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.

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 1 O2 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

ExoSD chips for high-purity immunomagnetic separation and high-sensitivity detection of gastric cancer cell-derived exosomes.

Gastric cancer cell-derived exosomes as biomarkers have a very high application potential to the non-invasive detection of early-stage gastric cancer. However, the small size of exosomes (30-150 nm) results in huge challenges in separating and detecting them from complex media (e.g., plasma, urine, saliva, and cell culture supernatant). Here we proposed a highly integrated exosome separation and detection (ExoSD) chip to immunomagnetic separate exosomes from cell culture supernatant in a manner of continuous flow, and to immunofluorescence detect gastric cancer cell-derived exosomes with high sensitivity. The ExoSD chip has achieved a high exosome recovery (>80%) and purity (>83%) at the injection rate of 4.8 mL/h. Furthermore, experimental results based on clinical serum samples of patients with gastric cancer (stages I and II) show that the detection rate of the ExoSD chip is as high as 70%. The proposed ExoSD chip has been successfully demonstrated as a cutting-edge platform for exosomes separation and detection. It can be served as a versatile platform to extend to the applications of separation and detection of the other cell-derived exosomes or cells.

Nanosensor-Based Flexible Electronic Assisted with Light Fidelity Communicating Technology for Volatolomics-Based Telemedicine.

Telemedicine provides an attractive vision for tele-monitoring human health conditions and, thus, offers the opportunity for timely preventing chronic disease. A key limitation of promoting telemedicine in clinic application is the lack of a noninvasive med-tech and effective monitoring platform, which should be wearable and capable of high-performance tele-monitoring of health risk. Here we proposed a volatolomics-based telemedicine for continuously and noninvasively assessing human health status through continuously tracking the variation of volatile markers derived from human breath or skin. Particularly, a nanosensor-based flexible electronic was specifically designed to serve as a powerful platform for implementing the proposed cost-effective healthcare. An all-flexible and highly packed makeup (all functional units were integrated in a 2*2*0.19 cm3 plate) enables an electronic, compact configuration and the capability of resisting negative impact derived from customers' daily movement. Notably, the nanosensor-based electronic demonstrates high specificity, quick response rate (t90% = 4.5 s), and desirable low detection limit (down to 0.117 ppm) in continuous tele-monitoring chronic-disease-related volatile marker (e.g., acetone). Assisted by the power saved light fidelity (Li-Fi) communicating technology, a clinic proof on the specifically designed electronic for noninvasively and uninterrupted assessing potential health risk (e.g., diabetics) is successfully implemented, with the accuracy of around 81%. A further increase in the accuracy of prewarning is predicted by excluding the impact of individual differences such as the gender, age, and smoking status of the customer. These promising pilot results indicate a bright future for the tailor-made nanosensing-device-supported volatolomics-based telemedicine in preventing chronic diseases and increasing patients' survival rate.

Ag-Modified 3D Reduced Graphene Oxide Aerogel-Based Sensor with an Embedded Microheater for a Fast Response and High-Sensitive Detection of NO2.

A chemiresistive gas sensor based on a three-dimensional Ag-modified reduced graphene oxide (3D Ag-rGO) aerogel is reported. We improve the graphene-based sensor performance by optimization of operating temperature, chemical modification, and new design of the material geometrical structure. The self-assembly and Ag nanoparticle (NP) decoration of the Ag-rGO aerogel are realized by a facile, one-step hydrothermal method. An integrated low-power microheater fabricated on a micromachined SiO2 membrane is employed to enhance the performance of the sensor with a fast response to NO2 and a shortened recovery time. The 3D Ag-rGO-based sensor at a temperature of 133 °C exhibits the highest response. At the same time, the response to other gases is suppressed while the response of the Ag-rGO sensor toward ammonia at 133 °C is reduced to half of the value at room temperature, demonstrating a greatly improved selectivity toward NO2. Additionally, the sensor exhibits a remarkably fast response to 50 ppb NO2 and a low limit of detection of 6.9 ppb.

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.