Bioinspired Adaptive Microdrugs Enhance the Chemotherapy of Malignant Glioma: Beyond Their Nanodrugs.

Solid nanoparticle-mediated drug delivery systems are usually confined to nanoscale due to the enhanced permeability and retention (EPR) effect. However, they remain a great challenge for malignant glioma chemotherapy because of poor drug delivery efficiency and insufficient tumor penetration resulting from the blood-brain barrier/blood-brain tumor barrier (BBB/BBTB). Inspired by biological microparticles (e.g., cells) with excellent adaptive deformation, we demonstrate that the adaptive microdrugs (even up to 3.0 µm in size) are more efficient than their nanodrugs (less than 200 nm in size) to cross BBB/BBTB and penetrate into tumor tissues, achieving highly efficient chemotherapy of malignant glioma. The distinct delivery of the adaptive microdrugs is mainly attributed to the enhanced interfacial binding and endocytosis via adaptive deformation. As expected, the obtained adaptive microdrugs exhibited enhanced accumulation, deep penetration, and cellular internalization into tumor tissues in comparison with nanodrugs, significantly improving the survival rate of glioblastoma mice. We believe that the bioinspired adaptive microdrugs enable them to efficiently cross physiological barriers and deeply penetrate tumor tissues for drug delivery, providing an avenue for the treatment of solid tumors. This article is protected by copyright. All rights reserved.

Thermally Prolonged NIR-II Luminescence Lifetimes by Cross-Relaxation.

Temperature regulates nonradiative processes in luminescent materials, fundamental to luminescence nanothermometry. However, elevated temperatures often suppress the radiative process, limiting the sensitivity of thermometers. Here, we introduce an approach to populating the excited state of lanthanides at elevated temperatures, resulting in a sizable lifetime lengthening and intensity increase of the near-infrared (NIR)-II emission. The key is to create a five-energy-level system and use a pair of lanthanides to leverage the cross-relaxation process. We observed the lifetime of NIR-II emission of Er3+ has been remarkably increased from 3.85 to 7.54 ms by codoping only 0.5 mol % Ce3+ at 20 °C and further increased to 7.80 ms when increasing the temperature to 40 °C. Moreover, this concept is universal across four ion pairs and remains stable within aqueous nanoparticles. Our findings emphasize the need to design energy transfer systems that overcome the constraint of thermal quenching, enabling efficient imaging and sensing.

[Progressive myoclonic epilepsy: a retrospective study of newly-diagnosed adult patients from a single center].

OBJECTIVE: To retrospectively analyze the clinical phenotype and pathogenic variants in patients with Progressive myoclonus epilepsy (PME). METHODS: Clinical data and results of genetic testing for 11 patients diagnosed with PME at the Department of Neurology, the First Affiliated Hospital of Zhejiang University School of Medicine from June 2017 to December 2022 were collected and analyzed. RESULTS: All of the patients, including 4 males and 7 females, had predominant action myoclonus. Three patients had myoclonus as the initial manifestation, whilst eight were diagnosed through genetic testing, including three cases with NEU1 gene variants, two with EPM2A gene variants (1 was novel), one with MT-TK gene variant, one with ATN1 gene variant, and one with CSTB gene variant. No pathogenic variant was identified in the remaining three cases. Among the eight patients with a genetic diagnosis, three were diagnosed with sialidosis, two with Lafora disease, one with Dentatorubral-pallidoluysian atrophy (DRPLA), one with Unverricht-Lundborg disease (ULD), and one with Myoclonic epilepsy with ragging red fibers (MERRF). CONCLUSION: Compared with pediatric patients, adult patients with PME represent a distinct subtype with slower progression and milder cognitive impairment.

Suppression of cracking in drying colloidal suspensions with chain-like particles.

The prevention of drying-induced cracking is crucial in maintaining the mechanical integrity and functionality of colloidal deposits and coatings. Despite exploring various approaches, controlling drying-induced cracking remains a subject of great scientific interest and practical importance. By introducing chain-like particles composed of the same material and with comparable size into commonly used colloidal suspensions of spherical silica nanoparticles, we can significantly reduce the cracks formed in dried particle deposits and achieve a fivefold increase in the critical cracking thickness of colloidal silica coatings. The mechanism underlying the crack suppression is attributed to the increased porosity and pore sizes in dried particle deposits containing chain-like particle, which essentially leads to reduction in internal stresses developed during the drying process. Meanwhile, the nanoindentation measurements reveal that colloidal deposits with chain-like particles exhibit a smaller reduction in hardness compared to those reported using other cracking suppression approaches. This work demonstrates a promising technique for preparing colloidal coatings with enhanced crack resistance while maintaining desirable mechanical properties.

Lanthanide Complex for Single-Molecule Fluorescent in Situ Hybridization and Background-Free Imaging.

Traditional single-molecule fluorescence in situ hybridization (smFISH) methods for RNA detection often face sensitivity challenges due to the low fluorescence intensity of the probe. Also, short-lived autofluorescence complicates obtaining clear signals from tissue sections. In response, we have developed an smFISH probe using highly grafted lanthanide complexes to address both concentration quenching and autofluorescence background. Our approach involves an oligo PCR incorporating azide-dUTP, enabling conjugation with lanthanide complexes. This method has proven to be stable, convenient, and cost-effective. Notably, for the mRNA detection in SKBR3 cells, the lanthanide probe group exhibited 2.5 times higher luminescence intensity and detected 3 times more signal points in cells compared with the Cy3 group. Furthermore, we successfully applied the probe to image HER2 mRNA molecules in breast cancer FFPE tissue sections, achieving a 2.7-fold improvement in sensitivity compared to Cy3-based probes. These results emphasize the potential of time-resolved smFISH as a highly sensitive method for nucleic acid detection, free of background fluorescence interference.

PIKfyve controls dendritic cell function and tumor immunity.

The modern armamentarium for cancer treatment includes immunotherapy and targeted therapy, such as protein kinase inhibitors. However, the mechanisms that allow cancer-targeting drugs to effectively mobilize dendritic cells (DCs) and affect immunotherapy are poorly understood. Here, we report that among shared gene targets of clinically relevant protein kinase inhibitors, high PIKFYVE expression was least predictive of complete response in patients who received immune checkpoint blockade (ICB). In immune cells, high PIKFYVE expression in DCs was associated with worse response to ICB. Genetic and pharmacological studies demonstrated that PIKfyve ablation enhanced DC function via selectively altering the alternate/non-canonical NF-κB pathway. Both loss of Pikfyve in DCs and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively controls DCs, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.

PAD4 controls tumor immunity via restraining the MHC class II machinery in macrophages.

Tumor-associated macrophages (TAMs) shape tumor immunity and therapeutic efficacy. However, it is poorly understood whether and how post-translational modifications (PTMs) intrinsically affect the phenotype and function of TAMs. Here, we reveal that peptidylarginine deiminase 4 (PAD4) exhibits the highest expression among common PTM enzymes in TAMs and negatively correlates with the clinical response to immune checkpoint blockade. Genetic and pharmacological inhibition of PAD4 in macrophages prevents tumor progression in tumor-bearing mouse models, accompanied by an increase in macrophage major histocompatibility complex (MHC) class II expression and T cell effector function. Mechanistically, PAD4 citrullinates STAT1 at arginine 121, thereby promoting the interaction between STAT1 and protein inhibitor of activated STAT1 (PIAS1), and the loss of PAD4 abolishes this interaction, ablating the inhibitory role of PIAS1 in the expression of MHC class II machinery in macrophages and enhancing T cell activation. Thus, the PAD4-STAT1-PIAS1 axis is an immune restriction mechanism in macrophages and may serve as a cancer immunotherapy target.

Capillary filling of star polymer melts in nanopores.

The topology of a polymer profoundly influences its behavior. However, its effect on imbibition dynamics remains poorly understood. In the present work, capillary filling (during imbibition and following full imbibition) of star polymer melts was investigated by molecular dynamics simulations with a coarse-grained model. The reversal of imbibition dynamics observed for linear-chain systems was also present for star polymers. Star polymers with short arms penetrate slower than the prediction of the Lucas-Washburn equation, while systems with long arms penetrate faster. The radius of gyration increases during confined flow, indicating the orientation and disentanglement of arms. In addition, the higher the functionality of the star polymer, the more entanglement points are retained. Besides, a stiff region near the core segments of the stars is observed, which increases in size with functionality. The proportion of different configurations of the arms (e.g., loops, trains, tails) changes dramatically with the arm length and degree of confinement but is only influenced by the functionality when the arms are short. Following full imbibition, the different decay rates of the self-correlation function of the core-to-end vector illustrate that arms take a longer time to reach the equilibrium state as the functionality, arm length, and degree of confinement increase, in agreement with recent experimental findings. Furthermore, the star topology induces a stronger effect of adsorption and friction, which becomes more pronounced with increasing functionality.

Personal Competence or Environmental Characteristics? Factors Influencing Happiness among Ageing Adults in Hong Kong Around the Period of COVID-19 Pandemic.

Drawing upon person-environment fit perspective, this study examines the joint and interactive influences of personal competence and environmental characteristics on the happiness of ageing adults around the period of COVID-19 pandemic. Data was collected in two rounds, before and during the pandemic, with 2,028 participants aged 55 years and older in Hong Kong. Personal competence encompassed financial status, physical health, and mental capital, while environmental characteristics included experiences of ageism, perceived social conditions, and age-friendly policies. Ordinary least squares regression was used to examine personal and environmental influences on happiness. Results indicated a significant decline in happiness following the onset of COVID-19 pandemic. Mental capital was found to have the strongest positive influence on happiness, followed by physical health, financial status, and social conditions. Mental capital mitigated the negative relationship between experiences of ageism and happiness. Practical interventions are informed to improve the well-being of ageing adults during pandemic.

Non-Faradaic optoelectrodes for safe electrical neuromodulation.

Nanoscale optoelectrodes hold the potential to stimulate optically individual neurons and intracellular organelles, a challenge that demands both a high-density of photoelectron storage and significant charge injection. Here, we report that zinc porphyrin, commonly used in dye-sensitized solar cells, can be self-assembled into nanorods and then coated by TiO2. The J-aggregated zinc porphyrin array enables long-range exciton diffusion and allows for fast electron transfer into TiO2. The formation of TiO2(e-) attracts positive charges around the neuron membrane, contributing to the induction of action potentials. Far-field cranial irradiation of the motor cortex using a 670 nm laser or an 850 nm femtosecond laser can modulate local neuronal firing and trigger motor responses in the hind limb of mice. The pulsed photoelectrical stimulation of neurons in the subthalamic nucleus alleviates parkinsonian symptoms in mice, improving abnormal stepping and enhancing the activity of dopaminergic neurons. Our results suggest injectable nanoscopic optoelectrodes for optical neuromodulation with high efficiency and negligible side effects.

Pumping Small Molecules Selectively through an Energy-Assisted Assembling Process at Nonequilibrium States.

In living organisms, precise control over the spatial and temporal distribution of molecules, including pheromones, is crucial. This level of control is equally important for the development of artificial active materials. In this study, we successfully controlled the distribution of small molecules in the system at nonequilibrium states by actively transporting them, even against the apparent concentration gradient, with high selectivity. As a demonstration, in the aqueous solution of acid orange (AO7) and TMC10COOH, we found that AO7 molecules can coassemble with transient anhydride (TMC10CO)2O to form larger assemblies in the presence of chemical fuel 1-ethyl-3-(3-(dimethylamino)propyl) carbodiimide hydrochloride (EDC). This led to a decrease in local free AO7 concentration and caused AO7 molecules from other locations in the solution to move toward the assemblies. Consequently, AO7 accumulates at the location where EDC was injected. By continuously injecting EDC, we could maintain a stable high value of the apparent AO7 concentration at the injection point. We also observed that this process which operated at nonequilibrium states exhibited high selectivity.

Removal characteristics of high concentration glyphosate in bioretention cells.

Glyphosate, as one of the most widely used pesticides, has been found in rainwater runoff. A bioretention cell with two types of fillers was constructed to explore removal of glyphosate in runoff an transformation of glyphosate in the filler. The type of filler had a significant impact on adsorption and degradation of glyphosate in the bioretention cell. The glyphosate removal efficiencies of coal cinder modified loess (CLB) and zeolite modified loess (ZLB) were 33.13-99.7% and 55.04-99.7%, respectively. Conversion of glyphosate in the bioretention cell occurred mainly in the upper layer of the filler. When the concentration of glyphosate in the runoff was 0.25 or 0.5 mg/L, the concentration of glyphosate degradation products at the two outlets along the way was as much as 26 times higher than that at the lowest outlet. Rainfall events promoted the migration of glyphosate and its degradation products within the filler. Glyphosate and its degradation products in ZLB were mainly distributed at 15 and 25 cm deep in the filler layer, while the highest concentrations in CLB were at 5 and 35 cm. Discontinuous runoff into the bioretention cell leads to continuous leaching and adsorption of glyphosate in the bioretention cell until complete degradation occurs.

Cross-domain Chirality Transfer in Self-Assembly of Chiral Block Copolymers.

Chirality transfer is essential to acquire helical hierarchical superstructures from the self-assembly of supramolecular materials. By taking advantage of chirality transfers at different length scales through intra-chain and inter-chain chiral interactions, helical phase (H*) can be formed from the self-assembly of chiral block copolymers (BCPs*). In this study, chiral triblock terpolymers, polystyrene-b-poly(ethylene oxide)-b-poly(L-lactide) (PS-PEO-PLLA), and polystyrene-b-poly(4-vinylpyridine)-b-poly(L-lactide) (PS-P4VP-PLLA) are synthesized for self-assembly. For PS-PEO-PLLA with an achiral PEO mid-block that is compatible with PLLA (chiral end-block), H* can be formed while the block length is below a critical value. By contrast, for the one with achiral P4VP mid-block that is incompatible with PLLA, the formation of H* phase would be suppressed regardless of the length of the mid-block, giving cylinder phase. Those results elucidate a new type of chirality transfer across the phase domain that is referred as cross-domain chirality transfer, providing complementary understanding of the chirality transfer at the interface of phase-separated domains.

Uncovering potential distinctive acoustic features of healing music.

Background: Music therapy is a promising complementary intervention for addressing various mental health conditions. Despite evidence of the beneficial effects of music, the acoustic features that make music effective in therapeutic contexts remain elusive. Aims: This study aimed to identify and validate distinctive acoustic features of healing music. Methods: We constructed a healing music dataset (HMD) based on nominations from related professionals and extracted 370 acoustic features. Healing-distinctive acoustic features were identified as those that were (1) independent from genre within the HMD, (2) significantly different from music pieces in a classical music dataset (CMD) and (3) similar to pieces in a five-element music dataset (FEMD). We validated the identified features by comparing jazz pieces in the HMD with a jazz music dataset (JMD). We also examined the emotional properties of the features in a Chinese affective music system (CAMS). Results: The HMD comprised 165 pieces. Among all the acoustic features, 74.59% shared commonalities across genres, and 26.22% significantly differed between the HMD classical pieces and the CMD. The equivalence test showed that the HMD and FEMD did not differ significantly in 9.46% of the features. The potential healing-distinctive acoustic features were identified as the standard deviation of the roughness, mean and period entropy of the third coefficient of the mel-frequency cepstral coefficients. In a three-dimensional space defined by these features, HMD's jazz pieces could be distinguished from those of the JMD. These three features could significantly predict both subjective valence and arousal ratings in the CAMS. Conclusions: The distinctive acoustic features of healing music that have been identified and validated in this study have implications for the development of artificial intelligence models for identifying therapeutic music, particularly in contexts where access to professional expertise may be limited. This study contributes to the growing body of research exploring the potential of digital technologies for healthcare interventions.

Anomalous segmental dynamics of supercooled polyrotaxane melts: A computer simulation study.

Polyrotaxanes, which consist of mechanically interlocked bonds with rings threaded onto soft polymer chains, exhibit unique mechanical properties and find applications in diverse fields. In this study, we investigate the anomalous segmental dynamics of supercooled polyrotaxane melts using coarse-grained molecular dynamics simulations. Our simulations reveal that the presence of rings effectively reduces the packing efficiency, resulting in well-contained local motion even below the glass transition temperature. We also observe variations in dynamical free volume, characterized by the Debye-Waller factor, which shows a minimum at a ring coverage of 0.1 on threading chains. Such a non-monotonic dependence on coverage shows great consistency in structural relaxation time and dynamic heterogeneity. Specifically, the high segmental mobility of threading linear chains at large coverage can be attributed to the increased dynamical free volume due to supported rigid rings. However, such anomalous segmental dynamics is limited to length scales smaller than one ring size. Beyond this characteristic length scale, the diffusion is dominated by topological constraints, which significantly reduce the mobility of polyrotaxanes and enhance the dynamic heterogeneity. These findings offer microscopic insights into the unique packing structures and anomalous segmental dynamics of supercooled polyrotaxane melts, facilitating the design of advanced materials based on mechanical interlocking polymers for various applications.

PLM-ARG: antibiotic resistance gene identification using a pretrained protein language model.

MOTIVATION: Antibiotic resistance presents a formidable global challenge to public health and the environment. While considerable endeavors have been dedicated to identify antibiotic resistance genes (ARGs) for assessing the threat of antibiotic resistance, recent extensive investigations using metagenomic and metatranscriptomic approaches have unveiled a noteworthy concern. A significant fraction of proteins defies annotation through conventional sequence similarity-based methods, an issue that extends to ARGs, potentially leading to their under-recognition due to dissimilarities at the sequence level. RESULTS: Herein, we proposed an Artificial Intelligence-powered ARG identification framework using a pretrained large protein language model, enabling ARG identification and resistance category classification simultaneously. The proposed PLM-ARG was developed based on the most comprehensive ARG and related resistance category information (>28K ARGs and associated 29 resistance categories), yielding Matthew's correlation coefficients (MCCs) of 0.983 ± 0.001 by using a 5-fold cross-validation strategy. Furthermore, the PLM-ARG model was verified using an independent validation set and achieved an MCC of 0.838, outperforming other publicly available ARG prediction tools with an improvement range of 51.8%-107.9%. Moreover, the utility of the proposed PLM-ARG model was demonstrated by annotating resistance in the UniProt database and evaluating the impact of ARGs on the Earth's environmental microbiota. AVAILABILITY AND IMPLEMENTATION: PLM-ARG is available for academic purposes at https://github.com/Junwu302/PLM-ARG, and a user-friendly webserver (http://www.unimd.org/PLM-ARG) is also provided.

Pathological Networking of Gray Matter Dendritic Density With Classic Brain Morphometries in OCD.

Importance: The pathogenesis of obsessive-compulsive disorder (OCD) may involve altered dendritic morphology, but in vivo imaging of neurite morphology in OCD remains limited. Such changes must be interpreted functionally within the context of the multimodal neuroimaging approach to OCD. Objective: To examine whether dendritic morphology is altered in patients with OCD compared with healthy controls (HCs) and whether such alterations are associated with other brain structural metrics in pathological networks. Design, Setting, and Participants: This case-control study used cross-sectional data, including multimodal brain images and clinical symptom assessments, from 108 patients with OCD and 108 HCs from 2014 to 2017. Patients with OCD were recruited from Shanghai Mental Health Center, Shanghai, China, and HCs were recruited via advertisements. The OCD group comprised unmedicated adults with a Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) diagnosis of OCD, while the HCs were adults without any DSM-IV diagnosis, matched for age, sex, and education level. Data were analyzed from September 2019 to April 2023. Exposure: DSM-IV diagnosis of OCD. Main Outcomes and Measures: Multimodal brain imaging was used to compare neurite microstructure and classic morphometries between patients with OCD and HCs. The whole brain was searched to identify regions exhibiting altered morphology in patients with OCD and explore the interplay between the brain metrics representing these alterations. Brain-symptom correlations were analyzed, and the performance of different brain metric configurations were evaluated in distinguishing patients with OCD from HCs. Results: Among 108 HCs (median [IQR] age, 26 [23-31] years; 50 [46%] female) and 108 patients with OCD (median [IQR] age, 26 [24-31] years; 46 [43%] female), patients with OCD exhibited deficient neurite density in the right lateral occipitoparietal regions (peak t = 3.821; P ≤ .04). Classic morphometries also revealed widely-distributed alterations in the brain (peak t = 4.852; maximum P = .04), including the prefrontal, medial parietal, cingulate, and fusiform cortices. These brain metrics were interconnected into a pathological brain network associated with OCD symptoms (global strength: HCs, 0.253; patients with OCD, 0.941; P = .046; structural difference, 0.572; P < .001). Additionally, the neurite density index exhibited high discriminatory power in distinguishing patients with OCD from HCs (accuracy, ≤76.85%), and the entire pathological brain network also exhibited excellent discriminative classification properties (accuracy, ≤82.87%). Conclusions and Relevance: The findings of this case-control study underscore the utility of in vivo imaging of gray matter dendritic density in future OCD research and the development of neuroimaging-based biomarkers. They also endorse the concept of connectopathy, providing a potential framework for interpreting the associations among various OCD symptom-related morphological anomalies.

Nitrogen removal performance of bioretention cells under polyethylene (PE) microplastic stress.

The use of bioretention cells as a stormwater control measure allows stormwater runoff to be collected and filtered, effectively removing microplastics and other pollutants from stormwater. This study investigated the effect of polyethylene microplastics (PE-MPs) retention on the bioretention cell, in terms of denitrification performance and microbial community structure. Four PE-MP exposures were compared at different concentrations of 0, 250, 500 and 1000 mg/L under alternating dry and wet period conditions. Results showed that the removal efficiency reduced by 14.99%, 28.37% and 18.59% with PE-MP concentrations of 250, 500 and 1000 mg/L. The NO3--N removal efficiency increased by 36.19%, 20.19% and 35.39%. After 8 days of dry conditions, the NO3--N removal efficiencies of the bioretention cells were reduced by 36.66%, 46.86% and 31.11% compared to those after 2 days of dry conditions. Microbial sequencing results indicated that the accumulation of PE-MPs changed the microbial community structure within the bioretention cell filler material, promoting the growth of bacteria such as Actinobacteria, Bacteroidetes and Firmicutes. Furthermore, PE-MPs reduced the relative abundance of nitrifying bacteria (e.g. Nitrospira) within the bioretention cell and promoted denitrifying bacteria (e.g. Dechloromonas and Hydrogenophaga), along with numerous other genera such as Azotobacter and Nocardia.

Bone disease imaging through the near-infrared-II window.

Skeletal disorders are commonly diagnosed by X-ray imaging, but the radiation limits its use. Optical imaging through the near-infrared-II window (NIR-II, 1000-1700 nm) can penetrate deep tissues without radiation risk, but the targeting of contrast agent is non-specific. Here, we report that lanthanide-doped nanocrystals can passively target the bone marrow, which can be effective for over two months. We therefore develop the high-resolution NIR-II imaging method for bone disease diagnosis, including the 3D bone imaging instrumentation to show the intravital bone morphology. We demonstrate the monitoring of 1 mm bone defects with spatial resolution comparable to the X-ray imaging result. Moreover, NIR-II imaging can reveal the early onset inflammation as the synovitis in the early stage of rheumatoid arthritis, comparable to micro computed tomography (µCT) in diagnosis of osteoarthritis, including the symptoms of osteophyte and hyperostosis in the knee joint.

Heterostructure particles enable omnidispersible in water and oil towards organic dye recycle.

Dispersion of colloidal particles in water or oil is extensively desired for industrial and environmental applications. However, it often strongly depends on indispensable assistance of chemical surfactants or introduction of nanoprotrusions onto the particle surface. Here we demonstrate the omnidispersity of hydrophilic-hydrophobic heterostructure particles (HL-HBPs), synthesized by a surface heterogeneous nanostructuring strategy. Photo-induced force microscopy (PiFM) and adhesion force images both indicate the heterogeneous distribution of hydrophilic domains and hydrophobic domains on the particle surface. These alternating domains allow HL-HBPs to be dispersed in various solvents with different polarity and boiling point. The HL-HBPs can efficiently adsorb organic dyes from water and release them into organic solvents within several seconds. The surface heterogeneous nanostructuring strategy provides an unconventional approach to achieve omnidispersion of colloidal particles beyond surface modification, and the omnidispersible HL-HBPs demonstrate superior capability for dye recycle merely by solvent exchange. These omnidispersible HL-HBPs show great potentials in industrial process and environmental protection.