MiLoPYP: self-supervised molecular pattern mining and particle localization in situ.

Cryo-electron tomography allows the routine visualization of cellular landscapes in three dimensions at nanometer-range resolutions. When combined with single-particle tomography, it is possible to obtain near-atomic resolution structures of frequently occurring macromolecules within their native environment. Two outstanding challenges associated with cryo-electron tomography/single-particle tomography are the automatic identification and localization of proteins, tasks that are hindered by the molecular crowding inside cells, imaging distortions characteristic of cryo-electron tomography tomograms and the sheer size of tomographic datasets. Current methods suffer from low accuracy, demand extensive and time-consuming manual labeling or are limited to the detection of specific types of proteins. Here, we present MiLoPYP, a two-step dataset-specific contrastive learning-based framework that enables fast molecular pattern mining followed by accurate protein localization. MiLoPYP's ability to effectively detect and localize a wide range of targets including globular and tubular complexes as well as large membrane proteins, will contribute to streamline and broaden the applicability of high-resolution workflows for in situ structure determination.

nextPYP: a comprehensive and scalable platform for characterizing protein variability in situ using single-particle cryo-electron tomography.

Single-particle cryo-electron tomography is an emerging technique capable of determining the structure of proteins imaged within the native context of cells at molecular resolution. While high-throughput techniques for sample preparation and tilt-series acquisition are beginning to provide sufficient data to allow structural studies of proteins at physiological concentrations, the complex data analysis pipeline and the demanding storage and computational requirements pose major barriers for the development and broader adoption of this technology. Here, we present a scalable, end-to-end framework for single-particle cryo-electron tomography data analysis from on-the-fly pre-processing of tilt series to high-resolution refinement and classification, which allows efficient analysis and visualization of datasets with hundreds of tilt series and hundreds of thousands of particles. We validate our approach using in vitro and cellular datasets, demonstrating its effectiveness at achieving high-resolution and revealing conformational heterogeneity in situ. The framework is made available through an intuitive and easy-to-use computer application, nextPYP ( http://nextpyp.app ).

Noise Analysis and Suppression Methods for the Front-End Readout Circuit of a Microelectromechanical Systems Gyroscope.

Circuit noise is a critical factor that affects the performances of an MEMS gyroscope. Therefore, it is essential to analyze and suppress the noises in the key analog circuits, which are the main noise sources. This study presents an optimized front-end readout circuit and noise suppression methods. First, the noise analysis of the front-end readout circuit is carried out with theoretical derivation to clarify the main noise contributors. To suppress the output noise, an improved readout circuit based on the T-resistor networks is proposed, and the corresponding noise equation is derived in detail. In addition, the noise analysis of the critical circuits of the detection and control system, such as the inverting amplifiers, the first-order low-pass filters, and the first-order high-pass filters, is carried out, and the noise suppression strategy with the optimization of the resistances and is proposed. Taking the inverting amplifier as an example, the theoretical derivation is verified by measuring and comparing the output noises of different resistance schemes. In addition, the output noises of the gyroscope before and after circuit optimization are measured. Experimental results demonstrate that the output noise with the circuit optimization is reduced from 60 µV/Hz1/2 to 30 µV/Hz1/2 and the bias instability is reduced from 3.8 deg/h to 1.38 deg/h. In addition, the ARW is significantly improved from 0.035 deg/h1/2 to 0.018 deg/h1/2, which indicates that the proposed noise analysis and suppression methods are effective and feasible.

Joint micrograph denoising and protein localization in cryo-electron microscopy.

Cryo-electron microscopy (cryo-EM) is an imaging technique that allows the visualization of proteins and macromolecular complexes at near-atomic resolution. The low electron doses used to prevent radiation damage to the biological samples result in images where the power of noise is 100 times stronger than that of the signal. Accurate identification of proteins from these low signal-to-noise ratio (SNR) images is a critical task, as the detected positions serve as inputs for the downstream 3D structure determination process. Current methods either fail to identify all true positives or result in many false positives, especially when analyzing images from smaller-sized proteins that exhibit extremely low contrast, or require manual labeling that can take days to complete. Acknowledging the fact that accurate protein identification is dependent upon the visual interpretability of micrographs, we propose a framework that can perform denoising and detection in a joint manner and enable particle localization under extremely low SNR conditions using self-supervised denoising and particle identification from sparsely annotated data. We validate our approach on three challenging single-particle cryo-EM datasets and projection images from one cryo-electron tomography dataset with extremely low SNR, showing that it outperforms existing state-of-the-art methods used for cryo-EM image analysis by a significant margin. We also evaluate the performance of our algorithm under decreasing SNR conditions and show that our method is more robust to noise than competing methods.

Variation of MEMS Thin Film Device Parameters under the Influence of Thermal Stresses.

With the advancement of semiconductor manufacturing technology, thin film structures were widely used in MEMS devices. These films played critical roles in providing support, reinforcement, and insulation in MEMS devices. However, due to their microscopic dimensions, the sensitivity of their parameters and performance to thermal stress increased significantly. In this study, a Pirani gauge sample with a multilayer thin film structure was designed and fabricated. Based on this sample, finite element modeling analysis and thermal stress experiments were conducted. The finite element modeling analysis employed a combination of steady-state and transient methods to simulate the deformation and stress distribution of the device at room temperature (25 °C), low temperature (-55 °C), and high temperature (125 °C). The thermal stress test involved placing the sample in a temperature cycling chamber for temperature cycling tests. After the tests, the resonant frequency and surface deformation of the device were measured to quantitatively evaluate the impact of thermal stress on the deformation and resonant frequency parameters of the device. After the experiments, it was found that the clamped-end beams made of Pt were a stress concentration area. Additionally, the repetitive thermal load caused the cantilever beam to move cyclically in the Z direction. This movement altered the deformation of the film and the resonant frequency. The suspended film exhibited concavity, and the overall trend of the resonant frequency was downward. Over time, this could even lead to the fracture of the clamped-end beams. The variation of mechanical parameters derived from finite element simulations and experiments provided an important reference value for device design improvement and played a crucial role in enhancing the reliability of thin film devices.

Characterization of Sand and Dust Pollution Degradation Based on Sensitive Structure of Microelectromechanical System Flow Sensor.

The effect of sand and dust pollution on the sensitive structures of flow sensors in microelectromechanical systems (MEMS) is a hot issue in current MEMS reliability research. However, previous studies on sand and dust contamination have only searched for sensor accuracy degradation due to heat conduction in sand and dust cover and have yet to search for other failure-inducing factors. This paper aims to discover the other inducing factors for the accuracy failure of MEMS flow sensors under sand and dust pollution by using a combined model simulation and sample test method. The accuracy of a flow sensor is mainly reflected by the size of its thermistor, so in this study, the output value of the thermistor value was chosen as an electrical characterization parameter to verify the change in the sensor's accuracy side by side. The results show that after excluding the influence of heat conduction, when sand particles fall on the device, the mutual friction between the sand particles will produce an electrostatic current; through the principle of electrostatic dissipation into the thermistor, the principle of measurement leads to the resistance value becoming smaller, and when the sand dust is stationary for some time, the resistance value returns to the expected level. This finding provides theoretical guidance for finding failure-inducing factors in MEMS failure modes.

Design of a Shock-Protected Structure for MEMS Gyroscopes over a Full Temperature Range.

Impact is the most important factor affecting the reliability of Micro-Electro-Mechanical System (MEMS) gyroscopes, therefore corresponding reliability design is very essential. This paper proposes a shock-protected structure (SPS) capable of withstanding a full temperature range from -40 °C to 80 °C to enhance the shock resistance of MEMS gyroscopes. Firstly, the shock transfer functions of the gyroscope and the SPS are derived using Single Degree-of-Freedom and Two Degree-of-Freedom models. The U-folded beam stiffness and maximum positive stress are deduced to evaluate the shock resistance of the silicon beam. Subsequently, the frequency responses of acceleration of the gyroscope and the SPS are simulated and analyzed in Matlab utilizing the theoretical models. Simulation results demonstrate that when the first-order natural frequency of the SPS is approximately one-fourth of the gyroscope's resonant frequency, the impact protection effect is best, and the SPS does not affect the original performance of the gyroscope. The acceleration peak of the MEMS gyroscope is reduced by approximately 23.5 dB when equipped with the SPS in comparison to its counterpart without the SPS. The anti-shock capability of the gyroscope with the SPS is enhanced by approximately 13 times over the full-temperature range. After the shock tests under the worst case, the gyroscope without the SPS experiences a beam fracture failure, while the performance of the gyroscope with the SPS remains normal, validating the effectiveness of the SPS in improving the shock reliability of MEMS gyroscopes.

Reliability of MEMS inertial devices in mechanical and thermal environments: A review.

The reliability of MEMS inertial devices applied in complex environments involves interdisciplinary fields, such as structural mechanics, material mechanics and multi-physics field coupling. Nowadays, MEMS inertial devices are widely used in the fields of automotive industry, consumer electronics, aerospace and missile guidance, and a variety of reliability issues induced by complex environments arise subsequently. Hence, reliability analysis and design of MEMS inertial devices are becoming increasingly significant. Since the reliability issues of MEMS inertial devices are mainly caused by complex mechanical and thermal environments with intricate failure mechanisms, there are fewer reviews of related research in this field. Therefore, this paper provides an extensive review of the research on the reliability of typical failure modes and mechanisms in MEMS inertial devices under high temperature, temperature cycling, vibration, shock, and multi-physical field coupling environments in the last five to six years. It is found that though multiple studies exist examining the reliability of MEMS inertial devices under single stress, there is a dearth of research conducted under composite stress and a lack of systematic investigation. Through analyzing and summarizing the current research progress in reliability design, it is concluded that multi-physical field coupling simulation, theoretical modeling, composite stress experiments, and special test standards are important directions for future reliability research on MEMS inertial devices.

Restoration of cervical lymphatic vessel function in aging rescues cerebrospinal fluid drainage.

Cervical lymphatic vessels (cLVs) have been shown to drain solutes and cerebrospinal fluid (CSF) from the brain. However, their hydrodynamical properties have never been evaluated in vivo. Here, we developed two-photon optical imaging with particle tracking in vivo of CSF tracers (2P-OPTIC) in superficial and deep cLVs of mice, characterizing their flow and showing that the major driver is intrinsic pumping by contraction of the lymphatic vessel wall. Moreover, contraction frequency and flow velocity were reduced in aged mice, which coincided with a reduction in smooth muscle actin expression. Slowed flow in aged mice was rescued using topical application of prostaglandin F2α, a prostanoid that increases smooth muscle contractility, which restored lymphatic function in aged mice and enhanced central nervous system clearance. We show that cLVs are important regulators of CSF drainage and that restoring their function is an effective therapy for improving clearance in aging.

Multiple-image super-resolution of cryo-electron micrographs based on deep internal learning.

Single-particle cryo-electron microscopy (cryo-EM) is a powerful imaging modality capable of visualizing proteins and macromolecular complexes at near-atomic resolution. The low electron-doses used to prevent radiation damage to the biological samples, however, result in images where the power of the noise is 100 times greater than the power of the signal. To overcome these low signal-to-noise ratios (SNRs), hundreds of thousands of particle projections are averaged to determine the three-dimensional structure of the molecule of interest. The sampling requirements of high-resolution imaging impose limitations on the pixel sizes that can be used for acquisition, limiting the size of the field of view and requiring data collection sessions of several days to accumulate sufficient numbers of particles. Meanwhile, recent image super-resolution (SR) techniques based on neural networks have shown state-of-the-art performance on natural images. Building on these advances, here, we present a multiple-image SR algorithm based on deep internal learning designed specifically to work under low-SNR conditions. Our approach leverages the internal image statistics of cryo-EM movies and does not require training on ground-truth data. When applied to single-particle datasets of apoferritin and T20S proteasome, we show that the resolution of the 3D structure obtained from SR micrographs can surpass the limits imposed by the imaging system. Our results indicate that the combination of low magnification imaging with in silico image SR has the potential to accelerate cryo-EM data collection by virtue of including more particles in each exposure and doing so without sacrificing resolution.

Research on Packaging Reliability and Quality Factor Degradation Model for Wafer-Level Vacuum Sealing MEMS Gyroscopes.

MEMS gyroscopes are widely applied in consumer electronics, aerospace, missile guidance, and other fields. Reliable packaging is the foundation for ensuring the survivability and performance of the sensor in harsh environments, but gas leakage models of wafer-level MEMS gyroscopes are rarely reported. This paper proposes a gas leakage model for evaluating the packaging reliability of wafer-level MEMS gyroscopes. Based on thermodynamics and hydromechanics, the relationships between the quality factor, gas molecule number, and a quality factor degradation model are derived. The mechanism of the effect of gas leakage on the quality factor is explored at wafer-level packaging. The experimental results show that the reciprocal of the quality factor is exponentially related to gas leakage time, which is in accordance with the theoretical analysis. The coefficients of determination (R2) are all greater than 0.95 by fitting the curves in Matlab R2022b. The stable values of the quality factor for drive mode and sense mode are predicted to be 6609.4 and 1205.1, respectively, and the average degradation characteristic time is 435.84 h. The gas leakage time is at least eight times the average characteristic time, namely 3486.72 h, before a stable condition is achieved in the packaging chamber of the MEMS gyroscopes.

A Non-Contact Fall Detection Method for Bathroom Application Based on MEMS Infrared Sensors.

The ratio of the elderly to the total population around the world is larger than 10%, and about 30% of the elderly are injured by falls each year. Accidental falls, especially bathroom falls, account for a large proportion. Therefore, fall events detection of the elderly is of great importance. In this article, a non-contact fall detector based on a Micro-electromechanical Systems Pyroelectric Infrared (MEMS PIR) sensor and a thermopile IR array sensor is designed to detect bathroom falls. Besides, image processing algorithms with a low pass filter and double boundary scans are put forward in detail. Then, the statistical features of the area, center, duration and temperature are extracted. Finally, a 3-layer BP neural network is adopted to identify the fall events. Taking into account the key factors of ambient temperature, objective, illumination, fall speed, fall state, fall area and fall scene, 640 tests were performed in total, and 5-fold cross validation is adopted. Experimental results demonstrate that the averages of the precision, recall, detection accuracy and F1-Score are measured to be 94.45%, 90.94%, 92.81% and 92.66%, respectively, which indicates that the novel detection method is feasible. Thereby, this IOT detector can be extensively used for household bathroom fall detection and is low-cost and privacy-security guaranteed.

Automated systematic evaluation of cryo-EM specimens with SmartScope.

Finding the conditions to stabilize a macromolecular target for imaging remains the most critical barrier to determining its structure by cryo-electron microscopy (cryo-EM). While automation has significantly increased the speed of data collection, specimens are still screened manually, a laborious and subjective task that often determines the success of a project. Here, we present SmartScope, the first framework to streamline, standardize, and automate specimen evaluation in cryo-EM. SmartScope employs deep-learning-based object detection to identify and classify features suitable for imaging, allowing it to perform thorough specimen screening in a fully automated manner. A web interface provides remote control over the automated operation of the microscope in real time and access to images and annotation tools. Manual annotations can be used to re-train the feature recognition models, leading to improvements in performance. Our automated tool for systematic evaluation of specimens streamlines structure determination and lowers the barrier of adoption for cryo-EM.

Assessment of arrhythmia mechanism and burden of the infarcted ventricles following remuscularization with pluripotent stem cell-derived cardiomyocyte patches using patient-derived models.

AIMS: Direct remuscularization with pluripotent stem cell-derived cardiomyocytes (PSC-CMs) seeks to address the onset of heart failure post-myocardial infarction (MI) by treating the persistent muscle deficiency that underlies it. However, direct remuscularization with PSC-CMs could potentially be arrhythmogenic. We investigated two possible mechanisms of arrhythmogenesis-focal vs. re-entrant-arising from direct remuscularization with PSC-CM patches in two personalized, human ventricular computer models of post-MI. Moreover, we developed a principled approach for evaluating arrhythmogenicity of direct remuscularization that factors in the VT propensity of the patient-specific post-MI fibrotic substrate and use it to investigate different conditions of patch remuscularization. METHODS AND RESULTS: Two personalized, human ventricular models of post-MI (P1 and P2) were constructed from late gadolinium enhanced (LGE)-magnetic resonance images (MRIs). In each model, remuscularization with PSC-CM patches was simulated under different treatment conditions that included patch engraftment, patch myofibril orientation, remuscularization site, patch size (thickness and diameter), and patch maturation. To determine arrhythmogenicity of treatment conditions, VT burden of heart models was quantified prior to and after simulated remuscularization and compared. VT burden was quantified based on inducibility (i.e. weighted sum of pacing sites that induced) and severity (i.e. the number of distinct VT morphologies induced). Prior to remuscularization, VT burden was significant in P1 (0.275) and not in P2 (0.0, not VT inducible). We highlight that re-entrant VT mechanisms would dominate over focal mechanisms; spontaneous beats emerging from PSC-CM grafts were always a fraction of resting sinus rate. Moreover, incomplete patch engraftment can be particularly arrhythmogenic, giving rise to particularly aberrant electrical activation and conduction slowing across the PSC-CM patches along with elevated VT burden when compared with complete engraftment. Under conditions of complete patch engraftment, remuscularization was almost always arrhythmogenic in P2 but certain treatment conditions could be anti-arrhythmogenic in P1. Moreover, the remuscularization site was the most important factor affecting VT burden in both P1 and P2. Complete maturation of PSC-CM patches, both ionically and electrotonically, at the appropriate site could completely alleviate VT burden. CONCLUSION: We identified that re-entrant VT would be the primary VT mechanism in patch remuscularization. To evaluate the arrhythmogenicity of remuscularization, we developed a principled approach that factors in the propensity of the patient-specific fibrotic substrate for VT. We showed that arrhythmogenicity is sensitive to the patient-specific fibrotic substrate and remuscularization site. We demonstrate that targeted remuscularization can be safe in the appropriate individual and holds the potential to non-destructively eliminate VT post-MI in addition to addressing muscle deficiency underlying heart failure progression.

Calibration Method of Accelerometer Based on Rotation Principle Using Double Turntable Centrifuge.

For linear accelerometers, calibration with a precision centrifuge is a key technology, and the input acceleration imposed on the accelerometer should be accurately obtained in the calibration. However, there are often errors in the installation of sample that make the calibration inaccurate. To solve installation errors and obtain the input acceleration in the calibration of the accelerometer, a calibration method based on the rotation principle using a double turntable centrifuge is proposed in this work. The key operation is that the sub-turntable is rotated to make the input axis of the accelerometer perpendicular to the direction of the centripetal acceleration vector. Models of installation errors of angle and radius were built. Based on these models, the static radius and input acceleration can be obtained accurately, and the calibration of the scale factor, nonlinearity and asymmetry can be implemented. Using this method, measurements of the MEMS accelerometer with a range of ±30 g were carried out. The results show that the discrepancy of performance obtained from different installation positions was smaller than 100 ppm after calibrating the input acceleration. Moreover, the results using this method were consistent with those using the back-calculation method. These results demonstrate that the effectiveness of our proposed method was confirmed. This method can measure the static radius directly eliminating the installation errors of angle and radius, and it simplifies the accelerometer calibration procedure.

Research on Decomposition of Offset in MEMS Capacitive Accelerometer.

In a MEMS capacitive accelerometer, there is an offset due to mechanical and electrical factors, and the offset would deteriorate the performance of the accelerometer. Reducing the offset from mechanism would benefit the improvement in performance. Yet, the compositions of the offset are complex and mix together, so it is difficult to decompose the offset to provide guidance for the reduction. In this work, a decomposition method of offset in a MEMS capacitive accelerometer was proposed. The compositions of the offset were first analyzed quantitatively, and methods of measuring key parameters were developed. Based on our proposed decomposition method, the experiment of offset decomposition with a closed-loop MEMS capacitive accelerometer was carried out. The results showed that the offset successfully decomposed, and the major source was from the fabricated gap mismatch in the MEMS sensor. This work provides a new way for analyzing the offset in a MEMS capacitive accelerometer, and it is helpful for purposefully taking steps to reduce the offset and improve accelerometer performance.

Enhancement of field emission of CNTs array by CO2-assisted chemical vapor deposition.

We present a new process to get in-situ-growth carbon nanotubes (CNTs) array device with good FE properties by CO2-assisted thermal chemical vapor deposition (CVD). Field Emission measurement shows that introducing CO2 into CNTs growth system leads to a significant enhancement in the emission properties, both the turn-on field and threshold field decrease. Raman, SEM and TEM investigation results showed that in this CO2-assisted thermal CVD, CO2 can remove amorphous carbon during CNTs growth process, and at the same time, it also creates more defects on the CNTs wall. Both can enhance FE properties of the CNTs at suitable CO2 concentrations.

A comprehensive, multiscale framework for evaluation of arrhythmias arising from cell therapy in the whole post-myocardial infarcted heart.

Direct remuscularization approaches to cell-based heart repair seek to restore ventricular contractility following myocardial infarction (MI) by introducing new cardiomyocytes (CMs) to replace lost or injured ones. However, despite promising improvements in cardiac function, high incidences of ventricular arrhythmias have been observed in animal models of MI injected with pluripotent stem cell-derived cardiomyocytes (PSC-CMs). The mechanisms of arrhythmogenesis remain unclear. Here, we present a comprehensive framework for computational modeling of direct remuscularization approaches to cell therapy. Our multiscale 3D whole-heart modeling framework integrates realistic representations of cell delivery and transdifferentiation therapy modalities as well as representation of spatial distributions of engrafted cells, enabling simulation of clinical therapy and the prediction of emergent electrophysiological behavior and arrhythmogenensis. We employ this framework to explore how varying parameters of cell delivery and transdifferentiation could result in three mechanisms of arrhythmogenesis: focal ectopy, heart block, and reentry.

Method of Measuring the Mismatch of Parasitic Capacitance in MEMS Accelerometer Based on Regulating Electrostatic Stiffness.

For the MEMS capacitive accelerometer, parasitic capacitance is a serious problem. Its mismatch will deteriorate the performance of accelerometer. Obtaining the mismatch of the parasitic capacitance precisely is helpful for improving the performance of bias and scale. Currently, the method of measuring the mismatch is limited in the direct measuring using the instrument. This traditional method has low accuracy for it would lead in extra parasitic capacitive and have other problems. This paper presents a novel method based on the mechanism of a closed-loop accelerometer. The strongly linear relationship between the output of electric force and the square of pre-load voltage is obtained through theoretical derivation and validated by experiment. Based on this relationship, the mismatch of parasitic capacitance can be obtained precisely through regulating electrostatic stiffness without other equipment. The results can be applied in the design of decreasing the mismatch and electrical adjusting for eliminating the influence of the mismatch.