Graphene-integrated mesh electronics with converged multifunctionality for tracking multimodal excitation-contraction dynamics in cardiac microtissues.

Cardiac microtissues provide a promising platform for disease modeling and developmental studies, which require the close monitoring of the multimodal excitation-contraction dynamics. However, no existing assessing tool can track these multimodal dynamics across the live tissue. We develop a tissue-like mesh bioelectronic system to track these multimodal dynamics. The mesh system has tissue-level softness and cell-level dimensions to enable stable embedment in the tissue. It is integrated with an array of graphene sensors, which uniquely converges both bioelectrical and biomechanical sensing functionalities in one device. The system achieves stable tracking of the excitation-contraction dynamics across the tissue and throughout the developmental process, offering comprehensive assessments for tissue maturation, drug effects, and disease modeling. It holds the promise to provide more accurate quantification of the functional, developmental, and pathophysiological states in cardiac tissues, creating an instrumental tool for improving tissue engineering and studies.

Rapid cell isolation in breastmilk in a non-clinical setting by a deterministic lateral displacement device and selective water and fat absorption.

Breastmilk is a reliable source of biomarker-containing, sloughed breast cells that have the potential to give valuable health insights to new mothers. Furthermore, known DNA-based markers for pregnancy-associated breast cancer are chemically stable and can be safely stored on a commercially available FTA® Elute Micro (EM) card, which can subsequently be mailed to a testing facility for the cost of a stamp. In theory, this archiving process can be performed by nonprofessionals in very low-resource settings as it simply requires placing a drop of breastmilk on an EM card. Although this level of convenience is paramount for new mothers, the low cell density of breastmilk complicates archiving on an EM card as such commercial products and associated protocols were designed for high-cell density physiological fluids such as blood. In this study, we present the use of a deterministic lateral displacement (DLD) device combined with porous superabsorbent polymers and hydrophobic sponges to achieve simple and low-cost cell enrichment in breastmilk. As the critical separation diameter in a DLD device is more heavily dependent on lithographically controlled pillar layout than fluid or flow properties, our use of DLD microfluidics allowed for the accommodation of both varying viscosities in human breastmilk samples and a varying pressure of actuation resulting from manual, syringe-driven operation. We demonstrate successful cell enrichment (>11×) and a corresponding increase in the DNA concentration of EM card elutions among breastmilk samples processed with our hybrid microfluidic system. As our device achieves sufficiently high cell enrichment in breastmilk samples while only requiring the user to push a syringe for 4 min with reasonable effort, we believe that it has high potential to expand EM card DNA archiving for diagnostic applications with low-cell density physiological fluids and in low-resource settings.

Patterning ganglionic eminences in developing human brain organoids using a morphogen-gradient-inducing device.

In early neurodevelopment, the central nervous system is established through the coordination of various neural organizers directing tissue patterning and cell differentiation. Better recapitulation of morphogen gradient production and signaling will be crucial for establishing improved developmental models of the brain in vitro. Here, we developed a method by assembling polydimethylsiloxane devices capable of generating a sustained chemical gradient to produce patterned brain organoids, which we termed morphogen-gradient-induced brain organoids (MIBOs). At 3.5 weeks, MIBOs replicated dorsal-ventral patterning observed in the ganglionic eminences (GE). Analysis of mature MIBOs through single-cell RNA sequencing revealed distinct dorsal GE-derived CALB2+ interneurons, medium spiny neurons, and medial GE-derived cell types. Finally, we demonstrate long-term culturing capabilities with MIBOs maintaining stable neural activity in cultures grown up to 5.5 months. MIBOs demonstrate a versatile approach for generating spatially patterned brain organoids for embryonic development and disease modeling.

Directional Cell Migration Guided by a Strain Gradient.

Strain gradients widely exist in development and physiological activities. The directional movement of cells is essential for proper cell localization, and directional cell migration in responses to gradients of chemicals, rigidity, density, and topography of extracellular matrices have been well-established. However; it is unclear whether strain gradients imposed on cells are sufficient to drive directional cell migration. In this work, a programmable uniaxial cell stretch device is developed that creates controllable strain gradients without changing substrate stiffness or ligand distributions. It is demonstrated that over 60% of the single rat embryonic fibroblasts migrate toward the lower strain side in static and the 0.1 Hz cyclic stretch conditions at ≈4% per mm strain gradients. It is confirmed that such responses are distinct from durotaxis or haptotaxis. Focal adhesion analysis confirms higher rates of contact area and protrusion formation on the lower strain side of the cell. A 2D extended motor-clutch model is developed to demonstrate that the strain-introduced traction force determines integrin fibronectin pairs' catch-release dynamics, which drives such directional migration. Together, these results establish strain gradient as a novel cue to regulate directional cell migration and may provide new insights in development and tissue repairs.

Imaging and detecting intercellular tensile forces in spheroids and embryoid bodies using lipid-modified DNA probes.

Cells continuously experience and respond to different physical forces that are used to regulate their physiology and functions. Our ability to measure these mechanical cues is essential for understanding the bases of various mechanosensing and mechanotransduction processes. While multiple strategies have been developed to study mechanical forces within two-dimensional (2D) cell culture monolayers, the force measurement at cell-cell junctions in real three-dimensional (3D) cell models is still pretty rare. Considering that in real biological systems, cells are exposed to forces from 3D directions, measuring these molecular forces in their native environment is thus highly critical for the better understanding of different development and disease processes. We have recently developed a type of DNA-based molecular probe for measuring intercellular tensile forces in 2D cell models. Herein, we will report the further development and first-time usage of these molecular tension probes to visualize and detect mechanical forces within 3D spheroids and embryoid bodies (EBs). These probes can spontaneously anchor onto live cell membranes via the attached lipid moieties. By varying the concentrations of these DNA probes and their incubation time, we have first characterized the kinetics and efficiency of probe penetration and loading onto tumor spheroids and stem cell EBs of different sizes. After optimization, we have further imaged and measured E-cadherin-mediated forces in these 3D spheroids and EBs for the first time. Our results indicated that these DNA-based molecular tension probes can be used to study the spatiotemporal distributions of target mechanotransduction processes. These powerful imaging tools may be potentially applied to fill the gap between ongoing research of biomechanics in 2D systems and that in real 3D cell complexes.

A method of gas sensor drift compensation based on intrinsic characteristics of response curve.

Sensor drift, which is an inevitable and challenging problem in gas sensing, seriously affects the detection performance of sensor. In this study, a new sensor drift compensation method, which is based on intrinsic characteristic of sensory response, is proposed. The dataset of gas sensor for two types of gas with a period of 36 months are collected and two features (one is steady-state feature, another is transient feature) are extracted. Their relationship, which is found to be certain for different months and sensors, is explored. Then, drift compensation method is processed based on this relationship, aiming to make the drifted sensor features adjusted to that of month 1, which is considered as having no drift phenomenon. Moreover, small amount of dataset is necessary for model building and it has strong scalability. Finally, SVM is employed for proving the performance of the drift compensation method proposed in this study. The results show the efficacy of 22 month of continuous monitoring, which has been enough for most application scenario, and almost 20% of increasement of correct classification rate of SVM after drift compensation, which indicates the effect of drift compensation method.

Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids.

De novo mutations and copy number deletions in NRXN1 (2p16.3) pose a significant risk for schizophrenia (SCZ). It is unclear how NRXN1 deletions impact cortical development in a cell type-specific manner and disease background modulates these phenotypes. Here, we leveraged human pluripotent stem cell-derived forebrain organoid models carrying NRXN1 heterozygous deletions in isogenic and SCZ patient genetic backgrounds and conducted single-cell transcriptomic analysis over the course of brain organoid development from 3 weeks to 3.5 months. Intriguingly, while both deletions similarly impacted molecular pathways associated with ubiquitin-proteasome system, alternative splicing, and synaptic signaling in maturing glutamatergic and GABAergic neurons, SCZ-NRXN1 deletions specifically perturbed developmental trajectories of early neural progenitors and accumulated disease-specific transcriptomic signatures. Using calcium imaging, we found that both deletions led to long-lasting changes in spontaneous and synchronous neuronal networks, implicating synaptic dysfunction. Our study reveals developmental-timing- and cell-type-dependent actions of NRXN1 deletions in unique genetic contexts.

Spectroscopic and modeling investigation of U(VI) removal mechanism on nanoscale zero-valent iron/clay composites.

Nanoscale zero-valent iron (nZVI)-based composites have been widely utilized in environmental cleanup due to their low cost, high adsorption performance and strong redox activity. Herein, removal mechanism of U(VI) on nZVI/clay composites was demonstrated by batch, XPS and modeling techniques. The batch experiments showed that nZVI/clay composites exhibited the high removal capacity (88.90 mg/g at pH 4.0) and good regeneration towards U(VI) from aqueous solution. The adsorbed U(VI) was mostly reduced to U(IV) by nZVI/clay composites according to XPS analysis. The removal process of U(VI) on nZVI/clay composites was satisfactorily fitted by surface complexation modeling using strong and weak sites, indicating the high chemisorption of U(VI) on nZVI/clay composites. However, the fitting results underestimated U(VI) adsorption at pH 7.0-9.0 due to the reduction of U(VI) into U(IV), whereas the overestimation of U(VI) at pH 4.0-6.0 could be attributed to fewer surface complexation reaction involved. These findings are crucial for the application of nZVI-based composites for the highly efficient removal of radionuclides in actual environmental remediation.

Clinicopathological and CT features of tumor spread through air space in invasive lung adenocarcinoma.

Objective: Tumor spread through air spaces (STAS) has recently been reported as a novel invasive pattern in lung adenocarcinoma. Thus, this study aimed to investigate the clinicopathological and radiological features in invasive lung adenocarcinoma with tumor STAS. Methods: Data of 503 invasive lung adenocarcinoma patients who underwent surgery between 1 January 2015 and 31 December 2021 were collected. The correlations between STAS presence and clinicopathological and radiological characteristics were analyzed. Statistical analysis was performed using SPSS 22.0. Results: Among the 503 patients with invasive adenocarcinoma, 247 (47.9%) and 262 (52.1%) patients were positive and negative for STAS, respectively. Compared to STAS-negative adenocarcinoma, STAS was more common in papillary, micropapillary, and solid tumors (p < 0.01); STAS was associated with advanced pT (p = 0.024), pN (p < 0.001), and pTNM (p < 0.001) stage, more lymph node metastases (p < 0.01), more pleural invasion (p < 0.01), and more neurovascular invasion (p = 0.025). The maximum diameter (p < 0.01), the maximum diameters of the solid component (p < 0.01), and the consolidation/tumor ratio (CTR, p < 0.01) were significantly larger in STAS-positive than in STAS-negative adenocarcinoma. Other common computed tomography (CT) features of adenocarcinomas, i.e., lobulation (p < 0.01), spiculation (p < 0.01), vacuole (p < 0.01), air bronchogram (p = 0.020), vascular convergence (p < 0.01), and pleural indentation (p < 0.01) were significantly associated with STAS. In a multivariable analysis, the maximal diameter of the solid component (odds ratio [OR], 2.505; 95% confidence interval [CI], 1.886-3.329), vacuole (OR, 3.301; 95% CI, 1.822-5.980), and spiculation (OR, 2.162; 95% CI, 1.221-3.829) were independent predictors of STAS. The area under the curve (AUC) of the maximal diameter of the solid component was 0.757 (95% CI, 0.714-0.799; p < 0.001), the sensitivity was 73.9%, and the specificity was 69.1% at a cutoff value of 1.18 cm. Conclusion: STAS was significantly correlated with several invasive clinicopathological and radiological characteristics, and the maximal diameter was an independent predictor of STAS. These results will prove helpful in identifying STAS-positive adenocarcinoma by CT before surgical resection.

Application of Surface Electromyography in Exercise Fatigue: A Review.

Exercise fatigue is a common physiological phenomenon in human activities. The occurrence of exercise fatigue can reduce human power output and exercise performance, and increased the risk of sports injuries. As physiological signals that are closely related to human activities, surface electromyography (sEMG) signals have been widely used in exercise fatigue assessment. Great advances have been made in the measurement and interpretation of electromyographic signals recorded on surfaces. It is a practical way to assess exercise fatigue with the use of electromyographic features. With the development of machine learning, the application of sEMG signals in human evaluation has been developed. In this article, we focused on sEMG signal processing, feature extraction, and classification in exercise fatigue. sEMG based multisource information fusion for exercise fatigue was also introduced. Finally, the development trend of exercise fatigue detection is prospected.

Bioinspired two-in-one nanotransistor sensor for the simultaneous measurements of electrical and mechanical cellular responses.

The excitation-contraction dynamics in cardiac tissue are the most important physiological parameters for assessing developmental state. We demonstrate integrated nanoelectronic sensors capable of simultaneously probing electrical and mechanical cellular responses. The sensor is configured from a three-dimensional nanotransistor with its conduction channel protruding out of the plane. The structure promotes not only a tight seal with the cell for detecting action potential via field effect but also a close mechanical coupling for detecting cellular force via piezoresistive effect. Arrays of nanotransistors are integrated to realize label-free, submillisecond, and scalable interrogation of correlated cell dynamics, showing advantages in tracking and differentiating cell states in drug studies. The sensor can further decode vector information in cellular motion beyond typical scalar information acquired at the tissue level, hence offering an improved tool for cell mechanics studies. The sensor enables not only improved bioelectronic detections but also reduced invasiveness through the two-in-one converging integration.

Boosting photocatalytic efficiency of MoS2/CdS by modulating morphology.

CdS-based composites as the highly efficient photocatalyst have been extensively investigated in recent years due to the suitable band gap and high photocatalytic efficiency. In this study, the effect of various factors (pH, U(VI) concentration, contents, and types of photocatalyst) on photocatalytic reduction of U(VI) by MoS2/CdS composite was investigated. The optimized experimental conditions (e.g., pH 7.0, 20 mg/g U(VI), and 1.0 g/L photocatalyst) was obtained by batch techniques. Approximately 97.5% of U(VI) was photo-catalytically reduced into U(IV) by 2.5 wt% MoS2/CdS composite within 15 min. After 5 cycles, 2.5 wt% MoS2/CdS composite still exhibited the high removal efficiency of U(VI) under 50-min irradiation, indicating the good stability. The photo-reduction mechanism of U(VI) on MoS2/CdS composite was attributed to the O-2 radicals by quenching experiments, ESR, and XPS analysis. The findings indicate that CdS-based catalyst has a great potential for the photocatalytic reduction of uranyl in actual environmental remediation.

Surface functionalization of poly(dimethylsiloxane) substrates facilitates culture of pre-implantation mouse embryos by blocking non-selective adsorption.

Poly(dimethylsiloxane) (PDMS) is widely used in biomedical settings such as microfluidics for its optical transparency, castability, gas permeability and relative biocompatibility. While PDMS devices with certain modifications or treatments have been used for mammalian pre-implantation embryo culture, it is unclear why native PDMS leads to significant embryo death. In this study, we employ Nile Red as a model hydrophobic small molecule to demonstrate that significant hydrophobic sequestration occurs on native PDMS substrates even with a bovine serum albumin-containing KSOM pre-equilibration. Our results suggest that this small molecule sequestration has detrimental effects on mouse embryo development in PDMS static culture wells, with 0% blastocyst development rates from embryos cultured on native PDMS. We found that prior saturation of the PDMS culture well with water vapour only rescues about 10% of blastocyst development rates, indicating osmolality alone is not responsible for the high rates of embryo arrest. We also present a safe and simple Pluronic F127 pretreatment for PDMS substrates that successfully circumvented the harmful effects of native PDMS, achieving a blastocyst and implantation rate akin to that of our polystyrene controls. Our results call into question how researchers and clinicians can account for the alterations in medium composition and embryo secretions when using hydrophobic substrates, especially in the mammalian embryo culture setting where minimum effective concentrations of peptides and amino acids are commonplace.

Condensation tendency and planar isotropic actin gradient induce radial alignment in confined monolayers.

A monolayer of highly motile cells can establish long-range orientational order, which can be explained by hydrodynamic theory of active gels and fluids. However, it is less clear how cell shape changes and rearrangement are governed when the monolayer is in mechanical equilibrium states when cell motility diminishes. In this work, we report that rat embryonic fibroblasts (REF), when confined in circular mesoscale patterns on rigid substrates, can transition from the spindle shapes to more compact morphologies. Cells align radially only at the pattern boundary when they are in the mechanical equilibrium. This radial alignment disappears when cell contractility or cell-cell adhesion is reduced. Unlike monolayers of spindle-like cells such as NIH-3T3 fibroblasts with minimal intercellular interactions or epithelial cells like Madin-Darby canine kidney (MDCK) with strong cortical actin network, confined REF monolayers present an actin gradient with isotropic meshwork, suggesting the existence of a stiffness gradient. In addition, the REF cells tend to condense on soft substrates, a collective cell behavior we refer to as the 'condensation tendency'. This condensation tendency, together with geometrical confinement, induces tensile prestretch (i.e. an isotropic stretch that causes tissue to contract when released) to the confined monolayer. By developing a Voronoi-cell model, we demonstrate that the combined global tissue prestretch and cell stiffness differential between the inner and boundary cells can sufficiently define the cell radial alignment at the pattern boundary.

Quantitative and Multiplexed Fluorescence Lifetime Imaging of Intercellular Tensile Forces.

Mechanical interactions between cells have been shown to play critical roles in regulating cell signaling and communications. However, the precise measurement of intercellular forces is still quite challenging, especially considering the complex environment at cell-cell junctions. In this study, we report a fluorescence lifetime-based approach to image and quantify intercellular molecular tensions. Using this method, tensile forces among multiple ligand-receptor pairs can be measured simultaneously. We first validated our approach and developed lifetime measurement-based DNA tension probes to image E-cadherin-mediated tension on epithelial cells. These probes were then further applied to quantify the correlations between E-cadherin and N-cadherin tensions during an epithelial-mesenchymal transition process. The modular design of these probes can potentially be used to study the mechanical features of various physiological and pathological processes.

Carbon materials for extraction of uranium from seawater.

With the rapid growth of population and industrialization, the energy crisis and environmental pollution as two main difficulties urgently need to be solved nowadays. The development and utilization of nuclear energy is of great significance for solving energy support, national security and environmental protection. As the raw material of nuclear energy, a lot of uranium in seawater provide a guarantee for the sustainable and green development of nuclear power plants. Recently, various new carbon-based materials (e.g., carbon nanofibers, multiwalled carbon nanotube, graphene) have been attracted widely intense interest in extraction of uranium from seawater due to large specific surface area, excellent acid-base resistance, high adsorption performance, environmental friendly and low cost. Thus, the systematic reviews concerning the extraction of uranium from seawater on various carbon-based materials were highly desirable. In this review, the extraction methods of uranium from seawater, including electrochemical, photocatalytic and adsorption methods are briefly introduced. Then the application and mechanism of four generation carbon-based materials on the extraction of uranium from seawater are systematically reviewed in details. Finally, the current challenges and future trends of uranium extraction from seawaters are proposed. This review provides the guideline for designing carbon-based materials with high adsorption capacity and exceptional selectivity for U(VI) extraction from seawater.

Patterning Neuroepithelial Cell Sheet via a Sustained Chemical Gradient Generated by Localized Passive Diffusion Devices.

Recent advances in human pluripotent stem cells (hPSCs)-derived in vitro models open a new avenue for studying early stage human development. While current approaches leverage the self-organizing capability of hPSCs, it remains unclear whether extrinsic morphogen gradients are sufficient to pattern neuroectoderm tissues in vitro. While microfluidics or hydrogel-based approaches to generate chemical gradients are well-established, these systems either require continuous pumping or encapsulating cells in gels, making it difficult for adaptation in standard biology laboratories and downstream analysis. In this work, we report a new device design that leverages localized passive diffusion, or LPaD for short, to generate a stable chemical gradient in an open environment. As LPaD is operated simply by media changing, common issues for microfluidic systems such as leakage, bubble formation, and contamination can be avoided. The device contains a slit carved in a film filled with solid gelatin and connected to a static aqueous morphogen reservoir. Concentration gradients generated by the device were visualized via DAPI fluorescent intensity and were found to be stable for up to 168 h. Using this device, we successfully induced cellular response of Madin-Darby canine kidney (MDCK) cells to the concentration gradient of a small-molecule drug, cytochalasin D. Furthermore, we efficiently patterned the dorsal-ventral axis of hPSC-derived forebrain neuroepithelial cells with the sonic hedgehog (Shh) signal gradient generated by the LPaD devices. Together, LPaD devices are powerful tools to control the local chemical microenvironment for engineering organotypic structures in vitro.