Microfluidic-Assisted Pneumatic Droplet Generators Designed for Multiscenario Biomanufacturing with Favorable Biocompatibility and Extendibility.

Droplets, tiny liquid compartments, are increasingly emerging in the biomedical and biomanufacturing fields due to their unique properties to serve as templates or independent reaction units. Currently, the straightforward and efficient generation of various functional droplets in a biofriendly manner remains challenging. Herein, a novel microfluidic-assisted pneumatic strategy is described for the customizable and high-throughput production of monodispersed droplets, and the droplet size can be precisely controlled via a simplified gas pressure regulation module. In particular, numerous uniform alginate microcarriers can be rapidly fabricated in an all-aqueous manner, wherein the encapsulated islet or liver cells exhibit favorable viability and biological functions. Furthermore, by changing the microchannel configuration, several fluid manipulation functions developed by microfluidic technology, such as mixing and laminar flow, can be successfully incorporated into this platform. The droplet generators with scalable functionality are demonstrated in many biomanufacturing scenarios, including on-demand distribution of cell-mimetic particles, continuous synthesis of biomedical metal-organic framework (MOF), controllable preparation of compartmental microgel, etc. These may provide sustainable inspiration for developing droplet generators and their applications in tissue and organ engineering, biomaterials design, bioprinting nozzles, and other fields.

Natural 7,8-secolignans from Schisandra sphenanthera fruit potently inhibit SARS-CoV-2 3CLpro and inflammation.

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), turned into a global pandemic, and there remains an urgent demand for specific/targeted drugs for the disease. The 3C-like protease (3CLpro) is a promising target for developing anti-coronavirus drugs. Schisandra sphenanthera fruit is a well-known traditional Chinese medicine (TCM) with good antiviral activity. This study found that the ethanolic extract displayed a significant inhibitory effect against SARS-CoV-2 3CLpro. Forty-four compounds were identified in this extract using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Combining molecular docking and in vitro experiments, we found that two epimeric 7,8-secolignans, rel-(1S,2R)-1-(3,4-dimethoxyphenyl)-2-methyl-3-oxobutyl-3,4-dimethoxybenzoate (2) and rel-(1S,2S)-1-(3,4-dimethoxyphenyl)-2-methyl-3-oxobutyl-3,4-dimethoxybenzoate (4), potently inhibited 3CLpro with IC50 values of 4.88 ± 0.60 µM and 4.75 ± 0.34 µM, respectively. Moreover, in vivo and in vitro experiments indicated that compounds 2 and 4 were potent in regulating the inflammatory response and preventing lung injury. Our findings indicate that compounds 2 and 4 may emerge as promising SARS-CoV-2 inhibitors via 3CLpro inhibition and anti-inflammatory mechanisms.

A Butyrate-Yielding Dietary Supplement Prevents Acute Alcoholic Liver Injury by Modulating Nrf2-Mediated Hepatic Oxidative Stress and Gut Microbiota.

Alcoholic liver disease (ALD) is a globally prevalent form of liver disease for which there is no effective treatment. Recent studies have found that a significant decrease in butyrate was closely associated with ALD development. Given the low compliance and delivery efficiency associated with oral-route butyrate administration, a highly effective butyrate-yielding dietary supplement, butyrylated high-amylose maize starch (HAMSB), is a good alternative approach. Here, we synthesized HAMSB, evaluated the effect of HAMSB on acute ALD in mice, compared its effect with that of oral administration of butyrate, and further studied the potential mechanism of action. The results showed HAMSB alleviated acute ALD in mice, as evidenced by the inhibition of hepatic-function impairment and the improvement in liver steatosis and lipid metabolism; in these respects, HAMSB supplementation was superior to oral sodium butyrate administration. These improvements can be attributed to the reduction of oxidative stress though the regulation of Nrf2-mediated antioxidant signaling in the liver and the improvement in the composition and function of microbiota in the intestine. In conclusion, HAMSB is a safe and effective dietary supplement for preventing acute ALD that could be useful as a disease-modifying functional food or candidate medicine.

Global hotspots and trends of nutritional supplements in sport and exercise from 2000 to 2024: a bibliometric analysis.

BACKGROUND: Nutritional supplements for sports and exercise (NSSE) can facilitate the exogenous replenishment of the body. This study provides the first extensive overview of NSSE research through bibliometric and visual analyses. METHODS: We searched the Web of Science Core Collection database for literature related to "NSSE" from 1st January 2000 to 8th March 2024. A total of 1744 articles were included. CiteSpace, VOSviewer, and Bibliometrix R package software were used to analyze the data. RESULTS: Research in the NSSE can be divided into steady growth, exponential growth, fluctuating stage, and surge stages. The United States is the most active country in this field. In recent years, the leading countries have been Croatia, Colombia, Slovenia, Chile, Egypt, China, and Thailand. The Australian Institute of Sports is the top research institution in terms of number of publications. Burke, LM from Australia published the most articles. Research in this area has primarily been published in Nutrients in Switzerland. The study population mainly consisted of men, and postmenopausal women were the main focus of the female group. Coronary heart and cardiovascular diseases continue to dominate research. CONCLUSION: Research on the NSSE is developing rapidly, with an annual growth trend. Insulin resistance, sports nutrition, inflammation, alpha-linolenic acid, limb strength performance, female sex, and gut microbiota are the focus of the current research and trends for future research. Future research should focus on improving the scientific training system for athletes and quality of training and life for the general public.

Hormetic responses to cadmium exposure in wheat seedlings: insights into morphological, physiological, and biochemical adaptations.

Cadmium is commonly recognized as toxic to plant growth, low-level Cd has promoting effects on growth performance, which is so-called hormesis. Although Cd toxicity in wheat has been widely investigated, knowledge of growth response to a broad range of Cd concentrations, especially extremely low concentrations, is still unknown. In this study, the morphological, physiological, and biochemical performance of wheat seedlings to a wide range of Cd concentrations (0-100 µΜ) were explored. Low Cd treatment (0.1-0.5 µM) improved wheat biomass and root development by enhancing the photosynthetic system and antioxidant system ability. Photosynthetic rate (Pn) was improved by 5.72% under lower Cd treatment (1 µΜ), but inhibited by 6.05-49.85% from 5 to 100 µΜ. Excessive Cd accumulation induced oxidative injury manifesting higher MDA content, resulting in lower photosynthetic efficiency, stunted growth, and reduction of biomass. Further, the contents of ascorbate, glutathione, non-protein thiols, and phytochelatins were improved under 5-100 µΜ Cd treatment. The ascorbate peroxidase activity in the leaf showed a hormetic dose-response characteristic. Correlation analysis and partial least squares (PLS) results indicated that antioxidant enzymes and metabolites were closely correlated with Cd tolerance and accumulation. The results of the element network, correlation analysis, and PLS showed a crucial role for exogenous Cd levels in K, Fe, Cu, and Mn uptake and accumulation. These results provided a deeper understanding of the hormetic effect of Cd in wheat, which would be beneficial for improving the quality of hazard and risk assessments.

Impact of Operator Experience on Left Atrial Appendage Occlusion Outcomes.

BACKGROUND: The relationship between long-term outcomes and operator experience for left atrial appendage occlusion (LAAO) is still unknown. OBJECTIVES: This study sought to explore the association between operator LAAO experience and one-year clinical outcomes. METHODS: The RECORD study (Registry to Evaluate Chinese Real-World Clinical Outcomes in Patients With AF Using the WATCHMAN Left Atrial Appendage Closure Technology; NCT03917563) was a multicenter, prospective registry that included patients with the WATCHMAN LAAO device (Boston Scientific) in China from April 1, 2019, to October 31, 2020. The current analyses included patients with solely LAAO from the registry; those who had concomitant LAAO and ablation/other procedures were excluded. The primary outcome was a composite endpoint of death, stroke, systemic embolism, and Bleeding Academic Research Consortium (BARC)-defined type 3 or 5 bleeding at 1 year. RESULTS: A total of 1,547 LAAO patients and 111 operators were included. The mean ± SD CHA2DS2-VASc and HAS-BLED scores of patients were 4.0 ± 1.8 and 2.5 ± 1.1, respectively. The mean ± SD age of operators was 47.0 ± 7.2 years, 15 (13.5%) were female, and 52 (46.8%) were electrophysiologists. Utilizing maximally selected log-rank statistics, the thresholds to categorize an experienced operator were performing ≥32 LAAOs annually or ≥134 LAAOs in total. Performing ≥32 LAAOs annually is the better criterion than ≥134 LAAOs in total (absolute net reclassification index: 25.79%; P < 0.001). Compared with the ≥32 LAAO annually group, the <32 group was associated with a 1.8-fold (HRadjusted: 1.79; 95% CI: 1.16-2.78; P = 0.009) increase in the risk of the primary endpoint, and such risk in the <32 group can be reduced by ∼12% after performing each additional 5 cases (HRadjusted per 5 cases: 0.88; 95% CI: 0.78-0.99; P = 0.033). CONCLUSIONS: Performing ≥32 LAAOs annually could be a threshold to categorize an experienced operator. Before reaching this threshold, the risk of death, stroke, systemic embolism, and BARC-defined type 3 or 5 bleeding decreased by 12% after every 5 cases performed.

Analysis of the primary factors influencing donor derived cell-free DNA testing in kidney transplantation.

The donor-derived cell-free DNA (ddcfDNA) is found in the plasma and urine of kidney transplant recipients and displays notable potential in diagnosing rejection, specifically antibody-mediated rejection (ABMR). Nonetheless, the quantitative methods of ddcfDNA lacking standardization and diverse detection techniques can impact the test outcomes. Besides, both the fraction and absolute values of ddcfDNA have been reported as valuable markers for rejection diagnosis, but they carry distinct meanings and are special in various pathological conditions. Additionally, ddcfDNA is highly sensitive to kidney transplant injury. The various sampling times and combination with other diseases can indeed impact ddcfDNA detection values. This review comprehensively analyses the various factors affecting ddcfDNA detection in kidney transplantation, including the number of SNPs and sequencing depths. Furthermore, different pathological conditions, distinct sampling time points, and the presence of complex heterologous signals can influence ddcfDNA testing results in kidney transplantation. The review also provides insights into ddcfDNA testing on different platforms along with key considerations.

Schisanhenol ameliorates non-alcoholic fatty liver disease via inhibiting miR-802 activation of AMPK-mediated modulation of hepatic lipid metabolism.

Non-alcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis, is a common metabolic liver disease worldwide. Currently, satisfactory drugs for NAFLD treatment remain lacking. Obesity and diabetes are the leading causes of NAFLD, and compounds with anti-obesity and anti-diabetic activities are considered suitable candidates for treating NAFLD. In this study, biochemical and histological assays revealed that a natural lignan schisanhenol (SAL) effectively decreased lipid accumulation and improved hepatic steatosis in free fatty acid (FFA)-treated HepG2 cells and high-fat diet (HFD)-induced NAFLD mice. Further, molecular analyses, microRNA (miRNA)-seq, and bioinformatics analyses revealed that SAL may improve NAFLD by targeting the miR-802/adenosine monophosphate-activated protein kinase (AMPK) pathway. Liver-specific overexpression of miR-802 in NAFLD mice significantly impaired SAL-mediated liver protection and decreased the protein levels of phosphorylated (p)-AMPK and PRKAB1. Dual-luciferase assay analysis further confirmed that miR-802 inhibits hepatic AMPK expression by binding to the 3' untranslated region of mouse Prkab1 or human PRKAA1. Additionally, genetic silencing of PRKAA1 blocked SAL-induced AMPK pathway activation in FFA-treated HepG2 cells. The results demonstrate that SAL is an effective drug candidate for treating NAFLD through regulating miR-802/AMPK-mediated lipid metabolism.

Lanthanide-doped upconversion nanoparticles as nanoprobes for bioimaging.

Upconversion nanoparticles (UCNPs) are a class of nanomaterials composed of lanthanide ions with great potential for paraclinical applications, especially in laboratory and imaging sciences. UCNPs have tunable optical properties and the ability to convert long-wavelength (low energy) excitation light into short-wavelength (high energy) emission in the ultraviolet (UV)-visible and near-infrared (NIR) spectral regions. The core-shell structure of UCNPs can be customized through chemical synthesis to meet the needs of different applications. The surface of UCNPs can also be tailored by conjugating small molecules and/or targeting ligands to achieve high specificity and selectivity, which are indispensable elements in biomedical applications. Specifically, coatings can enhance the water dispersion, biocompatibility, and efficiency of UCNPs, thereby optimizing their functionality and boosting their performance. In this context, multimodal imaging can provide more accurate in vivo information when combined with nuclear imaging. This article intends to provide a comprehensive review of the core structure, structure optimization, surface modification, and various recent applications of UCNPs in biomolecular detection, cell imaging, tumor diagnosis, and deep tissue imaging. We also present and discuss some of their critical challenges, limitations, and potential future directions.

Acyl-CoA synthetase 6 controls rod photoreceptor function and survival by shaping the phospholipid composition of retinal membranes.

The retina is light-sensitive neuronal tissue in the back of the eye. The phospholipid composition of the retina is unique and highly enriched in polyunsaturated fatty acids, including docosahexaenoic fatty acid (DHA). While it is generally accepted that a high DHA content is important for vision, surprisingly little is known about the mechanisms of DHA enrichment in the retina. Furthermore, the biological processes controlled by DHA in the eye remain poorly defined as well. Here, we combined genetic manipulations with lipidomic analysis in mice to demonstrate that acyl-CoA synthetase 6 (Acsl6) serves as a regulator of the unique composition of retinal membranes. Inactivation of Acsl6 reduced the levels of DHA-containing phospholipids, led to progressive loss of light-sensitive rod photoreceptor neurons, attenuated the light responses of these cells, and evoked distinct transcriptional response in the retina involving the Srebf1/2 (sterol regulatory element binding transcription factors 1/2) pathway. This study identifies one of the major enzymes responsible for DHA enrichment in the retinal membranes and introduces a model allowing an evaluation of rod functioning and pathology caused by impaired DHA incorporation/retention in the retina.

Guiding vector field and self-structuring learning network-based formation control of underactuated surface vessels in static obstacle environments with flexible performances.

To address the problem of underactuated surface vessel (USV) formation control in static obstacle environments with model uncertainties and time-varying external disturbances, a model-free formation control strategy is proposed in this paper. First, based on the guiding vector field (GVF), a composite GVF is developed to guide USV formation to the desired position and to avoid multiple static obstacles. Second, a flexible constraint strategy is introduced, and the constraint boundary conditions are appropriately relaxed to avoid singularities in the obstacle environment. Then, based on the Mexican hat wavelet function, the self-structuring fuzzy Mexican hat wavelet cerebellar model articulation controller (SCMAC), and a self-structuring fuzzy Mexican hat wavelet brain emotional learning controller (SBELC), are proposed to achieve model-free control. In addition, the self-structuring algorithm is embedded into SCMAC and SBELC to achieve autonomous optimization of the controller structure and to reduce the computational effort of the control system. The salient features in the proposed control strategy are as follows. First, the proposed model-free formation control strategy does not have to rely on accurate model information. Second, collisions are effectively avoided, and good control performance is guaranteed even under the influence of disturbances and static obstacles. Third, the proposed self-structuring algorithm achieves automatic construction of the controller structure. Finally, the signals in the control system are proven to be bounded, and the simulation results verify the feasibility and superiority of the proposed model-free control strategy.

Immunoinhibitory effects of hypoxia-driven reprogramming of EGR1hi and EGR3 positive B cells in the nasopharyngeal carcinoma microenvironment.

Regulatory B (Breg) cells is a type of immune cell that exhibit immunosuppressive behavior within the tumor microenvironment. However, the differentiation and regulatory mechanisms of these Breg cells remain unexplored. Single-cell transcriptome sequencing analysis of human nasopharyngeal carcinoma (NPC) revealed a significant enrichment of B cell subset characterized by high expression of EGR1 and EGR3 in the tumor microenvironment. Notably, in the hypoxic microenvironment, these B cells induce MAPK pathway activation, subsequently triggering the activation of transcription factors EGR1 and EGR3, which further modulate the expression of immunosuppressive factors like TGFB1 and IL10. In transplant experiments using primary B cells induced under hypoxia and co-transplanted with cancer cells, a significant increase in tumor growth was observed. Mechanism experiments demonstrated that EGR1hi and EGR3+ B cells further activate the maturation and immunosuppressive function of Treg cells through the secretion of IL16 and TNF-α. Hence, this study identifies the key transcription factors EGR1 and EGR3 as essential regulators and elucidates the differentiation of Breg cells under hypoxic conditions.

Standard: human intestine-on-a-chip.

Organs-on-chips are microphysiological systems that allow to replicate the key functions of human organs and accelerate the innovation in life sciences including disease modeling, drug development, and precision medicine. However, due to the lack of standards in their definition, structural design, cell source, model construction, and functional validation, a wide range of translational application of organs-on-chips remains a challenging. "Organs-on-chips: Intestine" is the first group standard on human intestine-on-a-chip in China, jointly agreed and released by the experts from the Chinese Society of Biotechnology on 29th April 2024. This standard specifies the scope, terminology, definitions, technical requirements, detection methods, and quality control in building the human intestinal model on a chip. The publication of this group standard will guide the institutional establishment, acceptance and execution of proper practical protocols and accelerate the international standardization of intestine-on-a-chip for translational applications.

Stability and chemical bonding in a series of inverse sandwich actinide boride clusters (An2B8) with δ bonding.

An inverse sandwich structure has been computationally predicted for uranium boride and extended to the series of actinide elements (An) from Th to Cm. The electronic structure and chemical bonding of these novel compounds have been analyzed using density functional theory and multireference wave-function based methods. We report the trends in electronic structure and bonding for An2B8, and found that (d-π)π and (d-p)δ are the most important factors in the stability of An2B8. The (f-p)δ bond provides extra stabilization for Pa2B8 and U2B8, owing to the extensive interactions of An-B8-An, resulting in a short distance for the Pa-Pa and U-U bonds.

GlyReShot: A glyph-aware model with label refinement for few-shot Chinese agricultural named entity recognition.

Chinese agricultural named entity recognition (NER) has been studied with supervised learning for many years. However, considering the scarcity of public datasets in the agricultural domain, exploring this task in the few-shot scenario is more practical for real-world demands. In this paper, we propose a novel model named GlyReShot, integrating the knowledge of Chinese character glyph into few-shot NER models. Although the utilization of glyph has been proven successful in supervised models, two challenges still persist in the few-shot setting, i.e., how to obtain glyph representations and when to integrate them into the few-shot model. GlyReShot handles the two challenges by introducing a lightweight glyph representation obtaining module and a training-free label refinement strategy. Specifically, the glyph representations are generated based on the descriptive sentences by filling the predefined template. As most steps come before training, this module aligns well with the few-shot setting. Furthermore, by computing the confidence values for draft predictions, the refinement strategy selectively utilizes the glyph information only when the confidence values are relatively low, thus mitigating the influence of noise. Finally, we annotate a new agricultural NER dataset and the experimental results demonstrate effectiveness of GlyReShot for few-shot Chinese agricultural NER.

DKPE-GraphSYN: a drug synergy prediction model based on joint dual kernel density estimation and positional encoding for graph representation.

Introduction: Synergistic medication, a crucial therapeutic strategy in cancer treatment, involves combining multiple drugs to enhance therapeutic effectiveness and mitigate side effects. Current research predominantly employs deep learning models for extracting features from cell line and cancer drug structure data. However, these methods often overlook the intricate nonlinear relationships within the data, neglecting the distribution characteristics and weighted probability densities of gene expression data in multi-dimensional space. It also fails to fully exploit the structural information of cancer drugs and the potential interactions between drug molecules. Methods: To overcome these challenges, we introduce an innovative end-to-end learning model specifically tailored for cancer drugs, named Dual Kernel Density and Positional Encoding (DKPE) for Graph Synergy Representation Network (DKPEGraphSYN). This model is engineered to refine the prediction of drug combination synergy effects in cancer. DKPE-GraphSYN utilizes Dual Kernel Density Estimation and Positional Encoding techniques to effectively capture the weighted probability density and spatial distribution information of gene expression, while exploring the interactions and potential relationships between cancer drug molecules via a graph neural network. Results: Experimental results show that our prediction model achieves significant performance enhancements in forecasting drug synergy effects on a comprehensive cancer drug and cell line synergy dataset, achieving an AUPR of 0.969 and an AUC of 0.976. Discussion: These results confirm our model's superior accuracy in predicting cancer drug combinations, providing a supportive method for clinical medication strategy in cancer.

An Integrated Optogenetic and Bioelectronic Platform for Regulating Cardiomyocyte Function.

Bioelectronic medicine is emerging as a powerful approach for restoring lost endogenous functions and addressing life-altering maladies such as cardiac disorders. Systems that incorporate both modulation of cellular function and recording capabilities can enhance the utility of these approaches and their customization to the needs of each patient. Here is report an integrated optogenetic and bioelectronic platform for stable and long-term stimulation and monitoring of cardiomyocyte function in vitro. Optical inputs are achieved through the expression of a photoactivatable adenylyl cyclase, that when irradiated with blue light causes a dose-dependent and time-limited increase in the secondary messenger cyclic adenosine monophosphate with subsequent rise in autonomous cardiomyocyte beating rate. Bioelectronic readouts are obtained through a multi-electrode array that measures real-time electrophysiological responses at 32 spatially-distinct locations. Irradiation at 27 µW mm-2 results in a 14% elevation of the beating rate within 20-25 min, which remains stable for at least 2 h. The beating rate can be cycled through "on" and "off" light states, and its magnitude is a monotonic function of irradiation intensity. The integrated platform can be extended to stretchable and flexible substrates, and can open new avenues in bioelectronic medicine, including closed-loop systems for cardiac regulation and intervention, for example, in the context of arrythmias.

Erratum: Long noncoding RNAs heat shock RNA omega nucleates TBPH and promotes intestinal stem cell differentiation upon heat shock.

[This corrects the article DOI: 10.1016/j.isci.2024.109732.].

Direct potentiometric bicarbonate/carbon dioxide sensing based on polymeric membranes doped with selective meso-bisubstituted calix[4]pyrrole ionophores.

We evaluated in this work the properties of a promising class of HCO3- ionophores, which have not been recognized previously. Three types of neutral or charged calix[4]pyrroles with meso-bisubstituted groups were evaluated as ionophores for polymeric membrane HCO3- selective electrodes. Optimizing membrane components, such as ionophores, lipophilic additives and plasticizers, yielded ISEs exhibiting Nernstian response to HCO3- with improved linear range and detection limits, while the selectivity sequence differs significantly from the Hofmeister series. Interference from important biological and environmental species was reduced significantly, especially that from SCN-, NO3-, Br- and Cl-, which are always at high concentrations in related samples. In order to provide more insights into the properties of the ionophores and performance of the proposed ISEs, the stability constants of anion-ionophore complexes in the membrane phase were determined. Studies on the influence of the sample solution pH demonstrated that the proposed ISEs can be employed in a wide pH range of 3.0-9.0 with fast response (<30 s), good reversibility and long shelf life. Moreover, the proposed ISEs were used to quantify the concentration of HCO3- and dissolved CO2 in mineral and beverage samples with good recoveries.