Fluorogenic chemical tools to shed light on CES1-mediated adverse drug interactions.

Studying factors that cause interindividual variability of carboxylesterase 1 (CES1) activity is currently difficult due to limited methods. Here, fluorogenic tools for measuring CES1 activity are developed and demonstrated to report on these factors in living cells. These tools enable experiments that will develop a deeper understanding of CES1 metabolism.

The CCT chaperonin and actin modulate the ER and RNA-binding protein condensation during oogenesis and maintain translational repression of maternal mRNA and oocyte quality.

The regulation of maternal mRNAs is essential for proper oogenesis, the production of viable gametes, and to avoid birth defects and infertility. Many oogenic RNA-binding proteins have been identified with roles in mRNA metabolism, some of which localize to dynamic ribonucleoprotein granules and others that appear dispersed. Here, we use a combination of in vitro condensation assays and the in vivo Caenorhabditis elegans oogenesis model to characterize the properties of the conserved KH-domain MEX-3 protein and to identify novel regulators of MEX-3 and three other translational regulators. We demonstrate that MEX-3 undergoes phase separation and appears to have intrinsic gel-like properties in vitro. We also identify novel roles for the chaperonin-containing tailless complex polypeptide 1 (CCT) chaperonin and actin in preventing ectopic RNA-binding protein condensates in maturing oocytes that appear to be independent of MEX-3 folding. The CCT chaperonin and actin also oppose the expansion of endoplasmic reticulum sheets that may promote ectopic condensation of RNA-binding proteins. These novel regulators of condensation are also required for the translational repression of maternal mRNA which is essential for oocyte quality and fertility. The identification of this regulatory network may also have implications for understanding the role of hMex3 phase transitions in cancer.

The CCT chaperonin and actin modulate the ER and RNA-binding protein condensation during oogenesis to maintain translational repression of maternal mRNA and oocyte quality.

The regulation of maternal mRNAs is essential for proper oogenesis, the production of viable gametes, and to avoid birth defects and infertility. Many oogenic RNA-binding proteins have been identified with roles in mRNA metabolism, some of which localize to dynamic ribonucleoprotein granules and others that appear dispersed. Here, we use a combination of in vitro condensation assays and the in vivo C. elegans oogenesis model to determine the intrinsic properties of the conserved KH-domain MEX-3 protein and to identify novel regulators of MEX-3 and the Lsm protein, CAR-1. We demonstrate that MEX-3 undergoes liquid-liquid phase separation and appears to have intrinsic gel-like properties in vitro . We also identify novel roles for the CCT chaperonin and actin in preventing ectopic RNA-binding protein condensates in maturing oocytes that appear to be independent of MEX-3 folding. CCT and actin also oppose the expansion of ER sheets that may promote ectopic condensation of RNA-binding proteins that are associated with de-repression of maternal mRNA. This regulatory network is essential to preserve oocyte quality, prevent infertility, and may have implications for understanding the role of hMex3 phase transitions in cancer. Significance statement: The molecular mechanisms that regulate phase transitions of oogenic RNA-binding proteins are critical to elucidate but are not fully understood.We identify novel regulators of RNA-binding protein phase transitions in maturing oocytes that are required to maintain translational repression of maternal mRNAs and oocyte quality.This study is the first to elucidate a regulatory network involving the CCT chaperonin, actin, and the ER for phase transitions of RNA-binding proteins during oogenesis. Our findings for the conserved MEX-3 protein may also be applicable to better understanding the role of hMex3 phase transitions in cancer.

SrTiO3 Nanotube-Based "Pneumatic Nanocannon" for On-Demand Delivery of Antibacterial and Sustained Osseointegration Enhancement.

Infection and aseptic loosening caused by bacteria and poor osseointegration remain serious challenges for orthopedic implants. The advanced surface modification of implants is an effective strategy for addressing these challenges. This study presents a "pneumatic nanocannon" coating for titanium orthopedic implants to achieve on-demand release of antibacterial and sustained release of osteogenic agents. SrTiO3 nanotubes (SrNT) were constructed on the surface of Ti implants as "cannon barrel," the "cannonball" (antibiotic) and "propellant" (NH4HCO3) were codeposited into SrNT with assistance of mussel-inspired copolymerization of dopamine and subsequently sealed by a layer of polydopamine. The encapsulated NH4HCO3 within the nanotubes could be thermally decomposed into gases under near-infrared irradiation, propelling the on-demand delivery of antibiotics. This coating demonstrated significant efficacy in eliminating typical pathogenic bacteria both in planktonic and biofilm forms. Additionally, this coating exhibited a continuous release of strontium ions, which significantly enhanced the osteogenic differentiation of preosteoblasts. In an implant-associated infection rat model, this coating demonstrated substantial antibacterial efficiency (>99%) and significant promotion of osseointegration, along with alleviated postoperative inflammation. This pneumatic nanocannon coating presents a promising approach to achieving on-demand infection inhibition and sustained osseointegration enhancement for titanium orthopedic implants.

A Highly Reversible Sn-Air Battery Possessing the Ultra-Low Charging Potential with the Assistance of Light.

Aqueous Sn-air batteries are attracting a great deal of interest in recent years due to the ultra-high safety, low cost, dendrite-free and highly reversible Sn anode. However, the slurry oxygen reduction/evolution reaction (ORR/OER) kinetics on the air cathodes seriously affect the Sn-air battery performances. Although various advanced catalysts have been developed, the charge overpotentials (~1000 mV) of these Sn-air batteries are still not satisfactory. Herein, iron oxide (Fe2O3) modified titanium dioxide (TiO2) nanorods with heterogeneous structure are firstly synthesized on Ti mesh (Fe2O3@TiO2/Ti), and the obtained Fe2O3@TiO2/Ti films are further applied as catalytic electrodes for Sn-air batteries. The core-shell heterogeneous structure of Fe2O3@TiO2/Ti can effectively facilitate the conversion of electrochemical intermediates and separation of photo-excited electrons and holes to activate oxygen-related reaction processes. Density functional theory (DFT) and experimental results also confirm that Fe2O3@TiO2/Ti can not only act as the electrocatalysts to improve ORR/OER properties, but also exhibit the superior photo-catalytic activity to promote charging kinetics. Hence, the Fe2O3@TiO2/Ti-based Sn-air batteries show ultra-low overpotential of ~40 mV, excellent rate capability and good cycling stability under light irradiation. This work will shed light on rational photo-assisted catalytic cathode design for new-type metal-air batteries.

Advance in Hippophae rhamnoides polysaccharides: Extraction, structural characteristics, pharmacological activity, structure-activity relationship and application.

Hippophae rhamnoides (Sea buckthorn) is an excellent medicinal and edible plant owing to its high nutritional and health-promoting properties. As an important bioactive component, H. rhamnoides polysaccharides (HRPs) have aroused wide attention due to their various pharmacological activities, including hepatoprotective, immuno-modulatory, anti-inflammatory, anti-oxidant, anti-tumor, hypoglycemic, anti-obesity, and so on. Nevertheless, the development and utilization of HRP-derived functional food and medicines are constrained to a lack of comprehensive understanding of the structure-activity relationship, application, and safety of HRPs. This review systematically summarizes the advancements on the extraction, purification, structural characteristics, pharmacological activities and mechanisms of HRPs. The structure-activity relationship, safety evaluation, application, as well as the shortcomings of current research and promising prospects are also highlighted. This article aims to offer a comprehensive understanding of HRPs and lay a groundwork for future research and utilization of HRPs as multifunctional biomaterials and therapeutic agents.

The conversion of monolignans to sesquilignans and dilignans is closely correlated to the regulation of Arctium lappa seed germination.

MAIN CONCLUSION: The secondary metabolic conversion of monolignans to sesquilignans/dilignans was closely related to seed germination and seedling establishment in Arctium lappa. Arctium lappa plants are used as a kind of traditional Chinese medicines for nearly 1500 years, and so far, only a few studies have put focus on the key secondary metabolic changes during seed germination and seedling establishment. In the current study, a combined approach was used to investigate the correlation among secondary metabolites, plant hormone signaling, and transcriptional profiles at the early critical stages of A. lappa seed germination and seedling establishment. Of 50 metabolites in methonolic extracts of A. lappa samples, 35 metabolites were identified with LC-MS/MS and 15 metabolites were identified with GC-MS. Their qualitative properties were examined according to the predicted chemical structures. The quantitative analysis was performed for deciphering their metabolic profiles, discovering that the secondary metabolic conversion from monolignans to sesquilignans/dilignans was closely correlated to the initiation of A. lappa seed germination and seedling establishment. Furthermore, the critical transcriptional changes in primary metabolisms, translational regulation at different cellular compartments, and multiple plant hormone signaling pathways were revealed. In addition, the combined approach provides unprecedented insights into key regulatory mechanisms in both gene transcription and secondary metabolites besides many known primary metabolites during seed germination of an important traditional Chinese medicinal plant species. The results not only provide new insights to understand the regulation of key medicinal components of 'ARCTII FRUCTUS', arctiin and arctigenin at the stages of seed germination and seedling establishment, but also potentially spur the development of seed-based cultivation in A. lappa plants.

Toxicity, physiological response, and biosorption mechanism of Dunaliella salina to copper, lead, and cadmium.

Background: Heavy metal pollution has become a global problem, which urgently needed to be solved owing to its severe threat to water ecosystems and human health. Thus, the exploration and development of a simple, cost-effective and environmental-friendly technique to remove metal elements from contaminated water is of great importance. Algae are a kind of photosynthetic autotroph and exhibit excellent bioadsorption capacities, making them suitable for wastewater treatment. Methods: The effects of heavy metals (copper, lead and cadmium) on the growth, biomolecules accumulation, metabolic responses and antioxidant response of Dunaliella salina were investigated. Moreover, the Box-Behnken design (BBD) in response surface methodology (RSM) was used to optimize the biosorption capacity, and FT-IR was performed to explore the biosorption mechanism of D. salina on multiple heavy metals. Results: The growth of D. salina cells was significantly inhibited and the contents of intracellular photosynthetic pigments, polysaccharides and proteins were obviously reduced under different concentrations of Cu2+, Pb2+ and Cd2+, and the EC50 values were 18.14 mg/L, 160.37 mg/L and 3.32 mg/L at 72 h, respectively. Besides, the activities of antioxidant enzyme SOD and CAT in D. salina first increased, and then descended with increasing concentration of three metal ions, while MDA contents elevated continuously. Moreover, D. salina exhibited an excellent removal efficacy on three heavy metals. BBD assay revealed that the maximal removal rates for Cu2+, Pb2+, and Cd2+ were 88.9%, 87.2% and 72.9%, respectively under optimal adsorption conditions of pH 5-6, temperature 20-30°C, and adsorption time 6 h. Both surface biosorption and intracellular bioaccumulation mechanisms are involved in metal ions removal of D. salina. FT-IR spectrum exhibited the main functional groups including carboxyl (-COOH), hydroxyl (-OH), amino (-NH2), phosphate (-P=O) and sulfate (-S=O) are closely associated with the biosorption or removal of heavy metalsions. Discussion: Attributing to the brilliant biosorption capacity, Dunaliella salina may be developed to be an excellent adsorbent for heavy metals.

Engineering tumor-oxygenated nanomaterials: advancing photodynamic therapy for cancer treatment.

Photodynamic therapy (PDT), a promising treatment modality, employs photosensitizers to generate cytotoxic reactive oxygen species (ROS) within localized tumor regions. This technique involves administering a photosensitizer followed by light activation in the presence of oxygen (O2), resulting in cytotoxic ROS production. PDT's spatiotemporal selectivity, minimally invasive nature, and compatibility with other treatment modalities make it a compelling therapeutic approach. However, hypoxic tumor microenvironment (TME) poses a significant challenge to conventional PDT. To overcome this hurdle, various strategies have been devised, including in-situ O2 generation, targeted O2 delivery, tumor vasculature normalization, modulation of mitochondrial respiration, and photocatalytic O2 generation. This review aims to provide a comprehensive overview of recent developments in designing tumor-oxygenated nanomaterials to enhance PDT efficacy. Furthermore, we delineate ongoing challenges and propose strategies to improve PDT's clinical impact in cancer treatment.

A novel antigenic epitope identified on the accessory protein NS6 of porcine deltacoronavirus.

Porcine deltacoronavirus (PDCoV) is a novel enteric coronavirus that can cause vomiting, watery diarrhea in pigs and the death of piglets. The open reading frame (ORF) 5 is one of the accessory genes in PDCoV genome and encodes an accessory protein NS6. To date, the function of NS6 is still unclear. In this study, the recombinant NS6 was successfully expressed in prokaryotic expression system and purified. To prepare monoclonal antibody (mAb), six-week-old female BALB/c mice were primed subcutaneously with purified NS6. A novel mouse mAb against NS6 was obtained and designated as 3D5. The isotype of 3D5 is IgG2b with kappa (κ) light chain. 3D5 can specifically recognizes the natural NS6 in swine testis (ST) cells infected with PDCoV and expressed NS6 in human embryonic kidney 293T (HEK 293T) cells transfected with mammalian vector. The minimal linear B cell epitope recognised by 3D5 on NS6 was 25VPELIDPLVK34 determined by peptide scanning and named EP-3D5. The sequence of EP-3D5 is completely conserved among PDCoV strains. Moreover, six to nine residues of EP-3D5 were identified to be conserved in non-PDCoV strains. These results provide valuable insights into the antigenic structure and function of NS6 in virus pathogenesis, and aid for the development of PDCoV epitope-associated diagnostics and vaccine design.

Towards a Deeper Understanding of Global Covariance Pooling in Deep Learning: An Optimization Perspective.

Global covariance pooling (GCP) as an effective alternative to global average pooling has shown good capacity to improve deep convolutional neural networks (CNNs) in a variety of vision tasks. Although promising performance, it is still an open problem on how GCP (especially its post-normalization) works in deep learning. In this paper, we make the effort towards understanding the effect of GCP on deep learning from an optimization perspective. Specifically, we first analyze behavior of GCP with matrix power normalization on optimization loss and gradient computation of deep architectures. Our findings show that GCP can improve Lipschitzness of optimization loss and achieve flatter local minima, while improving gradient predictiveness and functioning as a special pre-conditioner on gradients. Then, we explore the effect of post-normalization on GCP from the model optimization perspective, which encourages us to propose a simple yet effective normalization, namely DropCov. Based on above findings, we point out several merits of deep GCP that have not been recognized previously or fully explored, including faster convergence, stronger model robustness and better generalization across tasks. Extensive experimental results using both CNNs and vision transformers on diversified vision tasks provide strong support to our findings while verifying the effectiveness of our method.

Investigation of the Charge Accumulation Based on Stiffness Variation of the Micro-Shell Resonator Gyroscope.

In capacitive microelectromechanical system (MEMS) devices, the application of dielectric materials causes long-term charging problems in the dielectric layers or substrates, which especially affect the repeatability and stability of high-performance devices. Due to the difficulties of observation and characterization of charge accumulation, an accurate characterization method is needed to study the effect of charge and propose suppression methods. In this paper, we analyze the influence of charge accumulation on the MSRG and propose a characterization method for charge accumulation based on stiffness variation. Experiments are carried out to characterize the charge accumulation in MSRG, and the effect of temperature on the process is also investigated. In the experiment, the charge accumulation is characterized accurately by the variation of the frequency split and stiffness axes. Furthermore, the acceleration of the charge accumulation is observed at high temperatures, as is the higher additional voltage from the charge accumulation.

An Ultrasonic Target Detection System Based on Piezoelectric Micromachined Ultrasonic Transducers.

In this paper, an ultrasonic target detection system based on Piezoelectric Micromachined Ultrasonic Transducers (PMUTs) is proposed, which consists of the PMUTs based ultrasonic sensor and the sensor system. Two pieces of 3 × 3 PMUTs arrays with the resonant frequency of 115 kHz are used as transmitter and receiver of the PMUTs-based ultrasonic sensor. Then, the sensor system can calculate the target's position through the signal received by the above receiver. The static and dynamic performance of the proposed prototype system are characterized on black, white, and transparent targets. The experiment results demonstrated that the proposed system can detect targets of different colors, transparencies, and motion states. In the static experiments, the static location errors of the proposed system in the range of 200 mm to 320 mm are 0.51 mm, 0.50 mm and 0.53 mm, whereas the errors of a commercial laser sensor are 2.89 mm, 0.62 mm, and N\A. In the dynamic experiments, the experimental materials are the targets with thicknesses of 1 mm, 1.5 mm, 2 mm and 2.5 mm, respectively. The proposed system can detect the above targets with a maximum detection error of 4.00%. Meanwhile, the minimum resolution of the proposed system is about 0.5 mm. Finally, in the comprehensive experiments, the proposed system successfully guides a robotic manipulator to realize the detecting, grasping, and moving of a transparent target with 1 mm. This ultrasonic target detection system has demonstrated a cost-effective method to detect targets, especially transparent targets, which can be widely used in the detection and transfer of glass substrates in automated production lines.

A High-Sensitivity Bowel Sound Electronic Monitor Based on Piezoelectric Micromachined Ultrasonic Transducers.

Bowel sounds contain some important human physiological parameters which can reflect information about intestinal function. In this work, in order to realize real-time monitoring of bowel sounds, a portable and wearable bowel sound electronic monitor based on piezoelectric micromachined ultrasonic transducers (PMUTs) is proposed. This prototype consists of a sensing module to collect bowel sounds and a GUI (graphical user interface) based on LabVIEW to display real-time bowel sound signals. The sensing module is composed of four PMUTs connected in parallel and a signal conditioning circuit. The sensitivity, noise resolution, and non-linearity of the bowel sound monitor are measured in this work. The result indicates that the designed prototype has high sensitivity (-142.69 dB), high noise resolution (50 dB at 100 Hz), and small non-linearity. To demonstrate the characteristic of the designed electronic monitor, continuous bowel sound monitoring is performed using the electronic monitor and a stethoscope on a healthy human before and after a meal. Through comparing the experimental results and analyzing the signals in the time domain and frequency domain, this bowel sound monitor is demonstrated to record bowel sounds from the human intestine. This work displays the potential of the sensor for the daily monitoring of bowel sounds.

UniTVelo: temporally unified RNA velocity reinforces single-cell trajectory inference.

The recent breakthrough of single-cell RNA velocity methods brings attractive promises to reveal directed trajectory on cell differentiation, states transition and response to perturbations. However, the existing RNA velocity methods are often found to return erroneous results, partly due to model violation or lack of temporal regularization. Here, we present UniTVelo, a statistical framework of RNA velocity that models the dynamics of spliced and unspliced RNAs via flexible transcription activities. Uniquely, it also supports the inference of a unified latent time across the transcriptome. With ten datasets, we demonstrate that UniTVelo returns the expected trajectory in different biological systems, including hematopoietic differentiation and those even with weak kinetics or complex branches.

Breast microecology improvement using probiotics following needle aspiration in patients with lactational breast abscess: a multi-center randomized double-blind controlled trial.

Although oral probiotics can improve breast microecology and alleviate the inflammatory response, there are no data regarding cases with existing abscesses. We aimed to investigate the effect of Lactobacillus fermentum CECT5716 during needle aspiration in patients with lactational breast abscesses. Patients (aged 20-41 years) with lactational single-cavity breast abscesses (diameter 3-6 cm) from 12 hospitals were randomly assigned to the experimental (n = 51) and control groups (n = 50). Outcome measures included the abscess cure rate on treatment day-5, delactation rate, relieving pain rate, and number of needle aspirations until day-28. The experimental group's 5-day cure rate (43.1%) was significantly higher (p < 0.05). Breastfeeding continuation on day-5 did not differ significantly (experimental group: 88.2%, control group: 96.0%, p = 0.269). In the experimental and control groups, 19.6% and 14.0% of patients experienced moderate to severe pain on day-5, respectively, with no statistically significant differences (p = 0.451). Four patients in each group developed diarrhea, with adverse reaction rates of 7.84% and 8.0%, respectively. No adverse reactions were reported in the infants. L. fermentum can shorten the healing time in patients with lactational breast abscesses.Trial registration This study was registered in the Chinese Clinical Trial Registry ( http://www.chictr.org.cn ), registration number: ChiCTR2000032682, registration date: 6/May/ 2020; first entry date: 11/May/2020.

Studying the Interfacial Properties of Carbon/Glass Hybrid Composites via the Nanoindentation Method.

The mechanical properties of hybrid composite interfaces are critical in determining the overall properties of composite materials. To investigate the mechanical performance of hybrid composite interfaces, an accurate and efficient method must be developed. In this work, nanoindentation is used in this work to investigate the mechanical performance of the carbon/glass interface and the influence of the distance between carbon and the glass fibers on the modulus of the thermoset matrix. The results show that the interface sizes around the carbon and glass fibers are around 1.5 and 2.0 µm, respectively. The modulus around the carbon fibers is 5-11 GPa without the fiber effect, while that around the glass fibers is 4-10 GPa. The modulus of the matrix is not affected by the two types of fibers when the distance between them is greater than 4.5 µm.

Nonlinear Conductivity and Space Charge Characteristics of SiC/Silicone Rubber Nanocomposites.

To achieve a preferable compatibility between liquid silicone rubber (LSR) and cable main insulation in a cable accessory, we developed SiC/LSR nanocomposites with a significantly higher conductivity nonlinearity than pure LSR, whilst representing a notable improvement in space charge characteristics. Space charge distributions in polarization/depolarization processes and surface potentials of SiC/LSR composites are analyzed to elucidate the percolation conductance and charge trapping mechanisms accounting for nonlinear conductivity and space charge suppression. It is verified that SiC/LSR composites with SiC content higher than 10 wt% represent an evident nonlinearity of electric conductivity as a function of the electric field strength. Space charge accumulations can be inhibited by filling SiC nanoparticles into LSR, as illustrated in both dielectric polarization and depolarization processes. Energy level and density of shallow traps increase significantly with SiC content, which accounts for expediting carrier hopping transport and surface charge decay. Finite-element multiphysics simulations demonstrate that nonlinear conductivity acquired by 20 wt% SiC/LSR nanocomposite could efficiently homogenize an electric field distributed in high-voltage direct current (HVDC) cable joints. Nonlinear conductivities and space charge characteristics of SiC/LSR composites discussed in this paper suggest a feasible modification strategy to improve insulation performances of direct current (DC) cable accessories.

Carbonate-Based Fluorescent Chemical Tool for Uncovering Carboxylesterase 1 (CES1) Activity Variations in Live Cells.

Carboxylesterase 1 (CES1) plays a key role in the metabolism of endogenous biomolecules and xenobiotics including a variety of pharmaceuticals. Despite the established importance of CES1 in drug metabolism, methods to study factors that can vary CES1 activity are limited with only a few suitable for use in live cells. Herein, we report the development of FCP1, a new CES1 specific fluorescent probe with a unique carbonate substrate constructed from commercially available reagents. We show that FCP-1 can specifically report on endogenous CES1 activity with a robust fluorescence response in live HepG2 cells through studies with inhibitors and genetic knockdowns. Subsequently, we deployed FCP-1 to develop a live cell fluorescence microscopy-based approach to identify activity differences between CES1 isoforms. To the best of our knowledge, this is the first application of a fluorescent probe to measure the activity of CES1 sequence variants in live cells.

Human carboxylesterases and fluorescent probes to image their activity in live cells.

Human carboxylesterases (CESs) are serine hydrolases that are responsible for the phase I metabolism of an assortment of ester, amide, thioester, carbonate, and carbamate containing drugs. CES activity is known to be influenced by a variety of factors including single nucleotide polymorphisms, alternative splicing, and drug-drug interactions. These different factors contribute to interindividual variability of CES activity which has been demonstrated to influence clinical outcomes among people treated with CES-substrate therapeutics. Detailed exploration of the factors that influence CES activity is emerging as an important area of research. The use of fluorescent probes with live cell imaging techniques can selectively visualize the real-time activity of CESs and have the potential to be useful tools to help reveal the impacts of CES activity variations on human health. This review summarizes the properties of the five known human CESs including factors reported to or that could potentially influence their activity before discussing the design aspects and use considerations of CES fluorescent probes in general in addition to highlighting several well-characterized probes.