A nanofluidic spiking synapse.

Currently, the nanofluidic synapse can only perform basic neuromorphic pulse patterns. One immediate problem that needs to be addressed to further its capability of brain-like computing is the realization of a nanofluidic spiking device. Here, we report the use of a poly(3,4-ethylenedioxythiophene) polystyrene sulfonate membrane to achieve bionic ionic current-induced spiking. In addition to the simulation of various electrical pulse patterns, our synapse could produce transmembrane ionic current-induced spiking, which is highly analogous to biological action potentials with similar phases and excitability. Moreover, the spiking properties could be modulated by ions and neurochemicals. We expect that this work could contribute to biomimetic spiking computing in solution.

Test-retest reliability and time-of-day variations of perfusion imaging at rest and during a vigilance task.

Arterial spin-labeled perfusion and blood oxygenation level-dependent functional MRI are indispensable tools for noninvasive human brain imaging in clinical and cognitive neuroscience, yet concerns persist regarding the reliability and reproducibility of functional MRI findings. The circadian rhythm is known to play a significant role in physiological and psychological responses, leading to variability in brain function at different times of the day. Despite this, test-retest reliability of brain function across different times of the day remains poorly understood. This study examined the test-retest reliability of six repeated cerebral blood flow measurements using arterial spin-labeled perfusion imaging both at resting-state and during the psychomotor vigilance test, as well as task-induced cerebral blood flow changes in a cohort of 38 healthy participants over a full day. The results demonstrated excellent test-retest reliability for absolute cerebral blood flow measurements at rest and during the psychomotor vigilance test throughout the day. However, task-induced cerebral blood flow changes exhibited poor reliability across various brain regions and networks. Furthermore, reliability declined over longer time intervals within the day, particularly during nighttime scans compared to daytime scans. These findings highlight the superior reliability of absolute cerebral blood flow compared to task-induced cerebral blood flow changes and emphasize the importance of controlling time-of-day effects to enhance the reliability and reproducibility of future brain imaging studies.

An Ultrasensitive and Efficient microRNA Nanosensor Empowered by the CRISPR/Cas Confined in a Nanopore.

This work presents a clustered regularly interspaced short palindromic repeat (CRISPR)/Cas-nanopipette nano-electrochemistry (Cas = CRISPR-associated proteins) capable of ultrasensitive microRNA detection. Nanoconfinement of the CRISPR/Cas13a within a nanopipette leads to a high catalytic efficacy of ca. 169 times higher than that in bulk electrolyte, contributing to the amplified electrochemical responses. CRISPR/Cas13a-enabled detection of representative microRNA-25 achieves a low limit of detection down to 10 aM. Practical application of this method is further demonstrated for single-cell and real human serum detection. Its general applicability is validated by addressing microRNA-141 and the SARS-CoV-2 RNA gene fragment. This work introduces a new CRISPR/Cas-empowered nanotechnology for ultrasensitive nano-electrochemistry and bioanalysis.

Aggregation-Enabled Electrochemistry in Confined Nanopore Capable of Complementary Faradaic and Non-Faradaic Detection.

Electrochemistry that empowers innovative nanoscopic analysis has long been pursued. Here, the concept of aggregation-enabled electrochemistry (AEE) in a confined nanopore is proposed and devised by reactive oxygen species (ROS)-responsive aggregation of CdS quantum dots (QDs) within a functional nanopipette. Complementary Faradaic and non-Faradaic operations of the CdS QDs aggregate could be conducted to simultaneously induce the signal-on of the photocurrents and the signal-off of the ionic signals. Such a rationale permits the cross-checking of the mutually corroborated signals and thus delivers more reliable results for single-cell ROS analysis. Combined with the rich biomatter-light interplay, the concept of AEE can be extended to other stimuli-responsive aggregations for electrochemical innovations.

Metal-Organic Framework Nanofluidic Synapse.

Chemical synapse completes the signaling through neurotransmitter-mediated ion flux, the emulation of which has been a long-standing obstacle in neuromorphic exploration. Here, we report metal-organic framework (MOF) nanofluidic synapses in which conjugated MOFs with abundant ionic storage sites underlie the ionic hysteresis and simultaneously serve as catalase mimetics that sensitively respond to neurotransmitter glutamate (Glu). Various neurosynaptic patterns with adaptable weights are realized via Glu-mediated chemical/ionic coupling. In particular, nonlinear Hebbian and anti-Hebbian learning in millisecond time ranges are achieved, akin to those of chemical synapses. Reversible biochemical in-memory encoding via enzymatic Glu clearance is also accomplished. Such results are prerequisites for highly bionic electrolytic computers.

FABP5+ lipid-loaded macrophages process tumor-derived unsaturated fatty acid signal to suppress T-cell antitumor immunity.

BACKGROUND & AIMS: Tumour-associated macrophages (TAMs) contribute to hepatocellular carcinoma (HCC) progression. However, while the pro-tumour and immunosuppressive roles of lipid-loaded macrophages are well established, the mechanisms by which lipid metabolism enhances the tumour-promoting effects in TAMs remain unclear. METHODS: Single-cell RNA sequencing was performed on mouse and human HCC tumour samples to elucidate the landscape of HCC TAMs. Macrophages were stimulated with various long-chain unsaturated fatty acids (UFAs) to assess immunosuppressive molecules expression in vitro. Additionally, in vivo and in vitro studies were conducted using mice with macrophage-specific deficiencies in fatty acid-binding protein 5 (FABP5) or peroxisome proliferator-activated receptor (PPAR). RESULTS: Single-cell RNA sequencing identified a subpopulation of FABP5+ lipid-loaded TAMs characterized by enhanced immune checkpoint blocker ligands and immunosuppressive molecules in an oncogene-mutant HCC mouse model and human HCC tumours. Mechanistically, long-chain UFAs released by tumour cells activate PPARvia FABP5, resulting in TAM immunosuppressive properties. FABP5 deficiency in macrophages decreases immunosuppressive molecules expression, enhances T-cell-dependent antitumor immunity, diminishes HCC growth, and improves immunotherapy efficacy. CONCLUSIONS: This study demonstrates that UFAs promote tumourigenesis by enhancing the immunosuppressive tumour microenvironment via FABP5-PPAR signaling and provides a proof-of-concept for targeting this pathway to improve tumour immunotherapy.

Bridging Ionic Current Rectification and Resistive-Pulse Sensing for Reliable Wide-Linearity Detection.

As two mainstream ionic detection techniques, ionic current rectification (ICR) suffers from large fluctuations in trace level detection, while resistive-pulse sensing (RPS) encounters easy clogs in high-concentration detection. By rationally matching the nanopore size with the DNA tetrahedron (TDN), this work bridges the two techniques to achieve reliable detection with wide linearity. As a representative analyte, miRNA-10b could specifically combine with and release TDN from the interior wall, which thus induced the simultaneous generation of distinct ICR and RPS signals. The ICR signals could be attributed to the balance between the effective orifice and surface charge density of the inner wall, while the RPS signals were induced by the complex of miRNA-10b and TDN passing through the nanopore. Such an operation contributed to a wide detection range of 1 fM-1 nM with a good linearity. The feasibility of this method is also validated in single-cell and real plasma detection.

Single-Cell Caspase-3 Measurement Using a Biomimetic Nanochannel.

Direct single-cell caspase-3 (Casp-3) analysis has remained challenging. A study of single-cell Casp-3 could contribute to revealing the fundamental pathogenic mechanisms in Casp-3-associated diseases. Here, a biomimetic nanochannel capable of single-cell sampling and ionic detection of intracellular Casp-3 is devised, which is established upon the installment of target-specific organic molecules (luc-DEVD) within the orifice of a glass nanopipette. The specific cleavage of luc-DEVD by Casp-3 could induce changes of inner-surface chemical groups and charge properties, thus altering the ionic response of the biomimetic nanochannel for direct Casp-3 detection. The practical applicability of this biomimetic nanochannel is confirmed by probing intracellular Casp-3 fluctuation upon drug stimulation and quantifying the Casp-3 evolution during induced apoptosis. This work realizes ionic single-cell Casp-3 analysis and provides a different perspective for single-cell protein analysis.

Synergetic Enzyme-Incorporated Metal-Organic Framework and Polyoxometalate Nanozyme: Achieving Stable Tandem Catalysis for Organic Photoelectrochemical Transistor Bioanalysis.

Organic photoelectrochemical transistor (OPECT) has emerged as a promising technique for biomolecule detection, yet its operational rationale remains limited due to its short development time. This study introduces a stable tandem catalysis protocol by synergizing the enzyme-incorporated metal-organic frameworks (E-MOFs) with polyoxometalate (POM) nanozyme for sensitive OPECT bioanalysis. The zeolitic imidazolate framework-8 (ZIF-8) acts as the skeleton to protect the encapsulated glucose oxidase (GOx), allowing the stable catalytic generation of H2O2. With peroxidase-like activity, a phosphotungstic acid hydrate (PW12) is then able to utilize the H2O2 to induce the biomimetic precipitation on the photogate, ultimately resulting in the altered device characteristics for quantitative detection. This work reveals the potential and versatility of an engineered enzymatic system as a key enabler to achieve novel OPECT bioanalysis, which is believed to offer a feasible framework to explore new operational rationale in optoelectronic and bioelectronic detection.

Photoresponsive Hydrogen-Bonded Organic Frameworks-Enabled Organic Photoelectrochemical Transistors for Sensitive Bioanalysis.

A facile route for exponential magnification of transconductance (gm) in an organic photoelectrochemical transistor (OPECT) is still lacking. Herein, photoresponsive hydrogen-bonded organic frameworks (PR-HOFs) have been shown to be efficient for gm magnification in a typical poly(ethylene dioxythiophene):poly(styrenesulfonate) OPECT. Specifically, 450 nm light stimulation of 1,3,6,8-tetrakis (p-benzoic acid) pyrene (H4TBAPy)-based HOF could efficiently modulate the device characteristics, leading to the considerable gm magnification over 78 times from 0.114 to 8.96 mS at zero Vg. In linkage with a DNA nanomachine-assisted steric hindrance amplification strategy, the system was then interfaced with the microRNA-triggered structural DNA evolution toward the sensitive detection of a model target microRNA down to 0.1 fM. This study first reveals HOFs-enabled efficient gm magnification in organic electronics and its application for sensitive biomolecular detection.

Highly Light-Harvesting MOF-on-MOF Heterostructure: Cascading Functionality to Flexible Photogating of Organic Photoelectrochemical Transistor and Bienzyme Cascade Detection.

Recently, organic photoelectrochemical transistor (OPECT) bioanalysis has become a prominent technique for the high-performance detection of biomolecules. However, as a sensitive index of the OPECT, the dynamic regulation transconductance (gm) is still severely deficient. Herein, this work reports a new photosensitive metal-organic framework (MOF-on-MOF) heterostructure for the effective modulation of maximum gm and natural bienzyme interfacing toward choline detection. Specifically, the bidentate ligand MOF (b-MOF) was assembled onto the UiO-66 MOF (u-MOF) by a modular assembly method, which could facilitate the charge separation and generate enhanced photocurrents and offer a biophilic environment for the immobilization of choline oxidase (ChOx) and horseradish peroxidase (HRP) through hydrogen-bonded bridges. The transconductance of the OPECT could be flexibly altered by increased light intensity to maximal value at zero gate bias, and sensitive choline detection was achieved with a detection limit of 0.2 µM. This work reveals the potential of MOF-on-MOF heterostructures for futuristic optobioelectronics.

Dual Engine Boosts Organic Photoelectrochemical Transistor for Enhanced Modulation and Bioanalysis.

Organic photoelectrochemical transistor (OPECT) has shown substantial potential in the development of next-generation bioanalysis yet is limited by the either-or situation between the photoelectrode types and the channel types. Inspired by the dual-photoelectrode systems, we propose a new architecture of dual-engine OPECT for enhanced signal modulation and its biosensing application. Exemplified by incorporating the CdS/Bi2S3 photoanode and Cu2O photocathode within the gate-source circuit of Ag/AgCl-gated poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) channel, the device shows enhanced modulation capability and larger transconductance (gm) against the single-photoelectrode ones. Moreover, the light irritation upon the device effectively shifts the peak value of gm to zero gate voltage without degradation and generates larger current steps that are advantageous for the sensitive bioanalysis. Based on the as-developed dual-photoelectrode OPECT, target-mediated recycling and etching reactions are designed upon the CdS/Bi2S3, which could result in dual signal amplification and realize the sensitive microRNA-155 biodetection with a linear range from 1 fM to 100 pM and a lower detection limit of 0.12 fM.

Dual-Mode MXene-Based Phase-Change Composite Towards Enhanced Photothermal Utilization and Excellent Infrared Stealth.

Solar thermal collectors based on phase change materials (PCMs) are important to promote the civilian use of sustainable energy. However, simultaneously achieving high photothermal efficiency and rapid heat transfer of the PCM carrier typically involves a high proportion of functional materials, contradicting a satisfying energy storage density. In this work, a surface-engineered anisotropic MXene-based aerogel (LMXA) integrated with myristic acid (MA) to produce phase change composites (LMXA-MA) is reported, in which the laser-treated surface composed of the hierarchically-structured TiO2/carbon composites act as a light absorber to improve solar absorption (96.0%), while the vertical through-hole structure allows for fast thermal energy transportation from surface to the whole. As a result, LMXA-MA exhibits outstanding thermal energy storage (192.4 J·g-1) and high photothermal conversion efficiency (93.5%). Meanwhile, benefiting from the intrinsic low emissivity of MXene material, thermal radiation loss can be effectively suppressed by simply flipping LMXA-MA, enabling a long-term temperature control ability (605 s·g-1). The excellent heat storage property and switchable dual-mode also endow it with an infrared stealth function, which maintains camouflage for more than 240 s. This work provides a prospective solution for optimizing photothermal conversion efficiency and long-term thermal energy preservation from surface engineering and structural design.

Lubricating Microneedles System with Multistage Sustained Drug Delivery for the Treatment of Osteoarthritis.

Osteoarthritis (OA) is a typical joint degenerative disease that is prevalent worldwide and significantly affects the normal activities of patients. Traditional treatments using diclofenac (DCF) as an anti-inflammatory drug by oral administration and transdermal delivery have many inherent deficiencies. In this study, a lubricating microneedles (MNs) system for the treatment of osteoarthritis with multistage sustained drug delivery and great reduction in skin damage during MNs penetration is developed. The bilayer dissolvable MNs system, namely HA-DCF@PDMPC, is prepared by designating the composite material of hyaluronic acid (HA) and covalently conjugated drug compound (HA-DCF) as the MNs tips and then modifying the surface of MNs tips with a self-adhesive lubricating copolymer (PDMPC). The MNs system is designed to achieve sustained drug release of DCF via ester bond hydrolysis, physical diffusion from MNs tips, and breakthrough of lubrication coating. Additionally, skin damage is reduced due to the presence of the lubrication coating on the superficial surface. Therefore, the lubricating MNs with multistage sustained drug delivery show good compliance as a transdermal patch for OA treatment, which is validated from anti-inflammatory cell tests and therapeutic animal experiments, down-regulating the expression levels of pro-inflammatory factors and alleviating articular cartilage destruction.

High-Precision Single-Cell microRNA Therapy by a Functional Nanopipette with Sensitive Photoelectrochemical Feedback.

This work proposes the concept of single-cell microRNA (miR) therapy and proof-of-concept by engineering a nanopipette for high-precision miR-21-targeted therapy in a single HeLa cell with sensitive photoelectrochemical (PEC) feedback. Targeting the representative oncogenic miR-21, the as-functionalized nanopipette permits direct intracellular drug administration with precisely controllable dosages, and the corresponding therapeutic effects can be sensitively transduced by a PEC sensing interface that selectively responds to the indicator level of cytosolic caspase-3. The experimental results reveal that injection of ca. 4.4 × 10-20 mol miR-21 inhibitor, i.e., 26488 copies, can cause the obvious therapeutic action in the targeted cell. This work features a solution to obtain the accurate knowledge of how a certain miR-drug with specific dosages treats the cells and thus provides an insight into futuristic high-precision clinical miR therapy using personalized medicine, provided that the prerequisite single-cell experiments are courses of personalized customization.

Validated enhancement and temperature modulated absorbance of a WS2 monolayer based on a planar structure.

Transition-metal dichalcogenides (TMDCs), as emerging optoelectronic materials, necessitate the establishment of an experimentally viable system to study their interaction with light. In this study, we propose and analyze a WS2/PMMA/Ag planar Fabry-Perot (F-P) cavity, enabling the direct experimental measurement of WS2 absorbance. By optimizing the structure, the absorbance of A exciton of WS2 up to 0.546 can be experimentally achieved, which matches well with the theoretical calculations. Through temperature and thermal expansion strain induced by temperature, the absorbance of the A exciton can be tuned in situ. Furthermore, temperature-dependent photocurrent measurements confirmed the consistent absorbance of the A exciton under varying temperatures. This WS2/PMMA/Ag planar structure provides a straightforward and practical platform for investigating light interaction in TMDCs, laying a solid foundation for future developments of TMDC-based optoelectronic devices.

The Combination of Zhuli Decoction and N-butylphthalide Inhibits Cell Apoptosis Induced by CO Poisoning through the PI3K/AKT/GSK-3ß Signaling Pathway.

Carbon monoxide poisoning (COP) represents a significant global health burden, characterized by its morbidity and high mortality rates. The pathogenesis of COP-induced brain injury is complex, and effective treatment modalities are currently lacking. In this study, we employed network pharmacology to identify therapeutic targets and associated signaling pathways of Zhuli Decoction (ZLD) for COP. Subsequently, we conducted both in vitro and in vivo experiments to validate the therapeutic efficacy of ZLD in combination with N-butylphthalide (NBP) for acute COP-induced injury. Our network pharmacology analysis revealed that the primary components of ZLD exerted therapeutic effects through the modulation of multiple targets and pathways. The in vitro and in vivo experiments demonstrated that the combination of NBP and ZLD effectively inhibited apoptosis and up-regulated the activities of P-PI3K (Tyr458), P-AKT (Ser473), P-GSK-3ß (Ser9), and Bcl-2, thus leading to the protection of neuronal cells and improvement in cognitive function in rats following COP, which was better than the effects observed with NBP or ZLD alone. The rescue experiment further showed that LY294002, a PI3K inhibitor, significantly attenuated the therapeutic efficacy of NBP + ZLD. The neuroprotection effects of NBP and ZLD against COP-induced brain injury are closely linked to the activation of the PI3K/AKT/GSK-3ß signaling pathway.

Reproducibility and reliability of pancreatic pharmacokinetic parameters derived from dynamic contrast-enhanced magnetic resonance imaging.

BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with an extended Tofts linear (ETL) model for tissue and tumor evaluation has been established, but its effectiveness in evaluating the pancreas remains uncertain. PURPOSE: To understand the pharmacokinetics of normal pancreas and serve as a reference for future studies of pancreatic diseases. MATERIAL AND METHODS: Pancreatic pharmacokinetic parameters of 54 volunteers were calculated using DCE-MRI with the ETL model. First, intra- and inter-observer reliability was assessed through the use of the intra-class correlation coefficient (ICC) and coefficient of variation (CoV). Second, a subgroup analysis of the pancreatic DCE-MRI pharmacokinetic parameters was carried out by dividing the 54 individuals into three groups based on the pancreatic region, three groups based on age, and two groups based on sex. RESULTS: There was excellent agreement and low variability of intra- and inter-observer to pancreatic DCE-MRI pharmacokinetic parameters. The intra- and inter-observer ICCs of Ktrans, kep, ve, and vp were 0.971, 0.952, 0.959, 0.944 and 0.947, 0.911, 0.978, 0.917, respectively. The intra- and inter-observer CoVs of Ktrans, kep, ve, vp were 9.98%, 5.99%, 6.47%, 4.76% and 10.15%, 5.22%, 6.28%, 5.40%, respectively. Only the pancreatic ve of the older group was higher than that of the young and middle-aged groups (P = 0.042, 0.001), and the vp of the pancreatic head was higher than that of the pancreatic body and tail (P = 0.014, 0.043). CONCLUSION: The application of DCE-MRI with an ETL model provides a reliable, robust, and reproducible means of non-invasively quantifying pancreatic pharmacokinetic parameters.

Exoskeleton rehabilitation robot training for balance and lower limb function in sub-acute stroke patients: a pilot, randomized controlled trial.

PURPOSE: This pilot study aimed to investigate the effects of REX exoskeleton rehabilitation robot training on the balance and lower limb function in patients with sub-acute stroke. METHODS: This was a pilot, single-blind, randomized controlled trial. Twenty-four patients with sub-acute stroke (with the course of disease ranging from 3 weeks to 3 months) were randomized into two groups, including a robot group and a control group. Patients in control group received upright bed rehabilitation (n = 12) and those in robot group received exoskeleton rehabilitation robot training (n = 12). The frequency of training in both groups was once a day (60 min each) for 5 days a week for a total of 4 weeks. Besides, the two groups were evaluated before, 2 weeks after and 4 weeks after the intervention, respectively. The primary assessment index was the Berg Balance Scale (BBS), whereas the secondary assessment indexes included the Fugl-Meyer Lower Extremity Motor Function Scale (FMA-LE), the Posture Assessment Scale for Stroke Patients (PASS), the Activities of Daily Living Scale (Modified Barthel Index, MBI), the Tecnobody Balance Tester, and lower extremity muscle surface electromyography (sEMG). RESULTS: The robot group showed significant improvements (P < 0.05) in the primary efficacy index BBS, as well as the secondary efficacy indexes PASS, FMA-LE, MBI, Tecnobody Balance Tester, and sEMG of the lower limb muscles. Besides, there were a significant differences in BBS, PASS, static eye-opening area or dynamic stability limit evaluation indexes between the robotic and control groups (P < 0.05). CONCLUSIONS: This is the first study to investigate the effectiveness of the REX exoskeleton rehabilitation robot in the rehabilitation of patients with stroke. According to our results, the REX exoskeleton rehabilitation robot demonstrated superior potential efficacy in promoting the early recovery of balance and motor functions in patients with sub-acute stroke. Future large-scale randomized controlled studies and follow-up assessments are needed to validate the current findings. CLINICAL TRIALS REGISTRATION: URL: https://www.chictr.org.cn/index.html.Unique identifier: ChiCTR2300068398.

Investigation of the Effect of Tai Chi Training on Depressive Symptoms in Perimenopausal Women on the Basis of Serum Kynurenine Metabolites.

OBJECTIVE: To observe the effects of Tai Chi training on depression symptoms and serum kynurenine metabolites in perimenopausal women and explore the mechanism of Tai Chi training in anti-depression. METHODS: A total of 72 perimenopausal women with depression were randomly selected from Lishi District and divided into a Tai Chi training group (36 cases) and a control group (36 cases). At the same time, 36 perimenopausal healthy women were randomly selected as the normal group. The Tai Chi training group was intervened with 24 simplified Tai Chi exercises, and the depression self-rating scale was used to evaluate the depression status. The levels of tryptophan (Trp) and kynurenine (KYN) metabolites in serum were determined by high-performance liquid chromatography-ultraviolet detection. RESULTS: Before the experiment, compared with the normal healthy group, the depression self-rating scale scores, serum KYN and quinolinic acid (QUIN) levels, and KYN/Trp ratio of the control group and Tai Chi group were significantly increased (p < .01), and the serum kynurenic acid (KYNA) level was significantly decreased (p < .01). After the experiment, compared with the normal healthy group, the depression self-rating scale scores of the Tai Chi group were significantly decreased (p < .01), the serum KYNA content was increased (p < .01), the serum KYN and QUIN contents were significantly decreased (p < .01), and the KYN/Trp ratio was significantly decreased (p < .01). CONCLUSION: Tai Chi training can significantly improve depression symptoms in perimenopausal women. The mechanism of Tai Chi training in improving depression symptoms in perimenopausal women may be achieved by regulating abnormal kynurenine metabolism.

Depression is the most common psychological disorder in perimenopausal women. A series of active substances produced by tryptophan metabolism through kynurenine pathway are closely related to the occurrence and development of depression.One of China's unique traditional sports, Tai Chi is a fitness exercise that combines sport and medical treatment, suitable for groups of all ages and levels.Tai Chi training significantly improved depressive symptoms in perimenopausal women, and the mechanism may be through altering abnormal decreases in KYN metabolism.