Using Machine Learning to Construct the Blood-Follicle Distribution Models of Various Trace Elements and Explore the Transport-Related Pathways with Multiomics Data.

Permeabilities of various trace elements (TEs) through the blood-follicle barrier (BFB) play an important role in oocyte development. However, it has not been comprehensively described as well as its involved biological pathways. Our study aimed to construct a blood-follicle distribution model of the concerned TEs and explore their related biological pathways. We finally included a total of 168 women from a cohort of in vitro fertilization-embryo transfer conducted in two reproductive centers in Beijing City and Shandong Province, China. The concentrations of 35 TEs in both serum and follicular fluid (FF) samples from the 168 women were measured, as well as the multiomics features of the metabolome, lipidome, and proteome in both plasma and FF samples. Multiomics features associated with the transfer efficiencies of TEs through the BFB were selected by using an elastic net model and further utilized for pathway analysis. Various machine learning (ML) models were built to predict the concentrations of TEs in FF. Overall, there are 21 TEs that exhibited three types of consistent BFB distribution characteristics between Beijing and Shandong centers. Among them, the concentrations of arsenic, manganese, nickel, tin, and bismuth in FF were higher than those in the serum with transfer efficiencies of 1.19-4.38, while a reverse trend was observed for the 15 TEs with transfer efficiencies of 0.076-0.905, e.g., mercury, germanium, selenium, antimony, and titanium. Lastly, cadmium was evenly distributed in the two compartments with transfer efficiencies of 0.998-1.056. Multiomics analysis showed that the enrichment of TEs was associated with the synthesis and action of steroid hormones and the glucose metabolism. Random forest model can provide the most accurate predictions of the concentrations of TEs in FF among the concerned ML models. In conclusion, the selective permeability through the BFB for various TEs may be significantly regulated by the steroid hormones and the glucose metabolism. Also, the concentrations of some TEs in FF can be well predicted by their serum levels with a random forest model.

Intravital observation of high-scattering and dense-labeling hepatic tissues using multi-photon fluorescence microscopy.

Achieving high-resolution and large-depth microscopic imaging in vivo under conditions characterized by high-scattering and dense-labeling, as commonly encountered in the liver, poses a formidable challenge. Here, through the optimization of multi-photon fluorescence excitation window, tailored to the unique optical properties of the liver, intravital microscopic imaging of hepatocytes and hepatic blood vessels with high spatial resolution was attained. It's worth noting that resolution degradation caused by tissue scattering of excitation light was mitigated by accounting for moderate tissue self-absorption. Leveraging high-quality multi-photon fluorescence microscopy, we discerned structural and functional alterations in hepatocytes during drug-induced acute liver failure. Furthermore, a reduction in indocyanine green metabolism rates associated with acute liver failure was observed using NIR-II fluorescence macroscopic imaging.

Ascertaining sensitive exposure biomarkers of various metal(loid)s to embryo implantation.

Close relationships exist between metal(loid)s exposure and embryo implantation failure (EIF) from animal and epidemiological studies. However, there are still inconsistent results and lacking of sensitive metal(loid) exposure biomarkers associated with EIF risk. We aimed to ascertain sensitive metal(loid) biomarkers to EIF and provide potential biological explanations. Candidate metal(loid) biomarkers were measured in the female hair (FH), female serum (FS), and follicular fluid (FF) with various exposure time periods. An analytical framework was established by integrating epidemiological association results, comprehensive literature searching, and knowledge-based adverse outcome pathway (AOP) networks. The sensitive biomarkers of metal(loid)s along with potential biological pathways to EIF were identified in this framework. Among the concerned 272 candidates, 45 metal(loid)s biomarkers across six time periods and three biomatrix were initially identified by single-metal(loid) analyses. Two biomarkers with counterfactual results according to literature summary results were excluded, and a total of five biomarkers were further determined from 43 remained candidates in mixture models. Finally, four sensitive metal(loid) biomarkers were eventually assessed by overlapping AOP networks information, including Se and Co in FH, and Fe and Zn in FS. AOP networks also identified key GO pathways and proteins involved in regulation of oxygen species biosynthetic, cell proliferation, and inflammatory response. Partial dependence results revealed Fe in FS and Co in FH at their low levels might be potential sensitive exposure levels for EIF. Our study provided a typical framework to screen the crucial metal(loid) biomarkers and ascertain that Se and Co in FH, and Fe and Zn in FS played an important role in embryo implantation.

Hybrid neuromorphic hardware with sparing 2D synapse and CMOS neuron for character recognition.

Neuromorphic computing enables efficient processing of data-intensive tasks, but requires numerous artificial synapses and neurons for certain functions, which leads to bulky systems and energy challenges. Achieving functionality with fewer synapses and neurons will facilitate integration density and computility. Two-dimensional (2D) materials exhibit potential for artificial synapses, including diverse biomimetic plasticity and efficient computing. Considering the complexity of neuron circuits and the maturity of complementary metal-oxide-semiconductor (CMOS), hybrid integration is attractive. Here, we demonstrate a hybrid neuromorphic hardware with 2D MoS2 synaptic arrays and CMOS neural circuitry integrated on board. With the joint benefit of hybrid integration, frequency coding and feature extraction, a total cost of twelve MoS2 synapses, three CMOS neurons, combined with digital/analogue converter enables alphabetic and numeric recognition. MoS2 synapses exhibit progressively tunable weight plasticity, CMOS neurons integrate and fire frequency-encoded spikes to display the target characters. The synapse- and neuron-saving hybrid hardware exhibits a competitive accuracy of 98.8% and single recognition energy consumption of 11.4 µW. This work provides a viable solution for building neuromorphic hardware with high compactness and computility.

Engineered NIR-II fluorophores with ultralong-distance molecular packing for high-contrast deep lesion identification.

The limited signal of long-wavelength near-infrared-II (NIR-II, 900-1880 nm) fluorophores and the strong background caused by the diffused photons make high-contrast fluorescence imaging in vivo with deep tissue disturbed still challenging. Here, we develop NIR-II fluorescent small molecules with aggregation-induced emission properties, high brightness, and maximal emission beyond 1200 nm by enhancing electron-donating ability and reducing the donor-acceptor (D-A) distance, to complement the scarce bright long-wavelength emissive organic dyes. The convincing single-crystal evidence of D-A-D molecular structure reveals the strong inhibition of the π-π stacking with ultralong molecular packing distance exceeding 8 Å. The delicately-designed nanofluorophores with bright fluorescent signals extending to 1900 nm match the background-suppressed imaging window, enabling the signal-to-background ratio of the tissue image to reach over 100 with the tissue thickness of ~4-6 mm. In addition, the intraluminal lesions with strong negatively stained can be identified with almost zero background. This method can provide new avenues for future long-wavelength NIR-II molecular design and biomedical imaging of deep and highly scattering tissues.

d-Band Center of Rare Earth Oxides Determines Biotransformation-Induced Cell Membrane Damage.

Biotransformation of rare earth oxide (REO) nanoparticles on biological membranes may trigger a series of adverse health effects in biosystems. However, the physicochemical mechanism of the complicated biotransformation behavior remains elusive. By investigating the distinctly different biotransformation behavior of two typical REOs (Gd2O3 and CeO2) on erythrocyte membranes, we demonstrate that dephosphorylation by stripping phosphate from phospholipids correlates highly with the membrane destructive effects of REOs. Density functional theory calculations decode the decisive role of the d-band center in dephosphorylation. Furthermore, using the d-band center as an electronic descriptor, we unravel a universal structure-activity relationship of the membrane-damaging capability of 13 REOs (R2 = 0.82). The effect of ion release on dephosphorylation and physical damage to cell membranes by Gd2O3 are largely excluded. Our findings depict a clear physicochemical microscopic picture of the biotransformation of REOs on the nano-bio interface, providing a theoretical basis for safe application of REOs.

Exploring plant polyphenols as anti-allergic functional products to manage the growing incidence of food allergy.

The active substances derived from plants have received increasing attention owing to their wide range of pharmacological applications, including anti-tumor, anti-allergic, anti-viral, and anti-oxidative activities. The allergy epidemic is a growing global public health problem that threatens human health and safety. Polyphenols from plants have significant anti-allergic effects and are an important source of anti-allergic drug research and development. Here, we describe recent advances in the anti-allergic efficacy of plant polyphenols, including their comprehensive effects on cellular or animal models. The current issues and directions for future development in this field are discussed to provide a theoretical basis for the development and utilization of these active substances as anti-allergic products.

Adsorptive decontamination of antibiotics from livestock wastewater by using alkaline-modified biochar.

Efficient abatement of antibiotics from livestock wastewater is in urgent demand, but still challenging. In this study, alkaline-modified biochar with larger surface area (130.520 m2 g-1) and pore volume (0.128 cm3 g-1) was fabricated and explored for the adsorption of different types of antibiotics from livestock wastewater. Batch adsorption experiments demonstrated that the adsorption process was mainly determined by chemisorption and was heterogeneous, which could be moderately affected by the variations of solution pH (3-10). Furthermore, the computational analysis based on density functional theory (DFT) indicated that the -OH groups on biochar surface could serve as the dominant active sites for antibiotics adsorption due to the strongest adsorption energies between antibiotics and -OH groups. In addition, the antibiotics removal was also evaluated in multi-pollutants system, where biochar performed synergistic adsorption towards Zn2+/Cu2+ and antibiotics. Overall, these findings not only deepen our understandings on the adsorption mechanism between biochar and antibiotics, but also promote the application of biochar in the remediation of livestock wastewater.

An artificial neural network chip based on two-dimensional semiconductor.

Recently, research on two-dimensional (2D) semiconductors has begun to translate from the fundamental investigation into rudimentary functional circuits. In this work, we unveil the first functional MoS2 artificial neural network (ANN) chip, including multiply-and-accumulate (MAC), memory and activation function circuits. Such MoS2 ANN chip is realized through fabricating 818 field-effect transistors (FETs) on a wafer-scale and high-homogeneity MoS2 film, with a gate-last process to realize top gate structured FETs. A 62-level simulation program with integrated circuit emphasis (SPICE) model is utilized to design and optimize our analog ANN circuits. To demonstrate a practical application, a tactile digit sensing recognition was demonstrated based on our ANN circuits. After training, the digit recognition rate exceeds 97%. Our work not only demonstrates the protentional of 2D semiconductors in wafer-scale integrated circuits, but also paves the way for its future application in AI computation.

Long-term monitoring of intravital biological processes using fluorescent protein-assisted NIR-II imaging.

High spatial resolution, low background, and deep tissue penetration have made near-infrared II (NIR-II) fluorescence imaging one of the most critical tools for in vivo observation and measurement. However, the relatively short retention time and potential toxicity of synthetic NIR-II fluorophores limit their long-term application. Here, we report the use of infrared fluorescent proteins (iRFPs) as in vitro and in vivo NIR-II probes permitting prolonged continuous imaging (up to 15 months). As a representative example, iRFP713 is knocked into the mouse genome to generate a transgenic model to allow temporal and/or spatial expression control of the probe. To demonstrate its feasibility in a genuine diagnostic context, we adopt two liver regeneration models and successfully track the process for a week. The performance and monitoring efficacy are comparable to those of µCT and superior to those of indocyanine green dye. We are also able to effectively observe the pancreas, despite its deep location, under both physiological and pathological conditions. These results indicate that the iRFP-assisted NIR-II fluorescence system is suitable for monitoring various tissues and in vivo biological processes, providing a powerful noninvasive long-term imaging platform.

An instrument-free visual quantitative detection method based on clock reaction: the detection of thrombin as an example.

Instrument-free visual quantitative detection in chemical and biochemical analysis is of great significance in practical applications especially in point-of-care testing and in places where resources are limited. In this paper, we report the development of a time-based instrument-free visual quantitative detection method by employing a clock reaction, a type of chemical reaction displaying characteristic clocking behavior. The feasibility of the method was illustrated by the quantitative detection of thrombin in buffer solution using the lapse of time as the readout signal. The linear range of detection was from 1.3 to 43 nM (r2 = 0.990, n = 3) with a LOD of 0.9 nM, which is lower than the physiological concentrations of thrombin in the resting and activated blood, which range from low nanomolar to low micromolar, respectively. This method was also validated by detecting thrombin in the serum and a good recovery of nearly 100 ± 8.0% was obtained. To the best of our knowledge, this work is the first report that uses the characteristic time of a clock reaction as the readout signal in instrument-free colorimetry for quantitative bioanalysis.

Optical-electrical characteristic of green based on GaN micro-LED arrays.

A detailed theoretical derivation and calculation method of the difference coefficient between a light distribution pattern of a 30×20µm2 green micro-LED array and Lambert source is proposed first in this paper, to the best of our knowledge, which establishes an accurate relationship between external quantum efficiency and current efficiency (cd/A). The variation of capacitance with voltage and wavelength blueshift is illustrated by a carrier recombination mechanism. The current efficiency reaches 132.5 cd/A for the 60×50µm2 and 121.7 cd/A for the 25×15µm2 arrays, and the mechanism caused by size dependence is analyzed in detail combined with the classical ABC model.

NIR-II and visible fluorescence hybrid imaging-guided surgery via aggregation-induced emission fluorophores cocktails.

Fluorescence imaging-guided surgery is one of important techniques to realize precision surgery. Although second near-infrared window (NIR-II) fluorescence imaging has the advantages of high resolution and large penetration depth in surgical navigation, its major drawback is that NIR-II images cannot be detected by our naked eyes, which demands a high hand-eye coordination for surgeons and increases the surgical difficulty. On the contrary, visible fluorescence can be observed by our naked eyes but has poor penetration. Here, we firstly propose a kind of NIR-II and visible fluorescence hybrid navigation surgery assisted via a cocktail of aggregation-induced emission nanoparticles (AIE NPs). NIR-II imaging helps to locate deep targeted tissues and judge the residual, and visible fluorescence offers an easily surgical navigation. We apply this hybrid navigation mode in different animals and systems, and verify that it can accelerate surgical process and compatible with a visible fluorescence endoscopy. To deepen the understanding of lymph node (LN) labelling, the distribution of NPs in LNs after local administration is initially analyzed by NIR-II fluorescence wide-filed microscopy, and two fates of the NPs are summarized. An alternative strategy which combines indocyanine green and berberine is also reported as a compromise for rapidly clinical translation.

A 619-pixel machine vision enhancement chip based on two-dimensional semiconductors.

The rapid development of machine vision applications demands hardware that can sense and process visual information in a single monolithic unit to avoid redundant data transfer. Here, we design and demonstrate a monolithic vision enhancement chip with light-sensing, memory, digital-to-analog conversion, and processing functions by implementing a 619-pixel with 8582 transistors and physical dimensions of 10 mm by 10 mm based on a wafer-scale two-dimensional (2D) monolayer molybdenum disulfide (MoS2). The light-sensing function with analog MoS2 transistor circuits offers low noise and high photosensitivity. Furthermore, we adopt a MoS2 analog processing circuit to dynamically adjust the photocurrent of individual imaging sensor, which yields a high dynamic light-sensing range greater than 90 decibels. The vision chip allows the applications for contrast enhancement and noise reduction of image processing. This large-scale monolithic chip based on 2D semiconductors shows multiple functions with light sensing, memory, and processing for artificial machine vision applications, exhibiting the potentials of 2D semiconductors for future electronics.

Wafer-scale functional circuits based on two dimensional semiconductors with fabrication optimized by machine learning.

Triggered by the pioneering research on graphene, the family of two-dimensional layered materials (2DLMs) has been investigated for more than a decade, and appealing functionalities have been demonstrated. However, there are still challenges inhibiting high-quality growth and circuit-level integration, and results from previous studies are still far from complying with industrial standards. Here, we overcome these challenges by utilizing machine-learning (ML) algorithms to evaluate key process parameters that impact the electrical characteristics of MoS2 top-gated field-effect transistors (FETs). The wafer-scale fabrication processes are then guided by ML combined with grid searching to co-optimize device performance, including mobility, threshold voltage and subthreshold swing. A 62-level SPICE modeling was implemented for MoS2 FETs and further used to construct functional digital, analog, and photodetection circuits. Finally, we present wafer-scale test FET arrays and a 4-bit full adder employing industry-standard design flows and processes. Taken together, these results experimentally validate the application potential of ML-assisted fabrication optimization for beyond-silicon electronic materials.

Perfecting and extending the near-infrared imaging window.

In vivo fluorescence imaging in the second near-infrared window (NIR-II) has been considered as a promising technique for visualizing mammals. However, the definition of the NIR-II region and the mechanism accounting for the excellent performance still need to be perfected. Herein, we simulate the photon propagation in the NIR region (to 2340 nm), confirm the positive contribution of moderate light absorption by water in intravital imaging and perfect the NIR-II window as 900-1880 nm, where 1400-1500 and 1700-1880 nm are defined as NIR-IIx and NIR-IIc regions, respectively. Moreover, 2080-2340 nm is newly proposed as the third near-infrared (NIR-III) window, which is believed to provide the best imaging quality. The wide-field fluorescence microscopy in the brain is performed around the NIR-IIx region, with excellent optical sectioning strength and the largest imaging depth of intravital NIR-II fluorescence microscopy to date. We also propose 1400 nm long-pass detection in off-peak NIR-II imaging whose performance exceeds that of NIR-IIb imaging, using bright fluorophores with short emission wavelength.

Antioxidative and Immunomodulatory Activities of the Exopolysaccharides from Submerged Culture of Hen of the Woods or Maitake Culinary-Medicinal Mushroom, Grifola frondosa (Agaricomycetes) by Addition of Rhizoma gastrodiae Extract and Its Main Components.

Grifola frondosa (hen of the woods or maitake) is a famous culinary-medicinal mushroom, and its exopolysaccharides (EPSs) have biological activities with or without supplementation with exogenous additives. In this study, a Rhizoma gastrodiae extract was added to a G. frondosa fermentation system. P-hydroxylbenzaldehyde (HBA), the main product of R. gastrodiae, had the highest utilization rate in the fermentation process (42%). In addition, the EPSs of G. frondosa after addition of R. gastrodiae extract (REPS), of HBA (HEPS), or of a standard solution according to the main component ratio of R. gastrodiae extract (CEPS) were obtained. We then determined the antioxidant and immunomodulatory activities of EPS, REPS, HEPS, and CEPS. Overall, REPS showed the highest antioxidant activities compared with EPS and HEPS (P < 0.05) but similar to that of CEPS (P > 0.05). The half-inhibitory concentration (ED50) values of REPS (< 4 mg/mL) were lower than those of EPS, HEPS, and CEPS. Moreover, REPS was better able to stimulate phagocytosis and nitric oxide production of RAW 264.7 macrophages than were the others, without a significant difference from CEPS (P > 0.05). An interesting and important finding is that a R. gastrodiae extract can increase antioxidant and immunomodulatory activities of EPS preparations from G. frondosa, and the standard solution of the main components of the R. gastrodiae extract may be better for simulating fermentation performed by G. frondosa and biological activities of its major products.

Sensitive electrochemical detection of copper ions based on the copper(II) ion assisted etching of Au@Ag nanoparticles.

A new sensitive electrochemical sensor for the detection of copper ions based on the copper ion assisted etching of Au@Ag nanoparticles was developed in this work. Since copper ions could greatly catalyze the etching process of the silver shell of Au@Ag nanoparticles in the presence of thiosulfate solutions, leading to an obvious decrease of the linear sweep voltammetry (LSV) signals of silver, the concentration of the copper ions, therefore, can be measured. Under the optimized conditions, the electrochemical sensor exhibited excellent sensitivity and selectivity for Cu(2+), with wide linear ranges of 1 nM to 100 µM, and the detection limit of 0.3 nM. In addition, this method was successfully applied for the analysis of Cu(2+) in river water and exhibited good analytical performance.

Experimental analysis on the main contents of Rhizoma gastrodiae extract and inter-transformation throughout the fermentation process of Grifola frondosa.

Gastrodin (GA), p-hydroxylbenzaldehyde (HBA), p-hydroxybenzyl alcohol (gastrodigenin, HA) and parishin not only are the major active ingredients of Rhizoma gastrodiae, but exist transformed relations from each other throughout the fermentation process of Grifola frondosa in this work. We had found that parishin (non-free gastrodin) almost could completely transformed into gastrodin (GA, free gastrodin) after R. gastrodiae alcohol extract was sterilized by moist heat (121 °C, 30 min), but before was added into submerged cultivation of G. frondosa. However, interestingly and importantly, gastrodin re-synthesized of parishin after R. gastrodiae alcohol extract's addition into submerged cultivation of G. frondosa. In addition, the reduction of p-hydroxylbenzaldehyde and p-hydroxybenzyl alcohol in G. frondosa fermentation process reconfirmed that the G. frondosa strain 51616 really could synthesize gastrodin into parishin by submerged fermentation. This paper firstly also reported G. frondosa's effects on R. gastrodiae.

Enhancement of mycelial growth and polysaccharide production in Ganoderma lucidum (the Chinese medicinal fungus, 'Lingzhi') by the addition of ethanol.

Methanol, ethanol, 1-propanol and 2-propanol, at 1.5% (v/v), enhanced the growth and polysaccharide production of Ganoderma lucidum. Ethanol was the most effective at 1.5% (v/v) for increasing the biomass production, however, the maximal polysaccharide concentration was produced with 2% (v/v) ethanol in the medium. There was no new polysaccharide component produced by the addition of ethanol.