Engineering Modular DNA Reaction Networks for Signal Processing.

Diversified molecular information-processing methods have significant implications for nanoscale manipulation and control, monitoring and disease diagnosis of organisms, and direct intervention in biological activities. However, as an effective approach for implementing multifunctional molecular information processing, DNA reaction networks (DRNs) with numerous functionally specialized molecular structures have challenged them on scale and modular design, leading to increased network complexity, further causing problems such as signal leakage, attenuation, and cross-talk in network reactions. Our study developed a strategy for performing various signal-processing tasks through engineering modular DRNs composed of simple molecular structures. This strategy is based on a universal core unit with signal selection capability, and a timeadjustable signal self-resetting module is achieved by combing the core unit and self-resetting unit, which improves the time controllability of modular DRNs. In addition, multi-input and -output signal crosscatalytic and continuously adjustable signal delay modules were realized by combining core and threshold units, providing a flexible, precise method for modular DRNs to process the signal. The strategy simplifies the design of DRNs, helps generate design ideas for largescale integrated DRNs with multiple functions, and provides prospects in biocomputing, gene regulation, and biosensing.

Arbitrary Digital DNA Computing: A Programmable Molecular Perceptron Driven by Lambda Exonuclease for Lighting up Concatenated Circuits.

DNA circuits, as a type of biochemical system, have the capability to synchronize the perception of molecular information with a chemical reaction response and directly process the molecular characteristic information in biological activities, making them a crucial area in molecular digital computing and smart bioanalytical applications. Instead of cascading logic gates, the traditional research approach achieves multiple logic operations which limits the scalability of DNA circuits and increases the development costs. Based on the interface reaction mechanism of Lambda exonuclease, the molecular perceptron proposed in this study, with the need for only adjusting weight and bias parameters to alter the corresponding logic expressions, enhances the versatility of the molecular circuits. We also establish a mathematical model and an improved heuristic algorithm for solving weights and bias parameters for arbitrary logic operations. The simulation and FRET experiment results of a series of logic operations demonstrate the universality of molecular perceptron. We hope the proposed molecular perceptron can introduce a new design paradigm for molecular circuits, fostering innovation and development in biomedical research related to biosensing, targeted therapy, and nanomachines.

Impaired neuronal macroautophagy in the prelimbic cortex contributes to comorbid anxiety-like behaviors in rats with chronic neuropathic pain.

A large proportion of patients with chronic pain experience co-morbid anxiety. The medial prefrontal cortex (mPFC) is proposed to underlie this comorbidity, but the molecular and neuronal mechanisms are not fully understood. Here, we reported that impaired neuronal macroautophagy in the prelimbic cortical (PrL) subregion of the mPFC paralleled the occurrence of anxiety-like behaviors in rats with chronic spared nerve injury (SNI). Intriguingly, such macroautophagy impairment was mainly observed in a FOS/c-Fos+ neuronal subpopulation in the PrL. Chemogenetic inactivation of this comorbid anxiety-related neuronal ensemble relieved pain-induced anxiety-like behaviors. Rescuing macroautophagy impairment in this neuronal ensemble relieved chronic pain-associated anxiety and mechanical allodynia and restored synaptic homeostasis at the molecular level. By contrast, artificial disruption of macroautophagy induced early-onset co-morbid anxiety in neuropathic rats, but not general anxiety in normal rats. Taken together, our work identifies causal linkage between PrL neuronal macroautophagy dysfunction and comorbid anxiety in neuropathic pain and provides novel insights into the role of PrL by differentiating its contribution in pain-induced comorbid anxiety from its modulation over general anxiety-like behaviors.Abbreviation: AAV: adeno-associated viruses; ACC: anterior cingulate cortex; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG12: autophagy related 12; CAMK2/CaMKII: calcium/calmodulin-dependent protein kinase II; CNO: clozapine-N-oxide; CQ: chloroquine; DIA: data independent acquisition; DIO: double floxed inverse orf; DLG4/PSD-95: discs large MAGUK scaffold protein 4; Dox: doxycycline; GABA: γ-aminobutyric acid; GFP: green fluorescent protein; GO: gene ontology; Gi: inhibitory guanine nucleotide-binding proteins; HsCHRM4/M4D: human cholinergic receptor muscarinic 4; HsSYN: human synapsin; KEGG: Kyoto encyclopedia of genes and genomes; LAMP1: lysosomal-associated membrane protein 1; LC3-II: PE conjugated microtubule-associated protein 1 light chain3; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; mPFC: medial prefrontal cortex; P2A: 2A self-cleaving peptide; PPI: protein-protein interaction networks; PrL: prelimbic cortex; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; rtTA: reverse tetracycline-transactivator; SDS-PAGE: sodium dodecylsulfate-polyacrylamide gel electrophoresis; SHANK3: SH3 and multiple ankyrin repeat domains 3; SLC1A1/EAAC1: solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, systemXag), member 1; SNAP23: synaptosomal-associated protein 23; SNI:spared nerve injury; SQSTM1/p62: sequestosome 1; SYT3: synaptotagmin 3; TRE: tetracycline-responsive element; TRE3G: third-generation tetracycline-responsive element.

A signal transmission strategy driven by gap-regulated exonuclease hydrolysis for hierarchical molecular networks.

Exonucleases serve as efficient tools for signal processing and play an important role in biochemical reactions. Here, we identify the mechanism of cooperative exonuclease hydrolysis, offering a method to regulate the cooperative hydrolysis driven by exonucleases through the modulation of the number of bases in gap region. A signal transmission strategy capable of producing amplified orthogonal DNA signal is proposed to resolve the polarity of signals and byproducts, which provides a solution to overcome the signal attenuation. The gap-regulated mechanism combined with DNA strand displacement (DSD) reduces the unpredictable secondary structures, allowing for the coexistence of similar structures in hierarchical molecular networks. For the application of the strategy, a molecular computing model is constructed to solve the maximum weight clique problems (MWCP). This work enhances for our knowledge of these important enzymes and promises application prospects in molecular computing, signal detection, and nanomachines.

DNA-QLC: an efficient and reliable image encoding scheme for DNA storage.

BACKGROUND: DNA storage has the advantages of large capacity, long-term stability, and low power consumption relative to other storage mediums, making it a promising new storage medium for multimedia information such as images. However, DNA storage has a low coding density and weak error correction ability. RESULTS: To achieve more efficient DNA storage image reconstruction, we propose DNA-QLC (QRes-VAE and Levenshtein code (LC)), which uses the quantized ResNet VAE (QRes-VAE) model and LC for image compression and DNA sequence error correction, thus improving both the coding density and error correction ability. Experimental results show that the DNA-QLC encoding method can not only obtain DNA sequences that meet the combinatorial constraints, but also have a net information density that is 2.4 times higher than DNA Fountain. Furthermore, at a higher error rate (2%), DNA-QLC achieved image reconstruction with an SSIM value of 0.917. CONCLUSIONS: The results indicate that the DNA-QLC encoding scheme guarantees the efficiency and reliability of the DNA storage system and improves the application potential of DNA storage for multimedia information such as images.

Instability, changes, and internal structure of children's attitudes toward mathematics in primary school: A four-wave investigation.

The longitudinal person-oriented study aimed to explore profiles, stability, gender differences, and compositional relations of math attitudes by tracking Chinese third graders (Ntotal = 1013, Mage(T1) = 8.92 ± 0.46, Ngirls = 404) in four waves with 1-year intervals. Five profiles and unstable transitional probabilities were identified among the four waves. The relations between enjoyment to confidence and value shifted from reciprocity to enjoyment dominance, but value negatively predicted later enjoyment and confidence. Additionally, boys' advantages were significant in late elementary school (fifth, sixth grades) and girls benefited from initial positive attitudes. These findings suggest that Chinese students' math attitudes in middle childhood are unstable, shaped by internal and external environmental dynamics, and need to be further explored in cross-cultural research.

An electrochemically cleanable pH electrode based on an electrodeposited iridium oxide-ruthenium oxide-titanium composite.

Biological contamination is an important issue in environmental pH detection, and our prepared electrochemically cleanable electrode may be an effective solution. By electrodepositing an iridium oxide-ruthenium oxide composite on a titanium sheet substrate, the electrode shows a sensitivity of 59.4 mV per pH in the pH range of 2-12 with high reproducibility, low hysteresis, high selectivity and high stability. It is worth mentioning that the electrode was proved to be electrochemically cleanable from biological contamination. When the cleaning time was 30 minutes, the electrode sensitivity rose from 50 to 58 mV per pH. Furthermore, the pH sensor, assembled from the prepared iridium-ruthenium oxide electrode and a home-made Ag/AgCl electrode, has similar electrode properties to those of commercial glass electrodes, but is also mechanically strong and electrochemically cleanable, which is promising for long-term deployment in natural environments.

Dynamic Changes of the Infralimbic Cortex and Its Regulation of the Prelimbic Cortex in Rats with Chronic Inflammatory Pain.

The prelimbic cortex (PL) is actively engaged in pain modulation. The infralimbic cortex (IL) has been reported to regulate the PL. However, how this regulation affects pain remains unclear. In the present study, we recorded temporary hyper-activity of PL pyramidal neurons responding to nociceptive stimuli, but a temporary hypo-function of the IL by in vivo electrophysiological recording in rats with peripheral inflammation. Manipulation of the PL or IL had opposite effects on thermal hyperalgesia. Furthermore, the functional connectivity and chemogenetic regulation between the subregions indicated an inhibitory influence of the IL on the PL. Activation of the pathway from the IL to the PL alleviated thermal hyperalgesia, whereas its inhibition exacerbated chronic pain. Overall, our results suggest a new mechanism underlying the role of the medial prefrontal cortex in chronic pain: hypo-function of the IL leads to hyperactivity of the PL, which regulates thermal hyperalgesia, and thus contributes to the chronicity of pain.

In Silico-Predicted Dynamic Oxlipidomics MS/MS Library: High-Throughput Discovery and Characterization of Unknown Oxidized Lipids.

Nontargeted lipidomics using liquid chromatography-tandem mass spectrometry can detect thousands of molecules in biological samples. However, the annotation of unknown oxidized lipids is limited to the structures present in libraries, restricting the analysis and interpretation of experimental data. Here, we describe Doxlipid, a computational tool for oxidized lipid annotation that predicts a dynamic MS/MS library for every experiment. Doxlipid integrates three key simulation algorithms to predict libraries and covers 32 subclasses of oxidized lipids from the three main classes. In the evaluation, Doxlipid achieves very high prediction and characterization performance and outperforms the current oxidized lipid annotation methods. Doxlipid, combined with a molecular network, further annotates unknown chemical analogs in the same reaction or pathway. We demonstrate the broad utility of Doxlipid by analyzing oxidized lipids in ferroptosis hepatocellular carcinoma, tissue samples, and other biological samples, substantially advancing the discovery of biological pathways at the trace oxidized lipid level.

Unraveling the Formation Mechanism of Egg's Unique Flavor via Flavoromics and Lipidomics.

Egg products after thermal treatment possess a unique flavor and are favored by consumers. In this study, the key aroma-active compounds of egg yolk products and their formation mechanism during thermal treatment were investigated. The volatile aroma compounds in egg yolks were monitored using an electronic nose, gas chromatography-mass spectrometry (GC-MS) and gas chromatography-olfactometry-mass spectrometry (GC-O-MS), and the lipid molecular species were explored using ultra-high-performance liquid chromatography- mass spectrometry with a Q-Exactive HF-X Orbitrap (UPLC-Q-Exactive HF-X). A total of 68 volatile compounds were identified. Boiled eggs mainly derived their flavor from hexanal, 2-pentyl-furan, 2-butanone, 3-methyl-butanal and heptane. Meanwhile, fried eggs relied mainly on 14 compounds, the most important of which were 2-ethyl-3-methyl-pyrazine, 3-ethyl-2,5-dimethyl-pyrazine, 2-ethyl-3,5-dimethyl-pyrazine, nonanal and 2,3-diethyl-5-methyl-pyrazine, providing a baked and burnt sugar flavor. A total of 201 lipid molecules, belonging to 21 lipid subclasses, were identified in egg yolks, and 13 oxidized lipids were characterized using a molecular network. Phosphoethanolamines (PEs) containing polyunsaturated fatty acids were the primary flavor precursors contributing to the development of egg yolks' flavor, participating in lipid oxidation reactions and the Maillard reaction and regulating the production of aldehydes and pyrazine compounds. This study provides reference and guidance for the development of egg yolk flavor products.

Role of the In-Situ-Formed Surface (Pt-S-O)-Ti Active Structure in SO2-Promoted C3H8 Combustion over a Pt/TiO2 Catalyst.

Typically, SO2 unavoidably deactivates catalysts in most heterogeneous catalytic oxidations. However, for Pt-based catalysts, SO2 exhibits an extraordinary boosting effect in propane catalytic oxidation, but the promotive mechanism remains contentious. In this study, an in situ-formed tactful (Pt-S-O)-Ti structure was concluded to be a key factor for Pt/TiO2 catalysts with a substantial SO2 tolerance ability. The experiments and theoretical calculations confirm that the high degree of hybridization and orbital coupling between Pt 5d and S 3p orbitals enable more charge transfer from Pt to S species, thus forming the (Pt-S-O)-Ti structure with the oxygen atom dissociated from the chemisorbed O2 adsorbed on oxygen vacancies. The active oxygen atom in the (Pt-S-O)-Ti active structure is a robust site for C3H8 adsorption, leading to a better C3H8 combustion performance. This work can provide insights into the rational design of chemical bonds for high SO2 tolerance catalysts, thereby improving economic and environmental benefits.

Excess Mortality for Femoral Intertrochanteric Fracture Patients Aged 50 Years and Older Treated Surgically and Conservatively in Tianjin, China: A Cohort Study.

OBJECTIVE: Intertrochanteric fracture is one type of hip fracture, which is the most serious consequence of osteoporosis. Along with the growing elderly population, intertrochanteric fracture is expected to rise increasingly. The aim of this study was to assess excess mortality after intertrochanteric fractures and to identify the predictors of long-term mortality by therapy among patients aged 50 years and older in Tianjin. METHODS: This is a retrospective cohort study on mortality for 3029 patients aged 50 years and older in Tianjin experiencing an intertrochanteric fracture between December 26, 2014 and December 31, 2018. Data were from Tianjin Hospital Hip Fracture (THHF) cohort. Follow-up period was until March 31, 2022. Mortality, excess mortality, and comorbidities were analyzed and stratified by therapy and gender. Time dependent Cox models were performed to estimate the effects of the variables. RESULTS: Absolute mortality for all the patients was 5.90% at 3 months, 12.55% at 12 months, 19.92% at 24 months and 27.28% at 36 months. Absolute mortality for surgical group was 1.57% at 3 months, 4.77% at 12 months, 8.49% at 24 months and 12.07% at 36 months, significantly lower than conservative group: 10.50% at 3 months, 20.73% at 12 months, 31.96% at 24 months and 43.04% at 36 months. We found a substantially lower mortality (hazard ratio [HR] 0.34, 95% confidence internal, [CI]: 0.23-0.52, p = 0.000) among patients undergoing surgical therapy than those undergoing conservative therapy, even when controlled for gender, age, the length of hospital stay, and all the comorbidities. Female patients (HR 0.68, 95% CI: 0.58-0.79, p = 0.000) were less likely to die than male patients after an intertrochanteric fracture. Patients treated by the two methods were both found to have excess mortality rates compared to the general population, although in different levels. The excess mortality rates for patients in the conservative therapy group were 14.46% in males and 17.93% in females, while in the surgical therapy group, 2.78% in females and 4.37% in males. The comorbidities moderate or severe renal disease (HR 2.19, 95% CI: 1.61-2.98, p = 0.000), metastatic solid tumor (HR 6.35, 95% CI: 1.56-25.85, p = 0.010), hypoproteinemia (HR 1.22, 95% CI: 1.01-1.47, p = 0.034), and older age (HR 1.89, 95% CI: 1.73-2.08, p = 0.000) were also risk factors on mortality. A worse-case analysis for the primary outcome were performed as sensitivity analysis and it was consistent with the original conclusion. CONCLUSION: Intertrochanteric factures for people aged 50 years older were found to have excess mortality compared to the general population in Tianjin city, and preventing the fractures in the hip for elderly people was imperative. After controlling tfor comorbidities and age, female gender and surgical therapy were protective factors for the death after fractures, which could provide strong evidence for patients and surgeons to make decisions.

Ventral Hippocampal CA1 Pyramidal Neurons Encode Nociceptive Information.

As a main structure of the limbic system, the hippocampus plays a critical role in pain perception and chronicity. The ventral hippocampal CA1 (vCA1) is closely associated with negative emotions such as anxiety, stress, and fear, yet how vCA1 neurons encode nociceptive information remains unclear. Using in vivo electrophysiological recording, we characterized vCA1 pyramidal neuron subpopulations that exhibited inhibitory or excitatory responses to plantar stimuli and were implicated in encoding stimuli modalities in naïve rats. Functional heterogeneity of the vCA1 pyramidal neurons was further identified in neuropathic pain conditions: the proportion and magnitude of the inhibitory response neurons paralleled mechanical allodynia and contributed to the confounded encoding of innocuous and noxious stimuli, whereas the excitatory response neurons were still instrumental in the discrimination of stimulus properties. Increased theta power and theta-spike coupling in vCA1 correlated with nociceptive behaviors. Optogenetic inhibition of vCA1 pyramidal neurons induced mechanical allodynia in naïve rats, whereas chemogenetic reversal of the overall suppressed vCA1 activity had analgesic effects in rats with neuropathic pain. These results provide direct evidence for the representations of nociceptive information in vCA1.

Straightforward Synthesis of Pentagon-Embedded Expanded [11]Helicenes for Radiative Cooling Property.

Two new pentagon-embedded carbo[11]helicenes have been designed and synthesized in a three-step process, which are the first example of carbo[11]helicenes through the post-functionalization of twistacene. TD-DFT analyses indicate that both of them possess high enantiomerization barriers of 42.29 kcal/mol and 40.76 kcal/mol, respectively. They emit strong red fluorescence and can be chemically oxidized into stable cationic radicals upon addition of AgSbF6 evidenced by the bathochromic-shifted absorption spectra and the appearance of electronic paramagnetic resonance (EPR) signals. In addition, such helical derivatives can be chosen as radiative cooling materials in a glass model house, and the maxima of 5.4 °C for the former and 6.5 °C for the latter are found in the comparative tests, which might be caused by the NIR reflective response.

A Short-Time Real-World Study of Two Perfluoropropane Tamponade Methods in Pars Plana Vitrectomy for Retinal Detachment.

INTRODUCTION: This real-world study evaluated the efficacy, safety, and operative parameters of two perfluoropropane (C3F8) tamponade methods combined with pars plana vitrectomy (PPV) for retinal detachment (RD). METHODS: A retrospective study of 132 patients (132 eyes) with RD (pure C3F8 in 38 eyes, mixed C3F8 in 94 eyes). All eyes underwent PPV with C3F8 tamponade and were followed up for at least 3 months. Retinal reattachment rate, time of gas configuration and injection, C3F8 dosage, intraocular pressure (IOP), best corrected visual acuity, postoperative ocular inflammation, and patients' complaints were evaluated. RESULTS: The single-surgery retinal reattachment rates of the pure C3F8 group and mixed C3F8 group were 97.4% and 96.8%, respectively, with no significant difference (p = 1.00). The final retinal reattachment rates of the two groups were 100% and 97.2%, respectively, with no significant difference (p = 1.00). The gas configuration time, gas injection time, and C3F8 dosage were significantly less in the pure C3F8 group (all p < 0.001). Time, but not group, was the influencing factor of postoperative IOP changes in the two groups (p < 0.001, p = 0.547, respectively). Compared with the baseline, the IOP estimates of the pure C3F8 group showed a significant increase immediately after surgery (p < 0.001), and the mixed C3F8 group showed a significant increase immediately and 1-2 days after surgery (all p < 0.05). There was no statistical difference in ocular inflammation (p = 0.339) and patients' complaints of discomfort (p = 0.175) between the two groups. CONCLUSION: Both the two methods of C3F8 tamponade combined with PPV in RD patients showed good efficacy and safety, but the clinical operation of pure C3F8 tamponade was more convenient and eco-friendly.

HCN2 Channels in the Ventral Hippocampal CA1 Regulate Nociceptive Hypersensitivity in Mice.

Chronic pain is a significant health problem worldwide. Recent evidence has suggested that the ventral hippocampus is dysfunctional in humans and rodents, with decreased neuronal excitability and connectivity with other brain regions, parallel pain chronicity, and persistent nociceptive hypersensitivity. But the molecular mechanisms underlying hippocampal modulation of pain remain poorly elucidated. In this study, we used ex vivo whole-cell patch-clamp recording, immunofluorescence staining, and behavioral tests to examine whether hyperpolarization-activated cyclic nucleotide-gated channels 2 (HCN2) in the ventral hippocampal CA1 (vCA1) were involved in regulating nociceptive perception and CFA-induced inflammatory pain in mice. Reduced sag potential and firing rate of action potentials were observed in vCA1 pyramidal neurons from CFA-injected mice. Moreover, the expression of HCN2, but not HCN1, in vCA1 decreased in mice injected with CFA. HCN2 knockdown in vCA1 pyramidal neurons induced thermal hypersensitivity, whereas overexpression of HCN2 alleviated thermal hyperalgesia induced by intraplantar injection of CFA in mice. Our findings suggest that HCN2 in the vCA1 plays an active role in pain modulation and could be a promising target for the treatment of chronic pain.

Eggshell Biowaste-Derived Flexible and Self-Cleaning Films for Efficient Subambient Daytime Radiative Cooling.

The management of the abundant eggshell biowaste produced worldwide has become a problematic issue due to the generated odor and microorganisms after direct disposal of the eggshell biowaste in landfills. Herein, we propose a new method to convert the hazardous eggshell biowaste to valuable resources for energy management applications. Eggshell-based films are fabricated by embedding eggshell powders into a polymer matrix to achieve highly efficient subambient daytime radiative cooling. Benefiting from the Mie scattering of the eggshell particles/air pores in the solar spectrum and the strong emission of the eggshell in the mid-infrared (mid-IR) range, the eggshell-based films present a high reflection of 0.96 in the solar spectrum and a high emission of 0.95 in the mid-IR range, with notable average temperature reductions of 4.1 and 11 °C below the ambient temperature during daytime and nighttime, respectively. Moreover, the eggshell-based films exhibit excellent flexibility and self-cleaning properties, which are beneficial for practical long-term outdoor applications. Our proposed design provides a new means for environmentally friendly and sustainable management of eggshell biowaste.

Identification of Two Subsets of Subcompartment A1 Associated with High Transcriptional Activity and Frequent Loop Extrusion.

Three-dimensional genome organization has been increasingly recognized as an important determinant of the precise regulation of gene expression in mammalian cells, yet the relationship between gene transcriptional activity and spatial subcompartment positioning is still not fully comprehended. Here, we first utilized genome-wide Hi-C data to infer eight types of subcompartment (labeled A1, A2, A3, A4, B1, B2, B3, and B4) in mouse embryonic stem cells and four primary differentiated cell types, including thymocytes, macrophages, neural progenitor cells, and cortical neurons. Transitions of subcompartments may confer gene expression changes in different cell types. Intriguingly, we identified two subsets of subcompartments defined by higher gene density and characterized by strongly looped contact domains, named common A1 and variable A1, respectively. We revealed that common A1, which includes highly expressed genes and abundant housekeeping genes, shows a ~2-fold higher gene density than the variable A1, where cell type-specific genes are significantly enriched. Thus, our study supports a model in which both types of genomic loci with constitutive and regulatory high transcriptional activity can drive the subcompartment A1 formation. Special chromatin subcompartment arrangement and intradomain interactions may, in turn, contribute to maintaining proper levels of gene expression, especially for regulatory non-housekeeping genes.

Programming conformational cooperativity to regulate allosteric protein-oligonucleotide signal transduction.

Conformational cooperativity is a universal molecular effect mechanism and plays a critical role in signaling pathways. However, it remains a challenge to develop artificial molecular networks regulated by conformational cooperativity, due to the difficulties in programming and controlling multiple structural interactions. Herein, we develop a cooperative strategy by programming multiple conformational signals, rather than chemical signals, to regulate protein-oligonucleotide signal transduction, taking advantage of the programmability of allosteric DNA constructs. We generate a cooperative regulation mechanism, by which increasing the loop lengths at two different structural modules induced the opposite effects manifesting as down- and up-regulation. We implement allosteric logic operations by using two different proteins. Further, in cell culture we demonstrate the feasibility of this strategy to cooperatively regulate gene expression of PLK1 to inhibit tumor cell proliferation, responding to orthogonal protein-signal stimulation. This programmable conformational cooperativity paradigm has potential applications in the related fields.

Mucin1 induced trophoblast dysfunction in gestational diabetes mellitus via Wnt/ß-catenin pathway.

BACKGROUND: To elucidate the role of Mucin1 (MUC1) in the trophoblast function (glucose uptake and apoptosis) of gestational diabetes mellitus (GDM) women through the Wnt/ß-catenin pathway. METHODS: Glucose uptake was analyzed by plasma GLUT1 and GLUT4 levels with ELISA and measured by the expression of GLUT4 and INSR with immunofluorescence and Western blotting. Apoptosis was measured by the expression of Bcl-2 and Caspase3 by Western blotting and flow cytometry. Wnt/ß-catenin signaling measured by Western blotting. In vitro studies were performed using HTR-8/SVneo cells that were cultured and treated with high glucose (HG), sh-MUC1 and FH535 (inhibitor of Wnt/ß-catenin signaling). RESULTS: MUC1 was highly expressed in the placental trophoblasts of GDM, and the Wnt/ß-catenin pathway was activated, along with dysfunction of glucose uptake and apoptosis. MUC1 knockdown resulted in increased invasiveness and decreased apoptosis in trophoblast cells. The initial linkage between MUC1, the Wnt/ß-catenin pathway, and glucose uptake was confirmed by using an HG-exposed HTR-8/SVneo cell model with MUC1 knockdown. MUC1 knockdown inhibited the Wnt/ß-catenin signaling pathway and reversed glucose uptake dysfunction and apoptosis in HG-induced HTR-8/SVneo cells. Meanwhile, inhibition of Wnt/ß-catenin signaling could also reverse the dysfunction of glucose uptake and apoptosis. CONCLUSIONS: In summary, the increased level of MUC1 in GDM could abnormally activate the Wnt/ß-catenin signaling pathway, leading to trophoblast dysfunction, which may impair glucose uptake and induce apoptosis in placental tissues of GDM women.