An Integrated Neural Optrode with Modification of Polymer-Carbon Composite Films for Suppression of the Photoelectric Artifacts.

Optogenetics-based integrated photoelectrodes with high spatiotemporal resolution play an important role in studying complex neural activities. However, the photostimulation artifacts caused by the high level of integration and the high impedance of metal recording electrodes still hinder the application of photoelectrodes for optogenetic studies of neural circuits. In this study, a neural optrode fabricated on sapphire GaN material was proposed, and 4 µLEDs and 14 recording microelectrodes were monolithically integrated on a shank. Poly(3,4-ethylenedioxythiophene)/polystyrenesulfonate and multiwalled carbon nanotubes (PEDOT:PSS-MWCNT) and poly(3,4-ethylenedioxythiophene) and graphene oxide (PEDOT-GO) composite films were deposited on the surface of the recording microelectrode by electrochemical deposition. The results demonstrate that compared with the gold microelectrode, the impedances of both composite films reduced by more than 98%, and the noise amplitudes decreased by 70.73 and 87.15%, respectively, when exposed to light stimulation. Adjusting the high and low levels, we further reduced the noise amplitude by 48.3%. These results indicate that modifying the electrode surface by a polymer composite film can effectively enhance the performance of the microelectrode and further promote the application of the optrode in the field of neuroscience.

Characteristics of the Mixed Yogurt Fermented from Cow-Soy Milk in the Presence of Transglutaminase.

The mixed yogurt was fermented from Cow-Soy milk and modified by transglutaminase (TG). The effects of mixed milk and TG on the quality characteristics of mixed yogurt were investigated by texture characteristics, rheology (rheometer) and structure (scanning electron microscopy). The findings revealed that the mixed yogurt with 50% cow milk exhibited lower hardness, viscosity and consistency. Furthermore, when TG was added, the yogurt showed better rheological properties, sensory score and a more stable microstructure. Compared with the samples without TG modification, the viscosity and cohesiveness of the modified samples increased by 10% and 100%, respectively. The combination of cow milk and soy milk improved the texture of yogurt, and the TG addition further improved the physicochemical properties of yogurt. This finding provided a meaningful reference for the development of mixed yogurt with a suitable taste from animal and plant milk, and laid a basis for the practical application of mixed yogurt in the dairy industry, which will meet the requirements for dairy products for consumers in future.

Wireless Intelligent Patch for Closed-loop In Situ Wound Management.

Wound infections pose a major healthcare issue, affecting the well-being of millions of patients worldwide. Effective intervention and on-site detection are important in wound management. However, current approaches are hindered by time-consuming analysis and a lack of technology for real-time monitoring and prompt therapy delivery. In this study, a smart wound patch system (SWPS) designed for wireless closed-loop and in-situ wound management is presented. The SWPS integrates a microfluidic structure, an organic electrochemical transistor (OECT) based sensor, an electrical stimulation module, and a miniaturized flexible printed circuit board (FPCB). The OECT incorporates a bacteria-responsive DNA hydrogel-coated gate for continuous monitoring of bacterial virulence at wound sites. Real-time detection of OECT readings and on-demand delivery of electrical cues to accelerate wound healing is facilitated by a mobile phone application linked with an FPCB containing low-power electronics equipped with parallel sensing and stimulation circuitry. In this proof-of-concept study, the functionality of the SWPS is validated and its application both in vitro and in vivo is demonstrated. This proposed system expands the arsenal of tools available for effective wound management and enables personalized treatment.

Ultra-low frequency magnetic energy focusing for highly effective wireless powering of deep-tissue implantable electronic devices.

The limited lifespan of batteries is a challenge in the application of implantable electronic devices. Existing wireless power technologies such as ultrasound, near-infrared light and magnetic fields cannot charge devices implanted in deep tissues, resulting in energy attenuation through tissues and thermal generation. Herein, an ultra-low frequency magnetic energy focusing (ULFMEF) methodology was developed for the highly effective wireless powering of deep-tissue implantable devices. A portable transmitter was used to output the low-frequency magnetic field (<50 Hz), which remotely drives the synchronous rotation of a magnetic core integrated within the pellet-like implantable device, generating an internal rotating magnetic field to induce wireless electricity on the coupled coils of the device. The ULFMEF can achieve energy transfer across thick tissues (up to 20 cm) with excellent transferred power (4-15 mW) and non-heat effects in tissues, which is remarkably superior to existing wireless powering technologies. The ULFMEF is demonstrated to wirelessly power implantable micro-LED devices for optogenetic neuromodulation, and wirelessly charged an implantable battery for programmable electrical stimulation on the sciatic nerve. It also bypassed thick and tough protective shells to power the implanted devices. The ULFMEF thus offers a highly advanced methodology for the generation of wireless powered biodevices.

Co-selection mechanism for bacterial resistance to major chemical pollutants in the environment.

Bacterial resistance is an emerging global public health problem, posing a significant threat to animal and human health. Chemical pollutants present in the environment exert selective pressure on bacteria, which acquire resistance through co-resistance, cross-resistance, co-regulation, and biofilm resistance. Resistance genes are horizontally transmitted in the environment through four mechanisms including conjugation transfer, bacterial transformation, bacteriophage transduction, and membrane vesicle transport, and even enter human bodies through the food chain, endangering human health. Although the co-selection effects of bacterial resistance to chemical pollutants has attracted widespread attention, the co-screening mechanism and co-transmission mechanisms remain unclear. Therefore, this article summarises the current research status of the co-selection effects and mechanism of environmental pollutants resistance, emphasising the necessity of studying the co-selection mechanism of bacteria against major chemical pollutants, and lays a solid theoretical foundation for conducting risk assessment of bacterial resistance.

Structural basis of the American mink ACE2 binding by Y453F trimeric spike glycoproteins of SARS-CoV-2.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) enters the host cell by binding to angiotensin-converting enzyme 2 (ACE2). While evolutionarily conserved, ACE2 receptors differ across various species and differential interactions with Spike (S) glycoproteins of SARS-CoV-2 viruses impact species specificity. Reverse zoonoses led to SARS-CoV-2 outbreaks on multiple American mink (Mustela vison) farms during the pandemic and gave rise to mink-associated S substitutions known for transmissibility between mink and zoonotic transmission to humans. In this study, we used bio-layer interferometry (BLI) to discern the differences in binding affinity between multiple human and mink-derived S glycoproteins of SARS-CoV-2 and their respective ACE2 receptors. Further, we conducted a structural analysis of a mink variant S glycoprotein and American mink ACE2 (mvACE2) using cryo-electron microscopy (cryo-EM), revealing four distinct conformations. We discovered a novel intermediary conformation where the mvACE2 receptor is bound to the receptor-binding domain (RBD) of the S glycoprotein in a "down" position, approximately 34° lower than previously reported "up" RBD. Finally, we compared residue interactions in the S-ACE2 complex interface of S glycoprotein conformations with varying RBD orientations. These findings provide valuable insights into the molecular mechanisms of SARS-CoV-2 entry.

China's current forest age structure will lead to weakened carbon sinks in the near future.

Forests are chiefly responsible for the terrestrial carbon sink that greatly reduces the buildup of CO2 concentrations in the atmosphere and alleviates climate change. Current predictions of terrestrial carbon sinks in the future have so far ignored the variation of forest carbon uptake with forest age. Here, we predict the role of China's current forest age in future carbon sink capacity by generating a high-resolution (30 m) forest age map in 2019 over China's landmass using satellite and forest inventory data and deriving forest growth curves using measurements of forest biomass and age in 3,121 plots. As China's forests currently have large proportions of young and middle-age stands, we project that China's forests will maintain high growth rates for about 15 years. However, as the forests grow older, their net primary productivity will decline by 5.0% ± 1.4% in 2050, 8.4% ± 1.6% in 2060, and 16.6% ± 2.8% in 2100, indicating weakened carbon sinks in the near future. The weakening of forest carbon sinks can be potentially mitigated by optimizing forest age structure through selective logging and implementing new or improved afforestation. This finding is important not only for the global carbon cycle and climate projections but also for developing forest management strategies to enhance land sinks by alleviating the age effect.

Application of optical switching technology in a lunar laser ranging system based on a superconducting detector.

The TianQin laser ranging station has successfully obtained the effective echo signals of the all five corner-cube reflectors on the lunar surface by using a 1064 nm Nd:YAG laser with 100 Hz repetition frequency and a 2×2 array of superconducting nanowire single-photon detectors (SNSPDs). The application of the SNSPD in the lunar laser ranging system (LLRS) has demonstrated its detection ability, but it loses its superconducting state and cannot work under strong stray light conditions. In this paper, a high-speed optical switch experimental device based on 100 Hz is developed to solve the application problem of the SNSPD in the LLRS, and its main technical parameters are tested. The results show that the maximum running distance of the switch is 200 µm; the switching time is better than 2 ms; and the extinction ratio is better than 57 dB. Moreover, the application of the high-speed optical switch experimental device in the lunar laser ranging system is designed, and the effective detection time between two laser pulses (10 ms) is determined to be 6.1 ms.

Multi-Target Neural Differentiation (MTND) Therapeutic Cocktail to Suppress Brain Tumor.

Brain tumors have been proved challenging to treat. Here we established a Multi-Target Neural Differentiation (MTND) therapeutic cocktail to achieve effective and safe treatment of brain malignancies by targeting the important hallmarks in brain cancers: poor cell differentiation and compromised cell cycle. In-vitro and in-vivo experiments confirmed the significant therapeutic effect of our MTND therapy. Significantly improved therapeutic effects over current first-line chemo-drugs have been identified in clinical cells, with great inhibition of the growth and migration of tumor cells. Further in-vivo experiments confirmed that sustained MTND treatment showed a 73% reduction of the tumor area. MTND also induced strong expression of phenotypes associated with cell cycle exit/arrest and rapid neural reprograming from clinical glioma cells to glutamatergic and GABAergic expressing cells, which are two key neuronal types involved in many human brain functions, including learning and memory. Collectively, MTND induced multi-targeted genotypic expression changes to achieve direct neural conversion of glioma cells and controlled the cell cycle/tumorigenesis development, helping control tumor cells' malignant proliferation and making it possible to treat brain malignant tumors effectively and safely. These encouraging results open avenues to developing new therapies for brain malignancies beyond cytotoxic agents, providing more effective medication recommendations with reduced toxicity.

Worm Generator: A System for High-Throughput in Vivo Screening.

Large-scale screening of molecules in organisms requires high-throughput and cost-effective evaluating tools during preclinical development. Here, a novel in vivo screening strategy combining hierarchically structured biohybrid triboelectric nanogenerators (HB-TENGs) arrays with computational bioinformatics analysis for high-throughput pharmacological evaluation using Caenorhabditis elegans is described. Unlike the traditional methods for behavioral monitoring of the animals, which are laborious and costly, HB-TENGs with micropillars are designed to efficiently convert animals' behaviors into friction deformation and result in a contact-separation motion between two triboelectric layers to generate electrical outputs. The triboelectric signals are recorded and extracted to various bioinformation for each screened compound. Moreover, the information-rich electrical readouts are successfully demonstrated to be sufficient to predict a drug's identity by multiple-Gaussian-kernels-based machine learning methods. This proposed strategy can be readily applied to various fields and is especially useful in in vivo explorations to accelerate the identification of novel therapeutics.

Ferromagnetic Flexible Electronics for Brain-Wide Selective Neural Recording.

Flexible microelectronics capable of straightforward implantation, remotely controlled navigation, and stable long-term recording hold great promise in diverse medical applications, particularly in deciphering complex functions of neural circuits in the brain. Existing flexible electronics, however, are often limited in bending and buckling during implantation, and unable to access a large brain region. Here, an injectable class of electronics with stable recording, omnidirectional steering, and precise navigating capabilities based on magnetic actuation is presented. After simple transcriptional injection, the rigid coatings are biodegraded quickly and the bundles of magnetic-nanoparticles-coated microelectrodes become separated, ultra-flexible, and magnetic actuated for further minimally invasive three-dimensional interpenetration in the brain. As proof of concept, this paradigm-shifting approach is demonstrated for selective and multiplexed neural activities recording across distant regions in the deep rodent brains. Coupling with optogenetic neural stimulation, the unique capabilities of this platform in electrophysiological readouts of projection dynamics in vivo are also demonstrated. The ability of these miniaturized, remotely controllable, and biocompatible ferromagnetic flexible electronics to afford minimally invasive manipulations in the soft tissues of the mammalian brain foreshadows applications in other organ systems, with great potential for broad utility in biomedical science and engineering.

An implantable ultrasound-powered device for the treatment of brain cancer using electromagnetic fields.

Brain tumors have been proved challenging to treat. Here, we present a promising alternative by developing an implantable ultrasound-powered tumor treating device (UP-TTD) that electromagnetically disrupts the rapid division of cancer cells without any adverse effects on normal neurons, thereby safely inhibiting brain cancer recurrence. In vitro and in vivo experiments confirmed the significant therapeutic effect of the UP-TTD, with ~58% inhibition on growth rate of clinical tumor cells and ~78% reduction of cancer area in tumor-bearing rats. This UP-TTD is wireless ultrasound-powered, chip-sized, lightweight, and easy to operate on complex surfaces, with a largely boosting therapeutic efficiency and reducing energy consumption. Meanwhile, various treatment parameters could be tuned from the UP-TTD without increasing its size or adding circuits on the integrated chip. The tuning process was simulated and discussed, showing an excellent agreement with the experimental data. The encouraging results of the UP-TTD raise the possibility of a new modality for brain cancer treatment.

Differential neutralization and inhibition of SARS-CoV-2 variants by antibodies elicited by COVID-19 mRNA vaccines.

The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the emergence of new variant lineages that have exacerbated the COVID-19 pandemic. Some of those variants were designated as variants of concern/interest (VOC/VOI) by national or international authorities based on many factors including their potential impact on vaccine-mediated protection from disease. To ascertain and rank the risk of VOCs and VOIs, we analyze the ability of 14 variants (614G, Alpha, Beta, Gamma, Delta, Epsilon, Zeta, Eta, Theta, Iota, Kappa, Lambda, Mu, and Omicron) to escape from mRNA vaccine-induced antibodies. The variants show differential reductions in neutralization and replication by post-vaccination sera. Although the Omicron variant (BA.1, BA.1.1, and BA.2) shows the most escape from neutralization, sera collected after a third dose of vaccine (booster sera) retain moderate neutralizing activity against that variant. Therefore, vaccination remains an effective strategy during the COVID-19 pandemic.

3D Upconversion Barcodes for Combinatory Wireless Neuromodulation in Behaving Animals.

Upconversion techniques offer all-optical wireless alternatives to modulate targeted neurons in behaving animals, but most existing upconversion-based optogenetic devices show prefixed emission that is used to excite just one channelrhodopsin at a restricted brain region. Here, a hierarchical upconversion device is reported to enable spatially selective and combinatory optogenetics in behaving rodent animals. The device assumes a multiarrayed optrode format containing engineered upconversion nanoparticles (UCNPs) to deliver dynamic light palettes as a function of excitation wavelength. Three primary emissions at 477, 540, and 654 nm are selected to match the absorption of different channelrhodopsins. The UCNPs are barcode assembled to multiple nanomachined optical pinholes in a microscale pipette device to allow remotely addressable, spectrum programmable, and spatially selective optical interrogation of complex brain circuits. Using the unique device, the basolateral amygdala and caudoputamen circuits are selectively modulated and the associated fear or anxiety behavior in freely behaving rodents is successfully differentiated. It is believed that the 3D barcode upconversion device would be a great supplement to current optogenetic toolsets and opens up new possibilities for sophisticated neural control.

Effects of composting on the fate of doxycycline, microbial community, and antibiotic resistance genes in swine manure and broiler manure.

Aerobic composting is an economical and effective technology that is widely used to treat animal manure. To study the fate of doxycycline (DOX), the microbial community, and antibiotic resistance genes (ARGs) during composting, aerobic composting of broiler manure and swine manure was carried out under natural environmental conditions. Aerobic composting effectively removed DOX (with a removal rate > 97%) and most ARGs from animal manure. The microbial diversity and the numbers of ARGs were higher in composted swine manure compared with composted broiler manure. The microbial community structure changed during composting, and the dominant phyla of broiler manure and swine manure changed from Firmicutes to Bacteroidetes and Proteobacteria, respectively. DOX changed the structure and relative abundance of the microbial community during composting, and the relative abundance of multidrug resistance genes and mobile genetic elements (MGEs) increased, which might lead to the risk of transmission of resistance in the environment. The C / N ratio, DOX concentration, Firmicutes, intl1, and intl2 were the key factors driving the change in ARGs during composting. These results help to reveal the effects of DOX on microbial communities, ARGs, and MGEs during composting and clarify the possible ways to reduce the risk of resistance gene transmission in the environment.

Fish Capsules: A System for High-Throughput Screening of Combinatorial Drugs.

Large-scale screening of molecules heavily relies on phenotyping of small living organisms during preclinical development. However, deep profiling candidate therapeutics on whole animals typically requires laborious manipulations and anesthetic treatment using traditional techniques or automated tools. Here, a novel fish capsule system that combines automated zebrafish encapsulating technology and droplet microarray strategy for in vivo functional screening of mono/polytherapies is described. This platform enables automated, rapid zebrafish orientation and immobilization in agarose to generate large-scale fish capsules by using a microfluidic device. Based on the effect of discontinuous dewetting, the prompt trapping of fish capsules in the aqueous arrays is successfully demonstrate. This system provides the capability to integrate pharmaceutical treatments with real-time multispectral microscopic imaging in a simple, pipetting-free and highly parallel manner. Coupling with machine learning algorithms, a small library of compounds is screened and analyzed, and clues about how to exploit compound combinations as therapeutic candidates are obtained. It is believed that this proposed strategy can be readily applied to multiple fields and is especially useful in the exploration of combinatorial drugs with limited amounts of samples and resources to accelerate the identification of novel therapeutics for precision medicines.

Keggin-type polyoxometalates as Cu(II) chelators in the context of Alzheimer's disease.

Two Keggin polyoxometalates were used as new copper ligands to counteract the effects of CuII(Amyloid-ß) interaction. Their ability to remove CuII from CuII(Amyloid-ß), to stop CuII(Amyloid-ß) induced formation of reactive oxygen species and to restore apo-like self-assembly of CuII(Amyloid-ß) was shown.

Injectable Black Phosphorus Nanosheets for Wireless Nongenetic Neural Stimulation.

Neurons can be modified to express light-sensitive proteins for enabling stimulation with a high spatial and temporal resolution, but such techniques require gene transfection and systematical implantation. Here, a black phosphorus nanosheet-based injectable strategy is described for wireless neural stimulation both in vitro and in vivo without cell modifications. These nanosheets, with minimal invasiveness, high biocompatibility, and biodegradability, are anchored on cell membranes as miniature near-infrared (NIR) light transducers to create local heating for neural activity excitation. Based on cultured multielectrode-array recording, in vivo electrophysiology analysis, and open field behavioral tests, it is demonstrated that remotely applied NIR illumination can reliably trigger spiking activity in cultured neurons and rat brains. Excitingly, reliable regulation of brain function to control animal behaviors is also described. Moreover, this approach has shown its potential for future clinical use by successful high-frequency stimulation in cells and animals in this proof-of-concept study. It is believed that this new method will offer a powerful alternative to other neural stimulation solutions and potentially be of independent value to the healthcare system.

SARS-CoV-2 spike D614G change enhances replication and transmission.

During the evolution of SARS-CoV-2 in humans, a D614G substitution in the spike glycoprotein (S) has emerged; virus containing this substitution has become the predominant circulating variant in the COVID-19 pandemic1. However, whether the increasing prevalence of this variant reflects a fitness advantage that improves replication and/or transmission in humans or is merely due to founder effects remains unknown. Here we use isogenic SARS-CoV-2 variants to demonstrate that the variant that contains S(D614G) has enhanced binding to the human cell-surface receptor angiotensin-converting enzyme 2 (ACE2), increased replication in primary human bronchial and nasal airway epithelial cultures as well as in a human ACE2 knock-in mouse model, and markedly increased replication and transmissibility in hamster and ferret models of SARS-CoV-2 infection. Our data show that the D614G substitution in S results in subtle increases in binding and replication in vitro, and provides a real competitive advantage in vivo-particularly during the transmission bottleneck. Our data therefore provide an explanation for the global predominance of the variant that contains S(D614G) among the SARS-CoV-2 viruses that are currently circulating.

Dissecting Cellular Heterogeneity Based on Network Denoising of scRNA-seq Using Local Scaling Self-Diffusion.

Identifying the phenotypes and interactions of various cells is the primary objective in cellular heterogeneity dissection. A key step of this methodology is to perform unsupervised clustering, which, however, often suffers challenges of the high level of noise, as well as redundant information. To overcome the limitations, we proposed self-diffusion on local scaling affinity (LSSD) to enhance cell similarities' metric learning for dissecting cellular heterogeneity. Local scaling infers the self-tuning of cell-to-cell distances that are used to construct cell affinity. Our approach implements the self-diffusion process by propagating the affinity matrices to further improve the cell similarities for the downstream clustering analysis. To demonstrate the effectiveness and usefulness, we applied LSSD on two simulated and four real scRNA-seq datasets. Comparing with other single-cell clustering methods, our approach demonstrates much better clustering performance, and cell types identified on colorectal tumors reveal strongly biological interpretability.