Periodic magnetic modulation enhanced electrochemical analysis for highly sensitive determination of genomic DNA methylation.

DNA methylation aberrations have a strong correlation with cancer in early detection, diagnosis, and prognosis, which make them possible candidate biomarkers. Electrochemical biosensors offer rapid protocols for detecting DNA methylation status with minimal pretreatment of samples. However, the inevitable presence of background current in the time domain, including electrochemical noise and variations, limits the detection performance of these biosensors, especially for low concentration analytes. Here, we propose an ultrasensitive frequency-domain electrochemical analysis strategy to effectively separate the weak signals from background current. To achieve this, we employed periodic magnetic field modulation of magnetic beads (MBs) on and off the electrode surface to generate a periodic electrochemical signal for subsequent frequency-domain analysis. By capturing labeled MBs with as low as 0.5 pg of DNA, we successfully demonstrated a highly sensitive electrochemical method for determination of genome-wide DNA methylation levels. We also validated the effectiveness of this methodology using DNA samples extracted from three types of hepatocellular carcinoma (HCC) cell lines. The results revealed varying genomic methylation levels among different HCC cell lines, indicating the potential application of this approach for early-stage cancer detection in terms of DNA methylation status.

A novel intrarenal multimodal 2D/3D registration algorithm and preliminary phantom study.

Retrograde intrarenal surgery (RIRS) is a widely utilized diagnostic and therapeutic tool for multiple upper urinary tract pathologies. The image-guided navigation system can assist the surgeon to perform precise surgery by providing the relative position between the lesion and the instrument after the intraoperative image is registered with the preoperative model. However, due to the structural complexity and diversity of multi-branched organs such as kidneys, bronchi, etc., the consistency of the intensity distribution of virtual and real images will be challenged, which makes the classical pure intensity registration method prone to bias and random results in a wide search domain. In this paper, we propose a structural feature similarity-based method combined with a semantic style transfer network, which significantly improves the registration accuracy when the initial state deviation is obvious. Furthermore, multi-view constraints are introduced to compensate for the collapse of spatial depth information and improve the robustness of the algorithm. Experimental studies were conducted on two models generated from patient data to evaluate the performance of the method and competing algorithms. The proposed method obtains mean target error (mTRE) of 0.971 ± 0.585 mm and 1.266 ± 0.416 mm respectively, with better accuracy and robustness overall. Experimental results demonstrate that the proposed method has the potential to be applied to RIRS and extended to other organs with similar structures.

Retrospective Analysis of Death Cases of Oral Diphenidol Hydrochloride Poisoning.

OBJECTIVES: To explore the characteristics of postmortem examination, chemical examination and scene investigation of deaths caused by oral diphenidol hydrochloride poisoning, and so as to provide a reference for proper settlement and prevention of such deaths. METHODS: The data of 22 deaths caused by oral diphenidol hydrochloride poisoning in a city from January 2018 to August 2020 were collected, including case details, scene investigations, autopsies, chemical examinations and digital evidence. Thirty-one cases of deaths caused by oral diphenidol hydrochloride poisoning reported in previous literature were also collected. RESULTS: In the 53 oral diphenidol hydrochloride poisoning death cases, 50 cases were suicide, 2 cases were accidental, while 1 case was undetermined. Fifty-two cases were found in the medical records or crime scene investigation reports with doses ranging from 775 mg to 12 500 mg, and 23 deceased were detected with postmortem blood concentrations ranging from 2.71 mg/L to 83.1 mg/L. Clinical symptoms were recorded in 6 patients, including conscious disturbance and convulsion. Among the 45 cases which were performed with external examination, 23 cases autopsied. CONCLUSIONS: Most of the deceased of oral diphenidol hydrochloride poisoning were suicide. No significant correlation was found between dose and blood concentration through the retrospective analysis of cases.

Deep learning for gastroscopic images: computer-aided techniques for clinicians.

Gastric disease is a major health problem worldwide. Gastroscopy is the main method and the gold standard used to screen and diagnose many gastric diseases. However, several factors, such as the experience and fatigue of endoscopists, limit its performance. With recent advancements in deep learning, an increasing number of studies have used this technology to provide on-site assistance during real-time gastroscopy. This review summarizes the latest publications on deep learning applications in overcoming disease-related and nondisease-related gastroscopy challenges. The former aims to help endoscopists find lesions and characterize them when they appear in the view shed of the gastroscope. The purpose of the latter is to avoid missing lesions due to poor-quality frames, incomplete inspection coverage of gastroscopy, etc., thus improving the quality of gastroscopy. This study aims to provide technical guidance and a comprehensive perspective for physicians to understand deep learning technology in gastroscopy. Some key issues to be handled before the clinical application of deep learning technology and the future direction of disease-related and nondisease-related applications of deep learning to gastroscopy are discussed herein.

Research and Development of Ankle-Foot Orthoses: A Review.

The ankle joint is one of the important joints of the human body to maintain the ability to walk. Diseases such as stroke and ankle osteoarthritis could weaken the body's ability to control joints, causing people's gait to be out of balance. Ankle-foot orthoses can assist users with neuro/muscular or ankle injuries to restore their natural gait. Currently, passive ankle-foot orthoses are mostly designed to fix the ankle joint and provide support for walking. With the development of materials, sensing, and control science, semi-active orthoses that release mechanical energy to assist walking when needed and can store the energy generated by body movement in elastic units, as well as active ankle-foot orthoses that use external energy to transmit enhanced torque to the ankle, have received increasing attention. This article reviews the development process of ankle-foot orthoses and proposes that the integration of new ankle-foot orthoses with rehabilitation technologies such as monitoring or myoelectric stimulation will play an important role in reducing the walking energy consumption of patients in the study of human-in-the-loop models and promoting neuro/muscular rehabilitation.

A Novel Central Camera Calibration Method Recording Point-to-Point Distortion for Vision-Based Human Activity Recognition.

The camera is the main sensor of vison-based human activity recognition, and its high-precision calibration of distortion is an important prerequisite of the task. Current studies have shown that multi-parameter model methods achieve higher accuracy than traditional methods in the process of camera calibration. However, these methods need hundreds or even thousands of images to optimize the camera model, which limits their practical use. Here, we propose a novel point-to-point camera distortion calibration method that requires only dozens of images to get a dense distortion rectification map. We have designed an objective function based on deformation between the original images and the projection of reference images, which can eliminate the effect of distortion when optimizing camera parameters. Dense features between the original images and the projection of the reference images are calculated by digital image correlation (DIC). Experiments indicate that our method obtains a comparable result with the multi-parameter model method using a large number of pictures, and contributes a 28.5% improvement to the reprojection error over the polynomial distortion model.

In situ continuously monitoring of cancer cell invasion process based on impedance sensing.

Activation of invasion and metastasis is recognized as one of the hallmarks of cancer. There are 90% of cancer-related deaths due to metastasis and given that it is worthy of note to study cancer progression and metastasis. Owing to restricted tools used to underpin the study of tumor invasion process, an on-site platform was developed to monitor this event in vitro. We used interdigital gold electrodes to monitor the dynamic process of cancer cells invading into extracellular matrix in situ continuously. Influences of collagen concentration and number of cancer cells on the measured impedance was exhibited. In addition, the parameters used to demonstrate the experiment results were optimized. The change of impedance magnitude indicated the cell-matrix interaction during invasion process. The potential further use of this platform would be complementary in cell studies when concerning metastasis.

Novel endoscopic optical diagnostic technologies in medical trial research: recent advancements and future prospects.

Novel endoscopic biophotonic diagnostic technologies have the potential to non-invasively detect the interior of a hollow organ or cavity of the human body with subcellular resolution or to obtain biochemical information about tissue in real time. With the capability to visualize or analyze the diagnostic target in vivo, these techniques gradually developed as potential candidates to challenge histopathology which remains the gold standard for diagnosis. Consequently, many innovative endoscopic diagnostic techniques have succeeded in detection, characterization, and confirmation: the three critical steps for routine endoscopic diagnosis. In this review, we mainly summarize researches on emerging endoscopic optical diagnostic techniques, with emphasis on recent advances. We also introduce the fundamental principles and the development of those techniques and compare their characteristics. Especially, we shed light on the merit of novel endoscopic imaging technologies in medical research. For example, hyperspectral imaging and Raman spectroscopy provide direct molecular information, while optical coherence tomography and multi-photo endomicroscopy offer a more extensive detection range and excellent spatial-temporal resolution. Furthermore, we summarize the unexplored application fields of these endoscopic optical techniques in major hospital departments for biomedical researchers. Finally, we provide a brief overview of the future perspectives, as well as bottlenecks of those endoscopic optical diagnostic technologies. We believe all these efforts will enrich the diagnostic toolbox for endoscopists, enhance diagnostic efficiency, and reduce the rate of missed diagnosis and misdiagnosis.

The label-free separation and culture of tumor cells in a microfluidic biochip.

Circulating tumor cells (CTCs) from liquid biopsy have shown a strong correlation to the clinical outcome of cancer patients. The enumeration and cytological analysis of CTCs have attracted increasing efforts for cancer disease management amid immunotherapy and personalized medicine. However, both enumeration and cytological analysis are challenging due to the rarity of CTCs and the lack of integrated solutions for the minimal risk of cell loss in the course of CTC procurement. We report a simple microfluidic chip permitting a one-stop solution for streamlining the on-chip cell separation, capture, immunofluorescence assay and/or in situ culture of isolated cells devoid of risky manual steps. Our results showed effective trapping of single cells, doublets and cell lumps isolated from blood in the same device. On-chip immunostaining revealed normal cell morphology and the characterization of cell expansion uncovered an altered cell growth curve with a reduced lag phase as compared to the conventional culture despite closely matching cell growth rates. The cells were viable and functional for as long as 11 days inside our chip and cell migration was also readily observed, with lumps showing greater aggressiveness than single cells. With these results, we expect promising applications of our one-stop solution for liquid biopsy via CTCs.

A simple and low-cost screen printed electrode for hepatocellular carcinoma methylation detection.

There is a great demand for robust diagnostic and prognostic approaches for Hepatocellular Carcinoma (HCC). DNA methylation, a common epigenetic modification, has been found in many promoter regions of tumor suppressor genes. Hypermethylation of these gene promoters will repress the gene transcription and lead to the occurrence of cancers. The abnormal methyation level of the p16 gene promoter could be a promising marker for the detection of HCC. The adsorption affinities between different DNA bases and AuNPs are not the same. After bisulfite treatment and asymmetric PCR, methylation and unmethylation sequences can be changed into guanine-enriched and adenine-enriched sequences, respectively. A home-made gold nanoparticle modified screen printed carbon electrode (AuNP-SPCE) was employed to distinguish the adsorption affinities between guanine-enriched and adenine-enriched sequences, which could be used to analyze the level of DNA methylation. Several key experimental factors were investigated and optimized. The results had shown that the optimal AuNP electrodeposition time was 100 s and 15 min of adsorption could distinguish guanine-enriched and adenine-enriched sequences with a concentration of 100 nM at 25 °C. The detection limit of our AuNP-SPCE was 1.1 ng, and the assay had a good sensitivity of 10% methylation change and was able to distinguish only one methylated CpG site. What's more, the RSD over three assays with a disposable AuNP-SPCE was ≤7.2%. The assay was applied to real samples including cell lines and clinical tissues. Compared with normal hepatic cell lines and normal tissues, lower signals of HCC cell lines and cancer tissues were observed, respectively. It had shown a good discrimination of the abnormal methylation level of the p16 gene promoter.

A flexible cell concentrator using inertial focusing.

Cell concentration adjustment is intensively implemented routinely both in research and clinical laboratories. Centrifuge is the most prevalent technique for tuning biosample concentration. But it suffers from a number of drawbacks, such as requirement of experienced operator, high cost, low resolution, variable reproducibility and induced damage to sample. Herein we report on a cost-efficient alternative using inertial microfluidics. While the majority of existing literatures concentrate on inertial focusing itself, we identify the substantial role of the outlet system played in the device performance that has long been underestimated. The resistances of the outlets virtually involve in defining the cutoff size of a given inertial filtration channel. Following the comprehensive exploration of the influence of outlet system, we designed an inertial device with selectable outlets. Using both commercial microparticles and cultured Hep G2 cells, we have successfully demonstrated the automated concentration modification and observed several key advantages of our device as compared with conventional centrifuge, such as significantly reduced cell loss (only 4.2% vs. ~40% of centrifuge), better preservation of cell viability and less processing time as well as the increased reproducibility due to absence of manual operation. Furthermore, our device shows high effectiveness for concentrated sample (e.g., 1.8 × 106 cells/ml) as well. We envision its promising applications in the circumstance where repetitive sample preparation is intensely employed.

Study of the union method of microelectrode array and AFM for the recording of electromechanical activities in living cardiomyocytes.

Electrophysiology and mechanics are two essential components in the functions of cardiomyocytes and skeletal muscle cells. The simultaneous recording of electrophysiological and mechanical activities is important for the understanding of mechanisms underlying cell functions. For example, on the one hand, mechanisms under cardiovascular drug effects will be investigated in a comprehensive way by the simultaneous recording of electrophysiological and mechanical activities. On the other hand, computational models of electromechanics provide a powerful tool for the research of cardiomyocytes. The electrical and mechanical activities are important in cardiomyocyte models. The simultaneous recording of electrophysiological and mechanical activities can provide much experimental data for the models. Therefore, an efficient method for the simultaneous recording of the electrical and mechanical data from cardiomyocytes is required for the improvement of cardiac modeling. However, as far as we know, most of the previous methods were not easy to be implemented in the electromechanical recording. For this reason, in this study, a union method of microelectrode array and atomic force microscope was proposed. With this method, the extracellular field potential and beating force of cardiomyocytes were recorded simultaneously with a low root-mean-square noise level of 11.67 µV and 60 pN. Drug tests were conducted to verify the feasibility of the experimental platform. The experimental results suggested the method would be useful for the cardiovascular drug screening and refinement of the computational cardiomyocyte models. It may be valuable for exploring the functional mechanisms of cardiomyocytes and skeletal muscle cells under physiological or pathological conditions.

Antifouling Zwitterionic Coating via Electrochemically Mediated Atom Transfer Radical Polymerization on Enzyme-Based Glucose Sensors for Long-Time Stability in 37 °C Serum.

In this study, a versatile fabrication method for coating enzyme-based biosensors with ultrathin antifouling zwitterionic polymer films to meet the challenge of the long-time stability of sensors in vivo was developed. Electrochemically mediated atom transfer radical polymerization (eATRP) was applied to polymerize zwitterionic sulfobetaine methacrylate monomers on the rough enzyme-absorbed electrode surfaces; meanwhile, a refined overall bromination was developed to improve the coverage of polymers on the biosensor surfaces and to maintain the enzyme activity simultaneously for the first time. X-ray photoelectron spectroscopy and atomic force microscopy were used to characterize the properties of the polymer layers. The antifouling performance and long-time stability in 37 °C undiluted bovine serum in vitro were evaluated. The results showed that the polymer brush coatings diminished over 99% nonspecific protein adsorption and that the sensitivity of the evaluated sensor was maintained at 94% after 15 days. The overall sensitivity deviation of 7% was nearly 50% lower than that of the polyurethane-coated ones and also much smaller than the current commercially available glucose biosensors. The results suggested that this highly controllable electrodeposition procedure could be a promising method to develop implantable biosensors with long-time stability.

Comprehensive Study of the Effects of Nanopore Structures on Enzyme Activity for the Enzyme Based Electrochemical Biosensors Based on Molecular Simulation.

Assembly of biocompatible nanostructures to retain the enzyme activity and improve the biocatalytic ability is a decisive factor for enhancing the performance of enzyme biosensors. However, there is still a lack of molecular level understandings of the physicochemical interaction mechanism at the interface of biosensor electrodes and enzymes. Here, for the first time at molecular level, the effects of two classic biosensor electrode materials with different electrical properties and morphologies and glucose oxidase (GOD) on retaining the enzyme conformation were analyzed by molecular dynamics simulation. First, for the immobilization of GOD, the interfaces of zinc oxide (ZnO) with different electrical properties and 10 nm diameter ZnO nanopore were studied. Then, to simulate the sensing process when electric voltages are applied, positively charged gold planes and 10 nm diameter gold nanopore were investigated as well. The results showed that the nanopore structure was confirmed to be well adapted for the enzyme conformation retaining compared to the plane structure for both ZnO and gold materials, and they almost fit well with the sensitivity measurement results from many previously reported experimental studies. This study also indicates that molecular modeling of the interactions between biomolecules and functional nanostructures is helpful for developing high performance enzyme nanobiosensors.

Study of Artifact-Resistive Technology Based on a Novel Dual Photoplethysmography Method for Wearable Pulse Rate Monitors.

Pulse rate is one of the major physiological parameters for monitoring of cardiovascular conditions or excise states during daily life. However it is difficult to precisely measure the exact pulse rates as photoplethysmography (PPG) is easy to be affected by motion artifacts. Instead of using accelerometers followed by algorithms such as least mean square (LMS), recursive least square (RLS) and independent component analysis (ICA) or other equipment such as complex laser systems to measure displacement directly, a novel motion artifact estimation method which had lower computational complexity and higher signal dynamic range was studied and implemented, where a differential channel following green and red light PPG channels was applied to reduce the motion artifact caused by displacement of light emitting diode (LED), photo diode (PD) and tissue deformation before the analog signal was converted to digital form. A miniaturized, battery powered wrist worn artifact-resistive pulse rates monitoring system (PRMS) was presented to verify the proposed method. Four kinds of motions were performed and the results showed that the differential channel improved the morphology of the PPG signal and appeared to be artifact resistive during motions through light intensity control and high gain-phase consistency circuit design here.

Stereo matching of binocular laparoscopic images with improved densely connected neural architecture search.

PURPOSE: Stereo matching is a crucial technology in the binocular laparoscopic-based surgical navigation systems. In recent years, neural networks have been widely applied to stereo matching and demonstrated outstanding performance. however, this method heavily relies on manual feature engineering meaning that professionals must be involved in the feature extraction and matching. This process is both time-consuming and demands specific expertise. METHODS: This paper introduces a novel stereo matching framework DCStereo that realizes a fully automatic neural architecture design for the stereo matching of binocular laparoscopic images. The proposed framework utilizes a densely connected search space which enables a more flexible and diverse architecture composition. Furthermore, the proposed algorithm leverages the channel and path sampling strategies to reduce memory consumption during searching. RESULTS: Empirically, our searched DCStereo on the SCARED training dataset achieves a mean absolute error of 3.589 mm on the test dataset, which outperforms hand-crafted stereo matching methods and other approaches. Furthermore, when directly testing on the SERV-CT dataset, our DCStereo demonstrates better generalization ability than other methods. CONCLUSION: Our proposed approach leverages the neural architecture search technique and a densely connected search space for automatic neural architecture design in stereo matching of binocular laparoscopic images. Our method delivers advanced performance on the SCARED dataset and promising results on the SERV-CT dataset. These findings demonstrate the potential of our approach for improving clinical surgical navigation systems.

[Research progress of external tufted cells in olfactory glomerulus].

External tufted (ET) cells are the major excitatory elements coordinating the activities of glomerulars and mediating the input from the olfactory neurons to mitral cells. The ET cells participate in inter-and intra-glomerular microcircuits in the olfactory bulb, link the isofunctional odor columns within the same olfactory bulb, and play an important role in olfactory information processing. This paper reviews the research progress of the anatomy and physiological properties and electrophysiological modeling of ET cells, elaborate the problems and defects in the field. And then it further gives some proposals for the future research of electrophysiological properties, development of olfactory information coding and performance of modeling of ET cells.

Self-supervised representation learning using feature pyramid siamese networks for colorectal polyp detection.

Colorectal cancer is a leading cause of cancer-related deaths globally. In recent years, the use of convolutional neural networks in computer-aided diagnosis (CAD) has facilitated simpler detection of early lesions like polyps during real-time colonoscopy. However, the majority of existing techniques require a large training dataset annotated by experienced experts. To alleviate the laborious task of image annotation and utilize the vast amounts of readily available unlabeled colonoscopy data to further improve the polyp detection ability, this study proposed a novel self-supervised representation learning method called feature pyramid siamese networks (FPSiam). First, a feature pyramid encoder module was proposed to effectively extract and fuse both local and global feature representations among colonoscopic images, which is important for dense prediction tasks like polyp detection. Next, a self-supervised visual feature representation containing the general feature of colonoscopic images is learned by the siamese networks. Finally, the feature representation will be transferred to the downstream colorectal polyp detection task. A total of 103 videos (861,400 frames), 100 videos (24,789 frames), and 60 videos (15,397 frames) in the LDPolypVideo dataset are used to pre-train, train, and test the performance of the proposed FPSiam and its counterparts, respectively. The experimental results have illustrated that our FPSiam approach obtains the optimal capability, which is better than that of other state-of-the-art self-supervised learning methods and is also higher than the method based on transfer learning by 2.3 mAP and 3.6 mAP for two typical detectors. In conclusion, FPSiam provides a cost-efficient solution for developing colorectal polyp detection systems, especially in conditions where only a small fraction of the dataset is labeled while the majority remains unlabeled. Besides, it also brings fresh perspectives into other endoscopic image analysis tasks.

Highly selective electrosynthesis of H2O2 by N, O co-doped graphite nanosheets for efficient electro-Fenton degradation of p-nitrophenol.

The activity and selectivity of the cathode towards electrosynthesis of H2O2 are critical for electro-Fenton process. Herein, nickel-foam modified with N, O co-doped graphite nanosheets (NO-GNSs/Ni-F) was developed as a cathode for highly efficient and selective electrosynthesis of H2O2. Expectedly, the accumulation of H2O2 at pH= 3 reached 494.2 mg L-1 h-1, with the selectivity toward H2O2 generation reaching 93.0%. The synergistic effect of different oxygen-containing functional groups and N species on the performance and selectivity of H2O2 electrosynthesis was investigated by density functional theory calculations, and the combination of epoxy and graphitic N (EP + N) was identified as the most favorable configuration with the lowest theoretical overpotential for H2O2 generation. Moreover, NO-GNSs/Ni-F was applied in the electro-Fenton process for p-nitrophenol degradation, resulting in 100% removal within 15 min with the kinetic rate constant of 0.446 min-1 and 97.6% mineralization within 6 h. The efficient removal was mainly attributed to the generation of bulk ·OH. Furthermore, NO-GNSs/Ni-F exhibited excellent stability. This work provides a workable option for the enhancement of H2O2 accumulation and the efficient degradation of pollutants in electro-Fenton system.

Multi-Parameter Detection of Urine Based on Electropolymerized PANI: PSS/AuNPs/SPCE.

Urine analysis is widely used in clinical practice to indicate human heathy status and is important for diagnosing chronic kidney disease (CKD). Ammonium ions (NH4+), urea, and creatinine metabolites are main clinical indicators in urine analysis of CKD patients. In this paper, NH4+ selective electrodes were prepared using electropolymerized polyaniline-polystyrene sulfonate (PANI: PSS), and urea- and creatinine-sensing electrodes were prepared by modifying urease and creatinine deiminase, respectively. First, PANI: PSS was modified on the surface of an AuNPs-modified screen-printed electrode, as a NH4+-sensitive film. The experimental results showed that the detection range of the NH4+ selective electrode was 0.5~40 mM, and the sensitivity reached 192.6 mA M-1 cm-2 with good selectivity, consistency, and stability. Based on the NH4+-sensitive film, urease and creatinine deaminase were modified by enzyme immobilization technology to achieve urea and creatinine detection, respectively. Finally, we further integrated NH4+, urea, and creatinine electrodes into a paper-based device and tested real human urine samples. In summary, this multi-parameter urine testing device offers the potential for point-of-care testing of urine and benefits the efficient chronic kidney disease management.