide an overview of smart clothing systems and their cutting-edge applications in therapeutic care. Our report offers a comprehensive overview of current developments in electrochemical sensing fibers to researchers in the fields of wearables, flexible electronics, and electrochemical sensing, stimulating forthcoming development of next-generation "smart" fabrics-based electrochemical sensing.

Physiological and autophagy evaluation of different pear varieties (Pyrus spp.) in response to Botryosphaeria dothidea infection.

Ring rot disease is one of the most common diseases in pear orchards. To better understand the physiology, biochemistry and autophagic changes of different pear varieties after Botryosphaeria dothidea (B.dothidea) infection, we evaluated eight different pear varieties for B. dothidea resistance. The susceptible varieties had larger spot diameters, lower chlorophyll contents and higher malondialdehyde contents than the resistant varieties. In disease-resistant varieties, reactive oxygen species (ROS) levels were relatively lower, while the ROS metabolism (antioxidant enzyme activities and the ascorbic acid-glutathione cycle) was also maintained at higher levels, and it induced a significant upregulation of related gene expression. In addition, autophagy, as an important evaluation index, was found to have more autophagic activity in disease-resistant varieties than in susceptible varieties, suggesting that pathogen infestation drives plants to increase autophagy to defend against pathogens. In summary, the results of this study reveal that different resistant pear varieties enhance plant resistance to the disease through a series of physio-biochemical changes and autophagic activity after inoculation with B. dothidea. This study provides clear physiological and biochemical traits for pear disease resistance selection, potential genetic resources and material basis for pear disease control and disease resistance, breeding and points out the direction for research on the mechanism of pear resistance to B. dothidea.

Peer popularity and self-discipline as protective factors against depressive symptoms in Chinese adolescents: Do boys and girls benefit equally?

The current study examined the concurrent and longitudinal protective effects of peer popularity and self-discipline (control, planning, and the ability to prioritize important things) against depressive symptoms among adolescents. We used multilevel modeling to examine the data of 1676 adolescents aged 12-15 years from the China Family Panel Studies (CFPS) survey, a large-scale panel survey with a nationally representative sample. Results showed that both peer popularity and self-discipline predicted lower levels of depressive symptoms measured concurrently. The buffering effect of self-discipline against concurrent depressive symptoms was stronger for girls than for boys, especially in middle adolescence. Peer popularity additionally predicted lower levels of depressive symptoms 4 years later, and this effect was stronger for girls than for boys. These patterns of results were maintained after controlling for self-rated physical health and society-level factors. We discuss these findings against the background of distinct traditional gender roles.

Tumor-targeting hydroxyapatite nanoparticles for remodeling tumor immune microenvironment (TIME) by activating mitoDNA-pyroptosis pathway in cancer.

In recent years, immunotherapy has emerged as a promising strategy for treating solid tumors, although its efficacy remains limited to a subset of patients. Transforming non-responsive "cold" tumor types into immuno-responsive "hot" ones is critical to enhance the efficacy of immune-based cancer treatments. Pyroptosis, a programmed cell death mechanism, not only effectively eliminates tumor cells but also triggers a potent inflammatory response to initiate anti-tumor immune activities. This sheds light on the potential of pyroptosis to sensitize tumors to immune therapy. Hence, it is urgent to explore and develop novel treatments (e.g., nanomedicines) which are capable of inducing pyroptosis. In this study, we constructed tumor-targeting nanoparticles (CS-HAP@ATO NPs) by loading atorvastatin (ATO) onto chondroitin sulfate (CS) modified hydroxyapatite (HAP) nanoparticles (CS-HAP). CS was strategically employed to target tumor cells, while HAP exhibited the capacity to release calcium ions (Ca2+) in response to the tumor microenvironment. Moreover, ATO disrupted the mitochondrial function, leading to intracellular energy depletion and consequential changes in mitochondrial membrane permeability, followed by the influx of Ca2+ into the cytoplasm and mitochondria. CS and HAP synergetically augmented mitochondrial calcium overload, inciting the production of substantial amount of reactive oxygen species (ROS) and the subsequent liberation of oxidized mitochondrial DNA (OX-mitoDNA). This intricate activation process promoted the assembly of inflammasomes, most notably the NLRP3 inflammasome, followed by triggering caspase-1 activation. The activated caspase-1 was able to induce gasderminD (GSDMD) protein cleavage and present the GSDM-N domain, which interacted with phospholipids in the cell membrane. Then, the cell membrane permeability was raised, cellular swelling was observed, and abundant cell contents and inflammatory mediators were released. Ultimately, this orchestrated sequence of events served to enhance the anti-tumor immunoresponse within the organism.

Cultural values, parenting, and child adjustment in China.

To examine whether parents' cultural values are related to parenting practices and children's behavioural adjustment, mothers, fathers and children (N = 218) from two cities in China (Jinan and Shanghai) were interviewed when children were, on average, 10 years old. Mothers and fathers reported their endorsement of cultural values (individualism, collectivism, conformity), which were used to separately predict warmth and family obligation expectations reported by each parent, as well as children's report of parental psychological control, rule setting, knowledge solicitation and perceived family obligation expectations. Cross-informant (parents and child) composites of internalising and externalising behaviours were also obtained. The results showed that maternal individualism positively predicted parents' knowledge solicitation. Parental collectivism positively predicted their own warmth and family obligation expectations. Mothers' conformity positively predicted mothers' family obligation expectations, paternal warmth and children's perception of family obligation, whereas fathers' conformity only positively predicted fathers' family obligation expectations. These effects were largely consistent across regional subsamples, although mothers in Jinan were more collectivistic than mothers in Shanghai, and parents in Shanghai adopted less psychological control and more knowledge solicitation in parenting.

Association between the peripheral neutrophil-to-lymphocyte ratio and metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes frequently co-occur, imposing a tremendous medical burden. A convenient and effective MASLD indicator will be beneficial to the early diagnosis of disease. In the clinical laboratory, the neutrophil-to-lymphocyte ratio (NLR) is a readily accessible hematological marker. This study designed to determine the relation between the NLR and MASLD in type 2 diabetes patients. Methods: Data from 1,151 type 2 diabetes inpatients without infections, malignancy or hematological diseases who were recruited from 2016 through 2022 were analyzed in the retrospective study. The patients were stratified into NLR tertiles (total population: high NLR level > 2.18; middle NLR level: 1.58-2.18; low NLR level < 1.58), with additional subgroup stratification by sex (men: high NLR level > 2.21; middle NLR level: 1.60-2.21; and low NLR level < 1.60; women: high NLR level > 2.12; middle NLR level: 1.53-2.12; and low NLR level < 1.53). After adjusting for confounders (age, sex, weight, Glu, ALT and TG) associated with MASLD, the odds ratio (OR) and the corresponding 95% confidence interval (CI) of the NLR were obtained by using a binary logistic regression analysis to verify the correlation between the NLR and MASLD. Results: Compared to non-MASLD patients, MASLD patients had higher weight, blood glucose, insulin and C-peptide, worse liver function (higher ALT and GGT), lower HDL (all p < 0.05), and lower NLR (p < 0.001). The prevalence of MASLD was 43.75% (high NLR level), 55.21% (middle NLR level) and 52.22% (low NLR level) (p < 0.05). Compared to those of the high NLR level, the adjusted ORs and 95% CIs of the middle and low NLR levels were 1.624 (95% CI: 1.141-2.311) and 1.456 (95% CI: 1.025-2.068), for all subjects, while they were 1.640 (95% CI: 1.000-2.689) and 1.685 (95% CI: 1.026-2.766), for men. Conclusion: A low NLR is associated with a greater risk of MASLD.

Tip-Enhanced Sub-Femtomolar Steroid Immunosensing via Micropyramidal Flexible Conducting Polymer Electrodes for At-Home Monitoring of Salivary Sex Hormones.

Noninvasive testing and continuous monitoring of ultralow-concentration hormones in biofluids have attracted increasing interest for health management and personalized medicine, in which saliva could fulfill the demand. Steroid sex hormones such as progesterone (P4) and ß-estradiol (E2) are crucial for female wellness and reproduction; however, their concentrations in saliva can vary down to sub-pM and constantly fluctuate over several orders of magnitude. This remains a major obstacle toward user-friendly and reliable monitoring at home with low-cost flexible biosensors. Herein we introduce a 3D micropyramidal electrode architecture to address such challenges and achieve an ultrasensitive flexible electrochemical immunosensor with sub-fM-level detection capability of salivary sex hormones within a few minutes. This is enabled by micropyramidal electrode arrays consisting of a poly(3,4-ethylenedioxythiophene):poly(4-styrenesulfonate) (PEDOT:PSS) thin film as the coating layer and electrochemically decorated gold nanoparticles (AuNPs) to improve the antibody immobilization. The enhanced mass transport around the 3D tips provided by the micropyramidal architecture is discovered to improve the detection limit by 3 orders of magnitude, pushing it to as low as ∼100 aM for P4 and ∼20 aM for E2, along with a wide linear range up to µM. Accordingly, these hormones down to sub-fM in >1000-fold-diluted saliva samples can be accurately measured by the printed soft immunosensors, thus allowing at-home testing through simple saliva dilution to minimize the interfering substances instead of centrifugation. Finally, monitoring of the female ovarian hormone cycle of both P4 and E2 is successfully demonstrated based on the centrifuge-free saliva testing during a period of 4 weeks. This ultrasensitive and soft 3D microarchitected electrode design is believed to provide a universal platform for a diverse variety of applications spanning from accurate clinical diagnostics and counselling and in vivo detection of bioactive species to environmental and food quality tracing.

Expression and significance of cathepsin C and cathepsin D during pregnancy and Preeclampsia.

BACKGROUND: Cathepsin C (Cat C) is involved in the inflammatory-immune system and can be degraded by cathepsin D (Cat D). Preeclampsia (PE) and the inflammation-immunity relationship is currently a hot research topic, but there are still few studies. The aim was to investigate the expression and significance of Cat C and D in the serum of nonpregnant women, patients in various stages of pregnancy and patients with PE, and in the placenta of patients with normal pregnancy and PE. METHODS: Sixty young healthy nonpregnant women were selected: 180 normal pregnant women, including 60 each in the first, second, and third trimesters, and 100 women with PE, including 39 women with severe preeclampsia. The levels of Cat C and D in serum were detected by enzyme-linked immunosorbent assay (ELISA), and the expression levels of Cat C and D in placentas were detected by immunohistochemistry (IHC). RESULTS: The serum of Cat C in the first trimester was significantly lower than that in the nonpregnant group (P < 0.001), whereas Cat D was significantly higher than that in the nonpregnant group (P < 0.01). The levels of Cat C and D in the second trimester and third trimester were significantly higher than those in the first trimester (P < 0.05), but there was no significant difference in Cat C and D between the second trimester and third trimester. The levels of Cat C in the serum and placentas of patients with PE were significantly higher than those in the third trimester (P < 0.001) and positively correlated with the severity of PE (P < 0.001), whereas the levels of Cat D in the serum and placentas of patients with PE were significantly lower than those in the third trimester (P < 0.001) and negatively correlated with the severity of PE (P < 0.001). Age, primigravida proportion, and body mass index were significantly higher in the PE group than in the control group (P < 0.05), which were high-risk factors for PE. CONCLUSIONS: Cat C and D are associated with the maintenance of normal pregnancy. In patients with preeclampsia, a significant increase in Cat C and a significant decrease in Cat D levels may lead to the occurrence and development of preeclampsia.