Hydrogen Isotope Effect Endows a Breakthrough in Photoluminescent Covalent Organic Frameworks.

Luminescent covalent organic frameworks (LCOFs) have emerged as indispensable candidates in various applications due to their greater tunable emitting properties and structural robustness compared to small molecule emitters. An unsolved issue in this area is developing highly luminescent LCOFs of which the nonradiative quenching pathways were suppressed as much as possible. Here, a robust aminal-linked COF (DD-COF) possessing perdeuterated light-emitting monomers was designed and synthesized. The solid-state photoluminescence quantum yield of the DD-COF reaches 81%, significantly outcompeting all state-of-the-art LCOFs reported so far. The exceptional luminescent efficiency is attributed to the inhibition of different pathways of nonradiative decay, especially from bond vibrations where only substitution by a heavier isotope with a lower zero-point vibration frequency works. Furthermore, the prepared deuterated COF not only boosts higher photostability under UV irradiation but also enables superior fluorescence sensing performance for iodine detection compared to nondeuterated COF.

A Fully Elastic Wearable Electrochemical Sweat Detection System of Tree-Bionic Microfluidic Structure for Real-Time Monitoring.

Fresh sweat contains a diverse range of physiological indicators that can effectively reflect changes in the body. However, existing wearable sweat detection systems face challenges in efficiently collecting and detecting fresh sweat in real-time. Additionally, they often lack the necessary deformation capabilities, resulting in discomfort for the wearer. Here, a fully elastic wearable electrochemical sweat detection system is developed that integrates a sweat-collecting microfluidic chip, a multi-parameter electrochemical sensor, a micro-heater, and a sweat detection elastic circuit board system. The unique tree-bionic structure of the microfluidic chip significantly enhances the efficiency of fresh sweat collection and discharge, enabling real-time detection by the electrochemical sensors. The sweat multi-parameter electrochemical sensor offers high-precision and high-sensitivity measurements of sodium ions, potassium ions, lactate, and glucose. The electronic system is built on an elastic circuit board that matches perfectly to wrinkled skin, ensuring improved wearing comfort and enabling multi-channel data sampling, processing, and wireless transmission. This state-of-the-art system represents a significant advancement in the field of elastic wearable sweat detection and holds promising potential for extending its capabilities to the detection of other sweat markers or various wearable applications.

The Evolution of Microfluidic-Based Drug-Loading Techniques for Cells and Their Derivatives.

Conventional drug delivery techniques face challenges related to targeting and adverse reactions. Recent years have witnessed significant advancements in nanoparticle-based drug carriers. Nevertheless, concerns persist regarding their safety and insufficient metabolism. Employing cells and their derivatives, such as cell membranes and extracellular vesicles (EVs), as drug carriers effectively addresses the challenges associated with nanoparticle carriers. However, an essential hurdle remains in efficiently loading drugs into these carriers. With the advancement of microfluidic technology and its advantages in precise manipulation at the micro- and nanoscales, as well as minimal sample loss, it has found extensive application in the loading of drugs using cells and their derivatives, thereby fostering the development of drug-loading techniques. This paper outlines the characteristics and benefits of utilizing cells and their derivatives as drug carriers and provides an overview of current drug-loading techniques, particularly those rooted in microfluidic technology. The significant potential for microfluidic technology in targeted disease therapy through drug delivery systems employing cells and their derivatives, is foreseen.

Thermoelectric response of single quintuple layer sodium copper chalcogenides persisting at high temperature.

The thermoelectric transport properties of two-dimensional (2D) layered NaCuX (X = S, Se) are investigated by employing first-principles based Boltzmann transport theory. Single quintuple NaCuX layers have a relatively large Seebeck coefficient (S), electrical conductivity (σ) and hence power factor (PF = S2σ) for a p-type heavy doped region due to the valence band degeneracy. The largely reduced σ by dominant polar scattering leads to a PF up to 0.27 and 0.84 mW m-1 K-2 at 1200 K for p-type NaCuS and NaCuSe monolayers, respectively. The high polarizability of the Cu-X bonds in the CuX4 tetrahedra leads to anharmonic phonon behavior which produces an intrinsic lattice thermal conductivity (κl) as low as 1.03 and 0.75 W m-1 K-1 at 300 K for NaCuS and NaCuSe, respectively. The predicted figure of merit (zT) increases monotonically from around 0.25 at 300 K to 2.01 at 1200 K at an optimal carrier density of around 1 × 1013 cm-2 for p-type NaCuSe and from around 0.09 at 300 K to 1.15 at 1200 K at an optimal carrier density of around 1 × 1014 cm-2 for p-type NaCuS. These findings indicate that the NaCuS, especially NaCuSe, monolayers are promising 2D thermoelectric materials persisting at high temperature.

Thermoelectric response of Janus monolayer M2P2S3Se3 (M = Zn and Cd).

Thermoelectric transport properties of Janus monolayers M2P2S3Se3 (M = Zn and Cd) are investigated by the first-principles based transport theory. The Zn2P2S3Se3 and Cd2P2S3Se3 monolayers are indirect-gap semiconductors. The high polarizability of M-Se/S bonds in the MS3Se3 distorted octahedrons leads to anharmonic phonon behavior, which produces an intrinsic lattice thermal conductivity (κl) as low as 1.06 and 1.99 W m-1 K-1 at 300 K for Zn2P2S3Se3 and Cd2P2S3Se3 monolayers, respectively. The lower κl of the Zn2P2S3Se3 monolayer is mainly attributed to more pronounced flat modes of the phonon dispersion in a frequency range of 1-1.7 THz caused by the softer Zn-Se/S bonds. The polar optical phonon scattering of carriers surprisingly plays a dominant role in carrier transport of both the monolayers, which greatly suppresses the electrical conductivity and thereby the power factor by about an order of magnitude. The predicted figure of merit (zT) increases monotonically with the temperature at the optimal carrier density, and at the operating temperature of 1200 K, it reaches an optimal value of 0.86 at an optimal electron density of ∼1.5×1013 cm-2 for the n-type Zn2P2S3Se3 monolayer and 0.30 at an optimal electron density of ∼7×1012 cm-2 for the n-type Cd2P2S3Se3 monolayer.

Progress in Microfluidics-Based Exosome Separation and Detection Technologies for Diagnostic Applications.

Exosomes are secreted by most cell types and circulate in body fluids. Recent studies have revealed that exosomes play a significant role in intercellular communication and are closely associated with the pathogenesis of disease. Therefore, exosomes are considered promising biomarkers for disease diagnosis. However, exosomes are always mixed with other components of body fluids. Consequently, separation methods for exosomes that allow high-purity and high-throughput separation with a high recovery rate and detection techniques for exosomes that are rapid, highly sensitive, highly specific, and have a low detection limit are indispensable for diagnostic applications. For decades, many exosome separation and detection techniques have been developed to achieve the aforementioned goals. However, in most cases, these two techniques are performed separately, which increases operation complexity, time consumption, and cost. The emergence of microfluidics offers a promising way to integrate exosome separation and detection functions into a single chip. Herein, an overview of conventional and microfluidics-based techniques for exosome separation and detection is presented. Moreover, the advantages and drawbacks of these techniques are compared.

Frailty detection with routine blood tests using data from the english longitudinal study of ageing (ELSA).

PURPOSE: Frailty is a rising global health issue in ageing society. Easily accessible and sensitive tools are needed for frailty monitoring while routine blood factors can be potential candidates. METHODS: Data from 1907 participants (aged 60 years or above) were collected from the 4th to 9th wave of the English longitudinal study of ageing. 14 blood factors obtained from blood tests were included in the analysis. A 52-item frailty index (FI) was calculated for frailty evaluation. Logistic regression and Cox proportional hazards analysis were used to explore the relationships between baseline blood factors and the incidence of frailty over time respectively. All analyses were controlled for age and sex. RESULTS: The mean age of participants was 67.3 years and 47.2% of them were male. Our study identified that 8 blood factors (mean corpuscular haemoglobin, HDL, triglyceride, ferritin, hsCRP, dehydroepiandrosterone, haemoglobin, and WBC) involved in inflammatory, nutritional and metabolic processes were associated with frailty. The combined model with these 8 blood factors had an AUC of 0.758 at cross-sectional level. In the Cox proportional hazards analysis, higher triglyceride (HR: 1.30, 95%CI: 1.07 ~ 1.59), WBC (HR: 1.16, 95%CI: 1.05 ~ 1.28), and lower HDL (HR: 0.58, 95%CI: 0.38 ~ 0.90) at baseline were linked to greater risk of developing frailty within 10 years. Compared to adults without abnormal blood factors at baseline, the hazard ratios of participants with two or more abnormal blood factors were almost twofold higher in developing frailty over time. CONCLUSIONS: Routine blood factors, particularly triglyceride, HDL and WBC, could be used for frailty screening in clinical practice and estimate the development of frailty over time.

A stepwise multi-stage continuous dielectrophoresis separation microfluidic chip with microfilter structures.

The separation of target microparticles using microfluidic systems owns extensive applications in biomedical, chemical, and materials science fields. Integration of microfluidic sorting systems employing dielectrophoresis (DEP) technology has been widely investigated. However, enhancing separation efficiency, purity, stability, and integration remains a pressing issue. This study proposes a stepwise multi-stage continuous DEP separation microfluidic chip with a microfilter structure. By leveraging a stepwise electrode configuration, a gradient electric field is generated to drive target microparticles along the electric field gradient, thereby enhancing separation efficiency. Innovative integration of a microfilter structure facilitates simultaneous filtration and improves flow field distribution, thus enhancing system stability. Through the synergistic effect of stepwise electrodes and the microfilter structure, superior coupling of electric and flow fields is achieved, consequently improving the sorting purity, separation efficiency, and system stability of the DEP-based microfluidic sorting system. Validation through simulation and separation of polystyrene microspheres demonstrates the excellent particle separation performance of the proposed system. It evidently shows potential for seamless extension to various biological microparticle sorting applications, harboring significant prospects in the biomedical domain field.

Time and Space Dual-Blockade Strategy for Highly Invasive Nature of Triple-Negative Breast Cancer in Enhanced Sonodynamic Therapy Based on Fe-MOF Nanoplatforms.

Triple-negative breast cancer (TNBC), due to its high malignant degree and strong invasion ability, leads to poor prognosis and easy recurrence, so effectively curbing the invasion of TNBC is the key to obtaining the ideal therapeutic effect. Herein, a therapeutic strategy is developed that curbs high invasions of TNBC by inhibiting cell physiological activity and disrupting tumor cell structural function to achieve the time and space dual-blockade. The time blockade is caused by the breakthrough of the tumor-reducing blockade based on the ferroptosis process and the oxidation-toxic free radicals generated by enhanced sonodynamic therapy (SDT). Meanwhile, alkyl radicals from 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH) and 1O2 attacked the organelles of tumor cells under ultrasound (US), reducing the physiological activity of the cells. The attack of free radicals on the cytoskeleton, especially on the proteins of F-actin and its assembly pathway, achieves precise space blockade of TNBC. The damage to the cytoskeleton and the suppression of the repair process leads to a significant decline in the ability of tumor cells to metastasize and invade other organs. In summary, the FTM@AM nanoplatforms have a highly effective killing and invasion inhibition effect on invasive TNBC mediated by ultrasound, showcasing promising clinical transformation potential.

SELENOK-dependent CD36 palmitoylation regulates microglial functions and Aß phagocytosis.

Amyloid-beta (Aß) is a key factor in the onset and progression of Alzheimer's disease (AD). Selenium (Se) compounds show promise in AD treatment. Here, we revealed that selenoprotein K (SELENOK), a selenoprotein involved in immune regulation and potentially related to AD pathology, plays a critical role in microglial immune response, migration, and phagocytosis. In vivo and in vitro studies corroborated that SELENOK deficiency inhibits microglial Aß phagocytosis, exacerbating cognitive deficits in 5xFAD mice, which are reversed by SELENOK overexpression. Mechanistically, SELENOK is involved in CD36 palmitoylation through DHHC6, regulating CD36 localization to microglial plasma membranes and thus impacting Aß phagocytosis. CD36 palmitoylation was reduced in the brains of patients and mice with AD. Se supplementation promoted SELENOK expression and CD36 palmitoylation, enhancing microglial Aß phagocytosis and mitigating AD progression. We have identified the regulatory mechanisms from Se-dependent selenoproteins to Aß pathology, providing novel insights into potential therapeutic strategies involving Se and selenoproteins.

From Conventional to Microfluidic: Progress in Extracellular Vesicle Separation and Individual Characterization.

Extracellular vesicles (EVs) are nanoscale membrane vesicles, which contain a wide variety of cargo such as proteins, miRNAs, and lipids. A growing body of evidence suggests that EVs are promising biomarkers for disease diagnosis and therapeutic strategies. Although the excellent clinical value, their use in personalized healthcare practice is not yet feasible due to their highly heterogeneous nature. Taking the difficulty of isolation and the small size of EVs into account, the characterization of EVs at a single-particle level is both imperative and challenging. In a bid to address this critical point, more research has been directed into a microfluidic platform because of its inherent advantages in sensitivity, specificity, and throughput. This review discusses the biogenesis and heterogeneity of EVs and takes a broad view of state-of-the-art advances in microfluidics-based EV research, including not only EV separation, but also the single EV characterization of biophysical detection and biochemical analysis. To highlight the advantages of microfluidic techniques, conventional technologies are included for comparison. The current status of artificial intelligence (AI) for single EV characterization is then presented. Furthermore, the challenges and prospects of microfluidics and its combination with AI applications in single EV characterization are also discussed. In the foreseeable future, recent breakthroughs in microfluidic platforms are expected to pave the way for single EV analysis and improve applications for precision medicine.

Performance of a PLK1-based immune risk model for prognosis and treatment response prediction in breast cancer.

OBJECTIVE: Polo-like kinase 1 (PLK1), a serine/threonine-protein kinase, functions as a potent oncogene in the initiation and progression of tumor. The aim of this study is to assess potential correlations between PLK1 expression and immune infiltration in breast cancer (BRCA) and construct a PLK1-based immune risk model applicable for prognosis and treatment response prediction in BRCA. METHODS: We collected data on PLK1 gene expression in BRCA patients from The Cancer Genome Atlas (TCGA) database. Thereafter, we analyzed the associations of PLK1 expression with immune cell infiltration and immunomodulators, and established a prognostic risk model based on seven PLK1-associated immunomodulator genes and a nomogram for survival prediction. RESULTS: BRCA prognosis, clinical stage progression, and tumor classification were all shown to be substantially correlated with PLK1 expression. The PLK1 gene was significantly enriched in T cell and B cell receptors and molecules of the chemokine signaling pathways. Specifically, PLK1 expression was positively correlated with the CD8+ T cell and regulatory T cell (Tregs) activation and negatively correlated with M2 macrophage infiltration. The seven-genes-based risk model could serve as an independent prognostic factor of BRCA. The risk model was markedly correlated with the expression of programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1; both p < 0.001) immune checkpoints, and tumor mutation burden (TMB). High- and low-risk BRCA patients identified by the risk model responded differently to anti-PD-1 and/or anti-CTLA4 therapy, as well as common chemotherapy drugs, like cisplatin, paclitaxel, and gemcitabine. CONCLUSION: This PLK1-based immune risk model can effectively predict the prognosis and tumor progression of BRCA, identify gene mutations, and evaluate patient's response toward immunotherapy and chemotherapy regimens.

Design, synthesis and anti-AD effects of dual inhibitor targeting glutaminyl cyclase/GSK-3ß.

Alzheimer's disease (AD), multifactorial disease, is recognized as one of the most common forms of dementia, and the efficacy of anti-AD drugs is limited clinically. Up-regulated glutaminyl cyclase (QC) and glycogen synthase kinase-3ß (GSK-3ß) have been identified as two critical elements involved in AD recently. Here, a series of novel chemicals containing maleimide and imidazole motif were designed and synthesized as dual inhibitors targeting QC and GSK-3ß. Based on primary screening, compound 2 (2.26 µM), 5 (2.37 µM), 8 (1.34 µM), 21 (2.44 µM), 25 (0.36 µM), 27 (1.76 µM), 28 (1.04 µM), 33 (2.08 µM) and 34 (2.33 µM) exhibited notable human QC (hQC) inhibitory potency, while compound 1 (0.014 µM), 7 (0.04 µM), 8 (0.057 µM), 19 (0.034 µM), 24 (0.014 µM), 32 (0.032 µM), 38 (0.051 µM), 39 (0.044 µM), 44 (0.048 µM), 47 (0.011 µM), 49 (0.021 µM) and so on showed remarkable GSK-3ß inhibitory activities. And as expected, these chemicals possessed significant inhibitory potency on both hQC and GSK-3ß, such as compound 1 (2.80 and 0.014 µM), 8 (1.34 and 0.057 µM), 25 (0.36 and 0.15 µM), 27 (1.76 and 0.069 µM), 28 (1.04 and 0.090 µM), 33 (2.08 and 0.19 µM), 34 (2.33 and 0.11 µM), 35 (2.55 and 0.14 µM), 36 (2.34 and 0.11 µM), etc. Subsequent in vivo studies demonstrated that compound 8 attenuated cognitive deficits and decreased the anxiety-like behavior in 3 × Tg-AD mice. The treatment decreased both pE-Aß and Aß accumulation by inhibiting the activity of QC, and decreased the hyperphosphorylation of Tau by reducing the levels of GSK-3ß in the brains of AD mice. Results obtained in this research suggested that these novel compounds could be supposed as potential anti-AD agents targeting QC and GSK-3ß.

SELENOM Knockout Induces Synaptic Deficits and Cognitive Dysfunction by Influencing Brain Glucose Metabolism.

Selenium, a trace element associated with memory impairment and glucose metabolism, mainly exerts its function through selenoproteins. SELENOM is a selenoprotein located in the endoplasmic reticulum (ER) lumen. Our study demonstrates for the first time that SELENOM knockout decreases synaptic plasticity and causes memory impairment in 10-month-old mice. In addition, SELENOM knockout causes hyperglycaemia and disturbs glucose metabolism, which is essential for synapse formation and transmission in the brain. Further research reveals that SELENOM knockout leads to inhibition of the brain insulin signaling pathway [phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR/p70 S6 kinase pathway], which may impair synaptic plasticity in mice. High-fat diet (HFD) feeding suppresses the brain insulin signaling pathway in SELENOM knockout mice and leads to earlier onset of cognitive impairment at 5 months of age. In general, our study demonstrates that SELENOM knockout induces synaptic deficits via the brain insulin signaling pathway, thus leading to cognitive dysfunction in mice. These data strongly suggest that SELENOM plays a vital role in brain glucose metabolism and contributes substantially to synaptic plasticity.

Knockdown of the SELENOK gene induces ferroptosis in cervical cancer cells.

Selenoprotein K (SELENOK) is one of the endoplasmic reticulum (ER) proteins that mainly functions in the regulation of ER stress, calcium flux, and antioxidant defense. Reactive oxygen species (ROS) is one of the key indicators of ferroptosis, and SELENOK inhibition could disrupt ROS balance, and consequently might cause ferroptosis. However, there are no previous studies about the mechanism of SELENOK in ferroptosis by regulating ROS. In this study, we report the effect of SELENOK inhibition on cell proliferation, viability, iron recycling-associated proteins, ROS, antioxidant enzymes, and lipid peroxidation of cervical cancer cells (HeLa cells). The results showed that ROS levels and iron-dependent lipid peroxidation were significantly enhanced, whereas cell viability and proliferation were significantly downregulated, and resulted in marked reductions in tumor size after SELENOK knockdown. SELENOK knockdown also caused steep decreases in glutathione peroxidase 4/glutathione levels and deterioration in ROS scavenging ability, and exacerbated ferroptosis in HeLa cells. Our findings elucidated that SELENOK knockdown could shrink tumor size by regulating ferroptosis, which might provide a theoretical basis for treating cervical cancer.

Natural fucoidans inhibit coronaviruses by targeting viral spike protein and host cell furin.

Fucoidans are a class of long chain sulfated polysaccharides and have multiple biological functions. Herein, four natural fucoidans extracted from Fucus vesiculosus, F. serratus, Laminaria japonica and Undaria pinnatifida, were tested for their HCoV-OC43 inhibition and found to demonstrate EC50 values ranging from 0.15 to 0.61 µg/mL. That from U. pinnatifida exhibited the most potent anti-HCoV-OC43 activity with an EC50 value of 0.15 ± 0.02 µg/mL, a potency largely independent of its sulfate content. Comparison of the gene expression profiles of fucoidan-treated and untreated cells infected with HCoV-OC43 revealed that fucoidan treatment effectively diminished HCoV-OC43 gene expressions associated with induced chemokines, cytokines and viral activities. Further studies using a highly fucoidan-resistant HCoV-OC43 determined that fucoidan inhibited HCoV-OC43 infection via interfering with viral entry and led to the identification of the specific site on the N-terminal region of spike protein, that located adjacent to the host cell receptor binding domain, targeted by the virus. Furthermore, in a SARS-CoV-2 pseudovirus neutralization assay, fucoidan also blocked SARS-CoV-2 entry. In vitro and in vivo, fucoidan decreased SARS-CoV-2 viral loads and inhibited viral infection in Calu-3 or Vero E6 cells and SARS-CoV-2 infected hamsters, respectively. Fucoidan was also found to inhibit furin activity, and reported furin inhibitors were found to inhibit viral infection by wild type HCoV-OC43 or SARS-CoV-2. Accordingly, we conclude that fucoidans inhibit coronaviral infection by targeting viral spike protein and host cell furin to interfere with viral entry.

Geometric structure design of passive label-free microfluidic systems for biological micro-object separation.

Passive and label-free microfluidic devices have no complex external accessories or detection-interfering label particles. These devices are now widely used in medical and bioresearch applications, including cell focusing and cell separation. Geometric structure plays the most essential role when designing a passive and label-free microfluidic chip. An exquisitely designed geometric structure can change particle trajectories and improve chip performance. However, the geometric design principles of passive and label-free microfluidics have not been comprehensively acknowledged. Here, we review the geometric innovations of several microfluidic schemes, including deterministic lateral displacement (DLD), inertial microfluidics (IMF), and viscoelastic microfluidics (VEM), and summarize the most creative innovations and design principles of passive and label-free microfluidics. We aim to provide a guideline for researchers who have an interest in geometric innovations of passive label-free microfluidics.

Topology optimization based deterministic lateral displacement array design for cell separation.

Circulating tumor cell (CTC) can be used to guide cancer theranostics. How to isolate efficiently CTCs from blood owns great clinical requirement. Deterministic lateral displacement (DLD) is a pillar-array-based effective passive microfluidic method to separate cells based on their sizes. DLD is a potential CTC isolation tool. Pillar shape is one of the key priorities in DLD array design. Altered zigzag mode is a normally undesired phenomenon that leads zigzag particles away from flow direction. This work makes use of the altered zigzag mode to manipulate zigzag particles for the first time, and developed a novel DLD chip with topology optimized pillar shape and a wide DLD channel. The novel designing method based on topology optimization (TO) greatly increases lateral displacement of different sized cells, meanwhile demonstrates its universality and expansibility. The proposed structure has the ability to shorten the device and to manipulate cells flexibly. Bead experiment has been applied to determine the critical diameter of the DLD array. Numerical, bead and cell experiment have been carried out to verify the separation efficiency of the structure. The TO-based wide DLD channel promotes the separation efficiency.

Recent advances in microfluidic-based electroporation techniques for cell membranes.

Electroporation is a fundamental technique for applications in biotechnology. To date, the ongoing research on cell membrane electroporation has explored its mechanism, principles and potential applications. Therefore, in this review, we first discuss the primary electroporation mechanism to help establish a clear framework. Within the context of its principles, several critical terms are highlighted to present a better understanding of the theory of aqueous pores. Different degrees of electroporation can be used in different applications. Thus, we discuss the electric factors (shock strength, shock duration, and shock frequency) responsible for the degree of electroporation. In addition, finding an effective electroporation detection method is of great significance to optimize electroporation experiments. Accordingly, we summarize several primary electroporation detection methods in the following sections. Finally, given the development of micro- and nano-technology has greatly promoted the innovation of microfluidic-based electroporation devices, we also present the recent advances in microfluidic-based electroporation devices. Also, the challenges and outlook of the electroporation technique for cell membrane electroporation are presented.

Correction: Recent advances in microfluidic-based electroporation techniques for cell membranes.

Correction for 'Recent advances in microfluidic-based electroporation techniques for cell membranes' by Fei Wang et al., Lab Chip, 2022, 22, 2624-2646, https://doi.org/10.1039/D2LC00122E.