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Abstract Background Breast cancer (BC) is a great clinical challenge because of its aggressiveness and poor prognosis. Zinc Finger Protein 64 (ZFP64), as a transcriptional factor, is responsible for the development and progression of cancers. This study aims to investigate whether ZFP64 regulates stem cell-like properties and tumorigenesis in BC by the glycolytic pathway. Results It was demonstrated that ZFP64 was overexpressed in BC specimens compared to adjacent normal tissues, and patients with high ZFP64 expression had shorter overall survival and disease-free survival. The analysis of the association of ZFP64 expression with clinicopathological characteristics showed that high ZFP64 expression is closely associated with N stage, TNM stage, and progesterone receptor status. Knockdown of ZFP64 suppressed the viability and colony formation capacity of BC cells by CCK8 and colony formation assays. The subcutaneous xenograft models revealed that ZFP64 knockdown reduced the volume of formatted tumors, and decreased Ki67 expression in tumors. The opposite effects on cell proliferation and tumorigenesis were demonstrated by ZFP64 overexpression. Furthermore, we suggested that the stem cell-like properties of BC cells were inhibited by ZFP64 depletion, as evidenced by the decreased size and number of formatted mammospheres, the downregulated expressions of OCT4, Nanog, and SOX2 proteins, as well as the reduced proportion of CD44+/CD24− subpopulations. Mechanistically, glycolysis was revealed to mediate the effect of ZFP64 using mRNA-seq analysis. Results showed that ZFP64 knockdown blocked the glycolytic process, as indicated by decreasing glycolytic metabolites, inhibiting glucose consumption, and reducing lactate and ATP production. As a transcription factor, we identified that ZFP64 was directly bound to the promoters of glycolysis-related genes (ALDOC, ENO2, HK2, and SPAG4), and induced the transcription of these genes by ChIP and dual-luciferase reporter assays. Blocking the glycolytic pathway by the inhibition of glycolytic enzymes ENO2/HK2 suppressed the high proliferation and stem cell-like properties of BC cells induced by ZFP64 overexpression. Conclusions These data support that ZFP64 promotes stem cell-like properties and tumorigenesis of BC by activating glycolysis in a transcriptional mechanism.

ABSTRACT Phage-antibiotic synergy (PAS) represents a superior treatment strategy for pathogen infections with less probability of resistance development. Here, we aim to understand the molecular mechanism by which PAS suppresses resistance in terms of population evolution. A novel hypervirulent Klebsiella pneumoniae (KP) phage H5 was genetically and structurally characterized. The combination of H5 and ceftazidime (CAZ) showed a robust synergistic effect in suppressing resistance emergence. Single-cell Raman analysis showed that the phage-CAZ combination suppressed bacterial metabolic activities, contrasting with the upregulation observed with phage alone. The altered population evolutionary trajectory was found to be responsible for the contrasting metabolic activities under different selective pressures, resulting in pleiotropic effects. A pre-existing wcaJ point mutation (wcaJG949A) was exclusively selected by H5, conferring a fitness advantage and up-regulated activity of carbohydrate metabolism, but also causing a trade-off between phage resistance and collateral sensitivity to CAZ. The wcaJ point mutation was counter-selected by H5-CAZ, inducing various mutations in galU that imposed evolutionary disadvantages with higher fitness costs, and suppressed carbohydrate metabolic activity. H5 and H5-CAZ treatments resulted in opposite effects on the transcriptional activity of the phosphotransferase system and the ascorbate and aldarate metabolism pathway, suggesting potential targets for phage resistance suppression. Our study reveals a novel mechanism of resistance suppression by PAS, highlighting how the complexity of bacterial adaptation to selective pressures drives treatment outcomes.IMPORTANCEPhage-antibiotic synergy (PAS) has been recently proposed as a superior strategy for the treatment of multidrug-resistant pathogens to effectively reduce bacterial load and slow down both phage and antibiotic resistance. However, the underlying mechanisms of resistance suppression by PAS have been poorly and rarely been studied. In this study, we tried to understand how PAS suppresses the emergence of resistance using a hypervirulent Klebsiella pneumoniae (KP) strain and a novel phage H5 in combination with ceftazidime (CAZ) as a model. Our study reveals a novel mechanism by which PAS drives altered evolutionary trajectory of bacterial populations, leading to suppressed emergence of resistance. The findings advance our understanding of how PAS suppresses the emergence of resistance, and are imperative for optimizing the efficacy of phage-antibiotic therapy to further improve clinical outcomes.

Abstract Background Hyperuricemia can lead to synovial hyperplasia in the wrist. In severe cases, it can lead to the deposition of gouty stone in the carpal tunnel, resulting in increased pressure in the carpal tunnel and compression of the median nerve to cause carpal tunnel syndrome (CTS), which is called gouty carpal tunnel syndrome (GCTS). As for the surgical treatment of gouty carpal tunnel syndrome, scholars have different opinions on whether it is necessary to remove the superficial flexor tendon. The purpose of this study was to compare the clinical efficacy of trimming and resection of the diseased superficial flexor tendon in the treatment of gouty carpal tunnel syndrome. Methods Clinical data were collected from May 2016 to July 2021 from 10 patients (13 affected wrists) diagnosed with gouty carpal tunnel syndrome and classified into two groups according to the surgical modality: the diseased portion of the gout-eroded superficial finger tendon was trimmed in 9 wrists, and the diseased superficial finger flexor tendon was excised in 4 wrists. Values related to flexion and extension functions, 2-PD, DASH, BCTQ, VAS and recurrence in the affected fingers were compared between the two groups as well as before and after surgery in each group. Results All affected limbs used were cleared of gouty stones, finger numbness improved, no skin necrosis occurred, and all incisions healed at stage I. At follow-up (13.58 ± 5.53 months), there was no significant difference between groups in flexion and extension function, 2-PD, DASH, BCTQ, and VAS with respect to the affected fingers, and patients in both groups improved significantly before and after surgery. Treatment of only one wrist involved trimming to remove lesion-affected portions of tendon, which reappeared 1 year after surgery, and there was one case of poor recovery from greater piriformis muscle atrophy in both procedures. Conclusion Regarding surgical treatment of patients with gouty carpal tunnel syndrome in which the gouty stone has invaded the superficial flexor tendons of the fingers, the diseased superficial flexor tendons can be selectively excised, and the postoperative mobility of the affected fingers may not be impaired.

Abstract Adaptation to selective pressures is crucial for clinically important pathogens to establish epidemics, but the underlying evolutionary drivers remain poorly understood. The current epidemic of carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a significant threat to public health. In this study we analyzed the genome sequences of 794 CRKP bloodstream isolates collected in 40 hospitals in China between 2014 and 2019. We uncovered a subclonal replacement in the predominant clone ST11, where the previously prevalent subclone OL101:KL47 was replaced by O2v1:KL64 over time in a stepwise manner. O2v1:KL64 carried a higher load of mobile genetic elements, and a point mutation exclusively detected in the recC of O2v1:KL64 significantly promotes recombination proficiency. The epidemic success of O2v1:KL64 was further associated with a hypervirulent sublineage with enhanced resistance to phagocytosis, sulfamethoxazole-trimethoprim, and tetracycline. The phenotypic alterations were linked to the overrepresentation of hypervirulence determinants and antibiotic genes conferred by the acquisition of an rmpA-positive pLVPK-like virulence plasmid and an IncFII-type multidrug-resistant plasmid, respectively. The dissemination of the sublineage was further promoted by more frequent inter-hospital transmission. The results collectively demonstrate that the expansion of O2v1:KL64 is correlated to a repertoire of genomic alterations convergent in a subpopulation with evolutionary advantages.

Abstract Smart actuators that can convert external energy stimuli into mechanical energy output have great potential in industrial, biomedical, and military applications. However, the existed disadvantage such as complex fabrication process, single stimulus source, and the requirement of artificial energy restrict their further development. Herein, a MXene/polyethylene (PE)‐based soft actuator with multistimulus response and the ability to be driven by natural sunlight and human humidity is proposed through a simple method. Owing to the excellent electrical conductivity, high photothermal conversion capability, and surface hydrophilicity of MXene, the MXene/PE actuator exhibits rapid and large bending deformation in response to external multistimuli such as light, electricity, heat, and humidity. Owing to the simple preparation, and anisotropic, tailorable and programmable properties of the MXene/PE actuator, a soft robot that can crawl directionally under light conditions is constructed. In addition, based on the high sensitivity response of the actuator to light and humidity, smart clothing that can generate reversible bending deformation under natural sunlight as well as sweat conditions is developed. These results provide a new inspiration for the design of high‐performance soft actuators with multistimulus response, and demonstrate the potential applications of the MXene/PE actuators in smart devices, bionic robots, and wearable clothing.

The presence of strong ambient vibrations could have a negative impact on applications such as high precision inertial navigation and tilt measurement due to the vibration rectification error (VRE) of the accelerometer. In this paper, we investigate the origins of the VRE using a self-developed MEMS accelerometer equipped with an area-variation-based capacitive displacement transducer. Our findings indicate that the second-order nonlinearity coefficient is dependent on the frequency but the VRE remains constant when the displacement amplitude of the excitation is maintained at a constant level. This frequency dependence of nonlinearity is a result of several factors coupling with each other during signal conversion from acceleration to electrical output signal. These factors include the amplification of the proof mass’s amplitude as the excitation frequency approaches resonance, the nonlinearity in capacitance-displacement conversion at larger displacements caused by the fringing effect, and the offset of the mechanical suspension’s equilibrium point from the null position of the differential capacitance electrodes. Through displacement transducer and damping optimization, the second-order nonlinearity coefficient is greatly reduced from mg/g2 to μg/g2.

The geotechnical engineering field and indoor parameter test data are the foundation of engineering construction, design and evaluation. The existence of abnormal data often misleads the determination of parameters such as construction and design. Data anomaly detection is the most basic but extremely important task to ensure the safety and reliability of a project. Aiming at the blindness of detection due to the lack of model selection in traditional anomaly detection algorithms, this paper proposes an anomaly detection model system based on a combination of meta-learning outlier detection (MetaOD) and data mining algorithms. The system first selects the initial model class and its parameters suitable for different data types according to the characteristics of the data, averages the selected parameters of the same type of algorithm, and then uses the selected algorithm to diagnose data anomalies, thereby improving the anomaly accuracy of detection. To evaluate the effectiveness of the model, the machine learning test dataset (glass dataset) proposed by the University of California Irvine, is used for test analysis. The results show that the accuracy rate of anomaly detection using this model system reaches 96.41%, which is much higher than that of other detection algorithms. Finally, the model system is applied to the uniaxial compressive strength dataset of the Macau granite and the groundwater monitoring data of the Junchang Tunnel to carry out anomaly detection and analysis and to identify 9 and 10 abnormal points, respectively.

Background: CKLF like MARVEL transmembrane domain containing 6 (CMTM6) is an important programmed cell death 1 ligand 1 regulator (PD-L1). CMTM6 was reported as an important regulator of PD-L1 by promoting PD-L1 expression in tumor cells against T cells. However, the function of CMTM6 in cervical cancer is not well characterized. In addition, the role of CMTM6 in the induction of epithelial-mesenchymal transition (EMT) in the context of cervical cancer is unknown.Methods: In this study, we evaluated the role of CMTM6, including gene expression analysis, miRNA target regulation, and methylation characteristic, using multiple bioinformatics tools based on The Cancer Genome Atlas (TCGA) database. The expression of CMTM6 in cervical cancer tissues and non-cancerous adjacent tissues was assessed using immunohistochemistry. In vitro and in vivo function experiments were performed to explore the effects of CMTM6 on growth and metastasis of cervical cancer.Results: Human cervical cancer tissues showed higher expression of CMTM6 than the adjacent non-cancerous tissues. In vitro assays showed that CMTM6 promoted cervical cancer cell invasion, migration, proliferation, and epithelial-mesenchymal transition via activation of mitogen-activated protein kinase (MAPK) c-jun N-terminal kinase (JNK)/p38 signaling pathway. We identified transcription factors (TFs), miRNAs, and immune cells that may interact with CMTM6.Conclusion: These results indicate that CMTM6 is a potential therapeutic target in the context of cervical cancer.

Herein, an ultrasensitive DNAzyme-based fluorescence biosensor for detecting Cu2+ was designed using the cascade signal amplification strategy, coupling λ-exonuclease-assisted target recycling and mismatched catalytic hairpin assembly (MCHA). In the designed detection system, the target, Cu2+, can activate the Cu2+-dependent DNAzyme to cause a cleavage reaction, releasing ssDNA (tDNA). Then, tDNA binds to hairpin DNA (H0) with an overhanging 5′-phosphorylated terminus to form dsDNA with a blunt 5′-phosphorylated terminus, which activates the dsDNA to be digested by λ-Exo and releases tDNA along with another ssDNA (iDNA). Subsequently, the iDNA initiates MCHA, which can restore the fluorescence of carboxyfluorescein (FAM) previously quenched by tetramethylrhodamine (TAMRA), resulting in a strong fluorescent signal. Furthermore, MCHA efficiently improves the signal-to-noise ratio of the detection system. More importantly, tDNA recycling can be achieved with the λ-Exo digestion reaction to release more iDNA, efficiently amplifying the fluorescent signal and further improving the sensitivity to Cu2+ with a detection limit of 60 fM. The practical application of the developed biosensor was also demonstrated by detecting Cu2+ in real samples, proving it to be an excellent analytical strategy for the ultrasensitive quantification of heavy metal ions in environmental water sources.

Radiotherapy is an important therapeutic method for patients with cancer. However, radioresistance can cause treatment failure. Thus, there is an urgent need to investigate mechanisms of radioresistance and identity markers that could be used to predict radioresistance and prognosis of post-radiotherapy cancer patients. In the present study, we propose HOXA1 as a candidate biomarker of intrinsic radioresistance in multiple cancer types. By analyzing data from The Cancer Genome Atlas (TCGA), we found that HOXA1 was aberrantly upregulated in multiple cancers, and that elevated HOXA1 was significantly associated with poor prognosis of post-radiotherapy head and neck squamous cell carcinoma (HNSCC) and low-grade glioma (LGG) patients. Correlation analysis showed that HOXA1 expression was positively correlated with expression of EGFR, CDK6, and CAV1, which have been reported to enhance radioresistance. In addition, gene set enrichment analysis (GSEA) showed that the oxidative phosphorylation gene set was negatively enriched in HOXA1 high-expression samples in both HNSCC and LGG. Moreover, immunohistochemical assays indicated that high HOXA1 expression was significantly correlated with a high recurrence rate of nasopharyngeal carcinoma (NPC) after radiotherapy. Further in vitro experiments demonstrated that HOXA1 knockdown markedly attenuated the DNA repair capacity of NPC cells and sensibilized NPC cells to irradiation. Taken together, the results of this study demonstrate that HOXA1 has potential to be a predictive marker for radioresistance and post-radiotherapy prognosis that could help to guide individualized treatment in multiple cancer types.

Introduction and objectives: The oncogene diencephalon/mesencephalon homeobox 1 (DMBX1) is widely overexpressed in a variety of human cancers. The present study aimed to analyze the expression and clinical importance of DMBX1 in nonneoplastic tissues and tumor tissues from patients with hepatocellular carcinoma (HCC). Materials and methods: DMBX1 expression in HCC and adjacent nontumor tissues was analyzed using immunohistochemical staining. Chi-square tests were applied to compare DMBX1 expression between the tumors and the adjacent normal tissues. We explored the correlation of DMBX1 expression with clinicopathological factors and its effect on the prognosis of HCC. Finally, we investigated the role of DMBX1 in HCC via knockdown experiments, which analyzed changes in cell invasion, cell proliferation and epithelial-mesenchymal transition (EMT) biomarkers (E-cadherin, N-cadherin, vimentin). The mRNAs that were coexpressed with DMBX1 in HCC, based on the TCGA cohort (n = 366), were obtained from the cBioPortal database. Results: The average score for DMBX1 expression was significantly different (P

Inductive power transfer is a practical approach to recharging the autonomous underwater vehicles (AUVs). The performance of the magnetic coupler determines the system transfer capacity. The annular magnetic coupler is widely utilized in the underwater wireless charging system. However, this magnetic coupler has limitations on magnetic field distribution. The flux linkage occupies the center of the AUV, and hence, the electronics inside the AUV are susceptible to electromagnetic interference. Additionally, the weight of the annular magnetic coupler greatly increases the burden on AUV power supply. In this paper, the magnetic coupler structure evolution is analyzed and a dipole-coil-based magnetic coupler with a novel circumferential coupling manner is presented. The magnetic flux is perfectly confined by the coupling manner, and the magnetic coupler weight is reduced by dimension optimization. To implement the magnetic coupler, the Fe-based nanocrystalline soft magnetic material is taken into consideration. To validate the proposal, a wireless charging system is built. Experimental results show that the system transfers 630W under water with a DC-DC efficiency of 89.7%.

Inductive power transfer (IPT) is an optimal way for the unmanned aerial vehicle (UAV) wireless charging. The magnetic coupler is the key component in the IPT system, which determines the power transmission capacity and efficiency in IPT system. Due to the particularity of UAV application, the magnetic field height should be strictly limited to avoid the damage caused by high frequency magnetic field heat the UAV's metal equipment. A cross-type magnetic coupler with receiving coil placed on UAV's one landing gear was proposed to solve this problem, but it has the possibility of making UAV fuselage imbalance. Therefore, a novel cross-type magnetic coupler is proposed to overcome its difficulties in this paper, and most of magnetic fields are restrained to be lower than UAV's landing gear height h1 = 145mm, which will not cause damage to the UAV's equipment. And a simple and practical iterative method for designing the magnetic coupler geometry parameters is proposed, with simplification of the complex design process for the finite element analysis, improves the design efficiency. The experimental results show that the system can charge the 260W UAV normally with the system efficiency of 91.577% within the misalignment range of X-axis direction 25mm, Y-axis direction 40mm and rotation 25.

The epithelial-to-mesenchymal transition (EMT) is a cellular reprogramming process converting epithelial cells into mesenchymal cell morphology. Snail is a critical regulator of EMT by both suppressing epithelial gene expression and promoting mesenchymal gene expression. Expression and activity of Snail are tightly controlled at transcriptional and post-translational levels. It has previously been reported that Snail undergoes phosphorylation and ubiquitin-dependent proteasome degradation. Here, we report nuclear phosphatase SCP4/CTDSPL2 acts as a novel Snail phosphatase. SCP4 physically interacts with and directly dephosphorylates Snail. SCP4-mediated dephosphorylation of Snail suppresses the ubiquitin-dependent proteasome degradation of Snail and consequently enhances TGFβ-induced EMT. The knockdown of SCP4 in MCF10A mammary epithelial cells leads to attenuated cell migration. Collectively, our finding demonstrates that SCP4 plays a critical role in EMT through Snail dephosphorylation and stabilization.

In order to investigate the water inrush mechanism in completely weathered granite, a large-scale triaxial testing system is designed and manufactured, which can induce the mass transfer and monitor the flow properties. Using this system, the effects of water pressure and initial porosity on the mass transfer and flow properties were determined, and the relative critical conditions for water inrush were proposed. The results indicate that (1) the particle transfer could cause an increase in porosity, permeability, and water inflow, which is the essential reason for water inrush in completely weathered granite. (2) Due to the effect of particle transfer, the flow properties may change from a Darcy to a non-Darcy flow, which is a key signal for water inrush. (3) With the increase of water pressure, the mass transfer, permeability, and water inflow increased gradually, and a critical value (p=0.6 MPa) that caused the water inrush was obtained. Furthermore, with the decrease of initial porosity, the mass transfer and flow properties were suppressed rapidly, and a critical porosity (0.23) to anti-inrush was observed. The results obtained can provide an important reference for understanding the mechanism, forecasting the risk, and taking the effective control measures for water inrush.

Capacitive MEMS accelerometers with area-variable periodic-electrode displacement transducers found wide applications in disaster monitoring, resource exploration and inertial navigation. The bonding-induced warpage, due to the difference in the coefficients of thermal expansion of the bonded slices, has a negative influence on the precise control of the interelectrode spacing that is essential to the sensitivity of accelerometers. In this work, we propose the theory, simulation and experiment of a method that can alleviate both the stress and the warpage by applying different bonding temperature on the bonded slices. A quasi-zero warpage is achieved experimentally, proving the feasibility of the method. As a benefit of the flat surface, the spacing of the capacitive displacement transducer can be precisely controlled, improving the self-noise of the accelerometer to 6 ng/√Hz @0.07 Hz, which is about two times lower than that of the accelerometer using a uniform-temperature bonding process.

Encoder-like micro area-changed capacitive transducers are advantageous in terms of their better linearity and larger dynamic range compared to gap-changed capacitive transducers. Such transducers have been widely applied in rectilinear and rotational position sensors, lab-on-a-chip applications and bio-sensors. However, a complete model accounting for both the parasitic capacitance and fringe effect in area-changed capacitive transducers has not yet been developed. This paper presents a complete model for this type of transducer applied to a high-resolution micro accelerometer that was verified by both simulations and experiments. A novel optimization method involving the insertion of photosensitive polyimide was used to reduce the parasitic capacitance, and the capacitor spacing was decreased to overcome the fringe effect. The sensitivity of the optimized transducer was approximately 46 pF/mm, which was nearly 40 times higher than that of our previous transducer. The displacement detection resolution was measured as 50 pm/√Hz at 0.1 Hz using a precise capacitance detection circuit. Then, the transducer was applied to a sandwich in-plane micro accelerometer, and the measured level of the accelerometer was approximately 30 ng/√Hz at 1Hz. The earthquake that occurred in Taiwan was also detected during a continuous gravity measurement.

OBJECTIVE: To prospectively investigate the association between serum uric acid (SUA) level and incidence of impaired fasting glucose (IFG) in adult Chinese. METHODS: We evaluated 13,328 women and 41,350 men without diabetes and IFG. The participants were classified into quintile according to baseline level of SUA. Data were analyzed to examine the association between SUA levels and the incidence of IFG. We used Cox regression models to estimate the relative risk of IFG after adjusting for known risk factors. RESULTS: For men, the second quintile of SUA has the lowest cumulative incidence of IFG (29.9%); the fifth quintile of SUA has the highest cumulative incidence of IFG (35.6%). After corrected with Cox regression, the first quartile and the fourth quartile have higher cumulative incidence of IFG than the second quintile, with the HR of 1.11(1.05-1.17) and 1.07(1.01-1.13), respectively. For women, the first quartile of SUA has the lowest cumulative incidence of IFG (20.7%), while the fifth quintile of SUA has the highest cumulative incidence of IFG (30.0%). However, there is no significant difference in IFG between different quintile after adjusted with Cox regression. CONCLUSIONS: The results of this prospective study suggest that there is a higher risk of developing IFG in association with low or high SUA concentrations for men. These relationships were independent of other known risk factors. There is no significant correlation in the risk of developing IFG in association with SUA concentrations for women. Analyses excluding participants with hypertension or with hyperlipidemia and analyses with participants stratified by age reached similar conclusion.